The first two editions of Harrison’s Neurology in Clinical 
Medicine were unqualified successes.
For many physicians, neurologic diseases represent 
particularly challenging problems.
By the second edition, the section was 
considerably enlarged by Raymond D.
Adams, whose 
influence on the textbook was profound.
The third 
neurology editor, Joseph B.
Thanks also to Dr.
This new volume was championed by James Shanahan 
and impeccably managed by Kim Davis.
We live in an electronic, wireless age.
Information 
is downloaded rather than pulled from the shelf.
Some 
have questioned the value of traditional books in this 
new era.
Stephen L.
Hauser, MD
Preface xiv
NOTICE
Medicine is an ever-changing science.
Readers are encouraged 
to confirm the information contained herein with other sources.
This recommendation is of particular importance in connection with 
new or infrequently used drugs.
The genetic icons identify a clinical issue with an explicit genetic relationship.
Harrison’s Self-Assessment and Board Review, 18th ed.
New York, McGraw-Hill, 2012, ISBN 978-0-07-177195-5.
This page intentionally left blank 
SECTION I
 
INTRODUCTION TO 
NEUROLOGY
   Daniel  H.
Lowenstein   ■    Joseph  B.
Martin   ■    Stephen  L.
Hauser  
2
 Neurologic diseases are common and costly.
Are the pain-sensitive meninges 
involved?
A more detailed examina-
tion of a particular region of the CNS or PNS is often 
indicated.
In addition, this strategy safeguards against 
making serious errors.
The history also helps to bring a focus to the neuro-
logic examination that follows.
For example, a patient complains 
of weakness of the right arm.
What are the associated 
features?
Negative 
associations may also be crucial.
Other pertinent features of the  
history include the following:
1.
Temporal course of the illness.
2.
Patients’ descriptions of the complaint.
The same words 
often mean different things to different patients.
“Dizziness” may imply impending syncope, a 
sense of disequilibrium, or true spinning vertigo.
3.
Corroboration of the history by others.
4.
Family history.
Many neurologic disorders have an 
underlying genetic component.
5.
Medical illnesses.
Many neurologic diseases occur in 
the context of systemic disorders.
Patients with malig-
nancy may also present with a neurologic paraneo-
plastic syndrome (Chap.
44) or complications from 
chemotherapy or radiotherapy.
Various neurologic disorders occur 
with dysthyroid states or other endocrinopathies.
Most patients with coma in a hospital setting have a 
metabolic, toxic, or infectious cause.
6.
Drug use and abuse and toxin exposure.
It is essential to 
inquire about the history of drug use, both prescribed 
and illicit.
7.
Formulating an impression of the patient.
Use the 
opportunity while taking the history to form an 
impression of the patient.
Is the information forth-
coming, or does it take a circuitous course?
Is there 
evidence of anxiety, depression, or hypochondriasis?
Are there any clues to defects in language, memory, 
insight, or inappropriate behavior?
A screening examination done 
in this way can be completed in 3–5 min.
Several additional points about the examination are 
worth noting.
A single small-amplitude movement of the finger is 
sufficient for a normal response.
CN VII (facial)
Look for facial asymmetry at rest and with spontaneous 
movements.
Test eyebrow elevation, forehead wrin-
kling, eye closure, smiling, and cheek puff.
Any suspected problem should 
be followed up with formal audiometry.
11, 
17, and 24, respectively.
MOTOR EXAMINATION
• The bare minimum: Look for muscle atrophy and check 
extremity tone.
Tap the biceps, patellar, and Achilles reflexes.
Test 
for lower extremity strength by having the patient walk 
normally and on heels and toes.
The motor examination includes observations of mus-
cle appearance, tone, strength, and reflexes.
Check for muscle fasciculations, tenderness, and atrophy 
or hypertrophy.
Tone
Muscle tone is tested by measuring the resistance to 
passive movement of a relaxed limb.
Decreased 
tone is most commonly due to lower motor neuron or 
peripheral nerve disorders.
It is also helpful to palpate accessible muscles 
as they contract.
The 
normal reflex consists of plantar flexion of the toes.
Normally, the umbilicus 
will pull toward the stimulated quadrant.
With upper 
motor neuron lesions, these reflexes are absent.
In many instances stroking the 
back of the hand will lead to its release.
Check double simultaneous stimulation using 
light touch on the hands.
With patients 
who are uncooperative or lack an understanding of 
the tests, it may be useless.
The examination should be 
focused on the suspected lesion.
The  Romberg 
maneuver is primarily a test of proprioception.
A loss of balance 
with the eyes closed is an abnormal response.
Coordination refers to the orchestration and fluid-
ity of movements.
Part of this integration 
relies on normal function of the cerebellar and basal 
ganglia systems.
In the lower limb, the patient rapidly taps the foot 
against the floor or the examiner’s hand.
For all these 
movements, the accuracy, speed, and rhythm are noted.
Watching the patient walk is the most important part 
of the neurologic examination.
4); or (4) elec-
trophysiologic studies (Chap.
5).
17.
Daniel H.
Lowenstein  
11
 Knowledge of the basic neurologic examination is 
an essential clinical skill.
THE NEUROLOGIC SCREENING EXAM 
 CHAPTER 2 
   Martin A.
VIDEO ATLAS OF THE DETAILED NEUROLOGIC 
EXAMINATION 
 CHAPTER 3 
   William  P.
A computer calculates a “back projection” image from 
the 360° x-ray attenuation profi le.
Multidetector CT (MDCT) is now standard in most 
radiology departments.
4-1B and C).
CTA images are 
postprocessed for display in three dimensions to yield 
angiogram-like images (Fig.
4-1C, 4-2 E and F, and 
see Fig.
27-4).
CTA has proved useful in assessing the 
cervical and intracranial arterial and venous anatomy.
COMPLICATIONS
CT is safe, fast, and reliable.
Care must be taken to reduce exposure when imaging 
children.
Advanced soft-
ware that permits noise reduction may permit lower 
radiation doses.
The most frequent complications are 
associated with use of intravenous contrast agents.
Two 
broad categories of contrast media, ionic and non-
ionic, are in use.
As a result, ionic 
agents have been largely replaced by safer nonionic 
compounds.
A.
Noncontrast CT demonstrates subarachnoid hemorrhage 
and mild obstructive hydrocephalus.
B.
C.
A.
B.
C.
D.
E.
G.
H and I.
Field strength of the 
magnet is directly related to signal-to-noise ratio.
Rf pulses transiently excite the energy state of 
the hydrogen protons in the body.
Rf is administered 
at a frequency specific for the field strength of the mag-
net.
The echo is transformed 
by Fourier analysis into the information used to form 
an MR image.
The relaxation rate varies among 
normal and pathologic tissues.
Two relaxation rates, T1 and T2, influence the 
signal intensity of the image.
So-called 
T1-weighted (T1W) images are produced by keeping 
the TR and TE relatively short.
T2-weighted (T2W) 
images are produced by using longer TR and TE times.
4-6B).
Many different MR pulse sequences exist, and each 
can be obtained in various planes (Figs.
4-2, 4-3, 4-4).
4-6B).
4-5C).
MR images 
can be generated in any plane without changing the 
patient’s position.
Each sequence, however, must be 
obtained separately and takes 1–10 min on average to 
complete.
FIGURE 4-3
Cerebral abscess in a patient with fever and a right 
hemiparesis.
A.
B.
Approximately 0.2 mL/kg body weight 
is administered intravenously; the cost is ∼$60 per 
dose.
4-3A) and areas of the brain that 
normally are devoid of the BBB (pituitary, choroid 
plexus).
Renal failure does not occur.
A and B.
C.
The suspected diagnosis of herpes sim-
plex encephalitis was confirmed by CSF PCR analysis.
Renal disease (including solitary kidney, renal trans-
plant, renal tumor)
2.
Age >60 years
3.
History of hypertension
4.
History of diabetes
5.
The incidence of NSF in patients with severe renal 
dysfunction (GFR <30) varies from 0.19 to 4%.
A.
Noncontrast CT scan shows 
one hyperdense lesion in the right hemisphere (arrow).
B.
T2-weighted fast spin echo image shows subtle low-intensity 
lesions (arrows).
C.
Caution is advised for patients 
with a GFR below 45.
The patient lies on a table 
A B
C
that is moved into a long, narrow gap within the mag-
net.
Approximately 5% of the population experiences 
severe claustrophobia in the MR environment.
This can 
be reduced by mild sedation but remains a problem for 
some.
A.
B.
Coronal T2 FLAIR image demonstrates 
high signal glioma in left temporal lobe.
C.
MRI is considered safe for patients, even at very high 
field strengths (>3–4 T).
These provide a vascular flow map rather than the ana-
tomic map shown by conventional angiography.
spin echo MR images.
4-2G).
MRA can also be acquired during infusion of 
 contrast material.
Advantages include faster imaging 
times (1–2 min vs.
10 min), fewer flow-related arti-
facts, and higher-resolution images.
Recently, con-
trast-enhanced MRA has become the standard for 
extracranial vascular MRA.
Proper technique and timing 
of acquisition relative to bolus arrival are critical for 
success.
In rou-
tine spin echo imaging, images of the brain can be 
obtained in 5–10 min.
Fast MRI reduces patient and 
organ motion, permitting diffusion imaging and tractog-
raphy (Figs.
4-2H, 4-3, 4-4C, 4-6; and see Fig.
27-16), 
perfusion imaging during contrast infusion, fMRI, and 
kinematic motion studies.
4-3B).
4-6).
Irritated or infiltrated nerves will 
demonstrate high signal on T2W imaging.
Multiple images of glucose uptake 
activity are formed after 45–60 min.
A lower activity 
of FDG in the parietal lobes has been associated with 
Alzheimer’s disease.
FDG PET is used primarily for the 
detection of extracranial metastatic disease.
In patients with a suspected spinal block, MR is the 
preferred technique.
Adequate hydration before and 
after myelography will reduce the incidence of this 
complication.
Management of post–lumbar puncture headache is 
 discussed in Chap.
8.
Hearing loss is a rare complication of myelog-
raphy.
Intrathecal 
contrast reactions are rare, but aseptic  meningitis and 
encephalopathy may occur.
Seizures occur follow-
ing myelography in 0.1–0.3% of patients.
CT and plain films are 
obtained following the procedure.
Angiography has been replaced for many indications by 
CT/CTA or MRI/MRA.
The most feared complication of cerebral angiography is 
stroke.
35) prior to aortic aneurysm repair.
Many of these disorders place 
the patient at high risk of cerebral hemorrhage, stroke, 
or death.
Michael J.
The characteristics of the 
normal EEG depend on the patient’s age and level of 
arousal.
5-1 ) .
Digital systems are now widely used for recording 
the EEG.
With generalized tonic-clonic sei-
zures, the EEG is always abnormal during the episode.
Thus, 
the EEG cannot establish the diagnosis of epilepsy in 
many cases.
5-2).
Normal EEG showing a posteriorly situated 9-Hz alpha 
rhythm that attenuates with eye opening.
B.
Abnormal EEG 
showing irregular diffuse slow activity in an obtunded patient 
with encephalitis.
C.
D.
Periodic complexes occurring once 
every second in a patient with Creutzfeldt-Jakob disease.
Hori-
zontal calibration: 1 s; vertical calibration: 200 μV in A, 300 μV 
in other panels.
(From MJ Aminoff, ed: Electrodiagnosis in Clini-
cal Neurology, 5th ed.
A, earlobe; C, central; F, frontal; Fp, frontal polar; P, pari-
etal; T, temporal; O, occipital.
5-1).
The EEG generally slows 
in metabolic encephalopathies, and triphasic waves may 
be present.
5-1).
A.
B.
C.
Horizontal calibration: 1 s; verti-
cal calibration: 400 mV in A, 200 mV in B, and 750 mV in C.
(From MJ Aminoff, ed: Electrodiagnosis in Clinical Neurology, 
5th ed.
5-1) or subacute scle-
rosing panencephalitis.
Its presence, latency, and symmetry 
over the two sides of the scalp are noted.
The VEP findings are therefore 
helpful in indicating previous or subclinical optic neuri-
tis.
Normal VEPs 
may be elicited by flash stimuli in patients with cortical 
blindness.
The EP findings are sometimes of prognostic rel-
evance.
The procedure is painless and apparently 
safe.
Nevertheless, it is not used widely for clinical 
purposes.
Within each motor unit, all of the 
muscle fibers are of the same type.
Slight voluntary contraction of a muscle leads to acti-
vation of a small number of motor units.
5-3).
The number 
of units activated depends on the degree of voluntary 
activity.
A.
Spontaneous fibrillation 
potentials and positive sharp waves.
B.
Complex repetitive 
discharges recorded in partially denervated muscle at rest.
C.
Normal triphasic motor unit action potential.
D.
E.
Long-duration polyphasic motor unit action potential such as 
may be seen in neuropathic disorders.
SECTION I
Introduction to Neurology
32 of voluntary activity.
5-3).
Such 
information is important for prognostic purposes.
Various quantitative EMG approaches have been 
developed.
The technique of single-
fiber EMG is discussed separately below.
They may suggest the underlying pathologic basis 
in individual cases.
H-REFLEX STUDIES
The H reflex is easily recorded only from the soleus 
muscle (S1) in normal adults.
In disorders of neu-
romuscular transmission this safety factor is reduced.
Elizabeth Robbins    ■    Stephen L.
Hauser  
35
 In experienced hands, lumbar puncture (LP) is usually 
a safe procedure.
Bleeding com-
plications rarely occur in patients with platelet counts 
≥50,000/μL and an INR ≤1.5.
ANALGESIA 
 Anxiety and pain can be minimized prior to begin-
ning the procedure.
Topi-
cal anesthesia can be achieved by the application of a 
lidocaine-based cream.
POSITIONING 
 Proper positioning of the patient is essential.
6-1 ).
The spinal cord terminates 
at approximately the L1 vertebral level in 94% of indi-
viduals.
In the remaining 6%, the conus extends to the 
L2-L3 interspace.
LP is therefore performed at or below 
the L3-L4 interspace.
An alternative to the lateral recumbent position is the 
seated position.
The patient sits at the side of the bed, 
with feet supported on a chair.
The patient is instructed 
to curl forward, trying to touch the nose to the umbi-
licus.
LP 
is sometimes more easily performed in obese patients if 
they are sitting.
A pause of ∼15 s 
between injections helps to minimize the pain of the 
subsequent injection.
Approximately 
5–10 mini-boluses are injected, using a total of ∼5 mL 
of lidocaine.
Even a delay of 5 min will help to 
reduce pain.
If there is still no fluid, 
the stylet is reinserted and the needle is advanced slightly.
The needle can then be reinserted at the same 
level or at an adjacent one.
Once the SAS is reached, a manometer is attached 
to the needle and the opening pressure measured.
CSF is allowed to drip into collection tubes; it should 
not be withdrawn with a syringe.
Note that the shoulders and hips are in a vertical 
plane; the torso is perpendicular to the bed.
(From RP Simon 
et al [eds]: Clinical Neurology, 7th ed.
In general 20–30 mL 
may be safely removed from adults.
POST-LP HEADACHE
The principal complication of LP is headache, occur-
ring in 10–30% of patients.
Younger age and female 
gender are associated with an increased risk of post-LP 
headache.
Headache usually begins within 48 h but 
may be delayed for up to 12 days.
The longer the patient is upright, the 
longer the latency before head pain subsides.
The pain 
is usually a dull ache but may be throbbing; its location 
is occipitofrontal.
7]) and antiemetics.
For 
some patients, beverages with caffeine can provide tem-
porary pain relief.
This procedure is most often performed by 
a pain specialist or anesthesiologist.
The acute benefit may be due to compression of the CSF 
space by the clot, increasing CSF pressure.
Strategies to decrease the incidence of post-LP head-
ache are listed in Table 6-1.
6-2).
There is a low risk of needle dam-
age, e.g., breakage, with the Sprotte atraumatic needle.
CSF glu-
cose concentrations <2.2 mmol/L (<40 mg/dL) are 
abnormal.
bIgG index = CSF IgG (mg/dL) × serum albumin (g/dL)/serum IgG (g/
dL) × CSF albumin (mg/dL).
SECTION II
CLINICAL  
MANIFESTATIONS OF 
NEUROLOGIC DISEASE
   James P.
Rathmell       ■  Howard L.
Fields  
40
 The task of medicine is to preserve and restore health 
and to relieve suffering.
Understanding pain is essen-
tial to both of these goals.
The function of the pain sensory system is 
to protect the body and maintain homeostasis.
It is the 
physician’s responsibility to provide rapid and effective 
pain relief.
THE PAIN SENSORY SYSTEM 
 Pain is an unpleasant sensation localized to a part of the 
body.
These properties illustrate the duality of pain: it 
is both sensation and emotion.
7-1 ) .
In normal individuals, 
the activity of these fi bers does not produce pain.
7-1 ).
These fi bers are present 
in nerves to the skin and to deep somatic and visceral 
structures.
Some tissues, such as the cornea, are inner-
vated only by Aδ and C fi ber afferents.
Individual primary afferent nociceptors can respond 
to several different types of noxious stimuli.
Following injury and resultant sensitization, nor-
mally innocuous stimuli can produce pain.
Sensitization is of particular importance for pain and 
tenderness in deep tissues.
Nociceptor-induced inflammation
Primary afferent nociceptors also have a neuroeffec-
tor function.
7-2).
An example 
is substance P, an 11-amino-acid peptide.
Substance P 
is released from primary afferent nociceptors and has 
multiple biologic activities.
ganglion.
All sympathetic postganglionic fibers are 
unmyelinated.
They terminate in the 
dorsal horn of the spinal gray matter (Fig.
7-3).
The major neurotransmitter released is gluta-
mate, which rapidly excites dorsal horn neurons.
A.
Direct activation by intense pressure and consequent cell 
damage.
B.
Secondary activation.
Thus, inflam-
mation near the central diaphragm is usually reported as 
shoulder discomfort.
The spinothalamic path-
way is crucial for pain sensation in humans.
Interruption 
of this pathway produces permanent deficits in pain and 
temperature discrimination.
Spinothalamic tract axons ascend to several regions 
of the thalamus.
7-4).
One of the thalamic pro-
jections is to the somatosensory cortex.
This affective 
dimension of pain produces suffering and exerts potent 
control of behavior.
Because of this dimension, fear is a 
constant companion of pain.
7-4).
7-5).
A.
Trans-
mission system for nociceptive messages.
B.
Pain-
modulation network.
Pain-modulating circuits can enhance as well as sup-
press pain.
Paradoxically, damage to or dysfunction of these 
pathways can also produce pain.
These features are rare in 
other types of pain.
On examination, a sensory deficit 
is characteristically present in the area of the patient’s 
pain.
A variety of mechanisms contribute to neuropathic 
pain.
Damaged pri-
mary afferents may also develop sensitivity to norepineph-
rine.
Thus, both CNS and peripheral nervous 
system hyperactivity contribute to neuropathic pain.
This pain is often described as having a burning quality.
33).
Sometimes, treat-
ing the underlying condition does not immediately 
relieve pain.
Older age and history of 
gastrointestinal disease increase the risks of aspirin and 
NSAIDs.
NSAIDs can also 
increase blood pressure in some individuals.
Food and Drug Administration (FDA) for the 
treatment of pain.
bGabapentin in doses up to 1800 mg/d is FDA approved for postherpetic neuralgia.
Note: 5-HT, serotonin; NE, norepinephrine.
CHAPTER 7
Pain: Pathophysiology and Management
47 of NSAIDs, excluding aspirin.
OPIOID ANALGESICS Opioids are the most potent 
pain-relieving drugs currently available.
Respiratory depres-
sion is uncommon at standard analgesic doses, but can 
be life-threatening.
Opioid-related side effects can be 
reversed rapidly with the narcotic antagonist naloxone.
The physician should not hesitate to use opioid analgesics 
in patients with acute severe pain.
Table 7-1 lists the most 
commonly used opioid analgesics.
Opioids produce analgesia by actions in the CNS.
They activate pain-inhibitory neurons and directly 
inhibit pain-transmission neurons.
One striking example of this is norme-
peridine, a metabolite of meperidine.
Normeperidine 
produces hyperexcitability and seizures that are not 
reversible with naloxone.
Normeperidine accumulation 
is increased in patients with renal failure.
Common side effects include 
nausea, vomiting, constipation, and sedation.
The most 
serious side effect is respiratory depression.
Because of this, initiation of therapy requires titra-
tion to optimal dose and interval.
The most important 
principle is to provide adequate pain relief.
Because many patients are reluc-
tant to complain, this practice leads to needless suffering.
The 
patient can then titrate the dose to the optimal level.
The availability of new routes of administration has 
extended the usefulness of opioid analgesics.
Most 
important is the availability of spinal administration.
Opioids can be infused through a spinal catheter placed 
either intrathecally or epidurally.
In this way, side effects 
such as sedation, nausea, and respiratory depression can 
be minimized.
However, 
fixed-ratio combinations of an opioid with acetaminophen 
carry a special risk.
CHRONIC PAIN
Managing patients with chronic pain is intellectually 
and emotionally challenging.
The traditional 
medical approach of seeking an obscure organic pathol-
ogy is usually unhelpful.
There are several factors that can cause, perpetuate, 
or exacerbate chronic pain.
Finally, 
a variety of psychological conditions can exacerbate or 
even cause pain.
There are certain areas to which special attention 
should be paid in a patient’s medical history.
Relief of the pain with a sympathetic block 
is diagnostic.
Optimal therapy requires that each of 
these factors be looked for and treated.
There are no set criteria for predicting which 
patients will respond to these procedures.
Such referrals are 
clearly not necessary for all chronic pain patients.
For 
some, pharmacologic management alone can provide 
adequate relief.
Table 7-2 lists some of the painful conditions 
that respond to TCAs.
The TCAs that have been shown to relieve pain have 
significant side effects (Table 7-1; Chap.
53).
bControlled studies indicate benefit but not analgesia.
This pain has a characteristic brief, 
shooting, electric shock–like quality.
Transdermal fentanyl is another 
excellent option.
In contrast, opioid medications should 
be used as a second- or third-line drug class.
Drugs of dif-
ferent classes can be used in combination to optimize 
pain control.
Peter J.
Goadsby    ■    Neil H.
Raskin  
51
 Headache is among the most common reasons patients 
seek medical attention.
7 ).
Headache may originate from either or 
both mechanisms.
Philadelphia, Lippin-
cott, Williams & Wilkins, 2005.
SECTION II
Clinical Manifestations of Neurologic Disease
52 also be seen in migraine.
Migraine is a brain disorder, and best understood and 
managed as such.
Patients with recent onset of pain 
require prompt evaluation and appropriate treatment.
A complete neurologic examination is an essen-
tial first step in the evaluation.
Serious underlying conditions that are associated with 
headache are described next.
Brain tumor is a rare cause 
of headache and even less commonly a cause of severe 
pain.
The vast majority of patients presenting with 
severe headache have a benign cause.
MENINGITIS
Acute, severe headache with stiff neck and fever sug-
gests meningitis.
Lumbar puncture is mandatory.
Often 
there is striking accentuation of pain with eye move-
ment.
Meningitis is discussed in Chaps.
40 and 41.
Rarely, if the hemorrhage is small or below the 
foramen magnum, the head CT scan can be normal.
Intracranial hemorrhage is discussed in Chap.
28.
This pattern of symptoms 
results from migraine far more often than from brain 
tumor.
The headache of brain tumor disturbs sleep in 
about 10% of patients.
Brain tumors are discussed in Chap.
37.
TEMPORAL ARTERITIS
(See also Chap.
The average 
age of onset is 70 years, and women account for 65% 
of cases.
Headache is the dominant symptom and 
often appears in association with malaise and muscle 
aches.
Headache is usually worse at night and often 
aggravated by exposure to cold.
GLAUCOMA
Glaucoma may present with a prostrating headache 
associated with nausea and vomiting.
The headache 
often starts with severe eye pain.
On physical exami-
nation, the eye is often red with a fixed, moderately 
dilated pupil.
Glaucoma is discussed in Chap.
21.
The most common are 
migraine, tension-type headache, and cluster headache.
Migraine 
can often be recognized by its activators, referred to as 
triggers.
8-1).
CGRP receptor antagonists have now 
been shown to be effective in the acute treatment of 
migraine.
Data also support a role for dopamine in the patho-
physiology of migraine.
Most migraine symptoms 
can be induced by dopaminergic stimulation.
Mutations in the neuronal voltage-gated sodium 
channel SCN1A cause FHM 3.
Functional neuroim-
aging has suggested that brainstem regions in migraine 
(Fig.
8-3) are good candidates for specific involvement 
in primary headache.
Diagnosis and clinical features
Diagnostic criteria for migraine headache are listed in 
Table 8-4.
New York, Churchill 
Livingston, 1988; with permission.
FIGURE 8-2
Positron emission tomography (PET) activation in 
migraine.
Most patients with disabling head-
ache probably have migraine.
The Migraine Disability Assessment Score 
(MIDAS) is a well-validated, easy-to-use tool (Fig.
8-4).
Patient education is an important aspect of migraine 
management.
Most patients 
benefit by the identification and avoidance of spe-
cific headache triggers.
For most patients, this approach 
is, at best, an adjunct to pharmacotherapy.
Nonphar-
macologic measures are unlikely to prevent all migraine 
attacks.
Mild migraine attacks can usually be man-
aged by oral agents; the average efficacy rate is 50–70%.
Severe migraine attacks may require parenteral therapy.
Migraine therapy must be individualized; 
a standard approach for all patients is not possible.
Indeed, 
many undiagnosed migraineurs are self-treated with 
nonprescription NSAIDs.
A general consensus is that 
NSAIDs are most effective when taken early in the 
migraine attack.
The 
combination of acetaminophen, aspirin, and caffeine 
has been approved for use by the U.S.
On how many days in the last 3 months did you not do household work 
because of your headaches?
On how many days in the last 3 months did you have a headache?
2.
3.
4.
5.
A.
B.
............................
................................................................................
.....................
.................................................................
.........................................
..........................................
Write zero if you did not do the activity in the last 3 months.
*MIDAS Questionnaire
FIGURE 8-4 
MIDAS Questionnaire.
Local regulations and guidelines should be consulted.
Abbreviations: NSAIDs, nonsteroidal anti-inflammatory drugs; 5-HT, 5-hydroxytryptamine.
CHAPTER 8
Headache
59 tans are selective 5-HT1B/1D receptor agonists.
Side effects are common though often mild and tran-
sient.
Ergotamine preparations offer a nonselective means 
of stimulating 5-HT1 receptors.
The 
average oral ergotamine dose for a migraine attack is 
2 mg.
Important side effects of NSAIDs 
include dyspepsia and gastrointestinal irritation.
5-HT1 RECEPTOR AGONISTS
Oral Stimulation of 5-HT1B/1D receptors can stop an 
acute migraine attack.
Sumatriptan, 6 mg SC, is 
effective in ∼70–80% of patients.
Drug absorption 
is impaired during migraine because of reduced gas-
trointestinal motility.
In 
addition, dopamine antagonists decrease nausea/vom-
iting and restore normal gastric motility.
Nasal A nasal preparation of butorphanol is available 
for the treatment of acute pain.
Parenteral Narcotics are effective in the acute treat-
ment of migraine.
For example, IV meperidine (50–100 
mg) is given frequently in the emergency room.
This 
regimen “works” in the sense that the pain of migraine is 
eliminated.
However, this regimen is clearly suboptimal 
for patients with recurrent headache.
Narcotic craving and/or withdrawal can 
aggravate and accentuate migraine.
Drugs that have the capacity to stabilize migraine are 
listed in Table 8-7.
In addition, 
a number of other drugs appear to display prophylactic 
efficacy.
bNot available in the United States.
The probability of success with any one of the anti-
migraine drugs is 50–75%.
The headache may 
be episodic or chronic (present >15 days per month).
Pathophysiology
The pathophysiology of TTH is incompletely under-
stood.
Behavioral approaches including relaxation can also be 
effective.
There is no evidence for 
the efficacy of acupuncture.
Placebo-controlled trials 
of onabotulinum toxin type A in chronic TTH have not 
shown benefit.
Pain is usually severe and may occur more than once a 
day.
A core feature of cluster headache is periodicity.
Patients are generally perfectly well between episodes.
This 
phenomenon of unilateral photophobia/phonophobia is 
characteristic of TACs.
8-3).
cIndicates complete response to indomethacin.
However, treatment of acute attacks is required for all 
cluster headache patients at some time.
Many patients with acute clus-
ter headache respond very well to oxygen inhalation.
This should be given as 100% oxygen at 10–12 L/min for 
15–20 min.
It appears that high flow and high oxygen 
content are important.
Oral 
sumatriptan is not effective for prevention or for acute 
treatment of cluster headache.
When ergotamine (1–2 mg) is used, it is most 
effective when given 1–2 h before an expected attack.
Lithium (600–900 mg qd) appears to be particularly useful 
for the chronic form of the disorder.
The initial dose range is 
40–80 mg twice daily; effective doses may be as high 
as 960 mg/d.
Side effects such as constipation and leg 
swelling can be problematic.
A baseline ECG is recom-
mended for all patients.
Dose increases 
are usually made in 80-mg increments.
For patients on 
long-term verapamil, ECG monitoring every 6 months 
is advised.
Topira-
mate is helpful in some cases.
Piroxicam has been used, 
although it is not as effective as indomethacin.
Vera-
pamil, an effective treatment for cluster headache, does 
not appear to be useful for PH.
Secondary PH is more likely if the patient 
requires high doses (>200 mg/d) of indomethacin.
In 
patients with apparent bilateral PH, raised CSF pressure 
should be suspected.
It is important to note that indo-
methacin reduces CSF pressure.
When a diagnosis of 
PH is considered, MRI is indicated to exclude a pitu-
itary lesion.
Diagnosis
The pain of SUNCT/SUNA is unilateral and may be 
located anywhere in the head.
Each pattern may be seen 
in the context of an underlying continuous head pain.
Apart from trigeminal sensory disturbance, the neuro-
logic examination is normal in primary SUNCT.
34).
Secondary (Symptomatic) SUNCT
SUNCT can be seen with posterior fossa or pituitary 
lesions.
However, IV lidocaine, which arrests 
the symptoms, can be used in hospitalized patients.
The most effective treatment for prevention is 
lamotrigine, 200–400 mg/d.
Topiramate and gabapentin 
may also be effective.
Carbamazepine, 400–500 mg/d, 
has been reported by patients to offer modest benefit.
Greater occipital nerve injection has produced limited 
benefit in some patients.
Occipital nerve stimulation 
is probably helpful in an important subgroup of these 
patients.
Popula-
tion-based estimates suggest that about 4% of adults 
have daily or near-daily headache.
For patients with primary headaches, diagnosis of the 
headache type will guide therapy.
Anticonvulsants, such as topiramate, valproate, 
and gabapentin, are also useful in migraineurs.
Flunari-
zine can also be very effective for some patients, as can 
methysergide or phenelzine.
The residual 
symptoms probably represent the underlying headache 
disorder.
bSome patients may have headache >4 h/d.
One approach is to reduce the medication dose by 10% 
every 1–2 weeks.
IM chlor-
promazine can be helpful at night; patients must be ade-
quately hydrated.
The first priority 
is to distinguish between a primary and a secondary 
cause of this syndrome.
28).
The pain, which is occipitofrontal, is usually a dull 
ache but may be throbbing.
Post-LP headache usually begins within 
48 h but may be delayed for up to 12 days.
Its inci-
dence is between 10 and 30%.
Beverages with caffeine 
may provide temporary relief.
Postural orthostatic tachycardia syndrome (POTS 
[Chap.
8-5).
Initial treatment for low CSF volume headache is 
bed rest.
An ECG to screen for arrhythmia should 
be performed before administration.
If unsuccessful, an abdominal binder may be help-
ful.
If a leak can be identified, an autologous blood patch 
is usually curative.
Raised CSF Pressure Headache Raised CSF 
pressure is well recognized as a cause of headache.
Brain imaging can often reveal the cause, such as a 
space-occupying lesion.
Persistently raised intracranial pres-
sure can trigger chronic migraine.
It is generally worse with recumbency.
Visual 
obscurations are frequent.
Evaluation of patients suspected to have raised CSF 
pressure requires brain imaging.
It is most efficient to 
obtain an MRI, including an MR venogram, as the initial 
study.
An elevated opening pressure and 
improvement in headache following removal of CSF is 
diagnostic.
Initial treatment is with acetazolamide (250–500 mg 
bid); the headache may improve within weeks.
Complaints of dizziness, 
vertigo, and impaired memory can accompany the head-
ache.
Symptoms may remit after several weeks or persist 
for months and even years after the injury.
Typically the 
neurologic examination is normal and CT or MRI stud-
ies are unrevealing.
Chronic subdural hematoma may on 
occasion mimic this disorder.
Evaluation 
reveals no apparent cause for the headache.
Treatment is largely empirical.
The MAOI phenelzine may also be 
useful in carefully selected patients.
The headache usually 
resolves within 3–5 years, but it can be quite disabling.
Primary NDPH Primary NDPH occurs in both males 
and females.
Nausea, photophobia, and/or phonophobia 
occur in about half of patients.
At 24 months, ∼86% of patients are headache-free.
Featureless NDPH is one of the primary headache forms 
most refractory to treatment.
Standard preventive thera-
pies can be offered but are often ineffective.
The age of onset ranges from 11 to 58 years; women are 
affected twice as often as men.
The cause is unknown.
Topiramate can be 
helpful in some patients.
The mecha-
nism of this response is unclear.
It may be pre-
cipitated by any form of exercise; it often has the pul-
satile quality of migraine.
The mechanism of primary exertional headache is 
unclear.
The link to exercise is the 
main clinical clue that headache is of cardiac origin.
Pheochromocytoma may occasionally cause exertional 
headache.
Intracranial lesions and stenosis of the carotid 
arteries are other possible etiologies.
The 
pain usually begins as a dull bilateral headache that sud-
denly becomes intense at orgasm.
The headache can 
be prevented or eased by ceasing sexual activity before 
orgasm.
The latter arises from vigor-
ous sexual activity and is a form of low CSF pressure 
headache.
In 
about half of patients, sex headache will subside within 
6 months.
Migraine is probably more 
common in patients with sex headache.
TREATMENT Primary Sex Headache
Benign sex headaches recur irregularly and infrequently.
An alter-
native is the calcium channel–blocking agent diltiazem, 
60 mg tid.
Hypnic headache
This headache syndrome typically begins a few hours 
after sleep onset.
Daytime naps can also precipitate head pain.
Most patients are female, and the onset is usually after 
age 60 years.
Headaches are bilateral in most, but may 
be unilateral.
Photophobia or phonophobia and nausea 
are usually absent.
Case reports suggest that flunari-
zine, 5 mg nightly, can be effective.
John W.
Engstrom    ■    Richard A.
population is chronically disabled 
because of back pain.
9-1  and  9-2) .
The posterior portion of the spine consists of the ver-
tebral arches and processes.
Each arch consists of paired 
cylindrical pedicles anteriorly and paired laminae poste-
riorly.
The apposition of a superior and inferior facet consti-
tutes a  facet joint .
15-2  and  15-3 ).
The cervical nerve roots follow a short 
intraspinal course before exiting.
9-3 ) .
The nucleus 
pulposus of the intervertebral disk is not pain-sensitive 
under normal circumstances.
( From A Gauthier Cornuelle, DH Gronefeld: Radiographic Anatomy Posi-
tioning.
(From A Gauthier Cornuelle, DH Gronefeld: 
Radiographic Anatomy Positioning.
The site of the pain is near the affected part of the back.
Pain referred to the back may arise from abdominal or 
pelvic viscera.
The patient may 
occasionally complain of back pain only.
Pain of spine origin may be located in the back or 
referred to the buttocks or legs.
The pain may increase in 
postures that stretch the nerves and nerve roots.
The normal spine has a cervical and lumbar lordosis, 
and a thoracic kyphosis.
(From Adams and Victor’s 
Principles of Neurology, 9th ed.
Pain from hip disease may mimic the pain of lumbar 
spine disease.
Passive dorsiflexion of the foot during the maneu-
ver adds to the stretch.
Eliciting the SLR 
sign in the sitting position can help determine if the 
finding is reproducible.
The crossed SLR sign is less sensitive but more 
specific for disk herniation than the SLR sign.
The nerve 
or nerve root lesion is always on the side of the pain.
Breakaway weakness may be due 
to pain or a combination of pain and underlying true 
weakness.
Breakaway weakness without pain is almost 
always due to a lack of effort.
In the absence of risk factors, these imaging 
studies are rarely helpful in nonspecific ALBP.
5).
It occurs in 
up to 6% of adolescents.
The trunk may be shortened and the abdomen pro-
tuberant as a result.
A dimple or small lipoma may overlie 
the defect.
Most cases are asymptomatic and discovered 
incidentally during an evaluation for back pain.
MRI 
studies reveal a low-lying conus (below L1-L2) and a 
short and thickened filum terminale.
These 
terms are used loosely and do not clearly describe a spe-
cific anatomic lesion.
The pain is usually confined to 
the lower back, and there is no radiation to the buttocks 
or legs.
Patients with paraspinal muscle spasm often 
assume unusual postures.
Neurologic impairment is com-
mon, and early surgical treatment is indicated.
LUMBAR DISK DISEASE
This is a common cause of chronic or recurrent low 
back and leg pain (Figs.
9-3 and 9-4).
The 
cause is often unknown; the risk is increased in over-
weight individuals.
Disk herniation is unusual prior 
to age 20 years and is rare in the fibrotic disks of the 
elderly.
Genetic factors may play a role in predisposing 
some patients to disk disease.
The pain may be located 
in the low back only or referred to a leg, buttock, or 
hip.
The mechanism by which intervertebral disk injury 
causes back pain is controversial.
The inner annulus 
fibrosus and nucleus pulposus are normally devoid of 
innervation.
Clinical manifestations of specific nerve root 
lesions are summarized in Table 9-2.
For example, an absent knee 
reflex may be due to a femoral neuropathy or an L4 
nerve root injury.
Spine 
MRIs yield exquisite views of intraspinal and adjacent 
soft tissue anatomy.
The correlation of neuroradiologic findings 
to symptoms, particularly pain, is not simple.
Asymptomatic disk 
protrusions are also common and may enhance with 
contrast.
The correla-
tion between CT and EMG for localization of nerve 
root injury is between 65 and 73%.
Up to one-third 
of asymptomatic adults have a lumbar disk protrusion 
detected by CT or MRI scans.
Management of lumbar disk disease is discussed later 
in the chapter.
35), 
and Guillain-Barré syndrome (Chap.
46).
Combi-
ned involvement of the conus medullaris and cauda 
equina can occur.
CES is commonly due to a ruptured 
FIGURE 9-4 
Left L5 radiculopathy.
A.
Sagittal T2-weighted image on 
the left reveals disk herniation at the L4-L5 level.
B.
37).
Symptoms in the legs are usu-
ally bilateral.
Unlike vascular claudication, symptoms are often 
provoked by standing without walking.
Unlike lum-
bar disk disease, symptoms are usually relieved by sit-
ting.
Severe neurologic deficits, including paralysis 
and urinary incontinence, occur only rarely.
LSS can be acquired (75%), congenital, or due to a 
combination of these factors.
MRI provides the best definition of 
the abnormal anatomy (Fig.
9-5).
There is insufficient evi-
dence to support the use of epidural glucocorticoid 
injections.
Patients treated nonoperatively improve uncommonly.
A.
The image 
shows a normal thecal sac within the lumbar spinal canal.
The 
thecal sac is bright.
The lumbar roots are dark punctuate dots 
in the posterior thecal sac with the patient supine.
B.
The usefulness of therapeutic facet joint blocks for pain 
has not been rigorously studied.
Patients are often males below age 40.
Onset at a 
young age and back pain improving with exercise are 
characteristic.
Cancer-
related back pain tends to be constant, dull, unrelieved 
by rest, and worse at night.
By contrast, mechanical low 
back pain usually improves with rest.
MRI, CT, and 
CT-myelography are the studies of choice when spi-
nal metastasis is suspected.
A.
B.
Axial 
T2-weighted image.
SECTION II
Clinical Manifestations of Neurologic Disease
80 diagnosis is crucial.
The management of spinal metasta-
sis is discussed in detail in Chap.
37.
The primary source of infection is usu-
ally the urinary tract, skin, or lungs.
Intravenous drug 
use is a well-recognized risk factor.
Fever or an elevated white 
blood cell count is found in a minority of patients.
The intervertebral disk can also 
be affected by infection (diskitis), and very rarely by 
tumor.
Spinal epidural abscess (Chap.
The abscess may track over multiple spinal 
levels and is best delineated by spine MRI.
The MRI shows clumped nerve roots or loculations 
of cerebrospinal fluid within the thecal sac.
Clumped 
nerve roots may also occur with demyelinating poly-
neuropathy or neoplastic infiltration.
Treatment is usu-
ally unsatisfactory.
Dorsal column stimulation for pain relief has produced 
varying results.
Up to two-thirds 
of compression fractures seen on radiologic imaging are 
asymptomatic.
The risk of an additional vertebral fracture 
at 1 year following a first vertebral fracture is 20%.
If tumor is suspected, a bone biopsy or diagnostic search 
for a primary tumor is indicated.
The role of NSAIDs is controversial.
Both pain and disability are improved with bracing.
Spinal cord or nerve root compression 
can result from bony encroachment.
Occasionally, back pain 
 
CHAPTER 9
Back and Neck Pain
81 may be the first and only manifestation.
Fatty foods occaionally induce 
back pain associated with biliary disease.
The classic clinical triad of abdomi-
nal pain, shock, and back pain occurs in <20% of 
patients.
The typical patient at risk is an elderly male 
smoker with back pain.
Frequently, the diagnosis is 
initially missed because the symptoms and signs can 
be nonspecific.
Patients with suspected 
AAA should be evaluated with abdominal ultrasound, 
CT, or MRI.
The pain is referred to the sacral region.
Endo-
metriosis or uterine cancers may invade the uterosacral 
ligaments.
Menstrual pain may be felt in the sacral region.
Poorly localized, cramping pain can radiate down the 
legs.
Low back pain that radiates into 
one or both thighs is common in the last weeks of 
pregnancy.
Lesions 
of the bladder and testes do not often produce back 
pain.
Paraspinal lumbar 
pain may be a symptom of ureteral obstruction due to 
nephrolithiasis.
Exercises to strengthen the paraspinal and abdomi-
nal muscles are sometimes helpful.
IDIOPATHIC
The cause of low back pain occasionally remains 
unclear.
Full recovery can be expected in 85% 
of adults with ALBP without leg pain.
Risk factors for a 
serious cause of ALBP are shown in Table 9-1.
Labora-
tory and imaging studies are unnecessary if risk factors 
are absent.
The prognosis is generally excellent.
Many patients 
do not seek medical care and apparently improve on 
their own.
Edu-
cation is an important part of treatment.
Several randomized trials 
suggest that bed rest does not accelerate the pace of 
recovery.
Application of heat by heating pads 
or heated blankets is sometimes helpful.
Limiting the use of muscle relaxants to nighttime 
only may be an option for some patients.
In this setting, how-
ever, the benefit of opioid therapy or muscle relaxants is 
less clear.
In general, activity tolerance is 
the primary goal, while pain relief is secondary.
Trials of the latter suggest some benefit even for 
patients without evidence of depression.
Trials do not 
support the efficacy of selective serotonin reuptake 
inhibitors for back pain.
Behav-
ioral treatments may have effects similar in magnitude 
to exercise therapy.
Back pain is the most common reason for seeking 
complementary and alternative treatments.
The most 
common of these for back pain are spinal manipulation, 
acupuncture, and massage.
Biofeedback has not 
been studied rigorously.
Simi-
larly, there is little evidence to support the use of trigger 
point injections.
A few small trials have 
resulted in conflicting results for facet joint pain.
Each of these studies included patients with back pain 
and a degenerative disk, but no sciatica.
Both U.S.
These are generally designed as metal plates with a 
polyethylene cushion sandwiched in between.
This treat-
ment remains controversial for low back pain.
Systematic 
reviews suggest that the evidence is limited and effects 
are moderate.
Some observers have raised concern that chronic 
back pain may often be overtreated.
On the other hand, exercise therapy 
and treatment of depression appear to be underused.
Resumption of normal activity as much as possible 
is usually the best activity recommendation.
The utility of diagnostic nerve root blocks 
remains a subject of debate.
son for recommending spine surgery.
Some patients will want the fastest 
possible relief and find surgical risks acceptable.
The usual surgical procedure is a partial hemilami-
nectomy with excision of the prolapsed disk.
The costs associated with 
lumbar interbody fusion have increased dramatically in 
recent years.
35).
The decision to obtain imag-
ing should be based upon the nature of the injury.
A CT scan is the diagnostic procedure 
of choice for detection of acute fractures.
Up to 50% of persons reporting whip-
lash injury acutely have persistent neck pain 1 year later.
Severe initial symptoms have been associated 
with a poor long-term outcome.
Neck 
pain, stiffness, and a range of motion limited by pain 
are the usual manifestations.
A herniated cervical disk 
is responsible for ∼25% of cervical radiculopathies.
Cervical disk herniations are 
usually posterolateral near the lateral recess.
The cervi-
cal nerve roots most commonly affected are C7 and C6.
9-6); this compres-
sion accounts for 75% of cervical radiculopathies.
The 
roots most commonly affected are C7 and C6.
Combinations of radiculopathy and myelopathy 
may be present.
32), multiple 
sclerosis (Chap.
39), spinal cord tumors, or syringomy-
elia (Chap.
35).
EMG 
and nerve conduction studies can localize and assess 
the severity of the nerve root injury.
In advanced RA, synovitis of the atlantoaxial 
joint (C1-C2; Fig.
Radio-
logic evidence of atlantoaxial subluxation occurs in 30% 
of patients with RA.
Not surprisingly, the degree of 
subluxation correlates with the severity of erosive dis-
ease.
Surgery should be considered when myelopa-
thy or spinal instability is present.
MRI is the imaging 
modality of choice.
Pain is mild 
or absent.
Treatment consists of surgical resec-
tion of the anomalous band.
Blood pressure is 
reduced in the affected limb, and signs of emboli may be 
present in the hand.
Neurologic signs are absent.
Ultra-
sound can confirm the diagnosis noninvasively.
Venous TOS 
is due to subclavian vein thrombosis resulting in swell-
ing of the arm and pain.
The vein may be compressed by 
a cervical rib or anomalous scalene muscle.
Venography 
is the diagnostic test of choice.
The role of surgery in disputed TOS is controver-
sial.
The onset is 
often preceded by an infection.
The long thoracic nerve 
may be affected; the latter results in a winged scapula.
Recovery is generally good but may 
take up to 3 years to be complete.
Lesions of the radial or ulnar nerve can mimic a radic-
ulopathy at C7 or C8, respectively.
For further discussion of peripheral nerve disorders, 
see Chap.
45.
SHOULDER
Pain arising from the shoulder can on occasion mimic 
pain from the spine.
Exercises often include 
shoulder rolls and neck stretches.
Comparison to other conservative treatment 
measures is needed.
Fusions can be performed with a vari-
ety of techniques.
The durability of disk prosthe-
ses is uncertain.
Available data do not strongly support 
one surgical technique over another.
The onset is rapid, duration brief, and recovery spon-
taneous and complete.
The annual cost 
for syncope-related hospitalization in the United States 
is ∼$2 billion.
Syncope has a lifetime cumulative inci-
dence of up to 35% in the general population.
Neurally 
mediated syncope is the etiology in the vast majority of 
these cases.
In elderly adults, there is a sharp rise in the 
incidence of syncope after 70 years.
In population-based studies, neurally mediated syn-
cope is the most common cause of syncope.
The inci-
dence is slightly higher in females than males.
In young 
subjects there is often a family history in fi rst-degree 
relatives.
The prognosis after a single syncopal event for all 
age groups is generally benign.
10-1).
28).
10-2).
Blue denotes sympathetic neu-
rons and green parasympathetic neurons.
These include 
diaphoresis, pallor, palpitations, nausea, hyperventila-
tion, and yawning.
The 
eyes typically remain open and usually deviate upward.
Urinary but not fecal incontinence may occur.
Postictal 
confusion is rare, although visual and auditory halluci-
nations are sometimes reported.
B.
The same tracing expanded to show 80 s of the 
episode (from 80 to 200 s).
BP, blood pressure; bpm, beats 
per minute; HR, heart rate.
syncope.
Randomized controlled trials support this inter-
vention.
In these 
patients, dual-chamber pacing may be helpful.
10-3).
bHyperventilation (20 breaths) in a squatting position, rapid rise to standing, then Valsalva.
Visual blur-
ring may occur, likely due to retinal or occipital lobe 
ischemia.
33).
33), Parkinson’s disease (Chap.
30), demen-
tia with Lewy bodies (Chap.
29), and pure auto-
nomic failure (Chap.
33).
B.
The same tracing expanded to 
show 40 s of the episode (from 180 to 220 s).
BP, blood pres-
sure; bpm, beats per minute; HR, heart rate.
46 and 
47).
The mechanism of postprandial syncope 
is not fully elucidated.
Orthostatic hypotension is often iatrogenic.
Syncope due to bradycardia or 
asystole is referred to as a Stokes-Adams attack.
Ventricular tachyarrhythmias frequently cause syn-
cope.
Next, nonphar-
macologic interventions should be introduced.
Intravascular volume should be expanded 
by increasing dietary fluid and salt.
33).
SECTION II
Clinical Manifestations of Neurologic Disease
96 sudden death.
Structural disease may also contribute to other 
pathophysiologic mechanisms of syncope.
TREATMENT Cardiac Syncope
Treatment of cardiac disease depends upon the under-
lying disorder.
These 
disorders are best managed by physicians with special-
ized skills in this area.
Myoclonic jerks associated with syncope may 
be multifocal or generalized.
They are typically arrhyth-
mic and of short duration (<30 s).
Mild flexor and exten-
sor posturing also may occur.
These phenomena should be differentiated from 
the premonitory features of syncope.
Seizures, unlike syncope, are rarely pro-
voked by emotions or pain.
These symptoms are due to autonomic activation 
to counter the falling blood glucose.
Hunger, in par-
ticular, is not a typical premonitory feature of syncope.
There are 
no premonitory symptoms.
Cataplexy occurs in 60–75% 
of patients with narcolepsy.
Such patients are rarely injured despite numerous 
falls.
Autonomic Nervous System Testing (Chap.
33) Autonomic testing including tilt table testing can be 
performed in specialized centers.
The hemodynamic 
abnormalities demonstrated on tilt table test (Figs.
Currently, this test is rarely performed to evaluate 
patients with syncope.
Mark F.
Walker    ■     Robert B.
Faintness and syncope, which are 
discussed in detail in  Chap.
They may be paroxysmal or due to a fi xed unilateral or 
bilateral vestibular defi cit.
Bilateral lesions cause imbal-
ance and instability of vision when the head moves 
( oscillopsia ).
(2) 
is it vestibular?
and (3) if vestibular, is it peripheral or 
central?
Symmetric bilateral vestibular hypo-
function causes imbalance but no vertigo.
Causes of dizziness can be divided into episodes 
that last for seconds, minutes, hours, or days.
Attacks of migrainous vertigo and 
Ménière’s disease often last hours.
The range of eye movements and whether 
they are equal in each eye should be observed.
If the VOR is deficient, a 
catch-up saccade is seen at the end of the rotation.
bCombined vertical-torsional nystagmus suggests BPPV.
Dynamic visual acuity is a functional test that can 
be useful in assessing vestibular function.
The choice of ancillary tests should be guided by the 
history and examination findings.
Audiometry should 
be performed whenever a vestibular disorder is sus-
pected.
Pre-
dominantly low-frequency hearing loss is characteristic 
of Ménière’s disease.
TREATMENT Dizziness
Treatment of vestibular symptoms should be driven by 
the underlying diagnosis.
The pattern of spontaneous nystagmus, if pres-
ent, may be helpful (Table  11-1).
If the head impulse test 
is normal, an acute peripheral vestibular lesion is unlikely.
Benign paroxysmal positional vertigo
BPPV is a common cause of recurrent vertigo.
Superior 
(also called anterior) canal involvement is rare.
For 
posterior canal BPPV, the Epley maneuver is the most 
commonly used procedure.
Unlike BPPV, the vertigo persists 
even when the head is not moving.
Antiemetics may be helpful to 
relieve symptoms at the time of an attack.
Diuretics and sodium restriction are the 
initial treatments.
Full ablative procedures (vestibular nerve sec-
tion, labyrinthectomy) seldom are required.
The diagnosis often is not made until there is 
sufficient hearing loss to be noticed.
In the laboratory, responses to caloric testing are 
reduced.
Vestibular suppressant medications should not be used, 
as they will increase the imbalance.
Psychosomatic dizziness
Psychological factors play an important role in chronic 
dizziness.
Vestibular suppressant medications 
generally should be avoided.
Food and Drug Adminis-
tration, but most are not approved for the treatment of vertigo.
cFor motion sickness only.
dFor benign paroxysmal positional vertigo.
eFor Ménière’s disease.
fFor vestibular migraine.
gFor acute vestibular neuritis (started within three days of onset).
hFor psychosomatic vertigo.
Michael J.
31 ) or abnormal movements ( Chap.
30 ).
The 
mode of onset, distribution, and accompaniments of 
weakness help suggest its cause.
Weakness  is a reduction in the power that can be 
exerted by one or more muscles.
18 ), sometimes is mis-
taken for weakness.
The suffi x 
“-plegia” signifi es severe weakness or paralysis.
The distribution of weakness helps to indicate the 
site of the underlying lesion.
Tone  is the resistance of a muscle to passive stretch.
Spasticity is distinct from rigidity and paratonia, 
two other types of hypertonia.
Rigidity occurs with 
certain extrapyramidal disorders, such as Parkinson’s 
disease.
1) and, in 
particular, by an extensor plantar (Babinski) response.
47).
12-1).
These 
lesions produce weakness through decreased activation 
of the lower motor neurons.
Spasticity accompanies upper motor neuron weak-
ness but may not be present in the acute phase.
Upper 
motor neuron lesions also affect the ability to perform 
rapid repetitive movements.
Such movements are slow 
and coarse, but normal rhythmicity is maintained.
Finger-nose-finger and heel-knee-shin maneuvers are 
performed slowly but adequately.
12-2).
An absent 
stretch reflex suggests involvement of spindle afferent 
fibers.
Pyramidal neurons make direct monosynaptic 
connections with lower motor neurons.
Cor-
ticobulbar neurons are similar to corticospinal neurons but 
innervate brainstem motor nuclei.
The bulbospinal system 
sometimes is referred to as the extrapyramidal upper motor 
neuron system.
distribution and is influenced by preceding activity of the 
affected muscle.
The presence of other 
neurologic deficits helps localize the lesion.
Homon-
ymous visual field defects reflect either a cortical or a 
subcortical hemispheric lesion.
27).
Evaluation (Fig.
12-3) 
begins immediately with a CT scan of the brain and 
laboratory studies.
Subacute hemiparesis that evolves over days or weeks 
has an extensive differential diagnosis.
Loss of α 
motor neurons or disruption of their axons produces lower 
motor neuron weakness.
A tendon reflex requires the function of all the illustrated 
structures.
CHAPTER 12
Weakness and Paralysis
107
over days to weeks.
AIDS may present with subacute 
hemiparesis due to toxoplasmosis or primary CNS lym-
phoma.
35], and peripheral 
neuropathies).
It is important to image the spinal 
cord (Fig.
12-3).
35).
‡ If no abnormality detected, consider myelogram or brain MRI.
46), or myopathy (Chap.
48).
Subacute or chronic paraparesis with spasticity is caused 
by upper motor neuron disease.
35).
If an 
MRI of the spinal cord is normal, MRI of the brain 
may be indicated.
The major causes of intermittent weakness are listed 
in Table 12-2.
52).
Guillain-Barré 
syndrome (Chap.
In obtunded patients, evaluation begins with a CT 
scan of the brain.
An MRI is obtained of the clinically suspected site 
of pathology.
Myopathic weakness rarely is limited to one limb.
27); diagnostic possibilities are similar to those 
for acute hemiparesis.
Muscle disorders
  a.
Channelopathies (periodic paralyses)
 b.
Neuromuscular junction disorders
  a.
Myasthenia gravis
  b.
Lambert-Eaton myasthenic syndrome
4.
Central nervous system disorders
  a.
Transient ischemic attacks of the brainstem
  b.
Transient global cerebral ischemia
    c.
Multiple sclerosis
 
CHAPTER 12
Weakness and Paralysis
109 reflects plexus involvement.
In either case, an electrodiagnostic study 
is indicated.
45).
32).
Rarely, myopathies present with dis-
tal weakness (Chap.
48).
Electrodiagnostic studies help 
localize the disorder (Fig.
12-3).
48).
Diseases 
of the neuromuscular junction (such as myasthenia 
gravis [Chap.
Numbness does not occur with any of these diseases.
48) or neuromuscular junction dis-
order (Chap.
47).
Bilateral facial palsy with areflexia 
suggests Guillain-Barré syndrome (Chap.
46).
Asymmetric bulbar weakness usually is due to motor 
neuron disease.
49).
Gait dis-
orders have been described in 15% of individuals older 
than age 65 years.
By age 80 years, one person in four 
will use a mechanical aid to assist ambulation.
Among 
those 85 and older, the prevalence of gait abnormality 
approaches 40%.
Each year, 8% of individ-
uals age >75 years suffer a serious fall-related injury.
Hip fractures often result in hospitalization and nursing 
home admission.
Nearly 
one in fi ve elderly individuals voluntarily limits activity 
because of fear of falling.
These func-
tions are widely distributed in the central nervous sys-
tem.
Human patients with damage to 
these structures have impaired balance with standing 
and walking.
Boston, Little 
Brown, 1995.
prone to falls and injury.
Frailty, muscle weakness, 
and deconditioning also contribute to the risk.
There is a 
growing literature on the use of attentional resources 
to manage gait and balance.
Walking is vulnerable to neurologic 
disease at every level.
One problem with this approach is that 
many failing gaits look fundamentally similar.
Unique features of 
the failing gait are often overwhelmed by the adaptive 
response.
Some of the common patterns of abnormal gait 
are summarized next.
Gait disorders can also be classified 
by etiology, as listed in Table 13-1.
This disorder is 
both common and nonspecific.
It is, in essence, an adap-
tation to a perceived postural threat.
There may be an 
associated fear of falling.
The disorder reflects compro-
mise of corticospinal command and overactivity of spi-
nal reflexes.
The patient may walk on his or her toes.
In 
extreme instances, the legs cross due to increased tone 
in the adductors.
Upper motor neuron signs are present 
on physical examination.
Shoes often reflect an uneven 
pattern of wear across the outside.
The disorder may be 
cerebral or spinal in origin.
Myelopathy from cervical spondylosis is a common 
cause of spastic or spastic-ataxic gait.
Demyelinating dis-
ease and trauma are the leading causes of myelopathy in 
younger patients.
A family history 
should suggest hereditary spastic paraplegia (HSP; Chap.
32).
Genetic testing is now available for some of the 
common HSP mutations.
Spinal cord disor-
ders are discussed in detail in Chap.
35.
Other stiff-legged gaits include dystonia (Chap.
48) 
and stiff-person syndrome.
It 
often has a genetic basis.
In autoimmune stiff-person syn-
drome (Chap.
30) is common, affecting 
1% of the population age >55 years.
The stooped pos-
ture and shuffling gait are characteristic and distinctive 
features.
Patients sometimes accelerate (festinate) with 
walking or display retropulsion.
There may be difficulty 
with gait initiation (freezing) and a tendency to turn 
en bloc.
Imbalance and falls may develop as the disease 
progresses over years.
Falls within the first year suggest the possibility of pro-
gressive supranuclear palsy.
In Hun-
tington’s disease (Chap.
29), the unpredictable occur-
rence of choreic movements gives the gait a dancing 
quality.
The term lower 
body parkinsonism is also used to describe such patients.
18).
Lesions are frequently found in the deep fron-
tal white matter and centrum ovale.
Communicating hydrocephalus in adults also pres-
ents with a gait disorder of this type.
A lumbar puncture or dynamic test is 
necessary to confirm the presence of hydrocephalus.
Cerebellar gait ataxia
Disorders of the cerebellum have a dramatic impact on 
gait and balance.
Difficulty main-
taining balance when turning is often an early feature.
They show considerable variation in their tendency to 
fall in daily life.
30 and 33) 
and various forms of hereditary cerebellar degenera-
tion (Chap.
31).
Alcoholic cer-
ebellar degeneration can be screened by history and 
often confirmed by MRI.
In patients with ataxia, MRI 
demonstrates the extent and topography of cerebellar 
atrophy.
The sensory ataxia of tabetic 
neurosyphilis is a classic example.
The contemporary 
equivalent is the patient with neuropathy affecting 
large fibers.
Joint position and vibration sense 
are diminished in the lower limbs.
Table 13-2 compares sensory 
ataxia with cerebellar ataxia and frontal gait disorder.
Neuropathy may be associated with a degree 
of sensory imbalance, as described earlier.
Patients 
with myopathy or muscular dystrophy more typically 
exhibit proximal weakness.
Weakness of the hip gir-
dle may result in a degree of excess pelvic sway during 
locomotion.
Chronic toxicity from medi-
cations and metabolic disturbances can impair motor 
function and gait.
Mental status changes may be pres-
ent, and examination may reveal asterixis or myoclonus.
Static equilibrium is disturbed, and such patients are 
easily thrown off balance.
These disorders are important 
to recognize because they are often treatable.
Hysterical gait disorders are among 
the most spectacular encountered.
Initial awareness 
of an unsteady gait often follows a fall.
Stepwise evolu-
tion or sudden progression suggests vascular disease.
It is always important 
to review the use of alcohol and medications that affect 
gait and balance.
Gait observation provides an immediate sense of the 
patient’s degree of disability.
Watching the patient 
get out of a chair provides a good functional assess-
ment of balance.
Brain imaging studies may be informative in patients 
with an undiagnosed disorder of gait.
Patients with recurrent falls are at risk for subdural 
hematoma.
Imbalance implies a disturbance of equilibrium.
Neurologic examination 
will reveal a variety of cerebellar signs.
Vestibular 
disorders (Chap.
Not every patient 
has all manifestations.
Laboratory testing is available to explore vestibulo-ocu-
lomotor and vestibulospinal deficits.
Somatosensory deficits also produce imbalance and 
falls.
There is often a subjective sense of insecure bal-
ance and fear of falling.
44).
There may be reduced awareness of bal-
ance impairment.
Patients on sedating medications are 
also in this category.
Some of these are frail older persons with chronic dis-
eases.
Recurrent falls sometimes indicate the presence 
of serious balance impairment.
10 and 26).
Unlike gait problems that are apparent on observation, 
falls are rarely observed in the office.
The patient and 
family may have limited information about what trig-
gered the fall.
Injuries can complicate the physical 
examination.
While there is no standard nosology of 
falls, common patterns can be identified.
Boston, Little 
Brown, 1995.
They occasionally occur in healthy indi-
viduals with good balance compensation.
Frequent trip-
ping falls raise suspicion about an underlying neurologic 
deficit.
Patients with spasticity, leg weakness, or footdrop 
experience tripping falls.
Deconditioning of this sort is often 
treatable.
Patients who collapse from lack of pos-
tural tone present a diagnostic challenge.
Asterixis or epilepsy may impair postural sup-
port.
There may be a consistent direction to such 
falls.
The patient with cerebellar pathology may lean 
and topple over toward the side of the lesion.
Patients with progressive supranuclear palsy often fall 
over backward.
This sequence of events can result 
in a forward fall.
Gait freezing can also occur as the 
patient attempts to turn and change direction.
These patients often express subjective 
imbalance, apprehension, and fear of falling.
Deficits in 
joint position and vibration sense are apparent on physi-
cal examination.
Standing blood 
pressure should be recorded.
Specific treatment may 
be possible, once a diagnosis is established.
A home visit to look for environmental haz-
ards can be helpful.
Sensory balance training is another approach 
to improve balance stability.
Gail  Kang       ■  Nicholas B.
VIDEO LIBRARY OF GAIT DISORDERS 
 CHAPTER 14 
   Michael J.
Aminoff    ■     Arthur K.
Pain is considered sepa-
rately in  Chap.
7 .
Such symptoms are often painful.
This thresh-
old varies in accordance with how rapidly function is 
lost in sensory nerve fi bers.
5  ).
Paresthesias and 
dysesthesias are general terms used to denote posi-
tive sensory symptoms.
Another set of terms refers to sensory abnormalities 
found on examination.
Hyperesthesia  means pain or increased 
sensitivity in response to touch.
An example is elicitation of a painful sensation 
by application of a vibrating tuning fork.
It is possible not only to record from but also 
to stimulate single fibers in isolation.
15-1).
7).
This is the spinothalamic 
pathway or anterolateral system.
Some general principles pertain.
Further, examination 
may be limited in some patients.
Comparison of response 
on one side of the body to that on the other is essential.
Discretion must be used in pur-
suing this possibility.
Evaluation of stance 
and gait also tests the integrity of motor and cerebellar 
systems.
Areas of hypal-
gesia should be mapped by proceeding radially from the 
most hypalgesic site (Figs.
15-2, 15-3 and 15-4).
(From AH 
Ropper, RH Brown, in Adams and Victor’s Principles of Neu-
rology, 9th ed.
This is impractical in most settings.
Great auricular n.
Ant.
cut.
n.
of neck
Ant.
cut.
rami
of
  thor.
n’s.
T2
3
4
5
6
7
8
9
10
11
12
Lat.
cut.
rami
Supraclavicular n’s.
Med.
cut.
n.
of arm
 & intercostobrachial n.
Med.
cut.
n.
of forearm
Iliohypo-
gastric n.
Genital
branch of
genitofem.
n.
Dorsal n.
of penis
Scrotal branch of perineal n.
Obturator n.
Lat.cut.
n.
of calf
(from common peroneal n.)
Superficial peroneal n.
(from common peroneal n.)
Deep peroneal n.
(from common peroneal n.)
Intermed.
& med.
cut.
n’s.
of thigh (from femoral n.)
Lat.
cut.
n.
of thigh
Lat.
cut.
of forearm
(from musculocut.
n.)
Lower lat.cut.
n.
of arm
(from radial n.)
Axillary n.
(circumflex)
I
II
III
Ilio-
inguinal n.
Femoral
branch
of genito- 
femoral n.
(lumbo-inguinal n.)     
Saphenous n.
(from femoral n.)
Med.
& lat.
plantar n’s.
(from posttibial n.)
Sural n.
(from tibial n.)
Radial n.
Median n.
Ulnar n.
Great auricular n.
Greater
Lesser n.}  occipital nerves
Ant.
cut.
n.
of neck
T2
3
4
  5
   6
   7
    8
    9
     10
          11
          12
T1
L1
S1
Post.
rami of
lumbar sacral
& coccygeal n’s.
Lat.
cut.
rami         
Post.
cut.
rami
of
thor.
n’s.
C5
C6 Supraclavicular n’s.
Med.
cut.
n.
of arm
 & intercostobrachial n.
Post.
cut.
n.
of forearm
 (from radial n.)
Lat.
cut.
n.
of forearm
 (from musculocut n.) Med.
cut.
n.
of 
   forearm
Obturator n.
Superficial peroneal n.
(from common peroneal n.)
Lat.
cut.
n.of calf
(from common femoral n.)
Inf.
med.
cluneal n.
Inf.
lat.
cluneal n’s.
Lat.
plantar n.
Saphenous n.
Sural n.
Calcanean branches
of tibial & sural n’s.
Med.
plantar n.
Lat.
plantar n.
Superficial
peroneal
n.
Inf.
med.
n.
of thigh
Post cut.
n.
of thigh
Lower
Lat.
cut.
of arm
(from radial n.)
Post cut.
n.
of arm
(from radial n.)
Axillary n.
(circumflex)
Iliohypo-
gastric n.
Saphenous n.
(from femoral n.)
Med.
cut.
n.
of thigh
(from femoral n.)
Calcanean branches of
sural & tibial n’s.
Sural n.
(from tibial n.)
Radial n.
Median n.
Ulnar n.
FIGURE 15-2 
The cutaneous fields of peripheral nerves.
(Reproduced by permission from W Haymaker, B Woodhall: Peripheral Nerve Inju-
ries, 2nd ed.
Touch usually is tested with a wisp of cotton or a 
fine camel hair brush.
Normal individuals can do 
this accurately, with errors of 1 cm or less.
The sense of vibration is tested with a tuning fork 
that vibrates at 128 Hz.
If abnormal-
ities are found, more proximal sites can be examined.
(From D Sinclair: Mechanisms of 
Cutaneous Sensation.
Oxford, UK, Oxford University Press, 
1981; with permission from Dr.
Interside comparisons are important for all cor-
tical sensory testing.
The phenomenon 
is referred to as extinction or neglect.
Once again, interside comparison is 
of prime importance.
Inability to recognize numbers or 
letters is termed agraphesthesia.
Common standard objects such as keys, paper 
clips, and coins are best used.
Patients should be allowed to feel the object with only 
one hand at a time.
If they are unable to identify it in 
one hand, it should be placed in the other for compari-
son.
Their 
extent, configuration, symmetry, quality, and severity 
are the key observations.
Dysesthesias without sensory findings by examination 
may be difficult to interpret.
Sometimes distal dyses-
thesias have no definable basis.
15-2, 15-3 and 
15-4).
9).
45).
When dysesthesias reach the knees, they 
usually also have appeared in the fingertips.
12).
Sensory dissociation may occur with 
spinal cord lesions as well as small-fiber neuropathies.
Dysesthesias, if 
present at all, tend to be tingling or bandlike in quality.
Pain and numbness 
progress to sensory ataxia and impairment of all sensory 
modalities with time.
This condition is usually paraneo-
plastic or idiopathic in origin (Chaps.
44 and 45).
Spinal cord
(See also Chap.
35) If the spinal cord is transected, all 
sensation is lost below the level of transection.
Bladder 
and bowel function also are lost, as is motor function.
15-1 and 35-1).
The presence of upper motor 
neuron signs (Chap.
27-10).
The per-
sistent, unrelenting unilateral pain often is described in 
dramatic terms.
Dysesthesias or a sense of numbness may 
also occur and, rarely, a painful state.
S.
Andrew  Josephson    ■     Bruce L.
Delirium is a clinical diagnosis that can be made only 
at the bedside.
However, the 
long-term cognitive effects of delirium remain largely 
unknown and understudied.
Some episodes of delirium 
continue for weeks, months, or even years.
Even after an episode of 
delirium resolves, there may be lingering effects of the 
disorder.
The two most consistently identified risks are older 
age and baseline cognitive dysfunction.
Whether age 
and baseline cognitive dysfunction are truly indepen-
dent risk factors is uncertain.
Avoiding such risks remains a key compo-
nent of delirium prevention as well as treatment.
The relationship between delirium and demen-
tia (Chap.
Older patients in the ICU have especially high 
rates of delirium that range from 70 to 87%.
PATHOGENESIS
The pathogenesis and anatomy of delirium are incom-
pletely understood.
Deficiency of acetylcholine often plays a key role in 
delirium pathogenesis.
Other neurotransmitters are also likely to be 
involved in this diffuse cerebral disorder.
For example, 
increases in dopamine can also lead to delirium.
Not all individuals exposed to the same insult will 
develop signs of delirium.
Unfortunately, these scales do not identify 
the full spectrum of patients with delirium.
Baseline cogni-
tive impairment is common in patients with delirium.
The neurologic examination requires a careful assess-
ment of mental status.
In these cases, assessment only 
during morning rounds may be falsely reassuring.
Attention can be assessed while 
taking a history from the patient.
Common etiolo-
gies are listed in Table 16-1.
Prescribed, over-the-counter, and herbal medica-
tions are common precipitants of delirium.
In younger patients especially, illicit drugs and tox-
ins are common causes of delirium.
Systemic infections often cause delirium, especially 
in the elderly.
Pneumonia, skin infections such as cellulitis, 
and frank sepsis also can lead to delirium.
As a result, LP should be consid-
ered in any delirious patient with a negative workup.
These treatments often lead to prompt reso-
lution of delirium.
At night, a quiet, dark environment with 
limited interruptions by staff can assure proper rest.
ACKNOWLEDGMENT
In the 16th edition of Harrison’s Principles of Internal Medi-
cine, Allan H.
Allan H.
Ropper  
132
 Coma is among the most common and striking prob-
lems in general medicine.
Coma demands immediate 
attention and requires an organized approach.
Drowsiness 
and stupor are usually accompanied by some degree of 
confusion ( Chap.
16 ).
In the vegeta-
tive state, the eyelids may open, giving the appearance 
of wakefulness.
Respiratory and autonomic functions 
are retained.
28   ).
It is also usually 
the result of damage to the frontal lobes and its connec-
tions ( Chap.
18 ).
The special problem of coma in brain death is discussed 
later in this chapter.
The pupils are normally reactive.
Such individuals have 
written entire treatises using Morse code.
46), critical illness neuropathy (Chap.
28), and 
pharmacologic neuromuscular blockade.
17-1).
17-1A).
( A) Uncal; (B) central; (C) 
transfalcial; (D) foraminal.
17-2).
The distor-
tions may also entrap portions of the ventricular system, 
resulting in hydrocephalus.
17-1B).
Miotic pupils and drowsi-
ness are the heralding signs.
The result is a sequence of neurologic signs 
that corresponds to each affected level.
17-1D), which causes compression of the medulla, 
respiratory arrest, and death.
This 
lateral shift may be quantified on axial images of CT 
and MRI scans (Fig.
17-2).
Thus, in metabolic enceph-
alopathies, clouded consciousness and coma are in a 
continuum.
Simultaneous hypoxia and ischemia exhaust glucose 
more rapidly.
Apart from hyperammonemia, 
which of these mechanisms is of critical importance is 
not clear.
The mechanism of the encephalopathy of 
renal failure is also not known.
In hyperosmolar coma, the serum osmolarity 
is generally >350 mosmol/L.
Many 
drugs and toxins are capable of depressing nervous sys-
tem function.
The 
approach to the patient with coma from cranial trauma 
is discussed in Chap.
36.
Hypothermia itself causes 
coma only when the temperature is <31°C (87.8°F).
Aberrant respiratory patterns that reflect brainstem 
disorders are discussed later.
Lack of restless movements on one side or 
an outturned leg suggests a hemiplegia.
43).
The results of testing may vary from minute to 
minute, and serial examinations are most useful.
17-3).
Enlargement of the 
pupil contralateral to a hemispheral mass may occur 
but is infrequent.
Horizontal divergence of 
the eyes at rest is normal in drowsiness.
As coma deep-
ens, the ocular axes may become parallel again.
Spontaneous eye movements in coma often take 
the form of conjugate horizontal roving.
17-3).
The corneal (and pharyngeal) 
response may be lost for a time on the side of an acute 
hemiplegia.
Respiratory Patterns These are of less localiz-
ing value in comparison to other brainstem signs.
Shal-
low, slow, but regular breathing suggests metabolic or 
drug depression.
Tachy-
pnea occurs with lymphoma of the CNS.
A number of other cyclic 
breathing variations have been described but are of 
lesser significance.
calcium, osmolarity, and renal (blood urea nitrogen) 
and hepatic (NH3) function.
Nevertheless, if 
the source of coma remains unknown, a scan should be 
obtained.
The EEG (Chap.
The amount of background slowing of the 
EEG is a reflection of the severity of an encephalopa-
thy.
Arterial blood gas analysis is helpful in patients 
with lung disease and acid-base disorders.
6).
When cerebrovascular disease is the cause of coma, 
diagnosis can be difficult (Chap.
27).
The majority of medical causes of 
coma can be established without a neuroimaging study.
TABLE 17-1
DIFFERENTIAL DIAGNOSIS OF COMA
1.
Intoxications: alcohol, sedative drugs, opiates, etc.
b.
Shock from any cause
 e.
Postseizure states, status epilepticus, subclinical 
epilepsy
 f.
Hypertensive encephalopathy, eclampsia
 g.
Severe hyperthermia, hypothermia
 h.
Concussion
 i.
Acute  hydrocephalus
2.
Subarachnoid hemorrhage from ruptured aneurysm, 
arteriovenous malformation, trauma
b.
Acute bacterial meningitis
c.
Viral encephalitis
d.
Miscellaneous: fat embolism, cholesterol embolism, 
carcinomatous and lymphomatous meningitis, etc.
3.
Brainstem infarction due to basilar artery 
thrombosis or embolism
c.
Brain abscess, subdural empyema
d.
Epidural and subdural hemorrhage, brain contusion
e.
Brain tumor with surrounding edema
f.
Cerebellar and pontine hemorrhage and infarction
g.
Widespread traumatic brain injury
h.
Metabolic coma (see earlier) with preexisting focal 
damage
i.
Abbreviations: CSF, cerebrospinal fluid; RBCs, red blood cells; 
WBCs, white blood cells.
It is the only type 
of brain damage recognized as equivalent to death.
The heart rate is 
invariant and unresponsive to atropine.
The 
pupils are usually midsized but may be enlarged; they 
should not, however, be small.
Loss of deep tendon 
reflexes is not required because the spinal cord remains 
functional.
Babinski signs are generally absent and the 
toe response is often flexor.
co2 ten-
sion increases ∼0.3–0.4 kPa/min (2–3 mmHg/min) 
during apnea.
The test is usually stopped if there is serious cardiovas-
cular instability.
An isoelectric EEG may be used as a confirmatory test 
for total cerebral damage.
Fever and meningismus 
indicate an urgent need for examination of the CSF to 
diagnose meningitis.
The manage-
ment of raised ICP is discussed in Chap.
28.
The 
uniformly poor outcome of the persistent vegetative 
state has already been mentioned.
Metabolic comas have a far better prognosis 
than traumatic ones.
28-4).
In one case, a rudimen-
tary form of one-way communication could be estab-
lished.
It is prudent to avoid generalizations from these 
experiments.
The primary sensory and motor areas constitute 10% of 
the cerebral cortex.
18-1  ).
Dysarthria and mutism do not 
by themselves lead to a diagnosis of aphasia.
A deficit of nam-
ing (anomia) is the single most common finding in apha-
sic patients.
This is known as a one-way (or retrieval-
based) naming deficit.
FIGURE 18-1 
Lateral (top) and medial (bottom) views of the cerebral 
hemispheres.
The numbers refer to the Brodmann cyto-
architectonic designations.
The rest of the cerebral cortex contains asso-
ciation areas.
Reading should be assessed for defi-
cits in reading aloud as well as comprehension.
Writing 
is assessed for spelling errors, word order, and gram-
mar.
The syndromes outlined next 
are idealizations; pure syndromes occur rarely.
Language 
output is fluent but is highly paraphasic and circumlo-
cutious.
The output is 
therefore voluminous but uninformative.
And with 
it when that was downstairs was my teeth-tick…a…
den…dentith…my dentist.
And they happened to be 
in that bag…see?
How could this have happened?
Where my two…two little pieces 
of dentist that I use…that I…all gone.
This aphasia therefore has expressive as well 
as receptive components.
Repetition, naming, reading, 
and writing also are impaired.
Intracerebral hemorrhage, severe head 
trauma, and neoplasm are other causes.
In most other patients, prognosis for recovery of 
language function is guarded.
It is impov-
erished in function words but enriched in meaning-
appropriate nouns and verbs.
Speech is 
telegraphic and pithy but quite informative.
Go to hospital.
Dotor…kept me beside.
In 
addition to fluency, naming and repetition are impaired.
Patients 
with Broca’s aphasia can be tearful, easily frustrated, and 
profoundly depressed.
Insight into their condition is pre-
served, in contrast to Wernicke’s aphasia.
Visual fields are intact.
Mass 
lesions, including tumor, intracerebral hemorrhage, and 
abscess, also may be responsible.
Naming, repetition, 
reading, and writing also are impaired.
Naming and writing also are impaired.
Reading aloud is impaired, but reading comprehension 
is preserved.
Associated neurologic signs 
in conduction aphasia vary according to the primary 
lesion site.
The neurologic examination may be other-
wise intact, but a right hemiparesis also can exist.
Associated neu-
rologic findings may include hemianopia.
Isolation aphasia
This rare syndrome represents a combination of the 
two transcortical aphasias.
Comprehension is severely 
impaired, and there is no purposeful speech output.
Language output is fluent but parapha-
sic, circumlocutious, and uninformative.
Fluency may 
be interrupted by word-finding hesitations.
Patients cannot repeat spo-
ken language but have no difficulty naming objects.
Cerebrovascular lesions are the most common cause.
Pure alexia without agraphia
This is the visual equivalent of pure word deafness.
There is usu-
ally a right hemianopia, but the core language network 
remains unaffected.
This is known 
as a color anomia.
Recovery is the rule and involves an intermediate stage 
of hoarse whispering.
Writing, reading, and comprehen-
sion are intact, and so this is not a true aphasic syndrome.
The form that is encountered most frequently 
in clinical practice is known as ideomotor apraxia.
Buccofa-
cial apraxia involves apraxic deficits in movements of 
the face and mouth.
Limb apraxia encompasses apraxic 
deficits in movements of the arms and legs.
Its presence cannot be ascertained in patients 
with language comprehension deficits.
This aspect of language is known as prosody.
These are the “classic” aphasias 
described earlier in this chapter.
Language in PPA
The language impairment in PPA varies from patient 
to patient.
Distinct forms of agramma-
tism and/or word comprehension deficits also can arise.
The agrammatism consists of inappropriate word order 
and misuse of small grammatical words.
However, dysarthria is usually 
absent.
Alzheimer’s pathology is seen most fre-
quently in the logopenic variant.
The clinical subtyping 
of PPA thus may help predict the nature of the underly-
ing neuropathology.
18-2).
Subcortical com-
ponents of this network include the striatum and the 
thalamus.
The red 
and black areas show regions of task-related significant 
activation.
(Top) The subjects were asked to determine if 
two words were synonymous.
The activations are exclusively in the left hemisphere.
(Bot-
tom) The subjects were asked to shift spatial attention to a 
peripheral target.
The activations are predominantly in the 
right hemisphere.
18-3A).
Movement and distracting 
stimuli greatly exacerbate the difficulties of visual per-
ception.
Simultanagnosia sometimes can occur without 
the other two components of Bálint’s syndrome.
2.5 cm [3 to 4 in.
vs.
1 in.] 
in height), and all targets are embedded among foils.
18-3B).
Depending on the site of the lesion, a patient 
A
FIGURE 18-3
A.
Only targets 
on the right are circled.
This is 
a manifestation of left hemis-
patial neglect.
B.
This is a manifestation of simul-
tanagnosia.
It is important to distinguish visual object agno-
sia from anomia.
A patient with anomia cannot name 
the object but can describe its use.
Rarely, the responsible lesion 
is unilateral.
A disturbance in this function is known as an 
amnestic state.
Memories are stored in widely 
distributed form throughout the cerebral cortex.
This is known as confabula-
tion.
Adequate recall at the end 
of this interval requires offline storage, retention, and 
retrieval.
The assessment of memory can be quite challenging.
Bedside evaluations may detect only the most severe 
impairments.
Tem-
poral disorientation and poor recall of recent conver-
sations are early manifestations.
Transient global amnesia is a distinctive syndrome usually 
seen in late middle age.
Recurrences are noted in approximately 
20% of patients.
These syndromes tend to arise almost exclusively after 
bilateral lesions.
In these 
patients, the anterior temporal lobe and caudate nucleus 
are also atrophic.
Appropri-
ate intervention may be delayed while a treatable tumor 
keeps expanding.
Reactive depression is common in patients with 
higher cerebral dysfunction and should be treated.
In many cases, agitation may be controlled with reas-
surance.
Spontaneous improvement of cognitive deficits due  
to acute neurologic lesions is common.
The mechanisms for this recovery are incom-
pletely understood.
Prognosis for recovery from aphasia is best 
when Wernicke’s area is spared.
Cognitive rehabilita-
tion procedures have been used in the treatment of 
higher cortical deficits.
Some types 
of deficits may be more prone to recovery than others.
This is true only at the terminal 
stages.
There are other dementias in which memory is intact.
Maria Luisa  Gorno-Tempini    ■     Jennifer  Ogar    ■     Joel  Kramer  
■     Bruce  L.
Czeisler       ■  John W.
Winkelman       ■  Gary S.
For most, it is an occasional 
night of poor sleep or daytime sleepiness.
In addition, such problems may 
contribute to or exacerbate medical or psychiatric con-
ditions.
Since then, a distinct class of sleep and 
arousal disorders has been identifi ed.
At the extremes, infants and the elderly 
have frequent interruptions of sleep.
The EOG shows bursts of REM similar to 
those seen during eyes-open wakefulness.
20-1 ) .
After 
sleep onset, sleep usually progresses through NREM 
stages N1–N3 sleep within 45–60 min.
The percentage of 
slow-wave sleep is infl uenced by several factors, most 
notably age (see later).
The fi rst REM sleep episode usually occurs in 
the second hour of sleep.
Overall, REM sleep constitutes 20–25% of total sleep, 
and NREM stages N1 and N2 are 50–60%.
Age has a profound impact on sleep state organi-
zation (Fig.
20-1).
A different age profile exists for REM sleep than for 
slow-wave sleep.
Specific regions in the pons are associated with the 
neurophysiologic correlates of REM sleep.
These 
experimental manipulations are mimicked by patho-
logic conditions in humans and animals.
20-2).
?
(Copyright 
Charles J.
Awakenings from REM sleep are associated with 
recall of vivid dream imagery >80% of the time.
The 
reliability of dream recall increases with REM sleep epi-
sodes occurring later in the night.
Cardiac dysrhyth-
mias may occur selectively during REM sleep.
Respi-
ratory function also changes.
Endocrine function also varies with sleep.
A careful history is essential.
Similarly, the duration of 
the symptom influences diagnostic and therapeutic con-
siderations.
Short-term insomnia lasts from a few days to 3 
weeks.
Clocks can heighten the anxiety about 
the time it has taken to fall asleep.
Consistent, regular bedtimes 
and rising times should be maintained daily, including 
weekends.
A variety of sedative 
compounds are used for this purpose.
Alcohol and anti-
histamines are the most commonly used nonprescrip-
tion sleep aids.
The broad range of half-lives allows flexibility in 
the duration of sedative action.
The risk of priapism is small (~1 in 
10,000).
Behavioral therapies are the treatment modality of 
choice, with intermittent use of medications.
Time in bed can then be 
gradually expanded.
Recovery is generally 
rapid, usually within a few weeks.
Both hypoxia 
and hypocapnia are thought to be involved in the 
development of periodic breathing.
54).
Depressed patients 
also show decreased slow-wave sleep and reduced sleep 
continuity.
In mania and hypomania, sleep latency is increased 
and total sleep time can be reduced.
This is associated with impaired daytime alert-
ness.
Epilepsy may rarely present as a sleep complaint 
(Chap.
26).
Often the history is of abnormal behavior, 
at times with convulsive movements during sleep.
Diagnosis requires 
nocturnal polysomnography with a full EEG montage.
30), 
are also associated with disrupted sleep, presumably 
through secondary mechanisms.
However, the abnor-
mal movements themselves are greatly reduced during 
sleep.
Headache syndromes (migraine or cluster headache) 
may show sleep-associated exacerbations (Chap.
8) by 
unknown mechanisms.
Insomnia is a prominent early 
symptom.
The pathogenesis is a mutation in the prion gene 
(Chap.
43).
Treat-
ment of the underlying medical problem is the most 
useful approach.
Sleep disruption can also result from 
the use of medications such as glucocorticoids (see 
later).
One prominent association is between sleep disrup-
tion and asthma.
Cardiac ischemia may also be associated with sleep dis-
ruption.
The ischemia itself may result from increases in 
sympathetic tone as a result of sleep apnea.
Caffeine is perhaps the most com-
mon pharmacologic cause of insomnia.
Withdrawal leads to an REM 
sleep rebound.
A number of prescribed medications can 
produce insomnia.
Antidepressants, sympathomimet-
ics, and glucocorticoids are common causes.
The symptoms appear 
with inactivity and are temporarily relieved by move-
ment.
In contrast, paresthesias secondary to peripheral 
neuropathy persist with activity.
The 
prevalence is 1–5% of young to middle-age adults and 
10–20% of those aged >60 years.
Iron 
deficiency and renal failure may cause RLS, which is 
then considered secondary RLS.
Opioids, 
benzodiazepines, and gabapentin may also be of thera-
peutic value.
20-3).
It is often unclear whether it is an incidental finding 
or the cause of disturbed sleep.
When deemed to be 
the latter, PLMS is called PLMD.
Treat-
ment options include dopaminergic medications or 
benzodiazepines.
First, patients may be 
unaware of the extent of sleep deprivation.
Second, subjective descriptions of wak-
ing impairment vary from patient to patient.
Driving is particularly hazardous for patients with 
increased sleepiness.
Reaction time is equally impaired 
by 24 h of sleep loss as by a blood alcohol level of 
0.10 g/dL.
More than half of Americans admit to having 
fallen asleep while driving.
Each of 
those steps should be documented in the patient’s medi-
cal record.
RAT, right anterior tibialis; LAT, left anterior 
tibialis.
52), or 
endocrine deficiencies such as hypothyroidism or Addi-
son’s disease.
Some patients with 
objectively confirmed narcolepsy (see later) may show 
no evidence of cataplexy.
Once established, 
the disease is chronic without remissions.
Secondary 
forms of narcolepsy have been described (e.g., after 
head trauma).
The 
inheritance pattern of narcolepsy in humans is more 
complex than in the canine model.
Diagnosis
The diagnostic criteria continue to be a matter of 
debate.
The 
REM-related symptoms of the classic narcolepsy tetrad 
are variably present.
Chicago, Matrix Communications, 1989.
However, a history 
of cataplexy can be difficult to establish reliably.
Nocturnal sleep disruption is commonly observed in 
narcolepsy but is also a nonspecific symptom.
TREATMENT Narcolepsy
The treatment of narcolepsy is symptomatic.
Somno-
lence is treated with wake-promoting therapeutics.
20-3).
This is unfortunate since effective treatments are 
available.
Episodes 
are usually isolated but may be recurrent in 1–6% of 
patients.
The cause is unknown, though it has a familial 
basis in roughly one-third of cases.
Both sleep terrors and sleepwalking 
represent abnormalities of arousal.
The 
patient is usually unaware of the problem.
The typical 
age of onset is 17–20 years, and spontaneous remission 
usually occurs by age 40.
Sex distribution appears to be 
equal.
There are anecdotal reports of ben-
efit using benzodiazepines.
Approxi-
mately one-half of patients with RBD will develop 
Parkinson’s disease (Chap.
30) within 10–20 years.
Gastrointestinal discomfort is common.
Many more begin work between 4 A.M.
Sleep disturbance nearly doubles the risk 
of a fatal work accident.
TREATMENT Shift-Work Disorder
Caffeine is frequently used to promote wakefulness.
Properly timed exposure to bright light can facilitate 
rapid adaptation to night-shift work.
Modafinil 
(200 mg, taken 30–60 min before the start of each night 
shift) is approved by the U.S.
The goal should be to minimize 
both sleep deprivation and circadian disruption.
Patients tend to be young 
adults.
Typically, patients awaken from 
3 to 5 A.M.
each day, often several hours before their 
desired wake times.
20-2) that 
altered the circadian period.
The inter-
vals between symptomatic periods may last several 
weeks to several months.
Blood pressure of 
night workers with sleep apnea is higher than that of 
day workers.
In addition, both the toxicity and effective-
ness of drugs can vary during the day.
Anes-
thetic agents are particularly sensitive to time-of-day 
effects.
Jonathan C.
Light is absorbed 
by photopigment in two types of receptors: rods and 
cones.
In the human retina there are 100 million rods 
and 5 million cones.
The rods operate in dim (scoto-
pic) illumination.
The cones function under daylight 
(photopic) conditions.
The cone system is specialized 
for color perception and high spatial resolution.
There are a million ganglion 
cells in each retina and hence a million fi bers in each 
optic nerve.
The majority of fi bers synapse on cells in the 
lateral geniculate body, a thalamic relay station.
Cells 
in the lateral geniculate body project in turn to the 
primary visual cortex.
Pupil responses are medi-
ated by input to the pretectal olivary nuclei in the 
midbrain.
Circadian rhythms 
are timed by a retinal projection to the suprachiasmatic 
nucleus.
Visual orientation and eye movements are 
served by retinal input to the superior colliculus.
This activity, called  foveation , or looking, is 
governed by an elaborate efferent motor system.
In emmetropia, parallel rays from infinity are focused per-
fectly on the retina.
Sadly, this condition is enjoyed by 
only a minority of the population.
In myopia, the globe 
is too long, and light rays come to a focal point in front 
of the retina.
To 
compensate for presbyopia, an emmetropic patient must 
use reading glasses.
A patient already wearing glasses 
for distance correction usually switches to bifocals.
Testing vision through a 
pinhole aperture is a useful way to screen quickly for 
refractive error.
VISUAL ACUITY
The Snellen chart is used to test acuity at a distance of 
6 m (20 ft).
21-1).
If 6/6 (20/20) 
acuity is not present in each eye, the deficiency in vision 
must be explained.
Patients with a homonymous hemi-
anopia should not drive.
However, it is 
important to test the near response if the light response 
is poor or absent.
An eye with no light perception has no pupillary 
response to direct light stimulation.
21-2).
Subtle inequality in pupil size, up to 0.5 mm, is a 
fairly common finding in normal persons.
Anisocoria that increases in dim light 
indicates a sympathetic paresis of the iris dilator muscle.
Anisocoria that increases in bright light suggests a 
parasympathetic palsy.
The first concern is an oculo-
motor nerve paresis.
Acute pupillary dilation (mydriasis) can result 
from damage to the ciliary ganglion in the orbit.
The diagnosis is confirmed by placing a drop of dilute 
(0.125%) pilocarpine into each eye.
In this situation, normal strength (1%) pilo-
carpine causes no constriction.
A.
With dim background lighting, the pupils 
are equal and relatively large.
B.
Shining a flashlight into the 
right eye evokes equal, strong constriction of both pupils.
C.
(From P Levatin: Arch Oph-
thalmol 62:768, 1959.
Copyright © 1959 American Medical 
Association.
They are small with narcotic use (morphine, 
heroin) and large with anticholinergics (scopolamine).
Parasympathetic agents (pilocarpine, demecarium bro-
mide) used to treat glaucoma produce miosis.
The eyes 
should move rapidly and accurately in a single jump to 
their target.
If the eyes are straight, the corneal light reflex will be 
centered in the middle of each pupil.
To test eye align-
ment more precisely, the cover test is useful.
The patient 
is instructed to gaze upon a small fixation target in the 
distance.
One eye is covered suddenly while the second 
eye is observed.
If the second eye shifts to fixate on the 
target, it was misaligned.
If it does not move, the first eye 
is uncovered and the test is repeated on the second eye.
If neither eye moves, the eyes are aligned orthotropically.
The most popular office tests measure a 
range of thresholds from 800–40  s of arc.
Normal ste-
reoacuity is 40  s of arc.
Mutations of the blue cone pigment are 
exceedingly rare.
Ishihara color plates can be used to 
detect red-green color blindness.
Because color blindness is almost exclusively X-linked, 
it is worth screening only male children.
Acquired 
defects in color vision frequently result from disease 
of the macula or optic nerve.
Infarcts of the domi-
nant occipital lobe sometimes give rise to color anomia.
Affected patients can discriminate colors but cannot 
name them.
21-3).
21-3A).
Retinal lesions produce scotomas 
that correspond optically to their location in the fundus.
For example, a superior-nasal retinal detachment results 
in an inferior-temporal field cut.
Damage to the macula 
causes a central scotoma (Fig.
21-3B).
Optic nerve disease produces characteristic patterns 
of visual field loss.
21-3C).
This type of field 
defect mirrors the arrangement of the nerve fiber layer 
in the temporal retina.
It plots the retinal sensitivity to light in the central 
30° by using a gray scale format.
Areas of visual field loss 
are shown in black.
The examples of common monocular, 
prechiasmal field defects are all shown for the right eye.
21-3D).
About half the fibers in the optic nerve originate 
from ganglion cells serving the macula.
21-3E).
Pallor of the nasal rim of the optic 
disc is a less equivocal sign of optic atrophy.
At the optic chiasm, fibers from nasal ganglion cells 
decussate into the contralateral optic tract.
Crossed 
fibers are damaged more by compression than are 
uncrossed fibers.
As a result, mass lesions of the sel-
lar region cause a temporal hemianopia in each eye.
21-3G).
More symmetric compression of the optic chi-
asm by a pituitary adenoma (Fig.
21-3H).
21-3I).
21-3K).
Lesions of the primary visual cortex give rise to 
dense, congruous hemianopic field defects.
21-3L).
Destruction of both occipital lobes produces corti-
cal blindness.
A penlight with a blue filter will suf-
fice if a slit lamp is not available.
It is important to check for foreign bodies.
The 
eye should be reexamined the next day.
Minor abrasions 
may not require patching and cycloplegia.
Occa-
sionally it is a clue to an underlying bleeding disorder.
Pinguecula
Pinguecula is a small, raised conjunctival nodule at 
the temporal or nasal limbus.
Blepharitis
This refers to inflammation of the eyelids.
The most 
common form occurs in association with acne rosa-
cea or seborrheic dermatitis.
The eyelid margins usu-
ally are colonized heavily by staphylococci.
It can 
be incised and drained or injected with glucocorticoids.
Gentle pressure over the lacrimal sac evokes 
pain and reflux of mucus or pus from the tear puncta.
Dacryocystitis usually occurs after obstruction of the 
lacrimal system.
Conjunctivitis
Conjunctivitis is the most common cause of a red, irri-
tated eye.
Pain is minimal, and visual acuity is reduced 
only slightly.
The most common viral etiology is ade-
novirus infection.
It causes a watery discharge, a mild 
foreign-body sensation, and photophobia.
Bacterial 
infection tends to produce a more mucopurulent exu-
date.
Itching, redness, and 
epiphora are typical.
Atopic conjunctivitis occurs in sub-
jects with atopic dermatitis or asthma.
Patients may develop dry eye after radiation 
therapy if the treatment field includes the orbits.
Prob-
lems with ocular drying are also common after lesions 
affecting cranial nerve V or VII.
Dry eye is managed by frequent 
and liberal application of artificial tears and ocular lubri-
cants.
In severe cases the tear puncta can be plugged or 
cauterized to reduce lacrimal outflow.
In the United States, 
contact lenses play a major role in corneal infection and 
ulceration.
They should not be worn by anyone with 
an active eye infection.
The latter is accompanied by greater visual loss, 
pain, photophobia, redness, and discharge.
In severe cases, pus settles at the bottom of the anterior 
chamber, giving rise to a hypopyon.
A fungal etiology should always be considered 
in a patient with keratitis.
Herpes simplex
The herpesviruses are a major cause of blindness from 
keratitis.
Primary ocular infection generally is caused 
by herpes simplex type 1 rather than type 2.
Recurrent ocular infection arises 
from reactivation of the latent herpesvirus.
Viral erup-
tion in the corneal epithelium may result in the char-
acteristic herpes dendrite.
Involvement of the corneal 
stroma produces edema, vascularization, and iridocy-
clitis.
Herpes keratitis is treated with topical antiviral 
agents, cycloplegics, and oral acyclovir.
Topical gluco-
corticoids also carry the risk of prolonging infection and 
inducing glaucoma.
Herpes zoster ophthalmicus is 
treated with antiviral agents and cycloplegics.
Episcleritis resembles conjunctivitis, but it is a 
more localized process and discharge is absent.
The inflam-
mation and thickening of the sclera can be diffuse or 
nodular.
Episcleritis and scleritis should be treated with 
NSAIDs.
Dilatation 
of the pupil reduces pain and prevents the formation of 
synechiae.
It is more likely than anterior uveitis to be associated 
with an identifiable systemic disease.
21-4).
It usu-
ally is acquired by hematogenous seeding from a remote 
site.
Although 
most patients have ocular pain and injection, visual loss 
is sometimes the only symptom.
27).
Note that the veins are 
frosted with a white exudate.
Visual acuity improved from 
20/400 to 20/20 after treatment with intravenous methylpred-
nisolone.
CHAPTER 21
Disorders of Vision
183
an embolus that becomes stuck within a retinal arte-
riole (Fig.
21-5).
With prolonged interrup-
tion of blood flow, the inner retina suffers infarction.
21-6).
Emboli are composed 
of cholesterol (Hollenhorst plaque), calcium, or platelet-
fibrin debris.
21-7).
In addition, acute hypertension may pro-
duce visual loss from ischemic swelling of the optic disc.
Patients with acute hypertensive retinopathy should be 
treated by lowering the blood pressure.
The 
veins appear engorged and phlebitic, with numer-
ous retinal hemorrhages (Fig.
21-8).
The optic disc appears swollen and surrounded 
by nerve fiber layer splinter hemorrhages (Fig.
21-9).
AION is divided into two forms: arteritic and nonar-
teritic.
The nonarteritic form is most common.
No 
specific cause can be identified, although diabetes and 
hypertension are common risk factors.
No treatment is 
available.
Glucocorticoids should be started immediately, without 
waiting for the biopsy to be completed.
Vision can be salvaged in 
some patients by prompt blood transfusion and reversal 
of hypotension.
Optic neuritis
This is a common inflammatory disease of the optic 
nerve.
21-10), although optic disc pallor slowly 
developed over subsequent months.
For some patients, optic neuritis remains an isolated 
event.
CHAPTER 21
Disorders of Vision
185
multiple sclerosis after optic neuritis is 50%.
In summary, an MR scan is recommended in every 
patient with a first attack of optic neuritis.
Eventually 
optic atrophy ensues.
In toxic optic 
neuropathy, visual loss also can develop gradually and 
produce optic atrophy (Fig.
21-11) without a phase of 
acute optic disc edema.
Papilledema
This connotes bilateral optic disc swelling from raised 
intracranial pressure (Fig.
21-12).
Headache is a com-
mon but not invariable accompaniment.
Transient visual obscurations 
are a classic symptom of papilledema.
They can occur 
in only one eye or simultaneously in both eyes.
They 
usually last seconds but can persist longer.
Obscurations 
follow abrupt shifts in posture or happen spontaneously.
When obscurations are prolonged or spontaneous, the 
papilledema is more threatening.
SECTION II
Clinical Manifestations of Neurologic Disease
186
hemorrhage.
Visual field testing shows enlarged blind 
spots and peripheral constriction (Fig.
21-3F).
Evaluation of papilledema requires neuroimaging to 
exclude an intracranial lesion.
The majority of patients are young, 
female, and obese.
Weight 
reduction is vital but often unsuccessful.
Occasionally, emergency surgery is required for sud-
den blindness caused by fulminant papilledema.
Optic disc drusen
These are refractile deposits within the substance of the 
optic nerve head (Fig.
21-13).
They are unrelated to 
drusen of the retina, which occur in age-related macu-
lar degeneration.
Optic disc drusen are most common in 
people of northern European descent.
However, in many patients they 
are hidden beneath the surface, producing pseudopapill-
edema.
It is important to recognize optic disc drusen to 
avoid an unnecessary evaluation for papilledema.
No 
treatment is available.
Opacities develop in the vitre-
ous, casting annoying shadows on the retina.
This process, known as vitreous 
detachment, is a common involutional event in the elderly.
It is not harmful unless it damages the retina.
If such a lesion is found, laser 
application can forestall a retinal detachment.
FIGURE 21-13 
Optic disc drusen are calcified deposits of unknown etiol-
ogy within the optic disc.
They sometimes are confused with 
papilledema.
CHAPTER 21
Disorders of Vision
187 haze of blood.
Ultrasound is required to examine the 
interior of the eye for a retinal tear or detachment.
If the 
hemorrhage does not resolve spontaneously, the vitre-
ous can be removed surgically.
21-14).
The diagnosis is confirmed by oph-
thalmoscopic examination of the dilated eye.
Classic migraine
(See also Chap.
8) This usually occurs with a visual aura 
lasting about 20 min.
Migraine phenomena also remain visible in the dark 
or with the eyes closed.
Patients often 
have a long history of stereotypic attacks.
After the visual 
symptoms recede, headache develops in most patients.
Factitious (functional, nonorganic) visual loss
This is claimed by hysterics or malingerers.
CHRONIC VISUAL LOSS
Cataract
Cataract is a clouding of the lens sufficient to reduce 
vision.
Radiation therapy and glucocorticoid 
treatment can induce cataract as a side effect.
The only treatment for cataract is surgical extraction 
of the opacified lens.
Over a million cataract opera-
tions are performed each year in the United States.
The 
operation generally is done under local anesthesia on an 
outpatient basis.
More than 95% of patients who 
undergo cataract extraction can expect an improvement 
in vision.
A small open-
ing is made in the lens capsule with a laser to restore 
clarity.
In African Americans it is the 
leading cause of blindness.
The mechanism by which 
raised intraocular pressure injures the optic nerve is not 
understood.
21-15).
Careful documentation of serial examinations is 
helpful.
Detection of visual 
field loss by computerized perimetry also contributes to 
the diagnosis.
Finally, most patients with glaucoma have 
raised intraocular pressure.
Glaucoma is usually painless (except in angle-closure 
glaucoma).
Foveal acuity is spared until end-stage dis-
ease is reached.
The cup-to-disc ratio is about 0.7/1.0 in this patient.
CHAPTER 21
Disorders of Vision
189 nonexudative (dry) form and an exudative (wet) form.
21-16).
With time they become larger, 
more numerous, and confluent.
Treatment with vitamins C and E, beta-caro-
tene, and zinc may retard dry macular degeneration.
Central serous chorioretinopathy
This primarily affects males between the ages of 20 and 
50.
The cause of central serous chorioretinopathy is 
unknown.
Symptoms may resolve spontaneously if the 
retina reattaches, but recurrent detachment is common.
Laser photocoagulation has benefited some patients 
with this condition.
The retinopathy takes years to develop but eventually 
appears in nearly all cases.
Regular surveillance of the 
dilated fundus is crucial for any patient with diabetes.
It 
occurs sporadically or in an autosomal recessive, domi-
nant, or X-linked pattern.
They appear as scat-
tered yellow subretinal deposits.
21-17).
The name is actually a misnomer because reti-
nitis pigmentosa is not an inflammatory process.
A 
crinkled, cellophane-like membrane is visible on the 
retinal examination.
Epiretinal membrane is most com-
mon in patients over 50 years of age and is usually uni-
lateral.
Contraction of an epiretinal 
membrane sometimes gives rise to a macular hole.
Most 
macular holes, however, are caused by local vitreous 
traction within the fovea.
Vitrectomy can improve acu-
ity in selected cases.
Melanoma and other tumors
Melanoma is the most common primary tumor of the 
eye (Fig.
21-18).
It causes photopsia, an enlarging sco-
toma, and loss of vision.
A small melanoma is often diffi-
cult to differentiate from a benign choroidal nevus.
Serial 
examinations are required to document a malignant pat-
tern of growth.
Treatment of melanoma is controversial.
Options include enucleation, local resection, and irra-
diation.
Metastatic tumors to the eye outnumber primary 
tumors.
Breast and lung carcinomas have a special pro-
pensity to spread to the choroid or iris.
Leukemia and 
lymphoma also commonly invade ocular tissues.
PROPTOSIS
When the globes appear asymmetric, the clinician must 
first decide which eye is abnormal.
CHAPTER 21
Disorders of Vision
191 Horner’s syndrome can give the appearance of enoph-
thalmos.
A proptosis of only 2 mm 
in one eye is detectable from this perspective.
Graves’ ophthalmopathy
This is the leading cause of proptosis in adults.
The pro-
ptosis is often asymmetric and can even appear to be 
unilateral.
Radiation therapy is 
not effective.
Symptoms are pain, limited eye movements, 
proptosis, and congestion.
Imaging often shows swollen eye muscles 
(orbital myositis) with enlarged tendons.
By contrast, in 
Graves’ ophthalmopathy the tendons of the eye muscles 
usually are spared.
The diagnosis of orbital pseudotumor is dif-
ficult.
Blood cultures should be obtained, but 
they are usually negative.
Most patients respond to empiri-
cal therapy with broad-spectrum IV antibiotics.
Tumors
Tumors of the orbit cause painless, progressive proptosis.
Metastatic tumor to the orbit occurs frequently in breast 
carcinoma, lung carcinoma, and lymphoma.
Direct fistulas usually 
result from trauma.
The signs are more subtle, 
and the diagnosis frequently is missed.
Imaging shows an enlarged superior ophthalmic vein in 
the orbits.
Carotid cavernous shunts can be eliminated 
by intravascular embolization.
PTOSIS
Blepharoptosis
This is an abnormal drooping of the eyelid.
Acquired 
ptosis can develop so gradually that the patient is 
unaware of the problem.
Inspection of old photographs 
is helpful in dating the onset.
Fluctuating 
ptosis that worsens late in the day is typical of myasthe-
nia gravis.
The extra weight of these sagging 
tissues causes the lid to droop.
It occurs commonly in 
older patients, presumably from loss of connective tissue 
elasticity.
Myogenic ptosis
The causes of myogenic ptosis include myasthenia gra-
vis (Chap.
47) and a number of rare myopathies that 
manifest with ptosis.
In general, diplopia is a late symptom 
because all eye movements are reduced equally.
Patients have muscle wasting, 
myotonia, frontal balding, and cardiac abnormalities.
Examination 
of the pupil helps distinguish between these two pos-
sibilities.
In Horner’s syndrome, the eye with ptosis has 
a smaller pupil and the eye movements are full.
In an 
oculomotor nerve palsy, the eye with the ptosis has a 
larger or a normal pupil.
If it does, 
the diagnosis is monocular diplopia.
Occasionally it is a symptom of malingering or psychi-
atric disease.
However, subtle limitation of ocular excursions is often 
difficult to detect.
To avoid diplopia, vision is suppressed from the 
nonfixating eye.
In some children, this leads to impaired 
vision (amblyopia, or “lazy” eye) in the deviated eye.
Myasthenia gravis
(See also Chap.
47) This is a major cause of diplopia.
The pupils are always normal.
Fluctuating ptosis may be 
present.
Negative results from these tests do 
not exclude the diagnosis.
Botulism from food or wound 
poisoning can mimic ocular myasthenia.
This combination of findings is obvious.
More challeng-
ing is the diagnosis of early or partial oculomotor nerve 
palsy.
Neu-
roimaging should be obtained, along with a CT or MR 
angiogram.
Occasionally, a catheter arteriogram must be 
done to exclude an aneurysm.
Occasionally 
both superior recti are weak.
Isolated nuclear oculomo-
tor palsy is rare.
Oculomotor palsy 
also can result from midbrain torsion and hemorrhages 
during herniation.
Usually the patient complains of pain.
Diabetes, hypertension, and vascular disease are major 
risk factors.
Spontaneous recovery over a period of 
months is the rule.
The pupil also constricts upon 
attempted adduction, elevation, or depression of the 
globe.
Fibers 
exit the brainstem dorsally and cross to innervate the 
contralateral superior oblique.
The principal actions of 
this muscle are to depress and intort the globe.
A palsy 
therefore results in hypertropia and excyclotorsion.
The 
cyclotorsion seldom is noticed by patients.
Instead, they 
complain of vertical diplopia, especially upon reading 
or looking down.
This “head tilt 
test” is a cardinal diagnostic feature.
The trochlear nerve is particularly apt to suf-
fer injury after closed head trauma.
The free edge of the 
tentorium is thought to impinge on the nerve during 
a concussive blow.
Abducens nerve
The sixth cranial nerve innervates the lateral rectus 
muscle.
A palsy produces horizontal diplopia, worse 
on gaze to the side of the lesion.
Millard-Gubler syndrome from ventral pontine 
injury is similar except for the eye findings.
Unilateral or bilateral abducens palsy is a classic sign 
of raised intracranial pressure.
The diagnosis can be con-
firmed if papilledema is observed on fundus examina-
tion.
Treatment of abducens palsy is aimed at prompt cor-
rection of the underlying cause.
However, the cause 
remains obscure in many instances despite diligent eval-
uation.
Some cases may develop as a postinfectious mononeu-
ritis (e.g., after a viral flu).
Skull base 
tumors are easily missed even on contrast-enhanced 
neuroimaging studies.
In a patient 
with systemic malignancy, carcinomatous meningitis is 
a likely diagnosis.
Cytologic examination may be nega-
tive despite repeated sampling of the cerebrospinal fluid.
The cancer-associated Lambert-Eaton myasthenic syn-
drome also can produce ophthalmoplegia.
Often the 
ataxia is mild, and the reflexes are normal.
Antiganglio-
side antibodies (GQ1b) can be detected in about 50% of 
cases.
Supranuclear disorders of gaze
These are often mistaken for multiple ocular motor 
nerve palsies.
The disorder occurs in 
malnourished or alcoholic patients and can be reversed 
by thiamine.
Smooth pursuit is affected later in the course of the 
disease.
With time, 
this deficit resolves.
Parietal lesions disrupt smooth pursuit 
of targets moving toward the side of the lesion.
They project directly to the ipsilateral abdu-
cens nucleus.
21-19).
A patient with bilateral injury 
to the medial longitudinal fasciculus will have bilateral 
INO.
The 
patient’s only horizontal eye movement is abduction of 
the eye on the other side.
Vertical gaze
This is controlled at the level of the midbrain.
Dis-
tal basilar artery ischemia is the most common etiology.
It is a classic sign of 
hydrocephalus from aqueductal stenosis.
Pineal region 
tumors, cysticercosis, and stroke also cause Parinaud’s 
syndrome.
11).
This nystagmus is com-
monly referred to as congenital sensory nystagmus.
By convention, the 
nystagmus is named after the quick phase.
Jerk nystag-
mus can be downbeat, upbeat, horizontal (left or right), 
and torsional.
The pattern of nystagmus may vary with 
gaze position.
Some patients will be oblivious to their 
nystagmus.
Fine nys-
tagmus may be difficult to see on gross examination 
of the eyes.
Gaze-evoked nystagmus
This is the most common form of jerk nystagmus.
The subject compensates by making a cor-
rective saccade to maintain the deviated eye position.
Many normal patients have mild gaze-evoked nys-
tagmus.
There may be associated tinni-
tus and hearing loss.
Sudden shifts in head position may 
provoke or exacerbate symptoms.
Upbeat nystagmus is 
FIGURE 21-19 
Left internuclear ophthalmoplegia (INO).
A.
In primary posi-
tion of gaze the eyes appear normal.
B.
Horizontal gaze to 
the left is intact.
C.
On attempted horizontal gaze to the right, 
the left eye fails to adduct.
In mildly affected patients the eye 
may adduct partially or more slowly than normal.
Nystagmus 
is usually present in the abducted eye.
D.
When 
the saccades are confined to the horizontal plane, the 
term ocular flutter is preferred.
It 
has also been reported as a benign, transient phenom-
enon in otherwise healthy patients.
Shirley H.
VIDEO LIBRARY OF NEURO-OPHTHALMOLOGY 
 CHAPTER 22 
  Richard L.
Doty      ■  Steven M.
23-1  ).
When damaged, the 
receptor cells can be replaced by stem cells near the 
basement membrane.
Unfortunately, such replacement 
is often incomplete.
23-2  ).
The axons of the mitral and tufted cells synapse 
within the primary olfactory cortex (POC) (  Fig.
23-3  ).
23-4).
Each receptor type (red, green, blue) projects to a common 
glomerulus.
The neural activity within each glomerulus is 
modulated by periglomerular cells.
The number of taste receptor 
cells per taste bud ranges from zero to well over 100.
T2Rs sense a wide 
range of bitter substances but do not distinguish among 
them.
23-5).
TRC, taste receptor 
cell.
23-5).
This brain region is involved in 
the conscious recognition of taste qualities.
23-6).
The cribriform plate does not have to be fractured 
or show pathology for smell loss to be present.
Fewer than 10% of posttraumatic anosmic patients 
recover age-related normal function over time.
Numbers by each data point indicate sample sizes.
Note that 
women identify odorants better than men at all ages.
(From 
Doty et al: Science 226:1421, 1984.
Olfactory impairment in PD often 
predates the clinical diagnosis by at least 4 years.
The smell loss seen in iRBD is of the same magni-
tude as that found in PD.
iRBD may actually repre-
sent an early associated condition of PD.
Bell’s palsy 
is among the most common causes of CN VII injury 
that results in taste disturbance.
Indeed, over 250 medications 
have been reported to alter the ability to taste.
As with olfaction, a number of systemic disorders 
can affect taste.
Intermittent loss suggests the likelihood 
of an inflammatory process.
Pending litigation and the possibility of 
malingering should be considered.
The ORL examina-
tion should thoroughly assess the intranasal architecture 
and mucosal surfaces.
As with other sensory disorders, quantitative sen-
sory testing is advised.
A number of standardized olfactory and taste 
tests are commercially available.
Most evaluate the abil-
ity of patients to detect and identify odors or tastes.
In addi-
tion to electrogustometers, commercial chemical taste 
tests are now available.
Most employ filter paper strips 
impregnated with tastants, so no stimulus preparation 
is required.
Like the UPSIT, these tests have published 
norms for establishing the degree of dysfunction.
Other methods to improve sali-
vary flow include the use of mints, lozenges, or sugarless 
gum.
Treatments are limited for patients with chemosen-
sory loss or primary injury to neural pathways.
None-
theless, spontaneous recovery can occur.
A major and often overlooked element of therapy 
comes from chemosensory testing itself.
Importantly, quantitative testing places 
the patient’s problem into overall perspective.
Anil K.
24-1 ) .
A.
B.
High-resolution 
view of inner ear.
24-2).
Tympanoplasty 
is highly effective (>90%) in the repair of tympanic 
membrane perforations.
This is a slowly growing 
lesion that destroys bone and normal ear tissue.
Conductive hearing loss secondary to ossic-
ular erosion is common.
Surgery is required to remove 
this destructive process.
Hearing 
impairment usually presents between the late teens 
and the forties.
Fluoride therapy 
to prevent hearing loss from cochlear otosclerosis is of 
uncertain value.
Congenital malformations of the 
inner ear may be the cause of hearing loss in some 
adults.
With 
progression, the hearing loss involves all frequencies.
More importantly, the hearing impairment is associated 
with significant loss in clarity.
Although hearing aids are able 
to amplify sounds, they cannot restore the clarity of hearing.
Therapy is directed toward the 
control of vertigo.
A 2-g/d low-salt diet is the mainstay 
of treatment for control of rotatory vertigo.
Both lab-
yrinthectomy and vestibular nerve section abolish rota-
tory vertigo in >90% of cases.
Primary diseases of the central nervous system can 
also present with hearing impairment.
27).
A finding of conductive and sensory hearing loss in 
combination is termed mixed hearing loss.
These abnormalities can be surgically corrected.
An associated facial nerve injury is not 
uncommon.
Tinnitus is defined as the perception of a sound when 
there is no sound in the environment.
Tinnitus is often 
associated with either a conductive or sensorineural 
hearing loss.
The pathophysiology of tinnitus is not well 
understood.
Tinnitus may be the first symptom of a serious 
condition such as a vestibular schwannoma.
Nearly two-thirds of HHIs are 
nonsyndromic, and the remaining one-third are syn-
dromic.
Less than 5% is X-linked or maternally 
inherited via the mitochondria.
The contribution of genetics to presbycusis 
is also becoming better understood.
Susceptibility 
to noise-induced hearing loss may also be genetically 
determined.
There are >400 syndromic forms of hearing loss.
sensorineural vs.
bilateral involvement, nature of onset 
(sudden vs.
insidious), and rate of progression (rapid vs.
slow).
Hearing loss with otorrhea is most 
likely due to chronic otitis media or cholesteatoma.
Examination should include the auricle, external ear 
canal, and tympanic membrane.
Insuf-
flation of the ear canal is necessary to assess tympanic 
membrane mobility and compliance.
Careful inspection 
of the nose, nasopharynx, and upper respiratory tract 
is indicated.
The patient is asked to 
indicate whether the tone is louder by air conduction 
or bone conduction.
With a unilateral conductive hear-
ing loss, the tone is perceived in the affected ear.
With 
a unilateral sensorineural hearing loss, the tone is per-
ceived in the unaffected ear.
A 5-dB difference in hear-
ing between the two ears is required for lateralization.
Pure tone audiometry assesses hearing acuity for pure 
tones.
The test is administered by an audiologist and is 
performed in a sound-attenuated chamber.
Air- and bone-conduction thresholds 
are established for each ear.
The responses are measured in decibels.
An audiogram 
is a plot of intensity in decibels of hearing threshold 
versus frequency.
Pitch, on the other hand, does 
not directly correlate with frequency.
The percep-
tion of pitch changes slowly in the low and high fre-
quencies.
Pure tone audiometry establishes the presence and 
severity of hearing impairment, unilateral vs.
bilateral 
involvement, and the type of hearing loss.
Speech audiometry tests the clarity with which one 
hears.
The inten-
sity at which the patient can repeat 50% of the words 
correctly is the SRT.
Patients with a 
sensorineural hearing loss have variable loss of discrimi-
nation.
Compliance that does not change with change in 
pressure suggests middle-ear effusion (type B).
A reduction 
in the maximal compliance peak can be seen in otoscle-
rosis (type As).
During tympanometry, an intense tone elicits con-
traction of the stapedius muscle.
Assessment of acoustic reflex decay helps differentiate sen-
sory from neural hearing losses.
In neural hearing loss, 
the reflex adapts or decays with time.
The emissions may be 
spontaneous or evoked with sound stimulation.
CT is also ideal for the detection 
of bone erosion with chronic otitis media and choles-
teatoma.
Hearing aids are effective and well tolerated in patients 
with conductive hearing losses.
Hearing aids 
have been improved to provide greater fidelity and have 
been miniaturized.
This arrange-
ment is not possible with a self-contained, cosmetically 
acceptable device.
Unfortunately, CROS and 
BAHA devices are often judged by patients to be unsat-
isfactory.
Hearing aids with telecoils can also 
be used with properly equipped telephones in the same 
way.
Worldwide, nearly 200,000 
hearing impaired children and adults have received 
cochlear implants.
Tinnitus often accompanies hearing loss.
Therapy 
for tinnitus is usually directed toward minimizing the 
appreciation of tinnitus.
Relief of the tinnitus may be 
obtained by masking it with background music.
The use of a tinnitus masker is often followed 
by several hours of inhibition of the tinnitus.
Antide-
pressants have been shown to be beneficial in helping 
patients cope with tinnitus.
SECTION III
DISEASES OF THE  
NERVOUS SYSTEM
   Stephen  L.
Hauser    ■     M.
NEUROGENETICS 
 The landscape of neurology has been transformed by 
modern molecular genetics.
45).
Interestingly, 
the 16p deletion also is associated with epilepsy.
The understanding of 
the role of copy-number variation in human disease is 
still in its infancy.
Numerous diseases are known to result from 
abnormalities in alternative splicing.
Increased inclusion 
of exon 10–containing transcripts of MAPT can cause 
frontotemporal dementia.
Epigenetic processes appear 
to be dynamically active even in postmitotic neurons.
REF.
Iono-
tropic receptors are direct ion channels that open after 
engagement by the neurotransmitter.
53-1).
Addictive drugs share the property of increasing dopamine 
release in the nucleus accumbens.
Cocaine binds to dopamine trans-
porters and inhibits dopamine reuptake.
Not all cell-to-cell communication in the nervous 
system occurs via neurotransmission.
Mecha-
nisms that involve gap junctions have been related to a 
variety of neurologic disorders.
24).
25-1).
25-2).
The illus-
tration represents a composite of CNS and PNS myelin.
45).
39).
46).
The neurotrophins act at TrK and 
p75 receptors to promote survival of neurons.
However, in phase 3 clini-
cal trials, growth factors were ineffective in human ALS.
The new neurons made connec-
tions and improved performance in a memory task.
A major advance has been the development of 
induced pluripotent stem cells.
The establishment of appropriate 
neural connections and afferent control is also critical.
Sialidase, which cleaves 
one class of receptors for MAG, enhances axonal out-
growth.
25-3).
Experimental brain damage induced by hypoglyce-
mia also is attenuated by NMDA antagonists.
Excitotoxicity is not a single event but rather a cas-
cade of cell injury.
These channels offer a potential new therapeutic 
target for stroke.
Mitochondria are essential in controlling specific 
apoptosis pathways.
Deposition of β-amyloid is strongly implicated 
in the pathogenesis of Alzheimer’s disease.
Parkin, which causes autosomal 
recessive early-onset Parkinson’s disease, is a ubiqui-
tin ligase.
These two proteins are involved in transcription 
regulation as well as RNA metabolism.
Autophagy is the degradation of cystolic components 
in lysosomes.
Agents that upregulate gene transcription are neuropro-
tective in animal models of these diseases.
Familial 
frontotemporal degeneration (Chap.
This has allowed insights into how networks of neu-
rons operate to produce behavior.
These techniques have been 
used reliably in both behavioral and cognitive sciences.
25-4).
Other examples of the use of fMRI include the 
study of memory.
A.
In red, activation during right hand imita-
tion.
In blue, activation during left hand imitation.
B.
C.
Daniel  H.
The meaning of the term  seizure  needs to be carefully 
distinguished from that of epilepsy.
A fundamental principle is that seizures may be either 
focal or generalized.
Focal seizures are 
usually associated with structural abnormalities of the 
brain.
There are clear 
exceptions in both cases, however.
SEIZURES AND EPILEPSY 
 CHAPTER 26 
TABLE 26-1
 CLASSIFICATION OF SEIZURES 
1.
Generalized seizures   
  a.
Absence 
  Typical 
  Atypical  
  b.
Tonic clonic  
  c.
Clonic  
  d.
Tonic  
  e.
Atonic  
f.
Myoclonic      
3.
Focal seizures can also evolve into generalized 
seizures.
Three additional features of focal motor seizures 
are worth noting.
Third, in 
rare instances the seizure may continue for hours or 
days.
This condition, termed epilepsia partialis continua, is 
often refractory to medical therapy.
In such 
cases additional, detailed EEG studies may be helpful.
Contrac-
tion of the jaw muscles may cause biting of the tongue.
Bladder or bowel incon-
tinence may occur at this point.
Patients subsequently complain of headache, fatigue, and 
muscle ache that can last for many hours.
The postictal EEG 
shows diffuse slowing that gradually recovers as the 
patient awakens.
Consciousness is briefly 
impaired, but there is usually no postictal confusion.
28).
Epileptic spasms are such an example.
Abbreviations: GABA, γ-aminobutyric acid; PME, progressive myoclonus epilepsy.
and can be provoked by sleep deprivation.
Conscious-
ness is preserved unless the myoclonus is especially severe.
26-1).
The EEG suggested a right 
temporal lobe focus.
1.
However, febrile seizures occur only in a 
relatively small proportion of children.
2.
3.
Seizures are episodic.
The over-
all prevalence is 3–5% and even higher in some parts 
of the world such as Asia.
Patients often have a fam-
ily history of febrile seizures or epilepsy.
A simple febrile sei-
zure is a single, isolated event, brief, and symmetric in 
appearance.
Recurrences are much more 
likely when the febrile seizure occurs in the first year 
of life.
Childhood marks the age at which many of the well-
defined epilepsy syndromes present.
Head trauma is a common cause of epilepsy in ado-
lescents and adults.
Certain recognized causes of seizures are explained 
by these mechanisms.
The general physical examination includes a search 
for signs of infection or systemic illness.
Signs of head trauma and use of 
alcohol or illicit drugs should be sought.
1).
Testing of visual 
fields will help screen for lesions in the optic pathways 
and occipital lobes.
Details 
about the EEG are covered in Chap.
5.
26-2).
HISTORY AND EXAMINATION
The first goal is to determine whether the event was 
truly a seizure.
The history should also focus on risk factors and pre-
disposing events.
The EEG is always abnormal 
during generalized tonic-clonic seizures.
Thus, the 
EEG cannot establish the diagnosis of epilepsy in many 
cases.
Magnetoencephalography (MEG) provides another 
way of looking noninvasively at cortical activity.
MSI can be 
useful to localize potential seizure foci.
DIFFERENTIAL DIAGNOSIS OF 
SEIZURES
Disorders that may mimic seizures are listed in 
Table 26-6.
Two of 
the more common nonepileptic syndromes in the dif-
ferential diagnosis are detailed next.
SYNCOPE
(See also Chap.
from the lying or sitting position.
Headache or incon-
tinence usually suggests a seizure but may on occasion 
also occur with syncope.
Rarely, a syncopal episode can induce 
a full tonic-clonic seizure.
PSYCHOGENIC SEIZURES
Psychogenic seizures are nonepileptic behaviors that 
resemble seizures.
They are often part of a conver-
sion reaction precipitated by underlying psychological 
distress.
Video-EEG monitor-
ing is very useful when historic features are nondiagnos-
tic.
Whether to 
initiate therapy in a patient with a single seizure is contro-
versial.
Most 
patients with one or more of these risk factors should be 
treated.
Long-term use of some agents in adults, 
especially the elderly, can lead to osteoporosis.
Close 
follow-up is required to ensure these side effects are 
promptly recognized and reversed.
Oxcarbazepine also has fewer drug 
interactions than carbamazepine.
Lamotrigine tends 
to be well tolerated in terms of side effects.
This risk can be 
reduced by slow introduction and titration.
This is one of the main 
causes of acute phenytoin toxicity.
Topiramate can be used 
for both focal and generalized seizures.
bExtended-release product available.
This drug should generally 
be avoided in patients with preexisting bone marrow or 
liver disease.
Topiramate, 
zonisamide, phenytoin, and carbamazepine are suitable 
alternatives.
Topiramate, zonisamide, and felbamate may have 
similar broad efficacy.
This process may take months or longer if the baseline 
seizure frequency is low.
Starting doses are usually the lowest value listed 
under the dosage column in Table 26-9.
It is also useful to monitor free drug levels in such 
patients.
This is usually done by maintain-
ing the patient on the first drug while a second drug is 
added.
The dose of the second drug is then further opti-
mized based on seizure response and side effects.
Mono-
therapy should be the goal whenever possible.
In most cases it is 
preferable to reduce the dose of the drug gradually over 
2–3 months.
If there is no improvement, a 
third drug can be added while the first two are main-
tained.
Not all medically refractory patients are suitable 
candidates for resective surgery.
For 
GCSE, this is typically when seizures last beyond 
5 min.
GCSE is obvious when the patient is having overt 
convulsions.
However, after 30–45 min of uninter-
rupted seizures, the signs may become increasingly 
subtle.
Patients may have mild clonic movements of 
only the fingers or fine, rapid movements of the eyes.
There may be paroxysmal episodes of tachycardia, 
hypertension, and pupillary dilation.
In such cases, the 
EEG may be the only method of establishing the diag-
nosis.
Anticonvulsant therapy should then begin without delay; a 
treatment approach is shown in Fig.
26-3.
Depression should be 
treated through counseling or medication.
The horizontal bars indicate the approxi-
mate duration of drug infusions.
IV, intravenous; PE, phenytoin equivalents.
Loss of driving privileges is one of the most disrup-
tive social consequences of epilepsy.
Some patients may benefit from increases 
in antiepileptic drug dosages during menses.
Natural 
progestins or intramuscular medroxyprogesterone may 
be of benefit to a subset of women.
However, epilepsy poses some important risks 
to a pregnancy.
Valproic acid is strongly associated with an 
increased risk of adverse fetal outcomes (7–20%).
BREAST-FEEDING
Antiepileptic medications are excreted into breast milk 
to a variable degree.
Wade  S.
Smith  ■       Joey  D.
English    ■     S.
They cause ∼200,000 deaths each year in the 
United States and are a major cause of disability.
Cerebral ischemia  is caused by a 
reduction in blood fl ow that lasts longer than several 
seconds.
10 ).
28 ).
Tumors may present with acute neuro-
logic symptoms due to hemorrhage, seizure, or hydro-
cephalus.
Surprisingly, migraine can mimic stroke, even 
in patients without a significant migraine history.
When 
it develops without head pain (acephalgic migraine), the 
diagnosis may remain elusive.
Patients without any prior 
history of migraine may develop acephalgic migraine 
even after age 65.
8).
The metabolic process serves to 
“unmask” a prior deficit.
27-1).
SAH is discussed in Chap.
28.
anatomy, the site of occlusion, and likely systemic 
blood pressure.
27-15 and 27-16).
Focal cerebral infarction occurs via two distinct path-
ways (Fig.
Rounded boxes 
are diagnoses; rectangles are interventions.
Numbers are 
percentages of stroke overall.
SECTION III
Diseases of the Nervous System
258
to produce ATP.
Free radicals are produced by 
membrane lipid degradation and mitochondrial dys-
function.
Induced moderate hypothermia 
to mitigate stroke is the subject of continuing clinical 
research.
27-1).
The first goal is to prevent or reverse brain injury.
See text for details.
iNOS, inducible nitric oxide synthase; PARP, poly-A 
ribose polymerase.
Fever is detrimental and 
should be treated with antipyretics and surface cooling.
Edema peaks on the second or third day but can 
cause mass effect for ∼10 days.
Special vigilance is warranted for patients with cer-
ebellar infarction.
One-half of the patients were treated 
within 90 min.
Symptomatic intracerebral hemorrhage 
occurred in 6.4% of patients on rtPA and 0.6% on pla-
cebo.
Unlike the NINDS study, 
patients older than 85 years of age and diabetic 
patients were excluded.
Patients who awaken 
with stroke have the onset defined as when they went 
to bed.
Table 27-1 summarizes eligibility criteria and 
instructions for administration of IV rtPA.
Intraarterial treatment of basilar artery occlusions may also 
be beneficial for selected patients.
27-15).
Clopidogrel is being 
tested as a way to prevent stroke following TIA and 
minor ischemic stroke.
The U.S.
Use of SC unfraction-
ated heparin versus aspirin was tested in IST.
Heparin 
given SC afforded no additional benefit over aspirin 
and increased bleeding rates.
Several trials of LMWHs 
have also shown no consistent benefit in AIS.
Hypothermia is a powerful neuroprotective treatment in 
patients with cardiac arrest (Chap.
Use of clinical 
pathways and staff dedicated to the stroke patient can 
improve care.
ETIOLOGY OF ISCHEMIC STROKE
(Figs.
Judicious use of laboratory testing and imag-
ing studies completes the initial evaluation.
Neverthe-
less, nearly 30% of strokes remain unexplained despite 
extensive evaluation.
A com-
plete neurologic examination is performed to localize 
the site of stroke.
An ECG may demonstrate arrhythmias or reveal 
evidence of recent myocardial infarction (MI).
Cardioembolic stroke
Cardioembolism is responsible for ∼20% of all ischemic 
strokes.
These 
thrombi then detach and embolize into the arterial cir-
culation.
The thrombus may fragment or lyse quickly, 
producing only a TIA.
Alternatively, the arterial occlu-
sion may last longer, producing stroke.
Embolic strokes 
tend to be sudden in onset, with maximum neuro-
logic deficit at once.
A smaller embolus may occlude 
a small cortical or penetrating arterial branch.
A few pertinent aspects are highlighted here.
Nonrheumatic atrial fibrillation is the most com-
mon cause of cerebral embolism overall.
Patients with atrial fibrillation have an average 
annual risk of stroke of ∼5%.
The risk of stroke can be 
estimated by calculating the CHADS2 score (see Table 
27-3).
Left atrial enlargement is an additional risk factor 
for formation of atrial thrombi.
A.
B and C.
Diagram and reformatted CT angiogram 
of the common, internal, and external carotid arteries.
CHAPTER 27
Cerebrovascular Diseases
263
reduce stroke risk.
Mitral valve prolapse is not usually a 
source of emboli unless the prolapse is severe.
Both techniques are highly sensitive 
for detection of right-to-left shunts.
Bacterial endocarditis can cause valvular vegetations 
that can give rise to septic emboli.
Mycotic aneurysms caused 
by septic emboli give rise to SAH or intracerebral 
hemorrhage.
Less commonly, a diseased vessel 
may acutely thrombose.
bMay be associated with any hypercoagulable disorder.
Abbreviations: CNS, central nervous system; PAN, polyarteritis 
nodosa.
Abbreviations: Dose of aspirin is 50–325 mg/d; target INR for VKA is 2.5 unless otherwise specified.
Sources: Modified from DE Singer et al: Chest 133:546S, 2008; DN Salem et al: Chest 133:593S, 2008.
CHAPTER 27
Cerebrovascular Diseases
265 also vulnerable to atherosclerosis.
Carotid atheroscle-
rosis produces an estimated 10% of ischemic stroke.
It is more common in patients of Asian 
and African-American descent.
Recurrent stroke risk 
is ∼15% per year, similar to symptomatic untreated 
carotid atherosclerosis.
The dissection is usually painful and precedes 
the stroke by several hours or days.
Treating asymptomatic pseudoaneurysms following dis-
section is controversial.
The cause of dissection is usu-
ally unknown and recurrence is rare.
Most dissec-
tions heal spontaneously, and stroke or TIA is uncom-
mon beyond 2 weeks.
Small-vessel 
strokes account for ∼20% of all strokes.
27-4).
Prevention of other cardiovascular outcomes is not considered here.
Abbreviation: N/A, not applicable.
SECTION III
Diseases of the Nervous System
266
lipohyalinotic thickening.
These infarcts 
range in size from 3 mm to 2 cm in diameter.
Hyper-
tension and age are the principal risk factors.
Anterior cerebral a.
Internal carotid a.
Basilar a.
Basilar a.
Vertebral a.
Vertebral a.
Internal
carotid a.
Middle cerebral a.
Deep branches
of the basilar a.
Middle cerebral a.
Deep branches of the
middle cerebral a.
Note that these vessels are too small to be visualized 
on CT angiography.
Protein S deficiency and 
homocysteinemia may cause arterial thromboses as well.
Systemic lupus erythematosus with Libman-Sacks endo-
carditis can be a cause of embolic stroke.
Heparin prevents further thrombosis 
and reduces venous hypertension and ischemia.
Anticoagulation is often continued indefinitely if 
thrombophilia is diagnosed.
Sickle cell anemia (SS disease) is a common cause of 
stroke in children.
Fibromuscular dysplasia affects the cervical arteries 
and occurs mainly in women.
Occlusion is usually incom-
plete.
Involvement of the renal arteries is common and may 
cause hypertension.
The cause and natural history of 
fibromuscular dysplasia are unknown.
TIA or stroke 
generally occurs only when the artery is severely nar-
rowed or dissects.
Anticoagulation or antiplatelet ther-
apy may be helpful.
It 
rarely causes stroke as the internal carotid artery is usu-
ally not inflamed.
The cerebro-
spinal fluid (CSF) often shows pleocytosis, and the pro-
tein level is elevated.
Some cases follow the postpartum 
period and are self-limited.
27-5).
An inflammatory profile found on 
lumbar puncture favors an inflammatory cause.
With prompt recognition and treatment, many patients 
can make an excellent recovery.
No data exist 
on the value of any treatment.
Vascular inflammation 
is absent.
Areas of 
lacunar infarction are often seen also.
29).
Onset is 
usually in the fourth or fifth decade of life.
TIAs may arise 
from emboli to the brain or from in situ thrombosis of 
an intracranial vessel.
With a TIA, the occluded blood 
vessel reopens and neurologic function is restored.
Dramatic beading (arrows) 
typical of vasculopathy is seen.
This may indicate carotid stenosis as the cause 
or local ophthalmic artery disease.
This risk can be directly estimated using the 
well-validated ABCD2 method (Table 27-5).
There-
fore, urgent evaluation and treatment are justified.
27-1 
and 27-3).
The improvement characteristic of TIA 
is a contraindication to thrombolysis.
Risk of stroke is much greater in those with prior stroke 
or TIA.
Many cardiac conditions predispose to stroke, 
including atrial fibrillation and recent MI.
Also, the value of treating 
systolic hypertension in older patients has been clearly 
established.
Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood 
pressure.
Lancet 
369: 283, 2007.
Therefore, a statin 
should be considered in all patients with prior ischemic 
stroke.
Tobacco smoking should be discouraged in all 
patients.
Aspirin is the most widely studied antiplatelet 
agent.
This effect is permanent and 
lasts for the usual 8-day life of the platelet.
This effect is transient.
Clopidogrel rarely causes TTP 
but does not cause neutropenia.
Ongoing studies are currently addressing 
this question.
The accumu-
lated adenosine is an inhibitor of aggregation.
The resulting elevation 
in cyclic AMP inhibits aggregation of platelets.
This combination drug was 
studied in three trials.
Telmisartan also had no effect 
on these outcomes.
The principal side effect 
of dipyridamole is headache.
The absolute reduc-
tion varies considerably, depending on the particular 
patient’s risk.
Clearly, the likelihood of benefit far outweighs the risks 
of treatment.
However, there are no definitive 
data, and opinions vary.
Most physicians in North America recommend 81–325 
mg/d, while most Europeans recommend 50–100 mg.
Two doses of dabigatran were used: 110 mg/d and 
150 mg/d.
These patients generally should 
receive long-term anticoagulation.
VKAs 
are recommended long-term if atrial fibrillation persists.
A recent 
European study confirmed this finding.
Anticoagulation 
has not been directly compared with antiplatelet ther-
apy for carotid disease.
Both showed a substantial benefit for 
surgery in patients with a stenosis of ≥70%.
ECST found harm for 
patients with stenosis <30% treated surgically.
Nearly one-half of the strokes in the sur-
gery group were caused by preoperative angiograms.
It 
is possible that with longer follow-up, a clear benefit 
in women will emerge.
At present, carotid endarterec-
tomy in asymptomatic women remains particularly 
controversial.
This is of particular importance when the 
patient presents with a TIA and a normal examination.
27-4, and 27-6 through 27-14.
Occlusion 
of each major intracranial vessel has distinct clinical 
manifestations.
27-6, 27-7, 27-8, and 27-9).
27-6).
27-7).
Dysarthria is common because of facial 
weakness.
18).
Complete MCA syndromes occur most often when 
an embolus occludes the stem of the artery.
18), with or without arm 
weakness (frontal opercular syndrome).
27-7).
Deep branches of ant.
cerebral a.
Deep branches of middle cerebral a.
Middle cerebral a.
Anterior cerebral a.
KEY
Anterior
cerebral a.
Internal carotid a.
Middle cerebral a.
27-6).
This produces pure motor stroke or sen-
sory-motor stroke contralateral to the lesion.
Prerolandic a.
Sup.
division
middle cerebral a.
Lateral 
orbitofrontal a.
Temporopolar a.
Inf.
division
middle cerebral a.
Ant.
temporal a.
Post.
temporal a.
Angular a.
Post.
parietal a.
Ant.
parietal a.
Note 
the bifurcation of the middle cerebral artery into a superior 
and inferior division.
27-4, 27-6, 
and 27-8).
27-6).
Occlusion of a single A2 segment results in the 
contralateral symptoms noted in Fig.
27-8.
27-9).
The cortex 
supplied by the MCA territory is affected most often.
With a competent circle of Willis, occlusion may go 
Secondary
motor area
Medial
prerolandic a.
Callosomarginal a.
Frontopolar a.
Medial orbitofrontal a.
Ant.
cerebral a.
Post.
communicating a.
Penetrating
thalamosubthalamic
paramedian As.
Calcarine a.
Parietooccipital a.
Medial posterior choroidal a.
Pericallosal a.
Post.
parietal a.
Splenial a.
Post.
thalamic a.
Lateral posterior
choroidal a.
Post.
temporal a.
Ant.
temporal a.
Post.
cerebral 
stem
Visual
cortex
Sensory
cortex
Motor
cortex
Hippocampal As.
Medial 
rolandic a.
Sometimes there is massive infarction of the entire deep 
white matter and cortical surface.
27-8 and 27-9).
Patients typically 
describe a horizontal shade that sweeps down or up across 
the field of vision.
In most cases, these symptoms 
last only a few minutes.
Jaw claudication may result from low 
flow in the external carotid branches.
Bilateral common 
carotid artery occlusions at their origin may occur in 
Takayasu’s arteritis.
The vertebral arteries join to form 
the basilar artery at the pontomedullary junction.
27-4, 27-8, and 
27-9).
Occlusion of each 
vessel produces its own distinctive syndrome.
cerebral a.
Post.
communicating a.
Post.
cerebral a.
Medial posterior
choroidal a.
Ant.
temporal a.
Hippocampal a.
Post.
temporal a.
Post.
thalamic a.
Lateral posterior 
choroidal a.
Visual
cortex
Internal 
carotid a.
Ant.
choroidal a.
Mesencephalic
paramedian As.
Splenial a.
Parietooccipital a.
Calcarine a.
Signs and symptoms: Structures involved
  Peripheral territory (see also Fig.
27-12).
Homonymous hemi-
anopia (often upper quadrantic): Calcarine cortex or optic radia-
tion nearby.
Memory defect: Hippocampal lesion 
bilaterally or on the dominant side only.
Simultanagnosia, hemivisual neglect: Dominant 
visual cortex, contralateral hemisphere.
Complex hallucinations: Usually nondominant 
hemisphere.
Central territory.
Contralateral hemiplegia: Cerebral 
peduncle.
27-8 
and 27-9).
The precommunal, or P1, segment of the 
true posterior cerebral artery is atretic in such cases.
27-9 and 27-14).
2 7-14).
If the subthalamic nucleus is involved, con-
tralateral hemiballismus may occur.
It is persistent and 
responds poorly to analgesics.
Anticonvulsants (carbam-
azepine or gabapentin) or tricyclic antidepressants may 
be beneficial.
P2 syndromes
(See also Figs.
Contralateral homonymous hemiano-
pia with macula sparing is the usual manifestation.
Occasionally, only the upper quadrant of visual field is 
involved.
The defect usually clears because memory 
has bilateral representation.
The patient is often unaware of the blindness 
or may even deny it (Anton’s syndrome).
The second segment (V2) traverses 
the vertebral foramina from C6 to C2.
Atherothrombotic lesions have a predilection for 
V1 and V4 segments of the vertebral artery.
27-4 and 27-9).
Embolic occlusion or thrombosis of a V4 segment 
causes ischemia of the lateral medulla.
27-10).
Typically, lesions 
occlude either the proximal basilar and one or both 
vertebral arteries.
27-11, 27-12, 
27-13, and 27-14).
The pattern suggests 
12th n.
Descending 
sympathetic
tract
Dorsal 
spinocerebellar tract
10th n.
Note that in Figs.
Approximate regions involved 
in medial and lateral medullary stroke syndromes are shown.
Signs and symptoms: Structures involved
 1.
Many neurologists treat 
with heparin to prevent clot propagation.
More often, unequivocal 
signs of bilateral pontine disease are present.
Complete 
basilar thrombosis carries a high mortality.
As long as symptoms remain unilateral, con-
cern over pending basilar occlusion should be reduced.
6th n.
8th n.
Middle cerebellar
peduncle
 Restiform body
6th n.
nucleus
complex
Corticospinal and
corticobulbar tract
 7th n.
nucleus
Dorsal
cochlear 
nucleus
Descending tract
and nucleus of
5th n.
Approximate regions involved in medial and lateral 
inferior pontine stroke syndromes are shown.
Signs and symptoms: Structures involved
 1.
Partial 
syndromes occur frequently (Fig.
27-13).
Neurosurgical intervention may be 
lifesaving in such cases.
An occlusion close to the origin of the 
artery may cause corticospinal tract signs (Fig.
27-11).
27-11 through 27-13).
IMAGING STUDIES
See also Chap.
4.
sensory nucleus
5th n.
Approximate regions involved in medial and lateral 
midpontine stroke syndromes are shown.
Signs and symptoms: Structures involved
 1.
Carotid disease and intracranial vascular occlusions are 
readily identified with this method (Fig.
27-3).
28).
Approximate regions involved in medial and lateral 
superior pontine stroke syndromes are shown.
Signs and symptoms: Structures involved
 1.
27-1), and CTA and CT per-
fusion imaging may also be useful and convenient 
adjuncts.
MRI 
scanners with magnets of higher field strength produce 
more reliable and precise images.
27-16), as 
is fluid-attenuated inversion recovery (FLAIR) imaging 
(Chap.
4).
Using IV administration of gadolinium con-
trast, MR perfusion studies can be performed.
This 
sensitive technique images clotted blood within the 
dissected vessel wall.
Claustrophobia also limits its application.
Most acute stroke protocols use CT because of these 
limitations.
MRI may have particular utility in patients with 
Midbrain syndrome:
Lateral Medial
3rd n.
Approximate regions involved in medial and lateral 
midbrain stroke syndromes are shown.
Signs and symptoms: Structures involved
 1.
A.
CT perfusion 
mean-transit time map showing delayed perfusion of the left 
MCA distribution (blue).
B.
Predicted region of infarct (red) 
and penumbra (green) based on CT perfusion data.
C.
D.
The clot removed with 
a thrombectomy device (L5, Concentric Medical, Inc.).
E.
27-15).
27-16).
Bleeding into sub-
dural and epidural spaces is principally produced by 
trauma.
SAHs are produced by trauma and rupture of 
intracranial aneurysms (Chap.
28).
Intraparenchymal 
and intraventricular hemorrhage will be considered 
here.
27-1).
The 
location of the hemorrhage narrows the differential 
diagnosis to a few entities.
Table 27-6 lists the causes 
and anatomic spaces involved in hemorrhages.
FIGURE 27-16 
MRI of acute stroke.
A.
B.
C.
The occlusion is within the carotid terminus.
D.
The initial blood pressure 
should be maintained until the results of the CT scan 
are reviewed.
Whether these reductions 
in hematoma growth will translate to clinical benefit 
is unclear.
28).
It accounts for ∼10% of all strokes and is asso-
ciated with a 50% case fatality rate.
Incidence rates are 
particularly high in Asians and blacks.
Hypertension, 
trauma, and cerebral amyloid angiopathy cause the 
majority of these hemorrhages.
The small arteries in these areas seem 
most prone to hypertension-induced vascular injury.
Within 48 h macrophages begin to phago-
cytize the hemorrhage at its outer surface.
The hemorrhage gen-
erally presents as the abrupt onset of focal neurologic 
deficit.
Seizures are uncommon.
27-17).
Contralateral hemi-
paresis is therefore the sentinel sign.
The 
paralysis may worsen until the affected limbs become 
flaccid or extend rigidly.
In 
milder cases, edema in adjacent brain tissue may cause 
progressive deterioration over 12–72 h.
A prominent 
sensory deficit involving all modalities is usually present.
There may also be 
a homonymous visual field defect.
Patients may later develop a 
chronic, contralateral pain syndrome (Déjérine-Roussy 
syndrome).
In pontine hemorrhages, deep coma with quadriple-
gia usually occurs over a few minutes.
There is often 
prominent decerebrate rigidity and “pinpoint” (1 mm) 
pupils that react to light.
There is impairment of reflex 
FIGURE 27-17 
Hypertensive hemorrhage.
17).
Hyperpnea, 
severe hypertension, and hyperhidrosis are common.
Death often occurs within a few hours, but small hem-
orrhages are compatible with survival.
In mild cases there 
may be no other neurologic signs other than gait ataxia.
Dizziness or vertigo may be prominent.
Dys-
arthria and dysphagia may occur.
If the deep cerebellar 
nuclei are spared, full recovery is common.
Lobar hemorrhage
Symptoms and signs appear over several minutes.
Stiff neck and seizures are 
uncommon.
It accounts for some 
intracranial hemorrhages associated with IV throm-
bolysis given for MI.
Cocaine and methamphetamine are frequent causes of 
stroke in young (age <45 years) patients.
ICH, ischemic 
stroke, and SAH are all associated with stimulant use.
In cases of SAH, a saccular 
aneurysm is usually identified.
Presumably, acute hyper-
tension causes aneurysmal rupture.
Head injury often causes intracranial bleeding.
36).
Anticoagulant-related ICHs may evolve 
slowly, over 24–48 h.
Coagulopathy and thrombocyto-
penia should be reversed rapidly, as discussed later.
Skin and mucous 
membrane bleeding is usually evident and offers a diag-
nostic clue.
Hemorrhage into a brain tumor may be the first mani-
festation of neoplasm.
Glioblastoma multiforme in adults 
and medulloblastoma in children may also have areas of 
ICH.
Hypertensive encephalopathy is a complication of malig-
nant hypertension.
Microscopically, 
there are necrosis of arterioles, minute cerebral infarcts, 
and hemorrhages.
Primary intraventricular hemorrhage is rare.
Alternatively, bleeding 
can arise from periependymal veins.
Sepsis can cause small petechial hemorrhages throughout 
the cerebral white matter.
35).
Spinal 
hemorrhages usually present with sudden back pain and 
some manifestation of myelopathy.
Specific attention to the platelet 
count and PT/PTT are important to identify coagu-
lopathy.
CT imaging reliably detects acute focal hemor-
rhages in the supratentorial space.
Mass effect and 
edema may remain.
Images of flowing blood 
on MRI scan may identify AVMs as the cause of the 
hemorrhage.
Any identified coagulopathy 
should be reversed as soon as possible.
At present, little can be done about the hemorrhage 
itself.
Evacuation of supratentorial hematomas does not 
appear to improve outcome.
Tissue surrounding hematomas is displaced and 
compressed but not necessarily infarcted.
Surprisingly, ICP is often normal even with large 
intraparenchymal hemorrhages.
28).
These maneu-
vers will provide enough time to place a ventricu-
lostomy or ICP monitor.
Glu-
cocorticoids are not helpful for the edema from intra-
cerebral hematoma.
PREVENTION Hypertension is the leading cause 
of primary ICH.
Patients with amyloid angiopathy should avoid 
antithrombotic agents.
Abbreviation: ICH, intracerebral hemorrhage.
Sources: JC Hemphill et al: Stroke 32:891, 2001; JC Hemphill et al: 
Neurology 73:1088, 2009.
AVMs are prob-
ably congenital but cases of acquired lesions have been 
reported.
AVMs are more frequent in men, and rare 
familial cases have been described.
Headache (without bleeding) may be hemicranial 
and throbbing, like migraine, or diffuse.
Focal seizures, 
with or without generalization, occur in ∼30% of cases.
One-half of AVMs become evident as ICHs.
The risk of rerupture 
is ∼2–4% per year and is particularly high in the first 
few weeks.
This is seen most often with large 
AVMs in the territory of the MCA.
Headache at the onset of AVM rupture is 
not generally as explosive as with aneurysmal rupture.
Patients with asymptomatic AVMs have about an 
∼2–4% per year risk for hemorrhage.
Several angio-
graphic features can be used to help predict future 
bleeding risk.
Paradoxically, smaller lesions seem to 
have a higher hemorrhage rate.
A large-scale randomized trial is currently 
addressing this question.
These structures, unlike AVMs, are functional 
venous channels.
Surgical resection of these anoma-
lies may result in venous infarction and hemorrhage.
If resection of a cavernous malformation is 
attempted, the venous anomaly should not be disturbed.
If bleeding does occur, it rarely produces mass 
effect or significant symptoms.
No treatment options 
exist.
The pathogenesis is unclear.
Both KRIT1 and CCM2 have roles 
in blood vessel formation while PDCD10 is an apop-
totic gene.
Bleeding is usually of small volume, causing slight 
mass effect only.
Seizures may occur if the malformation 
is located near the cerebral cortex.
Radiation treatment has not been shown 
to be of benefit.
Dural arteriovenous fistulas are acquired connections 
usually from a dural artery to a dural sinus.
Patients 
may complain of a pulse-synchronous cephalic bruit 
(“pulsatile tinnitus”) and headache.
Surgical and endovascular techniques 
are usually curative.
These fistulas may form because 
of trauma, but most are idiopathic.
There is an associa-
tion between fistulas and dural sinus thrombosis.
J.
Claude  Hemphill, III        ■  Wade S.
Smith     ■     Daryl R.
The two principal types of edema 
are vasogenic and cytotoxic.
The 
BBB may be compromised in ischemia, trauma, infec-
tion, and metabolic derangements.
Typically, vasogenic 
edema develops rapidly following injury.
Early astrocytic swelling is a hallmark of ischemia.
17 ).
27-2 ).
Cytotoxic edema 
ensues, and ultimately necrotic cell death and tissue 
infarction occur.
An alternative pathway of cellular injury is apoptosis.
Excitotoxic-
ity and mechanisms of cell death are discussed in more 
detail in Chap.
25.
28-1).
CBF is also 
strongly influenced by pH and Paco2.
CBF increases 
with hypercapnia and acidosis and decreases with hypo-
capnia and alkalosis.
Significant 
increases in volume eventually result in increased ICP.
Elevated ICP diminishes cerebral perfu-
sion and can lead to tissue ischemia.
28-2).
An impaired level of consciousness is common in 
critically ill patients.
The approach to the comatose patient is discussed in 
Chap.
17; etiologies are listed in Table 17-1.
Cerebral 
perfusion is constant over a wide range of systemic blood 
pressure.
Perfusion is increased in the setting of hypoxia or 
hypercarbia.
BP, blood pressure; CBF, cerebral blood flow.
(Reprinted with permission from HM Shapiro: Anesthesiology 
43:447, 1975.
The 
EEG of metabolic encephalopathy typically reveals gen-
eralized slowing.
Monitoring of ICP can be an important tool in 
selected patients.
In gen-
eral, ICP should be maintained at <20 mmHg and CPP 
should be maintained at ≥60 mmHg.
In this setting, ventricular drainage of 
CSF is likely to be sufficient and most appropriate.
Fiberoptic ICP 
and brain tissue oxygen monitors are usually secured using 
a screwlike skull bolt.
Drain CSF via ventriculostomy (if in place)
2.
Elevate head of the bed; midline head position
3.
Hyperventilation—to PaCO2 30–35 mmHg
7.
Consider second-tier therapies for refractory ele-
vated ICP
a.
High-dose barbiturate therapy (“pentobarb coma”)
b.
Aggressive hyperventilation to PaCO2 <30 mmHg
c.
Hypothermia
d.
require immediate intervention.
If a 
ventriculostomy device is in place, direct drainage of 
CSF to reduce ICP is possible.
Early signs of elevated ICP include drowsiness and 
a diminished level of consciousness.
Neuroimaging 
studies may reveal evidence of edema and mass effect.
Hypotonic IV fluids should be avoided, and elevation of 
the head of the bed is recommended.
are grave prognostic signs.
17), dementia, visual 
agnosia (Chap.
In some circumstances, hypoxia 
may predominate.
28-4).
Numbers in parentheses are 
95% confidence intervals.
Tests denoted with an 
asterisk (*) may not be available in a timely and standard-
ized manner.
SSEP, somatosensory evoked potentials; NSE, 
neuron-specific enolase; FPR, false-positive rate.
28-5), with 
almost invariable involvement of the hippocampus.
Diagnosis
Diagnosis is based upon the history of a hypoxic-
ischemic event such as cardiac arrest.
Potential complications of hypothermia include coagu-
lopathy and an increased risk of infection.
Carbon monoxide and cyanide intoxication can also 
cause a delayed encephalopathy.
CHAPTER 28
Neurologic Critical Care
301 and sleep disturbance.
This is often attributed to medi-
cation effects, sleep deprivation, pain, and anxiety.
Current strategies focus on limiting the use of sedative 
medications when this can be done safely.
In the ICU setting, several metabolic causes of an 
altered level of consciousness predominate.
Hypercar-
bic encephalopathy can present with headache, confu-
sion, stupor, or coma.
This condition 
is broadly termed sepsis-associated encephalopathy.
Confusion, disorientation, agitation, and fluc-
tuations in level of alertness are typical.
Hyperreflexia and frontal 
release signs such as a grasp or snout reflex (Chap.
18) 
can be seen.
Abnormal movements such as myoclonus, 
tremor, or asterixis can occur.
MRI is useful in estab-
lishing the diagnosis (Fig.
Occasional cases present with lesions outside of the 
brainstem.
The characteristic clinical triad is that of ophthalmoplegia, 
ataxia, and global confusion.
If the disease is not treated, stupor, coma, and death may 
ensue.
The pupils are usually spared, but they may become 
miotic with advanced disease.
Rarely, amblyopia or myelopathy occurs.
Ataxia improves 
more slowly than the ocular motor abnormalities.
Apathy, drowsiness, and confusion 
improve more gradually.
There is frequently endothe-
lial proliferation, demyelination, and some neuronal loss.
These changes may be detected by MRI scanning (Fig.
28-7).
The amnestic defect is related to lesions in the 
dorsal medial nuclei of the thalamus.
FIGURE 28-6 
Central pontine myelinolysis.
FIGURE 28-7 
Wernicke’s disease.
The former include acute polyneuropathies such as 
Guillain-Barré syndrome (Chap.
46), neuromuscular 
junction disorders including myasthenia gravis (Chap.
47) and botulism, and primary muscle disorders such 
as polymyositis (Chap.
49).
The latter result either 
from the systemic disease itself or as a consequence of 
interventions.
Neurologic findings 
include diffuse weakness, decreased reflexes, and distal 
sensory loss.
Prolonged neuromuscular blockade does not appear 
to produce permanent damage to the PNS.
Muscle biopsy shows type II fiber atrophy.
Panfascicular 
muscle fiber necrosis may also occur in the setting of 
profound sepsis.
There may be associated ele-
vations in serum creatine kinase and urine myoglobin.
Acute quadriplegic myopathy has a good 
prognosis.
Some patients do have residual long-term weakness, 
with atrophy and fatigue limiting ambulation.
Monitoring with a peripheral nerve 
stimulator can help to avoid the overuse of these agents.
Excluding head trauma, the most common cause of 
SAH is rupture of a saccular aneurysm.
For patients who arrive alive at 
hospital, the mortality rate over the next month is about 
45%.
Unruptured, asymptomatic aneurysms are much 
less dangerous than a recently ruptured aneurysm.
Their risk of rupture is ∼6% in the first year 
after identification and may remain high indefinitely.
They often cause symptoms by compressing the adja-
cent brain or cranial nerves.
Approximately 85% 
of aneurysms occur in the anterior circulation, mostly on 
the circle of Willis.
About 20% of patients have multiple 
aneurysms, many at mirror sites bilaterally.
As an aneu-
rysm develops, it typically forms a neck with a dome.
The arte-
rial internal elastic lamina disappears at the base of the 
neck.
The media thins, and connective tissue replaces 
smooth-muscle cells.
Aneurysm size and site are 
important in predicting risk of rupture.
Clinical manifestations
Most unruptured intracranial aneurysms are completely 
asymptomatic.
At the moment of aneurysmal rup-
ture with major SAH, the ICP suddenly rises.
In ∼45% of cases, 
severe headache associated with exertion is the present-
ing complaint.
The headache is usually generalized, often 
with neck stiffness, and vomiting is common.
The deficits that result can include hemiparesis, aphasia, 
and abulia.
27).
Pain in or behind the 
eye and in the low temple can occur with an expanding 
MCA aneurysm.
Thunderclap headache is a variant of 
migraine that simulates an SAH.
For ruptured aneurysms, prognosis for good 
outcomes falls as the grade increases.
1.
Rerupture.
Rerupture is asso-
ciated with a 60% mortality rate and poor outcome.
SECTION III
Diseases of the Nervous System
306
Early treatment eliminates this risk.
2.
Hydrocephalus.
Hydrocephalus may clear spontaneously or 
require temporary ventricular drainage.
Subtle signs may be a lack 
of initiative in conversation or a failure to recover 
independence.
3.
Vasospasm.
Signs 
of ischemia appear 4–14 days after the hemorrhage, 
most often at 7 days.
The severity and distribution of 
vasospasm determine whether infarction will occur.
Spasm 
of major arteries produces symptoms referable to the 
appropriate vascular territory (Chap.
27).
All of these 
focal symptoms may present abruptly, fluctuate, or 
develop over a few days.
In most cases, focal spasm is 
preceded by a decline in mental status.
CT angiography is another method that 
can detect vasospasm.
4.
Hyponatremia.
Hyponatremia may be profound and 
can develop quickly in the first 2 weeks following 
SAH.
Laboratory evaluation and imaging
(Fig.
28-8) The hallmark of aneurysmal rupture is 
blood in the CSF.
CHAPTER 28
Neurologic Critical Care
307
thick in the cerebral fissures.
28-8C).
An 
asymptomatic troponin elevation is common.
Serious 
ventricular dysrhythmias are unusual.
An aneu-
rysm can be “clipped” by a neurosurgeon or “coiled” 
by an endovascular surgeon.
28-8D).
Risk of rebleeding was low, but more 
common in the coiling group.
A.
CT angiography revealing 
an aneurysm of the left superior cerebellar artery.
B.
C.
D.
High ICP refractory to treatment is a 
poor prognostic sign.
If headache or neck pain is severe, mild sedation and 
analgesia are prescribed.
Extreme sedation is avoided 
because it can obscure changes in neurologic status.
Seizures are uncommon at the onset of aneurysmal 
rupture.
Vasospasm remains the leading cause of morbidity 
and mortality following aneurysmal SAH.
This method is called “triple-H” (hypertension, hemodi-
lution, and hypervolemic) therapy.
Acute hydrocephalus can cause stupor or coma.
It 
may clear spontaneously or require temporary ventric-
ular drainage.
When chronic hydrocephalus develops, 
ventricular shunting is the treatment of choice.
All patients should have pneumatic compression 
stockings applied to prevent pulmonary embolism.
William  W.
Seeley   ■      Bruce  L.
Focal cerebral 
disorders are discussed in  Chap.
18  and illustrated in a 
video library in  Chap.
19   .
18 ).
Lesions of cortical-striatal pathways produce specifi c 
effects on behavior.
The dorsolateral prefrontal cortex 
bears connections with a central band of the caudate.
The 
lateral orbital frontal cortex connects with the ventrome-
dial caudate.
Lesions of this system cause impulsiveness, 
distractibility, and disinhibition.
THE CAUSES OF DEMENTIA 
 The single strongest risk factor for dementia is increasing 
age.
Whether 
dementia is an inevitable consequence of normal human 
aging remains controversial.
The many causes of dementia are listed in Table 29-1.
In patients under the age of 65, FTD rivals AD  
as the most common cause of dementia.
Other disorders listed in the table are uncom-
mon but important because many are reversible.
Subtle cumulative decline in episodic memory is a 
natural part of aging.
HISTORY The history should concentrate on the 
onset, duration, and tempo of progression.
A per-
sonality change, disinhibition, and weight gain or com-
pulsive eating suggest FTD, not AD.
A history of stroke with irregular stepwise progres-
sion suggests vascular dementia.
(2) Is there a treat-
able or reversible component to the dementia?
(3) Can 
the physician help to alleviate the burden on caregivers?
A broad overview of the approach to dementia is shown 
in Table 29-3.
Rapid pro-
gression with motor rigidity and myoclonus suggests 
CJD.
Gait dis-
turbance is common in vascular dementia, PD/DLB, or 
normal-pressure hydrocephalus (NPH).
Alcoholism creates risk for 
malnutrition and thiamine deficiency.
Hemiparesis or other focal neurologic deficits sug-
gest vascular dementia or brain tumor.
Dementia with a 
myelopathy and peripheral neuropathy suggests vitamin 
B12 deficiency.
thyroid dysfunction, Lyme disease, or vasculitis.
Dry, cool 
skin, hair loss, and bradycardia suggest hypothyroidism.
Neuropsychiatric assessment is important for diag-
nosis, prognosis, and treatment.
LABORATORY TESTS The choice of laboratory 
tests in the evaluation of dementia is complex.
Table 29-3 lists most screening tests for 
dementia.
They also help to establish a regional pat-
tern of atrophy.
Focal frontal and/or anterior tem-
poral atrophy suggests FTD.
Extensive white 
matter abnormalities correlate with a vascular etiology 
for dementia.
29-1).
The disease also exacts a heavy 
emotional toll on family members and caregivers.
AD, Alzheim-
er’s disease; MCI, mild cognitive impairment; PET, positron 
emission tomography.
Social graces, routine behavior, and 
superficial conversation may be surprisingly intact.
Lan-
guage becomes impaired—first naming, then compre-
hension, and finally fluency.
In some patients, aphasia is 
an early and prominent feature.
Apraxia emerges, and patients have trouble performing 
learned sequential motor tasks.
Simple calculations and clock reading become 
difficult in parallel.
In the late stages of the disease, some persons remain 
ambulatory but wander aimlessly.
Loss of judgment and 
reasoning is inevitable.
Loss of inhibitions and aggres-
sion may occur and alternate with passivity and with-
drawal.
Sleep-wake patterns are disrupted, and night-
time wandering becomes disturbing to the household.
Patients often look parkinsonian (Chap.
30) but rarely have a high-amplitude, rhythmic, resting 
tremor.
In end-stage AD, patients become rigid, mute, 
incontinent, and bedridden.
Help is needed with eating, 
dressing, and toileting.
Gener-
alized seizures may also occur.
The typical 
duration of AD is 8–10 years, but the course can range 
from 1 to 25 years.
29-2A, B).
29-2C, D).
The EEG in AD is normal or shows nonspecific slow-
ing.
Routine spinal fluid examination is also normal.
Simple clinical clues are useful in the differential diag-
nosis.
Resting tremor with stooped posture, brady-
kinesia, and masked facies suggest PD (Chap.
30).
35).
Early onset of a focal seizure suggests a metastatic or 
primary brain neoplasm (Chap.
37).
43).
43), or rare hereditary 
ataxias (Chap.
31).
EPIDEMIOLOGY
The most important risk factors for AD are old age and 
a positive family history.
Female sex may also be a risk factor indepen-
dent of the greater longevity of women.
Some AD patients 
have a past history of head trauma with concussion.
Diabetes 
increases the risk of AD threefold.
The characteris-
tic microscopic findings are neuritic plaques and NFTs.
Eventually, further amy-
loid polymerization and fibril formation lead to neuritic 
plaques (Fig.
Fluorodeoxyglucose PET scans of a normal control (C) and 
a patient with AD (D).
AD, Alzheimer’s disease; PET, positron emission 
tomography.
The normal function of 
Aβ is unknown.
APP has neurotrophic and neuroprotec-
tive properties.
The accumulation of Aβ in 
cerebral arterioles is termed amyloid angiopathy.
Finally, patients with AD often show comor-
bid DLB and vascular pathology.
One is the APP gene on 
chromosome 21.
Many 
develop a progressive dementia superimposed on their base-
line mental retardation.
Aβ peptide 
results from cleavage of APP by β and γ secretases 
(Fig.
29-4).
Presenilin-1 (PS-1) is on chromo-
some 14 and encodes a protein called S182.
Presenilin-2 (PS-2) is on chromosome 1 and 
encodes a protein called STM2.
Mutations in 
PS-1 are much more common than those in PS-2.
(Image 
courtesy of S.
Excess production of Aβ42 is a key ini-
tiator of cellular damage in Alzheimer’s disease.
Genetic testing for these uncommon 
mutations is now commercially available.
Apo 
ε participates in cholesterol transport and has three alleles: 
ε2, ε3, and ε4.
Conversely, many AD patients have no ε4 allele, 
and ε4 carriers may never develop AD.
Therefore, ε4 is 
neither necessary nor sufficient to cause AD.
Use of Apo ε testing in AD diagnosis remains 
controversial.
Loss of independence and change of environment may 
worsen confusion, agitation, and anger.
Communication 
and repeated calm reassurance are necessary.
Use of adult day care centers can be helpful.
Due to hepa-
totoxicity, tacrine is no longer used.
Memantine appears to act by blocking overex-
cited N-methyl-D-aspartate (NMDA) glutamate receptors.
Each of these compounds has 
only modest efficacy for AD.
This study 
seemed to confirm the results of two earlier case-con-
trolled studies.
This study 
markedly dampened enthusiasm for hormonal treat-
ments to prevent dementia.
Additionally, no benefit has 
been found in the treatment of AD with estrogen alone.
of multi-infarct dementia.
Euphoria, elation, depression, or aggres-
sive behaviors are common as the disease progresses.
Both 
pyramidal and cerebellar signs may be present.
A gait 
disorder is present in at least half of these patients.
Seizures and myoclonic 
jerks appear in a minority of patients.
Patients 
typically report previous discrete episodes of sudden neu-
rologic deterioration.
Recur-
rent strokes result in a stepwise disease progression.
Neu-
roimaging reveals multiple areas of infarction.
29-5).
Skin 
biopsy may show pathognomonic osmophilic gran-
ules in the media of arterioles.
The frequency of this disorder is 
unknown, and there are no effective treatments.
Unlike 
in AD, behavioral symptoms predominate in the early stages 
of FTD.
Progranulin is a growth factor that binds to 
tumor necrosis factor (TNF) receptors.
How progranu-
lin mutations lead to FTD is unknown.
In contrast, 
familial FTD with ALS has been linked to chromosome 
9.
Cognitive test-
ing typically reveals spared memory but impaired planning, 
judgment, or language.
Patients with FTD often 
show an absence of insight into their condition.
Findings at the bedside are dictated by the anatomic 
localization of the disorder.
29-6 and 
29-7).
29-8).
Loss of cortical serotonergic inner-
vation is seen in many patients.
In contrast to AD, the 
cholinergic system is relatively spared in FTD.
29-9).
Many 
FIGURE 29-6 
Frontotemporal dementia (FTD).
Areas of early and severe atrophy in each 
syndrome are highlighted (white arrowheads).
Semantic dementia shows prominent temporopolar atro-
phy, more often on the left.
These fea-
tures are common at presentation and often precede the 
motor syndrome.
Response to L-dopa is limited or absent; no other 
treatments exist.
Death occurs within 5–10 years of onset.
At autopsy, accumulation of hyperphosphorylated tau is 
seen within neurons and glia.
Furthermore, the behavioral syndromes 
seen with DLB differ from PSP (see later).
Patients with PD who 
develop dementia also show cortical atrophy on brain 
imaging.
Parkinson’s disease is discussed in detail 
in Chap.
30.
Some patients begin 
with a progressive nonfluent aphasia or a progressive 
motor speech disorder.
Classical Pick’s disease is 
seen in only 10–20% of patients with frontotemporal dementia.
Scale bar represents 50 microns.
(CP-13 antibody courtesy of P.
Davies.)
SECTION III
Diseases of the Nervous System
326 coiled bodies.
The condition is rarely familial, the cause is 
unknown, and there is no specific treatment.
Dementia can precede or follow 
the appearance of parkinsonism.
Exercise programs maximize motor function and protect 
against fall-related injury.
Antidepressants are often nec-
essary.
Prion diseases are discussed in 
detail in Chap.
43.
Huntington’s disease (HD) (Chap.
30) is an autoso-
mal dominant, degenerative brain disorder.
Depression, apathy, social with-
drawal, irritability, and intermittent disinhibition are 
common.
Delusions and obsessive-compulsive behavior 
may occur.
Disease duration is typically around 15 years 
but is quite variable.
Normal-pressure hydrocephalus (NPH) is a relatively 
uncommon but treatable syndrome.
This syndrome is a 
communicating hydrocephalus with a patent aqueduct 
of Sylvius (Fig.
29-10), in contrast to aqueductal ste-
nosis, in which the aqueduct is small.
None has proven to be spe-
cific or consistently useful.
A.
B.
Axial T2-weighted MR images demonstrate dilation of the 
lateral ventricles.
This patient underwent successful ventricu-
loperitoneal shunting.
SECTION III
Diseases of the Nervous System
328 during, and after lumbar CSF drainage.
Short-lasting improve-
ment is common.
Dementia can accompany chronic alcoholism (Chap.
56) 
and may result from associated malnutrition, especially of 
B vitamins, particularly thiamine.
Other poorly defined 
aspects of chronic alcoholism may, however, also pro-
duce cerebral damage.
Thiamine (vitamin B1) deficiency causes Wernicke’s 
encephalopathy (Chap.
28).
Dam-
age to the dorsomedial thalamus correlates most closely 
with the memory loss.
Confabulation is common, although not always present.
Mammil-
lary body atrophy may be visible on MRI in the chronic 
phase (Fig.
28-7).
35).
Damage to myelinated 
axons may also cause dementia.
CNS infections usually cause delirium and other acute 
neurologic syndromes.
41), may produce a dementing illness.
Between 
20 and 30% of patients in the advanced stages of HIV 
infection become demented (Chap.
42).
Cardinal features 
include psychomotor retardation, apathy, and impaired 
memory.
Primary and metastatic neoplasms of the CNS (Chap.
44).
If recurrent or persistent, the condition may be termed 
complex partial status epilepticus.
The cognitive disturbance 
often responds to anticonvulsant therapy.
The etiology 
may be previous small strokes or head trauma; some cases 
are idiopathic.
Such conditions include hypothyroidism; vas-
culitis; and hepatic, renal, or pulmonary disease.
Isolated vasculitis of the CNS (CNS granulomatous angi-
itis) (Chap.
Headache is common, and 
strokes and cranial neuropathies may occur.
Brain imag-
ing studies may be normal or nonspecifically abnormal.
CSF analysis reveals a mild pleocytosis or protein eleva-
tion.
The progno-
sis is often poor, although the disorder may remit spon-
taneously.
Some patients respond to glucocorticoids or 
chemotherapy.
Chronic metal exposure represents a rare cause of demen-
tia.
The key to diagnosis is to elicit a history of exposure 
at work or home.
Chronic lead poisoning from inad-
equately fire-glazed pottery has been reported.
The treatment is chelation therapy with 
agents such as ethylenediamine tetraacetic acid (EDTA).
Treatment is chelation therapy with dimercaprol 
(BAL).
The condition has been eliminated by the 
use of deionized water for dialysis.
Also, there may be loss of neurons in the substan-
tia nigra.
Chronic subdural hematoma (Chap.
Often 
the amnesia occurs in the setting of an emotional stimu-
lus or physical exertion.
The patient may seem confused and repeatedly ask 
about his or her location in place and time.
MLD is diagnosed by measur-
ing arylsulfatase A enzyme activity in white blood cells.
Adrenoleukodystrophy is diagnosed with measure-
ment of plasma very long chain fatty acids.
Diagnosis is made by 
finding curvilinear inclusions within white blood cells or 
neuronal tissue.
Psychogenic amnesia for personally important memories 
can be seen.
On recovery, there 
is a residual amnesia gap for the period of the fugue.
Psychiatric diseases may mimic dementia.
Patients in this condition may feel confused and unable 
to accomplish routine tasks.
Such patients respond to 
treatment of the underlying psychiatric illness.
Memory loss may also be part of a 
conversion disorder.
Discontinuation of the offending medication 
often improves mentation.
A proactive strategy has been shown to reduce the 
occurrence of delirium in hospitalized patients.
Nondrug behavior therapy has an important place in 
dementia management.
The primary goals are to make 
the patient’s life comfortable, uncomplicated, and safe.
Preparing lists, schedules, calendars, and labels can be 
helpful in the early stages.
Attempts to help 
or take over may be greeted with complaints, depression, 
or anger.
Hostile responses on the part of the caretaker 
are useless and sometimes harmful.
These areas need to be monitored, 
supervised, and made as safe as possible.
Antidepressants, such as SSRIs (Chap.
Anti-
convulsants are used to control seizures.
Agitation, hallucinations, delusions, and confusion are 
difficult to treat.
Caregiver guilt 
and burnout are common.
Caregivers should be encouraged to take advantage 
of day-care facilities and respite breaks.
Education and 
counseling about dementia are important.
C.
Warren  Olanow     ■     Anthony H.V.
PD affects men 
and women of all races, all occupations, and all coun-
tries.
30-1 ) .
These studies suggest 
that dopamine neurons are affected in midstage disease.
30-2 ) .
The basal ganglia play 
an important role in regulating normal motor behavior.
Among 
the different forms of parkinsonism, PD is the most com-
mon (approximately 75% of cases).
However, 
postmortem studies found a 24% error rate when these 
criteria were used.
With these revised criteria (known 
as the U.K.
brain bank criteria), the clinical diagnosis of 
PD is confirmed pathologically in 99% of cases.
30-3).
The penetrance 
of the most common LRRK2 mutation ranges from 28 
to 74%, depending on age.
SNc, substantia nigra pars compacta.
33).
SNc, substantia nigra pars compacta; STN, 
subthalamic nucleus.
33-2]) in MSA-c.
Patients frequently experience hyperextension of the 
neck with early gait disturbance and falls.
In later stages, 
speech and swallowing difficulty and dementia become 
evident.
Dementia may occur at any stage of 
the disease.
MRI frequently shows asymmetric cortical 
atrophy.
Other drugs that 
can cause secondary parkinsonism include tetrabenazine, 
amiodarone, and lithium.
ETIOLOGY AND PATHOGENESIS
Most PD cases occur sporadically (∼85–90%) and are of 
unknown cause.
However, no environ-
mental factor has yet been determined to cause PD.
(Courtesy of 
Dr.
However, MPTP or MPTP-like compounds have 
not been linked to sporadic PD.
MPTP has, however, 
proved useful for generating an animal model of the dis-
ease.
Each of these 
mechanisms offer potential targets for neuroprotective 
drugs.
30-4).
30-1).
Increased lev-
els of unwanted proteins could also result from impaired 
clearance.
Collectively, these findings implicate abnormal 
protein accumulation in the etiology of PD.
Mitochondrial dysfunction has also been implicated 
in familial PD.
Six different LRRK2 mutations have been linked to 
PD, with the Gly2019Ser being the commonest.
Whole-genome association studies have provided 
conflicting results.
30-5.
30-5).
There are, however, important limitations of levo-
dopa therapy.
Acute dopaminergic side effects include 
nausea, vomiting, and orthostatic hypotension.
These 
are usually transient and can generally be avoided by 
gradual titration.
Inhibitory connections are shown 
as blue arrows and excitatory connections as red arrows.
The striatum is the major input region and receives its major 
input from the cortex.
The striatum and GPi/SNr are con-
nected by direct and indirect pathways.
This concept led to the rationale for 
surgical therapies for PD.
30-6).
This loss of benefit is known as 
the wearing-off effect.
At the same time, many patients 
develop dyskinesias.
The cause of levodopa-induced motor complications 
is not precisely known.
30-5).
Striatal dopamine 
levels are normally maintained at a relatively constant 
level.
Levodopa-induced motor complica-
tions.
Behavioral alterations can be encountered in levodopa-
treated patients.
In general, dopamine agonists do not have comparable 
efficacy to levodopa.
Rotigotine is 
administered as a once-daily transdermal patch.
It is generally administered SC as a 
rescue agent for the treatment of severe “off” episodes.
However, 
infusions are cumbersome, and this approach has not 
been approved in the United States.
Acute side effects of dopamine agonists include 
nausea, vomiting, and orthostatic hypotension.
As 
with levodopa, these can usually be avoided by slow 
titration.
Patients should be informed about this poten-
tial problem and should not drive when tired.
Selegiline and rasagiline are relatively 
selective suicide inhibitors of the MAO-B enzyme.
MAO-B 
inhibitors are generally safe and well tolerated.
Two COMT inhibitors have been 
approved, tolcapone and entacapone.
There is also a 
combination tablet of levodopa, carbidopa, and enta-
capone (Stalevo).
This problem has 
not been encountered with entacapone.
Still, they can be helpful in indi-
vidual patients.
Amantadine also has historical importance.
Side effects include 
livido reticularis, weight gain, and impaired cognitive 
function.
A list of the major drugs and available dosage 
strengths is provided in Table 30-5.
SURGICAL TREATMENT Surgical treatments for
PD have been employed for more than a century.
Most surgical procedures for PD performed today 
utilize deep brain stimulation (DBS).
DBS simulates 
the effects of a lesion without necessitating a brain 
lesion.
In cases with intolerable 
side effects, stimulation can be stopped and the sys-
tem removed.
DBS for PD primarily targets the STN or the GPi.
Generally, drugs should be started in low doses and titrated to optimal dose.
Abbreviations: COMT, catechol-O-methyltransferase; MAO-B, monoamine oxidase type B.
SECTION III
Diseases of the Nervous System
344 paresthesias, depression, and rarely suicide).
While not all PD patients are candidates, the procedure 
is profoundly beneficial for many.
Several open-label studies reported 
positive results.
Anxiety can be treated with short-acting benzo-
diazepines.
Psychosis can be a major problem in PD.
Psychosis in 
PD often responds to low doses of atypical neurolep-
tics.
Hallucinations in PD patients are 
often a harbinger of a developing dementia.
Dementia in PD (PDD) is common, affecting as many 
as 80% of patients.
29).
These 
patients are particularly prone to have hallucinations 
and diurnal fluctuations.
It is likely that DLB and PDD represent a PD spec-
trum rather than separate disease entities.
Memantine, 
an antiglutamatergic agent, may also provide benefit for 
some PDD patients.
Autonomic disturbances are common and frequently 
require attention.
Orthostatic hypotension can be 
problematic and contribute to falling.
Low doses of fludrocortisol (Florinef) or midodrine 
control most cases.
If orthostatic hypotension is promi-
nent in early disease, MSA should be considered.
Sexual 
dysfunction can be helped with sildenafil or tadalafil.
Anticholinergic agents, such as Ditropan, may 
be helpful.
Constipation can be a very important prob-
lem for PD patients.
Agents that 
promote GI motility can also be helpful.
Restless leg syndrome, sleep apnea, 
and other sleep disorders should be treated as appropri-
ate.
REM behavior disorder (RBD) may precede the onset 
of motor features.
Low doses of clonazepam 
are usually effective in controlling this problem.
Canes and walkers may become 
necessary.
The 
needs of the caregiver should not be neglected.
Support groups for patients and 
caregivers may be useful.
However, no therapy has yet been proved 
to be disease-modifying.
The next important issue to address is when to ini-
tiate symptomatic therapy.
30-7.
Decision 
points include:
  a.
b.
c.
d.
e.
Source: Adapted from CW Olanow et al: Neurology 72:S1, 
2009.
Tremor is also 
assessed based on distribution, frequency, and related 
neurologic dysfunction.
It can present in childhood, but dramatically 
increases in prevalence over the age of 70 years.
The tremor is most often manifest as a postural 
or kinetic tremor.
It is typically bilateral and symmet-
ric, but may begin on one side and remain asymmetric.
Patients with severe ET can have an intention tremor 
with overshoot and slowness of movement.
The tremor is characteristically improved by 
alcohol and worsened by stress.
Subtle impairment of 
coordination or tandem walking may be present.
The major differential is 
a dystonic tremor (see later) or PD.
These typically begin after a 
latency of a few seconds (emergent tremor).
ETIOLOGY AND PATHOPHYSIOLOGY
The etiology and pathophysiology of ET are not 
known.
Candidate genes 
include the dopamine D3 receptor and proteins that 
map to the cerebellum.
However, the precise 
pathologic correlate of ET remains to be defined.
TREATMENT
Many cases are mild and require no treatment other 
than reassurance.
β Blockers or primidone are the standard drug 
therapies for ET and help in about 50% of cases.
The drug is contra-
indicated in patients with bradycardia or asthma.
Hand 
tremor tends to be most improved, while head tremor 
is often refractory.
Benefits have 
been reported with gabapentin and topiramate.
PRIMARY DYSTONIAS
Several gene mutations are associated with dystonia.
The majority of patients have an age of onset younger 
than 26 years (mean 14 years).
In severe cases, patients can suf-
fer disabling postural deformities that compromise 
mobility.
Why some gene carriers 
express dystonia and others do not is not known.
The 
precise pathology responsible for dystonia is not known.
DRD is typified by an excellent and sustained response 
to small doses of levodopa.
FOCAL DYSTONIAS
These are the most common forms of dystonia.
They 
typically present in the fourth to sixth decades and 
affect women more than men.
Most cases affect the adductor muscles 
and cause speech to have a choking or strained quality.
Less commonly, the abductors are affected, leading to 
speech with a breathy or whispering quality.
Muscle contractions can be painful, and associated 
with a secondary cervical radiculopathy.
Their cause is not 
known, but genetic factors, autoimmunity, and trauma 
have been suggested.
Focal dystonias are often associ-
ated with a high-frequency tremor that resembles ET.
SECONDARY DYSTONIAS
These develop as a consequence of drugs or other neu-
rologic disorders.
In these 
cases, dystonia often assumes a segmental distribution.
PATHOPHYSIOLOGY OF DYSTONIA
The pathophysiologic basis of dystonia is not known.
Further, ablation or stimulation of the globus pallidus 
can both induce and ameliorate dystonia.
Wilson’s disease 
should be ruled out in young patients with dystonia.
Levodopa should be tried in all cases of childhood-
onset dystonia to rule out DRD.
Clonazepam and diazepam are rarely effective.
Two serotypes of 
botulinum toxin are available (A and B).
Some patients fail to respond after having 
experienced an initial benefit.
DBS of the pal-
lidum can provide dramatic benefits for patients with 
primary DYT1 dystonia.
Better results are typically obtained in younger 
patients.
Patients may experience 
rhabdomyolysis with renal failure.
Patients should be 
managed in an ICU with protection of airway if required.
Spasms may be difficult to control, and anesthesia with 
muscle paralysis may be required.
60 years.
HD is characterized by rapid, nonpatterned, 
semipurposeful, involuntary choreiform movements.
Dysarthria, gait disturbance, and oculomotor 
abnormalities are common features.
Functional decline is often predicted by 
progressive weight loss despite adequate calorie intake.
The disease 
predominantly strikes the striatum.
30-8).
More diffuse cortical atrophy is seen in the 
middle and late stages of the disease.
Supportive stud-
ies include reduced metabolic activity in the caudate 
nucleus and putamen.
The larger the number of repeats, the ear-
lier the disease is manifest.
There is no adequate treatment for the cognitive or 
motor decline.
Most patients are of 
African descent.
FIGURE 30-8 
Huntington’s disease.
A.
Coronal FLAIR MRI shows 
enlargement of the lateral ventricles reflecting typical atrophy 
(arrows).
B.
Axial FLAIR image demonstrates abnormal high 
signal in the caudate and putamen (arrows).
Dopamine-block-
ing agents may control the chorea.
Syden-
ham’s chorea (originally called St.
Vitus’ dance) is more 
common in females and is typically seen in childhood 
(5–15 years).
Mutations in the VPS13A gene on chromosome 
9q21 encoding chorein have been described.
It is important to ensure that patients 
with these types of choreas do not have HD.
Prognosis is usually 
good, with spontaneous remission in later life.
Low-dose 
anticonvulsant therapy (e.g., carbamazepine) is usually 
effective if required.
Treatment is not 
indicated if the condition is mild and self-limited.
Proximal limb muscles tend to be pre-
dominantly affected.
Dopamine-blocking drugs can be helpful but 
can themselves lead to movement disorders.
In extreme 
cases, pallidotomy can be very effective.
TS is characterized by multi-
ple motor tics often accompanied by vocalizations (phonic 
tics).
A tic is a brief, rapid, recurrent, and seemingly pur-
poseless stereotyped motor contraction.
The risk of a family with 
one affected child having a second is about 25%.
Drug treatment is indicated when the tics are disabling 
and interfere with quality of life.
If these agents are 
not effective, antipsychotics can be employed.
Myoclonic jerks can be disabling when they interfere with 
normal movement.
Recent studies suggest that 
levetiracetam may be particularly effective.
ACUTE
Dystonia is the most common acute hyperkinetic drug 
reaction.
SUBACUTE
Akathisia is the commonest reaction in this category.
It 
consists of motor restlessness with a need to move that 
is alleviated by movement.
Therapy consists of remov-
ing the offending agent.
In severe cases, the trunk, limbs, and respira-
tory muscles may also be affected.
In contrast, abnormal 
movements may develop after stopping the offend-
ing agent.
Treatment primarily consists of stopping the offend-
ing agent.
Abrupt 
cessation of a neuroleptic should be avoided as acute 
withdrawal can induce worsening.
TD can persist after 
withdrawal of antipsychotics and can be difficult to 
treat.
Benefits may be achieved with valproic acid, anti-
cholinergics, or botulinum toxin injections.
In refrac-
tory cases, catecholamine depleters such as tetrabenazine 
may be helpful.
Tetrabenazine can be associated with 
dose-dependent sedation and orthostatic hypotension.
Valproic acid, anticholin-
ergics, and botulinum toxin may occasionally be ben-
eficial.
Neuroleptic medications can also be associated with 
a neuroleptic malignant syndrome (NMS).
Symptoms typically evolve within 
days or weeks after initiating the drug.
Myoclonus is often a prominent fea-
ture, in contrast to NMS, which it resembles.
Symptoms most commonly begin in the legs, but 
can spread to or even begin in the upper limbs.
The 
unpleasant sensation is often described as a creepy-
crawly feeling, paresthesia, or burning.
RLS is a heterogeneous condition.
The mean age of onset in 
genetic forms is 27 years, although pediatric cases are 
recognized.
The severity of symptoms is variable.
The neurologic examination is normal.
Most RLS sufferers have mild symptoms that do not 
require specific treatment.
General measures to improve 
sleep hygiene and quality should be attempted first.
Other drugs that 
can be effective include anticonvulsants, analgesics, and 
even opiates.
Iron infusion 
may also be helpful for severe primary RLS but requires 
expert supervision.
It is caused by mutations in the gene 
encoding a P-type ATPase.
About half of WD patients 
(especially younger patients) manifest with liver abnor-
malities.
The tremor is usually 
in the upper limbs, bilateral, and asymmetric.
KF rings represent the deposition of cop-
per in Descemet’s membrane around the cornea.
WD should always be considered in the differential 
diagnosis of a movement disorder in a child.
MRI shows symmet-
ric hyperintensity on T2-weighted images in the puta-
men, caudate, and pallidum.
However, correlation of 
imaging changes with clinical features is not good.
It is 
very rare for WD patients with neurologic features not 
to have KF rings.
Side effects are common and can to some degree be 
attenuated by coadministration of pyridoxine.
Trien-
tine and zinc are useful drugs for maintenance therapy.
KF rings tend 
to decrease after 3–6 months and disappear by 2 years.
Adherence to maintenance therapy is a major chal-
lenge in long-term care.
Tremor affecting the 
upper limbs is the most common psychogenic move-
ment disorder.
13).
Patients with hypochondriasis, factitious dis-
orders, and malingering have a poor prognosis.
Roger  N.
11 ).
Rarely, weakness of 
proximal leg muscles mimics cerebellar disease.
39 ).
Hyponatremia has also been associated with 
ataxia.
44 ).
43 ).
CT or MRI studies will 
reveal clinically significant processes of this type.
Acute surgical decompression may be required 
(Chap.
28).
Chronic etiologies of progressive ataxia include 
multiple sclerosis (Chap.
39) and congenital lesions such 
as a Chiari malformation (Chap.
35) or a congenital cyst 
of the posterior fossa (Dandy-Walker syndrome).
Rarely, dementia is present as well.
The 
clinical phenotypes of these SCAs overlap.
The geno-
type has become the gold standard for diagnosis and clas-
sification.
The most common disorders are discussed 
later.
Dysarthria, dysphagia, and oculo-
motor and facial palsies may also occur.
Extrapyramidal 
symptoms include rigidity, an immobile face, and par-
kinsonian tremor.
Dementia may be noted but is 
usually mild.
Impairment of sphincter function is com-
mon, with urinary and sometimes fecal incontinence.
Cerebellar and brainstem atrophy are evident on MRI 
(Fig.
31-1).
A few patients with 
38–40 CAG repeats have been described.
Transgenic mice carry-
ing SCA1 developed ataxia and Purkinje cell pathology.
Normal alleles con-
tain 15–32 repeats; mutant alleles have 35–77 repeats.
In most populations, it is the most common 
autosomal dominant ataxia.
Symptoms and signs
MJD has been classified into three clinical types.
Patellar and ankle 
clonus are common, as are extensor plantar responses.
There is no truncal titubation.
Pharyngeal weakness and spasticity cause difficulty with 
speech and swallowing.
MRI, magnetic resonance imaging; SCA1, 
spinocerebellar ataxia type 1.
Type 
II is the most common form of MJD.
Type II MJD can be distinguished 
from the clinically similar disorders SCA1 and SCA2.
The mean age of onset of symptoms in MJD is 
25 years.
Usually, 
patients retain full intellectual function.
Purkinje cell loss and granule cell loss occur in 
the cerebellar cortex.
Cell loss also occurs in the den-
tate nucleus and in the cranial nerve motor nuclei.
Spar-
ing of the inferior olives distinguishes MJD from other 
dominantly inherited ataxias.
GENETIC CONSIDERATIONS
The gene for MJD maps to 14q24.3-q32.
An earlier age of onset 
is associated with longer repeats.
MJD-ataxin codes for a ubiquitin protease, which 
is inactive due to expanded polyglutamines.
Missense mutations in this gene result in 
familial hemiplegic migraine.
The genetic defect is an expanded CAG 
repeat in the SCA7 gene at 3p14-p21.1.
The expanded 
repeat size in SCA7 is highly variable.
Marked anticipation has been recorded, especially with 
paternal transmission.
The mutation is not fully penetrant.
Other features include nystagmus, leg spas-
ticity, and reduced vibratory sensation.
Severely affected 
individuals are nonambulatory by the fourth to sixth 
decades.
MRI shows cerebellar atrophy.
Larger expansions are found in patients with ear-
lier onset.
The number of repeats is 49 in patients with 
DRPLA and f26 in normal individuals.
Startle, 
sudden change in posture, and exercise can induce epi-
sodes.
Acetazolamide or anticonvulsants may be thera-
peutic.
Patients with EA-2 have episodes of ataxia with 
nystagmus that can last for hours or days.
Stress, exer-
cise, or excessive fatigue may be precipitants.
The lower extremities are more severely 
involved than the upper ones.
Loss of vibratory and proprioceptive sen-
sation occurs.
The median age of death is 35 years.
Women have a significantly better prognosis than men.
Cardiac involvement occurs in 90% of patients.
Car-
diomegaly, symmetric hypertrophy, murmurs, and con-
duction defects are reported.
Musculo-
skeletal deformities are common and include pes cavus, 
pes equinovarus, and scoliosis.
MRI of the spinal cord 
shows atrophy (Fig.
31-2).
Slight atrophy of the cerebellum and cerebral gyri may 
occur.
The cerebral cortex is histologically normal 
except for loss of Betz cells in the precentral gyri.
The 
peripheral nerves are extensively involved, with a loss 
of large myelinated fibers.
There is homozygosity for expanded 
GAA repeats in >95% of patients.
Normal persons have 
7–22 GAA repeats, and patients have 200–900 GAA 
repeats.
Frataxin is a mitochondrial protein involved 
in iron homeostasis.
Defects 
in MTP result in impairment of formation and secre-
tion of VLDL in liver.
AVED is due to mutations in the gene for α-tocopherol 
transfer protein (α-TTP).
The inferior olives of the medulla may also have 
neuronal loss.
A poorly developed or absent thymus gland is the most 
consistent defect of the lymphoid system.
Defective DNA repair in AT 
fibroblasts exposed to ultraviolet light has been demon-
strated.
48).
Mass lesions must be recognized promptly and treated 
appropriately.
44).
Malabsorption syndromes leading to 
vitamin E deficiency may lead to ataxia.
Vitamin E 
therapy is indicated for these rare patients.
Hypothyroidism is easily treated.
There is no proven therapy for any of the autosomal 
dominant ataxias (SCA1 to SCA28).
Acetazolamide can reduce the dura-
tion of symptoms of episodic ataxia.
Robert  H.
Brown, Jr.
12 ).
In ALS, the motor neu-
ron cytoskeleton is typically affected early in the illness.
This is the basis for the term 
amyotrophy .
32-1 )  and brainstem to the lateral 
and anterior white matter columns of the spinal cord.
A remarkable feature of the disease is the selec-
tivity of neuronal cell death.
Within the motor system, there 
is some selectivity of involvement.
In the hands, a preponder-
ance of extensor over flexor weakness is common.
The latter 
leads to involuntary excess in weeping or laughing (pseu-
dobulbar affect).
Dementia is not a component of sporadic ALS.
A committee of the World Federation of Neurology 
has established diagnostic guidelines for ALS.
There are very rare reports of stabilization 
or even regression of ALS.
In most societies there is an 
incidence of 1–3 per 100,000 and a prevalence of 3–5 
per 100,000.
FAMILIAL ALS
Several forms of selective motor neuron disease are 
inheritable (Table 32-3).
Familial ALS (FALS) involves 
both corticospinal and lower motor neurons.
Rare mutations in other genes are also clearly impli-
cated in ALS-like diseases.
Mutations in senataxin, a heli-
case, cause an early adult-onset, slowly evolving ALS 
variant.
Kennedy’s syndrome is an X-linked, adult-
onset disorder that may mimic ALS, as described later.
These are readily identi-
fied by appropriate laboratory tests.
Rarely, ALS develops concurrently with features 
indicative of more widespread neurodegeneration.
Sandhoff  
disease
5q Hexosamini-
dase B
AR Childhood Ganglioside 
recycling
2.
AB variant 5q GM2-activator 
protein
AR Childhood Ganglioside 
recycling
3.
29).
In 
other cases, ALS develops simultaneously with a strik-
ing frontotemporal dementia.
PATHOGENESIS
The cause of sporadic ALS is not well defined.
The mutant protein is conformation-
ally unstable and prone to aberrant catalytic reactions.
It has recently been observed that mutations in the 
TDP43 and FUS/TLS genes also cause ALS.
In 
one trial, the survival rate at 18 months with riluzole was 
similar to placebo at 15 months.
Finger extension splints 
can potentiate grip.
Respiratory support may be life- 
sustaining.
This is highly effective in clearing airways and prevent-
ing aspiration pneumonia.
These facilitate oral com-
munication and may be effective for telephone use.
For this reason, a careful search for 
causes of secondary motor neuron disease is warranted.
DNA test-
ing is available.
In rare 
cases, spasticity may also be present, although it is gen-
erally absent.
Several clinical forms exist.
Though alert, afflicted infants are weak and 
floppy (hypotonic) and lack muscle stretch reflexes.
Death generally ensues within the first year of life.
MMCB is not typically associated with corticospi-
nal signs.
There are 
rare X-linked and autosomal dominant forms of appar-
ent SMA.
31).
The periph-
eral motor neurons and other neuronal systems are 
spared.
39).
35).
The clini-
cal course and laboratory testing will distinguish these 
possibilities.
FSP typically has a 
long survival, presumably because respiratory function is 
spared.
Some family members may have spas-
ticity without clinical symptoms.
More than 20 FSP genes have now been identified.
Another recessive variant is 
caused by defects in the paraplegin gene.
Louis (www.neuro.wustl.edu/neuromuscular).
Phillip  A.
Low    ■      John  W.
It regu-
lates blood pressure (BP), heart rate, sleep, and bladder 
and bowel function.
Hypo-
thalamic disorders that cause disturbances in homeostasis 
are discussed in  Chap.
38.
33-1 ) .
These are 
thinly myelinated.
Lesions of the 
efferent limb cause the most consistent and severe OH.
Some syndromes do not 
fi t easily into any classifi cation scheme.
Symptoms may be 
widespread or regional in distribution.
It is also important to 
recognize the modulating effects of age.
Specific symptoms of orthostatic intolerance are 
diverse (Table 33-3).
Early symptoms may be overlooked.
Cold feet may indicate periph-
eral vasomotor constriction.
Gastrointestinal autonomic dysfunction typically pres-
ents as severe constipation.
Autonomic disorders with brain involvement
  A.
Associated with multisystem degeneration
 1.
Multisystem degeneration: autonomic failure  
clinically prominent
  a.
Multiple system atrophy (MSA)
  b.
Parkinson’s disease with autonomic failure
  c.
Diffuse Lewy body disease (some cases)
 2.
Multisystem degeneration: autonomic failure  
clinically not usually prominent
 a.
Parkinson’s disease
 b.
Unassociated with multisystem degeneration  
(focal CNS disorders)
 1.
Disorders mainly due to cerebral cortex  
involvement
 a.
Frontal cortex lesions causing urinary/bowel  
incontinence
 b.
Partial complex seizures (temporal lobe or  
anterior cingulate)
c.
Cerebral infarction of the insula
  2.
Disorders of the limbic and paralimbic circuits
 a.
Shapiro’s syndrome (agenesis of corpus  
callosum, hyperhidrosis, hypothermia)
 b.
Autonomic seizures
 c.
Limbic encephalitis
  3.
Disorders of the hypothalamus
 a.
Wernicke-Korsakoff syndrome
 b.
Diencephalic syndrome
 c.
Neuroleptic malignant syndrome
 d.
Serotonin syndrome
 e.
Fatal familial insomnia
 f.
Antidiuretic hormone syndromes (diabetes 
 insipidus, inappropriate ADH secretion)
 g.
Disturbances of temperature regulation  
(hyperthermia, hypothermia)
  h.
Disturbances of sexual function
 i.
Disturbances of appetite
 j.
Disturbances of BP/HR and gastric function
 k.
Horner’s syndrome
  4.
Disorders of the brainstem and cerebellum
 a.
Posterior fossa tumors
  b.
Syringobulbia and Arnold-Chiari malformation
 c.
Disorders of BP control (hypertension,  
hypotension)
 d.
Cardiac arrhythmias
 e.
Central sleep apnea
 f.
Baroreflex failure
 g.
Horner’s syndrome
 h.
Vertebrobasilar and Wallenberg syndromes
 i.
Brainstem encephalitis
II.
Autonomic disorders with spinal cord involvement
A.
Traumatic quadriplegia
B.
Syringomyelia
C.
Subacute combined degeneration
D.
Multiple sclerosis and Devic’s disease
E.
Amyotrophic lateral sclerosis
F.
Tetanus
G.
Stiff-man syndrome
H.
Spinal cord tumors
III.
Autonomic neuropathies
A.
Acute/subacute autonomic neuropathies
1.
Subacute autoimmune autonomic  
ganglionopathy (AAG)
a.
Subacute paraneoplastic autonomic  
neuropathy
b.
Guillain-Barré syndrome
c.
Botulism
d.
Porphyria
e.
Toxic autonomic neuropathies
g.
Subacute cholinergic neuropathy
B.
Chronic peripheral autonomic neuropathies
1.
Distal small fiber neuropathy
2.
Combined sympathetic and parasympathetic 
failure
a.
Amyloid
b.
Diabetic autonomic neuropathy
c.
Autoimmune autonomic ganglionopathy  
(paraneoplastic and idiopathic)
d.
Sensory neuronopathy with autonomic failure
e.
Familial dysautonomia (Riley-Day syndrome)
f.
Diabetic, uremic, or nutritional deficiency
g.
Dysautonomia of old age
3.
Syncope results when the drop in BP impairs 
cerebral perfusion.
Neurocardiogenic and 
cardiac causes of syncope are considered in Chap.
10.
Standing time to first symptom and presyncope 
should be followed for management.
Physical examination includes measurement of supine 
and standing pulse and BP.
The Valsalva response is tested in the supine 
position.
There are four phases 
of BP and heart rate response to the Valsalva maneuver.
Increased 
total peripheral resistance arrests the BP drop ∼5–8 s 
after the onset of the maneuver.
Late phase II begins with 
a progressive rise in BP toward or above baseline.
Venous 
return and cardiac output return to normal in phase IV.
Sudomotor Function Sweating is induced by 
release of ACh from sympathetic postganglionic fibers.
CHAPTER 33
Disorders of the Autonomic Nervous System
385
ACh-induced sweating.
A reduced or absent response 
indicates a lesion of the postganglionic sudomotor 
axon.
The pattern of color 
changes is a measure of regional sweat secretion.
A 
postganglionic lesion is present if both QSART and TST 
show absent sweating.
In a preganglionic lesion, QSART 
is normal but TST shows anhidrosis.
A positive nitroglyc-
erin-stimulated test predicts recurrence of syncope.
SPECIFIC SYNDROMES OF ANS 
DYSFUNCTION
MULTIPLE SYSTEM ATROPHY (CHAP.
SECTION III
Diseases of the Nervous System
386
syndrome (MSA-c).
Although autonomic abnormalities are com-
mon in advanced Parkinson’s disease (Chap.
33-2).
MSA generally progresses relentlessly to death 7–10 
years after onset.
GI management includes frequent small meals, 
soft diet, stool softeners, and bulk agents.
Domperidone has been used in 
other countries but is not available in the United States.
Autonomic dysfunction is also a common feature in 
dementia with Lewy bodies (Chap.
29); the severity is 
usually less than that found in MSA or Parkinson’s dis-
ease.
In multiple sclerosis (MS; Chap.
Quadriparetic patients exhibit both supine 
hypertension and OH after upward tilting.
Associated symptoms can include flushing, headache, or 
piloerection.
In patients 
with supine hypertension, BP can be lowered by tilt-
ing the head upward.
Vasodilator drugs may be used to 
treat acute elevations in BP.
PERIPHERAL NERVE AND 
NEUROMUSCULAR JUNCTION DISORDERS
Peripheral neuropathies (Chap.
45) are the most com-
mon cause of chronic autonomic insufficiency.
47).
FIGURE 33-2 
Multiple system atrophy, cerebellar type (MSA-c).
Treatment of familial cases with 
liver transplantation can be successful.
The response of 
primary amyloidosis to melphalan and stem cell trans-
plantation has been mixed.
Death is usually due to car-
diac or renal involvement.
Pathologic examination 
reveals a loss of unmyelinated and myelinated nerve 
fibers.
OH is usually due to 
brainstem involvement.
28).
56).
Other prominent symptoms include anxiety, abdomi-
nal pain, nausea, and vomiting.
Abnormal autonomic 
function can occur both during acute attacks and during 
remissions.
Guillain-Barré syndrome (Chap.
46)
BP fluctuations and arrhythmias can be severe.
In general, the antibody 
titer correlates with the severity of autonomic failure.
Symptoms of cholinergic failure are also associated with 
a high antibody titer.
Onset of the neuropathy follows 
a viral infection in approximately half of cases.
Symptomatic management of OH, gastro-
paresis, and sicca symptoms is essential.
AAN can have a paraneoplastic basis (Chap.
44).
The neoplasm may be truly 
occult and possibly suppressed by the autoantibody.
The disorder begins in the middle decades 
and occurs in women more often than men.
The 
symptoms can be disabling, but the disease does not 
shorten life span.
Some studies have questioned 
the specificity of PAF as a distinct clinical entity.
Some 
cases are ganglionic antibody–positive and thus rep-
resent a type of AAN.
Between 10 and 15% of cases 
evolve into MSA.
Approximately half of 
affected patients report an antecedent viral infection.
Recurrent unexplained episodes of dysautonomia and 
fatigue also occur.
Some cases are due to an underlying limited autonomic 
neuropathy.
Reconditioning and a sustained 
exercise program are very important.
INHERITED DISORDERS
There are five known hereditary sensory and auto-
nomic neuropathies (HSAN I–V).
The most impor-
tant ones are HSAN I and HSAN III (Riley-Day syn-
drome; familial dysautonomia).
The responsible gene, 
on chromosome 9q, is designated SPTLC1.
SPTLC 
is an important enzyme in the regulation of ceramide.
Episodic abdominal crises and fever are 
common.
Pathologic examination of nerves reveals a 
loss of small myelinated and unmyelinated nerve fibers.
The defective gene, named IKBKAP, is also located on 
the long arm of chromosome 9.
Onset of symptoms is 
usually in adolescence; the condition tends to improve 
with age.
Topical antiperspirants are occasionally help-
ful.
More useful are potent anticholinergic drugs such 
as glycopyrrolate (1–2 mg PO tid).
T2 ganglionectomy 
or sympathectomy is successful in >90% of patients 
with palmar hyperhidrosis.
The surge 
can cause seizures, neurogenic pulmonary edema, and 
myocardial injury.
Phenylpropanol-
amine, now off the market, was in the past a potent 
cause of this syndrome.
Cocaine, including “crack,” 
can cause a hypertensive state with CNS hyperstimula-
tion.
The hyperadrenergic state with Guillain-Barré syn-
drome can produce a moderate autonomic storm.
Sepsis and 
encephalitis need to be excluded with appropriate stud-
ies.
The patient should be managed 
in an intensive care unit.
Treatment 
may need to be maintained for several weeks.
For 
chronic and milder autonomic storm, propranolol and/
or clonidine can be effective.
38).
CRPS type I is a regional pain syndrome that usu-
ally develops after tissue trauma.
Pain is the primary clinical feature of CRPS.
The pain is diffuse, spontane-
ous, and either burning, throbbing, or aching in qual-
ity.
The involved extremity is warm and edematous, 
and the joints are tender.
Increased sweating and hair 
SECTION III
Diseases of the Nervous System
390 growth develop.
In phase II (3–6 months after onset), 
thin, shiny, cool skin appears.
The natural history of typical CRPS may be more 
benign than reflected in the literature.
PATIENT EDUCATION Only a minority of patients 
with OH require drug treatment.
Other helpful measures may 
include keeping a BP log and dietary education (salt/
fluids).
SYMPTOMATIC TREATMENT Nonpharmaco-
logic approaches are summarized in Table 33-9.
Prolonged recumbency 
should be avoided when possible.
The 
hematocrit increases after 2–6 weeks.
A weekly mainte-
nance dose is usually necessary.
If these measures are not sufficient, drug treat-
ment may be necessary.
It has a duration of action of 2–4 h.
Midodrine 
should not be taken after 6 P.M.
Fludrocortisone will reduce 
OH, but it aggravates supine hypertension.
Potassium supplements are often 
necessary with chronic administration of fludrocortisone.
Sustained elevations of supine BP >180/110 mmHg 
should be avoided.
Postprandial OH may respond to several measures.
The subcutaneous dose ranges from 25 μg bid 
to 200 μg tid.
The patient should be taught to self-treat transient 
worsening of OH.
A daily glass of wine, if requested 
by the patient, can be taken shortly before bedtime.
M.
Flint  Beal   ■    Stephen  L.
Hauser  
392
 Symptoms and signs of cranial nerve pathology are com-
mon in internal medicine.
Disorders of ocular movement are discussed in 
 Chap.
21 , disorders of hearing in  Chap.
24 , and vertigo 
and disorders of vestibular function in  Chap.
11 .
34-1 ) .
Its motor part innervates the masseter and 
pterygoid masticatory muscles.
Middle-aged and elderly persons are affected primarily, 
and ∼60% of cases occur in women.
Remissions may be long-lasting, 
but in most patients the disorder ultimately recurs.
8) and from pain 
arising from diseases of the jaw, teeth, or sinuses.
Laboratory evaluation
An ESR is indicated if temporal arteritis is suspected.
Most patients require a maintenance dose of 
200 mg qid.
Doses >1200 mg daily provide no additional 
benefit.
If treatment is effective, it is usually con-
tinued for 1 month and then tapered as tolerated.
Baclofen may also 
be administered, either alone or in combination with an 
anticonvulsant.
The initial dose is 5–10 mg tid, gradually 
increasing as needed to 20 mg qid.
If drug treatment fails, surgical therapy should be 
offered.
This procedure requires a 
suboccipital craniotomy.
It is used less often now than in the past.
Most present with sensory loss on the 
face or with weakness of the jaw muscles.
Among infectious 
causes, herpes zoster and leprosy should be considered.
Rarely, an idiopathic form of trigeminal neuropathy is 
observed.
Gradual recovery is the rule.
34-2) The seventh cranial nerve supplies all the 
muscles concerned with facial expression.
The motor 
nucleus of the seventh nerve lies anterior and lateral to 
the abducens nucleus.
It then passes 
through the parotid gland and subdivides to supply the 
facial muscles.
The lower lid sags and falls away from the 
conjunctiva, permitting tears to spill over the cheek.
Food collects between the teeth and lips, and saliva may 
dribble from the corner of the mouth.
If the nerve to the stapedius is interrupted, there is 
hyperacusis (sensitivity to loud sounds).
The palpebral fissure becomes narrowed, and 
the nasolabial fold deepens.
Facial spasms, ini-
tiated by movements of the face, may develop (hemifacial 
spasm).
Anomalous regeneration of seventh nerve fibers 
may result in other troublesome phenomena.
BELL’S PALSY
The most common form of facial paralysis is Bell’s palsy.
Pain 
behind the ear may precede the paralysis for a day or 
two.
Taste sensation may be lost unilaterally, and hyper-
acusis may be present.
In some cases there is mild cere-
brospinal fluid lymphocytosis.
Approximately 
80% of patients recover within a few weeks or months.
The presence of incom-
plete paralysis in the first week is the most favorable 
prognostic sign.
A 
variety of other viruses have also been implicated less 
commonly.
Motor nucleus
VI n.
V n.
1
2
3
B
C
A
FIGURE 34-2 
The facial nerve.
(Adapted 
from MB Carpenter: Core Text of Neuroanatomy, 2nd ed.
Facial palsy that 
is often bilateral occurs in sarcoidosis and in Guillain-
Barré syndrome (Chap.
46).
Its cause is unknown.
Acoustic neuromas 
frequently involve the facial nerve by local compression.
MRI often shows swelling and enhancement 
of the facial nerve in idiopathic Bell’s palsy (Fig.
34-3).
Most cases 
appear related to vascular compression of the exit-
ing facial nerve in the pons.
Mild cases can be treated 
with carbamazepine, gabapentin, or, if these drugs fail, 
with baclofen.
46).
It usually begins in adolescence or early adult years and 
is slowly progressive.
The facial hair may turn white and fall 
out, and the sebaceous glands become atrophic.
Bilat-
eral involvement may occur.
A limited form of systemic 
sclerosis (scleroderma) may be the cause of some cases.
Treatment is cosmetic, consisting of transplantation of 
skin and subcutaneous fat.
It resembles trigeminal neu-
ralgia in many respects but is much less common.
Spasms of pain may be initiated by 
swallowing or coughing.
Cardiac symptoms—brady-
cardia or asystole, hypotension, and fainting—have  
been reported.
Very rarely, herpes zoster involves the glossopharyn-
geal nerve.
Loss of sensation at 
the external auditory meatus and the posterior pinna 
may also be present.
This nerve 
may be involved by infection with varicella zoster virus.
Dysphagia is also a symptom in some 
patients with myotonic dystrophy.
However, a substan-
tial number of cases of recurrent laryngeal palsy remain 
idiopathic.
Most 
but not all patients recover.
Iso-
lated lesions of unknown cause can occur.
Atrophy and 
fasciculation of the tongue develop weeks to months 
after interruption of the nerve.
The opposite is true of primary lesions 
within the brainstem.
A purely motor disorder 
without atrophy always raises the question of myasthenia 
gravis (Chap.
47).
As noted earlier, Guillain-Barré syn-
drome commonly affects the facial nerves bilaterally.
46).
28).
The cavernous sinus syndrome (Fig.
34-4) is a dis-
tinctive and frequently life-threatening disorder.
Anticoagulant therapy may benefit cases of primary 
thrombosis.
Repair or occlusion of the carotid artery may 
be required for treatment of fistulas or aneurysms.
The 
Tolosa-Hunt syndrome generally responds to glucocorti-
coids.
The syndrome is frequently responsive to 
glucocorticoids.
Ant.
cerebral a.
Int.
carotid a.
Ant.
clinoid process
Subarachnoid
space
Oculomotor (III) n.
Trochlear (IV) n.
Ophthalmic (VI) n.
Abducens (VI) n.
Maxillary (V2) n.
Hauser   ■    Allan  H.
Ropper  
400
 Diseases of the spinal cord are frequently devastating.
DISEASES OF THE SPINAL CORD 
 CHAPTER 35 
dorsal sensory roots.
CHAPTER 35
Diseases of the Spinal Cord
401 mately the first lumbar vertebral body.
The lower spinal 
nerves take an increasingly downward course to exit 
via intervertebral foramens.
15-2 and 15-3).
With 
severe and acute transverse lesions, the limbs initially 
may be flaccid rather than spastic.
The main features of transverse damage at each level 
of the spinal cord are summarized next.
Cervical Cord Upper cervical cord lesions produce 
quadriplegia and weakness of the diaphragm.
Useful 
markers for localization are the nipples (T4) and umbi-
licus (T10).
Leg weakness and disturbances of bladder 
and bowel function accompany the paralysis.
The bulbocaverno-
sus (S2-S4) and anal (S4-S5) reflexes are absent (Chap.
1).
Muscle strength is largely preserved.
Cauda equina syndromes are also discussed in 
Chap.
9.
35-1.
Partial forms are more common than the 
fully developed syndrome.
Spinal trauma, syringo-
myelia, and intrinsic cord tumors are the main causes.
C, cervical; D, distal; E, extensors; F, 
flexors; L, lumbar; P, proximal; S, sacral; T, thoracic.
The result is extensive bilateral 
tissue destruction that spares the posterior columns.
There is typically suboccipital pain spreading 
to the neck and shoulders.
The differentiating features are only 
relative and serve as clinical guides.
Consequently, a long duration 
of symptoms favors an intradural origin.
There may be only mild sensory symptoms 
or a devastating functional transection of the cord.
Paresthesias or numbness typically begins in the 
feet and ascends symmetrically or asymmetrically.
Rarely, pain is mild or absent.
MRI provides 
excellent anatomic resolution of the extent of spinal 
tumors (Fig.
If spinal cord compression is suspected, imaging 
should be obtained promptly.
Up to 40% of 
FIGURE 35-2 
Epidural spinal cord compression due to breast carci-
noma.
The low-intensity bone marrow signal in A signifies 
replacement by tumor.
Radiotherapy appears 
to be effective even for most classically radioresistant 
metastases.
Meningiomas (Fig.
Ther-
apy is by surgical resection.
Primary intramedullary tumors of the spinal cord 
are uncommon.
In adults, these 
lesions are ependymomas, hemangioblastomas, or low-
grade astrocytomas (Fig.
35-4).
FIGURE 35-4 
MRI of an intramedullary astrocytoma.
Irregular peripheral enhancement occurs within the 
mass (arrows).
especially in patients with advanced metastatic disease 
(Chap.
37), although these are not nearly as frequent as 
brain metastases.
Prompt recognition of this distinctive process will 
in most cases prevent permanent sequelae.
Aching pain 
is almost always present, either over the spine or in a 
radicular pattern.
As the abscess expands, further 
spinal cord damage results from venous congestion and 
thrombosis.
Once weakness and other signs of myelopa-
thy appear, progression may be rapid.
35-5).
MRI scans localize the abscess and exclude other 
causes of myelopathy.
A high cervical tap is 
sometimes the safest approach.
Blood 
cultures are positive in <25% of cases.
Therapeutic anti-
coagulation, trauma, tumor, or blood dyscrasias are predis-
posing conditions.
Rare cases complicate lumbar puncture 
or epidural anesthesia.
MRI and CT confirm the clinical 
suspicion and can delineate the extent of the bleeding.
FIGURE 35-5 
MRI of a spinal epidural abscess due to tuberculosis.
A.
Sagittal T2-weighted free spin-echo MR sequence.
B.
Hematomyelia pres-
ents as an acute painful transverse myelopathy.
28).
Diagnosis is by MRI 
or CT.
Therapy is supportive, and surgical intervention is 
generally not useful.
MRI of spinal cord with and without contrast (exclude 
compressive causes).
2.
3.
melitensis.
Also consider nasal/pharyngeal/anal cul-
tures for enteroviruses; stool O&P for Schistosoma ova.
4.
5.
6.
7.
Vascular causes: CT myelogram; spinal angiogram.
39); and infectious (primarily 
viral) causes.
Sharp midline or radiating back 
pain localized to the area of ischemia is frequent.
The antiphospholipid antibody syndrome is 
treated with anticoagulation.
Some will later mani-
fest additional symptoms of an immune-mediated disease.
Multiple sclerosis
MS (Chap.
39) may present with acute myelitis, par-
ticularly in individuals of Asian or African ancestry.
There are no adequate trials of therapy for MS-
associated transverse myelitis.
A 
course of plasma exchange is indicated for severe cases 
if glucocorticoids are ineffective.
NMO is discussed in Chap.
39.
The usefulness of spinal 
fluid ACE is uncertain.
As 
in the related disorder acute disseminated encephalo-
myelitis (Chap.
Nonetheless, the two processes are often difficult to 
distinguish.
Chronic viral myelitic infections, such as that due to 
HIV, are discussed later.
Schistosomiasis is an important cause of parasitic myeli-
tis in endemic areas.
mansoni.
In some cases, coughing or straining pro-
duces leg weakness or radiating arm or shoulder pain.
A tendon reflex in the arms is 
often diminished at some level, most often at the biceps 
(C5-C6).
In individual cases, radicular, myelopathic, or 
combined signs may predominate.
Cervical spondylo-
sis and related degenerative diseases of the spine are dis-
cussed in Chap.
9.
Most 
common are fistulas located posteriorly along the surface 
of the cord or within the dura.
Most patients have incomplete sensory, 
motor, and bladder disturbances.
Pain over the dorsal spine, 
dysesthesias, or radicular pain may be present.
Less commonly, AVM disorders are intramed-
ullary rather than dural.
Spinal bruits are infrequent but should be sought at 
rest and after exercise in suspected cases.
High-resolution MRI with contrast administration 
detects many but not all AVMs (Fig.
35-6).
Endovascular embolization 
FIGURE 35-6 
Arteriovenous malformation.
Numerous punctate 
flow voids indent the dorsal and ventral spinal cord (arrow).
These represent the abnormally dilated venous plexus 
supplied by a dural arteriovenous fistula.
This patient was a 54-year-old man with a 4-year 
history of progressive paraparesis.
Approxi-
mately half of patients have mild back or leg pain.
This presentation may resemble pri-
mary progressive MS or a thoracic AVM.
A progressive myelopathy may also result from HIV 
infection (Chap.
42).
Many 
young patients acquire a cervical-thoracic scoliosis.
35-7).
FIGURE 35-7 
MRI of syringomyelia associated with a Chiari malforma-
tion.
TREATMENT Syringomyelia
Treatment of syringomyelia is generally unsatisfactory.
Obstruction of fourth 
ventricular outflow is reestablished by this procedure.
Surgery may stabilize the 
neurologic deficit, and some patients improve.
Cases due to intramedullary spinal cord 
tumor are generally managed by resection of the tumor.
Diagnosis is facili-
tated by identification of earlier attacks such as optic 
neuritis.
MRI, CSF, and evoked-response testing are 
confirmatory.
The value of 
anti-B cell therapy in primary progressive MS is under 
investigation.
MS is discussed in Chap.
39.
Low levels of serum copper are 
found and often there is also a low level of serum ceru-
loplasmin.
Many cases 
are idiopathic.
The pathophysiology and pathology of 
the idiopathic form are not known.
Ataxia of 
the legs and gait due to loss of position sense occurs in 
half of patients.
Diabetic polyradiculopathy 
may simulate tabes.
32).
Sensory symptoms and signs are 
absent or mild, but sphincter disturbances may be pres-
ent.
The onset may be as early as the first year of life or 
as late as middle adulthood.
Only symptomatic therapies 
for the spasticity are currently available.
ADRENOMYELONEUROPATHY
This X-linked disorder is a variant of adrenoleukodys-
trophy.
OTHER CHRONIC MYELOPATHIES
Primary lateral sclerosis (Chap.
Sensory function is spared.
Treatment is with surgical release.
37) 
and rare paraneoplastic myelopathies.
The latter are most 
often associated with lung or breast cancer and anti-Hu 
antibodies (Chap.
44); NMO can also be paraneoplastic 
in origin (Chap.
39).
Metastases to the cord are probably 
more common than either of these in patients with can-
cer.
Often, a cause of intrinsic myelopathy can be identi-
fied only through periodic reassessment.
Even a com-
plete high cervical cord lesion may be compatible with 
a productive life.
Bladder areflexia due to acute spinal shock or 
conus lesions is best treated by catheterization.
Patients with acute cord injury are at risk for venous 
thrombosis and pulmonary embolism.
In cases of 
persistent paralysis, anticoagulation should probably be 
continued for 3 months.
Randomized controlled 
studies indicate that gabapentin or pregabalin is useful in 
this setting.
Management of chronic pain is discussed in 
Chap.
7.
Allan  H.
17 ).
The mechanism of amnesia is not 
known.
Amnesia is discussed in  Chap.
18 .
Trauma sufficient 
to cause prolonged unconsciousness usually produces 
some degree of contusion.
A hemiparesis or gaze preference is fairly typical of 
moderately sized contusions.
Con-
tusions in the temporal lobe may cause delirium or an 
aggressive, combative syndrome.
36-1) and 
some subarachnoid bleeding.
Blood in the cerebrospinal 
fluid (CSF) due to trauma may provoke a mild inflam-
matory reaction.
17), but small ischemic-hemorrhagic lesions in 
the midbrain and thalamus are as often the cause.
FIGURE 36-1
Traumatic cerebral contusion.
Noncontrast CT scan dem-
onstrating a hyperdense hemorrhagic region in the anterior 
temporal lobe.
Consequently, 
fractures are primarily markers of the site and severity of 
injury.
Severe 
orthostatic headache results from lowered pressure in 
the spinal fluid compartment.
Most fractures are linear and extend from the point 
of impact toward the base of the skull.
The location of an intermittent leak is rarely delineated, 
and many resolve spontaneously.
Fractures of the dorsum sella cause sixth or seventh 
nerve palsies or optic nerve damage.
Delayed palsy, the mechanism of which is 
unknown, has a good prognosis.
Dizziness,  
tinnitus, and high-tone hearing loss occur from cochlear 
concussion.
26).
The severity of injury 
roughly determines the risk of future seizures.
Penetrating inju-
ries have a much higher rate of subsequent epilepsy.
Acute subdural hematoma (Fig.
Stupor or coma, hemiparesis, and unilateral pupillary 
enlargement are signs of larger hematomas.
36-3).
Epidural hematoma (Fig.
36-4)
These evolve more rapidly than subdural hematomas 
and are correspondingly more treacherous.
Most patients are unconscious 
when first seen.
Compare to Fig.
36-4.
FIGURE 36-4
Acute epidural hematoma.
CHAPTER 36
Concussion and Other Head Injuries
419 sequence.
Chronic subdural hematoma (Fig.
Headache is common but 
not invariable.
The headache fluctuates in severity, some-
times with changes in head position.
CT without contrast initially shows a low-density 
mass over the convexity of the hemisphere (Fig.
36-5).
MRI 
reliably identifies subacute and chronic hematomas.
Small hematomas are resorbed, leaving only 
the organizing membranes.
Vasovagal syncope that follows 
injury may cause undue concern.
Generalized or frontal 
headache is common in the following days.
It may be 
migrainous (throbbing and hemicranial) in nature or 
aching and bilateral.
SECTION III
Diseases of the Nervous System
420 that can be anticipated after discharge.
A cerebral contu-
sion or hematoma is usually found.
Grade 3: Any LOC, either brief (seconds) or prolonged (minutes).
On-Site Evaluation
1.
Mental status testing
     a.
Orientation—time, place, person, circumstances of injury
     b.
Concentration—digits backward, months of year in reverse order
     c.
Finger-to-nose with eyes open and closed
3.
Pupillary symmetry and reaction
4.
Romberg and tandem gait
5.
Examine immediately and at 5-min intervals.
May return to contest if exam clears within 15 min.
Grade 2: Remove from contest, cannot return for at least 1 week.
Examine at frequent intervals on sideline.
Formal neurologic 
exam the next day.
If headache or other symptoms persist for 1 week or longer, CT or MRI scan is indicated.
If imaging 
shows abnormality, player is removed from play for the season.
Neurologic exam and, when indicated, CT or MRI scan will guide subsequent management.
The American Academy of Neurology, St.
Paul, MN, 1997.
After surgical removal of hematomas, most patients 
in this category improve over weeks.
Persistent cognitive problems are 
discussed later.
Management of raised ICP, a frequent 
feature of severe head injury, is discussed in Chap.
28.
Over 85% of patients with aggregate 
scores of <5 die within 24 h.
The syndrome 
simulates asthenia and anxious depression.
Intermediate 
scores correlate with proportional chances of recovery.
Care is taken to avoid prolonged use of drugs that 
produce dependence.
Headache may initially be treated 
with acetaminophen and small doses of amitryptiline.
Vestibular exercises (Chap.
Previ-
ously energetic and resilient individuals usually have the 
best recoveries.
Lisa  M.
DeAngelis   ■    Patrick  Y.
At least 
one-half of these tumors are malignant and associated 
with a high mortality rate.
Headache may be accompanied by nau-
sea or vomiting when intracranial pressure is elevated.
Focal or lateral-
izing fi ndings include hemiparesis, aphasia, or visual 
fi eld defect.
Lateralizing symptoms such as hemipare-
sis are typically subacute and progressive.
Language diffi  culties may be mistaken for con-
fusion.
CT scan should be reserved for 
those patients unable to undergo MRI (e.g., pacemaker).
Dural metastases or a dural lymphoma 
can have a similar appearance.
In such patients a brain biopsy may be helpful 
in determining a definitive diagnosis.
Neuroimaging is the only test necessary to diagnose a 
brain tumor.
However, 
symptomatic treatments apply to brain tumors of any 
type.
Patients with brain tumors who present with seizures, 
require anticonvulsant drug therapy.
The agents 
of choice are those drugs that do not induce the hepatic 
microsomal enzyme system.
These include levetirace-
tam, topiramate, lamotrigine, valproic acid, or lacos-
amide (Chap.
26).
A small minority of patients have a family history of 
brain tumors.
Some of these familial cases are associated 
with genetic syndromes (Table 37-2).
37-1).
The majority are primary glioblastomas.
The molecular subtypes of 
medulloblastomas are also being elucidated.
Grades I and II are con-
sidered low-grade, and grades III and IV high-grade, 
astrocytomas.
Low-grade astrocytoma
These tumors occur predominantly in children and 
young adults.
Grade I astrocytomas
Pilocytic astrocytomas (WHO grade I) are the most 
common tumor of childhood.
A slash indicates one or the other or both.
Fre-
quently they appear as cystic lesions with an enhanc-
ing mural nodule.
They are potentially curable if they 
can be completely resected.
They appear as nonenhancing 
tumors with increased T2/FLAIR signal (Fig.
37-2).
They generally present in the fourth 
and fifth decades of life as variably enhancing tumors.
This lesion did not enhance.
The 
tumors appear as ring-enhancing masses with central 
necrosis and surrounding edema (Fig.
37-3).
Note 
the decreased enhancement and mass effect.
Despite optimal therapy, glioblastomas invariably 
recur.
Reirradiation is rarely 
helpful.
37-4).
Whenever feasible, patients with recur-
rent disease should be enrolled in clinical trials.
Treatment involves radiotherapy 
and temozolomide chemotherapy.
Oligodendroglioma
Oligodendrogliomas account for approximately 15–20% 
of gliomas.
Some tumors have both an oligodendroglial as 
well as an astrocytic component.
These tumors present 
similarly to grade II astrocytomas in young adults.
The 
tumors are nonenhancing and often partially calcified.
They should be treated with surgery and, if necessary, 
radiotherapy and chemotherapy.
Patients with oligoden-
drogliomas have a median survival in excess of 10 years.
They 
are more responsive to therapy than grade III astrocytomas.
Median survival of patients with AO or AOA is approxi-
mately 3–6 years.
Ependymomas
Ependymomas are tumors derived from ependymal 
cells that line the ventricular surface.
Ependy-
momas that can be completely resected are potentially 
curable.
Partially resected ependymomas will recur and 
require irradiation.
Other less common gliomas
Gangliogliomas and pleomorphic xanthoastrocytomas occur 
in young adults.
They behave as more indolent forms of 
grade II gliomas and are treated in the same way.
Brainstem 
gliomas usually occur in children or young adults.
For unclear reasons, 
its incidence is increasing, particularly in immunocom-
petent individuals.
PCNSL in immunocompetent patients usually con-
sists of diffuse large B-cell lymphomas.
The 
periventricular location and diffuse enhancement pattern are 
characteristic of lymphoma.
immunocompromised with CD4 counts of less than 
50/mL.
On contrast-enhanced MRI, PCNSL usually appears 
as a densely enhancing tumor (Fig.
37-5).
Immuno-
competent patients have solitary lesions more often 
than immunosuppressed patients.
Frequently there is 
involvement of the basal ganglia, corpus callosum, or 
periventricular region.
Stereotactic biopsy is necessary 
to obtain a histologic diagnosis.
Bone 
marrow biopsy and testicular ultrasound are occasion-
ally performed.
Durable complete responses and long-term 
survival are possible with these treatments.
As a result 
radiotherapy is frequently omitted in older patients with 
PCNSL.
At least 50% of patients will eventually develop 
recurrent disease.
In organ 
transplant recipients, reduction of immunosuppression 
may improve outcome.
They present with headache, 
ataxia, and signs of brainstem involvement.
Seeding of the CSF is common.
A major 
goal of current research is to improve survival while 
minimizing long-term complications.
PINEAL REGION TUMORS
A large number of tumors can arise in the region of the 
pineal gland.
These typically present with headache, 
visual symptoms, and hydrocephalus.
Patients may 
have Parinaud’s syndrome characterized by impaired 
upgaze and accommodation.
They are now the most common pri-
mary brain tumor, accounting for approximately 32% 
of the total.
Their incidence increases with age.
They 
tend to be more common in women and in patients 
with neurofibromatosis type 2.
They also occur more 
commonly in patients with a past history of cranial 
irradiation.
Many meningiomas are found incidentally follow-
ing neuroimaging for unrelated reasons.
They can also 
present with headaches, seizures, or focal neurologic 
deficits.
37-6).
The main differential diagnosis 
of meningioma is a dural metastasis.
Larger, symptomatic lesions 
should be resected surgically.
If complete resection is 
achieved, the patient is cured.
These treat-
ments may also be helpful in patients whose tumor has 
recurred after surgery.
Hormonal therapy and chemo-
therapy are currently unproven.
Rarer tumors that resemble meningiomas include 
hemangiopericytomas and solitary fibrous tumors.
are treated with surgery and radiotherapy but have a 
higher propensity to recur.
37-7).
The differential diagnosis includes menin-
gioma.
Very small, asymptomatic lesions can be 
observed with serial MRIs.
Larger lesions should be 
treated with surgery or stereotactic radiosurgery.
The tumor can be seen to involve the internal auditory canal.
SECTION III
Diseases of the Nervous System
432 symptoms, and the patient’s preference.
PITUITARY TUMORS (CHAP.
38)
These account for approximately 9% of primary brain 
tumors.
They can be divided into functioning and 
nonfunctioning tumors.
Treatment involves surgery, radiother-
apy, or the combination of the two.
They typically occur in children and 
young adults with a long-standing history of seizures.
If 
the seizures are refractory, surgical resection is curative.
Epidermoid cysts
These consist of squamous epithelium surrounding a 
keratin-filled cyst.
They may present with headaches, cra-
nial nerve abnormalities, seizures, or hydrocephalus.
Treatment involves surgical resection.
Unlike epidermoid cysts, these tumors usually 
have a midline location.
Symptomatic dermoid cysts 
can be treated with surgery.
Most of these disorders have an autosomal dominance 
inheritance with variable penetrance.
It is an autosomal dominant dis-
order with full penetrance.
As with NF1, approxi-
mately half the cases arise from new mutations.
These patients 
may also have posterior subcapsular lens opacities and 
retinal hamartomas.
Patients frequently require anticonvulsants 
for seizures.
SEGAs often do not need treatment but 
occasionally require surgical resection.
There is emerg-
ing evidence that mTOR inhibitors may have activity  
in SEGAs.
Other tumor types such as ovarian and esophageal car-
cinoma rarely metastasize to the brain.
37-8).
Enhancement may be in a ring pat-
tern or diffuse.
Note the diffuse 
enhancement pattern and absence of central necrosis.
Brain metastases are single in 
approximately one-half of patients and multiple in the 
other half.
However, it is not curative.
Median survival is only 4–6 months.
Surgical resection can afford rapid symptomatic 
improvement and prolonged survival.
CHEMOTHERAPY Chemotherapy is rarely use-
ful for brain metastases.
of patients with brain metastases because they have a 
known systemic cancer.
37-9).
Demonstration of tumor cells in the CSF is defini-
tive and often considered the gold standard.
CSF cytologic exami-
nation is most useful in hematologic malignancies.
Nodules along the dorsal 
surface of the spinal cord (A) and cauda equina (B) are seen.
but is useful when present.
Systemic chemotherapy with agents that 
can penetrate the blood-CSF barrier may be helpful.
In addition, impaired CSF flow 
dynamics can compromise intrathecal drug delivery.
However, it 
compromises delivery of chemotherapy into the CSF.
The thoracic spine is affected 
most commonly, followed by the lumbar and then cer-
vical spine.
Leg weakness is 
seen in about 50% of patients as is sensory dysfunction.
Sphincter problems are present in about 25% of patients 
at diagnosis.
37-10).
Con-
trast is not needed to identify spinal or epidural lesions.
Any patient with cancer who has severe back pain 
should undergo an MRI.
TREATMENT Epidural Metastasis
Epidural metastasis requires immediate treatment.
Patients generally fare well if 
treated before there is severe neurologic deficit.
Acute toxicity
Acute cerebral toxicity usually occurs during RT to the 
brain.
There is no acute RT toxicity that affects the 
spinal cord.
Pseudoprogression can resolve on 
its own or, if very symptomatic, may require resection.
Leukoencephalopathy is seen most commonly after 
WBRT as opposed to focal RT.
Increased age is a 
risk factor for leukoencephalopathy but not for radia-
tion necrosis.
Necrosis appears to depend on an as yet 
unidentified predisposition.
The peripheral nervous system is relatively resistant 
to RT toxicities.
Peripheral nerves are rarely affected 
by RT, but the plexus is more vulnerable.
Radiation plexopathy is also more commonly associated 
with lymphedema of the affected limb.
Sensory loss and 
weakness are seen in both.
The taxanes also cause a predom-
inately sensory neuropathy.
Agents such as bortezomib 
and thalidomide also cause neuropathy.
Encephalopathy and seizures are common toxici-
ties from chemotherapeutic drugs.
Fludarabine also causes a 
severe global encephalopathy that may be permanent.
Bevacizumab and other anti-VEGF agents can cause 
posterior reversible encephalopathy syndrome.
Cispla-
tin can cause hearing loss and less frequently vestibular 
dysfunction.
Shlomo  Melmed   ■    J.
Abbreviations:  M, male; F, female.
For other abbreviations, see text.
Totowa, NJ, Humana, 
2005.
440
SECTION III
Diseases of the Nervous System
an array of specific hypothalamic releasing factors.
Each 
of these pituitary hormones elicits specific responses in 
peripheral target tissues.
38-1).
Pituitary tumors cause 
characteristic hormone-excess syndromes.
Hormone 
deficiency may be inherited or acquired.
Peripheral hormones feed back to regu-
late hypothalamic and pituitary hormones.
For abbreviations, 
see text.
38-2).
Posterior pituitary hormones are 
derived from direct neural extensions.
38-3).
The posterior pituitary is supplied by the inferior 
hypophyseal arteries.
Autosomal dominant or 
recessive Pit-1 mutations cause combined GH, PRL, 
and TSH deficiencies.
These patients usually present 
with growth failure and varying degrees of hypothy-
roidism.
The pituitary may appear hypoplastic on MRI.
Prop-1 is expressed early in pituitary development 
and appears to be required for Pit-1 function.
Because of 
gonadotropin deficiency, these individuals do not enter 
puberty spontaneously.
In some cases, the pituitary 
gland is enlarged.
TPIT mutations result in ACTH defi-
ciency associated with hypocortisolism.
Genetic 
abnormalities, in addition to KAL mutations, also can 
cause isolated GnRH deficiency.
GnRH deficiency prevents 
progression through puberty.
Females present with primary amenor-
rhea and failure of secondary sexual development.
Central diabetes insipidus may or may not be associ-
ated.
GnRH deficiency occurs in 75% of males and 
half of affected females.
Retinal degeneration begins in 
early childhood, and most patients are blind by age 30.
Multiple somatic 
defects also involve the skull, eyes, ears, hands, and feet.
Diminished hypothalamic oxytocin- and vasopressin- 
producing nuclei have been reported.
Consequently, diabetes insipidus occurs 
in half of patients with these disorders.
Growth retar-
dation is seen if attenuated GH secretion occurs before 
pubertal epiphyseal closure.
Hypogonadotropic hypo-
gonadism and hyperprolactinemia are also common.
Most 
patients manifest symptoms of progressive mass effects 
with headache and visual disturbance.
The erythro-
cyte sedimentation rate often is elevated.
Therefore, severe 
ophthalmoplegia or visual deficits are indications for 
early surgery.
Hypopituitarism is very common after 
apoplexy.
Empty sella
A partial or apparently totally empty sella is often an 
incidental MRI finding.
Hypopi-
tuitarism, however, may develop insidiously.
TSH and ACTH deficiency usually develop later in 
the course of pituitary failure.
PRL deficiency causes failure 
of lactation.
Provocative tests may be required to assess pituitary 
reserve (Table 38-3).
Effective dosage schedules are out-
lined in Table 38-4.
Note: For abbreviations, see text.
Note: For abbreviations, see text.
Note: For abbreviations, see text.
responsiveness to physiologic inhibitory pathways.
Hor-
mone production does not always correlate with tumor 
size.
True pituitary carcinomas with documented 
extracranial metastases are exceedingly rare.
Several etiologic genetic events have been implicated 
in the development of pituitary tumors.
Compelling evidence also favors growth factor pro-
motion of pituitary tumor proliferation.
Acromeg-
aly occurs in about 20% of these patients.
A subset of 
patients have mutations in the R1α regulatory subunit 
of protein kinase A (PRKAR1A).
The Gsα mutations occur postzygotically, leading 
to a mosaic pattern of mutant expression.
The disorder is associated with LOH at a chromosome 
11q13 locus distinct from that of MENIN.
Craniopharyngiomas are often large, cystic, and 
locally invasive.
About half of affected children present with 
growth retardation.
Most patients require lifelong pituitary hormone 
replacement.
Rarely, hydrocephalus develops.
Cyst contents range from CSF-like fluid to 
mucoid material.
Arachnoid cysts are rare and generate an 
MRI image that is isointense with cerebrospinal fluid.
Mucinous material may be obtained by fine-needle 
aspiration.
Meningiomas typically enhance on MRI and may 
show evidence of calcification or bony erosion.
Menin-
giomas may cause compressive symptoms.
Histiocytosis X includes a variety of syndromes asso-
ciated with foci of eosinophilic granulomas.
Rarely, the pituitary 
stalk may be involved.
Pituitary metastases occur in ∼3% of cancer patients.
Bloodborne metastatic deposits are found almost exclu-
sively in the posterior pituitary.
Rarely, pituitary stalk involvement results 
in anterior pituitary insufficiency.
Primary or metastatic lymphoma, leukemias, and plas-
macytomas also occur within the sella.
These tumors may 
overexpress hypothalamic neuropeptides, including 
GnRH, GHRH, and CRH.
Adults 
have more aggressive tumors; about a third are associ-
ated with neurofibromatosis.
Brain germ cell tumors may arise within the sellar 
region.
They rarely metastasize.
Many 
patients are GH-deficient with short stature.
Acute hyperthermia usually 
is due to a hemorrhagic insult, but poikilothermia may 
also occur.
Central disorders of thermoregulation result 
from posterior hypothalamic damage.
These patients are predisposed to cardiac arrhythmias, 
hypertension, and gastric erosions.
Bony inva-
sion may occur as well.
Bony erosion is 
rare, as is direct brain compression.
Microadenomas may present 
with headache.
34).
The stalk should be midline and vertical.
CT scan is reserved to define the extent of bony erosion 
or the presence of calcification.
38-4).
images.
If hormone 
hypersecretion is evident, specific therapies are indi-
cated.
21).
Homonymous cuts reflect post-
chiasmal lesions, and monocular field cuts prechiasmal 
lesions.
Loss of red perception is an early sign of optic 
tract pressure.
Early diagnosis reduces the risk of blind-
ness, scotomas, or other visual disturbances.
Additional 
hormonal evaluation may be indicated based on the 
results of these tests.
Occasionally, ultrastructural 
assessment by electron microscopy is required for diagnosis.
Most pituitary tumors 
are benign and slow-growing.
Thus, lifelong 
management and follow-up are necessary for these 
patients.
Ideally, adenoma recurrence should be pre-
vented.
38-5).
and 
fasting plasma 
cortisol mea-
sured at 8 A.M.
Operative mor-
tality rate is about 1%.
Transient diabetes insipidus and 
hypopituitarism occur in up to 20% of patients.
CSF leaks occur in 4% of 
patients.
Permanent side effects are rare after surgery 
for microadenomas.
A total of <50 Gy 
(5000 rad) is given as 180-cGy (180-rad) fractions divided 
over about 6 weeks.
In contrast, PRL- and GH-secreting tumor tissues 
are amenable to medical therapy.
Side Effects In the short term, radiation may cause 
transient nausea and weakness.
Alopecia and loss of 
taste and smell may be more long-lasting.
The use of stereotactic radiother-
apy may reduce damage to adjacent structures.
For prolacti-
nomas, dopamine agonists are the treatment of choice.
For acromegaly, somatostatin analogues and GH recep-
tor antagonists are indicated.
PRL is synthesized in lactotropes, 
which constitute about 20% of anterior pituitary cells.
These transient functional changes 
in the lactotrope population are induced by estrogen.
SECRETION
Normal adult serum PRL levels are about 10–25 μg/L 
in women and 10–20 μg/L in men.
Peak serum PRL 
levels (up to 30 μg/L) occur between 4:00 and 6:00 A.M.
The circulating half-life of PRL is about 50 min.
Pituitary dopamine type 
2 (D2) receptors mediate inhibition of PRL synthesis 
and secretion.
Breast suckling activates neu-
ral afferent pathways in the hypothalamus that induce 
PRL release.
With time, suckling-induced responses 
diminish and interfeeding PRL levels return to normal.
In men, attenuated LH 
secretion leads to low testosterone levels and decreased 
spermatogenesis.
These hormonal changes decrease libido 
and reduce fertility in patients with hyperprolactinemia.
Pregnancy and lactation are the important physi-
ologic causes of hyperprolactinemia.
Sleep-associated 
hyperprolactinemia reverts to normal within an hour of 
awakening.
Nipple stimulation and sexual orgasm also 
may increase PRL.
Chronic renal failure elevates PRL by decreasing 
peripheral clearance.
Plurihormonal adenomas (including GH 
and ACTH tumors) may hypersecrete PRL directly.
Hormonal agents that induce PRL 
include estrogens and TRH.
If hyperprolac-
tinemia develops before menarche, primary amenorrhea 
results.
Galac-
torrhea is present in up to 80% of hyperprolactinemic 
women.
Although usually bilateral and spontaneous, it 
may be unilateral or expressed only manually.
Patients 
also may complain of decreased libido, weight gain, and 
mild hirsutism.
Physiologic hypersecretion
Pregnancy
Lactation
Chest wall stimulation
Sleep
Stress
II.
Pituitary hypersecretion
Prolactinoma
Acromegaly
IV.
455
 
CHAPTER 38
Neurologic Disorders of the Pituitary and Hypothalamus
and oligospermia.
True galactorrhea is uncommon in 
men with hyperprolactinemia.
Some 
of these patients may harbor small microadenomas 
below visible MRI sensitivity (∼2 mm).
Galactorrhea may occur 
spontaneously, or it may be elicited by nipple pressure.
Acromegaly is associated with galactorrhea in about 
one-third of patients.
Both false-
positive and false-negative results may be encountered.
Hypothyroidism should be excluded by measuring TSH 
and T4 levels.
Granulomatous infiltrates occasionally 
respond to glucocorticoid administration.
In patients 
with irreversible hypothalamic damage, no treatment 
may be warranted.
Microadenomas are classified as <1 cm in diam-
eter and usually do not invade the parasellar region.
PRL lev-
els remain stable in most patients, reflecting the slow 
growth of these tumors.
About 5% of microadenomas 
progress in the long term to macroadenomas.
Presentation and diagnosis
Women usually present with amenorrhea, infertility, 
and galactorrhea.
For this reason, 
an MRI should be performed in all patients with hyper-
prolactinemia.
MRI, magnetic resonance imaging; PRL, prolactin.
enlargement; these patients should be monitored by 
regular serial PRL and MRI measurements.
38-6).
A nor-
malized PRL level does not ensure reduced tumor size.
However, tumor shrinkage usually is not seen in those 
who do not respond with lowered PRL levels.
Dopamine agonists 
suppress PRL secretion and synthesis as well as lacto-
trope cell proliferation.
These patients should be moni-
tored carefully for evidence of prolactinoma recurrence.
D2 receptor gene mutations in the pituitary 
have not been reported.
Cabergoline normalizes PRL and 
shrinks ∼70% of macroprolactinomas.
Cabergoline also may be effective in patients resistant to 
bromocriptine.
Adverse effects and drug intolerance are 
encountered less commonly than with bromocriptine.
Because it is short-acting, 
the drug is preferred when pregnancy is desired.
Most 
patients are controlled with a daily dose of ≤7.5 mg  
(2.5 mg tid).
These symptoms may persist in some 
patients.
In general, fewer side effects are reported with 
cabergoline.
Nonetheless, most 
authorities recommend strategies to minimize fetal 
exposure to the drug.
Surgical decompression may be indicated 
if vision is threatened.
Five distinct 
genes encode GH and related proteins.
SECRETION
GH secretion is controlled by complex hypothalamic 
and peripheral factors.
GHRH is a 44-amino-acid 
hypothalamic peptide that stimulates GH synthesis and 
release.
Surface receptors on the somatotrope regulate GH 
synthesis and secretion.
Inactivating mutations of the GHRH receptor cause 
profound dwarfism (discussed later).
These changes are paralleled by an 
age-related decline in lean muscle mass.
Integrated 24-h GH secretion is higher in women and 
is also enhanced by estrogen replacement.
GH secretion is profoundly influenced by nutritional 
factors.
β-Adrenergic blockage 
induces basal GH and enhances GHRH- and insulin-
evoked GH release.
ACTION
The pattern of GH secretion may affect tissue responses.
The 
liver and cartilage contain the greatest number of GH 
receptors.
A GH receptor antagonist (pegvisomant) is approved for 
treatment of acromegaly.
GH stimulates epiphyseal 
prechondrocyte differentiation.
The liver is the major source of circulating IGF-I.
GH deficiency and malnutrition usually are asso-
ciated with low IGFBP3 levels.
Serum IGF-I concentrations are profoundly affected 
by physiologic factors.
IGF-I concentrations are 
higher in women than in men.
IGF-I physiology
IGF-I has been approved for use in patients with GH-
resistance syndromes.
Longer-term subcutaneous IGF-I injections 
enhance protein synthesis and are anabolic.
Although 
bone formation markers are induced, bone turnover also 
may be stimulated by IGF-I.
Avascular 
femoral head necrosis has been reported.
Chronic excess 
IGF-I administration presumably would result in features 
of acromegaly.
Malnutrition 
impairs chondrocyte activity and reduces circulating 
IGF-I and IGFBP3 levels.
Linear bone growth rates are very high in infancy and 
are pituitary-dependent.
Peak 
growth rates occur during midpuberty when bone age is 
12 (girls) or 13 (boys).
Growth hormone insensitivity
This is caused by defects of GH receptor structure or 
signaling.
Very rarely, defective IGF-I, IGF-I receptor, or IGF-I 
signaling defects are also encountered.
Circulating GH receptor anti-
bodies may rarely cause peripheral GH insensitivity.
A nurturing environment restores growth rates.
Random GH 
measurements do not distinguish normal children from 
those with true GH deficiency.
Adequate adrenal and 
thyroid hormone replacement should be assured before 
testing.
Pituitary MRI 
may reveal pituitary mass lesions or structural defects.
The sequential order of hormone loss is usually 
GH → FSH/LH → TSH → ACTH.
Bone mineral content is reduced, 
with resultant increased fracture rates.
For other abbrevia-
tions, see text.
testing should be selected carefully on the basis of well-
defined criteria.
A significant proportion (∼25%) of truly GH-defi-
cient adults have low-normal IGF-I levels.
38-7).
Women 
require higher doses than men, and elderly patients 
require less GH.
Lumbar spine bone mineral 
density increases, but this response is gradual (>1 year).
Patients with type 2 
diabetes mellitus initially develop further insulin resis-
tance.
Headache, increased intracranial pres-
sure, hypertension, and tinnitus occur rarely.
To date, development of these potential side 
effects does not appear significant.
IGF, insulin-like growth factor.
Abbreviations: GH, growth hormone; PRL, prolactin.
The most common cause of GHRH-
mediated acromegaly is a chest or abdominal carcinoid 
tumor.
Excessive GHRH also may be elabo-
rated by hypothalamic tumors, usually choristomas or 
neuromas.
38-8).
The most significant clinical impact of GH excess 
occurs with respect to the cardiovascular system.
Laboratory investigation
Age- and sex-matched serum IGF-I levels are elevated 
in acromegaly.
Their clinical features began to 
diverge at the age of approximately 13 years.
When newer ultrasensitive GH assays are used, 
normal nadir GH levels are even lower (<0.05 μg/L).
About 20% of patients exhibit a paradoxical GH rise 
after glucose.
PRL should be measured, as it is elevated 
in ∼25% of patients with acromegaly.
Surgical resection of GH-secreting adenomas is the 
initial treatment for most patients (Fig.
38-9).
Irradiation is also relatively ineffective in 
normalizing IGF-I levels.
Somatostatin analogues 
may be required while awaiting the full benefits of 
radiotherapy.
Mandibular surgical 
repair may be indicated.
Soft tissue swelling 
improves immediately after tumor resection.
GH levels 
return to normal within an hour, and IGF-I levels are 
normalized within 3–4 days.
Octreotide acetate is 
an eight-amino-acid synthetic somatostatin analogue.
In 
contrast to native somatostatin, the analogue is relatively 
resistant to plasma degradation.
Fewer 
than 10% of patients do not respond to the analogue.
Side Effects Somatostatin analogues are well toler-
ated in most patients.
GH lev-
els, however, remain elevated as the drug does not have 
antitumor actions.
Side effects include reversible liver 
enzyme elevation, lipodystrophy, and injection site pain.
Tumor size should be monitored by MRI.
An advantage of radiation is 
that patient compliance with long-term treatment is 
not required.
Tumor mass is reduced, and GH levels are 
attenuated over time.
In summary, surgery is the preferred primary treat-
ment for GH-secreting microadenomas (Fig.
38-9).
GH, growth hormone; CNS, 
central nervous system; IGF, insulin-like growth factor.
and reaching a 
nadir about midnight.
Adrenal glucocorticoid secre-
tion, which is driven by ACTH, follows a parallel 
diurnal pattern.
The 
resulting cortisol elevation restrains the inflammatory 
response and enables host protection.
Rarely, TPIT or POMC mutations result in 
primary ACTH deficiency.
Some authorities 
advocate lower maintenance doses in an effort to avoid 
cushingoid side effects.
Doses should be increased sever-
alfold during periods of acute illness or stress.
ACTH-producing adenomas account for about 
10–15% of all pituitary tumors.
However, macroadenomas 
also are seen while some ACTH-expressing adenomas 
are clinically silent.
Cushing’s disease is 5–10 times 
more common in women than in men.
These pitu-
itary adenomas exhibit unrestrained ACTH secretion, 
with resultant hypercortisolemia.
Hematopoietic features of hypercortisolism 
include leukocytosis, lymphopenia, and eosinopenia.
Immune suppression includes delayed hypersensitivity.
In children and in 
young females, early osteoporosis may be particularly 
prominent.
Measurement of 24-h urine free cortisol (UFC) is a 
precise and cost-effective screening test.
Totowa, NJ, Humana, 1997.
The sensitivity of this test is >95%, with very 
rare false-positive results.
False-negative results may be 
encountered in patients with aberrant venous drain-
age.
Iatrogenic Cushing’s syndrome is excluded by history.
38-10).
The remission 
rate for this procedure is ∼80% for microadenomas but 
<50% for macroadenomas.
ACTH, adrenocorti-
cotropin hormone; MRI, magnetic resonance imaging.
*Not 
usually required.
tion with pituitary irradiation to block adrenal effects of 
persistently high ACTH levels.
Side effects include nausea and vomiting, rash, 
and exacerbation of acne or hirsutism.
It also may lead to hypoaldosteronism.
Glucocorticoid insuf-
ficiency is a potential side effect of agents used to block 
steroidogenesis.
The use of steroidogenic inhibitors has decreased 
the need for bilateral adrenalectomy.
Like TSH and hCG, LH and FSH are glycopro-
tein hormones that consist of α and β subunits.
Gonadotropin synthesis and release are dynami-
cally regulated.
38-3).
Estrogens act at 
both the hypothalamus and the pituitary to modulate 
gonadotropin secretion.
Progesterone slows GnRH pulse frequency but 
enhances gonadotropin responses to GnRH.
Inhibin selectively suppresses FSH, whereas activin stimu-
lates FSH synthesis.
In women, FSH regulates ovar-
ian follicle development and stimulates ovarian estrogen 
production.
LH mediates ovulation and maintenance 
of the corpus luteum.
Osteoporosis occurs in both untreated 
hypogonadal women and men.
Men have reduced sperm counts.
Normal 
responses vary according to menstrual cycle stage, age, 
and sex of the patient.
Generally, LH levels increase 
about threefold, whereas FSH responses are less pro-
nounced.
Testosterone gels are also avail-
able.
Gonadotropin 
therapy is used for ovulation induction.
Some adenomas 
express α subunits without FSH or LH.
PRL levels are usually slightly increased, also because 
of stalk compression.
Free α subunit levels may be elevated 
in 10–15% of patients with nonfunctioning tumors.
GnRH testing, how-
ever, is not helpful for making the diagnosis.
38-11).
Within 5–6 years 
after successful surgical resection, ∼15% of nonfunctioning 
tumors recur.
Radiotherapy may be 
deferred if no postoperative residual mass is evident.
TSH is structurally 
related to LH and FSH.
It shares a common α subunit 
with these hormones but contains a specific TSH β sub-
unit.
Consequently, single deter-
minations of TSH suffice to assess its circulating levels.
Moreover, free thyroid hormone levels are normal in 
these disorders, most of which are familial.
Total resection is not often achieved as 
most of these adenomas are large and locally invasive.
Stephen  L.
Hauser   ■    Douglas  S.
MS affects ∼350,000 individuals in 
the United States and 2.5 million individuals world-
wide.
39-1 ).
Conduction block 
occurs when the nerve impulse is unable to traverse 
the demyelinated segment.
Immunoreg-
ulatory effects of vitamin D could explain this apparent 
relationship.
A second factor seems to occur during adolescence.
Moreover, the fact that 
concentrated at the nodes) redistribute along the 
naked axon (Fig.
39-1).
Conduction 
block may be incomplete, affecting high- but not low- 
frequency volleys of impulses.
Epidemiology
MS is approximately threefold more common in women 
than men.
A.
B.
Two 
different populations of proinflammatory T cells are 
likely to mediate autoimmunity in MS.
High circu-
lating levels of IL-17 may also be a marker of a more 
severe course of MS.
At this time, however, 
a causal role for EBV is not definitively established.
Despite this, the influence of genetics on MS pathogen-
esis is substantial.
CLINICAL MANIFESTATIONS
The onset of MS may be abrupt or insidious.
Examination often reveals evidence of 
neurologic dysfunction, often in asymptomatic locations.
For example, a patient may present with symptoms in 
one leg but signs in both.
Exercise-induced weakness is a characteristic symp-
tom of MS.
The weakness is of the upper motor neu-
ron type (Chap.
12-2).
lesions to occur, both in experimental models and in 
human MS.
Thus, early in MS 
most disease activity is clinically silent.
Constipation occurs in >30% of patients.
Fecal urgency 
or bowel incontinence is less common (15%) but can be 
socially debilitating.
Cognitive dysfunction sufficient to impair activ-
ities of daily living is rare.
Facial weakness due to a lesion in the pons may resem-
ble idiopathic Bell’s palsy (Chap.
34).
11).
Hearing loss may also occur in MS but is uncommon.
12) is commonly associated with 
spontaneous and movement-induced muscle spasms.
More than 30% of MS patients have moderate to severe 
spasticity, especially in the legs.
This is often accom-
panied by painful spasms interfering with ambulation, 
work, or self-care.
These symptoms can 
be mild or may progress to severe visual loss.
Rarely, 
there is complete loss of light perception.
Visual symp-
toms are generally monocular but may be bilateral.
Periorbital pain (aggravated by eye movement) often 
precedes or accompanies the visual loss.
An afferent 
pupillary defect (Chap.
21) is usually present.
Fundu-
scopic examination may be normal or reveal optic disc 
swelling (papillitis).
Pallor of the optic disc (optic atro-
phy) commonly follows ON.
21).
Prominent 
nystagmus is often observed in the abducting eye, along 
with a small skew deviation.
A bilateral INO is partic-
ularly suggestive of MS.
It 
is often accompanied by a bandlike sensation of tightness 
around the torso.
Pain is a common symptom of MS, 
experienced by >50% of patients.
Pain can occur any-
where on the body and can change locations over time.
Ataxia usually manifests as cerebellar tremors (Chap.
31).
CHAPTER 39
Multiple Sclerosis and Other Demyelinating Diseases
479
1.
Secondary progressive MS (SPMS) always begins as 
RRMS (Fig.
39-2B).
SPMS produces a greater 
amount of fixed neurologic disability than RRMS.
SPMS appears to represent a late stage of the same 
underlying illness as RRMS.
1.
Primary progressive MS (PPMS) accounts for ∼15% of 
cases.
39-2C).
Despite these differences, PPMS appears 
to represent the same underlying illness as RRMS.
2.
Progressive/relapsing MS (PRMS) overlaps PPMS and 
SPMS and accounts for ∼5% of MS patients.
39-2D).
(see “Acute Attacks or Initial Demyelinating Episodes,” 
later).
Such heat-related symptoms probably result from 
transient conduction block (discussed earlier).
Rarely, 
it radiates into the arms.
It is generally self-limited but 
may persist for years.
They may be precipitated by 
hyperventilation or movement.
Trigeminal neuralgia, hemifacial spasm, and glossopharyn-
geal neuralgia (Chap.
It results 
from lesions of the corticobulbar tracts or brainstem 
course of the facial nerve.
DISEASE COURSE
Four clinical types of MS have been described (Fig.
39-2):
1.
There is often complete recov-
ery over the ensuing weeks to months (Fig.
39-2A).
Between attacks, patients are neurologically stable.
A.
Relapsing/
remitting MS.
B.
Secondary progressive MS.
C.
Primary pro-
gressive MS.
D.
Progressive/relapsing MS.
SECTION III
Diseases of the Nervous System
480 neurologic examination.
DIAGNOSIS
There is no definitive diagnostic test for MS.
Symptoms must last for >24 h and occur as distinct 
episodes that are separated by a month or more.
Lesions are multifocal within the brain, 
brainstem, and spinal cord.
Such leakage occurs 
AB
CD
FIGURE 39- 3 
MRI findings in MS.
A.
B.
Lesions in the anterior corpus callosum 
are frequent in MS and rare in vascular disease.
C.
D.
OCBs 
are detected by agarose gel electrophoresis.
Two or more 
OCBs are found in 75–90% of patients with MS.
DIFFERENTIAL DIAGNOSIS
No single clinical sign or test is diagnostic of MS.
Different criteria for the 
use of MRI in the diagnosis of MS have been proposed 
(Table 39-3).
These tests provide 
the most information when the pathways studied are 
clinically uninvolved.
Abnormalities on one or 
more EP modalities occur in 80–90% of MS patients.
The total CSF protein is usually normal or 
slightly elevated.
CHAPTER 39
Multiple Sclerosis and Other Demyelinating Diseases
483 20 years is ∼80%.
Conversely, with a normal brain MRI, 
the likelihood of developing MS is <20%.
Death can occur dur-
ing an acute MS attack, although this is distinctly rare.
More commonly, death occurs as a complication of MS 
(e.g., pneumonia in a debilitated individual).
Death can 
also result from suicide.
Glucocorticoids are  
used to manage either first attacks or acute exacerbations.
The likelihood of having benign MS is 
thought to be <20%.
Relative efficacy can only be 
determined from a non-biased head-to-head clinical 
trial.
Interferon-a IFN-β is a class I interferon originally 
identified by its antiviral properties.
IFN-β should be considered in patients with either 
RRMS or SPMS with superimposed relapses.
In patients 
with SPMS but without relapses, efficacy has not been 
established.
IFN-β-1a 
(Avonex), 30 μg, is administered by intramuscular injec-
tion once every week.
IFN-β-1a (Rebif), 44 μg, is admin-
istered by subcutaneous injection three times per week.
IFN-β-1b (Betaseron), 250 μg, is administered by subcu-
taneous injection every other day.
Rarely, more 
severe hepatotoxicity may occur.
In 
any event, side effects to IFN-β therapy usually subside 
with time.
Whether treatment provides any long-term benefit 
on the course of the illness is less clear.
Therefore, mild 
attacks are often not treated.
Physical and occupational 
therapy can help with mobility and manual dexterity.
Outpatient treatment is almost 
always possible.
However, the cost is high, and conclu-
sive evidence of efficacy is lacking.
An eighth, cladrib-
ine (Leustatin), is currently awaiting an FDA decision 
on its approval.
Glatiramer acetate, 20 mg, is administered by 
subcutaneous injection every day.
Injection-site reactions 
also occur with glatiramer acetate.
This systemic 
reaction is unpredictable, brief (duration <1 h), and tends 
not to recur.
outcomes of disability and relapse rate.
The reason for 
this clinical-radiologic dissociation is unresolved.
For-
tunately, however, there are few situations where mea-
surement of antibodies is necessary.
Glatiramer acetate reduces the attack rate (whether 
measured clinically or by MRI) in RRMS.
Therefore, glatiramer acetate should be considered 
in RRMS patients.
Its usefulness in progressive disease is 
entirely unknown.
dNew lesions seen on T2-weighted MRI.
ep = .001.
fp = .01.
gp = .05.
hNot FDA-approved at time of publication.
Possible side effects include hepatic toxicity, nau-
sea, and hair thinning.
Mitoxantrone received (from the FDA) 
the broadest indication of any current treatment for MS.
As a result, a cumula-
tive dose >140 mg/m2 is not recommended.
Fur-
thermore, >40% of women will experience amenorrhea, 
which may be permanent.
Its usefulness in the treat-
ment of progressive disease has not been studied.
Natalizumab, 300 μg, is administered by IV infusion 
each month.
Treatment with natalizumab is, in general, well 
tolerated.
The major concern with long-term treatment is the 
risk of PML.
It 
is well tolerated, and the oral dosing schedule makes it 
very convenient for patients.
However, as with any new therapy, long-term safety 
remains to be established.
Fingolimod, 0.5 
mg, is administered orally each day.
Treatment with fin-
golimod is also, in general, well tolerated.
IFN-β is probably ineffective in patients 
with SPMS who are not having acute attacks.
39-4).
The value of 
combination therapy is unknown.
IFN-β1a, or
2.
IFN-β1b, or
3.
Glatiramer acetate or
4.
IFN-β1a, or
2.
IFN-β1b
Intolerant or
poor response
1.
Mitoxantrone
2.
Azathioprine
3.
Methotrexate
4.
Pulse cyclophosphamide
5.
IVIg
6.
Ataxia/tremor is often intractable.
Wrist weights occasionally reduce tremor in the arm or 
hand.
Thalamotomy or deep-brain stimulation has been 
tried with mixed success.
Spasticity and spasms may improve with physical ther-
apy, regular exercise, and stretching.
Avoidance of triggers 
(e.g., infections, fecal impactions, bed sores) is extremely 
important.
Therefore, 
no evidence-based recommendation can be made with 
regard to its use in this setting.
PPMS No therapies have been convincingly shown 
to modify the course of PPMS.
A phase III clinical trial 
of glatiramer acetate in PPMS was stopped because of 
lack of efficacy.
A trial of mitoxantrone in 
PPMS is ongoing.
Patients should 
avoid costly or potentially hazardous unproven treat-
ments.
Many such treatments lack biologic plausibility.
PROMISING EXPERIMENTAL THERAPIES  
Numerous clinical trials are currently underway.
If these approaches fail, patients should be referred to a 
comprehensive pain management program.
Bladder dysfunction management is best guided by 
urodynamic testing.
Evening fluid restriction or fre-
quent voluntary voiding may help detrusor hyperreflexia.
Coadministration of pseu-
doephedrine (30–60 mg) is sometimes beneficial.
Loss of reflex bladder wall contraction may 
respond to bethanechol (30–150 mg/d).
However, both 
conditions often require catheterization.
Urinary tract infections should be treated promptly.
Patients with large postvoid residual urine volumes are 
predisposed to infections.
Prevention by urine acidifi-
cation (with cranberry juice or vitamin C) inhibits some 
bacteria.
Intermittent catheterization may 
help to prevent recurrent infections.
Treatment of constipation includes high-fiber diets 
and fluids.
Natural or other laxatives may help.
Fecal 
incontinence may respond to a reduction in dietary fiber.
Depression should be treated.
Patients with frequent nocturia may benefit from anti-
cholinergic medication at bedtime.
Cognitive problems may respond to the cholinester-
ase inhibitor donepezil hydrochloride (10 mg/d).
Heat sensitivity may respond to heat avoidance, air-
conditioning, or cooling garments.
Sexual dysfunction may be helped by lubricants to aid 
in genital stimulation and sexual arousal.
In contrast to MS, progressive 
symptoms do not occur in NMO.
ADEM is more common in children than adults.
Infec-
tion with measles virus is the most common antecedent 
(1 in 1000 cases).
Modern vaccines that do 
not require viral culture in CNS tissue have reduced the 
ADEM risk.
Attempts to demonstrate 
direct viral invasion of the CNS have been unsuccessful.
or mixed connective tissue disease.
Rare cases 
appear to be paraneoplastic and associated with breast, 
lung, or other cancers.
NMO is often idiopathic, how-
ever.
Seropositive patients have a very high 
risk for future relapses.
Typically, there are no remissions.
When acute MS presents as a solitary, usually cavitary, 
lesion, a brain tumor is often suspected.
In such cases, a 
brain biopsy is usually required to establish the diagnosis.
An antibody-mediated process appears to be responsible 
for most cases.
Fever reappears, and 
headache, meningismus, and lethargy progressing to coma 
may develop.
Seizures are common.
In ADEM due to chickenpox, cerebellar 
involvement is often conspicuous.
CSF protein is mod-
estly elevated (0.5–1.5 g/L [50–150 mg/dL]).
Lympho-
cytic pleocytosis, generally 200 cells/μL, occurs in 80% 
of patients.
Transient CSF oligoclonal 
banding has been reported.
The simultaneous onset of dis-
seminated symptoms and signs is common in ADEM and 
rare in MS.
Similarly, meningismus, drowsiness, coma, or 
seizures suggest ADEM rather than MS.
By 
contrast, oligoclonal bands in the CSF are more common 
in MS.
The prognosis reflects 
the severity of the underlying acute illness.
Children who recover may have persistent sei-
zures and behavioral and learning disorders.
Karen  L.
Roos   ■    Kenneth  L.
APPROACH  TO  THE
PATIENT 
Meningitis, Encephalitis, Brain Abscess,
 and Empyema 
  ( Fig.
Kernig’s and Brudzinski’s 
signs are also classic signs of meningeal irritation.
Immunocompromised?
History of recent head trauma, known
  cancer, sinusitis?
Haemophilus 
influenzae type b accounts for <10% of cases of bacterial 
meningitis in most series.
N.
meningitidis is the causative 
organism of recurring epidemics of meningitis every 
8 to 12 years.
ETIOLOGY
S.
The mortality rate remains 
∼20% despite antibiotic therapy.
The incidence of meningitis due to N.
In some patients the disease 
is fulminant, progressing to death within hours of symp-
tom onset.
Gram-negative meningitis 
can also complicate neurosurgical procedures, particu-
larly craniotomy.
aureus, Haemophilus sp., 
and Enterobacteriaceae.
Meningitis complicating endo-
carditis may be due to viridans streptococci, S.
aureus, S.
Group B streptococcus, or S.
L.
Infection is acquired by 
ingesting foods contaminated by Listeria.
The frequency of H.
More frequently, H.
influenzae causes meningitis 
in unvaccinated children and older adults, and non-b 
H.
influenzae is an emerging pathogen.
PATHOPHYSIOLOGY
The most common bacteria that cause meningitis,  
S.
pneumoniae and N.
meningitidis, initially colonize the 
nasopharynx by attaching to nasopharyngeal epithelial 
cells.
Some bacteria, such as 
S.
40-2).
40-2).
CSF, cerebrospinal fluid; SAS, subarachnoid 
space.
28).
The 
combination of interstitial, vasogenic, and cytotoxic 
edema leads to raised ICP and coma.
A decreased level of consciousness occurs in 
>75% of patients and can vary from lethargy to coma.
Nausea, vomiting, and photo-
phobia are also common complaints.
The most disastrous complication 
of increased ICP is cerebral herniation.
The diagnosis of bacte-
rial meningitis is made by examination of the CSF 
(Table 40-2).
The need to obtain neuroimaging stud-
ies (CT or MRI) prior to LP requires clinical judg-
ment.
The CSF glucose concentration is low when the 
CSF/serum glucose ratio is <0.6.
pneumoniae, 
N.
meningitidis, H.
influenzae type 
b, E.
pneumoniae, N.
meningitidis, Escherichia 
coli, L.
monocytogenes, H.
influenzae, and S.
agalactiae can 
be obtained based on the clinical suspicion of the men-
ingeal pathogen.
The latex agglutination (LA) test for 
the detection of bacterial antigens of S.
pneumoniae, N.
meningitidis, H.
influenzae type b, group B streptococ-
cus, and E.
The CSF LA 
test has a specificity of 95–100% for S.
pneumoniae and 
N.
How-
ever, the sensitivity of the CSF LA test is only 70–100% 
for detection of S.
pneumoniae and 33–70% for detec-
tion of N.
meningitidis antigens, so a negative test does 
not exclude infection by these organisms.
The test has a specificity of 85–100% and a 
sensitivity approaching 100%.
Petechial skin lesions, if present, should be biopsied.
Some patients with HSV 
encephalitis have a distinctive periodic pattern on EEG 
(discussed later).
Rickettsial disease can resemble bacterial meningi-
tis.
Most patients develop a characteristic rash 
within 96 h of the onset of symptoms.
The color of the lesions changes from bright 
red to very dark red, then yellowish-green to black.
Diag-
nosis is made by immunofluorescent staining of skin 
biopsy specimens.
Ehrlichioses are also transmitted by 
a tick bite.
These are small gram-negative coccobacilli 
of which two species cause human disease.
The clinical and laboratory man-
ifestations of the infections are similar.
Patients present 
with fever, headache, nausea, and vomiting.
Twenty 
percent of patients have a maculopapular or petechial 
rash.
A number of noninfectious CNS disorders can mimic 
bacterial meningitis.
Subarachnoid hemorrhage (SAH; 
Chap.
28) is generally the major consideration.
On occasion, subacutely evolving meningitis (Chap.
41) 
may be considered in the differential diagnosis of acute 
meningitis.
S.
pneumoniae and 
N.
meningitidis are the most common etiologic organ-
isms of community-acquired bacterial meningitis.
Due to 
the emergence of penicillin- and cephalosporin-resistant 
S.
Ceftriaxone or cefotaxime provide good coverage for 
susceptible S.
pneumoniae, group B streptococci, and 
H.
influenzae and adequate coverage for N.
meningiti-
dis.
pneumoniae and N.
meningitidis and greater activity against Enterobacter spe-
cies and Pseudomonas aeruginosa.
aeruginosa.
Ampicillin 
should be added to the empirical regimen for coverage  
of L.
aeruginosa are the most common 
etiologic organisms.
aeruginosa.
Meropenem is a carbapenem antibiotic that is highly 
active in vitro against L.
monocytogenes, has been dem-
onstrated to be effective in cases of meningitis caused 
by P.
aeruginosa, and shows good activity against pen-
icillin-resistant pneumococci.
Isolates of N.
CSF isolates of  
N.
Rifampin is not recommended in 
pregnant women.
All CSF isolates of S.
pneumoniae should 
be tested for sensitivity to penicillin and the cephalo-
sporins.
For S.
pneumoniae meningitis, an isolate 
of S.
Metronidazole
aDoses are as indicated in Table 40-1.
Isolates of S.
For MIC >1 μg/mL, vancomycin is the 
antibiotic of choice.
A 2-week course of intravenous antimicrobial therapy 
is recommended for pneumococcal meningitis.
Patients with S.
Patients with penicillin- and ceph-
alosporin-resistant strains of S.
Listeria Meningitis Meningitis due to L.
mono-
cytogenes is treated with ampicillin for at least 3 weeks 
(Table 40-3).
Staphylococcal Meningitis Meningitis due to 
susceptible strains of S.
aureus or coagulase-negative 
staphylococci is treated with nafcillin (Table 40-3).
In 
these patients, the CSF should be monitored during 
therapy.
aeruginosa, 
which should be treated with ceftazidime, cefepime, or 
meropenem (Table 40-3).
Dexamethasone does not alter TNF-α 
production once it has been induced.
influenzae 
and S.
25%, p = .03) including death (7 vs.
15%, p = .04).
The benefits were most striking in patients 
with pneumococcal meningitis.
pneumoniae meningitis.
Alternatively, 
vancomycin can be administered by the intraventricular 
route.
This has not been the case in clinical series.
Treatment of increased intracranial pressure is discussed 
in detail in Chap.
28.
PROGNOSIS
Mortality rate is 3–7% for meningitis caused by H.
influenzae, N.
meningitidis, or group B streptococci; 
15% for that due to L.
monocytogenes; and 20% for 
S.
pneumoniae.
Louis encephalitis virus Mumps
aImmunocompromised host.
Organisms are not seen on 
Gram’s stain of CSF.
CSF PCR 
tests are available for WNV but are not as sensitive as 
detection of WNV-specific CSF IgM.
During enteroviral infections, viral shedding 
in stool may persist for several weeks.
CSF oligoclonal gamma globulin bands occur in 
association with a number of viral infections.
The asso-
ciated antibodies are often directed against viral proteins.
Cases may either be 
sporadic or occur in clusters.
Coxsackievirus strains A9, B3, and B4 are more 
commonly associated with individual cases.
Meningitis outside the neonatal period 
is usually benign.
In 
rare cases, PMNs may predominate during the first 48 h 
of illness.
Treatment is supportive, and patients usually 
recover without sequelae.
Arbovirus infections occur predominantly in the sum-
mer and early fall.
Louis encephalitis virus, 
and the California encephalitis group of viruses.
In 
WNV epidemics, avian deaths may serve as sentinel 
infections for subsequent human disease.
Of these patients, 20% go on to have recurrent attacks 
of meningitis.
VZV meningitis should be suspected in the presence 
of concurrent chickenpox or shingles.
EBV is 
almost never cultured from CSF.
Diagnosis can be 
confirmed by detection of HIV genome in blood or 
CSF.
For further discussion of HIV infection, see 
Chap.
42.
Patients with meningitis have a CSF pleocy-
tosis that can exceed 1000 cells/μL in 25%.
Lympho-
cytes predominate in 75%, although CSF neutrophilia 
occurs in 25%.
Hypoglycorrhachia occurs in 10–30% of 
patients and may be a clue to the diagnosis when present.
CSF PCR is available in some diagnostic and research 
laboratories.
Some cases present with a marked CSF pleo-
cytosis (>1000 cells/μL) and hypoglycorrhachia (<30%).
Diagnosis is based on serology and/or culture of virus 
from CSF.
Fluid and electrolyte status 
should be monitored.
Data concerning treatment of HSV, EBV, and VZV menin-
gitis are extremely limited.
Patients who are less 
ill can be treated with oral drugs alone.
Patients with HIV  
meningitis should receive highly active antiretroviral ther-
apy (Chap.
42).
A live attenuated VZV vaccine (Varivax) is 
available in the United States.
An 
inactivated varicella vaccine is available for transplant  
recipients.
PROGNOSIS
In adults, the prognosis for full recovery from viral 
meningitis is excellent.
Focal or generalized seizures occur in many patients 
with encephalitis.
Louis encephalitis virus and the California encephalitis 
virus serogroup.
In rare 
cases, a pleocytosis may be absent on the initial LP but 
present on subsequent LPs.
CSF cell counts exceed 
500/μL in only about 10% of patients with encephali-
tis.
The 
sensitivity and specificity of CSF PCRs varies with the 
virus being tested.
In both 
situations a positive test makes the diagnosis almost cer-
tain (98–99%).
PCR results are generally not affected by ≤1 week 
of antiviral therapy.
Enteroviral CSF PCR appears to 
have a sensitivity and specificity of >95%.
The specificity 
of EBV CSF PCR has not been established.
and glycoprotein antigens have been detected in the 
CSF.
The lesions are typically hyperintense on T2-weighted 
images.
CT is 
less sensitive than MRI and is normal in up to 20–35% 
of patients.
DIFFERENTIAL DIAGNOSIS
Infection by a variety of other organisms can mimic 
viral encephalitis.
Motile 
trophozoites can be seen in a wet mount of warm, fresh 
CSF.
No effective treat-
ment has been identified, and mortality approaches 
100%.
Encephalitis can be caused by the raccoon pinworm 
Baylisascaris procyonis.
Most patients are children, and many have an associated 
eosinophilia.
The diagnostic 
procedure of choice in these patients is CSF PCR analysis 
for HSV.
The anatomic distribution of lesions may provide 
an additional clue to diagnosis.
Louis 
encephalitis virus, Japanese encephalitis virus), HSV, 
rabies, or L.
monocytogenes.
This 
percentage likely increases to >90% when FLAIR and DWI 
MR sequences are also utilized.
The CSF HSV PCR test may be negative in the first 72 h 
of symptoms of HSV encephalitis.
Negative CSF viral cultures are of no value in excluding the 
diagnosis of HSV or EBV encephalitis.
VZV CSF IgM antibodies may be present in patients with a 
negative VZV CSF PCR.
Both tests should be performed 
in patients with suspected VZV CNS disease.
The specificity of EBV CSF PCR for diagnosis of CNS 
infection is unknown.
Positive tests may occur in patients 
with a CSF pleocytosis due to other causes.
SECTION III
Diseases of the Nervous System
512 parkinsonian features.
PCR amplification 
of viral nucleic acid from CSF and saliva or tears may 
also enable diagnosis.
Geo-
logical Survey (USGS) websites (http://www.cdc.gov and 
http://diseasemaps.usgs.gov).
44); acute disseminated encephalo-
myelitis and related fulminant demyelinating disorders 
(Chap.
39); and lymphoma.
Finally, Creutzfeldt-Jakob 
disease (Chap.
43) can rarely present in an explosive 
fashion mimicking viral encephalitis.
TREATMENT Viral Encephalitis
Specific antiviral therapy should be initiated when 
appropriate.
Host cell 
enzymes then phosphorylate this compound to form a 
triphosphate derivative.
Prior to intravenous administration, acyclovir should 
be diluted to a concentration ≤7 mg/mL.
Care should 
be taken to avoid extravasation or intramuscular or sub-
cutaneous administration.
The alkaline pH of acyclovir 
can cause local inflammation and phlebitis (9%).
Dose 
adjustment is required in patients with impaired renal 
glomerular filtration.
Penetration into CSF is excellent, 
with average drug levels ∼50% of serum levels.
Ganciclovir is a synthetic nucleoside analogue of 
2′-deoxyguanosine.
The drug is preferentially phos-
phorylated by virus-induced cellular kinases.
Doses should be 
adjusted in patients with renal insufficiency.
Induction therapy 
for 14–21 days is followed by maintenance therapy  
(60–120 mg/kg per day).
Many patients 
experience fatigue and nausea.
Nephrotoxicity is 
common; the dose should be reduced if renal function 
deteriorates.
However, clinical trials are 
lacking.
Hemolysis, with resulting anemia, has been the 
major side effect limiting therapy.
In the case of EEE virus infection, nearly 80% of 
survivors have severe neurologic sequelae.
Of 32 acyclovir-treated patients, 
26 survived (81%).
Cranial nerve abnormalities and night 
sweats may be present.
This syndrome overlaps that of 
chronic meningitis, discussed in detail in Chap.
41.
ETIOLOGY
Common causative organisms include M.
tuberculosis, 
C.
neoformans, H.
capsulatum, C.
immitis, and T.
pallidum.
Initial infection with M.
tuberculosis is acquired by 
inhalation of aerosolized droplet nuclei.
These tubercles enlarge and are usually caseating.
Fungal infections are typically acquired by the 
inhalation of airborne fungal spores.
The pulmonary infection is often self-limited.
The most common 
pathogen causing fungal meningitis is C.
neoformans.
This fungus is found worldwide in soil and bird excreta.
H.
C.
T.
pallidum invades the CNS early in the 
course of syphilis.
Cranial nerves VII and VIII are most 
frequently involved.
Cultures of CSF take 4–8 weeks to 
identify the organism and are positive in ∼50% of adults.
Culture remains the gold standard to make the diagnosis 
of tuberculous meningitis.
PCR for the detection of 
M.
There may be eosinophils in the CSF in 
C.
immitis meningitis.
A reactive CSF cryptococcal antigen test establishes 
the diagnosis.
capsulatum.
It may be falsely positive in coccidioidal 
meningitis.
A reactive CSF FTA-ABS is not definitive evi-
dence of neurosyphilis.
The CSF FTA-ABS can be falsely 
positive from blood contamination.
A negative CSF VDRL 
does not rule out neurosyphilis.
A negative CSF FTA-
ABS or MHA-TP rules out neurosyphilis.
When the antimicrobial  
sensitivity of the M.
tuberculosis isolate is known, eth-
ambutol can be discontinued.
Dexametha-
sone therapy is recommended for HIV-negative patients 
with tuberculous meningitis.
The dose is 12–16 mg per 
day for 3 weeks, then tapered over 3 weeks.
Meningitis due to C.
Therapy should be extended 
for a total of 6 weeks in the patient with neurologic 
complications.
Follow CSF yeast cultures  
for sterilization rather than the cryptococcal antigen 
titer.
HIV-infected patients may 
require indefinite maintenance therapy with fluconazole  
200 mg/d.
Meningitis due to H.
capsulatum is treated 
with AmB (0.7–1.0 mg/kg per day) for 4–12 weeks.
A 
total dose of 30 mg/kg is recommended.
Therapy with 
AmB is not discontinued until fungal cultures are sterile.
C.
Intrathecal AmB 
(0.25–0.75 mg/d three times weekly) may be required 
to eradicate the infection.
Lifelong therapy with fluco-
nazole (200–400 mg daily) is recommended to prevent 
relapse.
The most common complication of fungal 
meningitis is hydrocephalus.
Patients who develop 
hydrocephalus should receive a CSF diversion device.
The standard criterion for treatment success 
is reexamination of the CSF.
The CSF should be reexam-
ined at 6-month intervals for 2 years.
Seizures occur in ∼20% of 
patients, predominantly in those with lesions abutting the 
cortex.
Almost all patients have an underlying immunosup-
pressive disorder.
It has been esti-
mated that up to 5% of AIDS patients will develop 
PML.
Diagnostic studies
The diagnosis of PML is frequently suggested by MRI.
PML 
lesions are not typically associated with edema or mass 
effect.
The CSF is typically normal, although mild elevation  
in protein and/or IgG may be found.
PCR amplification of JCV 
DNA from CSF has become an important diagnostic  
tool.
Patients with negative CSF PCR studies may require 
brain biopsy for definitive diagnosis.
Serologic studies are of no utility in diagnosis due to 
high basal seroprevalence level (>80%).
TREATMENT  Progressive  Multifocal 
Leukoencephalopathy
No effective therapy for PML is available.
Neither of these agents has been tested in random-
ized controlled clinical trials.
The frequency 
has been estimated at 1 in 100,000–500,000 measles 
cases.
An average of five cases per year are reported in 
the United States.
The incidence has declined dramati-
cally since the introduction of a measles vaccine.
Initial manifestations 
include poor school performance and mood and person-
ality changes.
Typical signs of a CNS viral infection, 
including fever and headache, do not occur.
Measles virus can be cultured from brain tissue using 
special cocultivation techniques.
TREATMENT Subacute Sclerosing Panencephalitis
No definitive therapy for SSPE is available.
After a latent period of 8–19 years, patients develop 
progressive neurologic deterioration.
The manifesta-
tions are similar to those seen in SSPE.
No therapy is 
available.
The term cerebritis is often employed to describe 
a nonencapsulated brain abscess.
In immunocompetent individuals 
the most important pathogens are Streptococcus spp.
(anaerobic, aerobic, and viridans [40%]), Enterobacteria-
ceae (Proteus spp., E.
coli sp., Klebsiella spp.
[25%]), 
anaerobes (e.g., Bacteroides spp., Fusobacterium spp.
[30%]), 
and staphylococci (10%).
neoformans.
Otogenic abscesses occur pre-
dominantly in the temporal lobe (55–75%) and cerebellum 
(20–30%).
In some series, up to 90% of cerebellar abscesses 
are otogenic.
milleri), Haemophilus spp., Bacteroides spp., Pseudomonas 
spp., and S.
aureus.
Hematogenous abscesses account for ∼25% of brain 
abscesses.
The microbiology 
of hematogenous abscesses is dependent on the primary 
source of infection.
aureus.
aureus (MRSA), S.
epidermidis, 
Enterobacteriaceae, Pseudomonas spp., and Clostridium 
spp.
Enterobacteriaceae and P.
aeruginosa are impor-
tant causes of abscesses associated with urinary sepsis.
Similar phenomena can 
occur with pulmonary arteriovenous malformations.
Streptococci are the most 
common pathogens in this setting.
The 
intact brain parenchyma is relatively resistant to infec-
tion.
Marked edema 
surrounds the lesion at this stage.
This stage correlates with the appearance of 
a ring-enhancing capsule on neuroimaging studies.
This gliotic process may contribute to the 
development of seizures as a sequelae of brain abscess.
Hemiparesis is the 
most common localizing sign of a frontal lobe abscess.
Nystagmus and ataxia are signs of a cerebellar 
abscess.
DIAGNOSIS
Diagnosis is made by neuroimaging studies.
MRI  
(Fig.
Aerobic and anaerobic bacterial cultures and 
mycobacterial and fungal cultures should be obtained.
Up 
to 10% of patients will also have positive blood cultures.
FIGURE 40-4
Pneumococcal brain abscess.
and vancomycin for coverage of 
staphylococci.
Meropenem plus vancomycin also provides 
good coverage in this setting.
All patients should receive a minimum of 
6–8 weeks of parenteral antibiotic therapy.
If the EEG is abnormal, anticonvulsant therapy 
should be continued.
Glucocorticoids should not be given routinely to 
patients with brain abscesses.
In modern series, 
the mortality rate is typically <15%.
solium.
Toxoplasmosis is a parasitic disease 
caused by T.
gondii and acquired from the ingestion of 
undercooked meat and from handling cat feces.
Cysticerci may develop in the brain 
parenchyma and cause seizures or focal neurologic defi-
cits.
Spinal cysticerci can mimic the 
presentation of intraspinal tumors.
Primary Toxoplasma infection is often asymptomatic.
However, during this phase parasites may spread to the 
CNS, where they become latent.
During this phase patients present with headache, fever, 
seizures, and focal neurologic deficits.
DIAGNOSIS
The lesions of neurocysticercosis are readily visual-
ized by MRI or CT scans.
The scolex can often be visualized 
on MRI.
Lesions may appear as contrast-enhancing lesions 
surrounded by edema.
In the presence of the characteristic  
neuroimaging abnormalities of T.
gondii infection, 
serum IgG antibody to T.
gondii should be obtained 
and, when positive, the patient should be treated.
Albendazole and prazi-
quantel are used in the treatment of neurocysticercosis.
The dose 
of albendazole is 15 mg/kg per day in two doses for  
8 days.
Antiepileptic therapy can be stopped once the follow-up 
CT scan shows resolution of the lesion.
Folinic acid is added to 
the regimen to prevent megaloblastic anemia.
40-5).
EPIDEMIOLOGY
SDE is a rare disorder that accounts for 15–25% of focal 
suppurative CNS infections.
SDE may also develop as a 
complication of head trauma or neurosurgery.
Subdural
empyema
Thrombosed
veins
Arachnoid
Dura mater
FIGURE 40-5
Subdural empyema.
Patients with underlying sinusitis frequently have 
symptoms related to this infection.
Seizures begin 
as partial motor seizures that then become secondarily 
generalized.
DIAGNOSIS
MRI (Fig.
40-6) is superior to CT in identifying SDE 
and any associated intracranial infections.
FIGURE 40-6
Subdural empyema.
TREATMENT Subdural Empyema
SDE is a medical emergency.
Patients with hospital-
acquired SDE may have infections due to Pseudomonas 
spp.
or MRSA and should receive coverage with a carba-
penem (e.g., meropenem) and vancomycin.
Metronidazole 
is not necessary for anti-anaerobic therapy when merope-
nem is being used.
Parenteral antibiotic therapy should be 
continued for a minimum of 3–4 weeks after SDE drainage.
Patients with associated cranial osteomyelitis may require 
longer therapy.
40-7).
As a result, epi-
dural abscesses are often smaller than SDEs.
The bacteriology of a cranial epidural 
abscess is similar to that of SDE (discussed earlier).
TREATMENT Epidural Abscess
Immediate neurosurgical drainage is indicated.
Metronidazole is not necessary for anti-anaerobic 
coverage in patients receiving meropenem.
When the 
organism has been identified, antimicrobial therapy can 
be modified accordingly.
Antibiotics should be contin-
ued for 3–6 weeks after surgical drainage.
Patients with 
associated osteomyelitis may require additional therapy.
The superior sagittal sinus is the largest of 
the venous sinuses (Fig.
40-8).
Infection can also spread to the 
superior sagittal sinus from nearby SDE or epidural 
abscess.
The superior sagittal sinus drains into the transverse 
sinuses (Fig.
40-8).
The transverse sinus becomes the 
sigmoid sinus before draining into the internal jugular 
vein.
The cavernous sinuses are inferior to 
the superior sagittal sinus at the base of the skull.
Bacteria in 
the facial veins enter the cavernous sinus via these veins.
There may be a rapid 
development of stupor and coma.
34-4).
There 
may be evidence of dilated, tortuous retinal veins and 
papilledema.
Headache and earache are the most frequent symptoms 
of transverse sinus thrombosis.
Sigmoid sinus and internal jugular vein thrombosis may 
present with neck pain.
527
   Walter  J.
Koroshetz   ■    Morton  N.
The causes 
are varied, and appropriate treatment depends on identi-
fi cation of the etiology.
These can 
occur alone or in combination.
34).
Meningeal inflam-
mation can encircle the cord, resulting in myelopathy.
Two clinical forms of chronic meningitis exist.
Balamuthia mandrillaris causing chronic meningoencephalitis in immunocompetent hosts.
Aphthous oral lesions, genital ulcers, and hypopyon sug-
gest Behçet’s syndrome.
Hepatosplenomegaly suggests 
lymphoma, sarcoid, tuberculosis, or brucellosis.
Herpetic 
lesions in the genital area or on the thighs suggest HSV-2 
infection.
Obstructive hydrocephalus 
usually requires direct ventricular drainage of CSF.
41-1).
Imaging studies are also useful to localize 
areas of meningeal disease prior to meningeal biopsy.
performed.
cantonensis, G.
spinigerum, 
B.
procyonis, or Toxocara canis infection, cysticercosis, 
schistosomiasis, echinococcal disease, T.
The diagnosis of fungal menin-
gitis may require large volumes of CSF for culture of 
sediment.
Occa-
sionally, empirical therapy must be initiated when all 
attempts at diagnosis fail.
THE IMMUNOSUPPRESSED PATIENT
Chronic meningitis is not uncommon in the course of 
HIV infection.
41-1).
Anthony S.
Fauci    ■     H.
Source: MMWR 42(No.
RR-17), December 18, 1992.
Con-
ditions listed in categories B and C must not have occurred.
Source: MMWR 42(No.
RR-17), December 18, 1992.
MORPHOLOGY OF HIV
Electron microscopy shows that the HIV virion is an 
icosahedral structure (Fig.
The structure of HIV-1 is 
schematically diagrammed in Fig.
42-1B.
42-2).
It is also expressed on the surface of monocytes/
macrophages and dendritic/Langerhans cells.
The two major co-receptors for HIV-1 
are CCR5 and CXCR4.
Electron micrograph of HIV.
B.
(Copyright by 
George V.
Kelvin.
HIV has evolved 
a powerful strategy to protect itself from APOBEC.
The viral protein Vif targets APOBEC for proteasomal 
degradation.
See text for description.
HIV-infected individuals may manifest white mat-
ter lesions as well as neuronal loss.
Astrocytes may play diverse roles in HIV neu-
ropathogenesis.
In addition, astrocyte-derived 
IL-6 can induce HIV expression in infected cells in 
vitro.
cruzi, or Acanthamoeba.
Over-
all, secondary diseases of the CNS occur in approximately 
one-third of patients with AIDS.
Most HIV-infected patients have some 
neurologic problem during the course of their disease.
Increased tone and deep 
tendon reflexes may be found in patients with spinal 
cord involvement.
Late stages may be complicated by 
bowel and/or bladder incontinence.
Some 
patients develop a state of agitation or mild mania.
These changes usually occur without significant changes 
in level of alertness.
As 
immunologic function declines, the risk and severity of 
HIV encephalopathy increase.
Less commonly, diffuse or focal spongiform changes 
occur in the white matter.
Areas of the brain involved 
in motor, language, and judgment are most severely 
affected.
The 
diagnosis of dementia depends upon demonstrating 
a decline in cognitive function.
However, changes in MMSE scores 
may be absent in patients with mild HIV-associated 
dementia.
42-3).
MRI may also reveal small areas of 
increased density on T2-weighted images.
Mild signs (snout response, slowed ocular or extremity movements) may 
be present.
Gait and strength are normal.
Can walk without assistance.
Ambulatory, but may require a single prop.
4 (End-stage) Nearly vegetative.
Intellectual and social comprehension and output are at a rudimentary level.
Nearly or absolutely mute.
Paraparetic or paraplegic with urinary and fecal incontinence.
Source: Adapted from JJ Sidtis, RW Price: Neurology 40:197, 1990.
FIGURE 42-3
AIDS dementia complex.
The lateral and third ventricles 
and the cerebral sulci are abnormally prominent.
CHAPTER 42
HIV Neurology
543 making a diagnosis of opportunistic infections.
Combination antiretroviral therapy is of benefit in 
patients with HIV-associated dementia.
Rarely, an acute 
encephalopathy due to encephalitis may occur.
CSF find-
ings include a lymphocytic pleocytosis, elevated protein 
level, and normal glucose level.
This syndrome, which 
cannot be clinically differentiated from other viral men-
ingitides (Chap.
Three main 
types of spinal cord disease are seen in patients with 
AIDS.
The first of these is a vacuolar myelopathy.
The clinical course is rapidly progressive over a 
period of weeks.
HIV neuropathy
Peripheral neuropathies are common in patients with 
HIV infection.
They occur at all stages of illness and 
take a variety of forms.
46).
Patients commonly 
present with progressive weakness, areflexia, and mini-
mal sensory changes.
Plasma exchange or IVIg has 
been tried with variable success.
It is more common in taller 
individuals, older individuals, and those with lower 
CD4 counts.
Presenting symp-
toms are usually painful burning sensations in the feet 
and lower extremities.
Motor 
changes are mild and are usually limited to weakness 
of the intrinsic foot muscles.
Treatment-naive patients may respond 
to cART.
The clinical significance of this 
as an isolated laboratory finding is unclear.
Profound muscle wasting, 
often with muscle pain, may be seen after prolonged 
zidovudine therapy.
It 
is reversible following discontinuation of the drug.
Red 
ragged fibers are a histologic hallmark of zidovudine-
induced myopathy.
This is a 120-
fold increase in incidence compared to the general 
population.
As HIV disease progresses, the 
risk of lymphoma increases.
Virtually any site in the body 
may be involved.
Approximately 60% of 
these cases are primary CNS lymphoma.
In one study, 
the incidence of Epstein-Barr positivity was 100%.
This 
malignancy does not have a predilection for any par-
ticular age group.
The median CD4+ T cell count at 
the time of diagnosis is ~50/μL.
Thus, CNS lymphoma 
generally presents at a later stage of HIV infection 
than systemic lymphoma.
This fact may at least in part 
explain the poorer prognosis for this subset of patients.
MRI or CT gener-
ally reveals a limited number (one to three) of 3- to 
5-cm lesions (Fig.
42-4).
The lesions often show 
ring enhancement on contrast administration and may 
occur in any location.
Locations that are most com-
monly involved with CNS lymphoma are deep in the 
white matter.
Contrast enhancement is usually less pro-
nounced than that seen with toxoplasmosis.
Systemic lymphoma is generally treated by 
the oncologist with combination chemotherapy.
Treatment of primary CNS lymphoma 
remains a significant challenge.
Palliative measures such as radia-
tion therapy provide some relief.
The prognosis remains 
poor in this group, with a 2-year survival of 29%.
The 
risk of many such infections correlates well with the 
CD4+ T cell count (Fig.
42-5).
Cryptococcosis
C.
neoformans is the leading infectious cause of men-
ingitis in patients with AIDS.
The incidence of 
seizures and focal neurologic deficits is low.
In addition to meningitis, patients may develop crypto-
coccomas and cranial nerve involvement.
Approximately 
one-third of patients also have pulmonary disease.
Uncommon manifestations of cryptococcal infection 
FIGURE 42-4
Central nervous system lymphoma.
Multiple enhancing lesions, some 
ring-enhancing, are present.
The prostate 
gland may serve as a reservoir for smoldering cryptococ-
cal infection.
A biopsy may be needed to make a diag-
nosis of CNS cryptococcoma.
Repeated lumbar puncture may be required to 
manage increased intracranial pressure.
Symptoms may 
recur with initiation of cART as an immune reconstitu-
tion syndrome.
Other fungi that may cause meningitis in 
patients with HIV infection are C.
immitis and H.
capsu-
latum.
Meningoencephalitis has also been reported due 
to Acanthamoeba or Naegleria.
It is 
most common in patients from the Caribbean and from 
France, where the seroprevalence of T.
gondii is around 
50%.
Cerebral toxoplasmo-
sis is thought to represent a reactivation of latent tissue 
cysts.
Patients diagnosed with HIV infection should be 
screened for IgG antibodies to T.
gondii during the time 
of their initial workup.
There 
is usually evidence of surrounding edema.
The definitive diag-
nostic procedure is brain biopsy.
If the patient is seronegative for T.
gondii, the likelihood that a mass lesion is due to toxo-
plasmosis is <10%.
In that setting, one may choose to 
be more aggressive and perform a brain biopsy sooner.
Fortu-
nately, the same daily regimen of a single double-strength 
tablet of TMP/SMX used for P.
jiroveci prophylaxis pro-
vides adequate primary protection against toxoplasmosis.
PML is the only known 
clinical manifestation of JC virus infection.
It is a late 
manifestation of AIDS and is seen in ~4% of patients 
with AIDS.
The cerebral hemispheres, cerebellum, and 
brainstem may all be involved.
Approxi-
mately 20% of patients experience seizures.
Ataxia, 
hemiparesis, visual field defects, aphasia, and sensory 
defects may occur.
Stud-
ies with other antiviral agents such as cidofovir have 
failed to show clear benefit.
Baseline HIV-1 viral load does not have 
independent predictive value of survival.
The presence of 
antibodies to Trypanosoma cruzi supports the diagnosis.
SECTION III
Diseases of the Nervous System
548 the initial AIDS-defining condition.
The majority of 
cases occur in patients with CD4+ T cell counts <200 
cells/μL.
T.
cruzi amasti-
gotes, or trypanosomes, can be identified from biopsy 
specimens or CSF.
Other CSF findings include ele-
vated protein and a mild (<100 cells/μL) lymphocytic 
pleocytosis.
Organisms can also be identified by direct 
examination of the blood.
Specific neurologic presentations
Stroke
Stroke may occur in patients with HIV infection.
It also appears that HIV infection itself can 
lead to an increase in carotid artery stiffness.
Seizures may be the 
presenting clinical symptom of HIV disease.
Of these 32 cases, 28 were due to toxoplasmosis and 4 
to lymphoma.
HIV-associated dementia accounted for 
an additional 24 new-onset seizures.
Stanley  B.
Prusiner    ■     Bruce  L.
43-1  ).
A.
NMR structure of Syrian ham-
ster recombinant (rec) PrP(90–231).
Presumably, the structure 
of the α-helical form of recPrP(90–231) resembles that of PrP C .
recPrP(90–231) is viewed from the interface where PrP Sc  is 
thought to bind to PrP C .
Shown are: α-helices A (residues 144–
157), B (172–193), and C (200–227).
Flat ribbons depict β-strands 
S1 (129–131) and S2 (161–163).
( A   , from SB Prusiner: N Engl J 
Med 344:1516, 2001; with permission.)   B.
Structural model of 
PrP Sc .
(Image prepared by C.
Prions are composed entirely 
of PrP Sc  molecules.
PrP Sc Disease-causing isoform of the prion 
protein.
This protein is the only identifi able 
macromolecule in purifi ed preparations of 
scrapie prions.
Pr PC Cellular isoform of the prion protein.
PrP C  is 
the precursor of PrP Sc .
PrP 27-30 
retains prion infectivity and polymerizes 
into amyloid.
PRNP  PrP gene located on human chromosome 20.
Prion rod An aggregate of prions composed 
largely of PrP 27-30 molecules.
Created 
by detergent extraction and limited 
proteolysis of PrP Sc .
Morphologically and 
histochemically indistinguishable from 
many amyloids.
SPECTRUM OF PRION DISEASES
The sporadic form of CJD is the most common prion dis-
order in humans.
Six diseases of animals are caused by prions (Table 
43-2).
Scrapie of sheep and goats is the prototypic prion 
disease.
In contrast 
to other prion diseases, CWD is highly communicable.
EPIDEMIOLOGY
CJD is found throughout the world.
sFI Humans Somatic mutation or spontaneous conversion of PrPC into PrPSc?
In humans, the PrP gene is desig-
nated PRNP and is located on the short arm of chro-
mosome 20.
43-2).
In the pres-
ence of detergent, PrP 27-30 polymerizes into amyloid.
This analysis was extended when patients with spo-
radic fatal insomnia (sFI) were identified.
Bar diagram of Syrian hamster PrP, 
which consists of 254 amino acids.
After processing of the 
NH2 and COOH termini, both PrPC and PrPSc consist of 209 
residues.
PrPSc acts as a template 
for the conversion of PrPC into nascent PrPSc.
fCJD, familial Creutzfeldt-Jakob disease; FFI, fatal familial insomnia.
CHAPTER 43
Prion Diseases
553 to be sufficiently low as to be not detected by routine 
bioassay.
The normal human PrP 
sequence contains five repeats of an eight-amino-acid 
sequence.
One case of CJD occurred 
after repair of an eardrum perforation with a pericar-
dium graft.
These patients received 
injections of hGH every 2–4 days for 4–12 years.
Four cases of CJD have occurred in women receiving 
human pituitary gonadotropin.
More than 190 cases of vCJD have 
occurred, with >90% of these in Britain.
Patients 
who survive for several years have variable degrees of 
cerebral atrophy.
Astrocytic gliosis is a constant but 
nonspecific feature of prion diseases.
Astro-
cytic processes filled with glial filaments form extensive 
networks.
Amyloid plaques have been found in ∼10% of CJD 
cases.
These plaques stain with antibodies raised 
against PrP.
They 
are often located adjacent to blood vessels.
Congophilic 
angiopathy has been noted in some cases of GSS disease.
Most patients with CJD 
present with deficits in higher cortical function.
Frequently the cerebellar deficits 
are rapidly followed by progressive dementia.
Unlike 
other involuntary movements, myoclonus persists dur-
ing sleep.
Dementia 
with myoclonus can also be due to Alzheimer’s disease 
(AD) (Chap.
29), dementia with Lewy bodies (Chap.
29), corticobasal degeneration (Chap.
26).
In other 
cases, incubation periods of up to 40 years have been 
suggested.
Clinical abnormalities in CJD 
are confined to the CNS.
Variations in the typical course appear in inherited 
and transmitted forms of the disease.
fCJD has an earlier 
mean age of onset than sCJD.
Rare sporadic 
cases have been identified.
DIFFERENTIAL DIAGNOSIS
Many conditions may mimic CJD superficially.
Demen-
tia with Lewy bodies (Chap.
29) is the most common 
disorder to be mistaken for CJD.
It can present in a sub-
acute fashion with delirium, myoclonus, and extrapyra-
midal features.
Other neurodegenerative disorders (Chap.
26).
Unlike CJD, fluctuations in severity typically occur in 
Hashimoto’s encephalopathy.
Myoclonus is 
exceptional with cerebral vasculitis, but focal seizures 
may confuse the picture.
Other diseases that can simulate CJD include neurosyphi-
lis, AIDS dementia complex (Chap.
42), progressive multi-
focal leukoencephalopathy (Chap.
40), diffuse intracranial tumor 
(gliomatosis cerebri; Chap.
In humans, the 
diagnosis of CJD can be established by brain biopsy if 
PrPSc is detected.
CT may be normal or show cortical atrophy.
MRI is 
valuable for distinguishing sCJD from most other condi-
tions.
43-3).
CSF is nearly always normal but may show pro-
tein elevation and, rarely, mild pleocytosis.
During the early phase of CJD, the EEG is 
usually normal or shows only scattered theta activity.
As CJD progresses, normal background 
rhythms become fragmentary and slower.
Whether such an approach can 
be used to treat CJD remains to be established.
Like the acridines, anti-PrP antibodies have been 
shown to eliminate PrPSc from cultured cells.
Unfortunately, the antibodies were ineffective in mice 
inoculated intracerebrally with prions.
Josep  Dalmau    ■     Myrna R.
In 60% of patients the neurologic symp-
toms precede the cancer diagnosis.
T cell–mediated 
cytotoxicity may contribute directly to cell death in these 
PNDs.
Thus both humoral and cellular immune mecha-
nisms participate in the pathogenesis of many PNDs.
44-1 ) .
Other PNDs are likely immune-mediated, although 
their antigens are unknown.
These include several syn-
dromes of infl ammatory neuropathies and myopathies.
In addition, many patients with typical PND syndromes 
are antibody-negative.
For still other PNDs, the cause remains quite 
obscure.
Abbreviations: CRMP, collapsing response-mediator protein; SCLC, small cell lung cancer.
there is evidence that prompt tumor control improves the 
neurologic outcome.
bAnti-VGKC-related proteins are pathogenic for some types of neuromyotonia.
cAnti-VGCC antibodies are pathogenic for LEMS.
dThese antibodies are strongly suspected to be pathogenic.
AB
(e.g.,  metastasis, infection), neuropathologic findings are 
not specific for PND.
In 
most PNDs the MRI findings are nonspecific.
44-2).
Note 
the abnormal hyperintensity involving the medial aspect of 
the temporal lobes.
CHAPTER 44
Paraneoplastic Neurologic Syndromes 
561 after the neurologic diagnosis.
Combined CT and 
PET scans often uncover tumors undetected by other 
tests.
It is often associated with dorsal root ganglia and 
autonomic dysfunction.
Patients with SCLC 
and these syndromes usually have anti-Hu antibodies in 
serum and CSF.
44-3); some patients develop hypersomnia, cata-
plexy, and severe hypokinesia.
The oncologic asso-
ciations of these antibodies are shown in Table 44-2.
AB C
FIGURE 44-3 
MRI and tumor of a patient with anti-Ma2-associated 
encephalitis.
The positive (brown) cells correspond to an intra-
tubular germ-cell neoplasm.
Less commonly, 
patients develop neuromyotonia or a mixed clinical picture 
(Morvan’s syndrome).
Encephalitis with N -methyl-D-aspartate (NMDA) recep-
tor antibodies (Fig.
In male patients the 
detection of a tumor is rare.
The neurologic disorder responds to treatment 
of the tumor and immunotherapy.
Neurologic symp-
toms often respond to immunotherapy and treatment 
of the tumor if found.
The examination usually shows 
downbeating nystagmus and, rarely, opsoclonus.
Opsoclonus-myoclonus may be cancer-
related or idiopathic.
Most patients 
do not have detectable antineuronal antibodies.
At least 50% of children with opsoclonus-myoclonus 
have an underlying neuroblastoma.
Hypotonia, ataxia, 
behavioral changes, and irritability are frequent accom-
panying symptoms.
Many patients are left with psycho-
motor retardation and behavioral and sleep problems.
Some patients with 
encephalomyelitis and rigidity have glycine receptor 
antibodies.
Symptoms improve with sleep and general 
anesthetics.
Electrophysiologic studies demonstrate con-
tinuous motor unit activity.
All 
modalities of sensation and any part of the body includ-
ing face and trunk can be involved.
Specialized sensa-
tions such as taste and hearing can also be affected.
Glucocorticoids occasionally produce clinical 
stabilization or improvement.
The benefit of IVIg and 
plasma exchange is not proved.
If demyelinating features predomi-
nate (Chap.
45), IVIg, plasma exchange, or glucocorti-
coids may improve symptoms.
The paraneoplastic variety has several 
distinctive features.
Treatment of the plasmacytoma or scle-
rotic lesions usually improves the neuropathy.
46).
SCLC and lymphoma are the pri-
mary tumors involved.
Glucocorticoids and cyclophos-
phamide often result in neurologic improvement.
CNS dysfunction, including mood changes, sleep disor-
der, or hallucinations, may occur.
Approximately 
20% of patients have serum antibodies to Caspr2-related 
proteins.
Phenytoin, carbamazepine, 
and plasma exchange improve symptoms.
Glucocorticoids and treatment of the underlying 
tumor rarely control the disorder.
The most commonly associated 
tumor is SCLC.
Melanoma-associated retinopathy 
affects patients with metastatic cutaneous melanoma.
The ERG shows reduced b waves 
with normal dark adapted a waves.
Some patients 
with paraneoplastic uveitis harbor anti-CV2/CRMP5 
antibodies.
33).
LAMBERT-EATON MYASTHENIC 
SYNDROME
LEMS is discussed in Chap.
47.
MYASTHENIA GRAVIS
Myasthenia gravis is discussed in Chap.
47.
POLYMYOSITIS-DERMATOMYOSITIS
Polymyositis and dermatomyositis are discussed in detail 
in Chap.
49.
Amato    ■     Richard  J.
Barohn  
566
 Peripheral nerves are composed of sensory, motor, and 
autonomic elements.
Most peripheral nerves 
are mixed and contain sensory and motor as well as 
autonomic fi bers.
Motor axons are usually large 
myelinated fi bers that conduct rapidly (approximately 
50 m/s).
Sensory fi bers may be any of the three types.
Autonomic nerves are 
also small in diameter.
The infl ammatory neuropathies are dis-
cussed in  Chap.
46 .
45-1 ) .
INFORMATION FROM THE HISTORY AND 
PHYSICAL EXAMINATION: SEVEN KEY 
QUESTIONS ( TABLE 45-1 ) 
  1.
What systems are involved?
33 ).
The majority of neuropathies are pre-
dominantly sensory in nature.
2.
What is the distribution of weakness?
and (2) Is the weakness focal and asymmet-
ric or is it symmetric?
Findings of an asymmetric or multifocal pattern of 
weakness narrows the differential diagnosis.
Some neu-
ropathic disorders may present with unilateral extremity 
weakness.
32).
3.
What is the nature of the sensory 
involvement?
15).
Severe proprioceptive loss also narrows the differ-
ential diagnosis.
CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; 
GBS, Guillain-Barré syndrome.
Patient Complaint: ?
Neuropathy
History and examination compatible with neuropathy?
Is entrapment or
 compression present?
Is a contributing systemic 
  disorder present?
4.
Is there evidence of upper motor neuron 
involvement?
5.
What is the temporal evolution?
It is important to determine the onset, duration, and evo-
lution of symptoms and signs.
Is the course monophasic, progres-
sive, or relapsing?
Most neuropathies are insidious and 
slowly progressive in nature.
A 
relapsing course can be present in CIDP and porphyria.
6.
Is there evidence for a hereditary 
neuropathy?
7.
Does the patient have any other medical 
conditions?
Each 
pattern has a limited differential diagnosis.
What systems are involved?
– Motor, sensory, autonomic, or combinations
2.
What is the distribution of weakness?
– Only distal versus proximal and distal
– Focal/asymmetric versus symmetric
3.
What is the nature of the sensory involvement?
Is there evidence of upper motor neuron involvement?
– Without sensory loss
– With sensory loss
5.
What is the temporal evolution?
– Acute (days to 4 weeks)
– Subacute (4 to 8 weeks)
– Chronic (>8 weeks)
6.
Is there evidence for a hereditary neuropathy?
– Family history of neuropathy
– Lack of sensory symptoms despite sensory signs
7.
Are there any associated medical conditions?
SECTION III
Diseases of the Nervous System
570 be valuable.
33).
In idiopathic cases of GBS 
and CIDP, there should not be pleocytosis in the CSF.
Some patients with GBS 
and CIDP have abnormal liver function tests.
Neu-
ropathy can be the initial manifestation of Sjögren’s syn-
drome.
Further, some patients can manifest sicca complex with-
out full-blown Sjögren’s syndrome.
44).
NERVE BIOPSIES
Nerve biopsies are now rarely indicated for evaluation of 
neuropathies.
The primary indication for nerve biopsy 
is suspicion for amyloid neuropathy or vasculitis.
Nerve biopsies should 
only be done if the NCS studies are abnormal.
SKIN BIOPSIES
Skin biopsies are sometimes used to diagnose a small-
fiber neuropathy.
However, it adds little to what one already knows 
from the clinical examination and EDx.
Both are associated 
with autosomal dominant inheritance, with a few excep-
tions.
Muscle stretch reflexes are unobtainable or reduced 
throughout.
(Frabin)
CMT2H AD 8q21.3 ?
Source: Modified from AA Amato, J Russell: Neuromuscular Disease.
New York, McGraw-Hill, 2008.
This results in patients having three cop-
ies of the PMP-22 gene rather than two.
CMT2
CMT2 tends to present later in life compared to CMT1.
Clinically, CMT2 is for the most part indistinguish-
able from CMT1.
The other genes associated with CMT2 are 
much less common.
Affected children 
are severely weak.
Motor NCVs are markedly slowed, 
typically 5–10 m/s or less.
Electrophysiologic and histologic evaluations can show 
demyelinating or axonal features.
CMT4 is genetically 
heterogenic (Table 45-4).
CMT1X accounts for approximately 10–15% of CMT 
overall.
Obligate women carri-
ers are frequently asymptomatic, but can develop signs and 
symptoms.
In men, motor NCVs in the arms and legs 
are moderately slowed (in the low to mid 30-m/s range).
CMT1X is caused by mutations in the con-
nexin 32 gene.
Connexins are gap junction structural 
proteins that are important in cell-to-cell communication.
These 
pressure-related mononeuropathies may take weeks or 
months to resolve.
These attacks are similar to those 
seen with idiopathic brachial plexitis (discussed later).
Attacks may occur in the postpartum period, follow-
ing surgery, or at other times of stress.
Most patients 
recover over several weeks or months.
EDx demon-
strate an axonal process.
HNA is caused by mutations in 
septin 9 (SEPT9).
Nevertheless, 
affected individuals can develop motor weakness and there 
can be overlap with CMT.
Of the HSANs, only HSAN1 typically presents in 
adults.
The HSAN1 is the most common of the HSANs 
and is inherited in an autosomal dominant fashion.
Affected 
individuals with HSAN1 usually manifest in the second 
through fourth decade of life.
HSAN1A is caused by 
mutations in the serine palmitoyltransferase long-chain base 
1 (SPTLC1) gene.
Some patients also 
manifest primarily with a dilated cardiomyopathy.
A 
decrease in α-galactosidase activity is evident in leuko-
cytes and cultured fibroblasts.
Patients with ALD manifest with 
CNS abnormalities.
35).
EDx is suggestive of a primary axonopathy with sec-
ondary demyelination.
Very 
long chain fatty acid (VLCFA) levels (C24, C25, and 
C26) are increased in the urine.
Laboratory evidence of 
adrenal insufficiency is evident in approximately two-
thirds of patients.
The diagnosis can be confirmed by 
genetic testing.
Subsequently, 
the proximal leg and arm muscles may become weak.
Serum phytanic acid levels are elevated.
Refsum disease is genetically heterogeneous but 
autosomal recessive in nature.
Less commonly, mutations in 
the gene encoding peroxin 7 receptor protein (PRX 7) 
are responsible.
35]).
Nerve biopsies reveal axonal degenera-
tion with demyelination and remyelination.
There is no 
specific treatment.
PORPHYRIA
Porphyria is a group of inherited disorders caused by 
defects in heme biosynthesis.
An acute attack of porphyria may begin with sharp 
abdominal pain.
Subsequently, patients may develop 
agitation, hallucinations, or seizures.
Several days later, 
back and extremity pain followed by weakness ensues, 
mimicking GBS.
Constipation, urinary retention, and 
incontinence can also be seen.
The CSF protein is typically normal or mildly elevated.
Liver function tests and hematologic parameters are usu-
ally normal.
Some patients are hyponatremic due to inap-
propriate secretion of antidiuretic hormone.
Specific enzyme activities can also be measured in erythro-
cytes and leukocytes.
The porphyrias are inherited in an autosomal domi-
nant fashion.
The pathogenesis of 
the neuropathy is not completely understood.
Treat-
ment with glucose and hematin may reduce the accu-
mulation of heme precursors.
Intravenous glucose is 
started at a rate of 10–20 g/h.
The majority of patients with FAP have 
mutations in the TTR gene.
Amyloid deposition may 
be evident in abdominal fat pad, rectal, or nerve biop-
sies.
Carpal tunnel syndrome (CTS) is common.
Amyloid 
deposition also occurs in the heart, kidneys, liver, and 
the corneas.
Gradually, the symptoms progress, leading to proximal 
and distal weakness and atrophy.
Over time, a mild generalized 
sensorimotor polyneuropathy develops.
Autonomic dys-
function does not occur.
ACQUIRED NEUROPATHIES
PRIMARY OR AL AMYLOIDOSIS
Besides FAP, amyloidosis can also be acquired.
However, the trunk can be involved and some manifest 
with a mononeuropathy multiplex pattern.
CTS occurs in 
25% of patients and may be the initial manifestation.
Patients generally 
die from their systemic illness (renal failure, cardiac disease).
The monoclonal protein may be composed of IgG, 
IgA, IgM, or only free light chain.
Lambda (λ) is more 
common than κ light chain (>2:1) in AL amyloidosis.
46).
Tingling, 
burning, deep aching pains may also be apparent.
NCS 
usually show reduced amplitudes and mild to moder-
ate slowing of conduction velocities (CVs).
Diabetic autonomic neuropathy
Autonomic neuropathy is typically seen in combina-
tion with DSPN.
300–1200 mg TID Cognitive changes, sedation, peripheral 
edema
Pregabalin p.o.
50–100 mg TID Cognitive changes, sedation, peripheral 
edema
Duloxetine p.o.
200–400 mg q 6–8 h Cognitive changes, dizziness, leukopenia, 
liver dysfunction
Phenytoin p.o.
50 mg qid Cognitive changes, GI upset
Third-Line
Mexiletine p.o.
Local erythema
Capsaicin 0.025%–0.075% 
cream
Apply cutaneously q.i.d.
Painful burning skin
Source: Modified from AA Amato, J Russell: Neuromuscular Disease.
New York, McGraw-Hill, 2008.
Sensory and motor NCS 
generally demonstrate features described earlier with 
DSPN.
Typically, patients present with severe pain in the low 
back, hip, and thigh in one leg.
Rarely, the diabetic poly-
radiculoneuropathy begins in both legs at the same time.
The neuropathy is often accompanied or heralded 
by severe weight loss.
CSF protein is usually elevated, while the 
cell count is normal.
ESR is often increased.
Nerve biopsies may demonstrate axonal degeneration 
along with perivascular inflammation.
Diabetic third nerve 
palsies are characteristically pupil-sparing (Chap.
21).
Treatment is correction of the 
hypothyroidism.
Sjögren’s syndrome is also associated 
with sensory neuronopathy/ganglionopathy.
The onset can be acute or 
insidious.
NCS 
demonstrate reduced amplitudes of sensory studies in the 
affected limbs.
Nerve biopsy demonstrates axonal degen-
eration.
There is no specific treatment for neuropathies related to 
Sjögren’s syndrome.
When vasculitis is suspected, immu-
nosuppressive agents may be beneficial.
The neuropathy often is responsive 
to immunomodulating therapies.
Less 
common are multiple mononeuropathies presumably 
secondary to necrotizing vasculitis.
Immunosuppressive therapy 
is beneficial in SLE patients with neuropathy due to 
vasculitis.
Patients with a GBS or CIDP-like neuropathy should 
be treated accordingly (Chap.
46).
Multiple mononeuropathies also occur.
The most com-
mon cranial nerve involved is the seventh nerve, which 
can be affected bilaterally.
Some patients develop radic-
ulopathy or polyradiculopathy.
With a generalized root 
involvement, the clinical presentation can mimic GBS 
or CIDP.
Some have features 
of a pure small-fiber neuropathy.
EDx reveals an axonal 
neuropathy.
Neurosarcoidosis may respond to treatment with gluco-
corticoids or other immunosuppressive agents.
A generalized peripheral 
neuropathy or a mononeuropathy multiplex occurs in 
6–14% of patients.
Nerve biopsy may reveal a loss of large myelinated 
fibers.
The neuropathy may be secondary to malabsorp-
tion of vitamins B12 and E.
However, some patients have 
no appreciable vitamin deficiencies.
The neuropathy does not appear 
to respond to a gluten-free diet.
Mononeuropathies can also occur, the most 
common of which is carpal tunnel syndrome.
EDx studies are 
consistent with a sensory greater than motor axonopa-
thy.
Sural nerve biopsy reveals both segmental demy-
elination and axonal loss.
47).
From 
a clinical and EDx standpoint, it can be quite difficult to 
distinguish these disorders.
Most specialists suggest that 
CIM is more common.
Both CIM and CIP develop as 
a complication of sepsis and multiple organ failure.
They 
usually present as an inability to wean a patient from a 
ventilator.
A coexisting encephalopathy may limit the 
neurologic exam, in particular the sensory examination.
Muscle stretch reflexes are absent or reduced.
The pathogenic basis of CIP is not 
known.
Neu-
ropathies are most common in patients with borderline 
leprosy.
Superficial cutaneous nerves of the ears and dis-
tal limbs are commonly affected.
Sen-
sory NCS are usually absent in the lower limb and are 
reduced in amplitude in the arms.
Leprosy is 
usually diagnosed by skin lesion biopsy.
Nerve biopsy can 
also be diagnostic, particularly when there are no appar-
ent skin lesions.
The tuberculoid form is characterized 
by granulomas, and bacilli are not seen.
Patients are generally treated with multiple drugs: dap-
sone, rifampin, and clofazimine.
Patients 
are generally treated for 2 years.
Erythema nodosum leprosum (ENL) is also treated with 
glucocorticoids or thalidomide.
Neurologic complications may develop 
during the second and third stages of infection.
Involvement of nerves is frequently asymmetric.
Some 
patients present with a polyradiculoneuropathy or mul-
tiple mononeuropathies.
EDx is suggestive of a primary 
axonopathy.
Nerve biopsies can reveal axonal degenera-
tion with perivascular inflammation.
Treatment is with 
antibiotics.
DIPHTHERITIC NEUROPATHY
Diphtheria is caused by the bacteria Corynebacterium diph-
theriae.
CSF protein can be elevated with or without 
lymphocytic pleocytosis.
EDx suggests a diffuse axonal 
sensorimotor polyneuropathy.
Antitoxin and antibiotics 
should be given within 48 h of symptom onset.
The neuropathy usually resolves 
after several months.
It is characterized by numbness and 
painful paresthesias involving the distal extremities.
EDx studies reveal features of active axonal degen-
eration.
The polyradiculoneuropathy may improve with 
antiviral therapy.
Weakness, numbness, paresthesias, and pain occur in the 
distribution of affected nerves.
Glucocorticoid treatment is indi-
cated for vasculitis directly due to HIV infection.
Patients develop sensory ataxia similar to 
idiopathic sensory neuronopathy/ganglionopathy.
NCS 
reveal reduced amplitudes or absence of SNAPs.
Treatment of postherpetic neuralgia is symptomatic 
(Table 45-6).
44).
The onset can be acute or insidiously progres-
sive.
Prominent loss of proprioception leads to sensory 
ataxia.
CSF may be nor-
mal or may demonstrate mild lymphocytic pleocytosis 
and elevated protein.
Treatment of 
the underlying cancer generally does not affect the course 
of PEM/SN.
However, occasional patients may improve 
following treatment of the tumor.
Peripheral neuropathy in BMT is often associ-
ated with graft-versus-host disease (GVHD).
EDx can be compatible 
with either an axonal or demyelinating process.
CSF 
may reveal lymphocytic pleocytosis and an elevated 
protein.
A monoclonal population of cells 
favors lymphomatous invasion.
The neuropathy may 
respond to treatment of the underlying lymphoma or 
immunomodulating therapies.
Clinical and EDx features of neu-
ropathy occur in as many as 40% of patients.
The most 
common pattern is that of a distal, axonal, sensory, or 
sensorimotor polyneuropathy.
Less frequently, a chronic 
demyelinating polyradiculoneuropathy may develop (see 
POEMS, Chap.
46).
Expanding plasmacytomas can compress cranial nerves 
and spinal roots as well.
A superimposed 
median neuropathy at the wrist is common.
Abdominal 
fat pad, rectal, or sural nerve biopsy can be performed to 
look for amyloid deposition.
NEUROPATHIES ASSOCIATED WITH 
MONOCLONAL GAMMOPATHY OF 
UNCERTAIN SIGNIFICANCE (SEE CHAP.
The more common neuropathies 
associated with these agents are discussed here.
Serum CK levels are usually elevated due 
to the superimposed myopathy.
Neurogenic MUAPs and 
reduced recruitment are found in more distal muscles.
Nerve biopsy demonstrates autophagic vacuoles within 
Schwann cells.
Vacuoles may also be evident in muscle 
biopsies.
Source: From AA Amato, J Russell: Neuromuscular Disease.
New York, McGraw-Hill, 2008.
Source: From AA Amato, J Russell: Neuromuscular Disease.
New York, McGraw-Hill, 2008.
AMIODARONE
Amiodarone can cause a neuromyopathy similar to 
chloroquine and hydroxychloroquine.
The neuromy-
opathy typically appears after patients have taken the 
medication for 2–3 years.
Nerve biopsy demonstrates 
a combination of segmental demyelination and axo-
nal loss.
COLCHICINE
Colchicine can also cause a neuromyopathy.
EDx reveals 
features of an axonal polyneuropathy.
Muscle biopsy 
reveals a vacuolar myopathy, while sensory nerves dem-
onstrate axonal degeneration.
Colchicine inhibits the 
polymerization of tubulin into microtubules.
Motor NCS are usually normal.
Nerve 
biopsy reveals a loss of large-diameter myelinated fibers 
and axonal degeneration.
Degeneration of dorsal root 
ganglion cells has been reported at autopsy.
NCS reveal absent or markedly reduced SNAP ampli-
tudes with relatively preserved CMAPs.
Nerve biopsy 
reveals axonal loss of fiber at all diameters.
ISONIAZID
One of the most common side effects of isonia-
zid (INH) is peripheral neuropathy.
INH 
inhibits pyridoxal phosphokinase, resulting in pyridox-
ine deficiency and the neuropathy.
Prophylactic admin-
istration of pyridoxine 100 mg/d can prevent the neu-
ropathy from developing.
NCS reveal decreased amplitudes of the SNAPs with 
normal motor studies.
NCS demonstrate decreased ampli-
tudes of the SNAPs and CMAPs with slightly slow 
CVs.
Sensation is generally preserved; however, the 
autonomic nervous system can be affected.
A 24-h urine collection demonstrates 
elevated levels of lead excretion.
The NCS may reveal 
reduced CMAP amplitudes, while the SNAPs are typ-
ically normal.
The pathogenic basis may be related to 
abnormal porphyrin metabolism.
The most important 
principle of management is to remove the source of the 
exposure.
Motor weakness can also develop.
CNS symp-
toms often overshadow the neuropathy.
EDx shows 
features of a primarily axonal sensorimotor polyneu-
ropathy.
The primary site of neuromuscular pathology 
appears to be the dorsal root ganglia.
The mainstay of 
treatment is removing the source of exposure.
Increased thirst, 
sleep disturbances, and psychotic behavior may be 
noted.
With severe intoxica-
tion, proximal weakness and involvement of the cranial 
nerves can occur.
Some patients require mechani-
cal ventilation due to respiratory muscle involvement.
The lethal dose of thallium is variable, ranging from 8 
to 15 mg/kg body weight.
Death can result in less than 
48 h following a particularly large dose.
NCS demon-
strate features of a primarily axonal sensorimotor poly-
neuropathy.
However, there may be 
no benefit once thallium has been absorbed.
Unfortu-
nately, chelating agents are not very efficacious.
ARSENIC
Arsenic is another heavy metal that can cause a toxic 
sensorimotor polyneuropathy.
An underappreciated cause of 
cobalamin deficiency is food-cobalamin malabsorption.
Complaints of numb hands typically appear before 
lower extremity paresthesias are noted.
The full clinical picture of 
subacute combined degeneration is uncommon.
EDx shows an axonal sensorimotor neuropathy.
CNS involvement produces abnormal somatosensory 
and visual evoked potential latencies.
The diagnosis is 
confirmed by finding reduced serum cobalamin levels.
In up to 40% of patients, anemia and macrocytosis are 
lacking.
Cobalamin deficiency can be treated with various 
regimens of cobalamin.
An oral 
cobalamin dose of 1000 μg per day should be sufficient.
Thiamine is water-soluble.
Dry beriberi refers to neuro-
pathic symptoms.
The term wet beriberi is used when car-
diac manifestations predominate (in reference to edema).
Symptoms of neuropathy follow prolonged defi-
ciency.
Pain may be the predomi-
nant symptom.
Blood and urine assays for thiamine are not reli-
able for diagnosis of deficiency.
EDx shows 
nonspecific findings of an axonal sensorimotor poly-
neuropathy.
Thiamine is 
usually given intravenously or intramuscularly at a dose 
of 100 mg/d.
Patients with cys-
tic fibrosis may also have vitamin E deficiency secondary 
to steatorrhea.
There are genetic forms of isolated vita-
min E deficiency not associated with lipid malabsorption.
Clinical features may not appear until many years after 
the onset of deficiency.
The onset of symptoms tends to 
be insidious, and progression is slow.
Vitamin E deficiency 
may present as an isolated polyneuropathy, but this is 
very rare.
Diagnosis is made by measuring α-tocopherol levels 
in the serum.
EDx shows features of an axonal neuropa-
thy.
Treatment is replacement with oral vitamin E, but 
high doses are not needed.
Vita-
min B6 toxicity was discussed earlier.
Vitamin B6 defi-
ciency is most commonly seen in patients treated with 
isoniazid or hydralazine.
Vitamin B6 deficiency can 
be detected by direct assay.
This same dose is appro-
priate for replacement in cases of nutritional deficiency.
PELLAGRA (NIACIN DEFICIENCY)
Pellagra is produced by deficiency of niacin.
When peripheral nerves are involved, the neuropathy is 
usually mild and resembles beriberi.
Treatment is with 
niacin 40–250 mg/d.
Most 
patients present with lower limb paresthesias, weakness, 
spasticity, and gait difficulties.
Large-fiber sensory func-
tion is impaired, reflexes are brisk, and plantar responses 
are extensor.
Excess zinc is an established cause of cop-
per deficiency.
Replacement 
consists of oral copper sulfate or gluconate 2 mg one 
to three times a day.
Thereafter, oral daily copper therapy can 
be resumed.
Neuropathy 
following weight loss surgery usually occurs in the first 
several months after surgery.
The initial manifestations are usually 
numbness and paresthesias in the feet.
In many cases, no 
specific nutritional deficiency factor is identified.
Management consists of parenteral vitamin supple-
mentation, especially including thiamine.
CSPN should 
be considered a distinct diagnostic subset of periph-
eral neuropathy.
The onset of CSPN is predominantly 
in the sixth and seventh decades.
However, 
tandem gait may be abnormal in a minority of cases.
Neither subjective nor objective evidence of weakness 
is a prominent feature.
Most patients have evidence of 
both large- and small-fiber loss on neurologic exam and 
EDx.
Approximately 10% of patients have only evi-
dence of small-fiber involvement.
Therapy primarily involves the control of 
neuropathic pain (Table 45-6) if present.
These drugs 
should not be used if the patient has only numbness and 
tingling but no pain.
The disorder does not lead to sig-
nificant motor disability over time.
The relatively benign 
course of this disorder should be explained to patients.
CTS is common and often misdiagnosed 
as thoracic outlet syndrome.
These often occur as a par-
tial form of brachial plexitis.
Triceps 
and brachioradialis strength is often normal, and triceps 
reflex is often intact.
The 
neuropathy affecting this nerve is also known as meral-
gia paresthetica.
Symptoms and signs consist of paresthe-
sias, numbness, and occasionally pain in the lateral thigh.
Symptoms are increased by standing or walking and are 
relieved by sitting.
There is normal strength and knee 
reflexes are intact.
The diagnosis is clinical, and further 
tests usually are not performed.
EDx is only needed to 
rule out lumbar plexopathy, radiculopathy, or femoral 
neuropathy.
If the symptoms and signs are classic, elec-
tromyography is not necessary.
Treatment con-
sists of weight loss and avoiding tight belts.
Rarely, locally injecting the nerve 
with an anesthetic can be tried.
There is no role for 
surgery.
Patients with femoral 
neuropathy have difficulty extending their knee and 
flexing the hip.
The quadriceps (patellar) 
reflex is diminished.
In addition, many sci-
atic neuropathies are idiopathic.
Sensory loss occurs in the 
entire foot and the distal lateral leg.
There is usually 
no pain.
Onset may be on awakening in the morning.
Peroneal neuropathy needs to be distinguished from 
L5 radiculopathy.
EDx can help localize the lesion.
Peroneal motor conduction velocity shows slowing 
and amplitude drop across the fibular head.
Manage-
ment consists of rapid weight loss and avoiding leg 
crossing.
Footdrop is treated with an ankle brace.
A 
knee pad can be worn over the lateral knee to avoid 
further compression.
Most cases spontaneously resolve 
over weeks or months.
9.
45-2).
There are several disorders commonly associated 
with brachial plexopathy.
IBPN usually presents with an acute onset of severe 
pain in the shoulder region.
The intense pain usually 
lasts several days to a few weeks, but a dull ache can 
persist.
However, as the pain dissipates, 
weakness and often sensory loss are appreciated.
Attacks 
can occasionally recur.
Additionally, the phrenic 
and anterior interosseous nerves may be concomitantly 
affected.
Any of these nerves may also be affected in iso-
lation.
EDx is useful to confirm and localize the site(s) 
of involvement.
Empirical treatment of severe pain with 
glucocorticoids is often used in the acute period.
Sec-
ondary tumors affecting the brachial plexus are more 
common and are always malignant.
These may arise 
from local tumors, expanding into the plexus.
Chest CT scans or MRI can demon-
strate extension of the tumor into the plexus.
45-3).
The 
obturator nerve arises from the ventral branches of the 
same lumbar rami.
45-4).
T12
Lateral femoral
cutaneous n.
Femoral n.
T12
Iliohypogastric n.
Ilioinguinal n.
Genitofemoral n.
Obturator n.
Lumbosacral trunk
L1
L2
L3
L4
L5
FIGURE 45-3 
Lumbar plexus.
Posterior divisions are in orange, anterior 
divisions are in yellow.
(From J Goodgold: Anatomical Cor-
relates of Clinical Electromyography.
Baltimore, Williams and 
Wilkins, 1974, p.
126, with permission.)
FIGURE 45-2 
Brachial plexus anatomy.
L, lateral; M, medial; P, poste-
rior.
(From J Goodgold: Anatomical Correlates of Clinical 
Electromyography.
Baltimore, Williams and Wilkins, 1974, p.
The causes of lumbosacral plexopathies are listed in 
Table 45-10.
Diabetic radiculopathy (discussed ear-
lier) is a fairly common cause of painful leg weakness.
Lumbosacral plexopathies are a well-recognized compli-
cation of retroperitoneal hemorrhage.
Radiation-induced plexopathy can develop months 
or years following therapy and is dose dependent.
Posterior divisions are in orange, 
anterior divisions are in yellow.
(From J Goodgold: Anatomi-
cal Correlates of Clinical Electromyography.
Baltimore, Wil-
liams and Wilkins, 1974, p.
Stephen  L.
Hauser  ■       Anthony  A.
The usual 
pattern is an ascending paralysis that may be fi rst noticed 
as rubbery legs.
Deep tendon refl exes attenuate or 
disappear within the fi rst few days of onset.
Bladder dys-
function may occur in severe cases but is usually tran-
sient.
Autonomic involvement is common and may occur 
even in patients whose GBS is otherwise mild.
These features require 
close monitoring and management and can be fatal.
These 
pains are self-limited and often respond to standard 
analgesics ( Chap.
7 ).
The most common 
variant is acute infl ammatory demyelinating polyneurop-
athy (AIDP).
In addition, a range 
of limited or regional GBS syndromes are also encoun-
tered.
33).
C.
It is likely that both cellular and humoral immune 
mechanisms contribute to tissue damage in AIDP.
46-1).
The neural targets are likely 
to be glycoconjugates, specifically gangliosides (Table 
46-2; Fig.
46-2).
jejuni 
infection.
Furthermore, isolates of C.
Sialic 
acid residues from pathogenic C.
Anti-GQ1b IgG antibodies are found in >90% of 
patients with MFS (Table 46-2; Fig.
jejuni infection.
B cells recognize glycoconjugates 
on C.
Some B cells, activated via a T cell–indepen-
dent mechanism, secrete primarily IgM (not shown).
SECTION III
Diseases of the Nervous System
602
of IgG are highest early in the course.
In addition, a monoclonal anti-
GQ1b antibody raised against C.
jejuni isolated from a 
patient with MFS blocked neuromuscular transmission 
experimentally.
Source: Modified from HJ Willison, N Yuki: Brain 125:2591, 2002.
Hence, recovery can take place rapidly as remyelination 
occurs.
Diagnosis
GBS is a descriptive entity.
Laboratory tests are 
helpful primarily to exclude mimics of GBS.
Tau 
increases in CSF may reflect axonal damage and pre-
dict a residual deficit.
A combination of the two therapies is not signifi-
cantly better than either alone.
IVIg is administered as five 
daily infusions for a total dose of 2 g/kg body weight.
Brief retreatment with 
the original therapy is usually effective in such cases.
Glucocorticoids have not been found to be effective in 
GBS.
Required for Diagnosis
1.
Progressive weakness of variable degree from mild 
paresis to complete paralysis
2.
Generalized hypo- or areflexia
 II.
Supportive of Diagnosis
1.
Clinical Features
a.
Symptom progression: Motor weakness rapidly 
progresses initially but ceases by 4 weeks.
Nadir 
attained by 2 weeks in 50%, 3 weeks 80%, and 
90% by 4 weeks.
b.
Demonstration of relative limb symmetry regard-
ing paresis.
c.
Mild to moderate sensory signs.
d.
e.
Recovery typically begins 2–4 weeks following 
plateau phase.
f.
g.
2.
Cerebrospinal Fluid Features Supporting Diagnosis
a.
Elevated or serial elevation of CSF protein.
b.
CSF cell counts are <10 mononuclear cell/mm3.
3.
Electrodiagnostic Medicine Findings Supportive of 
Diagnosis
a.
b.
Patchy reduction in NCV attaining values less 
than 60% of normal.
c.
Distal motor latency increase may reach 3 times 
normal values.
d.
F-waves indicate proximal NCV slowing.
e.
About 15–20% of patients have normal NCV 
findings.
f.
No abnormalities on nerve conduction studies 
may be seen for several weeks.
III.
Findings Reducing Possibility of Diagnosis
1.
Asymmetric weakness
2.
Failure of bowel/bladder symptoms to resolve
3.
Severe bowel/bladder dysfunction at initiation of 
disease
4.
Greater than 50 mononuclear cells/mm3 in CSF
5.
Well-demarcated sensory level
 IV.
Exclusionary Criteria
1.
2.
Source: AA Amato, D Dumitru, in D Dumitru et al (eds): Electrodiag-
nostic Medicine, 2nd ed.
Philadelphia, Hanley & Belfus, 2002.
The out-
look is worst in patients with severe proximal motor 
and sensory axonal damage.
Most cases occur in 
adults, and males are affected slightly more often than 
females.
Symptoms are 
both motor and sensory in most cases.
There is considerable variability from case 
to case.
A small 
proportion have cranial nerve findings, including exter-
nal ophthalmoplegia.
Death from CIDP is uncommon.
Diagnosis
The diagnosis rests on characteristic clinical, CSF, and 
electrophysiologic findings.
The CSF is usually acellular 
with an elevated protein level, sometimes several times 
normal.
Evidence of axonal loss, presum-
ably secondary to demyelination, is present in >50% of 
patients.
Other associated conditions include 
inflammatory bowel disease and lymphoma.
46-1).
If the dis-
order is mild, management can be expectant, awaiting 
spontaneous remission.
Early 
experience with anti-CD20 (rituximab) has also shown 
promise.
Use of these therapies requires periodic reas-
sessment of their risks and benefits.
Sensory fibers 
are relatively spared.
The arms are affected more fre-
quently than the legs, and >75% of all patients are 
male.
32).
Pathology reveals demyelination and 
mild inflammatory changes at the sites of conduction 
block.
Some refractory patients have 
responded to rituximab or cyclophosphamide.
Gluco-
corticoids and PE are not effective.
In most cases, Edx 
and pathologic features are consistent with a process of 
axonal degeneration.
Most patients are male and older than age 50 years.
46-1).
Demyelination and remyelination are the hallmarks 
of the lesions.
Symptoms 
of neuropathy are a common presenting complaint in 
patients with PAN.
The Edx findings are those of an 
axonal process.
Consti-
tutional symptoms are absent, and the course is more 
indolent than that of PAN.
Neurologic 
symptoms usually precede, by ≤6 months, the identi-
fication of SCLC.
Daniel B.
Treatment now available for MG is highly 
effective, although a specifi c cure has remained elusive.
PATHOPHYSIOLOGY 
 At the neuromuscular junction  ( Fig.
AChE, acetylcholinesterase.
See text for 
description of normal neuromuscular transmission.
Failure of transmission at many neuromuscular junctions 
results in weakness of muscle contraction.
The pathogenic antibodies are IgG, and are T cell-
dependent.
An additional 
10% of patients have thymic tumors (thymomas).
CLINICAL FEATURES
MG is not rare, having a prevalence of 2–7 in 10,000.
Overall, women 
are affected more frequently than men, in a ratio of 
∼3:2.
The cardinal features are weakness and fatigability 
of muscles.
The course of MG is often variable.
Remis-
sions are rarely complete or permanent.
The distribution of muscle weakness often has a 
characteristic pattern.
Facial weakness produces a 
“snarling” expression when the patient attempts to 
smile.
Weakness in chewing is most noticeable after 
prolonged effort, as in chewing meat.
Bul-
bar weakness is especially prominent in MuSK anti-
body–positive MG.
In ∼85% of patients, the weakness 
becomes generalized, affecting the limb muscles as well.
The limb weakness in MG is often proximal and may 
be asymmetric.
Despite the muscle weakness, deep ten-
don reflexes are preserved.
Anti-AChE medication is 
stopped 6–24 h before testing.
It is best to test weak 
muscles or proximal muscle groups.
An initial IV dose 
of 2 mg of edrophonium is given.
If definite improve-
ment occurs, the test is considered positive and is ter-
minated.
If there is no change, the patient is given an 
additional 8 mg IV.
False-negative or equivocal tests may also 
occur.
∼40% 
of AChR antibody–negative patients with generalized 
MG have anti-MuSK antibodies.
Source: From RT Johnson, JW Griffin (eds): Current Therapy in 
Neurologic Disease, 4th ed.
St.
Louis, Mosby Year Book, 1994; with 
permission.
Features of four of the most com-
mon forms of CMS are summarized in Table 47-2.
These autoantibod-
ies result in impaired release of ACh from nerve ter-
minals.
Treatment of LEMS involves plasmapher-
esis and immunosuppression, as for MG.
3,4-Diami-
nopyridine (3,4-DAP) and pyridostigmine may also 
be symptomatically helpful.
Pyridostigmine prolongs the 
action of ACh, allowing repeated interactions with 
AChRs.
Most commonly, botulism is caused 
by ingestion of improperly prepared food containing 
toxin.
Rarely, the nearly ubiquitous spores of C.
botu-
linum may germinate in wounds.
In infants the spores 
may germinate in the GI tract, and release toxin, caus-
ing muscle weakness.
Weakness 
may generalize to the limbs and may result in respira-
tory failure.
Reflexes are present early, but they may be 
diminished as the disease progresses.
Mentation is nor-
mal.
Antitoxin 
should be given as early as possible to be effective.
A 
preventive vaccine is available for laboratory workers 
or other highly exposed individuals.
Neurasthenia is the historic term for a myasthenia-like 
fatigue syndrome without an organic basis.
Abnormali-
ties of thyroid function (hyper- or hypothyroidism) may 
increase myasthenic weakness.
48).
Thymic abnor-
malities occur in ∼75% of patients, as noted earlier.
Hyperthy-
roidism occurs in 3–8% of patients and may aggravate 
the myasthenic weakness.
Thyroid function tests should 
be obtained in all patients with suspected MG.
Source: From RT Johnson, JW Griffin (eds): Current Therapy in 
Neurologic Disease, 4th ed.
St.
Louis, Mosby Year Book, 1993, p 
379; with permission.
Chronic infection 
of any kind can exacerbate MG and should be sought 
carefully.
Nearly all myasthenic patients 
can be returned to full productive lives with proper 
therapy.
47-2).
Pyridostigmine 
is the most widely used anticholinesterase drug.
Treatment is begun with a moderate dose, e.g., 
30–60 mg three to four times daily.
The maximum useful dose of pyridostig-
mine rarely exceeds 120 mg every 4–6 h during day-
time.
Overdosage with anticholinesterase medication 
may cause increased weakness and other side effects.
Atropine/
diphenoxylate or loperamide is useful for the treatment 
of gastrointestinal symptoms.
However, the 
improvement is typically delayed for months to years.
FVC, forced vital capacity.
We recommend 
maintenance immunotherapy after rebooting, to sus-
tain the beneficial effect.
Few patients are able to do 
without immunosuppressive agents entirely.
A dose of 
1–1.5 g bid is recommended.
Its mechanism of action 
involves inhibition of purine synthesis by the de novo 
pathway.
An initial dose of 50 mg/d should be used 
for several days to test for these side effects.
The beneficial effect of azathioprine 
takes 3–6 months to begin and even longer to peak.
In 
patients taking azathioprine, allopurinol should never 
be used to treat hyperuricemia.
Their beneficial effect appears more rapidly 
than that of azathioprine.
“Trough” blood levels are measured 12 h after the 
evening dose.
This treatment 
has the advantages of not requiring special equipment 
or large-bore venous access.
The usual dose is 2 g/kg, 
which is typically administered over 5 days (400 mg/kg 
per d).
If tolerated, the total dose of IVIg can be given 
over a 3- to 4-day period.
Crisis rarely occurs in properly 
managed patients.
The most common cause of crisis is intercurrent 
infection.
As discussed earlier, plasmapheresis or IVIg is frequently 
helpful in hastening recovery.
Conversely, not all 
“safe” drugs can be used with impunity in patients with 
MG.
47-3.
Azathioprine
Avoid allopurinol—combination may result in myelosup-
pression.
Anthony  A.
Amato    ■     Robert  H.
Brown, Jr.
Myasthenia gravis and related disorders are discussed 
in  Chap.
47 ; dermatomyositis, polymyositis, and inclu-
sion body myositis are discussed in  Chap.
49 .
However, asymmetric and predomi-
nantly distal weakness can be seen in some myopathies.
Muscle weakness 
 Symptoms of muscle weakness can be either intermit-
tent or persistent.
Disorders causing  intermittent weakness
 ( Fig.
Most muscle disorders cause  persistent weakness   ( Fig.
48-2 ) .
The dif-
ferential diagnosis is more restricted for other patterns 
of weakness.
Facial weakness (diffi culty with eye closure 
and impaired smile) and scapular winging  ( Fig.
48-3 )  
are characteristic of facioscapulohumeral dystrophy 
(FSHD).
The Gowers’ sign  ( Fig.
48-4 )  is particularly 
useful.
Examina-
tion reveals one of seven patterns of weakness.
The pattern 
of weakness in combination with the laboratory evaluation 
leads to a diagnosis.
48-5).
A waddling gait is caused by the inabil-
ity of weak hip muscles to prevent hip drop or hip dip.
Associated 
symptoms may help differentiate asthenia and pathologic 
fatigability.
There may be feelings of 
overwhelming stress and depression.
Thus, asthenia is not 
a myopathy.
Pathologic fatigability is accompanied by abnormal clinical 
or laboratory findings.
Fatigue without those supportive 
features almost never indicates a primary muscle disease.
Certain drugs cause 
true myalgia (Table 48-3).
Fibromyalgia is a common, yet poorly 
understood, type of myofascial pain syndrome.
The ESR is elevated, while 
serum CK, EMG, and muscle biopsy are normal.
Vision is threatened by ischemic optic 
neuritis.
Glucocorticoids can relieve the myalgias and 
protect against visual loss.
Localized muscle pain is most often traumatic.
The biceps brachii and Achilles tendons are 
particularly vulnerable to rupture.
Infection or neoplas-
tic infiltration of the muscle is a rare cause of localized 
muscle pain.
Cramps are abrupt in onset, 
short in duration, and may cause abnormal posturing 
of the joint.
The EMG shows firing of motor units, 
reflecting an origin from spontaneous neural discharge.
Muscle cramps often occur in neurogenic disorders, 
especially motor neuron disease (Chap.
32), radicu-
lopathies, and polyneuropathies (Chap.
45), but are not 
a feature of most primary muscle diseases.
Muscle cramps are 
also common during pregnancy.
A muscle contracture is different from a muscle cramp.
The muscle is unable to relax after an active muscle con-
traction.
The EMG shows electrical silence.
Muscle stiffness can refer to different phenomena.
Some patients with inflammation of joints and periar-
ticular surfaces feel stiff.
The gait becomes stiff and labored, with hyper-
lordosis of the lumbar spine.
The muscles 
relax during sleep.
Myotonia is a condition of prolonged muscle con-
traction followed by slow muscle relaxation.
Myotonia 
typically causes difficulty in releasing objects after a firm 
grasp.
Another sodium channelopa-
thy, paramyotonia congenita, also is associated with muscle 
stiffness.
The calf muscles remain very strong even late 
in the course of these disorders.
In contrast, muscle atrophy is char-
acteristic of other myopathies.
Atrophy of the humeral muscles is characteristic 
of facioscapulohumeral dystrophy (FSHD).
LABORATORY EVALUATION
A limited battery of tests can be used to evaluate a sus-
pected myopathy.
Serum enzymes
CK is the preferred muscle enzyme to measure in the 
evaluation of myopathies.
Electrodiagnostic studies
EMG, repetitive nerve stimulation, and nerve conduc-
tion studies (Chap.
5) are essential methods for evalu-
ation of the patient with suspected muscle disease.
Nevertheless, there are 
a number of limitations in currently available molecu-
lar diagnostics.
Many variations of the fore-
arm exercise test exist.
The test is performed by placing a small indwell-
ing catheter into an antecubital vein.
A baseline blood 
sample is obtained for lactic acid and ammonia.
A three- to four-
fold rise of lactic acid is typical.
If there is lack of 
effort, neither lactic acid nor ammonia will rise.
Patients 
with selective failure to increase ammonia may have 
myoadenylate deaminase deficiency.
Not all 
techniques are needed for every case.
A specific diag-
nosis can be established in many disorders.
Biopsied muscle tissue can be sent 
for metabolic enzyme or mitochondrial DNA analyses.
The boys fall frequently and have difficulty 
keeping up with friends when playing.
Running, 
jumping, and hopping are invariably abnormal.
By age  
5 years, muscle weakness is obvious by muscle test-
ing.
48-4]).
By age 12 years, most patients are wheelchair 
dependent.
By age 16–18 years, patients are predisposed 
to serious, sometimes fatal pulmonary infections.
Other 
causes of death include aspiration of food and acute gas-
tric dilation.
Congestive heart failure seldom occurs except with 
severe stress such as pneumonia.
Cardiac arrhyth-
mias are rare.
Laboratory features
Serum CK levels are invariably elevated to between 20 
and 100 times normal.
EMG demonstrates features typical 
of myopathy.
Connective tissue and fat replace 
lost muscle fibers.
The dystrophin gene is >2000 kb in size 
and thus is one of the largest identified human genes.
Many features overlap (see text).
Xp21.
The most common gene mutation is a deletion.
The size varies but does not correlate with disease 
severity.
Less often, Duch-
enne’s dystrophy is caused by a gene duplication or 
point mutation.
48-6).
Dystrophin binds 
to F-actin at its amino terminus and to β-dystroglycan 
at the carboxyl terminus.
The laminin heavy 
chain of skeletal muscle is designated laminin α2.
Colla-
gen proteins IV and VI are also found in the ECM.
These 
include caveolin-3, α7 integrin, and collagen VI.
Dystrophin localizes to the cytoplasmic face of 
the muscle cell membrane.
It complexes with two 
transmembrane protein complexes, the dystroglycans 
and the sarcoglycans.
Deficiency of one member of 
the complex may cause abnormalities in other compo-
nents.
This sequence 
of events occurs repeatedly during the life of a patient 
with muscular dystrophy.
Proximal muscles, especially of the lower extremities, 
are prominently involved.
As the disease progresses, 
weakness becomes more generalized.
Significant facial 
muscle weakness is not a feature.
Hypertrophy of mus-
cles, particularly in the calves, is an early and prominent 
finding.
Mental retardation may occur in Becker’s dystro-
phy, but it is not as common as in Duchenne’s.
LIMB-GIRDLE MUSCULAR DYSTROPHY
The syndrome of LGMD represents more than one 
disorder.
The LGMDs typically manifest with progres-
sive weakness of pelvic and shoulder girdle musculature.
Respiratory insufficiency from weakness of the dia-
phragm may occur, as may cardiomyopathy.
Disorders receive letters in the order 
in which they are found to have chromosomal linkage.
This results in an ever-expanding list of conditions.
The cardiomyopathy is potentially 
life threatening and may result in sudden death.
Some patients have a dilated cardiomyopathy.
Laboratory features
Serum CK may be elevated two- to tenfold.
EMG is 
myopathic.
ECGs demonstrate atrial and atrioventricular 
rhythm disturbances.
X-linked EDMD usually arises from defects in the 
emerin gene encoding a nuclear envelope protein.
48-7).
Stretching of contractures is difficult.
The position of 
the dystrophin-dystroglycan complex is also illustrated.
Calf muscle hypertrophy is 
seen in some patients.
Most patients have 
joint contractures of varying degrees at elbows, hips, 
knees, and ankles.
Contractures present at birth are 
referred to as arthrogryposis.
Respiratory failure may be 
seen in some cases.
The CNS is affected in some forms of CMD.
Three forms of congenital muscular dystrophy have 
severe brain impairment.
Patients are severely disabled in all three of 
these conditions.
In MEB disease and WWS, but not 
in FCMD, ocular abnormalities impair vision.
WWS is 
the most severe congenital muscular dystrophy, causing 
death by 1 year of age.
Laboratory features
Serum CK is markedly elevated in all of these con-
ditions.
The EMG is myopathic and muscle biopsies 
show nonspecific dystrophic features.
Skin biopsies can also demonstrate defects in laminin 
α2 chain.
All forms of CMD are inherited as autosomal reces-
sive disorders.
Chromosomal linkage and specific gene 
defects are presented in Table 48-8.
TREATMENT  Congenital Muscular Dystrophy
There is no specific treatment for CMD.
Proper wheel-
chair seating is important.
Management of epilepsy and 
cardiac manifestations is necessary for some patients.
MYOTONIC DYSTROPHY
Myotonic dystrophy is also known as dystrophia myo-
tonica (DM).
Frontal baldness is also characteristic of 
the disease.
Weakness of wrist extensors, finger extensors, and 
intrinsic hand muscles impairs function.
Ankle dorsi-
flexor weakness may cause footdrop.
Myotonia causes 
a slow relaxation of hand grip after a forced voluntary 
closure.
Advanced muscle wasting makes myotonia 
more difficult to detect.
Cardiac disturbances occur commonly in patients 
with DM1.
Complete heart block and sudden death can 
occur.
Mitral valve prolapse also occurs commonly.
DM2, or PROMM, has a distinct pattern of muscle 
weakness affecting mainly proximal muscles.
A very 
striking difference is the failure to clearly identify a con-
genital form of DM2.
Serum CK lev-
els may be normal or mildly elevated.
bThere is phenotypic overlap between disorders related to defective glycosylation.
Clinically, Walker-Warburg syndrome is more severe, with death by 1 year.
DM1 and DM2 are both autosomal dominant 
disorders.
New mutations do not appear to contribute 
to the pool of affected individuals.
A similar type of mutation 
has been identified in fragile X syndrome.
The unsta-
ble triplet repeat in myotonic dystrophy can be used 
for prenatal diagnosis.
Molded ankle-
foot orthoses help stabilize gait in patients with foot 
drop.
Excessive daytime somnolence with or without 
sleep apnea is not uncommon.
There are two forms of FSHD that have 
similar pathogenesis, as will be discussed.
Most patients 
have FSHD type 1 (95%), while approximately 5% have 
FSHD2.
FSHD1 and FSHD2 are clinically and his-
topathologically identical.
FSHD is not to be confused 
with the genetically distinct scapuloperoneal dystrophies.
Clinical features
The condition typically has an onset in childhood or 
young adulthood.
Loss of scapular stabi-
lizer muscles makes arm elevation difficult.
Scapular 
winging (Fig.
48-3) becomes apparent with attempts at 
abduction and forward movement of the arms.
Laboratory features
The serum CK level may be normal or mildly elevated.
EMG usually indicates a myopathic pattern.
The mus-
cle biopsy shows nonspecific features of a myopathy.
The cause or significance of this finding is 
unknown.
FSHD1 is associated with 
deletions of tandem 3.3-kb repeats at 4q35.
The dele-
tion reduces the number of repeats to a fragment of 
<35 kb in most patients.
Within these repeats lies the 
DUX4 gene, which usually is not expressed.
Scapular stabilization proce-
dures improve scapular winging but may not improve 
function.
The extraocular muscle impairment 
is less prominent in the early phase but may be severe 
later.
Mild weakness of the neck and extremities 
also occurs.
Laboratory features
The serum CK level may be two to three times normal.
Myopathic EMG findings are typical.
Oculopharyngeal dystrophy has an autosomal domi-
nant inheritance pattern with complete penetrance.
Large kindreds of Italian and of eastern European Jew-
ish descent have been reported.
Cricopha-
ryngeal myotomy may improve swallowing, although 
it does not prevent aspiration.
The major distal myopa-
thies are summarized in Table 48-9.
In the 
other conditions, serum CK is only slightly increased.
EMGs are myopathic.
In the MFMs, myotonic or pseu-
domyotonic discharges are common.
The affected genes and their gene products are listed 
in Table 48-9.
The gene for Welander’s disease awaits 
identification.
Laing’s-type distal myopathy can also be associated with 
a cardiomyopathy.
Sarcotubular myopathy 
is caused by mutations in TRIM-32 and is identical to 
LGMD2H.
Hypotonia 
and delay in motor milestones, particularly in walk-
ing, are common.
On examination, there is mild facial, 
neck-flexor, and proximal-extremity muscle weakness.
Legs are more affected than arms.
Most cases are nonpro-
gressive, but exceptions are well documented.
The serum CK level is usually normal.
Needle EMG 
demonstrates a myopathic pattern.
Autosomal dominant inheritance is characteristic; 
sporadic cases also occur.
Nemaline myopathy is clinically het-
erogeneous.
Nemaline myopathy usually presents 
in infancy or childhood with delayed motor milestones.
The course is nonprogressive or slowly progressive.
Facial and gen-
eralized muscle weakness, including respiratory muscle 
weakness, is common.
An adult-onset disorder with 
progressive proximal weakness may be seen.
Myocar-
dial involvement is occasionally present in both the 
childhood and adult-onset forms.
The serum CK level 
is usually normal or slightly elevated.
The EMG dem-
onstrates a myopathic pattern.
Occasionally, the rods are also 
apparent in myonuclei.
The muscle often shows type 1 
muscle fiber predominance.
Rods originate from the Z 
disk material of the muscle fiber.
Six genes have been associated with nemaline myop-
athy.
No specific treatment is available.
CENTRONUCLEAR (MYOTUBULAR) 
MYOPATHY
Three distinct variants of centronuclear myopathy 
occur.
The late infancy–early childhood form presents 
with delayed motor milestones.
Later, difficulty with 
running and stair climbing becomes apparent.
A mar-
fanoid, slender body habitus, long narrow face, and 
high-arched palate are typical.
Scoliosis and clubbed feet 
may be present.
Most patients exhibit progressive weak-
ness, some requiring wheelchairs.
A third 
variant, the late childhood–adult form, has an onset in 
the second or third decade.
Patients have full extraocu-
lar muscle movements and rarely exhibit ptosis.
45]).
Normal or slightly elevated CK levels occur in each 
of the forms.
In transverse sections, central nuclei 
are found in 25–80% of muscle fibers.
Carrier 
identification and prenatal diagnosis are possible.
No specific medical treatments are available 
at this time.
The infantile form is the most common, with onset of 
symptoms in the first 3 months of life.
Infants develop 
severe muscle weakness, cardiomegaly, hepatomegaly, 
and respiratory insufficiency.
Death usually occurs 
by 1 year of age.
In the childhood form, the picture 
resembles muscular dystrophy.
The heart may 
be involved, but the liver and brain are unaffected.
The heart and liver are not 
involved.
EMG discharges are very promi-
nent in the paraspinal muscles.
Electron 
microscopy reveals membrane-bound and free tis-
sue glycogen.
Enzyme analysis of dried blood spots is 
a sensitive technique to screen for Pompe’s disease.
Rarely, myoglobinuria may be seen.
Clinical muscle manifestations in these conditions 
usually begin in adolescence.
Acute renal failure accompanies significant pigmenturia.
Certain features help distinguish some enzyme defects.
CK levels >100 times normal are 
expected, accompanying myoglobinuria.
An 
impaired rise in venous lactate is highly indicative of a 
glycolytic defect.
Phospho-
glycerate kinase deficiency is X-linked recessive.
Training may enhance exercise tolerance, perhaps 
by increasing perfusion to muscle.
Oxidation of fatty acids occurs in the 
mitochondria.
CPT I is present 
on the inner side of the outer mitochondrial membrane.
Onset is usually in the teenage 
years or early twenties.
Strength is 
normal between attacks.
Episodes of rhabdomyolysis may produce severe 
weakness.
Serum CK levels and EMG findings are both usually 
normal between episodes.
Muscle biopsy does not show lipid accumu-
lation and is usually normal between attacks.
The diag-
nosis requires direct measurement of muscle CPT or 
genetic testing.
A mutation in the gene 
for CPT II (chromosome 1p36) causes the disease in 
some individuals.
Most individuals 
with myoadenylate deaminase deficiency have no symp-
toms.
Mitochondria play a key role in energy production.
A novel feature of mitochondria is their genetic com-
position.
Each mitochondrion possesses a DNA genome 
that is distinct from that of the nuclear DNA.
The 
genetics of mitochondrial diseases differ from the genet-
ics of chromosomal disorders.
Some patients with CPEO and ragged 
red fibers may not fulfill all of the criteria for KSS.
Death attributed to heart block occurs in 
∼20% of the patients.
Both mental retardation and dementia are 
common accompaniments to this disorder.
Serum CK 
levels are normal or slightly elevated.
Serum lactate and 
pyruvate levels may be elevated.
EMG is myopathic.
Nerve conduction studies may be abnormal related to 
an associated neuropathy.
KSS is a sporadic disorder.
Monitoring for 
cardiac conduction defects is critical.
Prophylactic pace-
maker implantation is indicated when ECGs demon-
strate a bifascicular block.
Onset is usually 
after puberty.
Fatigue, exercise intolerance, and com-
plaints of muscle weakness are typical.
Some patients 
notice swallowing problems.
A sensorineural hearing 
loss may be encountered.
Mild facial, neck flexor, and 
proximal weakness are typical.
Rarely, respiratory mus-
cles may be progressively affected and may be the direct 
cause of death.
Serum CK is normal or mildly elevated.
The resting lactate level is normal or slightly elevated 
but may rise excessively after exercise.
CSF protein is 
normal.
The EMG is myopathic, and nerve conduction 
studies are usually normal.
Ragged red fibers are prom-
inently displayed in the muscle biopsy.
In the chromosome 10q–
related disorder, mutations of the gene C10orf2 are 
found.
Autosomal recessive PEO has also been described with 
mutations in the POLG gene.
Exercise may improve function but will depend on 
the patient’s ability to participate.
The seizure disorder 
is an integral part of the disease and may be the initial 
symptom.
Cerebellar ataxia precedes or accompanies 
epilepsy.
It is slowly progressive and generalized.
Serum CK levels are normal or slightly increased.
The 
serum lactate may be elevated.
EMG is myopathic, and in 
some patients nerve conduction studies show a neuropa - 
thy.
The electroencephalogram is abnormal, corroborat-
ing clinical findings of epilepsy.
Typical ragged red fibers 
are seen on muscle biopsy.
MERRF is caused by mater-
nally inherited point mutations of mitochondrial tRNA 
genes.
Other tRNAlys 
mutations include base-pair substitutions T8356C and 
G8363A.
Only supportive treatment is possible, with spe-
cial attention to epilepsy.
The onset in the majority of patients is before 
age 20.
In its full expression, MELAS leads to 
dementia, a bedridden state, and a fatal outcome.
Serum 
lactic acid is typically elevated.
The CSF protein is also 
increased but is usually f1 g/L (100 mg/dL).
Muscle 
biopsies show ragged red fibers.
Neuroimaging dem-
onstrates basal ganglia calcification in a high percentage 
of cases.
Focal lesions that mimic infarction are present 
predominantly in the occipital and parietal lobes.
MELAS is caused by maternally inherited point 
mutations of mitochondrial tRNA genes.
The 
A3243G point mutation in tRNALeu(UUR) is the most 
common, occurring in ∼80% of MELAS cases.
Mutations have also been reported in mtDNA 
polypeptide-coding genes.
Two mutations were found in 
the ND5 subunit of complex I of the respiratory chain.
No specific treatment is available.
Supportive treat-
ment is essential for the strokelike episodes, seizures, and 
endocrinopathies.
The clinical phenotypes associated with MDS 
vary.
The heart may 
also be involved, resulting in life-threatening complica-
tions (Table 48-10).
Men are more often 
affected because of decreased penetrance in women.
Weakness usually affects proximal limb muscles more 
than distal.
Ocular and bulbar muscles are less likely to be 
affected.
Respiratory muscles are usually spared but when 
they are involved, the condition may prove fatal.
Weak-
ness may take as long as 24 h to resolve.
Life-threatening 
cardiac arrhythmias related to hypokalemia may occur 
during attacks.
Attacks of thyrotoxic periodic paralysis resemble 
those of primary HypoKPP.
Attacks abate with treatment of the underlying 
thyroid condition.
HypoKPP is caused by mutations in either of two 
genes.
48-8).
The chloride channel is envisioned to have 10 
membrane-spanning domains.
Muscle strength and ECG should be moni-
tored.
bMay be paradoxical in paramyotonia congenita.
Abbreviations: AD, autosomal dominant; PP, periodic paralysis.
SECTION III
Diseases of the Nervous System
642
30 min.
Only rarely is IV therapy necessary (e.g., when 
swallowing problems or vomiting is present).
Mannitol is the preferred vehicle for admin-
istration of IV potassium.
The long-term goal of therapy 
is to avoid attacks.
This may reduce late-onset, fixed 
weakness.
If attacks per-
sist on acetazolamide, oral KCl should be added.
The association of the four domains 
is thought to form a pore through which ions pass.
Sodium 
channel mutations are shown along with the phenotype that 
they confer.
See text for details.
patients require treatment with triamterine (25–100 
mg/d) or spironolactone (25–100 mg/d).
The fact that attacks 
are precipitated by potassium administration best defines 
the disease.
The onset is in the first decade; males and 
females are affected equally.
Attacks are brief and mild, 
usually lasting 30 min to 4 h.
Weakness affects proximal 
muscles, sparing bulbar muscles.
Attacks are precipitated 
by rest following exercise and fasting.
The symp-
toms are aggravated by cold, and myotonia makes the 
muscles stiff and painful.
Potassium may be slightly elevated but may also be 
normal during an attack.
In between attacks of weakness, 
the conduction studies are normal.
The EMG will often 
demonstrate myotonic discharges during and between 
attacks.
HyperKPP and potassium-aggravated myotonia 
are inherited as autosomal dominant disorders.
Muta-
tions of the voltage-gated sodium channel SCN4A 
gene (Fig.
48-8) cause these conditions.
For patients 
with frequent attacks, acetazolamide (125–1000 mg/d) 
is helpful.
We have found mexiletine to be helpful in 
patients with significant myotonia.
Myotonia is a prominent feature but worsens 
with muscle activity (paradoxical myotonia).
This is in 
contrast to classic myotonia in which exercise alleviates 
the condition.
Attacks of weakness are seldom severe 
enough to require emergency room treatment.
PC is usually associ-
ated with normokalemia or hyperkalemia.
Serum CK is usually mildly elevated.
Routine sen-
sory and motor nerve conduction studies are normal.
EMG reveals diffuse myotonic potentials in PC.
PC is inherited as an autosomal dominant condition; 
voltage-gated sodium channel mutations (Fig.
Patients with 
PC seldom seek treatment during attacks.
Oral adminis-
tration of glucose or other carbohydrates hastens recovery.
Patients should be advised to increase carbo-
hydrates in their diet.
The cardiac arrhythmias are potentially seri-
ous and life threatening.
In addition, the 
potassium levels differ among kindreds but are consis-
tent within a family.
Inheritance is autosomal dominant, 
with incomplete penetrance and variable expressivity.
The episodes of weakness may dif-
fer between patients because of potassium variability.
Acetazolamide may decrease the attack frequency and 
severity.
Symptoms are 
noted in infancy and early childhood.
The severity less-
ens in the third to fourth decade.
Myotonia is worsened 
by cold and improved by activity.
The gait may appear 
slow and labored at first but improves with walking.
Muscle hypertrophy is usually 
present.
Myotonic discharges are prominently displayed 
by EMG recordings.
Serum CK is normal or mildly elevated.
The muscle 
biopsy shows hypertrophied fibers.
48-8) that increase 
muscle cell excitability.
Many patients will not require 
treatment and learn that the symptoms improve with 
activity.
Medications that can be used to decrease myo-
tonia include quinine, phenytoin, and mexiletine.
ENDOCRINE AND METABOLIC 
MYOPATHIES
Many endocrine disorders cause weakness.
Muscle 
fatigue is more common than true weakness.
The cause 
of weakness in these disorders is not well defined.
Nearly all endocrine myopathies respond to treatment.
THYROID DISORDERS
Abnormalities of thyroid function can cause a wide 
array of muscle disorders.
Muscle cramps, pain, and 
stiffness are common.
Some patients have enlarged 
muscles.
EMG is typically normal.
Activ-
ity of deep tendon reflexes may be enhanced.
Some 
patients develop neck extensor weakness (part of the 
dropped head syndrome).
Serum CK levels are usually 
normal or slightly elevated.
Serum parathyroid hor-
mone levels are elevated.
Muscle biopsies show 
only varying degrees of atrophy without muscle fiber 
degeneration.
Hypoparathyroidism
An overt myopathy due to hypocalcemia rarely occurs.
Neuromuscular symptoms are usually related to local-
ized or generalized tetany.
Serum CK levels may be 
increased secondary to muscle damage from sustained 
tetany.
Muscle wasting may be 
striking.
A cushingoid appearance usually accompanies 
clinical signs of myopathy.
Adrenal insufficiency commonly causes muscle 
fatigue.
The degree of weakness may be difficult to 
assess but is typically mild.
The clinical picture is one 
of persistent muscle weakness.
Long-standing hyperal-
dosteronism may lead to proximal limb weakness and 
wasting.
These changes relate to hypokalemia and 
are not a direct effect of aldosterone on skeletal muscle.
Muscles often 
appear enlarged but exhibit decreased force gen-
eration.
The area of muscle infarction is hard and indurated.
CT 
or MRI can demonstrate focal abnormalities in the 
affected muscle.
Pain reflects the underlying bone dis-
ease (osteomalacia).
Vitamin E deficiency may result from 
malabsorption.
Progressive external oph-
thalmoplegia is a distinctive finding.
It has not been 
established that deficiency of other vitamins causes a 
myopathy.
Fatigue 
is usually a more significant problem than weakness, 
which is typically mild.
There is 
proximal limb weakness with bone pain.
Gangrenous calcification represents a separate, rare, 
and sometimes fatal complication of CRF.
In this con-
dition, widespread arterial calcification occurs and 
results in ischemia.
Extensive skin necrosis may occur, 
along with painful myopathy and even myoglobinuria.
Others impact practice to a lesser degree but are impor-
tant to consider in specific situations.
Glucocorticoids Acute, high-dose glucocorticoid 
treatment can cause acute 
quadriplegic myopathy.
Chronic steroid 
administration produces pre-
dominantly proximal weakness.
Zidovudine Mitochondrial myopathy with 
ragged red fibers.
Local injections cause muscle 
necrosis, skin induration, and 
limb contractures.
Muscle biopsy shows 
autophagic vacuoles.
SECTION III
Diseases of the Nervous System
646 statins), niacin (nicotinic acid), and ezetimibe.
Myalgia, 
malaise, and muscle tenderness are the most common 
manifestations.
Muscle pain may be related to exer-
cise.
Patients may exhibit proximal weakness.
Elevated serum CK is an important indi-
cation of toxicity.
Patients usually improve with drug cessation, 
although this may take several weeks.
Rare cases con-
tinue to progress after the offending agent is discontin-
ued.
In chronic steroid myopathy, 
the serum CK is usually normal.
Serum potassium may 
be low.
Calpain stains show diffusely reac-
tive atrophic fibers.
Withdrawal of glucocorticoids will 
improve the chronic myopathy.
In acute quadriplegic 
myopathy, recovery is slow.
Patients require supportive 
care and rehabilitation.
Myopathy is a well-
established complication of this agent.
The complication occurs in 
about 17% of patients treated with doses of 1200 mg/d 
for 6 months.
Serum CK is elevated and EMG is myopathic.
Ethanol is one of the most 
commonly abused substances with potential to dam-
age muscle.
Other potential toxins include cocaine, 
heroin, and amphetamines.
The effects of alcohol are more 
controversial.
Alcoholics are also prone to 
neuropathy (Chap.
56).
Elevated 
serum CK and myopathic EMG are characteristic of these 
reactions.
In all of these condi-
tions, counseling is essential to limit drug abuse.
This drug chelates copper and is used in the treatment 
of Wilson’s disease.
The incidence of this inflammatory 
muscle disease is about 1%.
Myasthenia gravis is also 
induced by D-penicillamine, with a higher incidence 
estimated at 7%.
In most cases, a cause-and-effect 
relationship is uncertain.
A complication of interest 
was related to L-tryptophan.
The product was withdrawn, and 
incidence of EMS diminished abruptly following this 
action.
OTHER DRUG-INDUCED MYOPATHIES
Certain drugs produce painless, largely proximal, muscle 
weakness.
Marinos  C.
CLINICAL FEATURES 
 The prevalence of the infl ammatory myopathies is esti-
mated at 1 in 100,000.
PM as a stand-alone entity is a 
rare disease.
DM affects both children and adults and 
women more often than men.
In advanced 
and rarely in acute cases, respiratory muscles may also be 
affected.
Severe weakness, if untreated, is almost always 
associated with muscle wasting.
Sensation remains 
normal.
48 ) or slowly progressive motor neu-
ron disorder ( Chap.
32 ).
This is in contrast to 
DM, in which the rash facilitates early recognition (dis-
cussed later).
PM mimics many other myopathies and is 
a diagnosis of exclusion.
In some patients, the rash is 
pruritic, especially on the scalp, chest, and back.
Dilated 
capillary loops at the base of the fingernails are also 
characteristic.
The weakness can be mild, moderate, or severe enough 
to lead to quadriparesis.
At times, the muscle strength 
appears normal, hence the term dermatomyositis sine myo-
sitis.
DM usually occurs alone but may overlap with 
scleroderma and mixed connective tissue disease.
Some patients present with falls because their knees col-
lapse due to early quadriceps weakness.
Dysphagia is common, occurring in up to 60% 
of IBM patients, and may lead to episodes of choking.
cHIV (human immunodeficiency virus) and HTLV-I (human T cell lymphotropic virus type I).
Other myotoxic drugs may cause myopathy but not an inflammatory myopathy (see text for details).
eParasites (protozoa, cestodes, nematodes), tropical and bacterial myositis (pyomyositis).
SECTION III
Diseases of the Nervous System
650 that presumably is age-related.
A subset of h-IBM that spares the quadriceps muscles 
has emerged as a distinct entity.
2.
Joint contractures, mostly in DM and especially in chil-
dren.
3.
4.
5.
6.
7.
If malignancy is clinically suspected, screening 
with whole-body PET scan should be considered.
49-1).
The remaining capillaries often have dilated lumens in 
response to the ischemic process.
Larger intramuscular 
blood vessels may also be affected in the same pattern.
Increased expression of type I interferon-
inducible proteins is also noted in these regions.
By contrast, in PM and IBM a mechanism of T 
cell–mediated cytotoxicity is likely.
Viruses have not been identified 
within the muscle fibers.
Key molecules involved in  
T cell–mediated cytotoxicity are depicted in Fig.
49-2.
VCAM-1
TCR
CD28 CTLA-4 LFA-1
Chemokines
(MCP-1, Mig, IP-10)
Infection?
Muscle fiber 
necrosis occurs via perforin granules released by the autoag-
gressive T cells.
Death of the muscle fiber 
is mediated by necrosis.
The best evidence of a viral connection in PM 
and IBM is with the retroviruses.
Histologic findings 
are identical to retroviral-negative PM or IBM.
AZT inhib-
its γ-DNA polymerase, an enzyme found solely in the 
mitochondrial matrix.
32).
The muscular dystrophies (Chap.
Identification of the MHC/CD8 lesion by muscle 
biopsy is helpful to identify cases of PM.
44).
47).
Repetitive 
nerve stimulation and single-fiber EMG studies aid in 
diagnosis.
46), transverse myeli-
tis (Chap.
35), a neurotoxin (Chap.
48), or a neuro-
tropic viral infection such as poliomyelitis or West 
Nile virus (Chap.
40).
48).
Pyomyositis, previously rare in the West, is now occa-
sionally seen in AIDS patients.
Most patients respond to glucocorticoid therapy, and 
the overall prognosis seems favorable.
The weakness can be severe.
Coexist-
ing interstitial lung disease and cardiomyopathy may be 
present.
The disorder may develop after a viral infec-
tion or in association with cancer.
Some patients have 
antibodies against signal recognition particle (SRP).
Muscle MHC-I expression is only slightly and focally 
upregulated.
Some patients respond to immu-
notherapy, but others are resistant.
It may be caused by group 
A β-hemolytic streptococcus, methicillin-sensitive S.
Systemic varicella is a predisposing factor in 
children.
As noted earlier, AZT causes a 
mitochondrial myopathy.
The muscle biopsy is either normal or discloses type II 
muscle fiber atrophy.
The muscle 
biopsy is usually normal or nonspecific.
52).
These patients do 
not have muscle weakness, and the muscle biopsy is 
normal.
The most sensitive enzyme is CK, which in active 
disease can be elevated as much as fiftyfold.
The CK is always elevated in patients with active PM.
MRI is not routinely used for the diagnosis of PM, 
DM, or IBM.
49-3, 
49-4, and 49-5).
49-3).
49-4).
The pres-
ence of perifascicular atrophy is diagnostic of DM, even 
in the absence of inflammation.
In IBM (Fig.
Careful muscle testing may reveal mild muscle weakness.
cSee text for details.
dAn adequate trial of prednisone or other immunosuppressive drugs is warranted in probable cases.
Electron microscopy dem-
onstrates filamentous inclusions in the vicinity of the 
rimmed vacuoles.
SECTION III
Diseases of the Nervous System
658 dysphagia, dyspnea, fever).
When strength improves, 
the serum CK falls concurrently; however, the reverse is 
not always true.
Agents used in the treat-
ment of PM and DM include the following:
1.
Glucocorticoids.
High-dose prednisone, 
at least 1 mg/kg per day, is initiated as early in the 
disease as possible.
2.
Other immunosuppressive drugs.
Approximately 75% of 
patients ultimately require additional treatment.
The dose is up to 3 mg/kg daily.
(2) 
Methotrexate has a faster onset of action than aza-
thioprine.
(3) Mycophenolate mofetil also has a faster 
onset of action than azathioprine.
At doses up to 2.5 
or 3 g/d in two divided doses, it is well tolerated for 
long-term use.
(5) Cyclo-
sporine has inconsistent and mild benefit.
(7) Tacro-
limus (formerly known as Fk506) has been effective in 
some difficult cases of PM.
3.
Immunomodulation.
A dose of 2 g/kg divided over 
2–5 days per course is recommended.
Uncontrolled 
observations suggest that IVIg may also be beneficial 
for patients with PM.
Neither plasmapheresis nor leu-
kapheresis appears to be effective in PM and DM.
IBM is generally resistant to immunosuppressive 
therapies.
Another trial of IVIg com-
bined with prednisone was ineffective.
Older patients, and those with associated cancer also 
have a worse prognosis.
DM responds more favorably 
to therapy than PM and thus has a better prognosis.
Up to 30% may be left with some 
residual muscle weakness.
Relapses may occur at any 
time.
IBM has the least favorable prognosis of the inflam-
matory myopathies.
In general, the older 
the age of onset in IBM, the more rapidly progressive is 
the course.
S.
Andrew  Josephson    ■     Martin A.
Common reasons 
for neurologic consultation include stroke ( Chap.
27 ), 
seizures ( Chap.
26 ), altered mental status ( Chap.
16 ), 
headache ( Chap.
8 ), and management of coma and 
other neurocritical care conditions (Chaps.
17 and 28).
The diagnosis in all of these conditions is clinical.
50-1).
However, this 
term has fallen out of favor because none of its ele-
ments are completely accurate.
Therefore, normal 
serum levels of these medications do not exclude them 
as inciting agents.
SECTION III
Diseases of the Nervous System
662 capability.
Seizures must be iden-
tified and controlled, often necessitating continuous EEG 
monitoring.
50-2).
This shower of microemboli results in a number of 
clinical syndromes.
More commonly, the 
emboli released are multiple and smaller.
Treatment primarily involves lowering the drug dosage 
or discontinuing the drug.
Hypernatremia leads to the loss of intracellular water, 
leading to cell shrinkage.
HYPONATREMIA
Hyponatremia is commonly defined as a serum sodium 
<135 mmol/L (<135 meq/L).
28-6), but now has been described 
elsewhere in the CNS.
Treatment of hyponatremia is dependent on the 
cause.
Hypertonic hyponatremia treatment focuses on 
the underlying condition, such as hyperglycemia.
Seizures can occur but are more common in 
states of low calcium.
Hypocalcemia in adults often follows surgical treatment 
of the thyroid or parathyroid.
Hypomag-
nesemia presents neurologically with seizures, tremor, and 
myoclonus.
High levels of magnesium, in con-
trast, lead to CNS depression.
45).
Imag-
ing with MR neurography may allow these causes to 
be distinguished definitively.
50-3A).
Sparing of the triceps is the rule when the 
nerve is injured in this location.
50-3B).
Sensory loss involves the lat-
eral aspect of the leg as well as the dorsum of the foot 
(Fig.
50-3C).
50-3D).
Rarely, attempts at femoral vein 
or arterial puncture can be complicated by injury to this 
nerve.
A.
Radial nerve.
B.
Ulnar nerve.
C.
Peroneal nerve.
D.
Femoral nerve.
E.
Lateral femoral cutaneous nerve.
50-3E).
There is no 
motor component to the nerve, and therefore weakness 
is not a part of this syndrome.
Symptoms often are wors-
ened by standing or walking.
The 
differential diagnosis of these symptoms includes hip 
problems such as trochanteric bursitis.
Andre  Furtado  ■       William P.
Dillon   
668
 FIGURE 51-1      
   Limbic encephalitis  ( Chap.
There was 
no enhancement on postgadolinium images (not shown).
Axial (C, D) T1-weighted images postgadolinium.
Of note, there was no evidence of restricted diffusion 
(not shown).
ADC map (D, E) demonstrates restricted diffusion of water 
molecules in the lesions (arrowheads).
Some of the lesions also show vasogenic 
edema.
B.
T1-weighted image pregadolinium demonstrates low sig-
nal in left anterior clinoid process (arrow).
C.
T1-weighted image postgadolinium demonstrates enhance-
ment of lesion (arrow).
FIGURE 51-16 
Middle cerebral artery stenosis (Chap.
SECTION III
Diseases of the Nervous System
684
FIGURE 51-17 
Lacunar infarction (Chap.
There is no evidence of restricted diffusion in the old infarct 
(arrow).
In some of these areas, there are small areas 
of tissue loss (encephalomalacia) (arrowheads).
SECTION III
Diseases of the Nervous System
686
FIGURE 51-19 
CNS vasculitis (Chap.
These 
abnormalities are suggestive of vasculitis.
CHAPTER 51
Atlas of Neuroimaging
687
FIGURE 51-20 
Superior sagittal sinus thrombosis (Chap.
These findings are suggestive of vasogenic 
edema with subarachnoid hemorrhage (arrowheads).
SECTION III
Diseases of the Nervous System
690
FIGURE 51-22 
Huntington’s disease (Chap.
There is also 
diffuse prominence of the sulci indicating generalized cortical 
atrophy.
Coronal T1-weighted image (D) demonstrates enlarged fron-
tal horns with abnormal configuration.
CHAPTER 51
Atlas of Neuroimaging
691
FIGURE 51-23 
Bell’s palsy (Chap.
Note that there is no evidence of a mass 
lesion.
SECTION III
Diseases of the Nervous System
692
FIGURE 51-24 
Spinal cord infarction (Chap.
T1-weighted MR image of the lumbar spine postgadolinium 
(B) demonstrates mild enhancement (arrow).
FIGURE 51-25 
Acute transverse myelitis (Chap.
Some of the lesions 
reveal concentric layers, typical of Baló’s concentric sclero-
sis (arrows).
There is also a small area of abnormal high signal in the 
precentral gyrus.
CHAPTER 51
Atlas of Neuroimaging
697
FIGURE 51-29 
Brachial plexopathy (Chap.
These 
findings are compatible with radiation-induced brachial 
plexopathy.
FIGURE 51-31 
CT facet fracture
Axial CT demonstrates fracture line along the C2 facet (arrow).
This is sug-
gestive of interspinous ligament injury.
Note the pad under 
the patient’s neck to maintain neck alignment during the 
scanning time.
Also noted is mass effect on the spinal 
cord (arrowheads).
CT is the imaging procedure of choice to 
detect acute hematoma.
There is also a large retropharyngeal hema-
toma (*).
Jefferson fracture is usually caused by axial 
impact to the head such as diving in shallow water.
1: Anterior vertebral body line; 2: Posterior ver-
tebral body line; 3: Spinolaminar line.
Note that the epidural fat is compressed but not involved (arrow).
Sagittal T2-weighted MRI (B) dis-
plays cord injury (arrow).
Criteria for the diagnosis of CFS have 
been developed by the U.S.
Centers for Disease Control 
and Prevention  ( Table 52-1 ) .
EPIDEMIOLOGY 
 CFS is seen worldwide, with adult prevalence rates 
varying between 0.2 and 0.4%.
Approximately 75% of all CFS patients are women.
The mean age of onset is between 29 and 35 years.
It is 
probable that many patients go undiagnosed and/or do 
not seek help.
Psychiatric 
illness and physical hyperactivity in adulthood raise the 
risk of CFS in later life.
Precipitating factors 
 Physical or psychological stress may elicit the onset of 
CFS.
Relatively high percentages of CFS follow 
Q fever and Lyme disease.
A third 
of all patients cannot recall a trigger.
Perpetuating factors
Once CFS has developed, numerous factors may impede 
recovery.
A patient’s focus on illness and avoidance of activities  
may perpetuate symptoms.
A lack of social  
support is another known perpetuating factor.
PATHOPHYSIOLOGY
The pathophysiology of CFS is unclear.
Neurophysiologic studies have 
shown altered CNS activation patterns during muscle 
contraction.
Evidence for immunologic dysfunction is inconsis-
tent.
The heart rate of CFS patients is often slightly 
above normal.
Serology for viral or bacterial infections is usually not 
helpful.
No specific abnormalities have been identified 
on MRI or CT scans.
Also, CFS is excluded if the 
chronic fatigue developed immediately after a depres-
sive episode.
Depression developing in the course of the 
fatigue, however, does not preclude CFS.
Next, 
potential fatigue-precipitating factors are sought.
52-1).
Countless anecdotes circulate 
regarding other traditional and nontraditional thera-
pies.
How have you felt during the last two weeks?
Please rate all four statements and per statement check the box that reflects your situation best.
1.
I tire easily No,
 that is not true
3.
I feel fit No,
 that is not true
4.
Walking 
or cycling is systematically increased, with set target 
heart rates.
Evidence that deconditioning is the basis 
for symptoms in CFS is lacking, however.
Not all patients benefit from CBT or GET.
Predictors of 
poor outcome are somatic comorbidity, current disability 
claims, and severe pain.
Messing   ■    John H.
Rubenstein   ■    Eric J.
54 .
Further discussion of alcoholism can 
be found in  Chap.
56 , opiate addiction in  Chap.
57 , and 
cocaine and other drugs of abuse in  Chap.
58 .
In the 1950s–1960s, psychological factors were held to 
underlie autism.
Finally, there is reduced cell size and increased 
cell density in the limbic areas of the brain.
For unknown reasons, ASDs affect four 
times as many boys as girls.
ASDs are also geneti-
cally heterogeneous.
Many of the genes linked to ASDs can also cause 
other illnesses.
They may be detrimental by 
altering the balance of excitatory vs.
Advanced paternal age, birth order, and season of birth 
have also been implicated.
This is accompanied by a reduc-
tion in cortical thickness.
Moreover, the responsible genes within the 
DiGeorge region have not yet been identified.
As for ASDs, the same allele may be a risk 
factor for multiple disorders.
However, it is unknown 
whether this is a primary or compensatory feature of the 
disorder.
54) to ameliorate the positive 
symptoms of schizophrenia.
MOOD DISORDERS
Mood disorders are divided into depressive and bipolar 
disorders.
Between 40–50% of the risk for depression appears to 
be genetic.
Depres-
sion and obesity/metabolic syndrome are important 
risk factors for each other.
53-1).
Depressed individu-
als show a small reduction in hippocampal size.
Furthermore, stress 
leads to a decrease in the birth of new neurons in the 
adult hippocampus.
Only a subset of the known interconnections among 
these brain regions is shown.
Also shown is the innervation 
of several of these brain regions by monoaminergic neurons.
In addition, there are strong connections between the 
hypothalamus and the VTA-NAc pathway.
SECTION V
Psychiatric Disorders
716 postmortem brains of depressed patients.
Thus the role 
of BDNF in regulating mood is highly brain-region 
specific.
The nature of these thera-
peutic drug-induced adaptations has not been identified 
with certainty.
53-1) provide the anatomic basis of their therapeu-
tic actions.
HDAC inhibitors 
have shown some antidepressant effects in animal mod-
els of depression.
However, there is no 
established pathology associated with addiction risk.
Patients who abuse alcohol or psychostimulants show 
reduced gray matter in the prefrontal cortex.
53-1).
Three major 
pathologic adaptations have been described.
corticotrophin releasing factor), and intracellular signal-
ing cascades.
Repeated administration of 
these drugs (Fig.
These 
changes contribute to the altered phenotype of the drug-
addicted state.
720
 MENTAL DISORDERS 
 CHAPTER 54 
   Victor I.
The biology of psychiatric and addictive dis-
orders is discussed in  Chap.
53  .
Par-
esthesias, gastrointestinal distress, and feelings of unreal-
ity are also common.
The lifetime prevalence of 
panic disorder is 1–3%.
Palpitations, pounding heart, or accelerated heart rate
 2.
Sweating
 3.
Trembling or shaking
  4.
Sensations of shortness of breath or smothering
 5.
Feeling of choking
  6.
Chest pain or discomfort
  7.
Nausea or abdominal distress
  8.
Feeling dizzy, unsteady, lightheaded, or faint
 9.
Derealization (feelings of unreality) or depersonaliza-
tion (being detached from oneself)
10.
Fear of losing control or going crazy
11.
Fear of dying
12.
Paresthesias (numbness or tingling sensations)
13.
Copyright 
© 2000 American Psychiatric Association.
TABLE 54-2 
DIAGNOSTIC CRITERIA FOR AGORAPHOBIA
1.
2.
3.
Copyright 
© 2000 American Psychiatric Association.
will fail to recognize the syndrome if direct questioning is 
not pursued.
Agents that block serotonin 
reuptake can prevent attacks.
The cornerstone of drug therapy is antidepressant med-
ication (Tables 54-3 through 54-5).
Food and Drug Administration 
(FDA) for this indication.
Homework assign-
ments and monitored compliance are important 
components of successful treatment.
Interestingly, family studies indicate that 
GAD and panic disorder segregate independently.
B.
The person finds it difficult to control the worry.
C.
D.
E.
F.
Copyright © 
2000 American Psychiatric Association.
Withdrawal must be closely monitored as 
relapses can occur.
Adverse effects of benzodiazepines generally parallel  
their relative half-lives.
It is usually more difficult to taper patients 
off shorter-acting benzodiazepines.
Buspirone is a nonbenzodiazepine anxiolytic agent.
However, it requires several weeks to take effect and 
requires thrice-daily dosing.
Benzodiazepines 
are contraindicated during pregnancy and breast-feeding.
Anticonvulsants with GABAergic properties may also 
be effective against anxiety.
Panic 
attacks may be triggered by the phobic stimulus or may 
occur spontaneously.
Common phobias 
include fear of closed spaces (claustrophobia), fear of 
blood, and fear of flying.
Examples include having to converse at a party, use 
public restrooms, and meet strangers.
The 
specific content of a phobia may vary across gender, 
ethnic, and cultural boundaries.
Phobic disorders are common, affecting ∼10% of the 
population.
2.
The person’s response involved intense fear,  
helplessness, or horror.
B.
The traumatic event is persistently reexperienced in 
one (or more) of the following ways:
     1 .
2.
Recurrent distressing dreams of the event.
3.
4.
5.
C.
Efforts to avoid thoughts, feelings, or conversations 
associated with the trauma
     2.
Efforts to avoid activities, places, or people that 
arouse recollections of the trauma
     3.
Inability to recall an important aspect of the trauma
     4.
Markedly diminished interest or participation in  
significant activities
     5.
Feeling of detachment or estrangement from others
     6.
Restricted range of affect (e.g., unable to have loving 
feelings)
     7.
Difficulty falling or staying asleep
     2.
Irritability or outbursts of anger
     3.
Difficulty  concentrating
     4.
Hypervigilance
     5.
Exaggerated  startle  response
E.
Duration of the disturbance (symptoms in criteria B, C, 
and D) is more than 1 month
F.
Copyright 
© 2000 American Psychiatric Association.
These changes theoretically facilitate the encoding 
of fear-based memories.
OCD has a lifetime prevalence of 2–3% 
worldwide.
Onset is usually gradual, beginning in early 
adulthood, but childhood onset is not rare.
Etiology and pathophysiology
A genetic contribution to OCD is suggested by twin 
studies.
Only 50–60% of 
patients with OCD show adequate improvement with 
pharmacotherapy alone.
When a therapeutic 
response is achieved, long-duration maintenance ther-
apy is usually indicated.
56 through 
58).
Virtually every class of medication includes some agent 
that can induce depression.
Hyperthyroid states may also present  
in a similar fashion, usually in geriatric populations.
The lifetime prevalence of depression in HIV-positive 
individuals has been estimated at 22–45%.
Some chronic disorders of uncertain etiology, such 
as chronic fatigue syndrome (Chap.
Depression is often 
undiagnosed, and, even more frequently, it is treated 
inadequately.
The presence of anxiety, panic, or agitation significantly 
increases near-term suicidal risk.
Dysthymic disorder exists in ∼5% of pri-
mary care patients.
1.
Insomnia or hypersomnia nearly every day
     5.
Fatigue or loss of energy nearly every day
     7 .
The symptoms do not meet criteria for a mixed episode
C.
Copyright 
© 2000 American Psychiatric Association.
Some 
patients experience multiple episodes that become 
more severe and frequent over time.
The duration of 
an untreated episode varies greatly, ranging from a few 
months to ≤1 year.
The pattern of recurrence and clinical 
progression in a developing episode are also variable.
Antidepressant treatment leads 
to normalization of these abnormalities.
The pathogenesis of depression is discussed in detail 
in Chap.
53.
54-1).
It is judicious to prescribe only a 10-day 
supply when suicide is a risk.
Geriatric 
patients may require a low starting dose and slow esca-
lation.
Second-generation antidepressants include amoxap-
ine, maprotiline, trazodone, and bupropion.
Long-term use 
of this drug carries a risk of tardive dyskinesia.
An extended-release preparation is available.
Serotoner-
gic agonists taken in combination should be monitored 
closely for this reason.
Sexual dysfunction fre-
quently results in noncompliance and should be asked 
about specifically.
SSRI, selective serotonin reuptake 
inhibitor; TCA, tricyclic antidepressant.
Unlike the SSRIs, venlafaxine has a 
relatively linear dose-response curve.
Mirtazapine is a TCA that has a 
unique spectrum of activity.
It is also strongly antihista-
minic and, as such, may produce sedation.
Transdermal selegiline may avert this risk at low dose.
Regardless of the treatment undertaken, the response 
should be evaluated after ∼2 months.
If this 
approach is unsuccessful, referral to a mental health spe-
cialist is advised.
Occasional empathic silence may be as 
helpful for the treatment alliance as verbal reassurance.
It may be difficult to distinguish 
mixed mania from agitated depression.
This pattern occurs 
in 15% of all patients, almost all of whom are women.
Bipolar disorder is common, affecting ∼1.5% of 
the population in the United States.
A detailed discussion of the pathogenesis of bipolar disor-
der is presented in Chap.
53.
Some 95% of a 
given dose is excreted unchanged through the kidneys 
within 24 h.
TABLE 54-10 
CRITERIA FOR A MANIC EPISODE
A.
Inflated  self-esteem  or  grandiosity
     2.
Decreased need for sleep (e.g., feels rested after 
only 3 h of sleep)
     3.
More talkative than usual or pressure to keep talking
     4.
Flight of ideas or subjective experience that 
thoughts are racing
     5.
The symptoms do not meet criteria for a mixed episode.
D.
E.
Copyright © 2000 American Psychiatric Association.
effect by interfering with the synthesis and release of 
thyroid hormones.
The recurrent nature of bipolar mood disorder 
necessitates maintenance treatment.
Loss of efficacy over time may  
be observed with any of the mood-stabilizing agents.
In such situations, an alternative agent or combina-
tion therapy is usually helpful.
Source: From GS Sachs et al: Postgrad Med April, 2000.
Onset is usually before age 30 years, 
and the disorder is persistent.
B.
Either of the following:
     1.
The symptoms are not intentionally produced or 
feigned (as in factitious disorder or malingering).
Copyright 
© 2000 American Psychiatric Association.
In true factitious illness, the sick role itself is gratifying.
Such an approach 
is doomed to failure and does not address the core issue.
Personality disorders have been grouped into three 
overlapping clusters.
Cluster A includes paranoid, schiz-
oid, and schizotypal personality disorders.
Individuals have 
a restricted emotional range and remain socially isolated.
Improvement 
may be subtle and observable only over time.
There are no patho-
gnomonic features.
However, marked 
variability in the course and individual character of 
symptoms is typical.
The four main subtypes of schizophrenia are catatonic, 
paranoid, disorganized, and residual.
Many individu-
als have symptoms of more than one type.
Prognosis depends not on symptom sever-
ity but on the response to antipsychotic medication.
A 
permanent remission without recurrence does occasion-
ally occur.
About 10% of schizophrenic patients commit 
suicide.
Schizophrenia is present in 0.85% of individuals 
worldwide, with a lifetime prevalence of ∼1–1.5%.
Drug causes 
should be ruled out in any case of newly emergent psy-
chosis.
Genetic factors are involved in at least a subset of individu-
als who develop schizophrenia.
Schizophrenia is observed 
in ∼6.6% of all first-degree relatives of an affected proband.
If both parents are affected, the risk for offspring is 40%.
The concordance rate for monozygotic twins is 50%, 
compared to 10% for dizygotic twins.
The pathogenesis of schizo-
phrenia is discussed in detail in Chap.
53.
cortices.
Conventional neuroleptics differ in their potency 
and side-effect profile.
Its principal disadvantage is a risk of blood 
dyscrasias.
Unlike other antipsychotics, clozapine 
does not cause a rise in prolactin level.
Que-
tiapine is distinct in having a weak D2 effect but potent 
α1 and histamine blockade.
Antipsychotic agents are effective in 70% of patients 
presenting with a first episode.
Improvement may be 
observed within hours or days, but full remission usually 
requires 6–8 weeks.
If medications are completely discontinued, 
however, the relapse rate is 60% within 6 months.
Akathisia may respond to 
beta blockers.
Weekly white blood cell counts are required, particularly 
during the first 3 months of treatment.
Close monitoring of plasma glucose and 
lipid levels are indicated with the use of these agents.
The 
prevalence increases with age, total dose, and dura-
tion of drug administration.
The risk associated with 
second-generation agents appears to be much lower.
The cause may involve formation of free radicals and 
perhaps mitochondrial energy failure.
Vitamin E may 
reduce abnormal involuntary movements if given 
early in the syndrome.
Drug treatment of schizophrenia is by itself insuffi-
cient.
Physicians are frequently 
the first point of contact for both victim and abuser.
Approximately 2 million older Americans and 1.5 mil-
lion U.S.
children are thought to experience some 
form of physical maltreatment each year.
Spousal abuse 
is thought to be even more prevalent.
Charles W.
Hoge  
742
 Neuropsychiatric sequelae are common in combat vet-
erans.
Certain events such as loss of a close friend in 
combat, leave indelible scars.
52).
PTSD
PTSD is the most common mental disorder docu-
mented following war-zone service.
54).
Misuse of alcohol or substances is most preva-
lent, often reflecting self-medication.
These 
responses only become symptoms when they impair 
functioning after warriors return home.
CONCUSSION/mTBI
TBI (Chap.
GCSs are usually normal (15 out of 15).
Nevertheless, mass 
population screening for concussion/mTBI was man-
dated for all U.S.
However, they need to be addressed within the 
context of all other war-related health concerns.
Were constantly on guard, watchful, or easily startled?
Felt numb or detached from others, activities, or your surroundings?
Prim Care Psychiatr 9:9, 2004.
PHQ-2 Depression Screen
2.
Over the last 2 weeks, how often have you been 
bothered by any of the following problems?
Feeling down, depressed, or hopeless.
Med Care 41:1284, 2003.
AUDIT-C Alcohol Screen
3a.
How often do you have a drink containing alcohol?
How many drinks containing alcohol do you have on a typical day when you are drinking?
1 or 2 (0) 3 or 4 (1) 5 or 6 (2) 7 or 9 (3) 10 or more (4)
3c.
How often do you have six or more drinks on one occasion?
Arch Intern 
Med 158:1789, 1998.
It is important to know that combat is not the only 
important trauma in a war-zone environment.
Rape, 
assault, and accidents also occur.
Mirtazapine use can cause drowsiness and 
weight gain.
All antidepressants have potential drug-drug 
interactions that must be considered.
Benzodiazepines, in particular, should be avoided 
in combat veterans.
8).
DISCLOSURE
This material has been reviewed by the Walter Reed Army 
Institute of Research.
There is no objection to its presentation 
and/or publication.
This page intentionally left blank 
SECTION VI
ALCOHOLISM  
AND DRUG  
DEPENDENCY
   Marc  A.
Unfortunately, most clinicians 
have had only limited education regarding these con-
ditions.
Con-
geners include methanol, butanol, acetaldehyde, hista-
mine, tannins, iron, and lead.
56-1 ) .
MEOS, microsomal ethanol-
oxidizing system.
Beverage alcohol is probably responsible for 
more overdose deaths than any other drug.
This alteration disappears almost 
as rapidly as it develops.
Subsequent decreases in 
blood levels contribute to symptoms of withdrawal.
Patients may also experi-
ence prominent and sometimes disturbing dreams.
In the United States, ∼40% of 
drinkers have at some time driven while intoxicated.
Approximately 
1% of alcoholics develop cerebellar degeneration or atrophy.
54).
Another common comorbid-
ity occurs with dependence on illicit substances.
Recovery is likely within several days to 
4 weeks of abstinence.
This contrib-
utes to an increase in fat accumulation in liver cells.
CANCER
As few as 1.5 drinks per day increases a woman’s risk 
of breast cancer 1.4-fold.
Exercise-induced increases in cardiac 
oxygen consumption are higher after alcohol intake.
Thus, heavy drinking is an important factor in mild to 
moderate hypertension.
Hormone irregularities should be reevaluated as they 
may disappear after a month of abstinence.
These 
differences reflect both cultural and genetic influences, 
as described later.
The lifetime risk for alcoholism among 
physicians is similar to that of the general population.
How often do you have a drink 
containing alcohol?
Never (0) to 4+ per 
week (4)
 2.
How many drinks containing 
alcohol do you have on a typical 
day?
1 or 2 (0) to 10+ (4)
 3.
How often do you have six or 
more drinks on one occasion?
Never (0) to daily or 
almost daily (4)
 4.
Never (0) to daily or 
almost daily (4)
 5.
Never (0) to daily or 
almost daily (4)
 6.
Never (0) to daily or 
almost daily (4)
 7.
How often during the last year 
have you had a feeling of guilt or 
remorse after drinking?
Never (0) to daily or 
almost daily (4)
 8.
Never (0) to daily or 
almost daily (4)
 9.
Have you or someone else been 
injured as a result of your drink-
ing?
No (0) to yes, during 
the last year (4)
10.
No (0) to yes, during 
the last year (4)
aThe AUDIT is scored by summing the 10 values.
A score >8 may 
indicate harmful alcohol use.
New York, Springer 2006.
While most CNS depressants are effective, benzo-
diazepines (Chap.
The rare patient with status epilepticus must be treated 
aggressively (Chap.
26).
Sleep 
medications have the danger of being misused and of 
rebound insomnia when stopped.
Thomas  R.
Two 
of the most important adverse effects of all these agents 
are overdose and dependence.
SECTION VI
Alcoholism and Drug Dependency
762 primarily associated with the mu receptor.
Thus, 
opiates acutely inhibit neuronal activity.
How-
ever, the “high” only occurs when the rate of change in 
dopamine is fast.
Opiate dependence and withdrawal are chronic 
effects related to the cyclic AMP system.
Epigenetic methyla-
tion changes also occur on the DNA of the mu receptor 
gene of opiate addicts.
DNA methylation inhibits gene 
transcription.
They then are conjugated 
to glucuronic acid and excreted in small amounts in feces.
The role of endogenous opioid peptides in opioid 
dependence is uncertain.
Symptoms of opioid withdrawal 
begin 8–10 h after the last dose.
Many of these symp-
toms reflect increased activity of the autonomic nervous 
system.
Lacrimation, rhinorrhea, yawning, and sweat-
ing appear first.
The acute course of withdrawal may last 7–10 days.
An 
increase in prolactin also contributes to the reduced 
sex drive in males.
Two other hormones affected are 
decreased thyrotropin and increased growth hormone.
In overdoses, aspiration 
pneumonia is a common complication due to loss of 
the choking reflex.
Opi-
ates may prolong QT intervals and lead to sudden death 
in some patients.
Alpha-2-ad-
renergic agonists are primarily used for detoxification.
methadone).
Clonidine, a centrally 
acting sympatholytic agent, has also been used for 
detoxification.
Clonidine has no narcotic action and is not 
addictive.
Lofexidine, a clonidine analogue with less 
hypotensive effect, is being developed for use.
methadone have been 
comparable.
Buprenorphine is combined with nal-
oxone at a 4:1 ratio in order to reduce its abuse liability.
A 
subcutaneous buprenorphine implant has also been tested, 
but results are not yet available.
Retention in office-based 
buprenorphine treatment has been greater than 70% at 
6-month follow-ups.
PREVENTION
Preventing opiate abuse represents a critically impor-
tant challenge for physicians.
The major sources of these drugs are family 
members, not drug dealers or the Internet.
Finally, phy-
sicians should never prescribe opiates for themselves.
Nancy  K.
Mello  ■       Jack  H.
COCAINE 
 Cocaine is a stimulant and a local anesthetic with potent 
vasoconstrictor properties.
The leaves of the  coca  plant 
( Erythroxylon coca ) contain ∼0.5–1% cocaine.
The drug 
 COCAINE AND OTHER COMMONLY 
ABUSED DRUGS 
 CHAPTER 58 
a Deceased.
Intravenous cocaine is often used concurrently 
with IV heroin.
The effects rarely last more 
than 1 h.
Cocaine has a short plasma half-life 
of approximately 45–60 min.
It is metabolized by plasma 
esterases, and cocaine metabolites are excreted in urine.
Hepatic necrosis may occur following chronic crack/
cocaine use.
Hashish is prepared from concentrated resin of 
C.
sativa and contains a THC concentration of between 
8 and 12% by weight.
Smoking is the most common 
mode of marijuana or hashish use.
During pyrolysis, 
>150 compounds in addition to THC are released in 
the smoke.
THC is quickly absorbed from the lungs into blood, 
and then rapidly sequestered in tissues.
Tolerance for marijuana-induced tachycardia 
develops rapidly among regular users.
Department of Justice in 2009.
Methamphetamine can be used by smoking, snorting, 
IV injection, or oral administration.
Methamphetamine 
abusers report that drug use induces feelings of euphoria 
and decreased fatigue.
Therapy of acute methamphetamine overdose is 
largely symptomatic.
Ammonium chloride may be use-
ful to acidify the urine and enhance clearance of the 
drug.
Hypertension may respond to sodium nitroprus-
side or α-adrenergic antagonists.
Sedatives may reduce 
agitation and other signs of central nervous system 
hyperactivity.
MDMA (3,4-methylenedioxymethamphetamine), or 
ecstasy, is a derivative of methamphetamine.
Ecstasy is usu-
ally taken orally but may be injected or inhaled; its effects 
last for 3–6 h.
The long-term consequences of 
recreational use of MDMA by young persons are poorly 
understood.
These effects of LSD may persist for 
12–18 h, even though the half-life of the drug is only 
3 h.
Treat-
ment of these disorders is best carried out in specialized 
psychiatric facilities.
Abrupt abstinence 
following continued use does not produce withdrawal 
signs or symptoms.
There have been no clinical reports 
of death caused by the direct effects of LSD.
PCP is easily synthesized; 
its abusers are primarily young people and polydrug users.
It is used orally, by smoking, by snorting, or by IV injec-
tion.
It is also used as an adulterant in THC, LSD, amphet-
amine, or cocaine.
Confirmation of PCP use is possible by deter-
mination of PCP levels in serum or urine.
PCP assays 
are available at most toxicologic centers.
PCP remains in 
urine for 1–5 days following high-dose intake.
There is no specific 
antidote or antagonist for PCP.
PCP excretion from the 
body can be enhanced by gastric lavage and acidifica-
tion of urine.
PCP, 
like LSD and mescaline, produces vasospasm of cerebral 
arteries at relatively low doses.
Flunitrazepam is typically 
used orally but can be snorted or injected.
Overdose can 
produce life-threatening respiratory depression and coma.
GHB is usu-
ally taken orally and has no distinctive color or odor.
In veterinary 
medicine, it is used for brief immobilization.
In clini-
cal medicine, it is used for sedation, analgesia, and to 
supplement anesthesia.
Like PCP, it binds to NMDA receptors and acts 
as an uncompetitive NMDA antagonist.
The extent to which 
chronic recreational use leads to memory impairment 
remains controversial.
There are 
relatively few controlled studies of multiple drug inter-
actions.
One determinant of 
polydrug use patterns is the relative availability and cost 
of the drugs.
This page intentionally left blank 
   Alexander  Kratz    ■     Michael A.
Pesce    ■     Robert C.
Basner
  ■     Andrew J.
A variety of factors can infl uence reference values.
Values supplied in 
this Appendix refl ect typical reference ranges in adults.
Pediatric reference ranges may vary signifi cantly  from 
adult values.
Therefore, both 
systems are provided in the Appendix.
In all other instances in the text the 
SI unit is followed by the traditional unit in parentheses.
8 P.M.–8 A.M.
JAMA 2001; 285:2486–97.
bIgG index = CSF IgG (mg/dL) × serum albumin (g/dL)/serum IgG 
(g/dL) × CSF albumin (mg/dL).
Abbreviation: M:E, myeloid to erythroid ratio.
Source: BJ Bain: Br J Haematol 94:206, 1996.
Philadelphia, Lippincott 
Williams & Wilkins, 2004.
Phil-
adelphia, Mosby, 2003.
Philadelphia, W.B.
Saunders Co., 2001.
Source: Values adapted from: American Society of Echocardiography, Guidelines and Standards.
http://www.asecho.org/i4a/pages/index.cfm?pageid=3317.
Accessed Feb 23, 2010.
A Manual of Uniform Laboratory Procedures, 2nd ed.
Salt Lake City, 
Utah, Intermountain Thoracic Society, 1984.
Daniel J.
Fink, Patrick M.
Sluss, 
James L.
Januzzi, and Kent B.
We also express our gratitude to 
Drs.
Amudha Palanisamy and Scott Fink for careful review of 
tables and helpful suggestions.
801 801
QUESTIONS
REVIEW AND 
SELF-ASSESSMENTa
Charles Wiener  ■   Cynthia D.
Brown   ■  Anna R.
Hemnes
DIRECTIONS: Choose the one best response to 
each question.
4.
You are concerned about the possibility of 
subarachnoid hemorrhage.
What is the most ap-
propriate initial test for diagnosis?
A.
Cerebral angiography
B.
CT of the head with IV contrast
C.
CT of the head without IV contrast
D.
Lumbar puncture
E.
Transcranial Doppler ultrasound
5.
A 74-year-old woman has a recent diagnosis of 
small cell lung cancer.
She is now complaining of 
headaches, and her family has noticed confusion as 
well.
Metastatic disease to the brain is suspected.
A 
mass lesion on magnetic resonance imaging (MRI) 
is demonstrated in the right parietal lobe.
Which 
MRI technique would best identify the extent of 
the edema surrounding the lesion?
A.
MR angiography
B.
FLAIR
C.
T1-weighted
D.
T2-weighted
E.
B and D
6.
A.
Acute renal failure
B.
Hyperthyroidism
C.
Hypocalcemia
D.
Lactic acidosis
E.
Nephrogenic systemic sclerosis
7.
A.
Brain abscess
B.
Herpes simplex encephalitis
C.
Locked-in syndrome
D.
Metabolic encephalopathy
E.
Nonconvulsive status epilepticus
1.
What is the name of this test?
A.
Babinski sign
B.
Dysdiadochokinesis
C.
Lhermitte symptom
D.
Pronator drift
E.
Romberg sign
2.
A positive test is a sign of:
A.
Abnormal sensation
B.
Early dementia
C.
Localized brainstem disease
D.
Potential weakness
E.
Underlying cerebellar dysfunction
3.
The symptoms involve both arms and 
legs.
She also has developed urinary incontinence 
over the past 24 hours.
Anal sphincter tone is 
decreased.
Babinski sign is positive.
Sensation is 
decreased in the extremities, but not in the face.
Cranial nerves are symmetric and intact, and men-
tal status is normal.
A.
Brainstem
B.
Cerebrum
C.
Cervical spinal cord
D.
Lumbar spinal cord
E.
New York: 
McGraw-Hill, 2012.
Review and Self-Assessment 802
8.
She 
has no medical history and takes no medications.
She experiences a brief loss of consciousness for 
about 20 seconds.
She has no seizure-like activity 
and immediately returns to her usual level of func-
tioning.
She is diagnosed with vasovagal syncope, 
and no follow-up testing is recommended.
Which 
of the following statements regarding neurally me-
diated syncope is TRUE?
A.
Neurally mediated syncope occurs when there are 
abnormalities of the autonomic nervous system.
B.
C.
D.
E.
The usual finding with cardiovascular monitoring is 
hypotension and tachycardia.
9.
She has 
a history of hypertension, diabetes mellitus, and 
chronic kidney disease (stage III).
She does recall 
at least two prior episodes of syncope similar to 
this one.
By the time she arrived in the emergency 
department, she reports feeling back to her usual 
self.
Witnesses report some jerking of her 
upper extremities.
She regained full consciousness 
in less than 2 minutes.
She is 
afebrile.
Her physical examination is unremarkable 
and includes a normal neurologic examination.
A.
CT scan of the head
B.
Electrocardiogram
C.
Fingerstick glucose measurement
D.
Orthostatic blood pressure measurement
E.
Tilt table testing
10.
A 48-year-old man presents to the emergency de-
partment complaining of dizziness.
He describes it 
as a sensation that the room is spinning.
All of the 
following would be consistent with a central cause 
of vertigo EXCEPT:
A.
Absence of tinnitus
B.
Gaze-evoked nystagmus
C.
Hiccups
D.
Inhibition of nystagmus by visual fixation
E.
Purely vertical nystagmus
11.
A 62-year-old woman presents complaining of se-
vere dizziness.
She notes it especially when she turns 
over in bed and immediately upon standing.
Her ini-
tial physical examination findings are normal.
Upon 
further testing, you ask the patient to sit with her 
head turned 45 degrees to the right.
You lower the 
patient to the supine position and extend the head 
backward 20 degrees.
This maneuver immediately 
reproduces the patient’s symptoms, and you note 
torsional nystagmus.
What is the most appropriate 
next step in evaluation and treatment of this patient?
A.
MRI of the brainstem
B.
Methylprednisolone taper beginning at 100 mg daily
C.
Repositioning (Epley) maneuvers
D.
Rizatriptan 10 mg orally once
E.
Valacyclovir 1000 mg three times daily for 7 days
12.
A 42-year-old man presents complaining of pro-
gressive weakness over a period of several months.
A disorder affecting lower motor neurons 
is suspected.
Decreased muscle tone
B.
Distal greater than proximal weakness
C.
Fasciculations
D.
Hyperactive tendon reflexes
E.
Severe muscle atrophy
13.
A 78-year-old man is seen in clinic because of re-
cent falls.
He reports gait difficulties with a sensa-
tion of being off balance at times.
One recent fall 
caused a shoulder injury requiring surgery to repair 
a torn rotation cuff.
In epidemiologic case series, 
what is the most common cause of gait disorders?
A.
Cerebellar degeneration
B.
Cerebrovascular disease with multiple infarcts
C.
Cervical myelopathy
D.
Parkinson’s disease
E.
Sensory deficits
Review and Self-Assessment 803
14.
A 65-year-old man presents complaining of fre-
quent falls and gait abnormalities.
He first noticed 
the difficulty about 6 months ago.
He has a history 
of hypertension and hypothyroidism and hyper-
lipidemia.
On neurologic exami-
nation, you observe his gait to be wide based with 
short, shuffling steps.
He has difficulty rising from 
his chair and initiating his gait.
Upon turning, he 
takes multiple steps and appears unsteady.
How-
ever, cerebellar testing results are normal, including 
heel-to-shin and Romberg testing.
He shows no evidence of muscle spasticity 
on passive movement.
His neurologic examination 
is consistent with which of the following causes?
A.
Alcoholic cerebellar degeneration
B.
Communicating hydrocephalus
C.
Neurosyphilis
D.
Multiple system atrophy
E.
Lumbar myelopathy
15.
Her initial blood pressure was 
70/40 mmHg with a heart rate of 130 beats/min.
She is volume resuscitated but requires dopamine 
to maintain an adequate blood pressure.
Her men-
tal status improved initially, but now she is agitated 
and pulling at her IV catheters.
She is screaming 
that she is trapped, and she is not oriented to place 
or year.
All of the following statements regarding 
the patient’s condition are true EXCEPT:
A.
An episode of delirium is associated with an in-
hospital mortality rate of 25% to 33%.
B.
C.
D.
Delirium is typically short-lived and does not persist 
longer than several days.
E.
Individuals who experience delirium have longer 
lengths of stay in the hospital.
16.
He was admitted 36 hours previously for treat-
ment of community-acquired pneumonia.
He re-
ceived treatment with levofloxacin 500 mg daily
 16.
( Continued)
  and required oxygen 2 L/min.
He has a medical 
history of tobacco abuse, diabetes mellitus, and hy-
pertension.
He reports alcohol intake of 2–4 beers 
daily.
Currently, the patient is agitated and pac-
ing his room.
He is reporting that he needs to leave 
the “meeting” immediately and go home.
He states 
that if he does not do this, someone is going to take 
his house and car away.
He has removed his IV and 
oxygen tubing from his nose.
He is noted to be somewhat tremulous 
and diaphoretic.
All of the following should be 
considered as part of the patient’s diagnostic work-
up EXCEPT:
A.
Arterial blood gas testing
B.
Brain imaging with MRI or head CT
C.
Fingerstick glucose testing
D.
More thorough review of the patient’s alcohol in-
take with his wife
E.
Review of the recent medications received by the 
patient
17.
Which of the 
following patients is at the highest risk for develop-
ing delirium?
A.
A 36-year-old man admitted to the medical ward 
with a deep venous thrombosis
B.
A 55-year-old man postoperative day 2 from a total 
colectomy
C.
A 68-year-old woman admitted to the intensive care 
unit (ICU) with esophageal rupture
D.
A 74-year-old woman in the preoperative clinic 
before hip surgery
E.
An 84-year-old man living in an assisted living 
facility
18.
A 28-year-old woman has severe head trauma after 
a motor vehicle accident.
She does not speak or follow any commands.
She breathes independently but is fed through a 
gastrostomy tube.
She can move all extremities
Review and Self-Assessment 804
 18.
( Continued)
  spontaneously but without purposeful movement.
What term best describes this patient’s condition?
A.
Coma
B.
Locked-in
C.
Minimally conscious state
D.
Persistent vegetative state
E.
Vegetative state
19.
There is concern that the patient 
has brain death.
What test is most commonly used 
to diagnose brain death in this situation?
A.
Apnea testing
B.
Cerebral angiography
C.
Demonstration of absent cranial nerve reflexes
D.
Demonstration of fixed and dilated pupils
E.
Performance of transcranial Doppler ultrasonography
20.
A.
Third-nerve compression and ipsilateral papillary 
dilation
B.
Catatonia
C.
“Locked-in” state
D.
Miotic pupils
E.
Respiratory arrest
21.
Which of the following is the most common find-
ing in aphasic patients?
A.
Alexia
B.
Anomia
C.
Comprehension
D.
Fluency
E.
Repetition
22.
After the stroke, an 
assessment reveals the findings shown in Figure 22.
What diagnosis does this figure suggest?
A.
Construction apraxia
B.
Hemianopia
C.
Hemineglect
D.
Object agnosia
E.
Simultanagnosia
23.
He works at a glass factory that requires him to 
work rotating shifts.
He notes the problem to be most severe when he 
is on the night shift.
Twice he has fallen asleep 
on the job.
( Continued)
  falls asleep again.
However, he feels fully 
functional at work on day and evening shifts.
He is up 
by about 3 pm when his children arrive home 
from school.
He drinks about 2 cups of coffee 
daily but tries to avoid drinking more than this.
He does not snore and has a body mass index of 
21.3 kg/m2.
All of the following are reasonable 
approaches to treatment in this man EXCEPT:
A.
Avoidance of bright light in the morning after his 
shifts
B.
Exercise in the early evening before going to work
C.
Melatonin 3 mg taken at bedtime on the morning 
after a night shift
D.
Modafinil 200 mg taken 30–60 minutes before 
starting a shift
E.
Strategic napping of no more than 20 minutes dur-
ing breaks at work
24.
She first notices the symptoms 
around 8 pm when she is sitting quietly watch-
ing television.
They inter-
fere with her ability to fall asleep about four times 
weekly.
She also some-
times takes a very hot bath to alleviate the symp-
toms.
During sleep, her husband complains that she 
kicks him throughout the night.
She has no history 
of neurologic or renal disease.
The physical examination findings, 
including thorough neurologic examination, are 
normal.
Her hemoglobin is 9.8 g/dL and hema-
tocrit is 30.1%.
The mean corpuscular volume is 
68 fL.
Serum ferritin is 12 ng/mL.
Which is the 
most appropriate initial therapy for this patient?
A.
Carbidopa/levodopa
B.
Hormone replacement therapy
C.
Iron supplementation
D.
Oxycodone
E.
Pramipexole
25.
A 20-year-old man presents for evaluation of ex-
cessive daytime somnolence.
He is finding it in-
creasingly difficult to stay awake during his classes.
Recently, his grades have fallen because whenever 
he tries to read, he finds himself drifting off.
He 
finds that his alertness is best after exercising or 
brief naps of 10–30 minutes.
Because of this, he 
states that he takes 5 or 10 “catnaps” daily.
The 
sleepiness persists despite averaging 9 hours of sleep 
nightly.
He describes these occurrences as 
a voice calling his name as he drifts off.
Once he had to lean against 
a wall to keep from falling down.
He undergoes 
an overnight sleep study and multiple sleep latency 
test.
There is no sleep apnea.
His mean sleep laten-
cy on five naps is 2.3 minutes.
In three of the five 
naps, rapid eye movement sleep is present.
Which 
of the following findings of this patient is most spe-
cific for the diagnosis of narcolepsy?
A.
Cataplexy
B.
Excessive daytime somnolence
C.
Hypnagogic hallucinations
D.
Rapid eye movement sleep in more than two naps 
on a multiple sleep latency test
E.
Sleep paralysis
26.
Which of the following is the most common sleep 
disorder in the U.S.
population?
A.
Delayed sleep phase syndrome
B.
Insomnia
C.
Obstructive sleep apnea
D.
Narcolepsy
E.
Restless legs syndrome
27.
In which stage of sleep are the parasomnias som-
nambulism and night terrors most likely to occur?
A.
Stage 1
B.
Stage 2
C.
Slow-wave sleep
D.
Rapid eye movement sleep
28.
A 44-year-old man is seen in the emergency de-
partment after a motor vehicle accident.
Which of
Review and Self-Assessment 806
 28.
( Continued)
  the following is most likely to be found on further 
evaluation?
A.
Retinal detachment
B.
Occipital lobe glioma
C.
Optic nerve injury
D.
Parietal lobe infarction
E.
Pituitary adenoma
29.
A 42-year-old construction worker complains of 
waking up with a red, painful left eye.
She often 
works without goggles at her construction site.
Her only current medication is lisinopril.
On examination, the left eye is diffusely red and 
sensitive to light.
The eyelids are normal.
In dim 
light, visual acuity is normal in both eyes.
All of 
the following diagnoses will explain her findings 
EXCEPT:
A.
Acute angle-closure glaucoma
B.
Anterior uveitis
C.
Corneal abrasion
D.
Posterior uveitis
E.
Transient ischemic attack
30.
A 75-year-old triathlete complains of gradually 
worsening vision over the past year.
It seems to 
be involving near and far vision.
He takes no regular medications.
Physical examination is normal except for bilateral 
visual acuity of 20/100.
There are no focal visual 
field defects and no redness of the eyes or eyelids.
Which of the following is the most likely diagnosis?
A.
Age-related macular degeneration
B.
Blepharitis
C.
Diabetic retinopathy
D.
Episcleritis
E.
Retinal detachment
31.
All of the following statements regarding olfaction 
are true EXCEPT:
A.
Decrements in olfaction may lead to nutritional 
deficiency.
B.
More than 40% of patients with traumatic anosmia 
will regain normal function over time.
C.
D.
E.
Women identify odorants better than men at all ages.
32.
A 64-year-old man is evaluated for hearing loss that 
he thinks is worse in his left ear.
His wife and chil-
dren have told him for years that he does not listen to 
them.
In ad-
dition, he reports a continuous buzzing that is louder 
in his left ear.
He denies any sensation of vertigo, 
headaches, or balance difficulties.
He has no family history of deafness, al-
though his father had hearing loss as he aged.
He has a 
medical history of hypertension, hyperlipidemia, and 
coronary artery disease.
Which of the following 
findings would you expect on physical examination?
A.
A deep tympanic retraction pocket seen above the 
pars flaccida on the tympanic membrane.
B.
Cerumen impaction in the external auditory canal.
C.
Hearing loss that is greater at lower frequencies on 
pure tone audiometry.
D.
E.
33.
Epilepsy
B.
Lambert-Eaton syndrome
C.
Migraine
D.
Parkinson’s disease
E.
Spinocerebellar ataxia
34.
Lambert-Eaton syndrome: acetylcholine
B.
Myasthenia gravis: acetylcholine
C.
Orthostatic tachycardia syndrome: serotonin
D.
Parkinson’s disease: dopamine
E.
Stiff-person syndrome: GABA
35.
These episodes 
had occurred every few months during high school 
and he never told anyone.
( Continued)
 when sleep deprived.
The episodes last 
about 3–5 minutes and stop spontaneously.
He has 
never lost consciousness.
During the episodes, he can 
communicate with friends.
Which of the following is 
the most accurate classification of his seizure disorder?
A.
Focal seizures with dyscognitive features
B.
Focal seizures without dyscognitive features
C.
Generalized seizure
D.
Myoclonic seizures
E.
Typical absence seizure
36.
The patient has a history 
of intractable focal seizures that rarely generalize.
Which of these additional historic fac-
tors is also likely to be present in this patient?
A.
History of febrile seizures
B.
Hypothyroidism
C.
Neurofibromas
D.
Recurring genital ulcers
E.
Type 2 diabetes mellitus
37.
He did not lose consciousness.
He was 
brought in 2 hours after symptom onset and is cur-
rently awake, alert, and oriented.
He has not had any 
further seizures but has been unable to move his left 
hand since his seizure.
His electrolytes and complete 
blood count are within normal limits.
A noncontrast 
CT scan of his head is unremarkable.
What is the best course of action at this time?
A.
Cerebral angiogram
B.
Lumbar puncture
C.
Magnetic resonance angiogram
D.
Psychiatric evaluation
E.
Reassess in a few hours
38.
He does 
not have a known seizure disorder.
There is no his-
tory of head trauma, stroke, or tumor.
The patient 
is unemployed, married, and takes no medication.
The 
patient is postictal.
His neck is difficult to maneu-
ver due to stiffness.
His white blood cell count is 
19,000/μL, hematocrit 36%, and platelets 200,000/
μL.
Urine toxicology screen is positive 
for cocaine metabolites.
Which next step is most ap-
propriate in this patient’s management?
A.
Electroencephalogram (EEG)
B.
IV loading with antiepileptic medication
C.
Lumbar puncture
D.
Magnetic resonance imaging
E.
Substance abuse counseling
39.
All of the following statements regarding epilepsy 
are true EXCEPT:
A.
The incidence of suicide is higher in epileptic pa-
tients than it is in the general population.
B.
Mortality is no different in patients with epilepsy 
than it is in age-matched controls.
C.
D.
E.
Tricyclic antidepressants lower the seizure threshold 
and may precipitate seizures.
40.
She has no identifying information, 
and her past medical history is unknown.
What is 
the most likely cause of her seizure?
A.
Amyloid angiopathy
B.
Fever
C.
Genetic disorder
D.
Illicit drug use
E.
Uremia
41.
A 36-year-old man is brought to the emergency 
department because of a seizure.
He had a brief seizure at home that stopped within
Review and Self-Assessment 808
 41.
( Continued)
  a few minutes.
On physical examination he 
is afebrile, hypertensive, and actively seizing.
All of 
the following are potential therapies for his condition 
EXCEPT:
A.
Carbamazepine
B.
Fosphenytoin
C.
Lorazepam
D.
Phenobarbital
E.
Valproate
42.
The most common cause of a cerebral embolism is:
A.
Atrial fibrillation
B.
Cardiac prosthetic valves
C.
Dilated cardiomyopathy
D.
Endocarditis
E.
Rheumatic heart disease
43.
A 54-year-old male is referred to your clinic for 
evaluation of atrial fibrillation.
He first noted the ir-
regular heartbeat 2 weeks ago and presented to his pri-
mary care physician.
He denies chest pain, shortness 
of breath, nausea, or gastrointestinal symptoms.
Past 
medical history is unremarkable.
There is no history 
of hypertension, diabetes, or tobacco use.
His medica-
tions include metoprolol.
The examination is notable 
for a blood pressure of 126/74 mmHg and a pulse of 
64 beats/min.
The jugular venous pressure is not ele-
vated.
His heart is irregularly irregular, with normal S1 
and S2.
The lungs are clear, and there is no peripheral 
edema.
An echocardiogram shows a left atrial size of 
3.6 cm.
Left ventricular ejection fraction is 60%.
There 
are no valvular or structural abnormalities.
Which of 
the following statements regarding his atrial fibrillation 
and stroke risk is true?
A.
He requires no antiplatelet therapy or anticoagula-
tion because the risk of embolism is low.
B.
C.
D.
His risk of an embolic stroke is less than 1%, and he 
should take a daily aspirin.
E.
He should be started on SC low-molecular-weight 
heparin and transitioned to warfarin.
44.
Aspirin
B.
Blood pressure control
 44.
( Continued)
C.
Clopidogrel
D.
Statin therapy
E.
Warfarin
45.
He has a past his-
tory of hypertension and hypercholesterolemia.
His medications include atorvastatin and enala-
pril.
He is alert but aphasic with upper and lower left 
extremity hemiparesis.
He is able to move his right 
side normally.
Anticoagulation
B.
Blood pressure lowering
C.
Hypothermia protocol
D.
Intracerebral stent placement
E.
IV thrombolysis
46.
The history and examination are most consis-
tent with which of the following?
A.
Alzheimer’s disease
B.
Binswanger’s disease
C.
Creutzfeldt-Jakob disease
D.
Multi-infarct dementia
E.
Vitamin B12 deficiency
47.
Her symptoms 
originally began approximately 3 years ago.
She also has had several more episodes of syn-
cope.
She has never had an injury from syncope.
A final recent symptom has been periodic flushing
Review and Self-Assessment 809
 47.
( Continued)
 and sweating.
Her only other medical history is re-
cent recurrent urinary tract infections.
Her medi-
cations are ropinirole 24 mg daily and nitrofuran-
toin 100 mg daily.
She reports no history of drug 
use.
Upon standing, her blood pres-
sure drops to 90/50 mmHg with a heart rate of 
110 beats/min.
Her ocular movements are full and 
intact.
She has recurrent motor movements of the 
right side of her face.
Deep tendon reflex-
es are brisk and 3+ in upper and lower extremities.
Three beats of myoclonus are present at the ankles 
bilaterally.
She walks with a spastic gait.
Strength is 
normal.
What is the most likely diagnosis?
A.
Corticobasal degeneration
B.
Diffuse Lewy body dementia
C.
Drug-induced Parkinson’s disease
D.
Multiple system atrophy with parkinsonian features
E.
Parkinson’s disease with inadequate treatment
48.
He states that he first noticed a slowing of 
his gait approximately 6 months ago.
He has diffi-
culty rising to a standing position and states that he 
shuffles when he walks.
In addition, he states that 
his right hand shakes more so than his left, and he 
is right handed.
His past medical history is significant for hyperten-
sion and hypercholesterolemia.
He drinks a glass 
of wine with dinner daily and is a lifelong non-
smoker.
On physical examination, he has masked 
facies.
His gait shows decreased arm swing with 
slow shuffling steps.
He turns en bloc.
A pill-rolling 
tremor is present on the right side.
There is cog-
wheel rigidity bilaterally.
Eye movements are full 
and intact.
There is no orthostatic hypotension.
A
 48.
You diagnose the patient with Parkinson’s disease.
The patient asks about his prognosis and likelihood 
of disability.
A.
B.
C.
D.
Levodopa should be started immediately to prevent 
the development of disabling rigidity.
E.
MAO inhibitors are contraindicated once the diag-
nosis of Parkinson’s disease is established.
49.
All of the following statements regarding restless 
legs syndrome (RLS) are true EXCEPT:
A.
Dopamine antagonists are effective therapy.
B.
Most patients develop symptoms before the age of 
30 years old.
C.
RLS may cause sleep disorder and daytime hyper-
somnolence.
D.
RLS is more common in Asians than in the general 
U.S.
population.
E.
Symptoms may involve the upper extremity.
50.
Which of the following statements regarding 
Alzheimer’s disease is true?
A.
Delusions are uncommon.
B.
It accounts for over half of the cases of significant 
memory loss in patients over 70 years of age.
C.
It typically presents with rapid (<6 months) signifi-
cant memory loss.
D.
Less than 5% of patients present with nonmemory 
complaints.
E.
Pathologically, the most notable abnormalities are in 
the cerebellar regions.
51.
He denies back pain.
His only medication 
is atorvastatin.
His left leg strength is notably
Review and Self-Assessment 810
 51.
( Continued)
  diminished in the hip flexors, hip adductors, quad-
riceps, and calf muscles.
There is atrophy of the 
quadriceps and calf.
His ankle and knee reflexes are 
increased on the left.
He has subtle weakness on 
the right quadriceps.
There are no sensory abnor-
malities in light touch, pinprick, temperature, or 
proprioception.
There are occasional fasciculations 
of the abdominal muscles.
Cervical spondylosis
B.
Foramen magnum tumor
C.
Lead poisoning
D.
Multifocal motor neuropathy with conduction block
E.
Vitamin C deficiency
52.
She has taken her pulse and it feels fast to her.
Sitting or lying down improves the 
symptoms.
She 
reports lightheadedness during the episode.
An 
ECG while symptomatic shows sinus tachycardia 
without any conduction abnormalities.
Which of 
the following is the most likely diagnosis?
A.
Addison’s disease
B.
Autoimmune autonomic neuropathy
C.
Diabetic neuropathy
D.
Multisystem atrophy
E.
Postural orthostatic tachycardia syndrome
53.
A 45-year-old male complains of severe right arm 
pain.
There was 
some arm swelling and warmth.
He was evaluated 
in an urgent care setting.
There were no radio-
graphic abnormalities and he was not treated.
Since 
the injury, the pain and swelling have persisted.
53.
There is no 
specific weakness or sensory change.
The patient’s 
pain most likely is due to:
A.
Acromioclavicular separation
B.
Brachial plexus injury
C.
Cervical radiculopathy
D.
Complex regional pain syndrome
E.
Subclavian vein thrombosis
54.
Which of the following criteria suggests the diag-
nosis of trigeminal neuralgia?
A.
Deep-seated, steady facial pain
B.
Elevated erythrocyte sedimentation rate (ESR)
C.
Objective signs of sensory loss on physical examina-
tion
D.
Response to gabapentin therapy
E.
None of the above
55.
On physical examination, she appears 
well with normal vital signs.
Detailed cranial nerve 
examination reveals no sensory or motor abnormali-
ties.
The remainder of her neurologic examination 
is normal.
What is the next step in her management?
A.
Brain MRI
B.
Brain MRI plus carbamazepine therapy
C.
Carbamazepine therapy
D.
Glucocorticoid therapy
E.
Referral to Otolaryngology for surgical cure
56.
Touching the lips or moving 
the tongue can initiate these intense spasms of pain.
The results of a physical examination are normal.
MRI of the head is also normal.
The most likely 
cause of this patient’s pain is:
A.
Acoustic neuroma
B.
Amyotrophic lateral sclerosis
C.
Meningioma
D.
Trigeminal neuralgia
E.
Facial nerve palsy
57.
The pain is not relieved by lying down or by wear-
ing a soft neck collar.
( Continued)
  from sleep.
The pain is severe and is impeding her 
daily activities.
She denies any arm pain or weak-
ness.
There is no history of prior back or neck pain, 
trauma, or arthritis.
She works as a postal delivery 
agent and her only physical activity is walking.
She 
is monogamous with her husband and has no illicit 
activities.
Her family history is notable for an aunt 
and mother with breast cancer.
Her MRI is shown 
in Figure 57.
Which is the most likely diagnosis?
A.
Cervical spondylosis
B.
Hematomyelia
C.
Metastatic breast cancer
D.
Spinal epidural abscess
E.
Spinal epidural hematoma
58.
A 34-year-old female complains of lower extrem-
ity weakness for the last 3 days.
She had had some low-grade fevers for the last 
week.
She denies recent travel.
Past medical history is 
unremarkable.
Physical examination is notable for a 
sensory level at the level of the umbilicus.
The lower 
extremities show +3/5 strength bilaterally proximally 
and distally.
Reflexes, cerebellar examination, and 
mental status are normal.
All of the following are ap-
propriate steps in evaluating this patient EXCEPT:
A.
Antinuclear antibodies
B.
Electromyography
C.
Lumbar puncture
D.
MRI of the spine
E.
Viral serologies
59.
Which of the following statements about syringo-
myelia is true?
A.
More than half the cases are associated with Chiari 
malformations.
59.
( Continued)
B.
Symptoms typically begin in middle age.
C.
Vibration and position sensation are usually diminished.
D.
Syrinx cavities are always congenital.
E.
Neurosurgical decompression is usually effective in 
relieving the symptoms.
60.
Head imaging was normal.
The patient’s physical examination is entirely 
normal except for a somewhat flattened affect.
Which 
of the following statements regarding his condition is 
true?
A.
He has an excellent prognosis.
B.
He meets the criteria for postconcussive syndrome 
and should improve over 1–2 months.
C.
He should avoid contact sports for 2 weeks.
D.
He is most likely malingering.
E.
Low-dose narcotics should be started for headache.
61.
A 68-year-old man is brought to the clinic by his 
wife for evaluation.
His only complaint is a mild 
but persistent, diffuse headache.
His head CT is 
shown in Figure 61.
What is the most likely diagnosis?
FIGURE 57
FIGURE 61
Review and Self-Assessment 812
 61.
( Continued)
A.
Acute epidural hematoma
B.
Acute subarachnoid hemorrhage
C.
Alzheimer’s disease
D.
Chronic subdural hematomas
E.
Normal-pressure hydrocephalus
62.
The fall was not witnessed; however, she was 
suspected to have hit her head.
She is not respon-
sive to verbal or light tactile stimuli.
At baseline she is 
able to converse but is frequently disoriented to place 
and time.
Immediately after triage she is taken for a 
CT scan of the head.
Which of the following is true 
regarding head injury and hematomas?
A.
B.
Epidural hematomas generally arise from venous 
sources.
C.
Epidural hematomas are common among the elderly 
with minor head trauma.
D.
Most patients presenting with epidural hematomas 
are unconscious.
E.
63.
A 49-year-old man is admitted to the hospital 
with a seizure.
He does not have a history of sei-
zures and he currently takes no medications.
He 
has AIDS and is not under any care at this time.
His physical examination is most notable for small, 
shoddy lymphadenopathy in the cervical region.
A head CT shows a ring-enhancing lesion in the 
right temporal lobe, with edema but no mass effect.
A lumbar puncture shows no white or red blood 
cells, and the Gram stain is negative.
His serum 
Toxoplasma IgG is positive.
He is treated with pyri-
methamine, sulfadiazine, and levetiracetam.
What 
is the best course of action for this patient at this 
time?
A.
Continue treatment for CNS toxoplasmosis.
B.
Dexamethasone.
C.
IV acyclovir.
D.
Stereotactic brain biopsy.
E.
Whole-brain radiation therapy.
64.
A laboratory workup reveals a decreased 
morning cortisol level of 1.9 μg/dL.
A.
Growth hormone
B.
Follicle-stimulating hormone
C.
Prolactin
D.
Thyroid-stimulating hormone
65.
The seizure lasted a short time and termi-
nated spontaneously.
Her initial 
CT scan showed no acute hemorrhage but was 
abnormal.
An MRI is obtained and is shown in 
Figure 65.
What is the most likely diagnosis in 
this patient?
A.
Brain abscess
B.
Glioblastoma
C.
Low-grade astrocytoma
D.
Meningioma
E.
Oligodendroglioma
FIGURE 65
Review and Self-Assessment 813
66.
All of the following hormones are produced by the 
anterior pituitary EXCEPT:
A.
Adrenocorticotropic hormone
B.
Growth hormone
C.
Oxytocin
D.
Prolactin
E.
Thyroid-stimulating hormone
67.
One day postpartum she complains of 
visual changes and severe headache.
Two hours 
after these complaints, she is found unresponsive 
and profoundly hypotensive.
She is intubated and 
placed on mechanical ventilation.
Physical exam is unremarkable.
Which 
of the following is most likely to reverse her hypo-
tension?
A.
Activated drotrecogin alfa
B.
Hydrocortisone
C.
Piperacillin/tazobactam
D.
T4
E.
Transfusion of packed red blood cells
68.
In addition, he reports 
low libido and decreased energy.
Physical examina-
tion shows frontal bossing and enlarged hands.
An 
MRI confirms that he has a pituitary mass.
Which 
of the following screening tests should be ordered 
to diagnose the cause of the mass?
A.
24-hour urinary free cortisol
B.
ACTH assay
C.
Growth hormone level
D.
Serum IGF-1 level
E.
Serum prolactin level
69.
All of the following are potential causes of hyper-
prolactinemia EXCEPT:
A.
Cirrhosis
B.
Hirsutism
C.
Nipple stimulation
D.
Opiate abuse
E.
Rathke’s cyst
70.
A 28-year-old woman presents to her primary 
care physician’s office with 1 year of amenorrhea.
She reports mild galactorrhea and headaches.
Al-
though she is sexually active, a urine pregnancy test
 70.
( Continued)
  is negative.
Which of the following represents the primary 
goal of bromocriptine therapy for her condition?
A.
Control of hyperprolactinemia
B.
Reduction in tumor size
C.
Resolution of galactorrhea
D.
Restoration of menses and fertility
E.
All of the above
71.
A 58-year-old man undergoes severe head trauma 
and develops pituitary insufficiency.
After recov-
ery, he is placed on thyroid hormone, testosterone, 
glucocorticoids, and vasopressin.
All of 
the following are potential signs or symptoms of 
growth hormone deficiency EXCEPT:
A.
Abnormal lipid profile
B.
Atherosclerosis
C.
Increased bone mineral density
D.
Increased waist:hip ratio
E.
Left ventricular dysfunction
72.
His laboratory evaluation shows 
a hypokalemic metabolic alkalosis.
Cushing’s syn-
drome is suspected.
Which of the following state-
ments regarding this syndrome is true?
A.
Basal ACTH level is likely to be low.
B.
Circulating corticotropin-releasing hormone is likely 
to be elevated.
C.
Pituitary MRI will visualize all ACTH-secreting 
tumors.
D.
Referral for urgent performance of inferior petrosal 
venous sampling is indicated.
E.
Serum potassium level below 3.3 mmol/L is sugges-
tive of ectopic ACTH production.
73.
She reports moderate compli-
ance with her medications but feels generally well.
A TSH is checked and is below the limits of de-
tection of the assay.
Which of the following is the 
next most appropriate action?
A.
Decrease levothyroxine dose to half of current dose.
B.
Do nothing.
C.
Order free T4 level.
D.
Order MRI of her brain.
E.
Order thyroid uptake scan.
Review and Self-Assessment 814
74.
She 
has been amenorrheic for several months.
Cush-
ing’s syndrome is suspected.
Which of the follow-
ing tests should be used to make the diagnosis?
A.
24-hour urine free cortisol
B.
Basal adrenocorticotropic hormone (ACTH)
C.
Corticotropin-releasing hormone (CRH) level at 8 am
D.
Inferior petrosal venous sampling
E.
Overnight 1-mg dexamethasone suppression test
75.
A patient visited a local emergency room 1 week 
ago with a headache.
What should 
be the next step in her management?
A.
Diagnose her with subclinical panhypopituitarism, 
and initiate low-dose hormone replacement.
B.
Reassure her and follow laboratory results closely.
C.
Reassure her and repeat MRI in 6 months.
D.
E.
76.
All of the following are frequent initial symptoms 
of multiple sclerosis EXCEPT:
A.
Optic neuritis
B.
Paresthesias
C.
Sensory loss
D.
Visual loss
E.
Weakness
77.
Which of the following is the most common clini-
cal classification of multiple sclerosis?
A.
Autoimmune autonomic neuropathy
B.
Primary progressive
C.
Progressive relapsing
D.
Relapsing/remitting
E.
Secondary progressive
78.
Depressed consciousness
B.
Focal neurologic abnormality
C.
Known central nervous system (CNS) mass lesion
D.
Positive Kernig’s sign
E.
Recent head trauma
79.
A 78-year-old man with diabetes mellitus presents with 
fever, headache, and altered sensorium.
His neck is stiff and he has photophobia.
CSF Gram stain is negative.
A.
Acyclovir
B.
Dexamethasone after antibiotics
C.
Dexamethasone prior to antibiotics
D.
IV γ globulin
E.
Valacyclovir
80.
A.
Immunocompromised patients
B.
Elderly patients
C.
Infants
D.
All of the above
81.
A.
Acetaminophen
B.
Acyclovir
C.
β-lactam antibiotics
D.
Ibuprofen
E.
Phenobarbital
82.
Variant Creutzfeldt-Jakob disease (vCJD) has been 
diagnosed in which of the following populations?
A.
New Guinea natives practicing cannibalism
C.
Patients accidentally inoculated with infected mate-
rial during surgical procedures
D.
Worldwide, in sporadic cases, mostly during the 
fifth and sixth decades of life
E.
A.
A 55-year-old woman presents with progressive 
incoordination.
She also has an unsteady 
gait.
MRI reveals atrophy of both lobes of the cer-
ebellum.
Serologic evaluation reveals the presence 
of anti-Yo antibody.
Which of the following is the 
most likely cause of this clinical syndrome?
A.
Non–small cell cancer of the lung
B.
Small cell cancer of the lung
C.
Breast cancer
D.
Non-Hodgkin’s lymphoma
E.
Colon cancer
85.
A 24-year-old man presents for evaluation of foot-
drop.
His right leg is more 
affected than his left leg.
He has not noted any sen-
sory changes.
He has several family members with 
similar complaints.
Knee and ankle jerk re-
flexes are unobtainable.
Calves are reduced in size 
bilaterally.
Upper extremity examination is normal.
Which of the following is the most likely diagnosis?
A.
Charcot-Marie-Tooth syndrome
B.
Fabry disease
C.
Guillain-Barré syndrome
D.
Hereditary neuralgic amyotrophy
E.
Hereditary sensory and autonomic neuropathy
86.
( Continued)
  past several weeks.
He also reports some difficulty 
walking.
His medications include niacin, aspirin, and iso-
niazid.
Which of the following is likely to reverse 
his symptoms?
A.
Cobalamin
B.
Levothyroxine
C.
Neurontin
D.
Pregabalin
E.
Pyridoxine
87.
She 
also reports tingling and burning in the same loca-
tion, but no weakness.
Her symptoms have been 
intermittently present for the last several months.
Which of the following statements regarding 
this condition is true?
A.
Autonomic neuropathy is rarely seen in combina-
tion with sensory neuropathy.
B.
C.
This is the most common cause of peripheral neu-
ropathy in developed countries.
D.
Tight glucose control from now on will reverse her 
neuropathy.
E.
None of the above is true.
88.
All the following cause primarily a sensory neu-
ropathy EXCEPT:
A.
Acromegaly
B.
Critical illness
C.
HIV infection
D.
Hypothyroidism
E.
Vitamin B12 deficiency
89.
A 50-year-old male complains of weakness and 
numbness in the hands for the last month.
He de-
scribes paresthesias in the thumb and the index and 
middle fingers.
The symptoms are worse at night.
He also describes decreased grip strength bilaterally.
He works as a mechanical engineer.
The patient de-
nies fevers, chills, or weight loss.
You consider the diagnosis of carpal
Review and Self-Assessment 816
 89.
( Continued)
  tunnel syndrome.
All the following are causes of 
carpal tunnel syndrome EXCEPT:
A.
Amyloidosis
B.
Chronic lymphocytic leukemia
C.
Diabetes mellitus
D.
Hypothyroidism
E.
Rheumatoid arthritis
90.
Which of the following bacteria have been im-
plicated in cases of Guillain-Barré syndrome?
A.
Bartonella henselae
B.
Campylobacter jejuni
C.
Escherichia coli
D.
Proteus mirabilis
E.
Tropheryma whippelii
91.
A 34-year-old female complains of weakness and 
double vision for the last 3 weeks.
The patient denies pain.
The 
symptoms are worse at the end of the day and with 
repeated muscle use.
You suspect myasthenia gravis.
All the following are useful in the diagnosis of myas-
thenia gravis EXCEPT:
A.
Acetylcholine receptor (AChR) antibodies
B.
Edrophonium
C.
Electrodiagnostic testing
D.
Muscle-specific kinase (MuSK) antibodies
E.
Voltage-gated calcium channel antibodies
92.
You intend to initiate therapy with anticho-
linesterase medications and glucocorticoids.
All of 
the following tests are necessary before instituting 
this therapy EXCEPT:
A.
MRI of mediastinum
B.
Purified protein derivative skin test
C.
Lumbar puncture
D.
Pulmonary function tests
E.
Thyroid-stimulating hormone
93.
All of the following lipid-lowering agents are as-
sociated with muscle toxicity EXCEPT:
A.
Atorvastatin.
B.
Ezetimibe.
C.
Gemfibrozil.
D.
Niacin.
E.
All of the above are associated with muscle toxicity.
94.
All of the following endocrine conditions are as-
sociated with myopathy EXCEPT:
A.
Hypothyroidism.
B.
Hyperparathyroidism.
C.
Hyperthyroidism.
D.
Acromegaly.
E.
All of the above are associated with myopathy.
95.
A 34-year-old woman seeks evaluation for weak-
ness.
She has noted tripping when walking, par-
ticularly in her left foot, for the past 2 years.
She has not seen a physician in 
many years and has no past medical history.
Her 
only medications are a multivitamin and calcium 
with vitamin D.
Her speech is mildly dysarthric, and the 
palate is high and arched.
Strength is 4/5 in the 
intrinsic muscles of the hand, wrist extensors, and 
ankle dorsiflexors.
What is the most likely diag-
nosis?
A.
Acid maltase deficiency (Pompe’s disease)
B.
Becker muscular dystrophy
C.
Duchenne muscular dystrophy
D.
Myotonic dystrophy
E.
Nemaline myopathy
96.
An elevation in which of the following serum en-
zymes is the most sensitive indicator of myositis?
A.
Aldolase
B.
Creatinine kinase
C.
Glutamic-oxaloacetic transaminase
D.
Glutamate pyruvate transaminase
E.
Lactate dehydrogenase
97.
A 64-year-old woman is evaluated for weakness.
For several weeks she has had difficulty brushing 
her teeth and combing her hair.
She has also noted 
a rash on her face.
Examination is notable for a 
heliotrope rash and proximal muscle weakness.
Serum creatine kinase (CK) is elevated and she is
Review and Self-Assessment 817
 97.
( Continued)
  diagnosed with dermatomyositis.
After evaluation 
by a rheumatologist, she is found to have anti-Jo-1 
antibodies.
She is also likely to have which of the 
following findings?
A.
Ankylosing spondylitis
B.
Inflammatory bowel disease
C.
Interstitial lung disease
D.
Primary biliary cirrhosis
E.
Psoriasis
98.
A 63-year-old woman is evaluated for a rash on her 
eyes and fatigue for 1 month.
She reports difficulty 
with arm and leg strength and constant fatigue, but 
no fevers or sweats.
She also notes that she has a red 
discoloration around her eyes.
She has hypothy-
roidism but is otherwise well.
On examination she 
has a heliotrope rash and proximal muscle weak-
ness.
Which of the following 
studies should be performed as well to look for as-
sociated conditions?
A.
Mammogram
B.
Serum antinuclear antibody measurement
C.
Stool examination for ova and parasites
D.
Thyroid-stimulating immunoglobulins
E.
Titers of antibodies to varicella zoster
99.
You are seeing your patient with polymyositis for 
follow-up.
He began a steroid taper 2 weeks 
ago.
He no longer needs a cane and his 
voice has returned to normal.
Laboratory data 
show a creatine kinase (CK) of 1300 U/L, which 
is unchanged from 2 months ago.
What is the most 
appropriate next step in this patient’s management?
A.
Continue current management.
B.
Continue high-dose steroids with no taper.
C.
Switch mycophenolate to methotrexate.
D.
Repeat muscle biopsy.
100.
For the last day 
she has complained about headache and confu-
sion.
Her medications include diltiazem, cyclospo-
rine, prednisone, and mycophenolate mofetil.
She 
is now awake but somnolent.
Her vital signs are 
normal except a blood pressure of 150/90 mmHg.
100.
Hearing is 
intact.
There is no nuchal rigidity.
Her cyclospo-
rine level is therapeutic.
The FLAIR image of her 
MRI is shown in Figure 100.
Which of the fol-
lowing is the most likely diagnosis?
A.
Acoustic neuroma
B.
Calcineurin-inhibitor toxicity
C.
Panhypopituitarism
D.
Streptococcal meningitis
E.
Tuberculous meningitis
101.
However, his wife re-
ports that he seems depressed and is often confused.
His short-term memory is poor and he exhibits no 
enthusiasm for teaching.
He has no fever or night 
sweats.
Current medications include lovastatin and 
lisinopril.
Which of 
the following is the most likely diagnosis?
A.
Multiple sclerosis
B.
Post–cardiac bypass brain injury
C.
Streptococcal meningitis
D.
Variant Creutzfeldt-Jacob disease
E.
West Nile virus encephalitis
FIGURE 100
Review and Self-Assessment 818
102.
A 24-year-old man is recovering from ARDS due 
to severe influenza A infection.
Passive splints were placed on his upper and 
lower extremities.
He is now extubated and awake, 
requiring only nasal oxygen.
The rest 
of the neurologic examination of the right leg and 
foot appears normal.
Which of the following is the 
most likely etiology of his defects?
A.
Cauda equina syndrome
B.
Femoral nerve injury
C.
L4 radiculopathy
D.
L5 radiculopathy
E.
Peroneal nerve injury
103.
Delusional disorder
B.
Impaired memory or concentration
C.
Muscle pain
D.
Sore throat
E.
Tender cervical or axillary lymph nodes
104.
Which of the following is a beneficial therapy for 
chronic fatigue syndrome?
A.
Bupropion
B.
Cognitive behavioral therapy
C.
Doxycycline
D.
Fluoxetine
E.
Olanzapine
105.
She 
feels lightheaded and dizzy.
She denies any immediate 
precipitating cause, although she has been under
105.
She does not take 
any medications and has no medical history.
She de-
nies tobacco, alcohol, or drug use.
On initial examina-
tion, she appears somewhat anxious and diaphoretic.
She is afebrile.
Her examination 
is normal.
Her arterial blood gas shows a pH of 7.52, 
PaCO2 of 28 mmHg, and PaO2 of 116 mmHg.
The 
ECG is normal as is a chest radiograph.
What is the 
next best step in the management of this patient?
A.
Initiate therapy with alprazolam 0.5 mg four times daily.
B.
Initiate therapy with fluoxetine 20 mg daily.
C.
Perform a CT pulmonary angiogram.
D.
E.
Refer for cognitive behavioral therapy.
106.
Duloxetine—Selective serotonin reuptake inhibitor
B.
Fluoxetine—Selective serotonin reuptake inhibitor
C.
Nortriptyline—Tricyclic antidepressant
D.
Phenelzine—Monoamine oxidase inhibitor
E.
Venlafaxine—Mixed norepinephrine/serotonin 
reuptake inhibitor and receptor blocker
107.
She is 
irritable with her husband and children and cries fre-
quently.
You con-
cur that post-traumatic stress disorder is likely.
What 
treatment do you recommend for this patient?
A.
Avoidance of alcohol
B.
Cognitive behavioral therapy
C.
Paroxetine 20 mg daily
D.
Trazodone 50 mg nightly
E.
All of the above
Review and Self-Assessment 819
108.
A 36-year-old man is being treated with venlafax-
ine 150 mg twice daily for major depression.
He 
has currently been on the medication for 4 months.
He has had 
one prior episode of major depression when he 
was 25.
He asks when he 
can safely discontinue his medication.
What is your 
advice to the patient?
A.
He should continue on the medication indefinitely 
as his depression is likely to recur.
B.
C.
D.
The medication can be discontinued safely now as 
his symptoms are well controlled.
E.
109.
A.
Coadministration with a carbonated beverage
B.
Concentration of alcohol of more than 20% by 
volume
C.
Concurrent intake of a high-carbohydrate meal
D.
Concurrent intake of a high-fat meal
E.
Concurrent intake of a high-protein meal
110.
Which of the following best reflects the effect of 
alcohol on neurotransmitters in the brain?
A.
Decreases dopamine activity
B.
Decreases serotonin activity
C.
Increases γ-aminobutyric acid activity
D.
Stimulates muscarinic acetylcholine receptors
E.
Stimulates N-methyl-D-aspartate excitatory gluta-
mate receptors
111.
A.
0.02
B.
0.08
C.
0.28
D.
0.40
E.
0.60
112.
B.
Approximately 60% of the risk for alcohol abuse 
disorders is attributed to genetics.
C.
Children of alcoholics have a 10-fold higher risk of 
alcohol abuse and dependence.
D.
E.
113.
A 42-year-old man with alcohol dependence is admit-
ted to the hospital for acute pancreatitis.
He typically drinks 24 12-ounce beers daily.
He is agitated, diaphoretic, and pacing his room.
He is 
oriented to person only.
His neurologic examination 
appears nonfocal, although he does not cooperate.
He 
is tremulous.
What is the next step in the manage-
ment of this patient?
A.
Administer a bolus of 1 L of normal saline and thia-
mine 100 mg IV.
B.
C.
Perform an emergent head CT.
D.
Perform two peripheral blood cultures and begin 
treatment with imipenem 1 g IV every 8 hours.
E.
Place the patient in four-point restraints and treat 
with haloperidol 5 mg IV.
114.
She has a medical history of stroke oc-
curring during a hypertensive crisis.
Which of the 
following medications could be considered?
A.
Acamprosate
B.
Disulfiram
Review and Self-Assessment 820
114.
( Continued)
C.
Naltrexone
D.
A and C
E.
All of the above
115.
What is the most common initial illicit drug of 
abuse among U.S.
adolescents?
A.
Benzodiazepines
B.
Heroin
C.
Marijuana
D.
Methamphetamines
E.
Prescription narcotics
116.
She uses IV heroin on a 
daily basis, often spending $100 or more per day 
on drugs.
The 
abscess is drained and packed, and the patient is 
initiated on therapy with IV clindamycin.
You are suspecting narcotic withdrawal.
All 
of the following symptoms are consistent with this 
diagnosis EXCEPT:
A.
Hyperthermia
B.
Hypotension
C.
Piloerection
D.
Sweating
E.
Vomiting
117.
Upon arrival at the scene,
117.
The patient was 
intubated in the field and naloxone 2 mg IM was 
administered.
His blood pressure is 82/50 
mmHg and heart rate is 70 beats/min.
A.
Activated charcoal
B.
Naloxone continuous infusion at a rate of 0.4 mg/h
D.
Urine drug screen, acetaminophen levels, and blood 
alcohol content
E.
All of the above
118.
Which of the following statements is TRUE with 
regard to the chronic effects of marijuana use?
A.
Chronic use of marijuana is associated with low 
testosterone levels.
B.
Chronic use of marijuana is the primary cause of 
amotivational syndrome.
C.
D.
Physical and psychological tolerance does not de-
velop in chronic users of marijuana.
E.
There is no withdrawal syndrome associated with 
cessation of marijuana use.
ANSWERS
1 and 2.
The answers are D and D, respectively.
(Chap.
The motor examination is further characterized by 
appearance, tone, strength, and reflexes.
Pronator drift is a 
useful tool for determining if upper extremity weakness is 
present.
Other tests of motor strength include tests of 
maximal effort in a specific muscle or muscle group.
It has many causes 
including cervical spondylosis and multiple sclerosis.
Romberg sign is performed with an individual standing 
with feet together and arms at the side.
The individual is 
then asked to close his or her eyes.
3.
The answer is C.
(Chap.
1) This patient likely has metastatic disease to the 
cervical spinal cord.
4.
The answer is C.
(Chap.
The procedure of choice 
for initial diagnosis is a CT of the head without IV con-
trast.
5.
The answer is E.
(Chap.
The two relaxation rates that 
influence the signal intensity of the image are T1 and T2.
T2 images are also more sensitive for detecting 
demyelination, infarction, or chronic hemorrhage.
6.
The answer is E.
(Chap.
However, 
gadolinium was recently linked to a rare disorder called 
nephrogenic systemic fibrosis.
The 
risk of this can be minimized if the patient is adequately 
hydrated.
Typically 
a patient is asked to hold metformin for 48 hours before 
and after a CT scan.
In very rare instances, administration of iodinated contrast 
can unmask hyperthyroidism.
7.
The answer is D.
(Chap.
The EEG generally slows in metabolic encephalopathies, 
and triphasic waves may be present.
8.
The answer is D.
(Chap.
10) Syncope is a common medical complaint that 
occurs when there is global cerebral hypoperfusion.
Syn-
cope accounts for 3% of all emergency department vis-
its and 1% of all hospitalizations.
The most common 
cause of syncope in young adults is neurally mediated 
syncope.
The incidence of neurally mediated syncope is 
higher in females and has a familial predisposition.
This results in hypotension with accom-
panying bradycardia.
Syncope occurs when blood flow to 
the brain drops abruptly.
Triggers of the reflex pathway 
are varied.
Individuals who 
faint at the sight of blood experience vasovagal syncope.
Reassurance and avoidance 
of triggers are the primary treatments.
Liberal intake of 
fluids and salt expand plasma volume and are protective 
against syncopal events.
9.
The answer is A.
(Chap.
Likewise, older individuals are at greater risk 
of cardiac syncope.
Hypoglycemia 
can present with syncope as well and needs to be consid-
ered in this case.
Neurologic causes of syncope include 
seizures and vertebrobasilar insufficiency.
10.
The answer is D.
(Chap.
Most dizziness is benign, self-limited, and 
must be distinguished from vertigo.
However, central lesions of the brainstem 
and cerebellum can also lead to vertigo.
By history, deafness or tinnitus is typically absent with 
central lesions.
Visual fixation 
does not, however, inhibit nystagmus in central lesions.
These include hiccups, diplopia, 
cranial neuropathies, and dysarthria.
11.
The answer is C.
(Chap.
By 
far, the most commonly affected canal is the posterior one.
Less commonly, 
the horizontal canal is affected, leading to horizontal nys-
tagmus.
The Epley maneuver is the most common 
repositioning procedure.
Thus, the use of rizatriptan would not be helpful.
12.
The answer is D.
(Chap.
Over time, 
Review and Self-Assessment 824
severe muscle atrophy can occur.
A Babinski sign should 
not be present.
13.
The answer is E.
(Chap.
13) Approximately 15% of individuals older 
than 65 years have an identifiable gait disorder.
By age 
80 years, 25% of individuals require a mechanical aid to 
assist ambulation.
In most 
case series, the most common cause of gait disorders is a 
sensory deficit.
Other common causes of gait disorders 
include myelopathy and multiple cerebrovascular in-
farcts.
14.
The answer is B.
(Chap.
In this case, the patient presents with signs 
of a frontal gait disorder or parkinsonism.
The patient may have difficulty rising from a 
chair and has a slow, hesitating start.
Likewise, there is 
great difficult with turning with multiple steps required to 
complete a turn.
The patient has very significant postural 
instability.
However, cerebellar signs are typically absent.
Communicating hydrocephalus also 
presents with a gait disorder of this type.
Character-
istics of cerebellar ataxia include a wide-based gait with 
variable velocity.
Gait initiation is normal, but the pa-
tient is hesitant during turns.
The stride is lurching and 
irregular.
Falls are a late event.
The heel-to-shin test is 
abnormal, and the Romberg test is variably positive.
Neurosyphilis and lumbar myelopathy are examples of 
sensory ataxia.
Sensory ataxia presents with frequent falls.
The gait with sensory ataxia, however, is narrow based.
Often the patient is noted to be looking down while 
walking.
The patient tends to walk slowly but have path 
deviation.
Gait is initiated normal, but the patient may 
have some difficulty with turning.
The Romberg test is 
typically unsteady and may result in falls.
15.
The answer is D.
(Chap.
For elderly 
patients in intensive care, the incidence rises to between 
70 and 87%.
However, it has been estimated the diagnosis 
is missed in one-third of individuals with delirium.
Delirium also has sig-
nificant associated morbidity and mortality.
However, the increased mortality is not simply limited 
to the hospital stay.
16.
The answer is B.
(Chap.
Although commonly ordered, brain 
imaging is most often not helpful in the evaluation of 
delirium.
17.
The answer is C.
(Chap.
Delirium is used to describe an acute confusional 
state.
There is often 
dramatic fluctuation between states.
Patients in the intensive care 
unit have especially high rates of delirium, ranging from 
70–87%.
The clinic setting represents the lowest risk.
18.
The answer is D.
(Chap.
A patient in a 
vegetative state can open the eyes spontaneously and of-
ten track objects.
At this point, the likelihood of meaningful 
recovery of mental faculties is almost zero.
A minimally 
conscious state is a less severe manifestation of bilateral 
cerebral injury.
19.
The answer is A.
(Chap.
If an individual is 
determined to have brain death, life-sustaining therapies 
are withdrawn.
Most hospitals have developed 
specific protocols to diagnose a patient with brain death.
Three essential elements should be demonstrated for the 
diagnosis of brain death.
Finally, there should be no evidence of medullary 
activity manifested by apnea.
This test is important for document-
ing the absence of medullary function.
At 
this point, ventilator support is stopped.
20.
The answer is E.
(Chap.
Coma may occur because of compression of 
the midbrain.
21.
The answer is B.
(Chap.
Indeed, anomia is present in all types of aphasia 
except pure word deafness or pure alexia.
Fluency is assessed by listening to 
spontaneous speech.
Alexia refers to the inability 
to read aloud or comprehend written language.
22.
The answer is C.
(Chap.
18) The parietofrontal area of the brain is respon-
sible for spatial orientation.
In addition, subcorti-
cal areas in the striatum and thalamus are also important.
This is an example of a target detection task.
A 
third finding in Balint’s syndrome is simultanagnosia.
23.
The answer is C.
(Chap.
The results of this lead to decreased alertness and increased 
errors during night shifts.
Night shift workers should be 
encouraged to wear dark sunglasses in the morning on the 
way home.
Sleep during the day is frequently disrupted 
in night shift workers.
Melatonin is not one of the recommended therapies 
for shift work sleep disorder.
24.
The answer is C.
(Chap.
20) This patient complains of symptoms that are 
consistent with restless legs syndrome (RLS).
Renal disease, neuropathy, and iron defi-
ciency are known secondary causes of RLS symptoms.
Pramipexole 
or ropinirole is recommended as first-line treatment.
Other options for treating RLS include 
narcotics, benzodiazepines, and gabapentin.
Hormone re-
placement therapy has no role in the treatment of RLS.
25.
The answer is A.
(Chap.
This neurotransmitter is released from 
a small number of neurons in the hypothalamus.
Of these symptoms, cataplexy is the 
most specific for the diagnosis of narcolepsy.
Cataplexy 
refers to the sudden loss of muscle tone in response to 
strong emotions.
It most commonly occurs with laugh-
ter or surprise but may be associated with anger as well.
During this 
time, individuals are aware of their surroundings and are 
not unconscious.
26.
The answer is B.
(Chap.
htm, accessed May 12, 2011) Insomnia is the most com-
mon sleep disorder in the population.
These symptoms occur despite 
adequate time and opportunity for sleep.
Insomnia can 
be further characterized as primary or secondary.
It is 
directly related to obesity and has an increased incidence 
in men and in older populations.
Narcolepsy affects 1 in 
4000 people and is caused by deficit of hypocretin (orex-
in) in the brain.
The symptoms have an onset with quiescence, 
especially at night, and are relieved with movement.
This disorder is most common in adolescence and 
young adulthood.
27.
The answer is C.
(Chap.
20) Parasomnias are abnormal behaviors or expe-
riences that arise from slow-wave sleep.
Typical treatment is a 
benzodiazepine.
There are no typical parasomnias that arise 
from stage I or stage II sleep.
REM parasomnias include 
nightmare disorder and REM-behavior disorder.
28.
The answer is E.
(Chap.
Crossed fibers 
are more damaged by compression than uncrossed fibers.
These lesions 
are often insidious and may be unnoticed by the patient.
They will escape detection by the physician unless each 
eye is tested separately.
Review and Self-Assessment 829
29.
The answer is E.
(Chap.
Uveitis requires slit-lamp exami-
nation for diagnosis.
The risk is re-
mote and rarely causes permanent vision loss.
The value 
of a complete funduscopic examination outweighs the risk 
of this rare event.
TIA is usually associated with atheroscle-
rosis.
If flow is restored quickly vision returns to normal.
30.
The answer is A.
(Chap.
It 
occurs as nonexudative (dry) or exudative (wet) forms.
The mechanism link for that association is un-
known.
The nonexudative form is associated with retinal 
drusen that leads to retinal atrophy.
Treatment with vita-
min C, vitamin E, beta-carotene, and zinc may retard the 
visual loss.
Acute visual loss may occur 
because of bleeding.
Retinal detachment is usually unilateral and causes visual 
loss and an afferent pupillary defect.
31.
The answer is B.
(Chap.
Fewer than 10% of patients with 
posttraumatic anosmia regain normal function.
Signifi-
cant decrements in smell are present in more than 50% of 
people older than 65 years old.
32.
The answer is E.
(Chap.
24) Hearing loss is a common complaint, partic-
ularly in older individuals.
In this age group, 33% have 
hearing loss to a degree that requires hearing aids.
The primary site of dam-
age is the hair cells of the inner ear.
Examination of the external auditory ca-
nal can identify cerumen or foreign body impaction.
In the Rinne’s test, air 
conduction is compared with bony conduction of sound.
A tuning fork is placed over the mastoid process and then 
in front of the external ear.
In the Weber test, the tuning fork is placed in 
the midline of the head.
Thus, the sound is expected to 
be greatest in the right ear on the Weber test.
Pure tone audiometry establishes the severity, type, and 
laterality of hearing loss.
33.
The answer is D.
(Chap.
Parkinson’s disease is 
the classic example of neurotransmitter system–mediated 
disease.
34.
The answer is C.
(Chap.
25) Synaptic neurotransmission is the predomi-
nant mechanism for neuronal communication.
Neurotransmitters bind to spe-
cific receptors that are either ionotropic or metabotropic.
Parkinson’s 
syndrome is related to selective cell death in the nigros-
triatal dopamine pathway.
Orthostatic tachycardia 
syndrome is related to mutations in the norepinephrine 
transporter.
35.
The answer is B.
(Chap.
Seizures are classified as focal or generalized.
They are fre-
quently associated with a structural lesion.
The terms “simple partial sei-
zure” and “complex partial seizure” have been eliminated.
36.
The answer is A.
(Chap.
An aura is common before the seizures.
There is postictal 
memory loss or disorientation.
Patients often have a his-
tory of febrile seizures or a family history of seizures.
MRI 
will show hippocampal sclerosis, a small temporal lobe, or 
enlarged temporal horn.
37.
The answer is E.
(Chap.
Overt deficits 
in strength are not compatible with a primary psychiat-
ric disorder.
38.
The answer is C.
(Chap.
In addition, acute cocaine in-
toxication is a plausible reason for this new-onset seizure.
Figure 26-2 illustrates the evaluation of the adult patient 
with a seizure.
MRI would be indicated if the patient had 
a negative metabolic and toxicologic screening.
39.
The answer is B.
(Chap.
The goal is to prevent seizures and minimize the side 
effects of therapy.
The minimal effective dose is deter-
mined by trial and error.
In choosing medical therapies, 
drug interactions are a key consideration.
In patients with 
epilepsy other considerations are critical.
Psychosocial se-
quelae such as depression, anxiety, and behavior problems 
may occur.
40.
The answer is D.
(Chap.
Fever rarely causes seizure in pa-
tients older than 12 years.
Amyloid angiopathy and uremia 
are more common in older adults.
41.
The answer is A.
(Chap.
GCSE 
is obvious when the patient is having overt convulsions.
However, after 30–45 minutes of uninterrupted seizures, 
the signs may become increasingly subtle.
Patients may 
have mild clonic movements of only the fingers or fine, 
rapid movements of the eyes.
There may be paroxysmal 
episodes of tachycardia, hypertension, and pupillary dila-
tion.
In such cases, the EEG may be the only method of 
establishing the diagnosis.
Carbam-
azepine is a first-line therapy for focal seizures.
Review and Self-Assessment 832
42.
The answer is A.
(Chap.
27) Cardioembolism accounts for up to 20% of all 
ischemic strokes.
If the thrombus lyses quickly, 
only a transient ischemic attack may develop.
If the arte-
rial occlusion lasts longer, brain tissue may die and a stroke 
will occur.
Atrial fibrillation 
is the most common cause of cerebral embolism overall.
This may be detected 
by bubble-contrast echocardiography.
43.
The answer is D.
(Chap.
27) Nonrheumatic atrial fibrillation is the most 
common cause of cerebral embolism overall.
The average annual 
risk of stroke is around 5%.
The risk of stroke can be estimated by calculating 
the CHADS2 score (see  Table 27-3).
Therefore, it is 
recommended that these patients only take aspirin daily 
for stroke prevention.
44.
The answer is E.
(Chap.
27) Numerous studies have identified key risk fac-
tors for ischemic stroke.
Hyperten-
sion is the most significant among these risk factors.
All 
cases of hypertension must be controlled in the setting of 
stroke prevention.
Antiplatelet therapy has been shown to 
reduce the risk of vascular atherothrombotic events.
A recent Euro-
pean study confirmed this finding.
45.
The answer is C.
(Chap.
There are 
no clinical findings that definitively distinguish ischemia 
from hemorrhage.
Subsequent 
studies using different dosing and timing ranges have not 
been as positive.
46.
The answer is D.
(Chap.
29) All the choices given in the question are causes 
of or may be associated with dementia.
Vitamin B12 deficiency may also lead to a 
subcortical type of dementia.
Brain imaging demonstrates multiple areas of stroke.
47.
The answer is D.
(Chap.
Orthostasis and autonomic 
symptoms are typically prominent.
On pathologic examination, α-synuclein–positive inclu-
sions would be seen in the affected areas.
Median sur-
vival after diagnosis is 6–9 years.
Corticobasal 
degeneration is a sporadic tauopathy that presents in the 
sixth to seventh decades.
Its 
progressive nature leads to spastic paraplegia.
Diffuse Lewy 
body disease has prominent dementia with parkinsonian 
features.
48.
The answer is C.
(Chap.
Choice of initial drug therapy is usually with 
dopamine agonists, levodopa, or MAO inhibitors.
Over this period, escalating doses are frequently 
required, and side effects may be limiting.
By 5 years, 
over half of individuals will require levodopa to control 
motor symptoms.
In this setting, deep-brain 
stimulation can alleviate disabling symptoms.
49.
The answer is D.
(Chap.
It is rare in 
Asians.
Symptoms most commonly begin in the legs, 
but can spread to or even begin in the upper limbs.
The mean age of onset in genetic forms is 27 years, 
although pediatric cases are recognized.
The severity of 
symptoms is variable.
The neurologic examination is normal.
Most RLS sufferers 
have mild symptoms that do not require specific treat-
ment.
Other 
drugs that can be effective include anticonvulsants, anal-
gesics, and even opiates.
Management of secondary RLS 
should be directed to correcting the underlying disorder.
50.
The answer is B.
(Chap.
So-
cial graces, routine behavior, and superficial conversation 
may be surprisingly intact.
Language becomes impaired—
first naming, then comprehension, and finally fluency.
In 
some patients, aphasia is an early and prominent feature.
Simple 
calculations and clock reading become difficult in parallel.
Loss of judgment and reasoning is inevitable.
In end-stage AD, 
patients become rigid, mute, incontinent, and bedridden.
Generalized seizures may also occur.
The typical duration of AD is 8–10 years, but 
the course can range from 1 to 25 years.
51.
The answer is E.
(Chap.
32) The combination of upper and lower mo-
tor neuron findings is highly suggestive of ALS.
MMCB is not typically associated with corticospinal signs.
52.
The answer is E.
(Chap.
There is no orthostat-
ic hypotension.
Approximately half 
of affected patients report an antecedent viral infection.
Recurrent, unex-
plained episodes of dysautonomia and fatigue also occur.
Expansion of fluid volume and 
postural training are initial approaches to treatment.
Reconditioning and a sustained ex-
ercise program are very important.
All of the other listed 
choices are associated with orthostatic hypotension.
53.
The answer is D.
(Chap.
CRPS type I is a regional pain syndrome that 
usually develops after tissue trauma.
Allodynia, hyperpathia, and 
spontaneous pain occur.
Pain is the primary clinical feature 
of CRPS.
The pain 
is diffuse, spontaneous, and either burning, throbbing, or 
aching in quality.
The involved extremity is warm and 
edematous, and the joints are tender.
Increased sweating 
and hair growth develop.
In phase II (3–6 months after 
onset), thin, shiny, cool skin appears.
54.
The answer is A.
(Chap.
34) Trigeminal neuralgia is a clinical diagnosis 
based entirely on patient history.
Symptoms are often, but 
not always, elicited by tactile stimuli on the face, tongue, 
or lips.
An elevated ESR is not part of the clinical syn-
drome.
First-line therapy is with 
carbamazepine, not gabapentin.
If treatment is ef-
fective, it is continued for 1 month then tapered.
55.
The answer is C.
(Chap.
Carbamazepine is first-line therapy.
Oxcarbazepine 
likely has equivalent efficacy to carbamazepine with less 
toxicity.
Lamotrigine, orphenytoin, and baclofen are other 
potential therapeutic options.
Steroids have no 
therapeutic role, as trigeminal neuralgia is not an inflam-
matory condition.
56.
The answer is D.
(Chap.
57.
The answer is C.
(Chap.
The low-intensity bone marrow 
signal in panel A of Figure 57 signifies replacement by 
tumor.
MRI is the optimal diagnostic modality to im-
age the spinal cord.
Therapeutic anticoagulation, 
trauma, tumor, or blood dyscrasias are predisposing condi-
tions.
Hematomyelia presents as an acute, pain-
ful transverse myelopathy.
58.
The answer is B.
(Chap.
35) This patient has a history and examination 
consistent with a myelopathy.
59.
The answer is A.
(Chap.
Symptoms typically 
begin in adolescence or early adulthood.
They may un-
dergo spontaneous arrest after several years.
More than 
half are associated with Chiari malformations.
Acquired 
cavitations of the spinal cord are referred to as syrinx cavi-
ties.
They may result from trauma, myelitis, infection, or 
tumor.
Vibration and 
position sensation are typically preserved.
MRI scans are the diagnostic modal-
ity of choice.
Surgical therapy is generally unsatisfactory.
Direct decompression of the cavity is of debatable benefit.
Although relief may occur, recurrence is common.
60.
The answer is A.
(Chap.
Transient loss of consciousness is com-
mon, as are confusion and amnesia.
Many patients do not 
lose consciousness but feel dazed, stunned, or confused.
Head imaging is typically normal.
The patient described fits this 
diagnosis; strict diagnostic criteria do not exist.
Typically 
patients will improve over a 6- to 12-month period.
Treatment is 
aimed at reassurance and relieving prominent symptoms.
Dizziness can be treated with Phenergan, which acts as a 
vestibular suppressant.
He should avoid contact sports at 
least until his symptoms resolve.
61.
The answer is D.
(Chap.
36) The head CT (Figure 61) shows chronic bilat-
eral subdural hematomas of varying age.
Some areas of re-
solving blood are contained in the more recently formed 
collection on the left.
During the isodense phase 
(2–6 weeks after injury), they may be difficult to discern.
Headache 
is common.
Underlying cortical damage may serve 
as a seizure focus.
62.
The answer is D.
(Chap.
They can be life-
threatening, and prompt evaluation and management are 
imperative.
Several clinical features allow these conditions 
to be distinguished from one another.
Subdural bleeding is 
typically slower than epidural bleeding due to their differ-
ent sources.
Small subdural bleeds are asymptomatic and 
often do not require evacuation.
A lacerated middle meningeal artery 
from an overlying skull fracture often causes these.
63.
The answer is D.
(Chap.
If the imaging 
shows clear improvement, continue antibiotics.
64.
The answer is A.
(Chap.
ACTH, prolactin, and gonadotropins have an 
intermediate sensitivity.
Early delayed radiation injury occurs 
within the first 4 months after therapy.
It is associated with 
increased white matter signal on MRI and is steroid re-
sponsive.
Late delayed radiation injury occurs more than 
4 months after therapy, typically 8–24 months.
65.
The answer is D.
(Chap.
37) The postgadolinium MRI shows multiple me-
ningiomas along the falx and left parietal cortex.
Menin-
giomas derive from the cells that give rise to the arachnoid 
granulations.
They are usually benign (WHO classification grade 1) 
and attached to the dura.
They rarely invade the brain.
Many meningiomas are found inci-
dentally following neuroimaging for unrelated reasons.
They can also present with headaches, seizures, or focal 
neurologic deficits.
The main differential diagnosis of meningioma is a 
dural metastasis.
Total surgical resection of a meningioma 
is curative.
They have 
a more benign course and are more responsive than other 
gliomas to cytotoxic therapy.
For low-grade oligodendro-
mas, the median survival is 7–8 years.
66.
The answer is C.
(Chap.
The 
posterior pituitary produces vasopressin and oxytocin.
67.
The answer is B.
(Chap.
38) The patient has evidence of Sheehan’s syn-
drome postpartum.
This leads to bilateral visual changes, 
headache, and meningeal signs.
Ophthalmoplegia may 
be observed.
In severe cases, cardiovascular collapse and 
altered levels of consciousness may be observed.
Labo-
ratory evaluation commonly shows hypoglycemia.
Pitu-
itary CT or MRI may show signs of sellar hemorrhage 
if present.
68.
The answer is D.
(Chap.
IGF-1 is 
made by the liver in response to growth hormone stimu-
lation.
69.
The answer is B.
(Chap.
Nipple stimulation, sleep, and stress may 
all increase prolactin levels.
Hypothalamic-pituitary stalk damage may 
also cause hyperprolactinemia.
70.
The answer is E.
(Chap.
The most 
common presentations are amenorrhea, infertility, and/or 
galactorrhea.
Microadenomas rarely progress to become 
macroadenomas.
71.
The answer is C.
(Chap.
38) Adult growth hormone deficiency is usually 
caused by hypothalamic or pituitary damage.
Thus, deficiency of 
growth hormone causes the opposite effects.
72.
The answer is E.
(Chap.
38) The patient has a clinical presentation con-
sistent with Cushing’s syndrome.
ACTH levels will be high, as this 
is the underlying cause of both types of Cushing’s syn-
drome.
Corticotropin-releasing hormone is rarely the 
cause of Cushing’s syndrome.
73.
The answer is C.
(Chap.
This, coupled with her symptoms, will aid in the 
determination of proper levothyroxine dosing.
There is 
no evidence of recurrent disease clinically; thus MRI is 
not useful.
74.
The answer is A.
(Chap.
38) The diagnosis of Cushing’s syndrome relies on 
documentation of endogenous hypercortisolism.
Rarely, pa-
tients have Cushing’s syndrome and elevated ACTH due 
to a CRH-releasing tumor.
In this case, CRH levels are 
elevated.
75.
The answer is B.
(Chap.
38) The identification of an empty sella is often 
the result of an incidental MRI finding.
Typically these 
patients will have normal pituitary function and should 
be reassured.
It is likely that the surrounding rim of pitu-
itary tissue is functioning normally.
Unless her clinical 
situation changes, repeat MRI is not indicated.
Endocrine 
malignancy is unlikely, and surgery is not part of the man-
agement of an empty sella.
76.
The answer is D.
(Chap.
39) The onset of multiple sclerosis (MS) may be 
abrupt or insidious.
Examination often reveals evidence of 
neurologic dysfunction, often in asymptomatic locations.
For example, a patient may present with symptoms in one 
leg but signs in both.
77.
The answer is D.
(Chap.
There 
is often complete recovery over the ensuing weeks to 
months.
Between attacks, patients are neurologically stable.
Sec-
ondary progressive MS (SPMS) always begins as RRMS.
SPMS produces a 
greater amount of fixed neurologic disability than RRMS.
SPMS 
appears to represent a late stage of the same underlying 
illness as RRMS.
Primary progressive MS (PPMS) ac-
counts for approximately 15% of cases.
These patients do 
not experience attacks but only a steady functional decline 
from disease onset.
Despite these differences, PPMS appears to represent the 
same underlying illness as RRMS.
Progressive/relapsing 
MS (PRMS) overlaps PPMS and SPMS and accounts for 
about 5% of MS patients.
Autoimmune autonomic neu-
ropathy is a distinct clinical syndrome not related to MS.
78.
The answer is D.
(Chap.
Kernig’s sign is elicited in a supine 
patient by flexing the thigh and knee.
79.
The answer is B.
(Chap.
Glucocorticoids can blunt this response by inhibiting tu-
mor necrosis factor and interleukin-1.
They work best if 
administered before antibiotics.
The dexamethasone was continued for 
4 days.
The benefits were most striking in pneumococ-
cal meningitis.
However, in this case the LP is highly suggestive 
of acute bacterial infection.
80.
The answer is D.
(Chap.
Ampicillin is the agent 
most often added to the initial empirical regimen to cover 
L.
monocytogenes.
81.
The answer is D.
(Chap.
Most causes of chronic (not recurrent) 
meningitis cause a predominance of mononuclear cells.
The differential for chronic meningitis is broad and a di-
agnosis is often difficult to make.
82.
The answer is E.
(Chap.
43) Prions are infectious particles that cause cen-
tral nervous system degeneration.
There has been a steady decline of cases of vCJD in Europe 
over the past decade.
Fa-
milial CJD (fCJD) is due to germ-line mutations that follow 
an autosomal dominant inheritance.
Kuru is due to infec-
tion through ritualistic cannibalism.
Sporadic cases of fatal 
insomnia (sFI) have been described.
83.
The answer is B.
(Chap.
Clinical abnormalities in CJD are confined to the CNS.
Both EEG and MRI can help differentiate 
CJD from these disorders.
These proteins cannot be 
measured from cerebrospinal fluid (CSF).
CSF in CJD is 
usually normal except for a minimally elevated protein.
Many patients with CJD have elevated CSF stress protein 
14-3-3.
84.
The answer is C.
(Chap.
Radiologic 
imaging reveals cerebellar atrophy.
Cerebellar ataxia may also be seen in Hodgkin’s 
lymphoma in association with anti-Tr antibodies.
85.
The answer is A.
(Chap.
45) Charcot-Marie-Tooth (CMT) syndrome is 
the most common type of hereditary neuropathy.
CMT1 
is the most common and is an inherited demyelinating 
sensorimotor neuropathy.
This would not fit the clinical pat-
tern described here.
Fabry disease is an X-linked 
disorder in which men are more commonly affected than 
women.
Burning pain in the hands and 
feet often is found in late childhood or early adult life.
86.
The answer is E.
(Chap.
45) One of the most common side effects of iso-
niazid treatment is peripheral neuropathy.
Prophylactic administration 
of pyridoxine can prevent the neuropathy from devel-
oping.
Symptoms are generally dysesthesias and sensory 
ataxia.
Impaired large-fiber sensory modalities are found 
on examination.
Cobalamin (B12) is not reduced in this 
condition and is unaffected by isoniazid.
Neurontin and 
pregabalin may alleviate symptoms but will not reverse 
the neuropathy.
There is no indication that hypothyroid-
ism is present.
87.
The answer is C.
(Chap.
Symptoms also may include 
tingling, burning, and deep, aching pains.
88.
The answer is B.
(Chap.
45) Peripheral neuropathy is a general term indi-
cating peripheral nerve disorders of any cause.
Mononeuropathy typically results 
from local compression, trauma, or entrapment of a nerve.
Polyneuropathy often results from a more systemic pro-
cess.
HIV infection causes a common, distal, symmetric, mainly 
sensory polyneuropathy.
Critical illness polyneuropathy is pre-
dominantly motor in presentation.
Patients typically pres-
ent with weakness that can be profound.
These patients 
may recover over the course of weeks to months.
89.
The answer is B.
(Chap.
45) Carpal tunnel syndrome is caused by the en-
trapment of the median nerve at the wrist.
Symptoms 
begin with paresthesias in the median nerve distribution.
With worsening, atrophy and weakness may develop.
Most cases are idiopathic other than those related 
to occupational or environmental associations.
This may be suspected when bilateral disease is apparent.
Acute or chronic leukemia is not typically associated with 
carpal tunnel syndrome.
90.
The answer is B.
(Chap.
Other implicated infec-
tions include Epstein-Barr virus, CMV, and Mycoplasma 
pneumoniae.
T.
whippelii is the etiologic agent of Whipple’s 
disease and B.
henselae is implicated in cat-scratch fever.
91.
The answer is E.
(Chap.
MG is 
not rare, affecting at least 1 in 7500 individuals.
Women 
are affected more frequently than men.
The key features of 
MG are weakness and fatigability.
Diplopia and ptosis are common 
initial complaints.
Weakness in chewing is noticeable af-
ter prolonged effort.
Speech may be affected secondary 
to weakness of the palate or tongue.
Swallowing may re-
sult from weakness of the palate, tongue, or pharynx.
In 
the majority of patients the weakness becomes general-
ized.
The diagnosis is suspected after the appearance of 
the characteristic symptoms and signs.
False-positive tests may occur in patients with other neu-
rologic diseases.
Testing for 
the specific antibodies to AChR are diagnostic.
Review and Self-Assessment 844
92.
The answer is C.
(Chap.
47) Except for lumbar puncture, all of the options 
listed are indicated at this time.
Thymic abnormalities are 
present in 75% of patients with myasthenia gravis.
Hyperthyroidism occurs in 3–8% of pa-
tients with myasthenia gravis and may aggravate weakness.
93.
The answer is E.
(Chap.
Proximal weakness may be found on examina-
tion.
In severe cases, rhabdomyolysis and myoglobinuria 
may occur, though most cases are mild.
After cessation, improve-
ment generally occurs after several weeks.
94.
The answer is E.
(Chap.
48) A number of endocrinologic conditions are as-
sociated with myopathy.
Both hypo- and hyperthyroidism 
are associated with proximal muscle weakness.
Hyperparathyroidism is as-
sociated with muscle weakness that is generally proximal.
Muscle wasting and brisk reflexes are also generally pres-
ent.
Serum CK levels may be normal or slightly elevated.
Serum calcium and phosphate levels show no correlation 
with clinical weakness.
Hypoparathyroid patients also of-
ten have myopathy due to hypocalcemia.
Patients with 
acromegaly usually have mild proximal weakness with-
out atrophy.
95.
The answer is D.
(Chap.
Myotonic dystro-
phy 1 (DM1) is the most common form and the most 
likely disorder in this patient.
The failure of relaxation 
after a forced hand-grip is characteristic of myotonia.
Percussion of the thenar eminence can also elicit myo-
tonia.
Cardiac conduction 
abnormalities and heart failure are also common in myo-
tonic dystrophy.
An electromyogram would 
confirm myotonia.
Genetic testing for DM1 would show 
a characteristic trinucleotide repeat on chromosome 19.
Other features 
of the disease overlap with DM1.
Otherwise, their fea-
tures are similar.
This disease is inherited in an autosomal dominant 
fashion.
96.
The answer is B.
(Chap.
CK is 
always elevated in active polymyositis and thus is consid-
ered most sensitive.
97.
The answer is B.
(Chap.
98.
The answer is A.
(Chap.
Exhaustive 
cancer searches are not recommended, however.
99.
The answer is A.
(Chap.
The goal of therapy is to improve strength.
If that goal is 
being achieved, no augmentation of therapy is necessary.
100.
The answer is B.
(Chap.
The diagnosis is clinical and radiographic.
CSF findings 
are nonspecific.
Acoustic neuroma would present 
on MRI with a discrete mass.
The radiologic and clinical 
appearance is not consistent with pituitary apoplexy.
101.
The answer is B.
(Chap.
vCJD is associated with ingestion of prion-contaminated 
product.
102.
The answer is E.
(Chap.
50) The peroneal nerve winds around the head 
of the fibula below the lateral aspect of the knee.
This 
superficial location makes it vulnerable to trauma.
Patients may present with footdrop (dorsiflexion defect) 
with weakness of foot eversion.
Cauda equina syndrome is 
usually a medical emergency to avoid permanent func-
tional loss.
The femoral nerve branches into anterior 
and posterior portions in the leg.
103.
The answer is A.
(Chap.
Criteria for 
the diagnosis of CFS have been developed by the U.S.
Centers for Disease Control and Prevention (see Table 
52-1).
CFS is seen worldwide, with adult prevalence rates 
 varying between 0.2% and 0.4%.
Approximately 75% of all CFS patients are women.
The 
mean age of onset is between 29 and 35 years.
It is prob-
able that many patients go undiagnosed and/or do not 
seek help.
104.
The answer is B.
(Chap.
Walking 
or cycling is systematically increased, with set target heart 
rates.
Evidence that deconditioning is the basis for symp-
toms in CFS is lacking, however.
Not all patients ben-
efit from CBT or GET.
Predictors of poor outcome are 
somatic comorbidity, current disability claims, and severe 
pain.
105.
The answer is D.
(Chap.
In this situation, no specific treatment 
is required.
The symptoms usually subside spontaneously over 
the course of an hour.
If 
a patient subsequently develops panic disorder, a variety 
of treatment options can be pursued.
The dose of medication 
for panic disorder is typically lower than the antidepres-
sant dose.
For fluoxetine, this would be 5–10 mg daily.
106.
The answer is A.
(Chap.
54) There are increasing numbers of antidepres-
sant medications available in a variety of classes.
Selec-
tive serotonin reuptake inhibitors (SSRIs) are the most 
commonly used antidepressant drugs.
Tricyclic 
antidepressants were commonly used in past decades for 
the treatment of depression.
Medica-
tions in this class include venlafaxine, desvenlafaxine, du-
loxetine, and mirtazapine.
There is a 
wide range of drug and food interactions that can lead to 
hypertensive crises.
Examples of medication in this class 
include phenelzine, tranylcypromine, and isocarboxazid.
107.
The answer is E.
(Chap.
54) Post-traumatic stress disorder (PTSD) was 
only added as a discrete disorder in 1980.
Treatment 
with antidepressant medications can decrease anxiety 
and avoidance behaviors.
Trazodone is often given 
at night for its sedating properties.
108.
The answer is B.
(Chap.
Treatment 
can be any of a number of medications across a variety of 
classes.
In this patient, a dosage increase yielded control 
of depressive symptoms at 4 months.
109.
The answer is A.
(Chap.
Several factors can increase the rate 
of absorption.
110.
The answer is C.
(Chap.
56) Alcohol has effects on many neurotransmit-
ters in the brain.
The effects on dopamine are thought to 
be important in alcohol craving and relapse.
111.
The answer is D.
(Chap.
At this level, decreases in cognitive and mo-
tor abilities are seen.
However, in in-
dividuals who drink heavily, tolerance begins to develop 
to alcohol.
112.
The answer is C.
(Chap.
How-
ever, this is to be differentiated from alcohol dependence.
However, there may be higher rates 
in Ireland, France, and Scandinavian countries.
This has been seen 
in Native Americans, Maoris, and the aboriginal tribes 
of Australia.
About 60% of the risk for alcohol use disorders is attrib-
uted to genetic influences.
113.
The answer is B.
(Chap.
Thus, the use of IV lorazepam or diazepam is preferred 
in this patient.
In some instances a continuous infusion may be 
required, although bolus dosing is preferred.
The other options listed are not appropriate for ini-
tial management of this patient.
Intravenous fluids and 
thiamine had been administered since hospital admis-
sion.
114.
The answer is D.
(Chap.
The two medications with the best 
risk-benefit ratio are acamprosate and naltrexone.
Acam-
prosate inhibits NMDA receptors, decreasing symptoms 
of prolonged alcohol withdrawal.
Naltrexone is an opi-
oid antagonist than can be administered orally or as a 
monthly injection.
115.
The answer is E.
(Chap.
The annual prevalence of heroin abuse 
is approximately 0.14% of the population.
In contrast, 
this prevalence is only one-third the rate of prescription 
opiate abuse.
Among prescription narcotics, oxycodone 
is the single most commonly abused drug.
Other com-
mon prescription narcotics that are abused include mor-
phine and hydrocodone.
Among health care profession-
als, meperidine and fentanyl are more frequently abused.
116.
The answer is B.
(Chap.
57) Tolerance and withdrawal begin within 6–8 
weeks of chronic daily opioid use.
This manifests 
as increased lacrimation, rhinorrhea, and sweating.
Hyper-
tension, hyperthermia, and tachypnea can occur as well.
Hypotension is not a symptom of opioid withdrawal.
117.
The answer is E.
(Chap.
In the emergency 
room, however, the patient remained hypotensive and 
unresponsive.
One could also consider 
sending for levels of aspirin or tricyclic antidepressants.
118.
The answer is C.
(Chap.
whitehousedrugpolicy.gov/publications/pdf/nsduh.
pdf, accessed July 25, 2011).
In addition, impaired judgment, cognition, 
and psychomotor performance are seen.
Occasionally, 
acute intoxication can lead to negative emotional re-
sponses as well.
A consensus about the chronic effects 
of marijuana usage is not clearly defined.
The physical effects of chronic marijuana use are also 
not clearly known.
Acutely, marijuana causes increased 
heart rate, but tolerance for this effect occurs rapidly.
Acute ingestion can also precipitate angina.
Most studies have not found an associa-
tion with emphysema.
The psychological tolerance that 
develops is more prominent and predictable.
See Brain abscess
epidural.
See Alzheimer’s disease (AD)
ADAMTS13, 775t
A-delta (Aδ) fibers, 40, 41
ADEM.
See also Alcohol use
absorption of, 752–753, 819, 847–848
abuse of.
See Infective endocarditis
Bacterial meningitis.
See Craniopharyngioma
meningioma.
See Meningioma
pituitary tumors.
See Brain abscess
cranial epidural abscess, 524, 524f
dementia due to, 328–329
empyema.
See Subdural empyema
encephalitis.
See Encephalitis
meningitis.
See Anterior cerebral artery
middle.
See Middle cerebral artery
posterior.
See Charcot-Marie-Tooth (CMT) disease
CMV.
See Cytomegalovirus (CMV) infections
CNS.
infections.
moderate/severe head injury, 745t.
See Cerebrospinal fluid (CSF)
CSTB gene, 235t
CT.
substance abuse, 716.
See Electroencephalography (EEG)
Ehrlichia chaffeensis, 500
Elderly.
See 
Electroencephalography (EEG)
electrophysiologic studies.
See Electrophysiologic 
studies
evoked potentials.
See Follicle-stimulating hormone (FSH)
FTD.
See Tension-type headache
Head drop, 648
Head impulse test, 99
Head injury, 415.
See Epidural hematoma
spinal, 406
subdural.
See Hereditary sensory and autonomic 
neuropathy (HSAN)
HSV infections.
See Limb-girdle muscular dystrophy 
(LGMD)
LH.
See Monoamine oxidase type B 
(MAO-B) inhibitors
MAOIs.
influenzae, 495, 496
incidence of, 495–496
increased ICP in, 503
L.
monocytogenes, 495, 496, 501t, 502, 841
M.
See also specific disorders
bipolar disorder.
See Huntington’s disease
hyperkinetic, 346, 347t.
See also specific disorders
PD.
See Parkinson’s disease (PD)
psychogenic, 356
tics, 347t, 352–353
Tourette’s syndrome.
See Tourette’s syndrome
Moyamoya disease, 268, 290
MPTP, 336–337
MRA.
See Magnetic resonance angiography (MRA)
MRF (myelin gene regulatory factor), 224
MRI.
See Magnetic resonance imaging (MRI)
MS.
See Multiple sclerosis (MS)
MSA.
See Myopathy(ies)
muscular dystrophy.
See Duchenne’s muscular dystrophy
Emery-Dreifuss.
infections, 514–515, 529t.
See also Muscular dystrophy
HIV-related, 544
Index 869
Myopathy(ies) (Cont.):
inflammatory.
See also specific disorders
atlas of, 668–701f
CT.
See Magnetic resonance angiography 
(MRA)
MRI.
See Magnetic resonance imaging (MRI)
myelography, 23–24
PET.
See also specific diseases
angiography in, 25
apoptosis in, 226–227
approach to the patient.
See Optic neuropathy
paraneoplastic syndromes, 564–565
peripheral.
See Neurofibromatosis type 1 (NF1)
NF1 gene, 425t, 432
NF2.
See Anti-NMDA receptor 
antibodies
Nocardia spp.
See Insomnia
narcolepsy.
See Meningitis
Streptomycin, 185
Stress disorders, 727, 727t
Stroke, 257.
See Intracranial 
hemorrhage
ischemic.
See Orthostatic 
hypotension
pathophysiology of, 90
in psychiatric disorders, 96, 97
vs.
See also Seizure(s)
characteristics of, 233–234
vs.
infections
chronic meningitis in, 530t.
See Thiamine
Vitamin B2.
See Riboflavin
Vitamin B6.
See Pyridoxine
Vitamin B12.
See Venous thromboembolism (VTE)
VZV infections.
breathtaking level of complexity far beyond the linear
sequence of the genome.
Noncoding DNA
The human genome contains some 3.2 billion DNA
base pairs.
Many of these proteins are recognizable homologs of
molecules expressed in humans.
What then separates humans
from worms?
There are five major classes of functional non–protein-
coding sequences in the human genome (Fig.
1.1):
• Promoter and enhancer regions that provide binding sites
for transcription factors.
• Binding sites for factors that organize and maintain higher
order chromatin structures.
• Noncoding regulatory RNAs.
• Mobile genetic elements (e.g., transposons) make up more
than a third of the human genome.
Chromosomes (as shown) can be visualized only during mitosis.
• SNPs occur across the genome—within exons, introns,
intergenic regions, and coding regions.
In
other words, the SNP and the causative genetic factor
are in linkage disequilibrium.
CNVs can be biallelic and simply duplicated or, alterna-
tively, deleted in some individuals.
1.2):
• Histones and histone-modifying factors.
The resulting DNA-histone
complex resembles a series of beads joined by short DNA
linkers.
The naked DNA of a single human cell is about
1.8 m long.
In most cases, this
structured DNA, termed chromatin, is not wound uni-
formly.
1.1).
In
general, only the regions that are “unwound” are available
for transcription.
In contrast, inactive genes have
histone marks that enable DNA compaction into hetero-
chromatin.
• Histone methylation.
• Histone acetylation.
• Histone phosphorylation.
• DNA methylation.
• Chromatin organizing factors.
Histones sit on 20- to 80-nucleotide stretches of linker DNA between nucleosomes.
Histone subunits are positively
charged, thus allowing compaction of negatively charged DNA.
DNA can also be methylated, leading to transcriptional inactivation.
that many other diseases are associated with inherited or
acquired epigenetic alterations.
1.3).
In
this way the target mRNA is posttranscriptionally silenced.
These
genomic sequences are transcribed but not translated.
lncRNAs
modulate gene expression by several mechanisms (Fig.
1.4).
Promote chromatin modification
Methylation,
acetylation
Ribosome
GENE SILENCING
D.
Multi-subunit complex
Figure 1.4 Roles of long noncoding RNAs (lncRNAs).
(A) lncRNAs can
facilitate transcription factor binding and thus promote gene activation.
(B) Conversely, lncRNAs can preemptively bind transcription factors to
inhibit transcription.
Conversely, many
enhancers are actually sites of lncRNA synthesis.
1.4).
1.5).
Cas9
then induces double-stranded DNA breaks at the site of
gRNA binding.
Predictably the technology has inspired
a vigorous debate regarding the ethics of its use.
1.6).
HDR is less efficient than NHEJ but has the capacity to introduce
precise changes in DNA sequence.
The figure shows geographic relationships but is not intended to be accurate to scale.
ER, Endoplasmic reticulum.
I.
Morphometric model, stereologic methods, and
normal morphometric data for rat liver.
The contents and location of cellular organelles are also
highly regulated.
1.7).
Proper localization of these molecules is important for cell
health.
(A) The plasma membrane is a bilayer of phospholipids, cholesterol, and associated proteins.
In
platelets, phosphatidylserine is also a cofactor in blood
• clotting.
The means by which
these proteins associate with membranes frequently reflects
function.
In general, proteins associate with the lipid bilayer by one
of four mechanisms.
• Peripheral membrane proteins may noncovalently associ-
ate with true transmembrane proteins.
The latter strategy is used to maintain cell
polarity (e.g., top/apical/free vs.
bottom/basolateral/
bound to extracellular matrix [ECM]) in epithelial cells.
This glycocalyx can form a chemical and
mechanical barrier.
Several mechanisms contribute to this transport.
Passive Diffusion.
Lipid bilay-
ers are also impermeant to ions due to their charge and
hydration.
Carriers and Channels (Fig.
1.8).
Ions
and small molecules can be transported by channel proteins
and carrier proteins.
Similar pores and channels also mediate
transport across organellar membranes.
For example, some transporters accommodate
glucose but reject galactose.
Receptor-mediated and fluid-phase uptake of material involves membrane bound vesicles.
They can subsequently fuse with
endosomes or recycle to the membrane.
Endocytosis of receptor-ligand pairs often involves clathrin-coated pits and vesicles.
After internalization the
clathrin disassembles and individual components can be re-used.
Other transporters are
ATPases.
Water movement into or out of cells is passive and
directed by solute concentrations.
Similar transport mechanisms also regulate
concentrations of other ions (e.g., Ca2+ and H+).
This is critical
to many processes.
Uptake of fluids or macromolecules by the cell is called
endocytosis.
Receptor-Mediated and Fluid-Phase Uptake (see Fig.
In both cases, activity
of the “pinchase” dynamin is required for vesicle release.
Macromolecules can also be exported from cells by
exocytosis.
Common examples include
peptide hormones (e.g., insulin) and cytokines.
We now return to the specifics of endocytosis (see Fig.
1.8).
• Caveolae-mediated endocytosis.
• Receptor-mediated endocytosis.
Trapped within these vesicles is also a gulp of
the extracellular milieu (fluid-phase pinocytosis).
Without recycling,
the plasma membrane would be rapidly depleted.
1.9).
In eukaryotic cells, there are three major classes of
cytoskeletal proteins.
1.9).
Examples
include:
• Vimentin, in mesenchymal cells (fibroblasts,
endothelium).
• Desmin in muscle cells forms the scaffold on which
actin and myosin contract.
• Neurofilaments are critical for neuronal axon structure
and confer both strength and rigidity.
• Glial fibrillary acidic protein is expressed in glial cells.
• Cytokeratins are expressed in epithelial cells.
gastrointestinal epithelium).
These fibrils are extremely dynamic
and polarized, with “ +” and “ −” ends.
• Mediate sister chromatid segregation during mitosis.
Similar complexes
also mediate interaction with the ECM.
Cell-cell junctions
are organized into three basic types (see Fig.
Adherens junctions are often closely
associated with and beneath tight junctions.
Desmosomes
are more basal and form several types of junctions.
Focal adhesion complexes are
composed of >100 proteins and localize at hemides-
mosomes.
Gap
junctions play a critical role in cell-cell communication.
It is also the initial site
of synthesis for secreted proteins.
1.6).
If a protein fails to appropriately fold
or oligomerize, it is retained and degraded within the
ER.
A good example of this is the most common mutation
of the CFTR protein in cystic fibrosis.
1.10B).
(A) Lysosomal degradation.
1.8).
(B) Proteosomal degradation.
If this is inadequate to cope with
the levels of misfolded proteins it can lead to apoptosis.
1.10).
These include proteosomes and peroxisomes.
The latter are responsible for catabolism of long-chained
fatty acids.
1.10).
Autophagy
is discussed in more detail in Chapter 2.
The material
is engulfed to form a phagosome that subsequently fuses
with lysosomes.
• Proteasomes play an important role in degrading cytosolic
proteins (see Fig.
1.11).
Details of mitochondrial functions follow:
• Energy generation.
Notably, the electron transport chain need not neces-
sarily be coupled to ATP generation.
TCA, Tricarboxylic acid.
lead to oxidative stress, characterized by increases in
intracellular reactive oxygen species.
• Intermediate metabolism.
• Cell death.
The role of mitochondria in cell death is
detailed in Chapter 2 and briefly mentioned here.
In turn,
these proteins activate intracellular programmed
cell death pathways.
CELLULAR ACTIVATION
Intercellular communication is essential to multicellular
organisms.
Receptors may be present on the cell
surface or within the cell (Fig.
1.12).
Depending on the receptor, ligand binding can:
1.
Open ion channels, typically at the synapse between
electrically excitable cells.
2.
Activate an associated GTP-binding regulatory protein
(G protein).
3.
Activate an endogenous or associated enzyme (often
a tyrosine kinase).
4.
1.12).
1.12).
Multiple signals at once,
in a certain ratio, may trigger yet another totally unique
response.
The signals that most cells respond to can be classified
into several groups.
• Danger and pathogens.
The involved
receptors are discussed in Chapters 3 and 6.
• Cell-cell contacts, mediated through adhesion molecules
and/or gap junctions.
• Cell-ECM contacts, mediated through integrins.
• Secreted molecules.
• Paracrine signaling.
Only cells in the immediate vicinity
are affected.
• Autocrine signaling occurs when molecules secreted by a
cell affect that same cell.
• Synaptic signaling.
• Endocrine signaling.
The released β-catenin can then
migrate to the nucleus and act as a transcription factor.
(B) Signaling from a
tyrosine kinase–based growth factor receptor.
Activated RAS interacts with and activates RAF (also known as MAP kinase
kinase kinase).
• Receptors associated with kinase activity.
Downstream
phosphorylation is a common pathway of signal transduc-
tion.
• Nuclear receptors.
• Other classes of receptors.
Normally,
β-catenin is continuously targeted for ubiquitin-
directed proteasomal degradation.
This is particularly true of signaling
pathways that rely on enzymatic activity.
• Nuclear (or cytoplasmic) localization of transcription
factors (see later).
• Transcription factor activation (or inactivation).
• Actin polymerization (or depolymerization).
• Protein degradation (or stabilization).
• Activation of feedback inhibitory (or stimulatory) loops.
Adaptor proteins play a key role in organizing intracel-
lular signaling pathways.
• DNA-binding domains permit specific binding to short
DNA sequences.
• Relieve blocks on cell cycle progression (thus promoting
replication).
• Prevent apoptosis.
1.12.
Epidermal Growth Factor (EGF) and Transforming
Growth Factor- α (TGF- α).
The ERB-B2 receptor (also known as HER-2) is
overexpressed in a subset of breast cancers.
Hepatocyte Growth Factor (HGF).
The receptor for HGF
is MET, which has intrinsic tyrosine kinase activity.
Consequently,
MET inhibitors are being evaluated for cancer therapy.
Platelet-derived Growth Factor (PDGF).
PDGF proteins are stored in cytoplasmic granules
and released by activated platelets.
Vascular Endothelial Growth Factor (VEGF).
Other VEGF inducers—produced at sites of inflammation
or wound healing—include PDGF and TGF- α.
Fibroblast Growth Factor (FGF).
FGF refers to a family
of growth factors with more than 20 members.
Transforming Growth Factor β (TGF-β).
It does
this by inhibiting lymphocyte proliferation and activity
of other leukocytes.
Animals lacking TGF-β have wide-
spread and persistent inflammation.
The ECM occurs in two basic forms: interstitial matrix
and basement membrane (Fig.
1.14).
• Interstitial matrix.
normal tissue architecture (Fig.
1.13).
• Scaffolding for tissue renewal.
Thus ECM disruption prevents
effective tissue regeneration and repair.
• Foundation for establishment of tissue microenvironments.
1.17C).
Both epithelial and
mesenchymal cells (e.g., fibroblasts) interact with ECM via integrins.
• Basement membrane.
The major constituents
are nonfibrillar type IV collagen and laminin.
Components of the Extracellular Matrix (Fig.
1.16).
Elastin.
1.15A).
Proteoglycans and Hyaluronan (see Fig.
1.15B).
bFGF regulation by association with
A.
Fibrillar collagen and elastin B.
Proteoglycan
the extracellular matrix
Figure 1.15 Extracellular matrix (ECM) components.
(A) Fibrillar collagen and elastic tissue structures.
(B) Proteoglycan structure.
Heparan sulfate binds bFGF secreted in the ECM.
FGF, Fibroblast growth factor.
1.15C).
Adhesive Glycoproteins and Adhesion Receptors.
1.17).
1.17A).
• Laminin is the most abundant glycoprotein in basement
membranes.
1.17B).
The N-terminus propeptide is variably processed depending on
the collagen chain.
mRNA, Messenger RNA.
inflammation (Chapter 3); they also play a critical role
in platelet aggregation (Chapter 4).
1.17C).
cells that are not actively cycling are in the G0 (gap 0) state
(Fig.
1.18).
Cells can enter G1 either from the G0 quiescent
cell pool or after completing a round of mitosis.
The cell cycle is regulated by activators and inhibitors.
1.19).
(C) Integrins and integrin-mediated signaling events at focal adhesion complexes.
Cyclin A-CDK2 and cyclin A-CDK1 are active in the S phase.
Cyclin B-CDK1 is essential
for the G2-to-M transition.
Two families of CDK inhibitors can block activity of CDKs and progression through the cell cycle.
The other family of three inhibitors, p21, p27, and p57, can
inhibit all CDKs.
There are several different CDKIs.
1.20).
• Symmetric division occurs when both daughter cells
retain self-renewal capacity.
• Embryonic stem (ES) cells are the most undifferentiated.
1.21).
They are normally protected within specialized
tissue microenvironments called stem cell niches.
1.22).
Another issue arises from the immunologic reactivity
of most stem cells.
Skin B.
Intestine C.
Liver
Figure 1.22 Stem cell niches in various tissues.
[A brief primer on the pathways that regulate
chromatin structure and accessibility].
[Overview of
endocytosis with specific emphasis on its role in modulating intracellular
signaling].
Choi AM, Ryter SW, Levine B: Autophagy in human health and disease,
N Engl J Med 368:651, 2013.
[Superb review concerning the physiologic
and pathophysiologic aspects of autophagy].
[Topical discussion about cellular
interactions and the mechanical basis of tissue maintenance].
[Mechanisms underlying
endoplasmic reticulum editing and cellular homeostasis].
[Excellent review of the
mechanisms and consequences of cellular autophagy].
[A well-written overview
of the intracellular architecture that directs and maintains polarity].
[Nice review of the general principles
of membrane architecture emphasizing domain organization].
[Solid review of the interplay between
cell metabolism, cell proliferation, and cell death].
Burke PJ: Mitochondria, bioenergetics and apoptosis in cancer, Trends
Cancer 3:857, 2017.
Friedman JR, Nunnari J: Mitochondrial form and function, Nature
505:335, 2014.
[Good overview of mitochondrial replication and response
to cellular injury].
[Review of the role of mitochondria in cell death pathways].
[Excellent overall review of cell
signaling and proliferation].
Morrison DK: MAP kinase pathways, Cold Spring Harb Perspect Biol
4:1, 2012.
[Review of mitogen-activated kinase signaling pathways].
1.23).
Concluding Remarks.
[Good review regarding
long noncoding RNA biology].
[An excellent review of the roles
played by noncoding RNAs].
[Overview of signaling pathways with an
emphasis on how these become dysregulated in malignancy].
[Very good review of
the fundamental concepts in stem cell biology].
Blau HM, Daley GQ: Stem cells in the treatment of disease, N Engl J
Med 380:1748, 2019.
[Excellent review on stem cell biology and its thera-
peutic potential].
De Los Angeles A, Ferrari F, Xi R et al: Hallmarks of pluripotency,
Nature 525:469, 2015.
Fuchs E, Chen T: A matter of life and death: self-renewal in stem cells,
EMBO Rep 14:39, 2013.
[A
focused review of applications of induced stem cell–derived endothelial
cells].
Martello G, Smith A: The nature of embryonic stem cells, Annu Rev
Cell Dev Biol 30:647, 2014.
[Good comprehensive overview of cell plasticity
and stemness].
Scadden DT: Nice neighborhood: emerging concepts of the stem cell
niche, Cell 157:41, 2014.
[Well-written paper describing the role of niche
in stem cell biology].
Traditionally, the study of pathology is divided into
general pathology and systemic pathology.
General
pathology is concerned with the common reactions of cells
and tissues to injurious stimuli.
In Chapter 1 we examined
the cellular and molecular properties of healthy cells.
• Clinical manifestations.
Hence, clini-
copathologic correlations are very important in the study
of disease.
Virtually all diseases start with molecular or structural
alterations in cells.
Virchow
emphasized the idea that individuals are sick because their
cells are sick.
• Etiology is the initiating cause of a disease.
The study of pathogenesis
is a central focus of pathology.
This, of course, is the goal of
precision medicine.
2.1).
2.1).
Unless the blood supply is
quickly restored, the cells suffer irreversible injury and die
(Fig.
2.2).
It results from diverse causes, includ-
ing ischemia (reduced blood flow), infection, and toxins.
There are two principal pathways of cell death, necrosis
and apoptosis.
Calcium may be deposited at sites of cell death, resulting
in pathologic calcification.
This adaptation leads to thickening of
the left ventricular wall (compare with the normal heart).
Most injurious stimuli can be
grouped into the following broad categories.
Hypoxia is an
extremely important and common cause of cell injury and
cell death.
Depending on the severity
of the hypoxic state, cells may adapt, undergo injury, or
die.
Chemical Agents and Drugs
The list of chemicals that may produce cell injury defies
compilation.
Even
oxygen at high concentrations is toxic.
These are discussed
further in Chapter 9.
In between are rickettsiae,
bacteria, fungi, and higher forms of parasites.
The ways
by which these biologic agents cause injury are diverse
(Chapter 8).
Nutritional Imbalances
Nutritional imbalances continue to be major causes of
cell injury.
Deficiencies of specific vitamins are found throughout
the world (Chapter 9).
Ironically, nutritional excess also
is an important cause of cell injury.
2.3).
The sequential structural changes in cell injury progressing
to cell death are illustrated in Fig.
The ultrastructural changes of reversible cell injury, visible by
electron microscopy (Fig.
2.6B), include the following:
1.
Plasma membrane alterations, such as blebbing, blunting, and
loss of microvilli
2.
Mitochondrial changes, including swelling and the appearance
of small amorphous densities
3.
Dilation of the ER, with detachment of polysomes
5.
Different injurious
stimuli induce death mainly by necrosis and/or apoptosis
(see Fig.
2.4 and Table 2.1).
Two features are consistently seen in reversibly injured cells.
Swelling of cells results from influx of water.
• Fatty change occurs in organs that are actively involved
in lipid metabolism (e.g., liver).
This
is discussed in Chapter 18.
• Other alterations are described in the following
sections.
A B C
Figure 2.5 Morphologic changes in reversible cell injury and necrosis.
(A) Normal kidney tubules with viable epithelial cells.
The ultrastructural features of these stages of cell injury are shown in Fig.
2.6.
(Courtesy Drs.
(A) Electron micrograph of a normal epithelial
cell of the proximal kidney tubule.
Note abundant microvilli (mv) lining the luminal surface (L).
(C) Proximal tubular cell showing late injury, expected to be irreversible.
(A, Courtesy Dr.
Brigitte Kaisslin, Institute of Anatomy, University of Zurich, Switzerland.
B, C,
Courtesy Dr.
Necrosis
Necrosis is a pathologic process that is the consequence
of severe injury.
All of these initiating triggers lead to irreparable damage
of numerous cellular components.
When damage to membranes is
severe, lysosomal enzymes enter the cytoplasm and digest
the cell.
2.6C).
Here the
chromatin condenses into a dense, shrunken basophilic mass.
2.7).The affected tissue has a firm texture.
A
localized area of coagulative necrosis is called an infarct.
(A) A wedge-shaped kidney infarct (yellow).
Figure 2.8 Liquefactive necrosis.
An infarct in the brain, showing
dissolution of the tissue.
This occurs
in the calamitous abdominal emergency known as acute pancreatitis
(Chapter 19).
2.10).
2.11).
2.8).
2.9).
Figure 2.11 Fibrinoid necrosis in an artery.
Figure 2.9 Caseous necrosis.
This phenomenon, called dystrophic calcification, is considered
later in the chapter.
It is estimated that humans turn
over almost 1 million cells per second!
Central to this process
is death of cells by apoptosis and their removal by phago-
cytes.
Cell death is critical for
involution of primordial structures and remodeling of
maturing tissues.
• Accumulation of misfolded proteins.
2.4
and Table 2.1).
During this process, there can be significant
tissue damage.
relatively normal, are more tightly packed.
This contrasts with
necrosis, in which an early feature is cell swelling, not shrinkage.
Chromatin condensation.
2.12B).
The nucleus itself may break up into two
or more fragments.
Formation of cytoplasmic blebs and apoptotic bodies.
2.12C).
Phagocytosis of apoptotic cells or cell bodies, usually
by macrophages.
2.12A).
2.12; see Fig.
2.4).
Cell shrinkage.
Cell size is reduced, the cytoplasm is dense
and eosinophilic (see Fig.
2.12A), and the organelles, although
A B
C
Figure 2.12 Morphologic features of apoptosis.
(A) Apoptosis of an epidermal cell in an immune reaction.
The cell is reduced in size and contains brightly
eosinophilic cytoplasm and a condensed nucleus.
(B, From Kerr JFR, Harmon BV: Definition and incidence of apoptosis: a historical perspective.
In Tomei LD, Cope FO, editors: Apoptosis: The Molecular
Basis of Cell Death.
Cold Spring Harbor, NY, 1991, Cold Spring Harbor Laboratory Press, pp 5–29; C, Courtesy Dr.
The presence of active caspases is therefore a marker
for cells undergoing apoptosis (see Fig.
2.12C).
2.13).
2.14).
• Anti-apoptotic.
2.14A).
VIABLE CELL B.
APOPTOSIS
thus protecting cells from apoptosis.
BH3-only proteins may also bind to and
block the function of BCL2 and BCL-XL.
2.14).
Thus, IAP inhibition permits initiation of the
caspase cascade.
This death domain is essential for delivering
apoptotic signals.
2.15).
The ligand
for Fas is called Fas ligand (FasL).
• Pro-apoptotic.
The precise mechanism
by which BAX-BAK oligomers permeabilize membranes
is not settled.
According to one model illustrated in Fig.
• Regulated apoptosis initiators.
Other
steps in apoptosis are less well-defined.
For instance, we
do not know how membrane blebs and apoptotic bodies
are formed.
tion of active caspase-8.
The combined activation of both pathways delivers
a fatal blow to the cells.
FADD,
Fas-associated death domain; FasL, Fas ligand.
• Necroptosis.
2.16).
As indicated in Fig.
This explains the morphologic similarity of necroptosis
with necrosis initiated by other injuries.
See text for details.
Caspase-1 and the closely related caspases-4 and -5
also induce death of the cells.
• Ferroptosis.
The newly formed autophagosome
fuses with lysosomes to form an autophagolysosome.
It is therefore prominent in atrophic cells exposed
to severe nutrient deprivation.
• Necroptosis is triggered by ligation ofTNFR1 and by proteins
found in RNA and DNA viruses.
• Necroptosis is caspase-independent and depends on the RIPK1
and RIPK3 complex.
• Release of cellular contents evokes an inflammatory reaction
as in necrosis.
Caspase-1 along with other
closely related caspases also cause death of the infected cell.
• Ferroptosis is an iron-dependent pathway of cell death induced
by lipid peroxidation.
It involves the delivery of
cytoplasmic materials to the lysosome for degradation.
It proceeds through several steps (Fig.
In the final stage, the digested materials are
released for recycling of metabolites.
See text for details.
LC3, Light chain 3.
This pathway of cell death is distinct from
necrosis and apoptosis, but the mechanism is unknown.
Nevertheless, autophagic vacuolization often precedes or
accompanies cell death.
This is an area of active
investigation, as discussed in Chapter 7.
In Huntington disease, mutant huntingtin impairs
autophagy.
Macrophage-specific deletion of Atg5 increases susceptibil-
ity to tuberculosis.
How these polymor-
phisms promote intestinal inflammation is not known.
• The consequences of cell injury depend on the type,
state, and adaptability of the injured cell.
How vulnerable
is a cell, for example, to loss of blood supply and hypoxia?
2.18).
The consequences of injury of each of these cellular com-
ponents are distinct but overlapping.
Thus,
in many ways, they are the arbiters of life and death of
cells.
In addition, mutations
in mitochondrial genes are the cause of some inherited
diseases (Chapter 5).
There are three major consequences of mitochondrial
damage.
• ATP depletion.
2.19).
ATP is produced in two ways.
Autophagy plays a role in host defense
against certain microbes.
ATP, Adenosine triphosphate; ROS, reactive oxygen species.
2.19).
• Cellular energy metabolism is altered.
As a consequence, glycogen
stores are rapidly depleted.
This reduces the intracellular pH, resulting in
decreased activity of many cytosolic enzymes.
Membrane damage may affect the integrity and functions
of all cellular membranes.
Several biochemical mechanisms may
contribute to membrane damage (Fig.
2.20):
• ROS.
Oxygen free radicals cause injury to cell membranes
by lipid peroxidation, discussed later.
• Decreased phospholipid synthesis.
• Increased phospholipid breakdown.
• Cytoskeletal abnormalities.
Damage to different cellular membranes has diverse
effects on cells.
• Mitochondrial membrane damage.
• Plasma membrane damage.
Two of these general pathways are
discussed next.
Free radicals are chemical species that have a
single unpaired electron in an outer orbit.
ROS are a type of oxygen-derived free radical whose
role in cell injury is well established.
The
properties of some of the most important free radicals are
summarized in Table 2.2.
Generation of Free Radicals
Free radicals may be generated within cells in several ways
(Fig.
2.21): •
The reduction-oxidation reactions that occur during normal
metabolic processes.
• Absorption of radiant energy (e.g., ultraviolet light, x-rays).
For example, ionizing radiation can hydrolyze water into
˙OH and hydrogen (H) free radicals.
• Rapid bursts of ROS are produced in activated leukocytes
during inflammation.
In addition, some intracellular oxidases (e.g.,
xanthine oxidase) generate O2•.
Defects in leukocytic
superoxide production lead to chronic granulomatous
disease (Chapter 6).
The production of ROS is increased by many injurious
stimuli.
These free radicals are removed by spontaneous decay and by specialized enzymatic systems.
thus sources of iron and O2• may cooperate in oxidative
cell damage.
Removal of Free Radicals
Free radicals are inherently unstable and generally decay
spontaneously.
2.21).
• As we have seen, free iron and copper can catalyze the
formation of ROS.
• Several enzymes act as free radical–scavenging systems
and break down H2 O2 and O2•.
Catalase, present in peroxisomes, decomposes H2 O2
(2H2 O2 → O2 + 2H2 O).
2.
3.
2.21):
• Lipid peroxidation in membranes.
• Oxidative modification of proteins.
• Lesions in DNA.
However,
it is now clear that free radicals can also trigger apoptosis.
2.23).
This process is called ER stress.
Diseases caused by
misfolded proteins are listed in Table 2.3.
2.22).
For this
reason, ischemia causes more rapid and severe cell and tissue
injury than hypoxia.
2.24 and shown earlier in Figs.
2.5 and
2.6.
The con-
sequences of ATP depletion were described earlier in the
Mitochondrial Damage section.
It
can also occur due to reduced venous drainage.
How does reperfusion injury occur?
Several mechanisms have been proposed:
• Oxidative stress.
• Intracellular calcium overload.
This, in turn, causes further cell injury.
• Inflammation.
The inflammation causes additional
tissue injury (Chapter 3).
• Activation of the complement system may contribute to
ischemia-reperfusion injury.
For unknown reasons, some
IgM antibodies have a propensity to deposit in ischemic
tissues.
The
morphologic changes shown here are indicative of reversible cell injury.
Further depletion of ATP results in cell death, typically by necrosis.
ER,
Endoplasmic reticulum.
Mammalian cells have developed protective responses
to deal with hypoxic stress.
Several promising investigational compounds that promote
HIF-1 signaling are being developed.
All of these may contribute to decreased cell and
tissue injury.
Because
many drugs are metabolized in the liver, this organ is a
major target of drug toxicity.
Here the major pathways of chemically induced
injury with selected examples are described.
Chemicals induce cell injury by one of two general
mechanisms:
• Direct toxicity.
Some chemicals injure cells directly by
combining with critical molecular components.
Cyanide
poisons mitochondrial cytochrome oxidase and thus
inhibits oxidative phosphorylation.
• Conversion to toxic metabolites.
These and other examples of chemical injury are described
in Chapter 9.
hypertrophied organ has no new cells, just larger cells.
• Pathologic hypertrophy.
The most common
stimulus for hypertrophy of skeletal and cardiac muscle is
increased workload.
2.2).
• Physiologic hypertrophy.
2.25).
Mechanisms of Hypertrophy
Hypertrophy is a result of increased cellular protein produc-
tion.
Much of our understanding of hypertrophy is based
on studies of the heart.
Hypertrophy
results from the action of growth factors and direct effects
on cellular proteins (Fig.
2.26):
• Mechanical sensors in the cell detect the increased load.
• Some of the signaling pathways stimulate increased
production of growth factors (e.g.
Death by necrosis and
apoptosis due to release of cytochrome c from mitochondria.
Complement may be
activated locally by IgM antibodies deposited in ischemic tissues.
• Chemicals may cause injury directly or by conversion into toxic
metabolites.
Such adaptations
may take several distinct forms.
The major known signaling pathways and their functional effects are shown.
In extreme cases, myocyte death can occur.
It can be physiologic or pathologic.
• Physiologic hyperplasia.
The classic
illustration of compensatory hyperplasia comes from the
study of liver regeneration.
The regulation of hematopoiesis
is discussed further in Chapter 13.
• Pathologic hyperplasia.
Endometrial hyperplasia is an example of abnormal
hormone-induced hyperplasia.
This form of
pathologic hyperplasia is a common cause of abnormal
uterine bleeding.
Atrophy can be
physiologic or pathologic.
Physiologic atrophy is common
during normal development.
Pathologic atrophy has several causes, and it can be local
or generalized.
Common causes of atrophy include the
following:
• Decreased workload (disuse atrophy).
The initial decrease in cell size is reversible
once activity is resumed.
• Loss of innervation (denervation atrophy).
Damage to the nerves leads to
atrophy of the muscle fibers supplied by those nerves
(Chapter 27).
• Diminished blood supply.
2.27).
This is called
senile atrophy.
• Inadequate nutrition.
This results
in marked muscle wasting (cachexia; Chapter 9).
Cachexia
is also seen in patients with chronic inflammatory diseases
and cancer.
• Loss of endocrine stimulation.
• Pressure.
Tissue compression for any length of time can
cause atrophy.
An enlarging benign tumor can cause
atrophy in the surrounding uninvolved tissues.
The fundamental cellular changes associated with atrophy
are similar in all of these settings.
The degradation of cellular proteins occurs mainly by the
ubiquitin-proteasome pathway.
An example
of residual bodies is lipofuscin granules, discussed later in the
chapter.
Autophagy
is associated with various types of cell injury, as discussed
earlier.
Figure 2.27 Atrophy.
(A) Normal brain of a young adult.
Note that loss of brain substance narrows the gyri and widens the sulci.
The most common epithelial metaplasia is columnar to squamous
(Fig.
2.28), as occurs in the respiratory tract in response to
chronic irritation.
However, the change to metaplastic
squamous cells comes with a price.
Thus, epithelial metaplasia,
in most circumstances, represents an undesirable change.
Unlike epithelial
metaplasia, this type of metaplasia is not associated with
increased cancer risk.
(A)
Schematic diagram.
There are four main mechanisms leading to abnormal
intracellular accumulations (Fig.
The resulting
disorders are called lysosomal storage diseases (Chapter 5).
Accumulation of carbon or
silica particles is an example of this type of alteration
(Chapter 15).
In many cases, if the overload can be controlled or
stopped, the accumulation is reversible.
Phospholipids are components of the myelin figures found
in necrotic cells.
Triglyceride and cholesterol accumula-
tions are discussed here.
2.30), but it also
occurs in the heart, muscle, and kidney.
Fatty liver is discussed in more detail in Chapter 18.
Cholesterol-laden macrophages (foam cells,
arrow) in a focus of gallbladder cholesterolosis.
(Courtesy Dr.
High-power detail of fatty change of the liver.
(Courtesy Dr.
By electron microscopy, they can be
amorphous, fibrillar, or crystalline in appearance.
2.32).
• Atherosclerosis.
• Xanthomas.
• Cholesterolosis.
2.31).
The mechanism of accumulation
is unknown.
• Niemann-Pick disease, type C.
(Courtesy Dr.
• Defective intracellular transport and secretion of critical
proteins.
• Accumulation of cytoskeletal proteins.
• Aggregation of abnormal proteins.
Abnormal or misfolded
proteins may deposit in tissues and interfere with normal
functions.
Certain forms of
amyloidosis (Chapter 6) fall in this category of diseases.
These disorders are sometimes called proteinopathies or
protein-aggregation diseases.
It is widely used as a descriptive his-
tologic term rather than a specific marker for cell injury.
Extracellular hyaline has been more difficult
to analyze.
Glycogen is a readily available source of glucose
stored in the cytoplasm of healthy cells.
Diabetes mellitus is the prime example of a disorder of
glucose metabolism.
Tattooing is a
form of localized, exogenous pigmentation of the skin.
The pigments do not usually evoke any
inflammatory response.
Lipofuscin is not injurious to the cell or its
functions.
Its importance lies in its being a telltale sign
of free radical injury and lipid peroxidation.
derived from the Latin (fuscus, brown), referring to brown
lipid.
2.33).
It is discussed
further in Chapter 25.
For practical purposes, melanin is
the only endogenous brown-black pigment.
Iron metabolism and
hemosiderin are considered in detail in Chapters 14 and
18.
Iron is normally carried by a specific transport protein
called transferrin.
In cells, it is stored in association with
a protein, apoferritin, to form ferritin micelles.
Ferritin is
a constituent of most cell types.
Hemosiderin
pigment represents aggregates of ferritin micelles.
Local or systemic excesses of iron cause hemosiderin to
accumulate within cells.
Local excesses result from hemor-
rhages in tissues.
The best example of localized hemosiderosis
is the common bruise.
In parallel, the iron released from heme is incorporated
into ferritin and eventually hemosiderin.
There are two forms
of pathologic calcification.
Calcification
is almost always present in the atheromas of advanced
atherosclerosis.
It also commonly develops in aging or
damaged heart valves, further hampering their function
(Fig.
2.34).
Massive deposits in the kidney (nephrocalcinosis) may in
time cause renal damage (Chapter 20).
It is markedly narrowed (stenosis).
They can be intracellular, extracellular, or in both locations.
In
the course of time, heterotopic bone may form in the focus
of calcification.
Some types of papillary cancers
(e.g., thyroid) are apt to develop psammoma bodies.
Serum calcium is
normal in dystrophic calcification.
Hypercalcemia also
accentuates dystrophic calcification.
Sadly, Toth and Hermes are nowhere to be found, henceCellular aging 67
the elixir remains a secret.
Individuals age because their cells age.
2.35).
Such findings suggest that aging
is associated with definable mechanistic alterations.
DNA Damage.
Several
lines of evidence point to the importance of DNA repair in
the aging process.
Cellular Senescence.
Aging is associated with progressive
replicative senescence of cells.
Two mechanisms are believed to
underlie cellular senescence:
• Telomere attrition.
Telomere length is maintained
by nucleotide addition mediated by an enzyme called
telomerase.
Similar data
exist for the role of autophagy and proteasomal degradation
of proteins.
Rapamycin has
multiple effects, including promotion of autophagy.
Abnor-
mal protein homeostasis can have many effects on cell
survival, replication, and functions.
In addition, it may lead
to accumulation of misfolded proteins, which can trigger
apoptosis.
Dysregulated Nutrient Sensing.
Paradoxical though it
may seem, eating less increases longevity.
• Insulin and insulin-like growth factor 1 (IGF-1) signaling
pathway.
• Sirtuins.
Sirtuins are a family of NAD-dependent protein
deacetylases.
Sirtuins are thought to promote the expression of several
genes whose products increase longevity.
This effect can be mim-
icked by rapamycin.
Telomere length is plotted against the number of cell
divisions.
In cancer cells, telomerase is often
reactivated.
This is
discussed more fully in Chapter 7.
• Activation of tumor suppressor genes.
This is
discussed further in Chapter 7.
Defective Protein Homeostasis.
Nagata S: Apoptosis and clearance of apoptotic cells, Annu Rev Immunol
36:489–517, 2018.
[An excellent review of the mechanisms by which apoptotic
cells and their fragments are cleared].
Necroptosis and Pyroptosis
Galluzzi L, Kepp O, Chan FK, et al: Necroptosis.
Mechanisms and
relevance to disease, Annu Rev Pathol 12:103–130, 2017.
[A current
review of necroptosis and its pathophysiologic significance].
[A review of
the mechanisms and consequences of pyroptosis].
[A review of newly discovered
pathways of cell death and possible therapeutic interventions].
[A description of the pathology of
various pathways of cell death].
[An excellent overview of the biochemistry and significance of necroptosis].
[An excellent discussion of the mechanisms
and significance of autophagy].
Doherty J, Baehrecke EH: Life, death and autophagy, Nat Cell Biol
20:1110–1117, 2018.
[A review of the link between autophagy and cell
death].
[An excellent review of the cell biology
and genetics of autophagy].
[A review of the control of
protein turnover and its role in atrophy of muscle].
[A review
of the mechanisms of hypertrophy, with an emphasis on the heart].
[A landmark review that suggests nine hallmarks
of aging and directions for future research].
• Nutrient sensing system:Caloric restriction increases longevity.
Mediators may be reduced IGF-1 signaling and increased
sirtuins.
[The role of mitochondria in cellular response to stress].
[The
molecular basis of reperfusion injury and possible therapeutic targets].
Hotchkiss RS, Strasser A, McDunn JE, et al: Cell death, N Engl J Med
361:1570–1583, 2009.
The mediators of defense include phagocytic
leukocytes, antibodies, and complement proteins.
The typical inflammatory reaction develops through a
series of sequential steps (Fig.
• Repair consists of a series of events that heal damaged
tissue.
• Components of the inflammatory response.
3.1).
• Harmful consequences of inflammation.
• Recognition of the noxious agent that is the initiat-
ing stimulus for inflammation.
These receptors are described in
more detail later.
• Recruitment of leukocytes and plasma proteins into the
tissues.
If the offending stimulus is
eliminated, the reaction subsides, and residual injury is
repaired.
Chronic inflammation may follow acute inflamma-
tion or arise de novo.
These signs are hallmarks of
acute inflammation.
These diseases and their pathogenesis are discussed in relevant
chapters.
This serious disorder is
discussed in Chapter 4.
• Mediators of inflammation.
• Acute and chronic inflammation.
IL-1 recruits leukocytes
and thus induces inflammation (see later).
These disorders are discussed later
in this and other chapters.
• Other cellular receptors involved in inflammation.
• Circulating proteins.
Other proteins called collectins also
bind to and combat microbes.
• Tissue necrosis elicits inflammation regardless of the cause
of cell death.
Inflammation is a major cause of
tissue injury in these diseases (Chapter 6).
• Cellular receptors for microbes.
• Sensors of cell damage.
It is one
of the earliest manifestations of acute inflammation.
3.1).
3.2).
Its presence
Hydrostatic
Colloid osmotic
pressure
pressure
A.
Plasma proteins
NORMAL
Fluid and protein leakage
B.
TRANSUDATE
(low protein content, few cells)
Figure 3.2 Formation of exudates and transudates.
Therefore the net flow of fluid across the vascular bed is almost nil.
The system of lymphatics and lymph
nodes filters and polices the extravascular fluids.
The
presence of red streaks near a skin wound is a telltale sign
of bacterial infection.
as vascular congestion and localized redness of the
involved tissue.
3.3).
It is elicited by histamine, bradykinin,
leukotrienes, and other chemical mediators.
Sunburn is a classic example of damage that results in
late-appearing vascular leakage.
Often the immediate and
delayed responses occur along a continuum.
A.
NORMAL
Vessel lumen
Leukocytes
Plasma proteins
Endothelium
Tissues
B.
Fluid leak from blood vessels results
in edema.
C.
These leukocytes perform the key function of eliminating
the offending agents.
Macrophages also
produce growth factors that aid in repair.
This process can be divided into sequential
phases (Fig.
3.4).
1.
In the lumen: margination, rolling, and adhesion to endothe-
lium.
Vascular endothelium in its normal state does not
bind circulating cells or allow their passage.
2.
Migration across the endothelium and vessel wall.
3.
Migration in the tissues toward a chemotactic stimulus.
This process of leukocyte redistribution is called
margination.
They are expressed on leukocytes and endothelial cells.
• Selectins.
The ligands for selectins are sialylated oligosac-
charides bound to mucin-like glycoproteins.
• Integrins.
Leukocytes normally express integrins in a
low-affinity state.
These chemokines bind to and activate
the rolling leukocytes.
Transmigration of
leukocytes occurs mainly in postcapillary venules.
After leukocytes pass through, the basement
membranes become continuous again.
These leu-
kocyte adhesion deficiencies are described in Chapter 6.
Both exogenous and endogenous substances
act as chemoattractants.
3.5).
3.6).
(Courtesy Dr.
Morris J.
Karnovsky, Harvard Medical School, Boston, Mass.)
of cellular infiltration.
(A) Early (neutrophilic) infiltrates and congested blood vessels.
(B) Later (mononuclear) cellular infiltrates.
(C) The
approximate kinetics of edema and cellular infiltration.
Phagocytosis
Phagocytosis involves sequential steps (Fig.
Phagocytic Receptors.
Therefore the
mannose receptor recognizes microbes and not host cells.
Macrophage scavenger
receptors bind a variety of microbes in addition to modified
LDL particles.
Macrophage integrins, notably MAC-1
(CD11b/CD18), may also bind microbes for phagocytosis.
Engulfment.
3.7).
This table lists the major differences between neutrophils and macrophages.
The reactions summarized above are described in the text.
into the phagolysosome (see Fig.
3.8).
During this process
the phagocyte may also release lysosome contents into the
extracellular space.
Different classes of cell surface receptors of leukocytes recognize different stimuli.
The receptors initiate responses that
mediate the functions of the leukocytes.
Only some receptors are depicted (see text for details).
Lipopolysaccharide (LPS) first binds to a circulating
LPS-binding protein (not shown).
IFN-γ, Interferon-γ.82 CHAPTER 3 Inflammation and Repair
1.
ENGULFMENT
Phagocyte membrane
zips up around
microbe 3.
During phagocytosis, granule contents may be
released into extracellular tissues (not shown).
iNOS, Inducible nitric oxide synthase; MPO, myeloperoxidase; ROS, reactive oxygen species.
oxide (NO), and these as well as lysosomal enzymes destroy
phagocytosed materials (see Fig.
3.8).
This is the final step
in the elimination of infectious agents and necrotic cells.
Reactive Oxygen Species.
Phagocyte oxidase is an
enzyme complex consisting of at least seven proteins.
O2• is converted into hydrogen peroxide (H2 O2),
mostly by spontaneous dismutation.
H2 O2 is not able to
efficiently kill microbes by itself.
The H2 O2-MPO-
halide system is the most potent bactericidal system of
neutrophils.
H2 O2 is also converted to hydroxyl radical
(˙OH), another powerful destructive agent.
These ROS are implicated in tissue damage
accompanying inflammation.
Nitric Oxide.
There are three different types of NOS:
endothelial (eNOS), neuronal (nNOS), and inducible (iNOS).
Lysosomal Enzymes and Other Lysosomal Proteins.
Neutrophils have two main types
of granules.
Different granule enzymes serve different functions.
Foremost among
these is α1-antitrypsin, which is the major inhibitor of
neutrophil elastase.
α2-Macroglobulin is another antiprotease found
in serum and various secretions.
3.9).
In this process, the nuclei of the neutrophils
are lost, leading to death of the cells.
NETs have also been
detected in the blood during sepsis.
(A) Healthy neutrophils with nuclei stained red and cytoplasm stained green.
(C) Electron micrograph of bacteria (staphylococci) trapped in
NETs.
This fact becomes
evident in the discussion of specific disorders throughout
this book.
Controlled secretion of granule contents is a normal
response of activated leukocytes.
These functions of macrophages are discussed
later in the chapter.
IL-17 induces the
secretion of chemokines that recruit other leukocytes.
Many mediators have
been identified and targeted therapeutically to limit inflam-
mation.
However, there is also some overlap (redundancy) in
the actions of the mediators.
• Mediators are either secreted by cells or generated from
plasma proteins.
• Enzymes and ROS may be released into the extracellular
environment.
• Antiinflammatory mediators terminate the acute inflammatory
reaction when it is no longer needed.
Histamine also causes contrac-
tion of some smooth muscles.
It is also a vasoconstrictor, but the
importance of this action in inflammation is unclear.
Active AAs
are derived from an esterified precursor found in membrane
phospholipids.
3.10).
They are generated by the actions of two
cyclooxygenases, called COX-1 and COX-2.
• Active mediators are produced only in response to offend-
ing stimuli.
These stimuli include microbial products and
substances released from necrotic cells.
• Most mediators are short-lived.
They quickly decay, or
are inactivated by enzymes, or they are otherwise scav-
enged or inhibited.
There is thus a system of checks and
balances that regulates mediator actions.
These built-in
control mechanisms are discussed with each class of
mediator.
• One mediator can stimulate the release of other mediators.
It is also found in basophils and platelets.
Neuropeptides (e.g., substance P) and cytokines (IL-1, IL-8)
may also trigger release of histamine.
Histamine causes dilation of arterioles and increases
the permeability of venules.
and a subscript numeral (e.g., 1, 2) that indicates the number
of double bonds in the compound.
Some of these enzymes have restricted tissue
distributions.
PGD2 also is
a chemoattractant for neutrophils.
• Lipoxygenase inhibitors.
Pharmacologic agents that inhibit
leukotriene production are useful in the treatment of
asthma.
These drugs
are useful in the treatment of asthma.
The general properties and functions of
cytokines are discussed in Chapter 6.
The cytokines involved
in acute inflammation are reviewed here (Table 3.7).
The production of TNF is induced by signals through TLRs
and other microbial sensors.
The actions of TNF and IL-1 contribute to the local and
systemic reactions of inflammation (Fig.
3.11).
The most
important roles of these cytokines in inflammation are the
following.
• Endothelial activation.
There are three different lipoxygenases, 5-lipoxygenase
being the predominant one in neutrophils.
These antiinflam-
matory drugs include the following.
Selective
COX-2 inhibitors are 200- to 300-fold more potent in
blocking COX-2 than COX-1.
The most important cytokines involved in inflammatory reactions are listed.
Many other cytokines may play lesser roles in inflammation.
• Activation of leukocytes and other cells.
IL-1 also stimulates Th17 responses, which in
turn induce acute inflammation.
• Systemic acute-phase response.
They have two main
functions.
• In acute inflammation.
Inflammatory chemokines are the
ones whose production is induced by microbes and other
stimuli.
• Maintenance of tissue architecture.
Cytokines also
play key roles in chronic inflammation; these are described
later.
The system consists
of more than 20 proteins, some of which are numbered C1
through C9.
The activation and functions of complement
are outlined in Fig.
3.12.
About 40 different chemokines and 20 different
receptors for chemokines have been identified.
A
subset of these chemokines acts primarily on neutro-
phils.
IL-8 (now called CXCL8) is typical of this group.
Its most important inducers
are microbial products and other cytokines, mainly IL-1
and TNF.
• C-C chemokines have the first two conserved cysteine
residues adjacent.
• C chemokines lack the first and third of the four conserved
cysteines.
The C chemokines (e.g., lymphotactin, XCL1)
are relatively specific for lymphocytes.
• CX3 C chemokines contain three amino acids between the
two cysteines.
The only known member of this class is
called fractalkine (CX3CL1).
Chemokines mediate their activities by binding to seven-
transmembrane G protein–coupled receptors.
Activation of complement by different pathways leads to cleavage of C3.
The complement system has three main functions (see
Fig.
3.12).
• Inflammation.
C5a is also a chemotactic agent for neutrophils,
monocytes, eosinophils, and basophils.
• Opsonization and phagocytosis.
• Cell lysis.
Inherited
deficiency of this inhibitor is the cause of hereditary
angioedema.
The complement system contributes to disease in several
ways.
These effects are similar to those of histamine.
Nerve fibers containing
substance P are prominent in the lung and gastrointestinal
tract.
Now, we are
wallowing in them!
• Kinins: Produced by proteolytic cleavage of precursors;mediate
vascular reaction, pain.
Figure 3.13 Serous inflammation.
3.13).
3.14A), and pleura.
3.14B).
Fibrinous exudates
may be dissolved by fibrinolysis and cleared by macrophages.
(A) Deposits of fibrin on the pericardium.
(A) Multiple bacterial abscesses (arrows) in the lung in a case of bronchopneumonia.
scarring.
A common example of
an acute suppurative inflammation is acute appendicitis.
They are produced by seeding of pyogenic bacteria into a
tissue (Fig.
3.15).
Abscesses have a central liquefied region
composed of necrotic leukocytes and tissue cells.
In time the abscess may
become walled off and ultimately replaced by connective
tissue.
3.16).
A B
Figure 3.16 The morphology of an ulcer.
(A) A chronic duodenal ulcer.
3.17).
• Complete resolution.
• Healing by connective tissue replacement (scarring, or fibrosis).
• Progression of the response to chronic inflammation
(discussed later).
If the injurious agent cannot be quickly eliminated,
the result may be chronic inflammation.
Fibrosis may dominate the
late stages.
• Prolonged exposure to potentially toxic agents, either
exogenous or endogenous.
Loss of function (functio laesa) results from pain and injury
to the tissues.
Causes of Chronic Inflammation
Chronic inflammation arises in the following settings.
These organisms often evoke an
immune reaction called delayed-type hypersensitivity
(Chapter 6).
Acute and chronic
inflammation may coexist, as in a peptic ulcer.
• Hypersensitivity diseases.
3.18).
• Tissue destruction, induced by the persistent offending
agent or by the inflammatory cells.
Macrophages
are professional phagocytes that eliminate microbes and
damaged tissues.
They also serve important roles in the
repair of injured tissues.
Here we review the development
and functions of macrophages.
3.19).
Circulating cells of this lineage
are known as monocytes.
Macrophages are normally dif-
fusely scattered in most connective tissues.
(A) In postnatal life, macrophages arise mainly from bone marrow progenitors and blood monocytes.
(B) The morphology of a monocyte and activated macrophage.
Different stimuli activate monocytes/macrophages to develop into functionally distinct
populations.
They phagocytose and
destroy microbes and dead tissues and can potentiate inflammatory reactions.
These processes
are discussed later in the chapter.
Thus, macrophages contribute to the initiation
and propagation of inflammatory reactions.
3.20).
Prolonged reactions involving T cells and macrophages may result in granuloma formation.
of long-lived memory cells.
• Th1 cells produce the cytokine IFN-γ, which activates
macrophages by the classical pathway.
Th2 cells are important in defense against helminthic
parasites and in allergic inflammation.
These T-cell subsets
and their functions are described in more detail in Chapter 6.
3.21).
The result is
a cycle of cellular reactions that fuel and sustain chronic
inflammation.
However,
the contribution of antibodies to most chronic inflammatory
disorders is unclear.
• Eosinophils are abundant in immune reactions mediated
by IgE and in parasitic infections (Fig.
3.22).
Epithelioid cells
and giant cells are apposed to the surface of the foreign
body.
3.21).
Figure 3.22 Focus of inflammation containing numerous eosinophils.
also may injure host epithelial cells.
Mast cells express on their surface the receptor
(FcεRI) that binds the Fc portion of IgE antibody.
This
pattern of inflammation has been called acute on chronic.
Some
activated macrophages may fuse, forming multinucleate
giant cells.
3.23).
The aggregates of
epithelioid macrophages are surrounded by a collar of lymphocytes.
Older granulomas may have a rim of fibroblasts and connective
tissue.
Grossly, this has a granular, cheesy
appearance and is therefore called caseous necrosis.
Healing of granulomas is accompanied
by fibrosis that may be extensive in involved organs.
In this disease the granuloma is referred
to as a tubercle.
Granulomas may also develop in some
immune-mediated inflammatory diseases.
• It is characterized by coexisting inflammation, tissue injury, and
attempted repair by scarring.
• The cellular infiltrate consists of macrophages, lymphocytes,
plasma cells, and other leukocytes.
The acute-phase response consists of several clinical and
pathologic changes.
NSAIDs, including aspirin, reduce
fever by inhibiting prostaglandin synthesis.
They also
bind chromatin, possibly aiding in clearing necrotic cell
nuclei.
Both processes involve the proliferation of
cells and close interactions between cells and the ECM.
Based on these criteria, the
tissues of the body are divided into three groups.
• Labile (continuously dividing) tissues.
These tissues
can readily regenerate after injury as long as the pool of
stem cells is preserved.
• Stable tissues.
3.24).
• Regeneration.
However, these
cells are capable of dividing in response to injury or loss
of tissue mass.
Stable cells constitute the parenchyma of
most solid tissues, such as liver, kidney, and pancreas.
With the exception of liver,
stable tissues have a limited capacity to regenerate after
• injury.
Permanent tissues.
The majority of neurons and cardiac muscle
cells belong to this category.
In permanent tissues, repair is typically
dominated by scar formation.
Cell proliferation is driven by signals provided by
growth factors and from the ECM.
Growth factors are typically produced by cells near the
site of damage.
Several growth factors are displayed at
high concentrations bound to ECM proteins.
The reality, although less dramatic, is still quite
impressive.
Following
partial hepatectomy, the liver regenerates by proliferation of surviving cells.
The process occurs in stages, including priming, followed by growth
factor–induced proliferation.
The main signals involved in these steps are
shown.
Once the mass of the liver is restored, the proliferation is
terminated (not shown).
repopulation from progenitor cells.
Which mechanism plays
the dominant role depends on the nature of the injury.
• Proliferation of hepatocytes following partial hepatectomy.
The process occurs in distinct
stages (Fig.
3.25).
Almost
all hepatocytes replicate during liver regeneration after
partial hepatectomy.
In the final, termination, phase, hepa-
tocytes return to quiescence.
• Liver regeneration from progenitor cells.
formation.
The subsequent steps are sum-
marized here (Fig.
3.26):
• Inflammation.
As the injurious agents and necrotic cells are
cleared, the inflammation resolves.
• Cell proliferation.
Each cell
type serves unique functions.
• Formation of granulation tissue.
• Regeneration of the liver is a classic example of repair by
regeneration.
(A) Inflammation.
3.27A).
• Deposition of connective tissue.
Granulation tissue is progres-
sively replaced by deposition of collagen.
3.27B).
The macrophages that are involved
in repair are mostly of the alternatively activated (M2) type.
We next describe the steps in the formation of granulation
tissue and the scar.
Angiogenesis
Angiogenesis is the process of new blood vessel develop-
ment from existing vessels.
• Migration of endothelial cells toward the area of tissue injury.
• Proliferation of endothelial cells just behind the leading front
(“tip”) of migrating cells.
• Remodeling into capillary tubes.
• Suppression of endothelial proliferation and migration and
deposition of the basement membrane.
Mechanisms of Angiogenesis.
Fibroblast growth factors
(FGFs), mainly FGF-2, stimulate the proliferation of endo-
thelial cells.
Collagen is stained blue by the trichrome stain; minimal mature collagen can be seen at this point.
It does this by
inhibiting lymphocyte proliferation and the activity of other
leukocytes.
Collagen
deposition is critical for the development of strength in a
healing wound site.
These cells contribute to the contrac-
tion of the scar over time.
After
its deposition, the connective tissue in the scar continues
to be modified and remodeled.
In tissue repair, angiogenesis occurs mainly by
sprouting of new vessels.
The steps in the process and the major signals
involved are illustrated.
The newly formed vessel joins up with other
vessels (not shown) to form the new vascular bed.
role in angiogenesis and the structural maturation of new
vessels.
Complete restoration can occur only in tissues
composed of stable and labile cells.
• The location of the injury is also important.
This is
called organization.
The activity of
the MMPs is tightly controlled.
• Multiple growth factors stimulate the proliferation of the cell
types involved in repair.
3.29).
• Within 24 hours, neutrophils are seen at the incision
margin, migrating toward the fibrin clot.
In some instances, however,
these effects of glucocorticoids are desirable.
In the latter, note the large amount of granulation tissue and
wound contraction.
the edge of the incision begin to show increased mitotic
activity.
• By day 5, neovascularization reaches its peak as granula-
tion tissue fills the incisional space.
Thus, new granulation tissue
is often edematous.
• During the second week, there is continued collagen
accumulation and fibroblast proliferation.
The leukocyte
infiltrate, edema, and increased vascularity are substan-
tially diminished.
The following are some common
examples.
• Venous leg ulcers (Fig.
These ulcers
fail to heal because of poor delivery of oxygen to the site
of the ulcer.
• Arterial ulcers (Fig.
The ischemia results in atrophy and then
necrosis of the skin and underlying tissues.
These lesions
can be quite painful.
• Diabetic ulcers (Fig.
3.30C) affect the lower extremities,
particularly the feet.
Histologically, these lesions are
characterized by epithelial ulceration (Fig.
3.30E) and
extensive granulation tissue in the underlying dermis
(Fig.
3.30F).
• Pressure sores (Fig.
The lesions are caused by mechanical pressure
and local ischemia.
When a surgical incision reopens internally or externally
it is called wound dehiscence.
In abdominal wounds it can be precipitated
by vomiting and coughing.
3.31A).
3.31B,
C).
Con-
sequently, large defects have a greater potential for
secondary, inflammation-mediated injury.
A greater volume of granulation tissue generally results
in a greater mass of scar tissue.
Ultimately the original granulation
tissue scaffold is converted into a pale, avascular scar.
The dermal appendages that have been destroyed in the
line of the incision are permanently lost.
Hence it is an important feature
in healing by secondary union.
As already
mentioned, the terms scar and fibrosis are used interchange-
ably.
Fibrosis
may be responsible for substantial organ dysfunction and
even organ failure.
These conditions are
discussed in the appropriate chapters throughout the book.
(A–D) External appearance of skin ulcers.
(E, F) Histologic appearance of a diabetic ulcer.
(E) Ulcer crater; (F) chronic
inflammation and granulation tissue.
Contraction in the size of a wound is an important part
of the normal healing process.
Contractures are commonly
seen after serious burns and can compromise the movement
of joints.
• Excessive production of ECM can cause keloids in the skin.
[A discussion
of the role of neutrophil extracellular traps in tissue injury and
resolution].
[A discussion of the diverse functions of
integrins].
[An excellent review of
neutrophil biology].
[An overview
of the roles of selectins in leukocyte recruitment].
Muller WA: Mechanisms of leukocyte transendothelial migration, Annu
Rev Pathol 6:323, 2011.
[A thoughtful review of the mechanisms by which
leukocytes traverse the endothelium].
[A review
of the mechanisms of leukocyte recruitment and leukocyte adhesion
deficiencies].
[A review of the mechanisms of neutrophil extracellular trap formation].
Dennis EA, Norris PC: Eicosanoid storm in infection and inflammation,
Nat Rev Immunol 15:511, 2015.
[A review of the proinflammatory and
antiinflammatory activities of eicosanoids].
[An overview of the functions of chemokines in host
defense and inflammation].
(A) Hypertrophic scar.
(B) Keloid.
(C) Microscopic appearance
of a keloid.
Note the thick connective tissue deposition in the dermis.
[A comprehensive
review of diseases caused by mutations in inflammasome-related
pathways].
Zlotnik A, Yoshie O: The chemokine superfamily revisited, Immunity
36:705–716, 2012.
Nathan C, Ding A: Nonresolving inflammation, Cell 140:871–882, 2010.
[A discussion of the abnormalities that lead to chronic inflammation].
[A modern review of host responses that contribute to tissue repair].
[A modern discussion of the biochemical
mechanisms of liver regeneration].
Novak ML, Koh TJ: Macrophage phenotypes during tissue repair, J
Leukoc Biol 93:875–881, 2013.
Depending on its severity and location,
edema may have minimal or profound effects.
The structural integrity of blood vessels is frequently
compromised by trauma.
4.1).
If the net rate of fluid movement exceeds
the rate of lymphatic drainage, fluid accumulates.
Edema fluids and effusions may be inflammatory or non-
inflammatory (Table 4.1).
Inflammation-related edema and
effusions are discussed in detail in Chapter 3.
In contrast,
noninflammatory edema and effusions are protein-poor fluids
called transudates.
4.2).
We will
now discuss the various causes of edema.
Either condition can injure the medullary
of lymphatic channels and lymph nodes.
This may result centers and cause death (Chapter 28).
Edema is most commonly seen in subcutaneous
tissues, the lungs, and the brain.
Subcutaneous edema can be
diffuse or more conspicuous in regions with high hydrostatic
pressures.
Affected tissues turn red (erythema)
because of increased delivery of oxygenated blood.
Conges-
tion is a passive process resulting from reduced venous
outflow of blood from a tissue.
It can be systemic, as in
cardiac failure, or localized, as in isolated venous obstruction.
As a result of increased hydrostatic pressures,
congestion commonly leads to edema.
within intact blood vessels or within the chambers of the
heart.
The general sequence of events leading to
hemostasis at a site of vascular injury is shown in Fig.
4.4.
4.4A).
• Primary hemostasis: the formation of the platelet plug.
4.4B).
• Secondary hemostasis: deposition of fibrin.
Vascular injury
exposes tissue factor at the site of injury.
In acute hepatic congestion, the
central vein and sinusoids are distended.
4.3A).
4.3B).
(B) Centrilobular
necrosis with degenerating hepatocytes and hemorrhage.
(Courtesy Dr.
(A) After vascular injury, neurohumoral
factors induce transient vasoconstriction.
A.
4.4C).
• Clot stabilization and resorption.
4.4D) and eventually lead to clot resorption and
tissue repair.
4.10).
4.4.
α-Granules have the
adhesion molecule P-selectin on their membranes (Chapter 3)
B.
4.4B).
4.5).
Platelets also adhere to exposed collagen via the platelet
collagen receptor Gp1a/IIa.
ADP acts by binding two G-protein–coupled
receptors.
P2Y1 and P2Y12.
All of these antiplatelet drugs are used in the
treatment of coronary artery disease.
• Platelet aggregation follows their activation.
Platelet contraction is
dependent on the cytoskeleton and consolidates the
aggregated platelets.
Aggregation is accomplished by
fibrinogen bridging GpIIb-IIIa receptors on different platelets.
ADP, Adenosine diphosphate.
Factors marked with an asterisk (*) are
vitamin K dependent as are protein C and S (not depicted).
blood vessels in vivo (Fig.
4.6).
However, clotting in vitro
and in vivo both follow the same general principles, as follows.
4.7).
4.6B).
Calcium ions hold the assembled components together and are essential for the reaction.
4.6A).
4.6B).
• Platelet activation.
4.6B).
Thrombin also
directly activates leukocytes.
ECM, Extracellular matrix; PDGF, platelet-
derived growth factor.
See Fig.
4.10 for additional anticoagulant activities
mediated by thrombin.
PARs also are expressed on
inflammatory cells, endothelium, and other cell types
(Fig.
• Anticoagulant effects.
4.9).
4.10).
• Platelet inhibitory effects.
NO is the product of endothelial nitric oxide
synthase eNOS.
• Anticoagulant effects.
Activated protein C/protein S
complex is a potent inhibitor of coagulation cofactors Va
and VIIIa.
• Fibrinolytic effects.
The presentation of abnormal
bleeding varies widely.
(B) Fatal intracerebral bleed.
following are general principles related to abnormal bleeding
and its consequences.
These bleeds typically take the
form of petechiae, minute 1- to 2-mm hemorrhages (Fig.
4.11A), or purpura, which are slightly larger (≥3 mm) than
petechiae.
• Generalized defects involving small vessels often present with
“palpable purpura” and ecchymoses.
Ecchymoses (some-
times simply called bruises) are hemorrhages of 1 to 2 cm
in size.
4.12).
Endothelial integrity is the
most important factor.
Injury to endothelial cells can alter local blood flow
and affect coagulability.
Abnormal blood flow (stasis or turbulence), in turn,
can cause endothelial injury.
Obviously, severe endothelial injury may trigger
thrombosis by exposing vWF and tissue factor.
Here it suffices to mention several of the major
prothrombotic alterations:
• Procoagulant changes.
• Antifibrinolytic effects.
These are listed below:
• Factor V Leiden.
This mutation renders factor
V resistant to cleavage and inactivation by protein C.
As
a result, an important antithrombotic counterregulatory
pathway is lost (see Fig.
4.10).
The inheritance pattern
for factor V Leiden is autosomal dominant.
• Prothrombin gene mutation.
• Other inherited causes.
• Homocysteinemia.
Elevated levels of homocysteine may
be inherited or acquired.
Acquired causes include
deficiency of vitamin B6, B12, and folic acid.
In
some cases (e.g., cardiac failure or trauma), stasis or vascular
injury may be most important.
In disseminated cancers, release of various procoagulants
from tumors predisposes to thrombosis.
The hypercoagulabil-
ity seen with advancing age may be due to reduced
endothelial PGI2 production.
Smoking and obesity promote
hypercoagulability by unknown mechanisms.
PF4-IgG immune complex (Fig.
It occurs in approximately 50% of cases and
affects both veins and arteries.
Diagnosis requires the demonstration of
anti–PF4-heparin antibodies.
APS may be primary or secondary.
Our focus here is on the primary form.
Diagnosis of APS is based
on clinical features and demonstration of aPL antibodies
in the serum.
Therapy of APS involves various forms of
anticoagulation.
Thrombi occurring in heart chambers or in the aortic lumen
are designated mural thrombi.
4.14B).
vegetations, and thrombocytopenia.
The pathogenesis of antiphospholipid syndrome is
complex and not fully understood.
Proteins that are recognized
by these antibodies include cardiolipin and β2-glycoprotein I.
(A) Thrombus in the left and right ventricular apices (arrows), overlying a white fibrous scar.
(B) Laminated thrombus in a
dilated abdominal aortic aneurysm (asterisks).
• Organization and recanalization.
4.15).
Postmortem clots can sometimes be mistaken for ante-
mortem venous thrombi.
Thrombi on heart valves are called vegetations, which may
be infected or sterile.
Thrombi accumulate additional platelets and
fibrin (discussed earlier).
• Embolization.
Thrombi dislodge and travel to other sites
in the vasculature (discussed later).
• Dissolution.
If unchecked, this may result in a mycotic aneurysm
(Chapter 11).
The clinical presenta-
tion depends on the involved site.
Venous Thrombosis (Phlebothrombosis).
Most venous
thrombi occur in the superficial or deep veins of the leg.
Superficial venous thrombi typically occur in the saphenous
veins in the setting of varicosities.
Such thrombi can cause
local congestion, swelling, pain, and tenderness, but rarely
embolize.
Regardless of the
specific clinical setting, advanced age also increases the risk
of DVT.
Arterial and Cardiac Thrombosis.
4.14B).
Both cardiac and
aortic mural thrombi are prone to embolization.
• Thrombosis causes tissue injury by local vascular occlusion or
by distal embolization.
DIC is discussed in greater detail along with other
bleeding diatheses in Chapter 14.
The vast majority of emboli are
dislodged thrombi, hence the term thromboembolism.
It is
somewhat more common in males than in females.
PE causes
about 100,000 deaths per year in the United States.
An
estimated 20% of individuals with PE die before or shortly
after a diagnosis is made.
In more than 95% of cases, PE
originates from leg DVT.
Hence the risk factors for PE are
the same as for DVT (see Table 4.2).
4.16).
• Most pulmonary emboli (60% to 80%) are clinically silent
because they are small.
• Multiple emboli over time may cause pulmonary hypertension
and right ventricular failure.
It
is fairly common, occurring in some 90% of individuals
with severe skeletal injuries (Fig.
4.17).
Fat embolism
syndrome is the term applied to the minority of patients
who become symptomatic.
Scuba and deep sea
divers, and underwater construction workers are all at risk.
Amniotic fluid embolism is an ominous complication
of labor and the immediate postpartum period.
4.18).
Figure 4.17 Bone marrow embolus in the pulmonary circulation.
The relatively uniform red
area on the right of the embolus is an early organizing thrombus.
Introduction of 300 to 500 mL of air at 100 mL/sec
may be fatal.
Entry of air in the pulmonary vasculature
does not merely block perfusion of downstream region.
Bubbles in the central nervous
system can cause mental impairment and even sudden onset
of coma.
• Red infarcts (Fig.
• White infarcts (see Fig.
4.19B).
In comparison,
in the lung hemorrhagic infarcts are the rule (see Fig.
4.19A).
(Courtesy
Dr.
Tissue infarction is a common and extremely important
cause of clinical illness.
Arterial thrombosis or arterial embolism underlies the
vast majority of infarctions.
(A) Hemorrhagic, roughly wedge-
shaped pulmonary red infarct.
• Tissue vulnerability to hypoxia.
Neurons undergo irreversible
damage when deprived of their blood supply for only
3 to 4 minutes.
• Hypoxemia.
Figure 4.20 Remote kidney infarct replaced by a large fibrotic scar.
The dominant histologic characteristic of infarction is ischemic
coagulative necrosis (Chapter 2).
Eventually a reparative response begins in the preserved
margins (Chapter 3).
However, most infarcts
are ultimately replaced by scar (Fig.
Factors That Influence Development of an Infarct.
• Rate of occlusion.
In both
of these forms of shock, acute vasodilation leads to
hypotension and tissue hypoperfusion.
Of these, 50% require treatment in
intensive care units.
Despite improvements in care, the mortality rate remains
around 50%.
4.21).
Markers of acute inflammation such
as C-reactive protein and procalcitonin are also elevated.
Additional details
are given in the text.
Current evidence suggests that both are triggered
simultaneously.
• Endothelial activation and injury.
Another
feature of sepsis is microvascular dysfunction.
These changes cause a mismatch in
oxygen needs and oxygen delivery.
• Induction of a procoagulant state.
Sepsis alters the expression of many factors so as to favor
coagulation.
4.10).
They also dampen fibrinolysis by increasing PAI-1 expres-
sion (see Fig.
4.10).
• Metabolic abnormalities.
Septic patients exhibit insulin
resistance and hyperglycemia.
• Organ dysfunction.
Mitochondrial damage resulting from oxidative stress
impairs oxygen use.
Thus, blood is shunted away from the skin to the
vital organs such as the heart and the brain.
With widespread tissue
hypoxia, vital organs are affected and begin to fail.
Myocardial
contractile function worsens, in part because of increased
NO synthesis.
• Shock of any form can lead to hypoxic tissue injury if not
corrected.
[An older but still useful
review of heart failure and fluid overload].
[An updated discussion of fibrinolysis and
its role in the regulation of coagulation].
[Advances in understanding the role
of tissue factor in coagulation].
[An excellent
review of the multiple functions of protein C].
Versteeg HH, Heemskerk JWM, Levi M et al: New fundamentals in
hemostasis, Physiol Rev 93:327, 2013.
[An update of several issues in
hemostasis].
Clin Appl Thromb Hemost
23:922, 2017.
[A short review on the central role of tissue factor in
coagulation].
[An exhaustive review of this common clinical
condition].
[An excellent clinical
and molecular discussion of genetic thrombophilic states].
Montagnana M, Lippi G, Danese: An overview of thrombophilia and
associated laboratory testing.
[A laboratory-oriented review of genetic and
acquired factors underlying thrombosis].
Prince M, Wenham T: Heparin-induced thrombocytopenia, Postgrad
Med J 94:453, 2018.
[A concise and up-to-date review of this serious clinical
disorder].
Nisio MD, van Es N, Buller H: Deep Vein thrombosis and pulmonary
embolism, Lancet 388, 2016.
[An excellent review of this important clinical
condition].
Clinical Features
The clinical manifestations of shock depend on the precipitat-
ing insult.
However, the cardiac, cerebral,
and pulmonary changes rapidly aggravate the situation.
Prognosis varies with the origin of shock and its duration.
[An excellent discussion of the pathogenesis
and clinical features of APS].
[An exhaustive review of an uncommon
but serious disorder].
Fukumoto LE, Fukomoto KD: Fat embolism syndrome, Nurs Clin North
Am 335, 2018.
[An excellent discussion of the pathophysiology and clinical
features of this disorder].
[A discussion of an uncommon syndrome with high
mortality].
Septic Shock
Cecconi M, Evans L, Levy M et al: Sepsis and septic shock, Lancet
392:75, 2018.
[A lucid and comprehensive review of septic shock].
Levi M, Poll TVD: Coagulation and sepsis, Thromb Res 149:38, 2017.
[A discussion of coagulopathy in sepsis].
Moskovitz JB, Levy ZD, Todd LS: Cardiogenic shock, Emerg Med Clin
North Am 645, 2015.
[A discussion of the pathophysiology of cardiogenic
shock].
[The emerging role of NETs in septic shock].
Pool R, Gomez H, Kellum JA: Mechanism of organ dysfunction in
sepsis, Crit Care Clin 34:63, 2018.
[An in-depth discussion of the multiple
mechanisms that contribute to organ dysfunction in sepsis].
Russell JA, Rush B, Boyd J: Pathophysiology of septic shock, Crit Care
Clin 34:43, 2017.
How many
more mutations remain hidden?
• Disorders related to mutations in single genes with large effects.
Here we build on that knowledge to discuss
the genetic basis of human diseases.
Genetic disorders are far more common than is widely
appreciated.
The lifetime frequency of genetic diseases is
estimated to be 670 per 1000.
A few important exceptions to this rule
are noted later.
• Chromosomal disorders.
These arise from structural or
numerical alteration in the autosomes and sex chromo-
somes.
Like monogenic disease, they are uncommon but
associated with high penetrance.
• Complex multigenic disorders.
These are far more common
than diseases in the previous two categories.
They are
caused by interactions between multiple variant forms
of genes and environmental factors.
Such variations in
genes are common within the population and are also
called polymorphisms.
Even normal
traits such as height and weight are governed by poly-
morphisms in several genes.
meaning of the sequence of the encoded protein, they
are often termed missense mutations.
5.1).
• Mutations within noncoding sequences.
Deleterious effects
may also result from mutations that do not involve the
exons.
Such is the case in certain forms of
hereditary anemias called thalassemias (Chapter 14).
Therefore translation cannot take place, and the gene
product is not synthesized.
• Deletions and insertions.
General principles relating to the effects of gene mutations
follow.
• Point mutations within coding sequences.
A point mutation
is a change in which a single base is substituted with a
different base.
Partial mRNA sequence of the β-globin chain of hemoglobin showing
codons for amino acids 38 to 40.
.
.
T ATC
Val
.
.
.
CTC GTG GTG ACC CCT T .
.
.
Val Thr Pro .
.
.
.
.
.
Leu
ABO A allele
Normal DNA GTT—.
.
.
F508
–– T—GGT
ATC
GTT
.
.
.
T —AT–
CF DNA .
.
.
—
lle————
Gly—
Val
lle
—
.
.
.
CTC GTG GT– ACC CCT T .
.
.
Because the deletion is a multiple of three, this is not a frameshift
mutation.
.
.
Leu Val Val Pro Leu .
.
.
5.2).
5.3 and 5.4).
• Alterations in protein-coding genes other than mutations.
As with
mutations, structural changes may occur in the germline
or be acquired in somatic tissues.
• Alterations in noncoding RNAs.
• Trinucleotide-repeat mutations.
Trinucleotide-repeat muta-
tions belong to a special category of genetic anomaly.
These mutations are characterized by amplification of
a sequence of three nucleotides.
In normal
populations the number of repeats is small, averaging
29.
To summarize, mutations can interfere with gene expres-
sion at various levels.
Transcription may be suppressed by
gene deletions and point mutations involving promoter
sequences.
Abnormal mRNA processing may result from
mutations affecting introns or splice junctions or both.
.
.
.
.
.– Arg
CGT
Normal HEXA allele
.
.
.
GAC .
.
.
ATA
TCT
ATC
CTA
TGC
– Arg –
Ile –
Ser –
Leu –
Ile –
Cys
CCC
Pro
TGA
Stop
C .
.
.
.
.
CGT
.
Tay-Sachs allele
.
.
.
This mutation is the major cause of Tay-Sachs disease in
Ashkenazi Jews.
These are discussed later in this
chapter.
It is beyond the scope of this book to review normal
human genetics.
Some fundamentals of DNA structure and
regulation of gene expressions were described in Chapter
1.
It is important here to clarify several commonly used
terms—hereditary, familial, and congenital.
Only some comments of medical relevance
are made.
About
80% to 85% of these mutations are familial.
The remainder
represent new mutations acquired de novo by an affected
individual.
Sickle cell anemia is caused by substitution of
normal hemoglobin (HbA) by hemoglobin S (HbS).
Histocompatibility and blood group antigens
are good examples of codominant inheritance.
Sickle
cell anemia is an example of pleiotropism.
Single-gene disorders
with nonclassic patterns of inheritance are described later.
Their siblings
are neither affected nor at increased risk for disease
development.
Many
new mutations seem to occur in germ cells of relatively
older fathers.
• Clinical features can be modified by variations in penetrance and
expressivity.
Some individuals inherit the mutant gene but
are phenotypically normal.
This is referred to as incomplete
penetrance.
Penetrance is expressed in mathematical terms.
Thus 50% penetrance indicates that 50% of those who
carry the gene express the trait.
2.
Table 5.1 lists common autosomal dominant disorders.
Many are discussed more logically in other chapters.
They occur when both alleles at
a given gene locus are mutated.
• Complete penetrance is common.
• Onset is frequently early in life.
• Many of the mutated genes encode enzymes.
In hetero-
zygotes, equal amounts of normal and defective enzyme
are synthesized.
Many others are discussed elsewhere in the text.
An illustrative condition
is glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Such red cells are at the same risk
for undergoing hemolysis as the red cells in hemizygous
males.
Most of the
X-linked conditions listed in Table 5.3 are covered
elsewhere in the text.
There are only a few X-linked dominant conditions.
They
are caused by dominant disease-associated alleles on the X
chromosome.
Vitamin D–
resistant rickets and Alport syndrome are examples of this
type of inheritance.
ensures that cells with half the usual complement of the
enzyme function normally.
Autosomal recessive disorders include almost all inborn
errors of metabolism.
The various consequences of enzyme
deficiencies are discussed later.
The more common of these
conditions are listed in Table 5.2.
Most are presented elsewhere;
a few prototypes are discussed later in this chapter.
X-Linked Disorders
All sex-linked disorders are X-linked, and almost all are
recessive.
X-linked recessive inheritance accounts for a small number
of well-defined clinical conditions.
Sons of heterozygous
women have, of course, one chance in two of receiving
the mutant gene.
Males and females are affected equally.
Female carriers usually
are protected because of random inactivation of one X
chromosome.
In either case, the consequence is a metabolic block.
Fig.
In this model the final product exerts feedback control
on enzyme 1.
M1, M2,
Products of a minor pathway.
of M1 and M2 also exists.
This special area of genetics, called pharma-
cogenetics, is of considerable clinical importance.
In some cases these genetic factors have a major impact
on drug sensitivity and adverse reactions.
Many are discussed
elsewhere in the text.
thus lead to an excess of M1 and M2.
If the end product
is a feedback inhibitor of the enzymes involved in the
early reactions (in Fig.
In some cases, transport is achieved by receptor-mediated
endocytosis.
Its prevalence is estimated to
be 1 in 5000.
Approximately 70% to 85% of cases are familial
and transmitted by autosomal dominant inheritance.
The
remainder are sporadic and arise from new mutations.
Each of these is discussed below.
• Fibrillin is the major component of microfibrils found in the
extracellular matrix (Chapter 1).
These fibrils provide a
scaffold on which tropoelastin is deposited to form elastic
fibers.
Most of these
are missense mutations that give rise to abnormal
fibrillin-1.
These can inhibit polymerization of fibrillin
fibers (dominant negative effect).
• TGF- β bioavailability.
It is
now established that fibrillin-1 controls the bioavailability
of TGF-β.
This schema is supported by two
sets of observations.
Similar
changes may affect the tricuspid and, rarely, the aortic valves.
This
genetic heterogeneity also poses formidable challenges in
the diagnosis of Marfan syndrome.
MORPHOLOGY
Skeletal abnormalities are the most striking feature of
Marfan syndrome.
Ocular changes take many forms.
Cardiovascular lesions are the most life-threatening features
of this disorder.
Unlike many other EDS subtypes, the skin
is not usually hyperextensible.
This is accom-
plished by N-terminal–specific and C-terminal–specific
peptidases.
Hence the mode of inheritance of EDSs encompasses
all three Mendelian patterns.
On the basis of clinical and
molecular characteristics, six variants of EDS have been
recognized.
These are listed in Table 5.5.
Although individu-
ally rare, the collective frequency of EDSs is 1 in 5000 births.
It is believed that most contortionists have one of the EDSs.
A predisposition to joint dislocation, however, is one of the
prices paid for this virtuosity.
The skin is extraordinarily
stretchable, extremely fragile, and easily bruised.
The basic defect in connective tissue
may lead to serious internal complications.
Affected patients have markedly reduced
levels of this enzyme.
To summarize, the common thread in EDSs is some
abnormality of collagen.
These disorders, however, are
extremely heterogeneous.
FH caused by LDL receptor mutations is one of the most
frequently occurring Mendelian disorders.
Myocardial
infarction may occur before age 20 years.
The chylomicron
remnants, rich in cholesterol, are then delivered to the liver.
The endogenous synthesis
of cholesterol and LDL begins in the liver (Fig.
5.6).
• The major tissues affected are the skeleton, eyes, and cardio-
vascular system.
Wound healing is poor.
Mutations in the LDL receptor gene (LDLR)
account for 80% to 85% of cases of FH.
The func-
tions of these genes in cholesterol metabolism are discussed
below.
ApoB-100, Apolipoprotein B-100 (ApoB);
HMG CoA, 3-hydroxy-3-methylglutaryl coenzyme A.
lipoprotein (VLDL) from the liver into the blood.
VLDL
particles are rich in triglycerides, but they contain lesser
amounts of cholesteryl esters.
In addition, they carry
apolipoproteins ApoB, ApoC, and ApoE on their surface.
ApoC
is lost, but ApoB and ApoE are retained.
After release from
the capillary endothelium, the IDL particles have one of two
fates.
In the liver cells, IDL is recycled to generate VLDL.
5.7).
Here the LDL
dissociates from the receptor, which is recycled to the surface.
The impact of mutations in these
genes is as follows:
• Mutations in LDLR gene.
5.6).
• Mutations in gene encoding ApoB.
This compromise in the binding of LDL particles
to its receptors increases serum LDL cholesterol.
• Activating mutation in the PCSK9 gene.
The molecular genetics of FH is extremely complex.
Each class is heterogeneous at the DNA level.
© 1990 by Annual Reviews.)
These can be classified into six groups (Fig.
5.8).
5.8).
Cholesterol also deposits along tendon
sheaths to produce xanthomas.
They contain a battery of hydrolytic enzymes, which
have two special properties.
First, they function in the acidic
milieu of the lysosomes.
the Golgi (Fig.
5.9).
The
cellular and molecular mechanisms of this linkage will be
discussed below.
The lysosomal enzymes catalyze the breakdown of a
variety of complex macromolecules.
5.10).
There are three general approaches to the treatment of
lysosomal storage diseases.
The most obvious is enzyme
replacement therapy, currently in use for several of these
diseases.
A more recent strategy is based on the
understanding of the molecular basis of enzyme deficiency.
Such molecular chaperone therapy is under active
investigation.
Such interconnectedness stems from
the multifunctionality of the lysosome.
Approximately 70 lysosomal storage diseases have been
identified.
Within each group are several entities,
each resulting from the deficiency of a specific enzyme.
• There is a tight linkage between autophagy, mitochondrial
functions, and lysosomes.
In particular, autophagy
is essential for turnover of mitochondria by a process
termed mitophagy.
This serves as a quality control system
whereby dysfunctional mitochondria are degraded.
Only a few of the more common conditions are
considered here.
The underlying enzyme defect, however,
is different for each.
Sufficient functional enzyme can then be rescued to ame-
liorate the effects of the inborn error.
Antenatal diagnosis
and carrier detection are possible by enzyme assays and
DNA-based analysis.
Patients usually survive into
adulthood.
As with Tay-Sachs disease, Niemann-Pick disease
types A and B are common in Ashkenazi Jews.
5.11A).
5.11B).
A B
Figure 5.11 Ganglion cells in Tay-Sachs disease.
(A) Under the light microscope, a large neuron has obvious lipid vacuolation.
Part of the nucleus is shown above.
(A, Courtesy Dr.
Individuals affected with types A and B as well as
carriers can be detected by DNA analysis.
NPC1 is membrane bound, whereas NPC2 is soluble.
Both
are involved in the transport of free cholesterol from the
lysosomes to the cytoplasm.
Niemann-Pick disease type C
is clinically heterogeneous.
It is the most common lysosomal storage
disorder.
Splenic and skeletal involvements dominate this
pattern of the disease.
It is found principally in Jews of
European stock.
Individuals with this disorder have
reduced but detectable levels of glucocerebrosidase
activity.
Longevity is shortened, but not markedly.
• Type II, or acute neuronopathic Gaucher disease, is the
infantile acute cerebral pattern.
This form has no predilec-
tion for Jews.
In these patients there is virtually no
detectable glucocerebrosidase activity in the tissues.
• A third pattern, type III, is intermediate between types
I and II.
5.12).
The neuronal involvement is diffuse, affecting all parts of the
nervous system.
Infants typically have a protuberant abdomen
because of hepatosplenomegaly.
Death
occurs usually within the first or second year of life.
Figure 5.12 Niemann-Pick disease in liver.
The hepatocytes and Kupffer
cells have a foamy, vacuolated appearance due to deposition of lipids.
(Courtesy Dr.
In type I disease, the spleen is enlarged, sometimes up
to 10 kg.
The lymphadenopathy is mild to moderate and is
body-wide.
Bone destruction occurs due to the secretion of cytokines by
activated macrophages.
Similar cells may be found
in both the alveolar septa and the air spaces in the lung.
5.13).
Periodic acid–Schiff staining is
usually intensely positive.
DNA testing is also available in select
populations.
Clinical Features
The course of Gaucher disease depends on the clinical
subtype.
Most commonly there is pancytopenia or thrombocytopenia
secondary to hypersplenism.
Pathologic fractures and bone
pain occur if there has been extensive expansion of the
marrow space.
Although the disease is progressive in adults,
it is compatible with long life.
In principle, heterozygotes can be identified by detec-
tion of mutations.
(A) Wright stain; (B) hematoxylin and eosin.
(Courtesy Dr.
However, such therapy is extremely expensive.
Substrate reduction therapy with
inhibitors of glucosylceramide synthetase is also being
evaluated.
They are abundant in
extracellular matrix, joint fluid, and connective tissue.
coronary arteries, and lesions in the brain are common
threads that run through all the MPSs.
Thus myocardial infarction and cardiac
decompensation are important causes of death.
Hurler syndrome, also
called MPS I-H, results from a deficiency of α-L-iduronidase.
It is one of the most severe forms of MPS.
Affected children
appear normal at birth but develop hepatosplenomegaly
by age 6 to 24 months.
Death occurs by age 6 to 10 years and
is often due to cardiovascular complications.
• Niemann-Pick disease types A and B are caused by a deficiency
of sphingomyelinase.
In type B, neuronal damage is not present.
Types II and III are
characterized by variable neuronal involvement.
Gaucher disease
has a strong association with Parkinson disease.
Hunter syndrome is associated with a milder clinical course.
5.14).
Glycogen is a storage form of glucose.
This
can be further degraded only by the debranching enzyme.
Asterisks mark the enzyme deficiencies associated with glycogen storage diseases.
Types V and VI result from deficiencies of muscle and liver
phosphorylases, respectively.
(Modified from Hers H, et al: Glycogen storage diseases.
On the
basis of pathophysiology glycogenoses can be divided into
three major subgroups (Table 5.7).
• Hepatic forms.
The liver is a key player in glycogen metabo-
lism.
5.15).
5.15).
• Myopathic forms.
5.16).
They are associated with glycogen storage in many
organs and death early in life.
5.16).
The liver is enlarged, and patients have hypoglycemia.
This subject is discussed
in Chapter 7.
Specific forms of familial tumors are described
in various chapters.
(B) Effects of an inherited deficiency of hepatic enzymes involved
in glycogen metabolism.
A B
Figure 5.16 Pompe disease (glycogen storage disease type II).
(A) Normal myocardium with abundant eosinophilic cytoplasm.
(Courtesy Dr.
This
is best illustrated in autoimmune diseases (Chapter 6).
For example,
type 2 diabetes has many of the features of a multifactorial
disorder.
It is well recognized that individuals often first
manifest this disease after weight gain.
Thus, obesity as
well as other environmental influences unmask the dia-
betic genetic trait.
Nutritional influences may cause even
monozygous twins to achieve different heights.
A culturally
deprived child cannot achieve his or her full intellectual
capacity.
Assigning a disease to this mode of inheritance must be
done with caution.
The study of chromosomes—karyotyping—is the basic tool
of the cytogeneticist.
The one most commonly used involves a Giemsa
stain and is hence called G banding.
A normal male karyotype
with G banding is illustrated in Fig.
5.17.
With standard G
banding, approximately 400 to 800 bands per haploid set
can be detected.
The resolution obtained by banding can be
markedly improved by obtaining the cells in prophase.
(Courtesy Dr.
For example, a male with
trisomy 21 is designated 47,XY, +21.
The regions are numbered (e.g., 1, 2, 3)
from the centromere outward.
5.17).
The normal chromosome complement is expressed as 46,XX
for females and 46,XY for males.
Any exact multiple of the
haploid number of chromosomes (23) is called euploid.
The usual causes for
aneuploidy are nondisjunction and anaphase lag.
The result is one
normal cell and one cell with monosomy.
Mosaicism affecting the sex chromosomes is relatively
common.
Autosomal mosaicism seems to be much less common
than that involving the sex chromosomes.
Deletion refers to loss of a portion of a chromosome (Fig.
5.18).
Most deletions are interstitial, but rarely terminal
deletions may occur.
One can specify in which regions and
at what bands the breaks have occurred.
The deleted end of the retained chromosome is
protected by acquiring telomeric sequences.
A ring chromosome is a special form of deletion.
5.18).
If significant
genetic material is lost, phenotypic abnormalities result.
This might be expressed as 46,XY,r(14).
5.18).
An
inversion involving only one arm of the chromosome is
known as paracentric.
If the breaks are on opposite sides of
the centromere, it is known as pericentric.
Inversions are
often fully compatible with normal development.
5.18).
An isochromosome
has morphologically identical genetic information in both
arms.
with monosomy for genes on the short arm of X and with
trisomy for genes on the long arm of X.
In a translocation, a segment of one chromosome is
transferred to another (see Fig.
5.18).
A balanced
translocation carrier, however, is at increased risk for produc-
ing abnormal gametes.
Typically the breaks occur close to the
centromeres of each chromosome.
Transfer of the segments
then leads to one very large chromosome and one extremely
small one.
Usually the small product is lost (see Fig.
Even in live-born infants the
frequency is approximately 0.5% to 1.0%.
Hence we focus attention on
those few that are most common.
In the United States the incidence in newborns is about 1
in 700.
Approximately 95% of affected individuals have
trisomy 21, so their chromosome count is 47.
FISH with
chromosome 21–specific probes reveals the extra copy of
chromosome 21 in such cases (Fig.
5.19).
The parents
of such children have a normal karyotype and are normal
in all respects.
Maternal age has a strong influence on the incidence
of trisomy 21.
5.20)—are usually readily evident, even at birth.
Down syndrome is a leading cause of severe intellectual
disability.
• Approximately 40% of the patients have congenital heart disease.
Cardiac
problems are responsible for the majority of the deaths
in infancy and early childhood.
The latter, most commonly,
is acute megakaryoblastic leukemia.
Currently the median age at death is 47 years (up from 25
years in 1983).
A
sampling of some of the observations follows.
• Gene dosage.
The majority of the protein coding genes
mapped to chromosome 21 are overexpressed.
Included
among these is the gene for amyloid-beta precursor
protein (APP).
• Mitochondrial dysfunction.
• Noncoding RNAs.
(Courtesy Dr.
Stuart Schwartz, Department of Pathology, University of
Chicago, Chicago, IL.)
older than age 45.
Symptoms in such cases are variable and milder, depending
on the proportion of abnormal cells.
Clearly, in cases of
translocation or mosaic Down syndrome, maternal age is
of no importance.
Much progress is being made in the molecular diagnosis
of Down syndrome prenatally.
Most laboratories require
confirmation of a positive screening test with conventional
karyotyping.
As noted in Fig.
5.20,
they share several karyotypic and clinical features with
trisomy 21.
As in Down syndrome, an association with increased
maternal age is also noted.
In contrast to trisomy 21, however,
the malformations are much more severe and wide ranging.
As a result, only rarely do infants survive beyond the first
year of life.
Most succumb within a few weeks to months.
In a very small number of cases
there is a deletion of 10p13-14.
Less frequently, these patients also have
immunodeficiency.
In addition, attention-deficit/
hyperactivity disorder is seen in 30% to 35% of affected
children.
5.21).
The molecular basis of this syndrome is not fully under-
stood.
The deleted region is large (approximately 1.5 Mb)
and includes 30 to 40 genes.
Approximately 30 candidate genes have been mapped
to the deleted region.
The 22q11.2 probe is in red, and the control probe,
localized to 22q, is in green.
(Courtesy Dr.
Thus, it seems that both X chromosomes
are required for normal growth as well as oogenesis.
For this reason
they are called pseudoautosomal regions.
These genes also
escape X inactivation.
For quite some time this was considered to be
the only gene of significance on the Y chromosome.
All of these are
believed to be testis-specific and are involved in spermato-
genesis.
In keeping with this, all Y chromosome deletions
are associated with azoospermia.
By comparison, the X
chromosome has 840 coding genes.
The following features
are common to all sex chromosome disorders.
The incidence of this condition is
reported to be approximately 1 in 660 live male births.
These features
are discussed briefly in relation to sex chromosomal
disorders.
In 1961, Mary Lyon outlined the idea of X-inactivation,
now commonly known as the Lyon hypothesis.
The XIST allele is switched off in the
active X chromosome.
Gynecomastia may be present.
Patients with Klinefelter syndrome develop
several comorbid conditions.
In addition there is a
higher prevalence of atrial and ventricular septal defects.
There is also an increased incidence of osteoporosis and
fractures due to sex hormonal imbalance.
Klinefelter syndrome is an important genetic cause of
reduced spermatogenesis and male infertility.
In others,
apparently normal tubules are interspersed with atrophic
tubules.
Mean plasma estradiol levels are elevated by an as yet
unknown mechanism.
The ratio of estrogens and testosterone
determines the degree of feminization in individual cases.
Classic Klinefelter syndrome is associated with a 47,XXY
karyotype (90% of cases).
Maternal and paternal
nondisjunction at the first meiotic division is roughly equally
involved.
Advanced maternal
age (>40 years) is a risk factor.
Why
then, do the patients with this disorder have hypogonadism
and associated features?
• One pathogenic mechanism is related to uneven dosage
compensation during X inactivation.
It is now known that
about 35% of the X-linked genes escape inactivation.
A similar mechanism
may also dictate some somatic features.
This implies
that the supernumerary X chromosome can regulate gene
expression on autosomes.
• Approximately 57% are missing an entire X chromosome,
resulting in a 45,X karyotype.
The latter may
have an almost normal appearance and may present only
with primary amenorrhea.
A very small number of
patients are able to conceive.
These patients are at a higher risk for development of a
gonadal tumor (gonadoblastoma).
Congenital heart disease is
also common, affecting 25% to 50% of patients.
Approximately 5% of young women initially
diagnosed with coarctation of aorta have Turner syndrome.
The principal clinical features in adolescents and adults are
illustrated in Fig.
5.22.
At puberty there is failure to develop
normal secondary sex characteristics.
The genitalia remain
infantile, breast development is inadequate, and there is little
pubic hair.
Some have
full-fledged metabolic syndrome.
During normal fetal
development, ovaries contain as many as 7 million oocytes.
Among the genes involved in the Turner
phenotype is the SHOX gene at Xp22.33.
Thus
both normal males and normal females have two copies of
this gene.
Haploinsufficiency of SHOX in Turner syndrome
is believed to give rise to short stature.
It is also expressed in the first
and second pharyngeal arches.
Clearly several other genes located on the
short arm of X chromosome are involved.
Growth hormone
and estradiol are used to treat Turner syndrome with a
reasonable degree of success.
Genetic sex is
determined by the presence or absence of a Y chromosome.
Gonadal sex is based on the histologic
characteristics of the gonads.
Ductal sex depends on the
presence of derivatives of the müllerian or wolffian ducts.
Phenotypic, or genital, sex is based on the appearance of the
external genitalia.
The term true hermaphrodite implies the presence of
both ovarian and testicular tissue.
It is the
most common cause of male sterility.
This group of disorders can be classified
into four categories.
All the disorders discovered so far are associated
with neurodegenerative changes.
Some general principles
apply to these diseases.
• The proclivity to expand depends strongly on the sex of
the transmitting parent.
5.23).
Much more needs to be learned before therapeutic
strategies can be developed.
UTR, Untranslated region.
FXS has a frequency of 1 in 1550 for affected males and
1 in 8000 for affected females.
5.24).
Males with FXS have marked intellectual disability.
The latter two affect 50% to 75% of males with
FXS.
As with other X-linked diseases, FXS affects males pre-
dominantly.
5.25).
• Risk of phenotypic effects: Risk depends on the position of
the individual in the pedigree.
In
the normal population, the number of CGG repeats is small,
ranging from 6 to 55 (average, 29).
The presence and severity
of clinical symptoms is related to the amplification of the
CGG repeats.
Thus, normal transmitting males and carrier
females carry 55 to 200 CGG repeats.
Expansions of this
size are called premutations.
In contrast, patients with FXS
Figure 5.24 Fragile X seen as discontinuity of staining.
(Courtesy Dr.
Note that in the first generation all sons are normal and all females are carriers.
However, only 50% of
females who inherit the full mutation are affected and only mildly.
(Courtesy Dr.
How this process takes place is quite
peculiar.
Carrier males transmit the repeats to their progeny
with small changes in repeat number.
Why only 50% of the females with the full mutation are
clinically affected is not clear.
The resulting absence
of FMRP is believed to cause the phenotypic changes.
5.26).
FRMP is a translation regulator.
Thus a reduction
in FMRP in FXS results in increased translation of the
bound mRNAs at synapses.
The pathogenesis of fragile X–associated primary
ovarian insufficiency is less well understood.
Aggregates
containing FMR1 mRNA have been detected in granulosa
cells and ovarian stromal cells.
Perhaps these aggregates
cause premature death of ovarian follicles.
Most such mutations produce neurodegenerative
disorders.
• In the normal population, there are about 29 to 55 CGG
repeats in the FMR1 gene.
When full mutations are transmitted to progeny, FXS occurs.
Synaptic
plasticity is essential for learning and memory.
This condition
is called fragile X–associated primary ovarian failure.
Affected
women have menstrual irregularities and decreased fertility.
They develop menopause approximately 5 years earlier than
controls.
How do premutations cause disease?
Several mitochondrial genes exist, however, that
are inherited in quite a different manner.
A feature unique
to mtDNA is maternal inheritance.
Hence the mtDNA complement of the zygote is derived
entirely from the ovum.
5.27).
Several other features apply to mitochondrial inheritance.
The remaining 13 genes encode subunits of the respiratory
chain enzymes.
tissue before oxidative dysfunction gives rise to disease.
Therefore the expres-
sion of disorders resulting from mutations in mtDNA is
quite variable.
Leber hereditary optic neuropathy is a
prototype of this type of disorder.
It is a neurodegenerative
disease that manifests as progressive bilateral loss of central
vision.
Visual impairment is first noted between ages 15
and 35, leading eventually to blindness.
These differences result from an epigenetic process
called imprinting.
In most cases, imprinting selectively
inactivates either the maternal or the paternal allele.
Other mecha-
nisms include histone H4 deacetylation and methylation
(Chapter 1).
The exact number of imprinted genes
is not known; estimates range from 200 to 600.
They are described next.
In most cases the breakpoints are the same, causing
a 5-Mb deletion.
It is striking that in all cases the deletion affects
the paternally derived chromosome 15.
The molecular basis of these two syndromes lies in the
process of genomic imprinting (Fig.
5.28).
Three mechanisms
are involved.
• Deletions.
When these are lost as a
result of a deletion, the person develops Prader-Willi
syndrome.
Only the maternally derived allele
of this gene is normally active.
gene on chromosome 15 gives rise to the Angelman
syndrome.
Deletions account for about 70% cases.
• Uniparental disomy.
Inheritance of
both chromosomes of a pair from one parent is called
uniparental disomy.
This is
the second most common mechanism, responsible for
20% to 25% cases.
• Defective imprinting.
In a small minority of patients (1%
to 4%), there is an imprinting defect.
The genetic basis of these two imprinting disorders is
now being unraveled.
Absence of UBE3A inhibits synapse formation
and synaptic plasticity.
The imprinting is tissue-specific
in that UBE3A is expressed from both alleles in most
tissues.
• In contrast to Angelman syndrome, no single gene has
been implicated in Prader-Willi syndrome.
These include the SNORP family of genes that
encode small nucleolar RNAs.
The importance of imprinting is not restricted to rare chro-
mosomal disorders.
For
such genes, only one functional copy exists in the individual.
These
patients have intellectual disability, ataxia, seizures, and inap-
propriate laughter.
comprehensive NGS-based approaches.
Proper
test design requires careful consideration of these factors.
This is not always the case,
however.
This clearly violates the laws
of Mendelian inheritance.
Studies indicate that gonadal
mosaicism may be responsible for such unusual pedigrees.
Prenatal testing should be offered for all fetuses at risk for
a cytogenetic abnormality.
It is most
commonly performed on peripheral blood DNA and is
targeted based on clinical suspicion.
The technical approaches are the same
as those used for germline Mendelian disorders.
Many options exist for subsequent
analysis, each with different strengths and weaknesses.
A
few of the more common options are described below:
• Sanger sequencing.
• Next-generation sequencing (NGS).
• Single-base primer extension.
The relative
amounts of normal/variant fluorescence are then detected
(Fig.
5.29).
• Restriction fragment length analysis.
As discussed
earlier, large expansions are not uncommon in FXS.
• Real-time PCR.
Such genomic-scale altera-
tions can be studied using a variety of hybridization-based
techniques.
• Amplicon length analysis.
Fig.
5.30 reveals how PCR analysis can be used
to detect this mutation.
It is used to detect numeric abnor-
malities of chromosomes (aneuploidy) (see Fig.
5.19), subtle
microdeletions (see Fig.
• Array-based comparative genomic hybridization.
• Single nucleotide polymorphism genotyping arrays.
5.31).
Genomic DNA is labeled and hybridized to
an array containing potentially millions of probe spots.
Copy number is determined by overall intensity, and genotype is determined by allelic ratio.
The
example shown is the p arm of chromosome 12 in a patient with pediatric leukemia.
Notably, unlike CGH arrays, SNP
arrays can identify loss of heterozygosity.
Microsatellites are usually less than
1 kb and are characterized by a repeat size of 2 to 6 bp.
Fig.
Special techniques are needed to detect DNA methylation.
Methylated
cytosines are protected from modification and remain
unchanged.
Nonetheless,
RNA analysis is critical in several areas of molecular diag-
nostics.
5.33).
• Spatial separation.
The specifics of this process are
platform-dependent.
• Local amplification.
Parallel sequencing.
Sequence reads
from NGS instruments are generally short, less than
500 bp.
However, it is worth describing the basic steps
necessary to process this type of data.
• Alignment.
• Variant calling.
• Variant annotation and interpretation.
Once completed by the clinical laboratory,
the annotated data are ready for reporting.
Most current clinical laboratory NGS
tests fall in this category.
In cancer testing, gene panels are widely used to perform
detailed tumor profiling.
• Whole-exome sequencing (WES).
WES is also used
in oncology to perform a very broad analysis, mostly in
the research setting.
• Whole-genome sequencing (WGS).
WGS is the most com-
prehensive type of DNA analysis that can be performed
on an individual.
Continuing technologic
advances may even extend the applications further.
[A nice review
of Marfan syndrome by a pioneer in the field].
Salik I, Rawla P: Marfan syndrome.
[Updated 2019 Feb 28].
In StatPearls
[internet], Treasure Island, FL, 2019, StatPearls Publishing.
Available
from: https://www.ncbi.nlm.nih.gov/books/NBK537339/?report=
classic.
[An up-to-date and well-written article on the clinical and molecular
features of Marfan syndrome].
Tinkle B, Castori M, Berglund B et al: Hypermobile Ehlers-Danlos
syndrome (a.k.a.
[Clinically
oriented review of the most common form of Ehlers-Danlos syndrome].
[A good accounting of low-density
lipoprotein metabolism in familial hypercholesterolemia].
[The various less
well-known genetic causes of familial hypercholesterolemia are discussed].
[A good and easy-to-
follow overview of familial hypercholesterolemia].
Sabatine MS: PCSK9 inhibitors: clinical evidence and implementation,
Nat Rev Cardiol 16:155, 2019.
[A discussion of lysosomal storage disorders
and neurodegenerative diseases].
[A review of ganglioside
metabolism and pathogenesis of Tay-Sachs disease].
Ferreiraa CR, Gahlc WA: Lysosomal storage diseases, Transl Sci Rare
Dis 2(1):2017.
[An exhaustive description of all the lysosomal storage
disorders].
[A detailed discussion of these disorders in
the pediatric population].
[This article discusses details of Pompe
disease].
[Current approaches for the treatment
of lysosomal storage disorders].
Schuchman EH, Desnick RJ: Types A and B Niemann-Pick disease,
Mol Genet Metab 120(1–2):27, 2017.
[This article discusses details of types
A and B Niemann-Pick disease].
[This article discusses details of Gaucher disease].
[An excellent discussion of treatment of genetic
disorders based on molecular pathogenesis].
[A discussion of the causes of
Down syndrome due to imbalance in gene expression].
[Utility of prenatal noninvasive testing of trisomies].
Zamponi Z, Helguera PR: The shape of mitochondrial dysfunction in
Down syndrome.
Dev Neurobiol Epub 2019.
[A discussion of emerging
evidence for the role of mitochondrial dysfunction in Down syndrome].
[An exhaustive and updated review
of pathogenesis of Klinefelter syndrome].
Skuse D, Printzlau F, Wolstencroft J: Sex chromosomal aneuploidies.
In Geschwind DH, Paulson HL, Klein C, editors: Handbook of clinical
neurology, 2018, p 147.
(3rd series) Neurogenetics, Part 1 355, [An
excellent overview of sex chromosomal disorders].
[A discussion of
the loss of synaptic plasticity in the pathogenesis of fragile X syndrome].
[A well-
balanced discussion of the genetic basis of fragile X syndrome and related
disorders].
[A
succinct update on the molecular basis of fragile X syndrome and related
conditions].
[An excellent up-to-date review].
[A well-written review of Prader-Willi syndrome].
But the immune
system is itself capable of causing tissue injury and disease.
This chapter is devoted to diseases caused by too little or
too much immunologic reactivity.
If microbes breach epithelial boundaries, other
defense mechanisms come into play.
They capture
protein antigens and display peptides for recognition by
T lymphocytes.
The mechanisms of immunity fall into two broad
categories (Fig.
6.1).
It develops more
slowly than innate immunity, but is even more powerful
in combating infections.
By convention, the term immune
response usually refers to adaptive immunity.
The receptors and components of innate
immunity have evolved to serve these purposes.
They are
thought to be sources of inflammatory cytokines during
early phases of immune reactions.
• Other cell types.
Several other cell types can sense and
react to microbes.
• Plasma proteins.
In addition to these cells, several soluble
proteins play important roles in innate immunity.
These microbial structures are
called pathogen-associated molecular patterns.
6.2).
Several
classes of these receptors have been identified.
Toll-like receptors.
A family of related proteins was
later shown to be essential for host defense against microbes.
Mammals have 10 TLRs, each recognizing a different set of
microbial molecules.
The TLRs are present in the plasma
membrane and endosomal vesicles (see Fig.
6.2).
RIG,
retinoic acid-inducible gene.
stimulate the production of the antiviral cytokines, type I
interferons.
NOD-like receptors and the inflammasome.
NOD-like receptors
(NLRs) are cytosolic receptors named after the founding
member NOD-2.
6.3).
As
discussed later, IL-1 is a mediator of inflammation that
recruits leukocytes and induces fever.
NK cells make up approximately 5%
to 10% of peripheral blood lymphocytes.
This phenomenon
is known as antibody-dependent cellular cytotoxicity
(ADCC).
6.4).
Thus, these receptors
enable NK cells to recognize damaged or infected cells.
The inhibitory
receptors prevent NK cells from killing normal cells.
Reactions of Innate Immunity
The innate immune system provides host defense by two
main reactions.
• Inflammation.
The recruited
leukocytes destroy microbes and ingest and eliminate
damaged cells.
The innate immune response also triggers
the repair of damaged tissues.
These processes are
described in Chapter 3.
• Antiviral defense.
ATP, Adenosine triphosphate; IL, interleukin; TLR, Toll-like
receptor.
which result from T and B lymphocyte reactions against self
antigens).
The autoinflammatory syndromes respond very
well to treatment with IL-1 antagonists.
The inflammasome
pathway may also play a role in many common disorders.
Other cellular receptors for microbial products.
These receptors stimulate
the production of antiviral cytokines.
The major classes of lymphocytes and their functions in
adaptive immunity are illustrated in Fig.
6.5.
The process of lymphocyte differentia-
tion into effector and memory cells is summarized later.
We start with a consideration of the diversity of T and B
lymphocytes.
This
fundamental concept is called clonal selection.
The result
is that NK cells are activated and the infected cells are killed.
NK cells recognize virus-infected cells, as described
above.
The
nature of some of these signals is described later.
Innate immunity, unlike adaptive immunity, does not
have memory or fine antigen specificity.
B and T lymphocytes are the cells of adaptive immunity.
NK cells are discussed earlier.
encoded in the genome.
T Lymphocytes
There are three major populations of T cells, which serve
distinct functions.
Each T cell recognizes
a specific cell-bound antigen by means of an antigen-specific
TCR.
6.6), each having a variable (antigen-
binding) region and a constant region.
6.6).
The CD3 and ζ proteins are invariant (i.e.,
identical) in all T cells.
Together with the TCR, these proteins
form the TCR complex.
However, the functions of γδ T cells are not established.
The functions of NK-T cells are also not
well defined.
These include CD4, CD8, CD28, and integrins.
CD4 and CD8 are expressed on two mutually exclusive
subsets of αβ T cells.
Normally, approximately 60% of mature
T cells are CD4+, and about 30% are CD8+.
Most
CD8+ cells function as CTLs that destroy host cells harboring
microbes.
CD4 and CD8 serve as coreceptors in T-cell activa-
tion.
Integrins are
adhesion molecules that promote the attachment of T-cells
to APCs.
B lymphocytes develop from precursors in the bone marrow.
B cells recognize antigen via the B-cell
antigen receptor complex.
6.7).
CD4 and CD28 are also
involved in T-cell activation.
Immature DCs within the
epidermis are called Langerhans cells.
Thus, macrophages function as antigen-presenting
cells in T-cell activation.
• Macrophages also participate in the effector phase of humoral
immunity.
Macrophages efficiently phagocytose and
destroy microbes that are opsonized (coated) by IgG
or C3b.
Primary Lymphoid Organs.
These organs are described
in Chapter 13.
Secondary Lymphoid Organs.
CD21 is a receptor for a
complement component that also promotes B-cell activation.
(Courtesy Dr.
B cells also express several other molecules that are essential
for their responses.
CR2 is also used by Epstein-Barr virus (EBV) as a
receptor to enter and infect B cells.
Several features of DCs
account for their key role in antigen presentation.
6.8).
Blood entering the spleen flows through a network of
sinusoids lined by macrophages and DCs.
They respond to
antigens that enter through breaches in the epithelium.
6.8).
The T lymphocytes are
concentrated in the paracortex, adjacent to the follicles.
(A) The histology of a lymph
node, with an outer cortex containing follicles and an inner medulla.
(Courtesy Drs.
The genes
encoding HLA molecules are clustered on a small segment
of chromosome 6 (Fig.
6.9).
This, as we see subsequently, constitutes
a formidable barrier in organ transplantation.
• Class I MHC molecules are expressed on all nucleated cells
and platelets.
6.9).
The extracellular region of the α chain is divided
into three domains: α1, α2, and α3.
The α1 and α2 domains
form a cleft, or groove, where peptides bind.
Peptide-loaded MHC
A.
(A) The location of genes in the HLA complex.
The relative
locations, sizes, and distances between genes are not to scale.
(B) Schematic diagrams and crystal structures of class I and
class II HLA molecules.
(Crystal structures are courtesy Dr.
P.
6.9).
The combination of HLA alleles in each individual is
called the HLA haplotype.
MHC molecules play several key roles in regulating T
cell–mediated immune responses.
Cytokines contribute to different types of immune
responses.
These cytokines include TNF, IL-1, IL-12,
type I IFNs, IFN-γ, and chemokines (Chapter 3).
Some cytokines serve mainly to limit and terminate
immune responses; these include TGF-β and IL-10.
They are produced by marrow stromal cells,
T lymphocytes, macrophages, and other cells.
Examples
include GM-CSF and other CSFs, and IL-3.
The knowledge gained about cytokines has numerous
practical therapeutic applications.
Microbes and their protein
antigens are captured by DCs that are resident in epithelia
and tissues.
These cells carry their antigenic cargo to draining
lymph nodes (Fig.
6.10).
6.6).
6.10).
6.11).
Cells of the Th1
subset secrete the cytokine IFN-γ, which is a potent
macrophage activator.
Naïve T cells recognize MHC-associated
peptide antigens displayed on dendritic cells.
CD8+ cytotoxic T lymphocytes (CTLs) kill infected cells harboring microbes in the cytoplasm.
APC,
Antigen-presenting cell.
pathway of macrophage activation, which is associated with
tissue repair and fibrosis (Chapter 3).
By
destroying the infected cells, CTLs eliminate the reservoirs
of infection.
6.12).
Antibody
responses to most protein antigens require T cell help and are
said to be T-dependent.
These populations may be capable of converting from one
to another.
Some activated T cells produce multiple cytokines and do not fall into a distinct subset.
Polysaccharides and lipids stimulate secretion mainly of
IgM antibody.
Helper T cells also
stimulate the production of antibodies with high affinities for
the antigen.
This process, called affinity maturation, improves
the quality of the humoral immune response.
The humoral immune response combats microbes in many
ways (see Fig.
6.12).
Antibodies bind to microbes and prevent
them from infecting cells, thus neutralizing the microbes.
Some antibodies serve special roles at particular
anatomic sites.
Most circulating IgG antibodies have half-lives of about
3 weeks.
Generation of memory cells underlies the effectiveness
of vaccination.
B cells are
activated to become plasma cells, which secrete antibodies.
Innate immune reactions
often manifest as inflammation.
Innate immunity, unlike adaptive
immunity, does not have fine antigen specificity or memory.
Immune
responses against self, or autologous, antigens, cause
autoimmune diseases.
We will return to this concept when
we consider autoimmunity.
This is followed by diseases caused by a defective immune
system, called immunodeficiency diseases.
Hypersensitivity implies an excessive or
harmful reaction to an antigen.
There are several important
general features of hypersensitivity disorders.
(A) Kinetics of the immediate and late-phase reactions.
(Courtesy Dr.
Antibodies may also interfere with cellular
functions and cause disease without tissue injury.
These reactions
are often called allergy, and the antigens that elicit them are
allergens.
Immediate hypersensitivity may occur as a sys-
temic disorder or as a local reaction.
Sometimes, within minutes
the patient goes into a state of shock, which may be fatal.
Local reactions are diverse and vary depending on the portal
of entry of the allergen.
Many local type I hypersensitivity reactions have two
well-defined phases (Fig.
6.13).
These Th2-mediated disorders show a
characteristic sequence of events (Fig.
6.14), described next.
IL-13
enhances IgE production and acts on epithelial cells to
stimulate mucus secretion.
Over time,
the Th2 cells become the dominant contributors to the local
cytokine response.
Mast cells are bone marrow–derived cells
that are widely distributed in the tissues.
The granules
also contain acidic proteoglycans that bind basic dyes such
as toluidine blue.
Similar to other granulocytes, basophils can be recruited
to inflammatory sites.
In the first step of activation,
the antigen binds to the IgE antibodies on the mast cell
surface.
• Leukotrienes.
Leukotrienes C4 and D4 are the most potent
vasoactive and spasmogenic agents known.
Leukotriene B4 is highly che-
motactic for neutrophils, eosinophils, and monocytes.
• Prostaglandin D2.
This is the most abundant mediator
produced in mast cells by the cyclooxygenase pathway.
It causes intense bronchospasm and increases mucus
secretion.
• Platelet-activating factor (PAF).
Its role in imme-
diate hypersensitivity reactions is not well established.
Cytokines.
Eosinophils are
often an abundant leukocyte population in these reactions
(see Fig.
6.13C).
The Th2 cytokine IL-5 is the most potent eosinophil-
activating cytokine known.
PAF, Platelet-activating factor.
de novo synthesis and release of additional mediators
including lipid products and cytokines (Fig.
6.15).
Granule contents.
The most important mast cell–derived
amine is histamine (Chapter 3).
• Enzymes.
• Proteoglycans.
These include heparin, a well-known
anticoagulant, and chondroitin sulfate.
The proteoglycans
serve to package and store the amines in the granules.
Lipid mediators.
The major lipid mediators are arachidonic
acid–derived products (Chapter 3).
A propensity to develop immediate
hypersensitivity reactions is called atopy.
A positive
family history of allergy is found in 50% of atopic individuals.
How the disease-
associated polymorphisms influence the development of
allergies is not known.
Environmental factors are also important in the develop-
ment of allergic diseases.
Thus, paradoxically,
improved hygiene in early childhood may increase allergies
later in life.
This hypothesis, however, is difficult to prove,
and the underlying mechanisms are not defined.
These reactions can lead
to a wide spectrum of injury and clinical manifestations
(Table 6.2).
Laryngeal edema results
in hoarseness and further compromises breathing.
The risk of anaphylaxis must be borne in
mind when certain therapeutic agents are administered.
6.16A).
This mechanism is probably effective in destroying only
cells and microbes with thin cell walls.
The antibody-dependent
mechanisms that cause tissue injury and disease are illus-
trated in Fig.
6.16 and described next.
These reactions are
the cause of several important diseases (Table 6.3).
A.
(A) Opsonization of cells by antibodies and complement components and ingestion by phagocytes.
(C) Antireceptor antibodies disturb
the normal function of receptors.
cytotoxicity (ADCC).
The
contribution of ADCC to common hypersensitivity diseases
is uncertain.
6.16B).
The leukocytes are activated by engagement of their C3b
and Fc receptors.
6.16C).
The converse (i.e., antibody-mediated stimulation
of cell function) is the basis of Graves disease.
Examples of immune complex disorders and the antigens
involved are listed in Table 6.4.
The pathogenesis of systemic immune complex disease
can be divided into three phases (Fig.
6.17).
1.
Formation of immune complexes.
2.
Deposition of immune complexes.
In the next phase, the
circulating antigen-antibody complexes are deposited
in vessels.
Inflammation and tissue injury.
Once immune complexes are
deposited in the tissues, they initiate an acute inflamma-
tory reaction.
In fact, serum C3 levels can, in some cases, be used to
monitor disease activity.
2.15).
6.31 and 6.32).
(macrophages), which express receptors for the Fc tails of lgG
and for complement proteins.
The result is depletion of the
opsonized cells.
The inflammatory
reaction causes tissue injury.
6.18).
The inflammatory reactions stimulated by CD4+ T cells
can be divided into sequential stages.
A form of
chronic serum sickness results from repeated or prolonged
exposure to an antigen.
Included in this category are membranous
glomerulonephritis and several vasculitides.
(B) In some diseases, CD8+ cytotoxic T lymphocytes directly kill tissue cells.
APC, Antigen-presenting cell.
Inflammation mediated by Th17 (and
Citrullinated self proteins?
Th1?) cytokines; role of antibodies
and immune complexes?
CTLs, Cytotoxic T lymphocytes.
6.19).
6.20).
The granuloma in the center shows
several multinucleate giant cells.
(Courtesy Dr.
Contact dermatitis is a common example of tissue injury
resulting from DTH reactions.
Chemicals
may also modify HLA molecules, making them appear
foreign to T cells.
These often manifest as skin rashes.
They also play a role in
reactions against viruses.
A B
Figure 6.19 Delayed type hypersensitivity reaction in the skin.
(Courtesy Dr.
In the target cell cytoplasm, perforin
facilitates the release of the granzymes from the complex.
Subsequent exposure to the antigen results
in the secretion of cytokines.
The classical T cell–mediated inflam-
matory reaction is DTH.
CD8+ T cells also secrete
IFN-γ.
b An autoimmune basis of these disorders is suspected, but the supporting
evidence is not strong.
The clinical manifestations of autoimmune disorders are
extremely varied.
A growing
number of diseases have been attributed to autoimmunity
(Table 6.6).
How, then, does one define pathologic autoimmunity?
6.21).
Each of these is considered briefly.
The mechanisms
of central tolerance eliminate these potentially dangerous
lymphocytes.
This process is called negative selection or clonal deletion.
Central tolerance, however, is imperfect.
The principal mechanisms of central and peripheral self-tolerance in T and B cells are
illustrated.
These mechanisms include the following:
• Anergy.
Several mechanisms of T-cell anergy
have been demonstrated in various experimental systems.
Anergy also affects mature B cells in peripheral tissues.
• Suppression by regulatory T cells.
6.21), but they may also be induced in
peripheral lymphoid tissues.
Regulatory T cells may
suppress immune responses by multiple mechanisms.
• Deletion by apoptosis.
T cells that recognize self antigens
may receive signals that promote their death by
apoptosis.
Depletion of T cells occurs not only in the
thymus, discussed earlier, but also in the periphery.
Unopposed Bim
triggers apoptosis by the mitochondrial pathway (Chapter
2).
A second mechanism involves the Fas-Fas ligand
system.
The engagement of Fas by FasL induces apoptosis by
the death receptor pathway (Chapter 2).
Self-reactive B cells may also
be deleted by FasL on T cells engaging Fas on the B cells.
This is the postulated mechanism
for post-traumatic orchitis and uveitis.
Understanding why tolerance fails in these diseases
is an important goal of immunologists.
6.22).
• Abnormal display of self antigens.
• Inflammation or an initial innate immune response.
Role of Susceptibility Genes
Most autoimmune diseases are complex multigenic dis-
orders.
has a genetic component.
Many autoimmune diseases are associated with different class
II HLA alleles.
Three recently described genetic associa-
tions are especially interesting.
The net
result is excessive lymphocyte activation.
The data are from
European-derived populations.
b Anti-CCP Ab = antibodies directed against cyclic citrullinated peptides.
Data are
from patients who test positive for these antibodies in the serum.
Courtesy Dr.
Michelle Fernando, Imperial College London.
the vast majority of individuals who inherit this allele never
develop ankylosing spondylitis.
Modified from Zenewicz LA, Abraham C, Flavell RA, Cho JH: Unraveling the genetics of autoimmunity.
These genes include
AIRE, CTLA4, PD1, FAS, FASL, and IL2 and its receptor
CD25.
Two mechanisms have been postulated to explain the link
between infections and autoimmunity (Fig.
6.23).
First,
infections may upregulate the expression of costimulators
on APCs.
Second, some microbes may
express antigens that share amino acid sequences with self
antigens.
This phenomenon is called molecular mimicry.
More subtle
molecular mimicry may be involved in classic autoimmune
diseases as well.
Microbes may induce other abnormalities that promote
autoimmune reactions.
Infections may protect against some autoimmune
diseases.
With this background, we can proceed to a discussion
of specific autoimmune diseases.
Table 6.6 lists both systemic
and organ-specific autoimmune disorders.
ANAs.
The pattern of nuclear fluorescence
suggests the type of antibody present in the patient’s serum.
Four basic patterns are recognized (Fig.
It was updated in 2012
by the Systemic Lupus International Collaborating Clinics.
Some details have been omitted from the table.
% positive refers to the approximate % of patients who test positive for each antibody.
The table was compiled with the help of Dr.
(D) Nucleolar pattern is typical of antibodies against nucleolar proteins.
• Speckled pattern refers to the presence of uniform or
variable-sized speckles.
This pattern is reported most often
in patients with systemic sclerosis.
• Centromeric pattern.
Nevertheless, the staining pattern
is considered of diagnostic value, and the test remains
in use.
In addition to ANAs, lupus patients have a host of other
autoantibodies.
Antiphospholipid
antibodies are present in 30% to 40% of lupus patients.
• TLR engagement by nuclear DNA and RNA contained
in immune complexes may activate B lymphocytes.
These
TLRs function normally to sense microbial products,
including nucleic acids.
• Type I interferons play a role in lymphocyte activation
in SLE.
It may be that nucleic
acids engage TLRs on DCs and stimulate the production
of interferons.
In other words, self nucleic acids mimic
their microbial counterparts.
Therefore, these antibodies are sometimes referred to as
lupus anticoagulant.
Genetic Factors.
SLE is a genetically complex disease with
contributions from MHC and multiple non-MHC genes.
Many lines of evidence support a genetic predisposition.
• Family members of patients have an increased risk of
developing SLE.
Immunologic Factors.
Environmental Factors.
• Exposure to ultraviolet (UV) light exacerbates the disease
in many individuals.
A Model for the Pathogenesis of SLE.
6.25).
UV irradiation and other
environmental insults lead to the apoptosis of cells.
Inad-
equate clearance of the nuclei of these cells results in a large
burden of nuclear antigens.
The nucleic acid components engage TLRs and stimulate
B cells to produce more autoantibodies.
If cell nuclei are exposed, however, the ANAs can bind to
them.
Related to this phenomenon is the LE cell, which is readily
seen when blood is agitated in vitro.
The demonstration of LE cells in vitro was used in the
past as a test for SLE.
Sometimes, LE cells are found in pericardial or
pleural effusions in patients.
These are examples of antibody-mediated (type II)
hypersensitivity.
• Antiphospholipid antibody syndrome.
Some patients develop these autoantibodies and the
clinical syndrome without associated SLE.
They are said
to have the primary antiphospholipid antibody syndrome
(Chapter 4).
which further enhance the immune response and cause more
apoptosis.
Mechanisms of Tissue Injury.
Different autoantibodies
are the cause of most of the lesions of SLE.
• Most of the systemic lesions are caused by immune
complexes (type III hypersensitivity).
DNA–anti-DNA
complexes can be detected in the glomeruli and small
blood vessels in animal models.
T-cell infiltrates are
also frequently seen in the kidneys and may be involved in
tissue damage.
IFN, Interferon;
TLRs, Toll-like receptors.
MORPHOLOGY
The morphologic changes in SLE are extremely variable.
The
frequency of individual organ involvement is shown in Table 6.11.
Blood Vessels.
The arteritis is characterized by fibrinoid necrosis of the vessel
walls.
In chronic stages, vessels undergo fibrous thickening with
luminal narrowing.
Kidney.
Table compiled with the assistance of Dr.
Meenakshi Jolly, Rush Medical Center,
Chicago, Ill.
it can be subclassified as Class IV segmental (IV-S) or Class
IV global (IV-G).
Involved glomeruli show proliferation of
endothelial, mesangial, and epithelial cells (Fig.
6.26B), with the
latter producing cellular crescents that fill Bowman’s space
(Chapter 20).
6.26C).
Immune
complexes can be readily detected by electron microscopy
(Fig.
6.26D) and immunofluorescence (Fig.
6.26E).
Lesions
may progress to scarring of glomeruli.
Hypertension and mild to severe renal
insufficiency are also common.
Changes in the interstitium and tubules are frequently present
in lupus nephritis.
Rarely, tubulointerstitial lesions may be
the dominant abnormality.
Skin.
Urticaria, bullae, maculopapular lesions, and ulcerations also
occur.
Exposure to sunlight incites or accentuates the erythema.
6.27A).
Joints.
CNS.
No clear morphologic abnormalities account for the
neuropsychiatric symptoms of SLE.
Pericarditis and Other Serosal Cavity.
Inflammation of the
serosal lining membranes may be acute, subacute, or chronic.
During the acute phases, the mesothelial surfaces are sometimes
covered with fibrinous exudate.
Pleural and
pericardial effusions may be present.
Cardiovascular System.
Involvement may manifest as damage
to any layer of the heart.
Symptomatic or asymptomatic pericardial
involvement is present in up to 50% of patients.
Suffice it to say that class I is the least
common and class IV is the most common pattern.
• Focal lupus nephritis (class III) is defined by involvement of
fewer than 50% of glomeruli.
6.26A).
The clinical presentation
ranges from mild hematuria and proteinuria to acute renal
insufficiency.
Red blood cell casts in the urine are common
when the disease is active.
Some patients progress to diffuse
glomerulonephritis.
• Diffuse lupus nephritis (class IV) is the most common and severe
form of lupus nephritis.
Extracapillary proliferation is not prominent in this case.
(B) Diffuse proliferative glomerulonephritis.
Note the marked increase in cellularity
throughout the glomerulus (H&E stain).
(D) Electron micrograph of a renal glomerular capillary loop from a patient with lupus nephritis.
Subendothelial dense deposits (arrowheads) correspond to “wire loops” seen by light microscopy.
B (with arrow) refers to the basement membrane.
(E)
Deposition of IgG antibody in a granular pattern, detected by immunofluorescence.
(A–C, Courtesy Dr.
Helmut Rennke, Department of Pathology,
Brigham and Women’s Hospital, Boston, Mass.
D, Courtesy Dr.
E, Courtesy Dr.
Splenomegaly, capsular thickening, and follicular
hyperplasia are common features.
Lungs.
None
of these changes is specific for SLE.
Other Organs and Tissues.
LE, or hematoxylin, bodies in the
bone marrow or other organs are strongly indicative of SLE.
It may be acute or insidious in its onset.
(A, Courtesy Dr.
Jag Bhawan, Boston
University School of Medicine, Boston, Mass.
B, Courtesy Dr.
6.28).
Figure 6.28 Libman-Sacks endocarditis of the mitral valve in lupus
erythematosus.
The vegetations attached to the margin of the thickened
valve leaflet are indicated by arrows.
(Courtesy Dr.
The course of the disease is variable and unpredictable.
Rarely, death ensues within weeks to months.
Disease flares are usually
treated with corticosteroids or other immunosuppressive
drugs.
The
most common causes of death are renal failure and intercur-
rent infections.
Coronary artery disease is also becoming
an important cause of death.
As mentioned earlier, involvement of skin along with
multisystem disease is fairly common in SLE.
Secondly, most
patients have mild systemic symptoms consistent with SLE.
There is a strong association with antibodies to the SS-A
antigen and with the HLA-DR3 genotype.
Although multiple organs
are affected, renal and CNS involvement is distinctly uncom-
mon.
There are serologic and genetic differences from classic
SLE, as well.
Abundant evidence supports the autoimmune nature
of the disease.
(A) Enlargement of the salivary gland.
(A) Courtesy Dr.
(B)
Courtesy Dr.
Eventually
the lymphocytic infiltrate becomes extensive (Fig.
6.29B), and
lymphoid follicles with germinal centers may appear.
The ductal
lining epithelial cells may show hyperplasia, thus obstructing the
ducts.
In some cases, the lymphoid infiltrate may be
so intense as to give the appearance of a lymphoma.
Indeed, these
patients are at high risk for development of B-cell lymphomas.
ANAs are detected in 50% to 80% of patients by immuno-
fluorescence assay.
A host of other organ-specific and
non–organ-specific antibodies have also been identified.
These antibodies are
thus considered serologic markers of the disease.
The significance of such associations in disease
causation or manifestations is not clear.
The result is inflammation, tissue damage, and, eventually,
fibrosis.
The nature of the autoantigens recognized by these lym-
phocytes is also mysterious.
Clinical Features
Sjögren syndrome occurs most commonly in women between
50 and 60 years of age.
As might be expected, symptoms
result from inflammatory destruction of the exocrine glands.
These are more common in patients with high
titers of antibodies specific for SS-A.
In contrast to SLE,
glomerular lesions are extremely rare in Sjögren syndrome.
The combination of lacrimal and salivary gland inflam-
mation was once called Mikulicz disease.
As mentioned earlier, the involved glands show intense
inflammatory infiltrates.
About 5% of Sjögren
patients develop lymphoma, an incidence that is 40-fold
greater than normal.
Visceral involvement occurs late; hence, the clinical course
is relatively benign.
6.30).
• Autoimmunity.
EXTERNAL STIMULI?
GENETIC SUSCEPTIBILITY EXTERNAL STIMULI?
Other cytokines recruit leuko-
cytes and propagate the chronic inflammation.
• Vascular damage.
Intimal proliferation is evident in
the digital arteries of patients with systemic sclerosis.
Capillary dilation with leaking, as well as destruction, is
also common.
Nailfold capillary loops are distorted early
in the course of disease, and later they disappear.
Eventually, widespread narrowing
of the microvasculature leads to ischemic injury and
• scarring.
Fibrosis.
with degeneration of collagen fibers, which become eosinophilic.
6.31B).
6.31C).
Sometimes the
tips of the fingers undergo autoamputation.
Alimentary Tract.
The alimentary tract is affected in approxi-
mately 90% of patients.
Loss of villi and microvilli in
the small bowel sometimes produces a malabsorption syndrome.
Musculoskeletal System.
In a small subset of patients (approximately
10%), inflammatory myositis may develop.
Kidneys.
Lungs.
Heart.
Clinical impairment by myocardial involvement, however,
is less common.
MORPHOLOGY
Virtually all organs may be involved in systemic sclerosis.
Skin.
(A) Normal skin.
(B) Skin biopsy from a patient with systemic sclerosis.
Loss of blood supply has led to cutaneous ulcerations.
(C, Courtesy Dr.
6.31C).
The disease tends to be more severe in people of
African descent, especially women.
Virtually all patients have ANAs that react with a variety
of nuclear antigens.
Two ANAs strongly associated with
systemic sclerosis have been described.
In general, these patients live longer than those
with diffuse visceral involvement at the outset.
vessels and showing strong evidence of an immunologic
pathogenic mechanism.
Noninfectious vasculitis is encountered in
many clinical settings.
6.32).
Many medical conditions
long viewed as confined to single organs are part of the
IgG4-RD spectrum.
The disease most often affects middle-age and older men.
Since most clinical trans-
plants are allografts, the discussion is focused on these.
These diseases are described
in Chapter 27.
The disease is
characterized serologically by high titers of antibodies to
U1 ribonucleoprotein.
The disease may, over time, evolve into classic SLE or
systemic sclerosis.
(A) Bile duct showing sclerosing cholangitis.
(B) Sclerotic area of the bile duct with storiform
fibrosis.
(C) Submandibular gland with infiltrates of lymphocytes and plasma cells and whorls of fibrosis.
These are called the direct and indirect pathways of
recognition of alloantigens.
For this reason, immune
responses to allografts are stronger than responses to
pathogens.
The activation of these B cells typically requires
T cell help.
Each type of rejection is mediated
by a particular kind of immune response.
(A) Deposition of antibody on endothelium and activation of complement causes thrombosis.
6.33A).
to vascular damage.
MORPHOLOGY
Acute cellular (T cell–mediated) rejection may produce two
different patterns of injury.
6.34B).
As
might be expected, the inflammatory infiltrates contain activated
CD4+ and CD8+ T lymphocytes.
• The vascular pattern shows inflammation of vessels (type II)
(Fig.
6.34C) and sometimes necrosis of vessel walls (type III).
6.33B).
Neutrophils rapidly accumulate within arterioles, glomeruli, and
peritubular capillaries.
Affected kidneys are nonfunctional and have to be
removed.
6.35A).
The
resultant inflammation and endothelial damage cause
graft failure.
6.34A).
6.35C).
Small vessels also may show focal thrombosis.
(A) Destruction of graft cells by T cells.
Collapsed tubules are outlined by wavy basement membranes.
(C) Rejection vasculitis in
a kidney graft.
(Courtesy Drs.
6.36A).
Alloantibodies also
contribute to chronic rejection.
The rejection of these grafts is described
in the relevant chapters.
6.36B).
6.36D).
(A) Graft damage caused by antibody deposition in vessels.
(C) Immunoperoxidase stain shows C4d deposition in peritubular capillaries
and a glomerulus.
(Courtesy Dr.
Thus, tacrolimus inhibits T cell responses.
Plasmapheresis is used in cases of severe antibody-mediated
rejection.
Although immunosuppression prolongs graft survival,
it carries its own risks.
The price paid in the form of increased
susceptibility to opportunistic infections is not small.
One
of the most frequent infectious complications is reactivation
of polyoma virus.
(A) Graft arteriosclerosis caused by T-cell cytokines and antibody deposition.
(B) Graft arteriosclerosis in a cardiac
transplant.
An artery showing prominent arteriosclerosis is shown (bottom
right).
(B, Courtesy of Dr.
Richard Mitchell, Department of Pathology, Brigham and Women’s Hospital, Boston, Mass.
C and D, Courtesy of Dr.
Several features
distinguish HSC transplants from solid-organ transplants.
• Acute GVHD occurs within days to weeks after allogeneic
HSC transplantation.
6.37A).
• Chronic GVHD may follow the acute syndrome or may
occur insidiously.
6.37B).
The changes may resemble
systemic sclerosis (discussed earlier).
Chronic liver disease
manifested by cholestatic jaundice is also frequent.
Damage to the gastrointestinal tract may cause esophageal
strictures.
Not surprisingly, patients experience
recurrent and life-threatening infections.
The epidermis is thinned, signifying atrophy.
The underlying dermis shows
thickening of collagen bundles, indicative of sclerosis.
(B, Courtesy Dr.
The latter graft-versus-leukemia effect can be
quite dramatic.
Immunodeficiency is a frequent complication of HSC
transplantation.
Affected individuals
are profoundly immunosuppressed and are easy prey to
infections.
This usually results from activation of latent
infection.
Cytomegalovirus-induced pneumonitis can be a
fatal complication.
• Chronic rejection.
Dominated by arteriosclerosis, this type
is caused by T-cell activation and antibodies.
• Types and mechanisms of rejection of solid organ grafts:
• Hyperacute rejection.
• Acute cellular rejection.
T cells destroy graft parenchyma
(and vessels) by cytotoxicity and inflammatory reactions.
We conclude with
immune defects associated with some systemic diseases.
Some of the defects whose molecular basis is
defined are summarized next.
Defects in Leukocyte Function
• Inherited defects in leukocyte adhesion.
• Inherited defects in phagolysosome function.
• Inherited defects in microbicidal activity.
• Defects in TLR signaling.
Rare defects have been described
in various TLRs and their signaling molecules.
• Deficiency of C2 is the most common complement protein
deficiency.
Modified in part from Gallin JI: Disorders of phagocytic cells.
It is associated with
recurrent pyogenic infections.
There is also an increased
incidence of immune complex–mediated glomerulonephri-
tis.
These individuals also show increased
susceptibility to infections.
• A deficiency of C1 inhibitor (C1 INH) gives rise to
hereditary angioedema.
This autosomal dominant disorder is
more common than complement deficiency states.
These immunodeficiencies result from
abnormalities in lymphocyte maturation or activation.
The
mutations responsible for many of these diseases have now
been identified (Fig.
6.38).
Without HSC transplantation,
death occurs within the first year of life.
X-linked SCID.
Autosomal Recessive SCID.
The remaining forms of SCID
are autosomal recessive disorders.
Hence
there may be a greater reduction in the number of T lym-
phocytes than of B lymphocytes.
This
blocks the development of T and B cells.
Mutations of JAK3 therefore have the
same effects as mutations in the γc chain.
The histologic findings in SCID depend on the underlying
defect.
The affected genes are indicated in parentheses for some of the disorders.
lymphoid cells.
Current trials are using
new vectors with safety features built in.
It is one of the more common
forms of primary immunodeficiency.
These organisms are normally opsonized by antibodies and
cleared by phagocytosis.
• Germinal centers of lymph nodes, Peyer patches, the
appendix, and tonsils are underdeveloped.
• Plasma cells are absent throughout the body.
• T cell–mediated reactions are normal.
The treatment of X-linked agammaglobu-
linemia is replacement therapy with immunoglobulins.
In
the past, most patients succumbed to infection in infancy
or early childhood.
Prophylactic IVIG therapy allows most
individuals to reach adulthood.
In
addition, the appearance of the mouth, ears, and facies may
be abnormal.
Ig levels may be normal or
reduced, depending on the severity of the T-cell deficiency.
In the remaining patients, the disease is
inherited in an autosomal recessive pattern.
The numbers of B and T cells in the blood are
normal.
Both sporadic and inherited forms of the disease occur.
In familial forms, there is no single pattern of inheritance.
These B
cells, however, are not able to differentiate into plasma cells.
However, the known mutations explain less
than 10% of cases.
Patients typically present with recurrent sinopulmonary
pyogenic infections.
In addition, about 20% of patients have
recurrent herpesvirus infections.
Serious enterovirus infec-
tions causing meningoencephalitis may also occur.
lamblia.
In the United States, it occurs
in about 1 in 600 individuals of European descent.
It is far
less common in people of African descent and Asians.
Affected individuals have extremely low levels of both serum
and secretory IgA.
Most individuals with IgA deficiency are asymptomatic.
Symp-
tomatic patients commonly present with recurrent sinopul-
monary infections and diarrhea.
The basis of the increased frequency
of autoimmune and allergic diseases is not known.
IgM levels in the serum are low,
but levels of IgG are usually normal.
Paradoxically the
levels of IgA and IgE are often elevated.
Patients are also
prone to developing B-cell lymphomas.
The only
treatment is HSC transplantation.
The immunologic defects
are of variable severity and may affect both B and T cells.
The T-cell defects, which are usually less pronounced,
are associated with thymic hypoplasia.
The most serious secondary immunodeficiency
is AIDS, which is described next.
The magnitude
of this modern plague is truly staggering.
Although initially
recognized in the United States, AIDS is a global problem.
Only about 80% of HIV-infected people
living worldwide know their status.
There is some good news.
Furthermore, improved antiviral therapies have
resulted in fewer people dying of the disease.
The
literature on HIV and AIDS is vast.
This includes about 5% who are
intravenous drug users as well.
Heterosexual transmission has
declined modestly since 2011 in the United States.
• HIV infection of the newborn.
In this regard, syphilis, chancroid,
and herpes are particularly important.
Of these three,
intravenous drug users constitute by far the largest group.
Currently, this risk is estimated to be 1 in more
than 2 million units of blood transfused.
• As alluded to earlier, mother-to-infant transmission is the
major cause of pediatric AIDS.
The reported transmission rates vary
from 7% to 49% in different parts of the world.
Spread by insect
bites is virtually impossible.
6.39).
The HIV-1 RNA genome contains the gag, pol, and env
genes, which are typical of retroviruses (Fig.
6.40).
The functions
of other accessory proteins are indicated in Fig.
6.40.
The central nervous
system (CNS) is also affected.
Profound immune deficiency, primarily affecting cell-
mediated immunity, is the hallmark of AIDS.
The functions of selected genes are shown.
Active viral replication is associated with more
infection of cells and progression to AIDS.
This is followed by a more detailed review of the
interaction between HIV and its cellular targets.
6.41).
The molecules and mechanisms of each of these
steps are understood in considerable detail.
Infection of Cells by HIV.
6.41).
Binding to CD4 is not sufficient for
infection, however.
HIV gp120 must also bind to other cell
surface molecules (coreceptors) for entry into the cell.
Chemokine receptors, particularly CCR5 and CXCR4, serve
this role.
(Modified with permission from Wain-Hobson S:
HIV.
One on one meets two, Nature 384:117, 1996.
Only rare
homozygotes for the mutation have been found in African
or East Asian populations.
Viral Replication.
6.41).
In quiescent T cells, HIV cDNA
may remain in the cytoplasm in a linear episomal form.
After integration, the
provirus may be silent for months or years, a form of latent
infection.
These mutations inhibit further DNA replica-
tion by mechanisms that are not fully defined.
Imagine now a
latently infected CD4+ cell that encounters an environmental
antigen.
These, in turn, stimulate
more HIV production, loss of additional CD4+ T cells, and
more infection.
The molecular mechanism
of this type of cell death is not known.
This form of cell death may play a role in spread of the
infection.
• Fusion of infected and uninfected cells with formation
of syncytia (giant cells) can occur.
Fused cells usually die within a few hours.
This
property of syncytia formation is generally confined to
the T-tropic X4 type of HIV-1.
Low-level chronic or latent infection of T cells is an
important feature of HIV infection.
FDCs in the germinal centers of lymph nodes are potential
reservoirs of HIV.
Infected T follicular helper
cells in the germinal centers are also reservoirs of HIV.
Impaired humoral immunity renders these patients
lymph nodes are latently infected.
CD4+ T cells play a pivotal role in regulating both cel-
lular and humoral immune responses.
In certain tissues,
such as the lungs and brain, as many as 10% to 50% of
macrophages are infected.
This property of HIV-1 is dependent on the
viral vpr gene.
pneumoniae and H.
influenzae, both of
which require antibodies for effective opsonization and
clearance.
The clinical
syndrome of CNS abnormalities is called HIV-associated
neurocognitive disorder (HAND).
It is believed
that HIV is carried into the brain by infected T cells or
monocytes.
The mechanism of HIV-induced damage of the
brain remains obscure.
Included among the soluble
factors are the usual culprits, such as IL-1, TNF, and IL-6.
In addition, nitric oxide induced in neuronal cells by gp41
has been implicated.
Direct damage of neurons by soluble
HIV gp120 has also been postulated.
Natural History of HIV Infection
The virus typically enters through mucosal epithelia.
6.42 and 6.43).
Few infected cells are detectable in the blood
and other tissues.
DCs in epithelia at sites of virus entry capture the virus
and then migrate into the lymph nodes.
Once in lymphoid
tissues, DCs may pass HIV on to CD4+ T cells through
direct cell-to-cell contact.
Within days after the first exposure
to HIV, viral replication can be detected in the lymph nodes.
This corresponds to the early
acute phase of HIV infection.
(B) Immune response to HIV
infection.
The humoral
immune response to HIV peaks at about 12 weeks.
This typically
occurs 3 to 6 weeks after infection, and resolves spontaneously
in 2 to 4 weeks.
6.42).
Therefore, this phase of HIV disease is called the
clinical latency period.
Not unexpectedly, HIV RNA levels increase as the host
begins to lose the battle with the virus.
Asymptomatic, acute (primary) HIV, or persistent generalized lymphadenopathy A1 A2 A3
B.
Symptomatic, not A or C conditions B1 B2 B3
C.
immune control is not entirely clear, but several mechanisms
have been proposed.
Autoimmune thrombocytopenia may also be noted
(Chapter 14).
Exceptions to this typical course are
rapid progressors and long-term nonprogressors.
A brief summary of selected opportunistic infec-
tions is provided here.
States.
In contrast to infection with atypical mycobacteria, M.
tuberculosis infection manifests early in the course of AIDS.
• A variety of opportunistic infections target the CNS.
Cryptococcosis occurs in about 10% of AIDS patients.
It causes progressive multifocal
leukoencephalopathy (Chapter 28).
• Other infections preferentially involve the gastrointestinal
tract and genitalia.
These patients have
chronic, profuse, watery diarrhea with massive fluid
loss.
avium-intracellulare.
Kaposi Sarcoma.
Coincident
with the AIDS epidemic, the incidence of tuberculosis has
risen dramatically.
In addition, KS
lesions display chronic inflammatory cell infiltrates.
Many
of the features of KS suggest that it is not a malignant tumor
(despite its ominous name).
Exactly how HHV8 infection leads to KS is still unclear.
These include a viral homologue of cyclin D and
several inhibitors of p53.
HIV-mediated immune
suppression may aid in widespread dissemination of HHV8
in the host.
HHV8 infection is not restricted to endothelial cells.
Clinically, AIDS-associated KS is quite different from
the sporadic form (Chapter 11).
These tumors also tend to be more aggressive than
classic KS.
Lymphomas.
6.44).
By adulthood, most normal individuals are infected
with EBV.
These
patients are also chronically infected with pathogens that
may lead to B-cell stimulation.
HIV infection results in several changes that may cooperate to produce
B-cell lymphomas.
• Germinal center B-cell hyperplasia in the setting of early
HIV infection.
What then explains
the increased risk of lymphoma?
Several other EBV-related proliferations also merit
mention.
Other Tumors.
These drugs are given in combination to reduce the emergence
of drug-resistant mutants.
Many AIDS-
associated disorders, such as P.
jirovecii infection and KS,
are very uncommon now.
ART also has reduced the transmis-
sion of the virus, especially from infected mothers to newborns.
This occurs
despite increasing CD4+ T-cell counts and decreasing viral
load.
MORPHOLOGY
The anatomic changes in the tissues are neither specific nor
diagnostic.
Common pathologic features of AIDS include oppor-
tunistic infections, KS, and B-cell lymphomas.
Lesions in the CNS are described
in Chapter 28.
The lymph nodes are depleted of lymphocytes, and the organized
network of FDCs is disrupted.
For example, myco-
bacteria may not evoke granuloma formation because CD4+ cells
are deficient.
With progres-
sive accumulation, it encroaches on and produces pressure
atrophy of adjacent cells.
In fact,
more than 20 different proteins can aggregate to form
amyloid.
Physical Nature of Amyloid.
6.45).
Chemical Nature of Amyloid.
This form of amyloid is
discussed in Chapter 28.
The proteins that form
amyloid fall into two general categories (Fig.
(C) Electron micrograph of
7.5- to 10-nm amyloid fibrils.
be localized to a single organ, such as the heart.
Among these, the most frequently
associated condition is rheumatoid arthritis.
However,
increased production of SAA by itself is not sufficient for
the deposition of amyloid.
There are two possible explana-
tions for this.
Heredofamilial Amyloidosis
A variety of familial forms of amyloidosis have been
described.
Most of them are rare and occur in limited
geographic areas.
It is sometimes associated with
widespread amyloidosis.
These familial amyloidotic polyneuropa-
thies have been described in different parts of the world.
As mentioned earlier, in all of these genetic disorders, the
fibrils are made up of mutant TTR.
With new dialysis
filters, the incidence of this complication has decreased
substantially.
In medullary carcinoma
of the thyroid, the presence of amyloid is a helpful diagnostic
feature.
Amyloid of Aging
Several well-documented forms of amyloid deposition occur
with aging.
Those who are symptomatic
present with a restrictive cardiomyopathy and arrhythmias
(Chapter 12).
The amyloid in this form is derived from
normal TTR.
The localization of amyloid deposits in the
hereditary syndromes is varied.
6.47A).
As the amyloid accumulates, it encroaches on the cells, in time
surrounding and destroying them.
The pattern of organ involvement in different clinical forms
of amyloidosis is variable.
Kidney.
Nonetheless, a few generalizations can be made.
(B) Note the yellow-green birefringence of the deposits when observed by polarizing microscope.
(C) Amyloidosis of the kidney.
The glomerular
architecture is almost totally obliterated by the massive accumulation of amyloid.
(A, B, Courtesy Dr.
Renal failure is
a common cause of death.
Cardiac amyloidosis may present as
an insidious congestive heart failure.
Gastrointestinal amyloidosis may be entirely asymptomatic,
or it may present in a variety of ways.
The test is
quite specific, but its sensitivity is low.
The prognosis for individuals with generalized amyloi-
dosis is poor.
6.47C).
Spleen.
For completely mysterious reasons, one of two patterns of
deposition is seen.
Liver.
The deposits may be inapparent grossly or may cause
moderate to marked hepatomegaly.
6.47).
Vascular involvement is frequent.
Even with extensive involvement,
liver function is usually preserved.
Heart.
Amyloidosis of the heart (Chapter 12) may occur in
any form of systemic amyloidosis.
Other Organs.
It may be present in so-called
plaques as well as blood vessels (Chapter 28).
The
symptoms depend on the magnitude of the deposits and
on the sites or organs affected.
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The only hope
for controlling cancer lies in learning more about its causes
and pathogenesis.
If the polyp has glandular tissue, it is called an adeno-
matous polyp (Fig.
7.1).
Tumor originally described swelling caused by
inflammation, but is now equated with neoplasm.
Oncology
(Greek oncos = tumor) is the study of tumors or neoplasms.
In some
tumors, connective tissue is scant, and the neoplasm is soft
and fleshy.
Predictably,
the patient generally survives.
Exceptions arise, however,
A B
Figure 7.1 Colonic polyp.
Nevertheless, the designation “malignant” always raises a
red flag.
Malignant neoplasms of epithelial cell origin
are called carcinomas.
Carcinomas may be further qualified.
7.2).
Figure 7.2 Mixed tumor of the parotid gland.
7.3).
The nomenclature of the more common types of tumors
is presented in Table 7.1.
Included in this list are some
inappropriate but deeply entrenched names.
Alternatively, ominous-sounding terms are
applied to some trivial lesions.
Hamartomas are disorganized
masses composed of cells indigenous to the involved tissue.
Note the presence of hair, sebaceous material, and a tooth.
Choristoma is the term applied to a heterotopic
(misplaced) rest of cells.
In general, benign
tumors are well differentiated (Figs.
7.4 and 7.5).
Note the normal-
looking (well-differentiated), colloid-filled thyroid follicles.
(Courtesy Dr.
One may get so close to the tree
that one loses sight of the forest.
In well-differentiated benign
tumors, mitoses are usually rare and are of normal
configuration.
In well-differentiated tumors, these features
may be quite subtle.
7.6).
7.7), a morphologic appearance that is
highly predictive of malignant behavior.
7.8).
Pleomorphism refers to variation in cell
size and shape.
7.9).
• Abnormal nuclear morphology.
This tumor is considered
moderately well differentiated because gland formation is seen.
The
malignant glands have invaded the muscular layer of the colon.
(Courtesy
Dr.
•
Metaplasia is defined as the replacement of one type of cell
with another type (Chapter 2).
Metaplasia is nearly always
found in association with tissue damage, repair, and
regeneration.
Often the replacing cell type is better suited
to some alteration in the local environment.
Unfortunately, the
metaplastic epithelium is prone to malignant transforma-
tion.
• Carcinoma in situ.
7.10).
Carcinoma in situ is often
seen in the skin, breast, bladder, and uterine cervix.
With
removal of inciting causes, even moderately severe dysplasias
may be completely reversible.
Even carcinoma in situ may
persist for years before it becomes invasive.
Note the marked cellular and nuclear pleomorphism,
hyperchromatic nuclei, and tumor giant cells.
(Courtesy Dr.
Abnormally large nucleoli are also commonly
seen.
• Mitoses.
The presence of mitoses, however, does
not equate with malignancy.
7.8).
• Loss of polarity.
Sheets or large masses of
tumor cells grow in a disorganized fashion.
• Other changes.
Low-power view shows that the epithelium is entirely replaced by atypical dysplastic cells.
There is no orderly
differentiation of squamous cells.
The basement membrane is intact, and there is no tumor in the subepithelial stroma.
accumulation of all the mutations that are needed to induce
a fully malignant phenotype.
7.11).
There are a few
exceptions to this rule, however.
7.12).
Most malignant tumors do not recognize normal
anatomic boundaries.
(A) The tan-colored,
encapsulated small tumor is sharply demarcated from the whiter breast
tissue.
(B, Courtesy Dr.
(A, Courtesy Dr.
Trace Worrell, University of Texas Southwestern Medical School, Dallas, Tex.; B, Courtesy Dr.
All malignant tumors can metas-
tasize, but some do so very infrequently.
It is evident then that the properties of invasiveness
and metastasis are separable.
Blood cancers (leukemias and
lymphomas) are a special case.
There are innumerable exceptions,
however.
Seeding of Body Cavities and Surfaces.
Most often involved is the peritoneal cavity (Fig.
7.13), but any body cavity—pleural, pericardial, subarach-
noid, and joint spaces—may be affected.
Sometimes, mucus-secreting
Figure 7.13 Involvement of omentum by metastatic ovarian carcinoma.
(Courtesy Dr.
Hematogenous Spread.
Hematogenous spread is typical
of sarcomas but is also seen with carcinomas.
Several factors influence the patterns of vascular metas-
tasis.
Understandably, the liver and the lungs (Fig.
(Courtesy Dr.
Lymphatic Spread.
7.14).
Sarcomas also sometimes use this
route.
The pattern of spread follows the natural
routes of lymphatic drainage.
(A) Liver studded with metastatic cancer.
(B) Microscopic view of lung metastasis.
A colonic adenocarcinoma has formed a
metastatic nodule in the lung.
(B, Courtesy Dr.
Unfortunately, most cancers
have not read pathology textbooks!
The basis of tissue-specific
patterns of metastasis is discussed later.
Certain cancers have a curious propensity for growth
within large veins.
Remarkably, such intravenous growth may not be
accompanied by widespread metastasis.
The distinguishing features of benign and malignant
tumors are summarized in Table 7.2 and Fig.
7.16.
7.17.
The most common
tumors in men arise in the prostate, lung, and colon/rectum.
In women, cancers of the breast, lung, and colon/rectum
are the most frequent.
• Benign tumors are slow growing,while malignant tumors generally
grow faster.
Carcinomas tend to spread
via lymphatics,whereas sarcomas prefer the hematogenous route.
2019 ESTIMATED CANCER INCIDENCE BY SITE AND SEX
B.
Excludes basal cell and squamous cell skin cancers and in situ carcinomas except
urinary bladder.
• Diet.
• Obesity.
The most overweight individuals in the U.S.
• Reproductive history.
• Environmental carcinogens.
Race is not a discrete biologic variable, but it can define
groups at risk for certain cancers.
7.18).
Among the best-established environmental factors affect-
ing cancer risk are the following.
• Infectious agents.
Specific
infectious agents and their associated cancers are discussed
later in this chapter.
• Smoking.
Age
Age has an important influence on the risk of cancer.
Most
carcinomas occur in adults older than 55 years of age.
A decline
in immune competence in older individuals may also be a
factor.
(A) Most common cancers in men by country.
(B) Variation in breast cancer incidence in women by
country.
These are
discussed in Chapter 10 and elsewhere in the text.
lesions, and immunodeficiency states.
Immunodeficiency states predispose to
virus-induced cancers.
Each of these acquired predisposing
conditions is described next.
• Chronic inflammation.
• Precursor lesions.
These changes may take the form of hyperplasia, meta-
plasia, or dysplasia.
Precursor lesions consisting of
hyperplasias often stem from chronic exposure to trophic
factors.
Other “at
risk” lesions consist of benign neoplasms.
• Immunodeficiency and cancer.
The geographic variation is thought to
mainly stem from different environmental exposures.
• Nonlethal genetic damage lies at the heart of carcinogenesis.
these individuals have a higher than normal incidence
of chronic infection with viruses.
The relationship
between infections, immunity, and cancer is discussed
later in this chapter.
See text for details.
Thus, in
genetic parlance, oncogenes are dominant over their
normal counterparts.
As a result, mutated tumor
suppressor genes usually behave in a recessive fashion.
Such a finding indicates that two “doses”
of the gene are essential for normal function.
7.19).
7.19).
7.20).
Evolution of a renal cell carcinoma (left panel) and Darwin’s finches (right panel).
Thus,
there is great interest in treating cancers with drugs that
correct epigenetic abnormalities.
Traditionally, the
functional consequences of these alterations were described
one gene at a time.
These changes are illustrated in Fig.
7.21 and consist of the
following:
• Self-sufficiency in growth signals.
• Insensitivity to growth-inhibitory signals.
• Altered cellular metabolism.
• Evasion of apoptosis.
Tumors are resistant to programmed
cell death.
• Limitless replicative potential (immortality).
• Sustained angiogenesis.
(Modified from Hanahan D, Weinberg
RA.
Hence,
tumors must induce angiogenesis.
• Ability to invade and metastasize.
• Ability to evade the host immune response.
Cancer cells exhibit
a number of alterations that allow them to evade the
host immune response.
Cells expressing oncoproteins are thus freed
from normal checkpoints and proliferate excessively.
This view has merit, and we will follow it in our initial
description of their activities.
Growth Factors.
Growth Factor Receptors.
GDP, Guanosine
diphosphate; GTP, guanosine triphosphate.
cytoplasmic tyrosine kinase domain (Chapter 1).
• ERBB2 encodes a different member of the receptor tyrosine
kinase family, HER2.
Unfortunately, these targeted therapies are usually not
curative in advanced cancers.
Downstream Components of the Receptor Tyrosine Kinase
Signaling Pathway.
Thus, GAPs prevent uncontrolled RAS activity.
• Mutations in kinases of the PI3K family are also very common
in certain cancers.
For example, about 30% of breast
carcinomas have PI3K gain-of-function mutations.
Here,
like BRAF, it activates a cascade of serine/threonine
kinases, including AKT.
AKT phosphorylates more than
150 proteins and constitutes a major signaling node.
Nonreceptor Tyrosine Kinases.
An important
example of this oncogenic mechanism involves the ABL tyro-
sine kinase.
Unfortunately, treatment of this “addiction” to
BCR-ABL does not lead to cure.
An example of this type of mutation is
found in the nonreceptor tyrosine kinase JAK2.
JAK/STAT activation alters the expression of
target genes that bind STAT transcription factors.
Transcription Factors.
MYC.
• MYC activates the expression of many genes that are involved
in cell growth.
• Some MYC target genes, like D cyclins, are directly
involved in cell cycle progression.
7.23), are those with the highest levels of MYC.
• In some contexts, MYC upregulates expression of telomerase.
Sometimes deregula-
tion involves genetic alterations of MYC itself.
The
functionally identical NMYC and LMYC genes are also
amplified in neuroblastomas (Fig.
7.24) and small cell cancers
of the lung, respectively.
The
integration involves other autosomes such as 4, 9, or 13.
Thus, there is seemingly no end
to the ways in which MYC may be deregulated in cancer
cells.
Cyclins and Cyclin-Dependent Kinases.
Amplification of the CDK4 gene also
occurs in melanomas, sarcomas, and glioblastomas.
• Loss-of-function mutations in genes that inhibit G1/S progres-
sion.
In molecular
terms, Knudson’s hypothesis can be stated as follows
(Fig.
7.25): •
Two mutations (hits), involving both alleles of RB are
required to produce retinoblastoma.
• Activation of RAS by point mutations (many cancers).
• Activation of PI3K and BRAF serine/threonine kinases by
point mutations (many cancers).
Tumor suppressor proteins
control a series of checkpoints that prevent uncontrolled
growth.
Ultimately, the growth inhibitory pathways may prod the
cells into apoptosis.
In
the sporadic form, both RB mutations in the tumor-founding retinal cell are acquired.
functions are listed in Table 7.7.
RB: Governor of Proliferation.
Its function may be com-
promised in two different ways.
• Loss-of-function mutations involving both RB alleles.
7.26).
The latter then activates
transcription of S-phase genes.
And, conversely, why are acquired mutations of
RB not found in all kinds of cancer?
TP53: Guardian of the Genome.
Less commonly, individuals inherit one
mutated TP53 allele.
TP53 encodes
the protein p53, which is tightly regulated at several levels.
Like RB, the transforming proteins
of several DNA viruses bind p53 and promote its degrada-
tion.
As a result, p53 is
virtually undetectable in normal cells.
• DNA damage and hypoxia.
The types of
damage sensed by ATM and ATR are different, but the
downstream effects are similar.
Once triggered, both ATM
and ATR stimulate the phosphorylation of p53 and
MDM2.
• “Oncogenic” stress.
p14/
ARF binds MDM2 and displaces p53, again allowing p53
levels to rise in the cell.
7.27).
• Transient p53-induced cell cycle arrest.
Rapid onset,
p53-mediated cell cycle arrest may be considered a
primordial response to DNA damage.
This pause in cell cycling
is welcome, as it gives the cells “breathing time” to repair
DNA damage.
The cells may then revert to a normal state.
• p53-induced senescence.
How cells become fixed in
the senescence state is unclear.
Senescent cells, while not normal,
cannot divide and therefore cannot develop into tumors.
• p53-induced apoptosis.
Thus the DNA repair pathway is stimulated first as
p53 begins to accumulate.
Thus
there is still much to be learned about the nuances of p53
function.
Moreover, once a cancer is
established, its p53 status has important therapeutic implica-
tions.
As with other
tumor suppressor genes, both copies of APC must be lost
for an adenoma to arise.
7.28).
WNT molecules signal by binding to cell surface recep-
tors of the frizzled (FRZ) family.
This stimulates several
pathways, the central one involving APC and β-catenin.
A major function of the APC protein is to hold β-catenin
activity in check.
Thus
β-catenin, the target of APC, is itself a proto-oncoprotein.
E-Cadherin.
This pause allows cells to repair DNA damage.
• The majority of human cancers demonstrate biallelic loss-of-
function mutations in TP53.
• Like RB, p53 is inactivated by viral oncoproteins, such as the
E6 protein of HPV.
Other Tumor Suppressor Genes.
The full panoply of tumor
suppressor genes is still being defined.
Tumor suppressor genes all appear to impact one or more
of the hallmarks of cancer.
APC: Gatekeeper of Colonic Neoplasia.
APC and β-catenin are components of the
WNT signaling pathway.
This complex leads to the destruction of β-catenin, and intracellular levels of β-catenin are low.
those that arise in the esophagus, colon, breast, ovary, and
prostate.
CDKN2A.
p16
also appears to be important in induction of cellular senes-
cence (described later).
TGF- β Pathway.
PTEN.
VHL.
Somatic mutations of VHL also
occur in a subset of sporadic renal cell carcinomas (Chapter
20).
Thus, VHL is part of the system
that regulates cellular responses to oxygen levels.
STK11.
development of thousands of colonic polyps and early-onset
colon carcinoma.
• Acquired somatic APC mutations are found in about 70% of
sporadic colon carcinomas.
• Germline loss-of-function mutations cause autosomal dominant
familial melanoma.
TGF-β pathway: potent inhibitor of cellular proliferation in normal
tissues.
PTEN: encodes a lipid phosphatase that is an important negative
regulator of PI3K/AKT signaling.
• Biallelic loss of function common in diverse cancers.
• Acquired biallelic loss-of-function mutations are common in
sporadic renal cell carcinoma.
7.29
and include the following:
• Receptor tyrosine kinase/PI3K/AKT signaling.
• MYC.
Autophagy.
7.29 and
Chapter 2).
If this adaptation fails, the cells die of starvation.
tissues such as the bone marrow).
Most tumors are PET-
positive, and rapidly growing ones are markedly so.
It
follows that growing cells do rely on mitochondrial metabo-
lism.
So how is this reprogramming of metabolism triggered
in growing normal and malignant cells?
Oncometabolism.
7.30).
According to the model, loss of TET2 activity
leads to abnormal patterns of DNA methylation.
These drugs are now being used to treat leu-
kemias with IDH mutations.
• Stress may induce cells to consume their components in a
process called autophagy.
7.31).
7.31):
• Loss of TP53 function.
• Overexpression of anti-apoptotic members of the BCL2 family.
Overexpression of BCL2 is a common event leading to
the protection of tumor cells from apoptosis.
The resulting overabundance of BCL2 protects
the transformed lymphocytes from apoptosis.
How can it be that cancer cells
have seemingly discovered the proverbial fountain of eternal
youth?
• Evasion of senescence.
As discussed in Chapter 2, most
normal human cells have the capacity to divide 60 to 70
times.
• Evasion of mitotic crisis.
7.32).
Replication of somatic cells, which do not express
telomerase, leads to shortened telomeres.
In the presence of competent checkpoints, cells undergo arrest and enter nonreplicative senescence.
If cells fail to
reexpress telomerase, they eventually undergo mitotic catastrophe and death.
likely to expire in this fashion.
However, cells in crisis
that reactivate telomerase can restore their telomeres and
survive.
Whatever the mechanism, telomere maintenance is seen
in virtually all types of cancers.
In 85% to 95% of tumors
it is due to expression of telomerase.
• Self-renewal.
7.33).
Angio-
genesis is thus an essential facet of malignancy.
How do growing tumors develop a blood supply?
Early in their development, most human tumors
do not induce angiogenesis.
• Driver mutations in certain tumor suppressors and oncogenes
favor angiogenesis.
Conversely, gain-of-function mutations in RAS
or MYC upregulate the production of VEGF.
These agents are now a part of the armamen-
tarium that oncologists use against cancers.
Why
is the metastatic process so inefficient?
The answer is
uncertain but undoubtedly relates to the complexity of the
process.
Sequential steps involved in the
hematogenous spread of a tumor.
7.34).
Throughout, we touch on some of the proposed molecular
mechanisms that underlie the process.
As shown in Fig.
7.34, tumor cells interact with the ECM
at several stages in the metastatic cascade.
This process is repeated in
reverse when tumor cells extravasate at a distant site.
Tumor cells detach from each other because of
reduced adhesiveness and attract inflammatory cells.
Proteases secreted
from tumor cells and inflammatory cells degrade the basement membrane.
Binding of tumor cells to proteolytically generated binding sites and tumor
cell migration follow.
ECM, Extracellular matrix.
inflammatory cells) to do so.
Also, what determines why metastases ultimately appear
where they do in the body?
While definitive answers to these questions are not known,
clues have emerged.
7.34), which are believed to
enhance tumor cell survival in the circulation.
However, many
exceptions to this “rule” exist.
Such migration is
accomplished by the binding of CD44 to hyaluronate on
high endothelial venules.
Solid tumors also often express
of cancers.
The third step in invasion involves changes in how
tumor cells attach to ECM proteins.
Additionally, the matrix itself is modified in ways that
promote invasion and metastasis.
• Some tissues may provide a favorable “soil” for the growth
of tumor seedlings.
Even when metastatic cells take root and survive within
distant tissues, they may fail to grow.
• The metastatic site of many tumors can be predicted by the
location of the primary tumor.
Many tumors arrest in the first
capillary bed they encounter (lung and liver, most commonly).
What host effector systems recognize tumor
cells?
How do tumors evade these host mechanisms?
And
how can immune reactions against tumors be exploited
therapeutically?
7.36).
• Cell-cell contacts are lost by the inactivation of E-cadherin
through a variety of pathways.
EBV, Epstein-Barr virus; MHC, major histocompatibility complex.
• Overexpressed or aberrantly expressed normal cellular proteins.
It may be surprising that the immune
system is able to respond to this normal self antigen.
Thus, for all practical purposes,
these antigens are tumor-specific.
Prototypic of this group
is the melanoma antigen gene (MAGE) family.
• Tumor antigens produced by oncogenic viruses.
The cellular effectors that mediate immunity
are described in Chapter 6.
Here we focus on the CTL
response to tumor antigens.
7.37), allowing the antigens to be
recognized by naïve CD8+ CTLs.
Activated macrophages also exhibit cytotoxicity against
tumor cells in vitro.
Several
mechanisms appear to be operative (Fig.
7.38).
• Selective outgrowth of antigen-negative variants.
7.39).
• Secretion of immunosuppressive factors.
Tumors may secrete
several products that inhibit the host immune response.
TGF-β is secreted in large quantities by many tumors
and is a potent immunosuppressant.
• Induction of regulatory T cells (Tregs).
• Engagement of pathways that inhibit T-cell activation.
PD-1, like CTLA-4, inhibits T-cell
activation.
MHC, Major histocompatibility complex.
• Combination of checkpoint inhibitors with other therapeutic
agents.
7.39).
Germline loss-of-function mutations in at least
four different genes can produce HNPCC syndrome.
Nucleotide Excision Repair Factors.
UV radiation causes
cross-linking of pyrimidine residues, preventing normal
DNA replication.
Such DNA damage is repaired by the
nucleotide excision repair system.
Several genes are involved
in nucleotide excision repair.
Several mechanisms contribute to genomic instability in
cancer cells.
DNA Mismatch Repair Factors.
With
“proofreading” function lost, errors accumulate throughout
the genome.
Some of these errors may by chance create
driver mutations, and with time a cancer may result.
One
of the hallmarks of mismatch-repair defects is microsatellite
instability.
Microsatellites are tandem repeats of one to six
nucleotides found throughout the genome.
In normal people
the length of these microsatellites remains constant.
Somatic driver muta-
tions in ATM also are common in certain types of lym-
phoid neoplasms.
Mutations in two genes, BRCA1
and BRCA2, account for 25% of cases.
7.32).
DNA Polymerase.
Regulated Genomic Instability in Lymphoid Cells.
BRCA1 and
BRCA2, which are mutated in familial breast cancers, are involved
in DNA repair.
• T and B cells undergo regulated genomic instability during
somatic gene rearrangements.
Errors in this process are an
important cause of lymphoid neoplasms.
• Removal of growth suppressors.
The growth of epithelial
cells is normally suppressed by cell–cell and cell–ECM
interactions.
• Enhanced resistance to cell death.
• Inducing angiogenesis.
Inflammatory cells release numerous
factors, including VEGF, which stimulate angiogenesis.
• Activating invasion and metastasis.
• Evading immune destruction.
In addition, whole chromosomes may be gained
or lost.
7.32), it can be
an early event that initiates the transformation process.
Whatever technol-
ogy is used, the study of chromosomal changes in tumor
cells is important.
Chromosomal Translocations.
Notable examples of oncogenes activated by chro-
mosomal translocations are listed in Table 7.8.
Overexpression of a proto-oncogene caused by transloca-
tion is exemplified by Burkitt lymphoma.
7.23), placing it close to the immunoglobulin heavy chain
(IGH) gene.
The genetic notation for the translocation is
t(8;14)(q24;q32).
7.23).
BCR-ABL fusion genes encode
chimeric BCR-ABL proteins with constitutive tyrosine kinase
activity.
7.40).
How this fusion gene functions is now reasonably
well understood.
Normal RAR α binds to DNA
and activates transcription in the presence of retinoids.
There also is evidence that
ATRA-bound PML-RARA complexes are degraded more
rapidly.
Deletions.
Chromosomal deletions are another very common
structural abnormality in tumor cells.
Gene Amplification.
Such amplification may produce up to
several hundred copies of the oncogene in the tumor cell.
staining regions.
7.24).
ERBB2 amplification
occurs in about 20% of breast cancers.
Complex Chromosomal Rearrangements.
Gene amplification generally increases the expression
and function of oncogenes.
• Global changes in DNA methylation.
• Changes in histones.
Cancer cells often demonstrate changes in histones near
genes that influence cellular behavior.
Remarkably, in some cancers, driver mutations occur in
the histone genes themselves.
These altered
appearances stem from disturbances of chromatin organiza-
tion.
• The epigenome is a therapeutic target.
• Cancers likely exhibit considerable epigenetic heterogeneity.
One consequence of such
heterogeneity may be drug resistance.
The best characterized of these noncoding RNAs are
microRNAs.
What
is the evidence that this is so?
These are also described in subsequent chapters.
the Danish Chimney Sweeps Guild ruled that its members
must bathe daily.
No public health measure since that time
has achieved as much in controlling a form of cancer!
Subsequently, hundreds of chemicals have been shown to
be carcinogenic in animals.
Some of the major agents are
listed in Table 7.10.
Chemical Carcinogenesis
As discussed earlier, carcinogenesis is a multistep process.
It causes permanent DNA damage (mutations).
Application of promoters
leads to proliferation and clonal expansion of initiated
(mutated) cells.
With this brief overview,
initiation and promotion can be examined in more detail
(Fig.
7.41).
Their targets are DNA, RNA, and proteins, and in some
cases these interactions cause cell death.
The mutated cell then passes on
the DNA lesions to its daughter cells.
This is not to say that mutations induced by carcinogens
occur in an entirely random fashion.
The risk
of induced cancer is low, but its existence dictates judicious
use of such agents.
7.41).
Many other occupational carcinogens are listed in
Table 7.10.
Most indirect carcinogens are metabolized by cytochrome
P-450–dependent monooxygenases.
Approximately
10% of the white population carry a highly inducible form
of this gene.
Molecular Targets of Chemical Carcinogens.
There is no single or unique
alteration associated with cancer initiation.
Hence, polymorphisms of endogenous
enzymes such as cytochrome P-450 may influence
carcinogenesis.
The incidence peaked during 1988–1992
and then declined.
Of these, UVB is believed to be
responsible for the induction of cutaneous cancers.
UVB light is carcinogenic because of its ability to cause
pyrimidine dimers to form in DNA.
The evidence is voluminous, and a few examples suffice.
Many individuals pioneering the use of x-rays developed
skin cancers.
Most telling is the follow-up of survivors
of the atomic bombs dropped on Hiroshima and Nagasaki.
Most frequent are myeloid leukemias (tumors of granulocytes
and their precursors; see Chapter 13).
Cancer of the thyroid
follows closely but only in young patients.
In the intermediate
category are cancers of the breast, lungs, and salivary glands.
• UV rays induce the formation of pyrimidine dimers within DNA,
leading to mutations.
Therefore UV rays can give rise to skin
cancers.
Despite intense
scrutiny, however, only a few viruses have been linked
with human cancer.
Our discussion focuses on human
oncogenic viruses as well as the role of the bacterium H.
pylori in gastric cancer.
HHV8 is discussed in Chapters 6 and 11.
Although not a DNA virus, HCV is also associated with
cancer and is discussed here briefly.
Human Papillomavirus.
At least 70 genetically distinct
types of HPV have been identified.
Some types (e.g., 1, 2,
4, and 7) cause benign squamous papillomas (warts) in
humans.
These
cancers are sexually transmitted diseases caused by chronic
HPV infection.
What explains the variation in cancer risk among HPV
strains?
7.42).
• Oncogenic activities of E6.
Oncogenic RNA Viruses
Human T-Cell Leukemia Virus Type 1.
Worldwide, it is estimated that 15 to 20 million people are
infected with HTLV-1.
In leukemic cells, however,
viral integration shows a clonal pattern.
7.26).
TERT,
Telomerase reverse transcriptase.
• Oncogenic activities of E7.
E7 also inactivates the CDK inhibitors p21 and p27.
Thus,
it is evident that HPV proteins promote many of the
hallmarks of cancer.
However,
infection with HPV itself is not sufficient for carcinogenesis.
Cotransfection
with a mutated RAS gene results in full malignant trans-
formation.
Epstein-Barr Virus.
This probably occurs in the tonsils
following exposure to the virus in saliva.
Concurrently, LMP-1 prevents apoptosis
by activating BCL2.
EBNA-2
transactivates several host genes, including cyclin D and
the SRC family of proto-oncogenes.
A morphologically
identical lymphoma occurs sporadically throughout the
world.
• All affected patients have elevated antibody titers against
viral capsid antigens.
(2) The EBV genome is found in
only 15% to 20% of Burkitt lymphomas outside of endemic
regions.
Given these observations, how then does EBV contribute
to the genesis of endemic Burkitt lymphoma?
One possibility
is shown in Fig.
7.43.
These cells persist indefinitely,
even in the face of normal immunity.
Lymphoma cells may326 CHAPTER 7 Neoplasia
can evolve into monoclonal neoplasms.
Nasopharyngeal carcinoma also is strongly associated with
EBV.
This tumor is endemic in southern China, parts of
Africa, and the Inuit population of the Arctic.
Hepatitis B and C Viruses.
Worldwide, 70% to 85% of
hepatocellular carcinomas are associated with infection
with HBV or HCV.
CTLs, Cytotoxic T lymphocytes.
The role played by EBV is more direct in B-cell lym-
phomas arising in immunosuppressed patients.
Although not a DNA virus, HCV is also strongly linked
to the pathogenesis of liver cancer.
The molecular mecha-
nisms used by HCV are less well defined than are those of
HBV.
Helicobacter pylori
First incriminated as a cause of peptic ulcers, H.
Indeed, H.
The proposed scenario for the development of gastric
adenocarcinoma in the setting of H.
The H.
pylori genome also contains genes
directly implicated in oncogenesis.
Although H.
This sequence takes decades to
complete and occurs in only 3% of infected patients.
H.
Their molecular pathogenesis is incom-
pletely understood but seems to involve strain-specific H.
It is thought that H.
pylori infection leads
to the appearance of H.
pylori–reactive T cells, which in turn
stimulate a polyclonal B-cell proliferation.
At this stage, eradica-
tion of H.
pylori by antibiotic therapy “cures” the lymphoma
by removing the antigenic stimulus for T cells.
HPV: an important cause of benign warts, cervical cancer, and
oropharyngeal cancer.
• HPV cancers can be prevented by vaccination against high-risk
HPV types.
HBV and HCV: cause of 70% to 85% of hepatocellular carcinomas
worldwide.
H.
pylori: implicated in gastric adenocarcinoma and MALToma.
• Pathogenesis of H.
• H.
• Chronic H.
It is likely that additional mechanisms underlying
cancer cachexia await discovery.
These occur in
about 10% of persons with cancer.
• In affected patients they can cause significant clinical
problems and may even be lethal.
• They may mimic metastatic disease and therefore con-
found treatment.
A classification of paraneoplastic syndromes and their
presumed origins is presented in Table 7.11.
A few comments
on some of the more common and interesting syndromes
follow.
Endocrinopathies are frequently encountered paraneoplastic
syndromes.
Cushing syndrome
is the most common endocrinopathy.
Approximately 50%
of affected individuals have carcinoma of the lung, chiefly
the small-cell type.
The precursor of corticotropin is a
large molecule known as pro-opiomelanocortin.
The former
is not found in serum of patients with excess corticotropin
produced by the pituitary.
Neoplasms in the gut, both benign and malignant,
may cause obstruction as they enlarge.
Mortality is generally the consequence of atrophy of the
diaphragm and other respiratory muscles.
Only the second
mechanism is considered to be paraneoplastic.
As its name implies, PTHRP has
partial structural homology to parathyroid hormone (PTH).
association of squamous cell carcinomas with PTHRP-
induced hypercalcemia.
It occurs rarely as a genetically
determined disease in juveniles or adults (Chapter 25).
These skin changes may appear before the cancer is
discovered.
Hypertrophic osteoarthropathy is encountered in 1% to 10%
of patients with lung carcinoma.
Rarely, other forms of cancer
are involved.
The cause is unknown.
• Grading.
• Staging.
The major staging system currently in use is
the American Joint Committee on Cancer Staging.
TNM staging varies for
specific forms of cancer, but there are general principles.
The primary lesion is characterized as T1 to T4 based on
increasing size.
T0 is used to indicate an in situ lesion.
This method permits histologic evalu-
ation within minutes.
Better to wait a day or two,
despite the delay, than to perform inadequate or unnecessary
surgery.
Fine-needle aspiration of tumors is another approach that
is widely used.
While it may
be confounded by sampling errors, in experienced hands
it is rapid and quite reliable.
Cytologic smears provide yet another method for cancer
detection (Chapter 22).
7.44).
Histologic and Cytologic Methods.
The laboratory
diagnosis of cancer is, in most instances, not difficult.
Radiation changes in the skin or mucosa can be similar to
those associated with cancer.
Sections taken from a healing
fracture can mimic an osteosarcoma.
It must be adequate, representa-
tive, and properly preserved.
• Determination of site of origin of metastatic tumors.
Many
cancer patients present with metastases.
• Detection of molecules that have prognostic or therapeutic
significance.
In general, receptor-positive breast cancers have a
better prognosis than receptor-negative tumors.
so-called targeted therapies, drugs that are directed at
Flow Cytometry.
Flow cytometry rapidly and quantitatively
mutated oncoproteins.
Immunohistochemistry.
• Categorization of undifferentiated malignant tumors.
There are no malignant cells.
(Courtesy Dr.
P.
K.
(Courtesy Dr.
These include B-cell and T-cell lymphomas
and leukemias as well as myeloid neoplasms.
Circulating Tumor Cells.
Molecular Diagnostics and Cytogenetics.
• Diagnosis of malignant neoplasms.
• Prognosis of malignant neoplasms.
• Detection of minimal residual disease.
• Diagnosis of hereditary predisposition to cancer.
Such analysis usually requires detection
of a specific mutation or sequencing of the entire gene.
The latter is necessary when several different cancer-
associated mutations are known to exist.
• Guiding therapy with oncoprotein-directed drugs.
• Identifying mechanisms of drug resistance: liquid biopsies.
Thus, we are living in the age of “omics”!
7.46), which provide a snapshot of all of
the genetic alterations that exist in a particular tumor.
The main impact of cancer genome sequencing to date
has been in the area of research.
One goal of these analyses is to
identify therapeutically “actionable” genetic lesions.
Other clinically useful information is obtained, however.
Each of the 24 chromosomes in the cancer is
displayed in a circle.
c, Copy
number profiles, showing copy number losses (in red) and copy gains (in
blue).
d, Point mutations, represented as red dots.
additional tests of this type.
7.47).
7.48).
In principle, all of these diverse
“BRAFomas” are candidates for treatment with BRAF
inhibitors.
Thus, what lies ahead is not the replacement of one set of
techniques by another.
A host of tumor markers have been described, and new
candidates are identified every year.
Only a few have stood
the test of time and proved to have clinical usefulness.
Prostatic carcinoma can be suspected when elevated
levels of PSA are found in the blood.
However, PSA screening
highlights problems encountered with virtually every tumor
marker.
Furthermore, there is no PSA level that
ensures that a person does not have prostate cancer.
These
limitations are discussed in detail in Chapter 18.
(Courtesy
Dr.
An alternative approach is to
measure many cancer-associated markers simultaneously.
Get ready!
• Assays of circulating tumor cells and tumor DNA are under
development.
Their utility lies in their ability to follow
response to therapy.
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Frank • Alexander J.
In these regions of the world, five of the ten leading
causes of death are infectious diseases.
Thus, their
presence is diagnostic of an infection.
Most skin infections are
initiated by mechanical injury of the epidermis.
The injury
may range from minor trauma to large wounds, burns, and
pressure-related ulcers.
The gastrointestinal
tract has several local defenses.
Uptake through M cells Poliovirus, Shigella spp., Salmonella spp.
Antimicrobial defensins are produced by gut
epithelial cells.
Peristalsis can clear organisms, preventing their local
overgrowth.
Many common gastrointestinal
pathogens are resistant to local defenses.
• Bacterial colonoization and toxin production.
Other bacteria
establish an infection and produce damaging toxins.
Examples include V.
These organisms
elaborate potent exotoxins that are responsible for
symptomatic disease.
• Adhesion and mucosal invasion.
Attachment induces the host cell to endo-
cytose the virus, leading to viral entry and replication.
Other organisms establish disease when local or systemic
defenses are impaired.
in patients with neutropenia.
Urogenital Tract
Urine contains small numbers of low-virulence bacteria.
The urinary tract is protected from infection by regular
emptying during micturition.
Urinary tract pathogens (e.g.,
E.
Expulsion
of urine from the bladder eliminates microbes.
Antibiotics can kill the lactobacilli
and allow overgrowth of yeast, causing vaginal candidiasis.
Examples
include gonococcal and chlamydial conjunctivitis.
8.1).
Pathogens
can spread within the body in several ways.
Pathogens vary in hardiness in the environment.
Most pathogens are transmitted from person to person
by respiratory, fecal-oral, or sexual routes.
cholera,
Shigella spp., C.
jejuni, and S.
enterica.
There are several additional routes of transmission.
To enter the
body, microbes penetrate the epithelial or mucosal barriers.
Infection may
remain localized at the site of entry or spread to other sites in the body.
However, certain viruses and bacterial toxins may also travel through
nerves.
Microbes undergo continuous evolution to combat
host defenses.
8.2).
• Antigenic variation.
and trypanosomes).
• Resistance to antimicrobial peptides.
Pathogens, such as
Shigella spp., S.
• Resistance to killing by phagocytes.
The carbohydrate capsule
on the surface of many bacteria (S.
S.
• Evasion of apoptosis and manipulation of host cell metabolism.
• Resistance to cytokine-, chemokine- and complement-mediated
host defense.
• Evasion of recognition by CD8 + cytotoxic T lymphocytes (CTLs)
and CD4 + helper T cells.
Tumors
exploit the same mechanisms to suppress destructive
immune responses (Chapter 7).
Opportunistic
organisms (e.g., Aspergillus spp.
and Pseudomonas spp.) cause
significant disease in these patients.
tuberculosis).
Age-related decline in
immune function may increase infections in the elderly.
pneumoniae in people with sickle cell disease
due to loss of splenic macrophages, and P.
aeruginosa in
burns due to barrier disruption.
Finally, malnutrition can
impair immune defenses.
pneu-
moniae, H.
influenzae, and S.
aureus, as well as a few viruses
(rotavirus and enteroviruses).
aureus, some gram-negative bacteria, and fungi.
The granulomatous inflammatory
reaction to M.
pneumoniae), and
impaired TLR3 responses are associated with childhood
HSV encephalitis.
The predilection for viruses
to infect certain cells and not others is called tropism.
A major
determinant of tissue tropism is the presence of viral
receptors on host cells.
This is presumably one way in which viruses
evolve to infect, survive within cells, and spread.
Other tropisms are explained by cell-lineage–spe-
cific factors.
Physical barriers can contribute to tissue tropism.
8.3):
• Direct cytopathic effects.
unaffected.
• Antiviral immune responses.
• Transformation of infected cells.
Mechanisms of Bacterial Injury
Bacterial Virulence.
Pathogenic bacteria have virulence genes that encode proteins
responsible for these properties.
An example of the impor-
tance of such genes can be found in the various strains of
S.
enterica.
All S.
Differences in a rela-
tively small number of virulence genes determine whether
an isolate of S.
enterica causes life-threatening typhoid fever
or self-limited enteritis.
Virulence genes are frequently found
grouped together in clusters called pathogenicity islands.
aureus.
aureus), competence for genetic transformation (S.
pneu-
moniae), or generation of biofilms (P.
aeruginosa).
Bacterial Adherence to Host Cells.
Bacteria use various
surface structures to attach to host cells and tissues.
Adhesins
have a broad range of host cell specificity.
• Pili are filamentous structures on the surface of bacteria
that act as adhesins.
The precise tissue-tropism of E.
Pili can be
targets of the host antibody response and, in turn, some
bacteria such as N.
gonorrhoeae vary their pili to escape
from the host immune system.
Intracellular Bacteria.
Bacteria have evolved a variety of
mechanisms for entering host cells.
M.
Some gram-
negative bacteria use a type III secretion system to enter
epithelial cells.
Shigella spp.
and E.
coli inhibit host protein synthesis, replicate
rapidly, and lyse the host cell within hours.
M.
L.
In the cytoplasm, L.
An example of the latter is the
migration of infected macrophages carrying M.
tuberculosis
from the lung to draining lymph nodes and other more
distant sites.
Bacterial Toxins.
Any bacterial substance that contributes
to illness can be considered a toxin.
Exotoxins are secreted bacterial proteins that cause
cellular injury and disease.
They can be classified into broad
categories by their mechanism of action.
• Enzymes.
These enzymes
have roles in tissue destruction and abscess formation.
For example, exfoliative toxins produced by S.
• Toxins that alter intracellular signaling or regulatory pathways.
A-B toxins are made by many bacteria including
Bacillus anthracis, V.
cholerae, and some strains of E.
coli.
The
high levels of cytokines can lead to systemic inflammatory
response syndrome.
• Pathogens can induce immune responses that cause tissue
damage.
Similarly, in a patient
who is not immunocompromised, M.
There are five major histologic patterns of tissue reaction
in infections (Table 8.3).
3.15).
Masses of dying and dead neutrophils and liquefactive
necrosis of the tissue form pus.
How destructive the lesions are depends on their
location and the organism involved.
For example, S.
Bacterial pharyngitis
(S.
In addition, spirochetes and helminths provoke chronic
inflammatory responses.
For example, plasma
cells are abundant in the primary and secondary lesions of
syphilis (Fig.
8.4), whereas lymphocytes predominate in
HBV infection or viral infections of the brain.
• Infectious agents cause death or dysfunction by directly interact-
ing with the host cells.
Focal cell
damage in the skin may cause epithelial cells to become
detached, forming blisters (Fig.
8.5).
Finally, viruses can contribute to
the development of malignant neoplasms (Chapter 7).
At the other
extreme, macrophages may become filled with organisms,
as occurs in M.
tuberculosis,
Histoplasma capsulatum, schistosome eggs).
Figure 8.5 Herpesvirus blister in mucosa.
See Fig.
The parasite E.
8.6] or the constrictive fibrous pericarditis in tuberculosis).
Infections
that typically involve a specific organ are discussed in other
chapters.
In recent years, such outbreaks have occurred
several times each year in the United States.
There is only one serotype of
measles virus.
Three cell-surface receptors have been identified for measles
hemagglutinin protein.
Measles can replicate in a variety of cell types, including
epithelial cells and leukocytes.
Hence, the rash is less frequent in people with deficien-
cies in cell-mediated immunity.
Subacute sclerosing panencephalitis
Fi e 8.7 Measles giant cells in the lung.
immunocompromised individuals) are rare late complications
of measles.
Antibody-mediated immunity to measles virus protects
against reinfection.
8.7).
Like
measles virus, mumps virus is a member of the Paramyxo-
viridae family.
Mumps virus also can spread to other sites, including the
CNS, testis, ovary, and pancreas.
Poliovirus, like other enteroviruses, is transmitted by the
fecal-oral route.
The neurologic features and neuropathology of
poliovirus infection are described in Chapter 28.
West Nile virus is transmitted by
mosquitoes to birds and to mammals.
Infected birds develop
prolonged viremia and are the major reservoir for the virus.
Humans are incidental hosts.
A macu-
lopapular rash is seen in approximately one-half of cases.
Immunosuppressed persons
and older adults appear to be at the greatest risk for severe
disease.
Rare complications include hepatitis, myocarditis,
and pancreatitis.
The testicular damage can lead to scarring,
atrophy, and, if severe, sterility.
Poliovirus is a spherical, unencapsulated RNA virus
of the enterovirus genus.
Damage to blood vessels is often prominent.
A second outbreak
in the Democratic Republic of Congo occurred in 2019.
Ebola carries a very high mortality
rate, about 40% during the 2019 outbreak.
Two viral
proteins, VP24 and VP35, inhibit the action of type I IFN.
Large outbreaks occurred in the State of
Yap in 2007 and French Polynesia in 2013 to 2014.
Zika virus is transmitted by Aedes mosquitos, primarily
Aedes aegypti.
The rate of adverse
effects on newborns has been higher in Brazil than in other
nations.
There are
four serotypes of dengue virus.
The clinical manifestations ranged
from mild to severe respiratory illness.
The vast majority of
individuals who contract the virus recover after a flu-like
disease.
The genomic sequence shows COVID-19 is
related to bat coronaviruses and the SARS coronavirus.
Dissemination
of the infection and tissue injury stem from reactivation of
the latent virus.
The viruses that most frequently establish
latent infections in humans are herpesviruses.
8.8).
(A) Subcortical band of degenerating cells
with prominent calcifications.
(B) Cortex with degenerating neurons
(arrows).
No viral proteins appear to be
produced during latency.
HSV-1 is also the major
cause of fatal sporadic encephalitis in the United States.
8.9).
Due to cell fusion, HSV
also produces inclusion-bearing multinucleated syncytia.
Gingivostomatitis, which is usually encountered in children,
is caused primarily by HSV-1.
Genital herpes is more often caused by HSV-2 than by
HSV-1.
Two forms of corneal lesions are caused by HSV (Chapter
29).
Herpes epithelial keratitis shows typical virus-induced
cytolysis of the superficial epithelium.
Herpes simplex encephalitis is described in Chapter 28.
Herpes esophagitis is frequently compli-
cated by superinfection with bacteria or fungi.
Chickenpox is mild in children but more severe in
adults and in immunocompromised people.
Shingles is a
source of morbidity in older and immunosuppressed persons.
Also like HSV, VZV evades
immune responses and establishes a latent infection in
sensory ganglia.
Figure 8.10 Skin lesion of chickenpox (varicella-zoster virus) with
intraepithelial vesicle.
show intraepithelial vesicles (Fig.
8.10) with intranuclear inclusions
in epithelial cells at the base of the vesicles.
Similar to HSV, patients with mutations in TLR3 have an
increased risk of VZV encephalitis.
MORPHOLOGY
The chickenpox rash occurs approximately 2 weeks after
respiratory infection.
Lesions appear in multiple waves centrifugally
from the torso to the head and extremities.
Note the ganglion cell necrosis and associated inflammation.
(Courtesy Dr.
Transmission of CMV can occur by several routes,
depending on the age group affected.
CD4+ T cells, γδ T cells,
and NK cells are known to play a role in immune control of
the infection.
Thus, CMV both hides
from and actively suppresses immune responses.
Figure 8.12 Cytomegalovirus: distinct nuclear and ill-defined cytoplasmic
inclusions in the lung.
CMV causes focal necrosis with minimal inflammation in virtually
any organ.
Congenital Infections.
Infection acquired in utero may
take many forms.
In approximately 95% of cases, it is
asymptomatic.
Cytomegalic inclusion disease
resembles erythroblastosis fetalis.
Perinatal Infections.
Subtle effects on
hearing and intelligence later in life have been reported in
some studies.
CMV Mononucleosis.
In healthy young children and
adults, the disease is nearly always asymptomatic.
8.12).
Within the cytoplasm of infected cells, smaller basophilic
inclusions can also be seen.
The diagnosis is made by
serology.
CMV in Immunosuppressed Individuals.
In the past, CMV was the most common
opportunistic viral pathogen in AIDS.
The pneumonitis can progress to full-blown acute respiratory
distress syndrome.
HIV and HBV infection are described in
Chapters 6 and 18, respectively.
Oncogenic viruses can stimulate cell
growth and survival by a variety of mechanisms.
Only
infectious mononucleosis is discussed here.
Some people develop
hepatitis, meningoencephalitis, and pneumonitis.
EBV infects B cells and possibly epithelial
cells of the oropharynx.
Infection of B cells may take one of two forms.
These
so-called heterophile antibodies are detected in diagnostic tests
for mononucleosis.
The symptoms of infectious mononucleosis appear on
initiation of the host immune response.
The liver is usually involved to some degree, although hepa-
tomegaly is at most moderate.
This histologic picture is similar to that of other forms
of viral hepatitis.
One or more complications
occasionally supervene.
Splenic rupture
can occur even with minor trauma, leading to hemorrhage
that may be fatal.
This rare inherited immunodeficiency is char-
acterized by an ineffective immune response to EBV.
Patients
are usually normal until they are acutely infected with EBV,
often during adolescence.
In more than half the cases, EBV
causes an acute overwhelming infection that may be fatal.
tions related to hypogammaglobulinemia.
Similar changes commonly occur in the tonsils and lymphoid
tissue of the oropharynx.
The spleen is enlarged in most cases, weighing between 300
and 500 g.
It is usually soft and fleshy, with a hyperemic cut surface.
Staphylococcal Infections
S.
8.14).
S.
aureus is a pyogenic
gram-positive coccus that forms clusters resembling bunches
of grapes.
The general characteristics of S.
aureus infection
are reviewed in the following sections.
Infections of specific
organs are described in other chapters.
Coagulase-negative
staphylococci, such as S.
S.
saprophyticus is a common cause of urinary tract infection
in young women.
Pathogenesis
S.
S.
S.
Selected examples of the most common
or clinically significant infections are discussed next.
S.
aureus Toxins.
S.
aureus produces multiple membrane-
damaging (hemolytic) toxins.
S.
aureus γ-toxin and leukocidin lyse
red cells and phagocytes, respectively.
The exfoliative A and B toxins produced by S.
Superantigens produced by S.
aureus cause food poisoning
and toxic shock syndrome (TSS).
aureus during
use.
It is now clear that TSS can be caused by growth of S.
aureus at many sites, most commonly the vagina and infected
surgical sites.
If not promptly treated, it
can be fatal.
TSS can also be caused by S.
pyogenes.
Superantigens
produced by S.
Antibiotic resistance is a growing problem in treatment
of S.
aureus infections.
Methicillin-resistant S.
aureus (MRSA)
are resistant to nearly all penicillin and cephalosporin
antibiotics.
As a result, empirical treatment of
S.
aureus infections with cephalosporin antibiotics is not
recommended.
face, axillae, groin, legs, and submammary folds.
Hidradenitis is chronic suppurative infection of apocrine glands,
most often in the axilla.
S.
aureus lung infections (Fig.
8.15) have a polymorphonuclear
infiltrate similar to that of S.
pneumoniae infections (see Fig.
3.18B),
but they cause much more tissue destruction.
aureus infection
of the nasopharynx or skin.
These bacteria are gram-positive cocci that grow in pairs or
chains.
aureus causes pyogenic inflammation that is
distinctive for its local destruction of host tissue.
A furuncle, or boil, is a focal
suppurative inflammation of the skin and subcutaneous tissue.
They may be solitary, or multiple, or recur in successive crops.
3.18B).
S.
S.
Streptococcus
mutans is the major cause of dental caries.
Pathogenesis
The different species of streptococci produce many virulence
factors and toxins.
S.
pyogenes, S.
agalactiae, and S.
pneumoniae
have capsules that resist phagocytosis.
S.
S.
pyogenes secretes
a phage-encoded pyrogenic exotoxin that causes fever and
rash in scarlet fever.
Virulent S.
Although the antiphagocytic
capsule is the most important virulence factor of S.
S.
Figure 8.16 Streptococcal erysipelas.
distribution on the face (Fig.
8.16).
Microabscesses may be formed, but tissue necrosis is usually minor.
Scarlet fever, associated with pharyngitis caused by S.
pyogenes,
is most common between 3 and 15 years of age.
S.
pneumoniae is an important cause of lobar pneumonia
(Chapter 15).
Respiratory diphtheria causes pharyngeal or, less often,
nasal or laryngeal infection.
Damage to the heart, nerves,
and other organs may be present.
C.
diphtheriae produces a phage-
encoded A-B toxin that blocks host cell protein synthesis.
This inhibits EF-2 function, which is required for
the translation of mRNA into protein.
Erysipelas is caused by exotoxins from superficial infec-
tion with S.
pyogenes.
monocytogenes infection.
In pregnant women,
L.
monocytogenes causes an amnionitis that may result in
abortion, stillbirth, or neonatal sepsis.
L.
monocytogenes is a facultative intracellular pathogen.
The bacteria bind to receptors on host epithelial cells and
macrophages and are phagocytosed.
This generates force to propel
the bacteria into adjacent, uninfected host cells.
Accordingly,
an effective host response to L.
MORPHOLOGY
Inhaled C.
The bacteria also form satellite
lesions in the esophagus or lower airways.
8.17).
Outbreaks of L.
In the United States, all clinical isolates of L.
monocytogenes have been typed for epidemiologic surveillance
MORPHOLOGY
In acute infections, L.
monocytogenes evokes an exudative pattern
of inflammation with numerous neutrophils.
The meningitis due
to L.
The finding of gram-positive bacilli in the
CSF is virtually diagnostic.
More varied lesions may be
encountered in neonates and immunosuppressed adults.
In infections of longer
duration, macrophages appear in large numbers, but granulomas
are rare.
Infants born with L.
A smear of the meconium will disclose
the gram-positive bacilli.
Livestock become infected by spores in their
environment or feed.
In 1979, accidental release of B.
anthracis spores
Figure 8.17 Membrane of diphtheria (arrow) lying within a transverse
bronchus.
(Courtesy Dr.
Robin A.
In 2001, 22 people in the United States were infected with
B.
anthracis, mostly through domestic bioterrorism with
spores delivered in the mail.
Bacteremia is rare.
• Inhalational anthrax occurs when airborne spores are
inhaled.
Frequently,
meningitis develops from bacteremia.
Inhalational anthrax
rapidly leads to shock and frequently death within 1 to
2 days.
• Gastrointestinal anthrax is usually contracted by eating
undercooked meat contaminated with B.
anthracis.
Mortality is approximately 40%.
Pathogenesis
B.
anthracis produces potent toxins and an antiphagocytic
polyglutamyl capsule.
The mechanisms of action of anthrax
toxins are well understood (Fig.
8.18).
There are two A
subunits and one B subunit.
PA is not toxic, but it serves to
deliver the toxic EF and LF into cells.
The bacterium releases
each subunit as a separate protein.
PA binds to a cell surface
receptor that is highly expressed on endothelial cells.
In the cytoplasm, EF binds to calcium and
calmodulin to form an adenylate cyclase.
LF has a different
mechanism of action.
LF is a protease that destroys mitogen-
activated protein kinase kinases (MAPKKs).
The
mechanism of cell death caused by dysregulation of MAPKs
is not understood.
Hemorrhagic lung lesions
associated with vasculitis are also present in about one-half of
cases.
B.
8.19).
are aerobic gram-positive bacteria found
in soil that cause opportunistic infections.
The organism
grows in distinctive branched chains.
In culture, Nocardia
form thin aerial filaments resembling hyphae.
Despite this
morphologic similarity to molds, Nocardia are true bacteria.
Nocardia spp.
Respiratory infection with
Nocardia spp.
In some cases, Nocardia spp.
infections
disseminate from the lungs to the CNS.
Infections of the
Ca2+
Calmodulin
Lethal
factor
MAPKKs
Edema
factor
cAMP
?
EDEMA
CELL DEATH
Figure 8.18 Mechanism of action of anthrax toxins.
pneumoniae
and cephalosporin-resistant N.
gonorrhoeae.
Only a few
gram-negative bacteria are discussed in this section.
Anaerobic gram-negative organisms are
considered later in this chapter.
Gram-negative bacterial
infections are usually diagnosed by culture.
Neisserial Infections
Neisseria spp.
Pathogenic Neisseria
spp.
usually lack this ability.
The two clinically sig-
nificant Neisseria spp.
are N.
meningitidis and N.
gonorrhoeae.
N.
The organism is a common colonizer of the oropharynx
and is spread by the respiratory route.
There are several
capsular serotypes of N.
meningitidis, however five of them
cause most cases of meningitis.
N.
Highly
effective conjugate vaccines for N.
meningitidis (A, C,
W, and Y), and recombinant protein vaccines are available
for serogroup B.
Even in the absence of preexisting immunity, only a small
fraction of people infected with N.
meningitidis develop
meningitis.
The bacteria must invade respiratory epithelial
cells and enter the blood.
The importance of complement as
a first-line defense against N.
If N.
meningitidis escapes the host response,
the consequences can be severe.
Although antibiotic treatment
greatly reduces the mortality of N.
meningitidis infection,
about 10% of infected patients still die.
The pathology of
pyogenic meningitis is discussed in Chapter 28.
N.
It is second only to C.
tra-
chomatis among bacterial STIs.
Infection in men causes
urethritis.
In women, N.
(Courtesy Dr.
Lev
Grinberg, Department of Pathology, Hospital 40, Ekaterinburg, Russia, and
Dr.
N.
brasiliensis causes
skin infections following injuries contaminated with soil.
MORPHOLOGY
Nocardia spp.
appear in tissue as slender gram-positive organisms
arranged in branching filaments (Fig.
8.20).
Irregular staining gives
the filaments a beaded appearance.
Nocardia spp.
Nocardia spp.
elicit a
suppurative response with central liquefaction and surrounding
granulation and fibrosis.
Granulomas do not form.
Gram-Negative Bacterial Infections
There are a large number of gram-negative bacterial patho-
gens.
Note
the beaded, branched gram-positive organisms and leukocytes.
(Courtesy
Dr.
Infection is
diagnosed by culture and PCR tests.
Ceftriaxone-resistant N.
gonorrhoeae is
rare but has been detected in Canada and Japan.
Although N.
Like N.
meningitidis, N.
Neonatal
N.
gonorrhoeae infection causes conjunctivitis that may lead
to blindness and, rarely, sepsis.
Pathogenesis
Neisseria spp.
Adherence of N.
to epithelial cells and promote entry of bacteria
into cells.
Neisseria spp.
use antigenic variation as a strategy to
escape the immune response.
The existence of multiple
capsular serotypes of N.
In addition, Neisseria spp.
• Expression of different OPA proteins.
These changes
shift the reading frame of the gene so that it encodes
new sequences.
Thus, Neisseria spp.
can
express one, none, or multiple OPA proteins at any time.
Infants younger than 1 year
of age are at highest risk of death.
Children with pertussis
can have coughing spells for up to 10 weeks.
It is hypothesized that modifica-
tions of B.
pertussis may also be playing a role, but this
is unproven.
Pathogenesis
B.
pertussis colonizes the brush border of the bronchial
epithelium and also invades macrophages.
Virulence factors of B.
Pertussis toxin
is a typical A-B toxin that is composed of five subunits.
B.
MORPHOLOGY
Bordetella spp.
8.21).
Unless superinfected, the lung
alveoli remain open and intact.
MORPHOLOGY
Pseudomonas spp.
8.22).
aeruginosa infection.
Bronchial obstruction caused by mucus plugging and subsequent
P.
aeruginosa infection are frequent complications of cystic fibrosis.
Despite antibiotic treatment and the host immune response,
chronic P.
aeruginosa infection may result in bronchiectasis and
pulmonary fibrosis (Chapter 15).
In skin burns, P.
aeruginosa proliferates widely, penetrating deeply
into the veins and spreading hematogenously.
DIC is a frequent complication of
P.
aeruginosa bacteremia.
(Images courtesy Dr.
Many
people with cystic fibrosis die of pulmonary failure secondary
to chronic infection with P.
aeruginosa.
This bacterium can be
very resistant to antibiotics, making these infections difficult
to treat.
It often infects extensive skin burns, which can lead
to sepsis.
P.
Pathogenesis
P.
aeruginosa produces several toxins that contribute to local
tissue damage.
Wild rodents in the rural western United States are
infected with Y.
pestis and are the source of about 10 to 15
human cases every year.
In 2017, an outbreak in Madagascar
resulted in over 2400 cases and more than 200 deaths.
Y.
enterocolitica and Y.
pseudotuberculosis are genetically similar
to Y.
The bacterial gene regulation shifts on sensing reloca-
tion from the insect gut to the human host.
Y.
Over several days, the surface
of the primary lesion erodes to produce an irregular, painful ulcer.
The base
of the ulcer is covered by shaggy, yellow-gray exudate.
MORPHOLOGY
Y.
Fulminant bacteremia also induces DIC with widespread
hemorrhages and thrombi.
As the lesion enlarges, its borders
become raised and indurated.
Silver stains (e.g., the Warthin-
Starry stain) may also demonstrate the organism.
Chancroid (Soft Chancre)
Chancroid is an acute, ulcerative STI caused by Haemophilus
ducreyi.
They are weakly gram-positive.
• Replication in macrophages.
M.
Coronin activates the phosphatase calcineurin, leading
to inhibition of phagosome-lysosome fusion.
Despite the
bacteremia, most people at this stage are asymptomatic
or have a mild flulike illness.
• Innate immunity.
Multiple pathogen associated molecular
patterns (Chapter 6) made by M.
tuberculosis are recog-
nized by innate immune receptors.
Mycobacterial lipo-
arabinomannan binds TLR2, and unmethylated CpG
nucleotides bind TLR9.
These interactions initiate and
enhance the innate and adaptive immune responses to
M.
tuberculosis, as described below.
• The Th1 response.
Stimulation of TLR2 by mycobacterial
ligands promotes production of IL-12 by dendritic cells.
• Th1-mediated macrophage activation and killing of bacteria.
Th1 cells, both in lymph nodes and in the lung, produce
IFN-γ.
IFN-γ is the critical mediator that activates mac-
rophages and enables them to contain the M.
tuberculosis
infection.
Second,
IFN-γ stimulates expression of inducible nitric oxide (NO)
synthase, which produces NO.
Third, IFN-γ
mobilizes antimicrobial peptides (defensins) against the
bacteria.
tuberculosis.
• Granulomatous inflammation and tissue damage.
tuberculosis, and the leading
infectious cause of death worldwide.
The mortality due to tuberculosis is
falling by 3% per year.
Tuberculosis flourishes wherever there is poverty, crowd-
ing, and chronic debilitating illness.
It is important that infection with M.
tuberculosis be
differentiated from active disease.
Viable organisms may remain dormant in such lesions for
decades.
Infection by M.
8.23).
Early in infection, M.
The steps in infection are
as follows:
• Entry into macrophages.
M.
(A) Events occurring during early infection, before activation of T-cell–
mediated immunity.
(B) The initiation and consequences of T-cell–mediated immunity.
IFN-γ, interferon-gamma; MHC, major histocompatibility complex; MTb, M.
tuberculosis; TNF, tumor necrosis factor.
• Host susceptibility to disease.
In summary, immunity to M.
tuberculosis is primarily
mediated by Th1 cells, which stimulate macrophages to
kill the bacteria.
tuberculosis (Fig.
8.24).
Clinically significant disease develops in about 5%
of newly infected people.
With primary tuberculosis, the
source of the organism is exogenous.
The diagnosis of progressive
primary tuberculosis in adults can be difficult.
(Modified from a sketch provided by Professor R.
K.
Secondary tuberculosis is the pattern of disease that
arises in a previously sensitized host.
On the other hand,
cavitation occurs readily in the secondary form.
Localized secondary tuberculosis may be asymptomatic.
When manifestations appear, they are usually insidious in
onset.
Some degree of hemoptysis is
present in about one-half of all cases of pulmonary tuber-
culosis.
Pleuritic pain may result from extension of the
infection to the pleural surfaces.
Extrapulmonary manifesta-
tions of tuberculosis are legion and depend on the organ
system involved.
There
are several tests available for detection of M.
tuberculosis in
patients with active disease.
Comprehensive antibiotic
susceptibility testing can only be performed by culture.
PCR
amplification of M.
tuberculosis DNA allows for even more
rapid diagnosis.
An FDA-approved PCR test is available
that identifies both the presence of M.
tuberculosis and, if
the organism is detected, whether it is resistant to rifampin.
tuberculosis
antigens.
tuberculosis.
tuberculosis, which induces a visible and palpable indura-
tion that peaks in 48 to 72 hours.
bovis that is
used as a vaccine in some countries.
False-positive results
are uncommon with IGRAs.
Tuberculosis is a leading cause of death in people with
AIDS.
All stages of HIV infection are associated with an
increased risk of tuberculosis.
tuberculosis in check.
MORPHOLOGY
Primary Tuberculosis.
In most cases,
the center of this focus undergoes caseous necrosis.
8.25).
In approximately 95% of cases, development
of cell-mediated immunity controls the infection.
8.26A to C).
This is the usual response in people who have developed cell-mediated immunity to the
organism.
granulomas coalesce that they become macroscopically visible.
The granulomas are usually enclosed within a fibroblastic rim
punctuated by lymphocytes.
Multinucleated giant cells are present
in the granulomas.
8.26D).
Secondary Tuberculosis.
8.27).
Histologically, the active lesions show characteristic coalescent
tubercles with central caseation.
Figure 8.27 Secondary pulmonary tuberculosis.
The apical lesion expands
into adjacent lung and eventually erodes into bronchi and vessels.
The cavities, now free of inflammation,
may persist or become fibrotic.
8.28).
In HIV-negative individuals, lymphadenitis tends
to be unifocal and localized.
Healing creates strictures.
tuberculosis and very fastidious M.
leprae.
The
prevalence of NTM disease has increased worldwide.
Of the
150 NTM species, the most frequent human pathogens are
Mycobacterium avium complex (MAC), M.
abscessus complex,
and M.
kansasii.
The prevalence of specific species of NTM
varies in different geographic regions of the world.
Treat-
ment differs for these pathogens, so identifying the specific
organism is important.
It has been difficult to distinguish
M.
avium and M.
Newer
molecular methods are better able to distinguish these two
species, as well as M.
chimaera in the same complex.
Patients are feverish, with
drenching night sweats and weight loss.
NTM biofilm
development on medical devices is a well-documented source
of a number of recent cases.
Figure 8.28 Miliary tuberculosis of the spleen.
In advanced cases of lepro-
matous leprosy, M.
leprae is present in sputum and blood.
People can also have intermediate forms of disease, called
borderline leprosy.
As with M.
Also, antibody production is low.
Occasionally, most often in the lepromatous
form, antibodies are produced against M.
leprae antigens.
Some leprosy patients have a mixed Th1/
Th2 cytokine pattern.
This pattern is more
common in patients with acquired immunodeficiencies.
8.29).
Granulomas, lymphocytes, and
tissue destruction are rare.
Neuronal involvement dominates tuberculoid leprosy.
8.30).
Contractures, paralyses, and autoamputation of fingers or
toes may ensue.
The presence of granulomas
and absence of bacteria reflect strong T-cell immunity.
leprae.
8.31).
Because of the abundant
bacteria, lepromatous leprosy is referred to as multibacillary.
Most skin lesions are hypo-
esthetic or anesthetic.
Lesions in the nose may cause persistent
inflammation and bacilli-laden discharge.
leprae that mainly affects the skin and
peripheral nerves.
M.
It prolifer-
ates best at 32° to 34°C, the temperature of the human skin.
Like M.
tuberculosis, M.
tuberculosis that immunization
with BCG confers some protection against M.
leprae infection.
M.
leprae.
People with the less severe tuberculoid leprosy have
dry, scaly skin lesions that lack sensation.
They often have
asymmetric involvement of large peripheral nerves.
Other closely related treponemes cause yaws (T.
pallidum
subsp.
pertenue) and pinta (T.
pallidum subsp.
carateum).
The
causative spirochete, T.
pallidum subsp.
pallidum, hereafter
referred to simply as T.
8.32).
Transplacental
transmission of T.
pallidum occurs readily, and active disease
during pregnancy results in congenital syphilis.
T.
pallidum
cannot be easily grown in culture.
Loss of sensation and trophic changes
in the hands and feet follow the nerve lesions.
Treponema pallidum
subsp.
Figure 8.31 Lepromatous leprosy.
Acid-fast bacilli (“red snappers”) within
macrophages.
The chancre heals
with or without therapy.
Secondary Syphilis.
This stage is marked by painless,
superficial lesions of the skin and mucosal surfaces.
It occurs
2 to 10 weeks after the primary chancre in approximately
75% of untreated people.
Silvery-gray super-
ficial erosions may form on the oral, pharyngeal, and genital
mucous membranes.
Lymphadenopathy, mild fever, malaise,
and weight loss are also common in secondary syphilis.
Secondary syphilis lasts several weeks, and then
the person enters the latent stage of the disease.
Tertiary Syphilis.
These may occur alone
or in combination.
• Neurosyphilis may be symptomatic or asymptomatic.
Symptomatic neurosyphilis is discussed in Chapter 28.
Gummas are rare because
of the use of effective antibiotics.
Congenital Syphilis.
Much of the pathology of syphilis can
be ascribed to the ischemia produced by the vascular lesions.
The pathogenesis of endarteritis is unknown.
The immune response to T.
The infiltrating
CD4+ T cells are Th1 cells that may activate macrophages to
kill the bacteria.
In many patients,
the organism persists despite these host responses.
A protein
in the outer membrane of T.
Syphilis is divided into three stages, with distinct
clinical and pathologic manifestations (Fig.
8.33).
Primary Syphilis.
Hepatomegaly and skeletal abnormalities are common.
Late
manifestations develop in nearly one-half of untreated
children with neonatal syphilis.
Serologic Tests for Syphilis.
Serology remains the mainstay
of diagnosis of syphilis.
Serologic tests include nontrepo-
nemal antibody tests and antitreponemal antibody tests.
pallidum.
Treponemal antibody tests measure antibodies
that specifically react with T.
pallidum.
These include the
fluorescent treponemal antibody absorption test and the T.
pallidum enzyme immunoassay test.
There is only one FDA-approved point-of-care test in the
United States.
• Both types of test are very sensitive (>95%) for secondary
syphilis.
• Treponemal tests are very sensitive for tertiary and latent
syphilis.
• Treponemal tests, which are nonquantitative, remain
positive, even after successful therapy.
8.34).
8.4).
Red lesions in the mouth or vagina
contain the most organisms and are the most infectious.
Tertiary syphilis most frequently involves the aorta,
the CNS, and the liver, bones, and testes.
The aortitis is
caused by endarteritis of the vasa vasorum of the proximal aorta.
8.35 for the
histopathology of syphilis).
(Courtesy Dr.
Eighth-nerve deafness
and optic nerve atrophy develop secondary to meningovascular
syphilis.
afzelii and B.
garinii in Europe
and Asia.
These are each transmitted from rodents or, for
B.
garinii from birds, to people by Ixodes deer ticks.
Lyme
disease is endemic in the United States, Europe, and Asia.
Most cases occur
in the northeastern states and the upper Midwest.
In endemic
areas, B.
burgdorferi infects up to 50% of ticks, which may
also be infected with Ehrlichia spp.
and Babesia spp.
Serology
is the main method of diagnosis, but PCR can be done on
infected tissue.
Lyme disease involves multiple organ systems and is
divided into three stages (Fig.
8.36).
This lesion,
called erythema migrans, may be accompanied by fever
and lymphadenopathy.
The rash spontaneously disap-
pears in 4 to 12 weeks.
In Europe, B.
• The third stage, late disseminated disease, manifests many
months after the tick bite.
B.
burgdorferi usually causes a
chronic arthritis sometimes with severe damage to large
joints.
Less often, patients will have polyneuropathy and
encephalitis that vary from mild to debilitating.
Lyme
encephalopathy is less common in Europe than in the
United States.
Pathogenesis
B.
burgdorferi does not produce endotoxin or exotoxins that
damage the host.
The inflammatory lesions are likely triggered by T cells
and cytokines.
They occur in most organs
but particularly in skin, subcutaneous tissue, bone, and joints.
8.35).
The rash of congenital syphilis is more severe than that of
adult secondary syphilis.
It is a bullous eruption of the palms and
soles of the feet associated with epidermal sloughing.
The liver is often severely affected in congenital syphilis.
Gummas are occasionally found in the liver,
even in early cases.
The lungs may be affected by a diffuse
interstitial fibrosis.
(Figure modified from Dr.
Charles Chiu,
University of California, San Francisco, Calif.
burgdorferi escapes
the antibody response through antigenic variation.
B.
Environmental anaerobes also cause disease (tetanus, botu-
lism, and gas gangrene).
Abscesses are usually
caused by mixed anaerobic and facultative aerobic bacterial
infections.
The bacteria found in head and neck abscesses reflect
oral and pharyngeal microbiota.
Common anaerobes at
this site include the gram-negative bacilli Prevotella spp.
and Porphyromonas spp., often mixed with the facultative S.
aureus and S.
pyogenes.
and Clostridium spp., as well
as gram-negative Bacteroides fragilis and E.
coli.
coli or
S.
agalactiae.
MORPHOLOGY
Skin lesions caused by B.
burgdorferi are characterized by edema
and a lymphocytic-plasma cell infiltrate.
In late Lyme disease,
there may be extensive erosion of the cartilage in large joints.
difficile colitis with antibiotic treatment).
Otherwise, these lesions
pathologically resemble those of the common pyogenic infections.
If the respiratory
muscles are affected, botulism can lead to death.
C.
difficile.
There
has been significant success in treatment of C.
Clostridial Infections
Clostridium spp.
Four types of disease are caused by Clostridium
spp.:
• C.
perfringens, C.
Spontaneous gas gangrene due to
C.
septicum is highly associated with an underlying
malignancy.
• C.
• C.
• C.
The bacteria release toxin and cause pseudo-
membranous colitis (Chapter 17).
Pathogenesis
C.
C.
perfringens
secretes 14 toxins, the most important of which is α-toxin.
This toxin has multiple actions.
It also has a sphingomyelinase activity that
contributes to nerve sheath damage.
Ingestion of food contaminated with C.
perfringens causes
a brief diarrhea.
C.
The neurotoxins produced by C.
botulinum and C.
tetani
both inhibit release of neurotransmitters, resulting in
paralysis.
Botulism toxin, eaten in contaminated foods or
absorbed from wounds infected with C.
botulinum, binds
gangliosides on motor neurons and is transported into the
cell.
perfringens; these
are described next.
8.37).
Gas bubbles caused by bacterial
fermentation appear within the gangrenous tissues.
C.
trachomatis
causes lymphogranuloma venereum, a chronic, ulcerative
disease.
Rectal strictures are particularly
common in women.
dusk-colored, wedge-shaped infarcts in the small bowel, particularly
in neutropenic people.
Regardless of the site of entry, when C.
perfringens disseminates hematogenously, there is widespread
formation of gas bubbles.
Chlamydial Infections
C.
trachomatis is a small gram-negative bacterium that is an
obligate intracellular pathogen.
C.
trachomatis exists in two
forms during its unique life cycle.
The infectious form, called
the elementary body, is metabolically inactive.
The diseases caused by C.
The venereal infections caused by
C.
trachomatis are discussed here.
Genital infection by C.
trachomatis is the most common
bacterial STI in the world.
In 2016, approximately 1.6 million
cases of genital chlamydia were reported to the CDC.
Genital C.
gonorrhoeae.
Unlike N.
gonorrhoeae urethritis, C.
trachomatis
urethritis in men may be asymptomatic and so may go
untreated.
Both N.
gonorrhoeae and C.
trachomatis frequently
cause asymptomatic infections in women.
C.
MORPHOLOGY
The features of C.
Organisms are not visible in Gram-stained smears or
sections.
Regional lymphadenopathy
is common, usually occurring within 30 days of infection.
The latter, in turn, may cause
local lymphatic obstruction, lymphedema, and strictures.
It is associated
with wars and poverty, when individuals live in close
contact with poor hygiene.
• Scrub typhus (caused by Orientia tsutsugamushi) is transmit-
ted by chiggers (mites).
These
bacteria predominantly infect monocytes (E.
chaffeensis)
or neutrophils (A.
phagocytophilum).
Rash
occurs in approximately 40% of people with E.
chaffeensis
infections.
Subsequent CTL responses are critical for elimination of
rickettsial infections.
CTLs lyse infected cells, reducing
bacterial proliferation.
Figure 8.38 Typhus nodule in the brain.
in a minority of cases.
8.38).
Scrub typhus, or mite-borne infection, is usually a milder
version of typhus fever.
The rash is usually transitory or might
not appear.
Vascular necrosis or thrombosis is rare, but there
may be a prominent inflammatory lymphadenopathy.
Rocky Mountain Spotted Fever.
akari, R.
africae, and R.
8.39).
A noncar-
diogenic pulmonary edema causing adult respiratory distress
MORPHOLOGY
Typhus Fever.
Yeast Infections
Candidiasis
C.
albicans is the most prevalent fungal pathogen of
humans.
glabrata, C.
tropicalis, C.
parapsilosis,
and C.
krusei being more frequent.
This section will focus
on C.
albicans.
Most C.
Residing normally in the skin, mouth, gastrointestinal tract,
and vagina, Candida spp.
usually live as benign commensals
and seldom produce disease in healthy people.
These infec-
tions may be confined to the skin or mucous membranes or
may disseminate widely.
In otherwise healthy people, C.
albicans causes vaginitis and diaper rash.
albicans can spread to the bloodstream.
Pathogenesis
A single strain of C.
albicans can be successful as a commensal
or a pathogen.
There is no known environmental reservoir
for C.
albicans, unlike other Candida spp., and C.
C.
albicans can shift
between nine distinct cell shapes.
These variants can exhibit altered colony morphology, cell
shape, antigenicity, and virulence.
C.
C.
The ability of C.
C.
(Courtesy Dr.
Ehrlichiosis and anaplasmosis have similar presentations.
The rash is nonspecific and can be macular, maculopapular, or
petechial.
8.40).
Cell
walls give fungi their shape.
Yeasts are round to oval and
mainly reproduce by budding.
Some yeasts, such as C.
Molds consist of threadlike filaments (hyphae)
that grow and divide at their tips.
They can produce round
cells called conidia that easily become airborne, disseminating
the fungus.
• Neutrophils and macrophages phagocytose C.
albicans,
and oxidative killing by these phagocytes is a first line
of host defense.
The important role of neutrophils and
macrophages is illustrated by the increased risk of C.
albicans infection in individuals with neutropenia or
defects in NADPH oxidase or myeloperoxidase.
• C.
The Th17 responses elicited by C.
albicans
promote the recruitment of neutrophils and monocytes
(Chapter 6).
These responses are critical for protection
against C.
Deep under the surface, there is mucosal hyperemia and
inflammation.
C.
8.41).
C.
It is usually
associated with intense itching and a thick, curdlike discharge.
8.41).
A BC
Figure 8.41 The morphology of Candida infections.
(A) Severe candidiasis of the distal esophagus.
(B) Hematoxylin and eosin stain of esophageal
candidiasis reveals the dense mat of Candida spp.
(C) Characteristic pseudohyphae and budding yeast of Candida spp.
(C, Courtesy Dr.
It has subsequently been linked
to cryptococcal infections in other regions of the world.
Because most current tests used to diagnose cryptococcal
infections do not distinguish between C.
gatti and C.
neo-
formans, the true incidence of infections caused by these
two agents is currently uncertain.
Based on findings from
areas where C.
gattii is now specifically monitored, it appears
that C.
gattii is more likely than C.
C.
gattii is associated
with certain species of trees, is found in soil, and, like C.
neoformans, is acquired by inhalation.
Pathogenesis
Cryptococcus spp.
Cryptococcus
spp.
Cryptococcus spp.
Cryptococcus spp.
also produce small (micro) cells of 2 to 4 µm that may
be adapted for growth in macrophages.
• Melanin production.
• Enzymes.
Phospholipases degrade cell wall components
and may aid tissue invasion.
Urease helps neutralize the
reactive oxygen species and pH of the phagocytic cell.
• Differential cellular response to phagocytes.
A mechanism
has been hypothesized to explain the success of the C.
gattii strain in the Northwestern U.S.
Further investigation of these pathogenic pathways
is needed for complete understanding.
such as armpits or webs of the fingers and toes (intertrigo); and
penile skin (balanitis).
Candida spp.
In the
latter group, the tricuspid valve is involved.
Candida auris Infections
C.
auris is an emerging pathogen associated with multiple
nosocomial infections on five continents.
Increased colonization and infection
with non-albicans Candida spp.
are attributed in part to
increased use of prophylactic antifungal agents.
There is
an association of C.
Colonization
with C.
auris has been reported in nares, groin, axilla, and
rectum.
Mortality in patients with invasive C.
C.
Cryptococcosis
Two species of cryptococcus are known to cause disease in
humans, C.
neoformans and C.
gattii, both of which grow as
encapsulated yeasts.
It has long been recognized that
although C.
Many
of these patients receive high-dose corticosteroids, a major
risk factor for C.
neoformans infection.
C.
MORPHOLOGY
Cryptococcus spp.
have yeast forms, but not pseudohyphal or hyphal
forms, in human hosts.
8.42) and can be detected in blood or CSF with various
immunoassays.
C.
The
cysts have a characteristic cup-shaped appearance, or they are
oval with a central dot.
Clusters of organisms in bronchoal-
veolar lavage fluid may be 200 µm in diameter.
The nucleus
and mitochondria are visible by Wright-Giemsa stain.
8.43).
Fluorescein-conjugated
antibody stains are commonly used to diagnose these infec-
tions.
Many Pneumocystis spp.
exist, and each species is host-
specific.
No environmental source or external reservoir
outside of humans has been identified for P.
Most people
are infected transiently early in life, with subsequent effective
clearance.
Extrapulmonary findings with P.
Infection with P.
jirovecii induces both
a humoral and cellular immune response.
capsulatum,
and Coccidioides immitis.
This section discusses some impor-
tant hyaline (transparent) molds.
The major lesions caused by Cryptococcus spp.
are in
the CNS, involving the meninges, cortical gray matter, and
basal nuclei.
The host response to cryptococci is extremely
variable.
8.42).
In severely
immunosuppressed persons, C.
neoformans may disseminate
widely to the skin, liver, spleen, adrenals, and bones.
Suppuration also may occur, as
well as a rare granulomatous arteritis of the circle of
Willis.
Pneumocystis Infections
P.
The organism can cause a
AB
Figure 8.43 Pneumonia caused by Pneumocystis jirovecii.
(A) Alveoli of lung filled with foamy exudate (arrow) and interstitial inflammation.
(B) Silver stain of
alveoli, showing cysts of Pneumocystis jirovecii stained black (arrows).
Ann M.
Aspergillus fumigatus
is the most common pathogenic species of the fungus.
Pathogenesis
Aspergillus spp.
are transmitted as airborne conidia, and the
lung is the major portal of entry.
The small size of A.
fumigatus
spores, approximately 2 to 3 µm, enables them to reach
alveoli.
As conidia grow and form hyphae, these molecules
are exposed.
Both receptors activate
phagocytes to ingest and kill the conidia.
In immunosup-
pressed states, conidia can germinate into hyphae, which
then invade tissues.
Neutrophils
produce reactive oxygen intermediates that kill hyphae.
Invasive aspergillosis is highly associated with neutropenia
and impaired neutrophil defenses.
The antioxidant
defenses include melanin pigment, mannitol, catalases, and
superoxide dismutases.
Aflatoxin is made by Aspergillus spp.
Sensitization to Aspergillus spores
produces an allergic alveolitis (Chapter 15).
People with aspergillomas usually have
recurrent hemoptysis.
Invasive aspergillosis is an opportunistic infection that is
confined to immunosuppressed hosts.
8.44A).
8.44B).
by morphology alone.
A B
Figure 8.44 Aspergillus infection.
(A) Invasive aspergillosis of the lung in a bone marrow transplant patient.
Neutrophils
have a key role in killing hyphae after germination by directly
damaging hyphae walls.
PARASITIC INFECTIONS
Protozoal Infections
Protozoa are unicellular eukaryotic organisms.
Most protozoal infections are diagnosed by
microscopic examination of blood smears or lesions.
vivax, P.
ovale, P.
knowlesi, and P.
8.45).
Meningoencephalitis or
ophthalmitis
Bloodstream Plasmodium spp.
Malaria
Babesia spp.
Babesiosis
Trypanosoma spp.
Note
the irregular width and near right-angle branching of the hyphae.
Compare
with Aspergillus, Fig.
8.44.Parasitic infections 389
after initial infection.
The infection of the liver and develop-
ment of merozoites is called the exoerythrocytic stage.
This
stage is asymptomatic.
Upon lysis of the red cell, the
new merozoites infect additional red cells.
Several features of P.
falciparum account for its greater
pathogenicity:
• P.
• P.
Adhesive
polypeptides, including P.
8.46).
• In P.
Host resistance to Plasmodium can be intrinsic or acquired.
The
mutations fall into four broad classes.
Pathogenesis
The life cycles of the Plasmodium spp.
are similar, although
P.
falciparum differs in ways that contribute to its greater
virulence.
P.
vivax, P.
ovale, P.
knowlesi, and P.
P.
The life cycle of Plasmodium spp.
8.46).
During P.
falciparum
infection, rupture usually occurs within 8 to 12 weeks.
In
contrast, P.
vivax and P.
Both exoerythrocytic and
erythrocytic stages are depicted.
ICAM-1, Intercellular adhesion molecule
1; RBC, red blood cell.
(Drawn by Dr.
vivax because they do
not have the Duffy antigen.
P.
Each haploid P.
falciparum
genome has multiple genes encoding variants of these
parasite proteins.
CTLs may also be important in resistance to P.
falciparum.
In some, the myocardium shows focal interstitial
infiltrates.
duncani
and B.
venatorum.
The white-footed mouse is the reservoir
for B.
microti, and in some areas, nearly all mice have a
persistent low-level parasitemia.
B.
Babesia spp.
parasitize
red cells and cause fever and hemolytic anemia.
Macrophages with
engulfed parasitized red cells are also numerous.
With progression of malaria, the liver becomes enlarged and
pigmented.
In cerebral malaria caused by P.
falciparum, brain vessels
are plugged with parasitized red cells (Fig.
8.47).
superficially resemble P.
8.48).
The level of B.
There are several forms
of disease that are caused by different Leishmania spp.
Old
World (L.
major, L.
tropica, L.
donovani, and L.
New World (L.
mexicana, L.
braziliensis,
and L.
chagasi) refers to the Western Hemisphere (parts of
Mexico, Central America, and South America).
A few cases
have been acquired in Texas and Oklahoma.
Leishmania spp.
manipulate innate host defenses to
facilitate their entry and survival in phagocytes.
Promas-
tigotes produce two abundant surface glycoconjugates that
contribute to their virulence.
Thus, the parasite becomes coated
with C3b but avoids destruction by the membrane attack
complex.
To escape killing by neutrophils, Leishmania spp.
Leishmania spp.
Amastigotes reproduce in macrophage phagolysosomes,
which normally have a pH of 4.5.
Leishmania spp.
In addition, macrophages
downregulate the transferrin receptor and remove iron from
the phagosome.
The primary mechanisms of resistance and susceptibility
to Leishmania spp.
are determined by Th1 and Th2 responses.
Parasite-specific CD4+ Th1 cells are needed to control
Leishmania spp.
in mice and humans.
Leishmania spp.
evade
host immunity by impairing the development of the Th1
response.
By contrast,
mouse strains that are susceptible to leishmaniasis mount
a dominant Th2 response.
Leishmaniasis is endemic throughout the Middle
East, South Asia, Africa, and Latin America.
It may also
be epidemic, as is tragically the case in Sudan, India, Ban-
gladesh, and Brazil.
Culture, PCR, or histologic examination is used to
diagnose the infection.
Pathogenesis
The life cycle of Leishmania spp.
Mammals, including
rodents, dogs, and foxes, are reservoirs of Leishmania spp.
When sandflies bite infected humans or animals, macro-
phages harboring amastigotes are ingested.
How far the amastigotes spread throughout the body
depends on the specific Leishmania spp.
by
inhibiting the microbicidal activity of macrophages.
MORPHOLOGY
Leishmania spp.
In the late
stages, the liver becomes increasingly fibrotic.
Hemorrhages
related to thrombocytopenia may also be fatal.
Mucocutaneous leishmaniasis is found only in the New
World.
Microscopically, they contain
aggregates of foamy macrophages stuffed with Leishmania
organisms.
Figure 8.49 Giemsa stain of a tissue macrophage with Leishmania
donovani parasites.
fly (vector) populations.
A few hundred cases are reported
per year.
brucei rhodesiense) or from other
humans (T.
brucei gambiense).
Diagnosis is made by microscopic examination of
blood smears, lymph node, or chancre.
In this way,
African trypanosomes cause waves of fever before they
finally invade the CNS.
Trypanosomes have many VSG
genes, only one of which is expressed at a time.
The parasite
uses an elegant mechanism to turn VSG genes on and off.
To ensure
exposure to lysosomes, T.
T.
cruzii evades the complement
system activation by expressing complement regulatory
proteins.
• The presence of persistent T.
For
example, cross-reactive antibodies may induce electro-
physiologic dysfunction of the heart.
In addition, damage to the myenteric plexus causes dilation
of the colon (megacolon) and esophagus.
Figure 8.50 Slender bloodstream parasites of African trypanosomiasis.
8.50) concentrate in capillary
loops, such as the choroid plexus and glomeruli.
T.
cruzi parasites infect many animals,
including cats, dogs, and rodents.
At the site of skin entry, there may be
a transient, erythematous nodule.
Diagnosis can be made by a blood smear in the
acute case, but is made more commonly by serology.
MORPHOLOGY
In lethal acute myocarditis, the changes are diffusely distributed
throughout the heart.
Chronic Chagas cardiomyopathy
often has to be treated by cardiac transplantation.
Toxoplasmosis
Although millions of people carry the ubiquitous parasitic
protozoa T.
gondii without symptoms due to control by
their immune systems, T.
It is estimated that 11% of the US population
6 years of age and older has been infected.
In some regions
of the world, 95% of the population has been infected.
T.
Another route of infection
is vertical transmission during pregnancy.
Rarely, infec-
tion occurs via blood transfusion or organ transplantation.
Myocarditis and pneumonitis are two other
common manifestations in AIDS patients.
Pathogenesis
The cat is the only definitive host, and humans are a
dead-end host.
Unsporulated oocysts are shed in cat feces,
which sporulate in the environment.
The sporozoites
transform into tachyzoites that localize to tissues and develop
into bradyzoites.
Cats become infected after ingestion of
intermediate hosts.
T.
Bobbi S.
To avoid
clearance of the tachyzoites, T.
gondii also inhibits autophagy
of the parasite-containing vacuole.
Although
diagnosis is usually through serologic testing, cysts may be observed
in biopsies (Fig.
Tachyzoites may be observed with
periodic acid-Schiff, Giemsa, or hematoxylin and eosin stains.
Tissue
cysts can vary in size from 5 to 100 µm.
Intact cysts can remain
for the life of the host without causing inflammation.
The cyst
wall is thin and contains crescent-shaped bradyzoites of approxi-
mately 1.5 by 7 µm.
Metazoal Infections
Metazoa are multicellular, eukaryotic organisms with organ
systems.
It occurs sporadically in the United States, including in
Appalachia.
In immunocompetent hosts, S.
to
increase infective larvae production.
Figure 8.52 Strongyloides hyperinfection in a patient treated with
high-dose cortisone.
(Courtesy Dr.
These can grow to many
meters in length and produce mild abdominal symptoms.
The most serious manifestations result from encystment
in the brain (neurocysticercosis).
Convulsions, increased
intracranial pressure, and other neurologic disturbances
may occur.
Viable T.
When the cysticerci die
and degenerate, an inflammatory response develops.
In humans, these parasites live only in the gut
and do not form cysticerci.
For E.
granulosus the
definitive host is the dog, and the usual intermediate hosts
are sheep.
For E.
multilocularis the fox is the most important
definitive host, and rodents are intermediate hosts.
Eggs
hatch in the duodenum and larvae invade the liver, lungs,
or bones.
Hyperinfection with S.
There are many adult
worms, larvae, and eggs in the crypts of the duodenum and ileum
(Fig.
8.52).
Both diseases are caused by larvae that develop
after ingestion of tapeworm eggs.
T.
New proglottids
develop behind the scolex.
T.
spiralis, T.
nativa, or T.
britovi.
There are an estimated
10,000 cases in the world each year.
In the United States
the number of T.
Pathogenesis
The life cycle of T.
spiralis begins in the human intestine
but ends within muscle as humans are dead-end hosts.
In
the human gut, T.
In striated skeletal muscle,
T.
T.
In animal models of T.
Figure 8.53 Portion of a cysticercus cyst in the skin.
8.53).
E.
In time a dense
fibrous capsule forms.
Daughter cysts often develop within the
large mother cyst.
Larvae in the heart do not encyst and are difficult to
identify, because they die and disappear.
T.
8.54).
Coiled larvae are approximately 1 mm long and are
Trichinosis
Trichinella spp.
mansoni and S.
japonicum).
haematobium,
bladder walls, allowing the eggs to be shed in stool or urine,
respectively.
Infection of freshwater snails completes the
life cycle.
This immune response to S.
mansoni and S.
Figure 8.54 Multiple coiled Trichinella spiralis larvae within skeletal muscle
cells.
MORPHOLOGY
In early S.
mansoni or S.
japonicum infections, white, pinhead-sized
granulomas are scattered throughout the gut and liver.
8.55).
The affected organs and hence the site of major
disease vary with the species.
Shistosoma mansoni and S.
japonicum affect the liver and the gut predominantly.
Most
deaths are due to hepatic cirrhosis, which is caused by S.
mansoni in Latin America, Africa, and the Middle East and
by S.
japonicum and S.
mekongi in East Asia.
By contrast, S.
Severe hepatic fibrosis
is a serious manifestation of chronic schistosomiasis.
The life cycle of Schistosoma spp.
There is minimal skin
reaction.
Mosquitoes
that bite infected individuals take up the microfilariae and
can transmit the disease.
The genomes of W.
bancrofi and
B.
Wolbachia spp.
impair nematode survival and fertility.
Immune responses to the filarial worms produce damage
to the human host.
Figure 8.56 Pipe-stem fibrosis of the liver due to chronic Schistosoma
japonicum infection.
In late S.
mansoni or S.
japonicum infections, inflammatory
patches or pseudopolyps may form in the colon.
8.56).
In S.
The most frequent complication of S.
8.57).
Frequently
there is hydrocele and lymph node enlargement.
(B.
malayi [90%] or B.
timori [10%]), which
are responsible for 120 million infections worldwide.
Figure 8.57 Massive edema and elephantiasis caused by filariasis of the
leg.
(Courtesy Dr.
Willy Piessens, Harvard School of Public Health, Boston,
Mass.)
MORPHOLOGY
O.
Keratitis is sometimes
accentuated by treatment with antifilarial drugs (Mazzotti reaction).
deposits; the epidermis is thickened and hyperkeratotic.
Over time, the
dilated lymphatics develop polypoid infoldings.
It is transmitted by black flies and affects 17 million
people in Africa, South America, and Yemen.
infections in Africa and
South America.
Adult O.
The presence of an STI in a child, unless acquired
during birth, strongly suggests sexual abuse.
Some pathogens, such as Chlamydia trachomatis and N.
gonorrhoeae, are almost always spread by sexual intercourse,
whereas others, such as Shigella spp.
and E.
• Infection with one STI-associated organism increases the risk
for additional STIs.
This is mainly because the risk factors
are the same for all STIs.
In addition, the epithelial injury
caused by N.
gonorrhoeae or C.
Perinatally acquired C.
Syphilis frequently causes miscar-
riage.
Untreated HIV infection may be fatal to children
infected with the virus prenatally or perinatally.
Syphilis is discussed earlier in this chapter, and other
STIs are described in Chapters 21 and 22.
Table 8.8 lists the history of diseases that have emerged
over the past half century.
pylori gastritis, HBV and HCV, and Legionella
pneumophila.
Some infectious agents are new to humans,
such as HIV causing AIDS, and B.
burgdorferi causing Lyme
disease.
avium-
intracellulare, P.
jirovecii, and Cryptosporidium parvum).
Finally,
infectious diseases that are common in one area may be
introduced into a new area.
tuberculosis, N.
gonorrhoeae, S.
aureus, and K.
pneumoniae.
auris, and
some of the Babesia spp.
Agents of Bioterrorism.
Other category A agents
include B.
anthracis, Yersinia pestis, and Ebola virus.
Many
of these agents are food-borne or water-borne.
Examples
include Brucella spp.
and V.
cholerae.
Examples include Hantavirus and Nipah virus.
Changes in the environment occasionally
drive rates of infectious diseases.
[A concise presentation of a model of C.
[A
short discussion of Th1 and Th2 immune responses to M.
lesion rather than at its center, particularly if there is necrosis.
The presence of
specific IgM antibody shortly after the onset of symptoms
is diagnostic.
In the United States in 2018, there were nearly
3 million occupational injuries and illnesses.
Disease related
to malnutrition is even more pervasive.
In this chapter, we first consider the emerging problem
of the health effects of climate change.
During 2018, the global land temperature was
1.1°C warmer than the 20th century average.
9.1A), ozone (an
important air pollutant, discussed later), and methane.
9.1B).
(A, Courtesy Dr.
Richard
21st century.
Different computer models plot anticipated rises in global
located around the globe.
• Malnutrition, caused by changes in local climate that
disrupt crop production.
TOXICITY OF CHEMICAL AND
PHYSICAL AGENTS
Toxicology is defined as the science of poisons.
It studies
the distribution, effects, and mechanisms of action of toxic
agents.
We now consider some basic principles relevant to the
effects of toxic chemicals and drugs.
• The definition of a poison is not straightforward.
It is basi-
cally a quantitative concept that depends on dosage.
9.2).
• Chemicals may act at the site of entry or at other sites
following transport through the blood.
If repair is not effective, short-term
and long-term effects develop.
9.2 and 9.3) occur in two phases.
In phase I reactions,
chemicals undergo hydrolysis, oxidation, or reduction.
Water-soluble
compounds are readily excreted.
• The most important catalyst of phase I reactions is the
cytochrome P-450 enzyme system.
There is great variation in the activity of CYPs among
individuals.
Known CYP inducers include environmental
chemicals, drugs, smoking, alcohol, and hormones.
In
contrast, fasting or starvation can decrease CYP activity.
Air is
precious to life, but can also carry many potential causes
of disease.
Here we consider these hazards in outdoor and indoor air.
It may seem that
air pollution is a modern phenomenon, but this is hardly
the case.
Except for some comments on smoking, pollutant-caused
lung diseases are discussed in Chapter 15.
Major health effects
of outdoor pollutants are summarized in Table 9.1.
Ozone,
sulfur dioxide, particulates, and CO are discussed here.
This layer protects life on earth by
absorbing the most dangerous UV radiation emitted by the
sun.
These chemicals are released by industrial emissions
and motor vehicle exhaust.
Of greater concern is acute toxicity.
The mor-
phologic changes are not specific and stem from systemic hypoxia.
Only
a few comments about other agents are made here.
Radon is the number
one cause of lung cancer among nonsmokers, according
to EPA estimates.
Overall, radon is the second leading
cause of lung cancer.
Radon is responsible for about 21,000
lung cancer deaths every year.
About 2,900 of these deaths
occur among people who have never smoked.
Formaldehyde is classified
as a carcinogen for humans and animals.
Lead exposure may
occur through contaminated air, food, and water.
A dramatic case of lead contamination
of drinking water occurred in Flint, Michigan, in 2014–2016.
As a result, 6000 to 12,000 resi-
dents developed very high lead levels in their blood.
A more permeable blood–brain barrier
in children creates a high susceptibility to brain damage.
The main clinical features of lead poisoning in children and
adults are shown in Figs.
9.4 and 9.5.
9.6).
Iron incorporation into heme is impaired, leading to micro-
cytosis (small red cells) and anemia.
The diagnosis
of lead poisoning requires constant vigilance.
Lead toxicity in a pregnant woman may impair brain
development in the fetus.
The gastrointestinal tract is also a major source of clinical
manifestations.
Lead colic is characterized by severe, poorly
localized abdominal pain.
Chronic renal damage leads eventually to interstitial fibrosis and
renal failure.
Decreases in uric acid excretion can lead to gout
(saturnine gout).
Alchemists
tried (without much success) to produce gold from mercury.
9.5).
Even more distinctive
is a punctate basophilic stippling of the red cells.
Brain damage is prone to occur in children.
(Courtesy Dr.
G.
W.
In some areas of the world,
mercury used in gold mining has contaminated rivers and
streams.
Almost 90% of ingested methyl mercury is absorbed in the
gastrointestinal tract.
Ingested mercury can
injure the gut and cause ulcerations and bloody diarrhea.
In the kidneys, mercury can cause acute tubular necrosis
and renal failure.
Chronic exposure can cause nephrotic
syndrome.
It may be released into the environment from mines and
smelting industries.
• Skin changes consisting of hyperpigmentation and hyper-
keratosis occur with chronic exposure.
Cadmium can contaminate the soil
and plants directly or through fertilizers and irrigation water.
Food is the most important source of cadmium exposure
for the general population.
Cadmium exposure
can also cause skeletal abnormalities associated with
calcium loss.
Industrial exposures to toxic
agents are as varied as the industries themselves.
Human
diseases associated with occupational exposures are listed
in Table 9.2.
Lower levels may cause liver and kidney toxic-
ity.
Occupational exposure to benzene and 1,3-butadiene
increases the risk of leukemia.
• Cadmium from nickel-cadmium batteries and chemical fertilizers
can contaminate soil.
Excess cadmium causes obstructive lung
disease and kidney damage.
Data from Leigh JP, et al: Occupational injury and illness in the United States.
DDT was banned in the United States in 1973.
Acute DDT poisoning in humans causes neurologic
toxicity.
• Nonpesticide organochlorines include PCBs and dioxin
(TCDD).
It can be accompanied by abnormali-
ties in the liver and CNS.
BPA has long
been known as a potential endocrine disruptor.
The extent of the human health risks
associated with BPA remains uncertain.
• Inhalation of mineral dusts causes chronic, nonneoplastic
lung diseases called pneumoconioses.
Expo-
sure to these agents nearly always occurs in the workplace.
Pneumoconioses and their pathogenesis are
discussed in Chapter 13.
Effects of Tobacco
Smoking is the most readily preventable cause of death
in humans.
Of these, almost 2.5 million died
as a result of inhalation of second-hand smoke.
Indeed,
tobacco is the leading exogenous cause of human cancers,
including 90% of lung cancers.
Of people alive today, an estimated 500 million
will die of tobacco-related illnesses.
The cumulative effects of
smoking over time are striking.
9.7).
Lung cancer mortality decreases by 21% within 5
years, but the excess risk persists for 30 years.
The number of potentially noxious chemicals in tobacco
smoke is extraordinary.
Smoking and Lung Cancer.
9.8).
Moreover, smoking
increases the risk of other carcinogenic influences.
9.9).
Smoking and Other Diseases.
9.10).
• The toll taken by nonmalignant conditions associated with
smoking is even more terrible.
Measured
at age 75, the difference in survival between smokers and nonsmokers is
7.5 years.
Nicotine, an alkaloid present in tobacco leaves, is strongly
addictive.
Recent studies indicate that in addition
to being addictive, nicotine has other untoward effects.
Smoking exacerbates asthma and increases
the risk for pulmonary tuberculosis.
The Health Consequences of
Smoking—50 Years of Progress: A Report of the Surgeon General.
COPD,
Chronic obstructive pulmonary disease.
• Smoking also harms the developing fetus.
Birth weights of infants born to mothers
who stopped smoking before pregnancy are, however,
normal.
9.10).
It is clear
that the transient pleasure of smoking comes with a heavy
long-term price.
By the end of
2019 close to 2000 cases had been reported to the CDC,
with 42 fatalities.
The pathogenesis of this outbreak is
under intense investigations.
disease, and cerebrovascular disease.
It is estimated that alcohol consumption is
responsible for more than 80,000 deaths annually.
Worldwide, alcohol accounts for
approximately 3.3 million deaths per year (5.9% of all
deaths).
Less than
10% is excreted unchanged in the urine, sweat, and breath.
The rate of metabolism affects the
blood alcohol level.
Chronic alcoholics develop tolerance
to alcohol.
9.11).
Cessation
of smoking reduces the risk of lung cancer.
• Smokeless tobacco use is an important cause of oral cancers.
Oxidation of acetaldehyde by aldehyde dehydrogenase (ALDH) occurs in mitochondria.
ADH oxidation is the most important route; catalase is involved in only 5% of ethanol metabolism.
Oxidation through CYPs may also generate reactive
oxygen species (not shown).
(From Parkinson A: Biotransformation of xenobiotics.
Catalase
is of minor importance, being responsible for only about
5% of alcohol metabolism.
Several toxic effects result from ethanol metabolism.
Listed
here are only the most important of these.
Its deficiency is a main cause of the accumula-
tion of fat in the liver of alcoholics.
The increase in the
NADH/NAD ratio in alcoholics also causes lactic
acidosis.
• ROS generation.
The adverse effects of ethanol can be classified as acute
or chronic.
The gastric changes are acute gastritis
and ulceration.
Consequently, there is stimulation and disordered cortical,
motor, and intellectual behavior.
Respiratory arrest may follow.
• The liver is the main site of chronic injury.
• Neurologic effects.
• Cardiovascular effects.
Alcohol has diverse effects on the
cardiovascular system.
• Pancreatitis.
Excessive alcohol intake increases the risk
of acute and chronic pancreatitis (Chapter 19).
• Fetus.
• Carcinogenesis.
As mentioned earlier,
alcohol and cigarette smoke synergize in the causation
of various cancers.
• Malnutrition.
Ethanol is a substantial source of energy
(empty calories).
Not all is gloom and doom, however.
It seems that the old saying is true,
at least with respect to alcohol—all things in moderation!
Stupor and coma develop at higher
levels.
9.12).
Older adults (above 65 years) are much more likely to
suffer from adverse drug reactions.
B
Figure 9.12 Adverse drug reaction.
Skin pigmentation caused by
minocycline, a long-acting tetracycline derivative.
(A) Diffuse blue-gray
pigmentation of the forearm.
(B) Deposition of drug metabolite/iron/
melanin pigment particles in the dermis.
(Courtesy Dr.
Warfarin is
an antagonist of vitamin K, and dabigatran is a direct inhibi-
tor of thrombin.
As a result, maintaining anticoagulation
in a relatively safe therapeutic range can be problematic.
They act by inhibiting ovulation or preventing
implantation.
Transdermal and implantable for-
mulations have also become available.
Nevertheless, there
is good evidence to support the following conclusions.
• Breast carcinoma.
The prevailing opinion is that OCs do
not increase breast cancer risk.
• Endometrial cancer and ovarian cancers.
• Cervical cancer.
OCs may increase risk of cervical carci-
nomas in women infected with human papillomavirus.
• Thromboembolism.
• Cardiovascular disease.
• Hepatic adenoma.
Acetaminophen
Acetaminophen is the most commonly used analgesic in
the United States.
It is present in more than 300 products,
alone or in combination with other agents.
However, subsequent randomized clinical trials have
produced decidedly mixed results.
But during the past few years
there has been a reappraisal of the risks and benefits of
MHT.
There
is no increase in the risk for ovarian cancer.
However, MHT should not be used for prevention of
cardiovascular disease or other chronic diseases.
• MHT increases the risk of stroke and VTE including deep
vein thrombosis and pulmonary embolism.
The risks of VTE and stroke appear to be lower with
transdermal than oral routes of estrogen.
The effect of
route of administration continues to be studied.
The
CNS changes may progress to convulsions and coma.
The
morphologic consequences of chronic salicylism are varied.
Approximately, 450,000
people died in 2015 as a result of drug use.
Common drugs of abuse are listed
in Table 9.6.
Considered here are cocaine, opioids, amphet-
amines, and marijuana, among others.
Cocaine sold on the street is liberally diluted
with talcum powder, lactose, or other look-alikes.
It can be
snorted or dissolved in water and injected subcutaneously
or intravenously.
See text for details.
GSH, Glutathione; NAPQI, NAPQI, N-acetyl-p-benzoquinoneimine.
(Courtesy Dr.
Xavier Vaquero, Department of Pathology, University of
Washington, Seattle, Wash.)
(Fig.
9.13).
Some
patients also show evidence of concurrent renal damage.
From Hyman SE: A 28-year-old man addicted to cocaine, JAMA 286:2586, 2001.
sound it makes when heated to produce vapors that are
inhaled.
The pharmacologic actions of cocaine and crack
are identical, but crack is far more potent.
Experimental animals will press a lever more than 1000 times
and forgo food and drink to obtain it.
The acute and chronic effects of cocaine on various organ
systems are as follows.
• Cardiovascular effects.
9.14).
• CNS.
• Effects on pregnancy.
Neurologic development may be impaired in the fetus
of a pregnant woman who is a chronic drug user.
• Other effects.
Of
these deaths, 40% were from prescription opioids.
Heroin is a street drug derived from the poppy plant that
is closely related to morphine.
Use of heroin is even more
harmful than cocaine use.
The effects on the CNS are varied and include euphoria,
hallucinations, somnolence, and sedation.
• Infections.
Infectious complications are common.
• Skin.
Cutaneous lesions are probably the most frequent
telltale sign of heroin addiction.
Acute changes include
abscesses, cellulitis, and ulcerations due to subcutaneous
injections.
• Kidneys.
Kidney disease is a relatively common hazard.
Amphetamines and Related Drugs
Methamphetamine.
Some of the
most important adverse effects of heroin follow.
• Sudden death.
The yearly mortality
among heroin users in the United States is estimated to
be between 1% and 3%.
• Pulmonary injury.
Not much is known about the long-term deleterious
effects of any of these agents.
On the other hand, therapeutic uses for psychoactive
drugs are emerging.
About 5% to 10% of THC is
absorbed when it is smoked in a hand-rolled cigarette
(“joint”).
Marijuana use causes euphoria and a sense of
relaxation.
The functional and organic CNS consequences of
marijuana smoking have received the most scrutiny.
Marijuana cigarettes contain a large number of carcinogens
that are also present in tobacco.
Whether marijuana causes physical dependence and
addiction remains controversial.
These drugs include various stimulants,
depressants, analgesics, and hallucinogens (Table 9.6).
• Overdose of acetaminophen may cause centrilobular liver
necrosis, leading to liver failure.
Early treatment with agents
that restore GSH levels may limit toxicity.
Each type is considered separately.
Mechanical Trauma
Mechanical forces may inflict a variety of forms of damage.
Bone and head injuries
result in unique damage and are discussed elsewhere
(Chapters 26 and 28).
Details
about the practice of forensic pathology can be found in
specialized textbooks.
Thermal Injury
Both excessive heat and excessive cold are important causes
of injury.
• Superficial burns (formerly known as first-degree burns)
are confined to the epidermis.
• Partial-thickness burns (formerly known as second-degree
burns) involve injury to the dermis.
• Full-thickness burns (formerly known as third-degree burns)
extend to the subcutaneous tissue.
Shock, sepsis, and respiratory insufficiency are the
greatest threats to life in burn patients.
As a result, virtually all burns become colonized
with bacteria.
aureus,
and fungi, particularly Candida species, may also be involved.
Removal of the burn wound decreases
infection and reduces the need for reconstructive surgery.
• Heat cramps result from loss of electrolytes via sweating.
Cramping of voluntary muscles, usually in association
with vigorous exercise, is the hallmark.
Heat-dissipating
mechanisms are able to maintain normal core body
temperature.
• Heat exhaustion is probably the most common hyperthermic
syndrome.
• Heat stroke is associated with high ambient temperatures,
high humidity, and exertion.
Hyperkalemia, tachycardia, arrhythmias,
and other systemic effects are common.
RYR1 regulates the release of
calcium from the sarcoplasm.
• Malignant hyperthermia, despite the name, is not caused
by exposure to high temperatures.
Such changes are typical of trench foot.
Lightning is a classic cause of high-voltage electrical
injury.
Ionizing radiation is a double-edged sword.
Radiation Units.
This is an expression of the
amount of radiation emitted by a source.
The
cGy terminology has now replaced the Rad in medical
practice.
For the same absorbed
dose, various types of radiation produce different amounts
of damage.
The effective dose of x-rays in
radiographs and CT is commonly expressed in mil-
liSieverts (mSv).
For x-radiation, 1 mSv = 1 mGy.
Main Determinants of Biologic Effects of Ionizing Radia-
tion.
• Rate of delivery significantly modifies the biologic effect.
• Field size has a great influence on the consequences of
irradiation.
• Cell proliferation.
9.15).
• Oxygen effects and hypoxia.
• Vascular damage.
These changes
may appear months or years after exposure (Fig.
9.16).
Fig.
9.17 shows the overall consequences of radiation
exposure.
These consequences vary according to the dose
of radiation and type of exposure.
Several abnormal nuclear morphologies may be seen.
Early changes occur in hours to weeks; late changes occur
in months to years.
ARDS, Acute respiratory distress syndrome.
Acute Effects on Hematopoietic and Lymphoid
Systems.
After a brief rise in the circulating
neutrophil count, neutropenia appears within several days.
Neutrophil counts reach their nadir, often at counts near zero,
during the second week.
If the patient survives, recovery
of a normal granulocyte count may require 2 to 3 months.
when evaluating irradiated tissues for the possible persistence of
tumor cells.
Vascular changes and interstitial fibrosis are also prominent
in irradiated tissues (Fig.
9.18).
During the immediate postirradia-
tion period, vessels may show only dilation.
Affected vessels may rupture or thrombose.
Total-Body Irradiation.
Doses below 1 Sv produce minimal
symptoms, if any.
(A) Normal salivary gland.
(B) Fibrosis
caused by radiation.
(C) Fibrosis and vascular changes consisting of fibrointimal thickening and arteriolar sclerosis.
I, Thickened intima; V, vessel lumen.
(Courtesy Dr.
Anemia
appears after 2 to 3 weeks and may persist for months.
Fibrosis.
9.18).
9.19 and 9.20).
DNA Damage and Carcinogenesis.
The most serious damage to DNA
consists of DSBs.
Note the markedly thickened pericardium.
Cancer Risks From Exposures to Radiation.
Any cell
capable of division that has sustained a mutation has the
potential to become cancerous.
It is
believed that the risk of secondary cancers following irradia-
tion is greatest in children.
Radon gas is a ubiquitous
product of the spontaneous decay of uranium.
of these components are missing from the diet.
There are several conditions that may lead to primary
or secondary malnutrition.
• Poverty.
• Acute and chronic illnesses.
Failure to recognize these
nutritional needs may delay recovery.
• Chronic alcoholism.
• Ignorance and failure of diet supplementation.
Ignorance about the nutritional content of foods is also
a contributing factor.
• Self-imposed dietary restriction.
• Other causes.
Worldwide
about 50 million children are affected by SAM.
In addition to loss
of life, wars also exact a heavy toll on refugees who live in
abject poverty.
The sections that follow barely skim the surface of
nutritional disorders.
Other
nutrients and nutritional issues are discussed in the context
of specific diseases.
(A) Marasmus.
(B) Kwashiorkor.
The infant shows generalized edema, seen as ascites and puffiness of the face, hands, and legs.
At two ends of
SAM are marasmus and kwashiorkor.
These two compartments are regulated differently,
as detailed subsequently.
The diagnosis of SAM is obvious in its most severe forms.
Recent studies suggest a role for the gut
microbiome in the pathogenesis of SAM.
Marasmus.
Marasmus develops when the diet is severely
lacking in calories (Fig.
9.21A).
A child is considered to
have marasmus when weight falls to 60% of normal for sex,
height, and age.
In addition to muscle
proteins, subcutaneous fat is also mobilized and used as
fuel.
Kwashiorkor.
9.21B).
The prevalence of kwashiorkor
also is high in lower income countries of Southeast Asia.
9.21).
The weight of children with severe kwashiorkor typically
is 60% to 80% of normal.
However, the true loss of weight
is masked by the increased fluid retention (edema).
In further
contrast with marasmus, there is relative sparing of subcu-
taneous fat and muscle mass.
The modest loss of these
compartments may also be masked by edema.
Malnutrition in the Upper Income World.
well to full-strength, milk-based diets.With treatment, the mucosal
changes are reversible.
Depending on the predominant factor, the red cells
may be microcytic, normocytic, or macrocytic.
Cachexia.
Because of its common association with cancer,
cachexia is discussed in Chapter 7.
Anorexia
nervosa has the highest death rate of any psychiatric disorder.
The clinical findings in anorexia nervosa are generally
similar to those in SAM.
In addition, effects on the endocrine
system are prominent.
In addition, dehydration
and electrolyte abnormalities are frequently present.
The
skin becomes dry and scaly.
9.22).
9.23).
Retinol is then transported in chylomicrons to the liver for
esterification and storage.
Uptake in liver cells takes place
through the apolipoprotein E receptor.
Function.
In humans, the main functions of vitamin A are
the following:
• Maintenance of normal vision.
be present.
In bulimia, binge eating is the norm.
Large amounts of
food, principally carbohydrates, are ingested, followed by
induced vomiting.
The distinction between fat-soluble and water-soluble
vitamins is important.
• Metabolic effects of retinoids.
The association of RXR and
PPARγ thus explains the metabolic effects of retinoids
on adipogenesis.
• Enhancing immunity to infections.
Vitamin A Deficiency.
The
pathologic effects of vitamin A deficiency are summarized
in Fig.
9.24.
As already discussed, vitamin A is a component of
rhodopsin and other visual pigments.
Persistent deficiency gives rise to epithelial metaplasia and
keratinization.
The most devastating changes occur in the
eyes and are referred to as xerophthalmia (dry eye).
via neurons from the retina to the brain.
• Cell growth and differentiation.
Both RAR and RXR have three isoforms, α, β, and γ.
Not depicted are night blindness and immune deficiency.
Vitamin A Toxicity.
Both short-term and long-term excesses
of vitamin A may produce toxic manifestations.
Metabolism of Vitamin D.
This reaction results in the synthesis
of cholecalciferol, known as vitamin D3.
Herein, the term
vitamin D is used to refer to this compound.
The main steps of vitamin D metabolism are summarized
as follows:
1.
9.25).
Functions.
The receptors for
1,25-dihydroxyvitamin D are present in most cells of the
body.
Effects of Vitamin D on Calcium and Phosphorus
Homeostasis.
• Stimulation of calcium reabsorption in the kidney.
TRPV5 expression is also
regulated by PTH in response to hypocalcemia.
• Interaction with PTH in the regulation of blood calcium.
Vitamin D maintains calcium and phosphorus at
supersaturated levels in the plasma.
The parathyroid
glands have a key role in the regulation of extracellular
calcium concentrations.
• Mineralization of bone.
9.26A).
When hypocalcemia occurs due to vitamin D deficiency
(Fig.
Deficiency States.
In all of these situations, vitamin D deficiency can be
prevented by a diet high in fish oils.
(B) Detail of a rachitic costochondral junction in which the palisades of cartilage is lost.
Darker trabeculae are well-formed bone; paler
trabeculae consist of uncalcified osteoid.
(C) Rickets: note bowing of legs due to formation of poorly mineralized bones.
(B, Courtesy Dr.
Andrew E.
During the nonambulatory
stage of infancy, the head and chest sustain the greatest stresses.
An excess of osteoid produces
frontal bossing and a squared appearance to the head.
9.26C).
It was not
until 1932 that ascorbic acid was identified and synthesized.
All but the most restricted diets provide
adequate amounts of vitamin C.
Function.
Ascorbic acid has many functions affecting a
variety of processes:
• Collagen synthesis.
• Neurotransmitter synthesis.
Synthesis of norepinephrine
requires hydroxylation of dopamine, a step that requires
vitamin C.
• Antioxidant functions.
• Modulating the immune response.
Deficiency States.
Consequences of vitamin C deficiency
(scurvy) are illustrated in Fig.
9.28.
Nonskeletal Effects of Vitamin D.
Vitamin D Toxicity.
Vitamin C Excess.
Simi-
larly, there is no evidence that large doses of vitamin C
protect against cancer development.
It is
caused by diets low in protein but normal in calories.
It is caused by diets severely lacking in both protein
and nonprotein calories.
Bulimia is a condition in which food binges
alternate with induced vomiting.
Vitamin D is a key regulator of
calcium and phosphate homeostasis.
• Vitamin C and members of the vitamin B family are water-soluble.
Vitamin C is needed for collagen synthesis and collagen cross-
linking and tensile strength.
B vitamins have diverse roles in
cellular metabolism.
How does
one measure fat accumulation?
BMI is calculated as
(weight in kilograms)/(height in meters)2, or kg/m2.
In the
United States, obesity has reached epidemic proportions.
The etiology of obesity is complex and incompletely
understood.
Genetic, environmental, and psychologic factors
are involved.
However, simply put, obesity is a disorder of
energy homeostasis.
The hypothalamus is the master regula-
tor of energy homeostasis.
9.29 and 9.30).
• The peripheral or afferent system generates signals from
various sites.
The afferent systems
provide signals to the central processing system in the
brain.
Two sets of
neurons participate in central processing (see Fig.
9.30).
Here these signals inhibit anabolic circuits and
activate catabolic circuits.
This in turn reduces the energy stores, and energy sufficiency signals are blunted.
(AgRP).
These first-order neurons communicate with
second-order neurons.
See text for details.
NPY/AgRP neurons also directly inhibit
POMC/CART neurons, thus blunting their anorexigenic
effect.
The orderly functioning
of these two pedals maintains energy homeostasis.
Leptin.
Leptin is secreted by fat cells, and its output is
regulated by the adequacy of fat stores.
BMI and body fat
stores are directly related to leptin secretion.
In persons of stable weight, the activities of
these pathways are balanced.
The neurohumoral mediators
of leptin-induced energy expenditure are less well defined.
Both POMC/CART and NPY/AgRP neurons express insulin
receptors.
Adiponectin.
Its serum levels are lower in obese
than in lean individuals.
Adiponectin binds to two receptors, AdipoR1 and
AdipoR2.
Gut Hormones.
Gut peptides act as short-term meal initia-
tors and terminators.
They include ghrelin, PYY, and
GLP-1 (glucagon-like peptide-1), among others.
Its injection
in rodents elicits voracious feeding, even after repeated
administration.
Ghrelin acts centrally by activating orexigenic NPY/AgRP
neurons.
PYY and GLP-1 are secreted from endocrine cells in the
ileum and colon.
Plasma levels of PYY and GLP-1 are low
during fasting and increase shortly after food intake.
Adipose Tissue.
BAT has the
unique property of expending energy by nonshivering
thermogenesis.
BAT is abundant in newborns and is located
primarily in interscapular and supraclavicular areas.
Lesser
amounts are present around kidneys, aorta, heart, pancreas,
and trachea.
Until recently, it was thought that BAT is lost
in adults.
However, recent imaging studies have revealed
that some BAT is preserved in adolescents and adults.
Much
effort is now focused on how BAT can be preserved in
adulthood and activated to burn energy.
Role of the Gut Microbiome.
The relevance
of the mouse models to human obesity is tantalizing but
remains to be proven.
Differences between the gut micro-
biome of obese and lean humans have also been reported.
Whether this difference is causal or just an association is
unclear.
9.31).
(Modified from Renehan AG, et al: and cancer.
This in turn stimulates secretion of IL-1, which induces
systemic inflammation.
The following associations are worthy
of note.
Inflammation induced by IL-1 and other factors likely
contributes to insulin resistance.
• Nonalcoholic fatty liver disease is commonly associated with
obesity and type 2 diabetes.
It can progress to fibrosis
and cirrhosis (Chapter 18).
• Cholelithiasis (gallstones) is six times more common in obese
than in lean subjects.
Hypoventilation
syndrome is a constellation of respiratory abnormalities
in very obese persons.
The greater the body burdens of fat,
the greater the trauma to joints with the passage of time.
The
underlying mechanisms are unknown and are likely to be
multiple.
• Elevated insulin levels.
9.31).
For example, hyperinsulinemia causes a rise in levels of
free insulin-like growth factor 1 (IGF-1).
IGF-1 is a
mitogen, and its receptor, IGFR-1, is highly expressed
in many human cancers.
• As discussed earlier, adiponectin secretion from adipose
tissue is reduced in obese individuals.
Adiponectin sup-
presses cell proliferation and promotes apoptosis.
It does
so in part by promoting the actions of p53 and p21.
In
obese individuals these antineoplastic actions of adipo-
nectin may be compromised.
Bile acid
metabolites produced by these bacteria may function
as carcinogens.
KEY CONCEPTS
OBESITY
• Obesity is a disorder of energy regulation.
A few examples suffice here.
This is called primary prevention.
We know some, but not all, the answers.
Of these, the effect on kisses is the
best established!
[A large European study relating all-cause mortality and
particulate inhalation].
Hon KL, Fung CK, Leung AKC: Childhood lead poisoning: an overview,
Hong Kong Med J 23:616, 2017.
[A discussion of lead poisoning in
childhood].
[A comprehensive paper on heavy metal poisoning].
[A discussion of alcohol usage
and cancer at different dose levels].
https://
www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-
disease.html.
[CDC report on severe lung injury associated with use of
flavored e-cigarettes].
[A discussion of
accumulating evidence for association of type 2 diabetes and tobacco smoking].
[A summation of the evidence linking e-cigarette use
and disease].
[A comprehensive report by the US Surgeon General on the health
effects of smoking].
JAMA Internal Medicine published
online February 11, 2019.
E1 [A short article on the magnitude of the
US opioid crisis].
National Institute on Drug Abuse (NIDA).
https://www.drugabuse.gov
updated in June 2019.
[An extensive discussion of the effects of marijuana
use and abuse including possible addiction].
Million M, Diallo A, Raoult R: Review.
Gut microbiota and malnutrition,
Microb Pathog 106:127, 2017.
[An excellent discussion of the potential
role of microbiome in pathogenesis of malnutrition].
Padayatty SJ, Levine M: Vitamin C: the known and unknown and
Goldilocks, Oral Dis 22:463, 2016.
[A detailed discussion of vitamin C
physiology and diseases associated with deficiency].
[A broad overview of the role of dietary supplements including vitamins
in disease prevention].
Sarri JC: Vitamin A metabolism in rod and cone visual cycles, Annu
Rev Nutr 32:125, 2012.
[A discussion of the biochemical mechanism of
vitamin A in vision].
[An appraisal of the
possible role of vitamin C in sepsis management].
[A review of several large studies linking obesity with
all-cause mortality].
[A discussion of neurohumoral mechanisms and
obesity].
[A balanced review of the role of
the microbiome in obesity].
[A discussion of the
role of brown adipose tissue in energy homeostasis].
[A discussion of the high risk
of cardiovascular disease with obesity in a South Asian population].
Gonzalez-Muniesa P, Martinez-Gonzalez M-A, Hu FB et al: Obesity,
Nat Rev Dis Primers 3:1, 2017.
[A general review of obesity with focus
on visceral and truncal obesity].
[A discus-
sion of the association of cancers with obesity].
[An excellent discussion of energy homeostasis including neurohumoral
mechanisms].
Zhao VW, Scherer PE: Adiponectin, the past two decades, J Mol Cell
Biol 8:93, 2016.
Husain • Selene C.
The chances for survival of infants improve with
each passing week.
Once the infant survives the first year
of life, the outlook brightens measurably.
Perhaps 20% of fertilized ova are so
anomalous that they are blighted at early stages.
Others
may be compatible with early fetal development, only to
a The prior contributions of Dr.
Anirban Maitra to this chapter are
gratefully acknowledged.
453454 CHAPTER 10 Diseases of Infancy and Childhood
Figure 10.1 Examples of malformations.
(A and C, Courtesy Dr.
Reade
Quinton; B, Courtesy Dr.
10.1).
Develop-
mental anomalies may present in several patterns.
10.2).
A variety
of environmental agents may cause disruptions (see
later).
Deformations are common
problems, affecting approximately 2% of newborn infants
to varying degrees.
The most common underlying factor responsible for
deformations is uterine constraint.
Thus, even the normal fetus is subjected to
some degree of uterine constraint.
Several factors increase
Figure 10.2 Disruption of morphogenesis by an amniotic band.
(Courtesy Dr.
For example, clubfeet can occur as a com-
ponent of Potter sequence, described later.
• A sequence is a cascade of anomalies triggered by one
initiating aberration.
A good example
is the oligohydramnios (or Potter) sequence (Fig.
10.3).
10.4).
The hips may be dislocated.
Nodules in the amnion
(amnion nodosum) are frequently present.
Note the flattened
facial features and deformed right foot (talipes equinovarus).
primordium.
Virtually all chromosomal syndromes are associated with
congenital malformations.
Examples include Down syndrome
and other trisomies, Turner syndrome, and Klinefelter
syndrome.
Most chromosomal disorders arise during
gametogenesis and hence are not familial.
disturbances.
These in combination are labeled the fetal
alcohol syndrome (also discussed in Chapter 9).
In light of these findings, it is best to avoid nicotine
exposure altogether during pregnancy.
1.
10.5).
During this period, organs are being crafted
out of the germ cell layers.
Instead, the fetus is susceptible to growth
restriction or injury to already formed organs.
2.
This is
illustrated by the following representative examples.
• Valproic acid is an antiepileptic and a recognized
teratogen during pregnancy.
Conversely, excessive exposure
to retinoic acid is also teratogenic.
Rupture
of membranes (ROM) before the onset of labor can be
spontaneous or induced.
In contrast, PROM refers to
spontaneous ROM occurring after 37 weeks of gestation.
• Intrauterine infection: This is a major cause of preterm
labor with and without intact membranes.
Maternal malnutrition (in
particular, prolonged hypoglycemia) may also affect fetal
growth.
Fetal infection should be considered in all infants with
FGR.
In some cases the
placenta (and the baby) may be small without any detectable
underlying cause.
Pathogenesis
The fundamental defect in RDS is pulmonary immaturity
and deficiency of surfactant.
At birth,
the first breath of life requires high inspiratory pressures
to expand the lungs.
The
hypoxemia itself further impairs surfactant synthesis, and
a vicious cycle ensues.
The role of glucocorticoids
is particularly important.
intrauterine stress and FGR that increase corticosteroid
release lower the risk of developing RDS.
This may explain, in part, why infants
of diabetic mothers have a higher risk of developing RDS.
Microscopically, alveoli are poorly
developed, and those that are present are collapsed (Fig.
10.7).
In uncomplicated cases, recovery begins
to occur within 3 or 4 days.
• Retinopathy of prematurity has a two-phase pathogenesis.
Treatment with mesenchymal stem cells has potential
but remains experimental.
It occurs in approximately
1 in 10 very-low-birth-weight infants (<1500 g).
Approxi-
mately 2500 cases occur annually in the United States.
The pathogenesis of NEC is uncertain but multifacto-
rial.
Perhaps alteration in the microbiome on enteral feeding
Figure 10.7 Hyaline membrane disease.
There are eosinophilic thick
hyaline membranes lining the dilated alveoli.
Fine rales can then be heard over both lung fields.
Critical to these
objectives is the ability to assess fetal lung maturity accu-
rately.
A large number of inflammatory mediators have
been associated with NEC.
Probiotic therapies are being evaluated for preven-
tion of NEC.
Such
infections may be acquired in utero or around the time of
birth.
As stated earlier, preterm birth is a common and
unfortunate consequence of infection.
10.8).
Figure 10.8 Necrotizing enterocolitis (NEC).
10.10).
The mother thus
becomes sensitized to the foreign antigen.
Thus, Rh
disease is uncommon with the first pregnancy.
chorionic villi.
10.9).
There is no effective protection against ABO reactions.
There are two consequences of excessive destruction of
red cells in the neonate (see Fig.
10.10).
• Anemia is a direct result of red cell loss.
Cardiac hypoxia may lead to cardiac decompensation
and failure.
• Jaundice develops because hemolysis produces unconju-
gated bilirubin (Chapter 18).
Bilirubin also passes through
the infant’s poorly developed blood-brain barrier.
10.13).
Fetal anemia, not
caused by Rh- or ABO-associated antibodies, can also result
in hydrops.
10.9).
In up to 20% of cases, the cause remains unknown.
Several
factors account for this.
First, most anti-A and anti-B antibod-
ies are of the IgM type and hence do not cross the placenta.
Second, neonatal red cells express blood group antigens A
and B poorly.
Therefore, the firstborn
may be affected.
(A) There is generalized accumulation of fluid in the fetus.
(Courtesy Dr.
The most serious threat in fetal hydrops is CNS damage,
known as kernicterus (Fig.
The biochemical abnormality in PKU is an inability to
convert phenylalanine into tyrosine.
The remainder is converted
to tyrosine by the phenylalanine hydroxylase system (Fig.
10.14).
coined the term in 1908, the number of recognized metabolic
diseases has increased exponentially.
Mitochondrial disorders (Chapter 5) form a distinct entity
by themselves.
About one-third of these children are never able to walk,
and two-thirds cannot talk.
Long-term toxicity in galactosemia has been variously
imputed to these metabolic intermediates.
The liver,
eyes, and brain bear the brunt of the damage.
Similar changes may occur in the cerebral
cortex and white matter.
These infants fail to thrive almost from birth.
Vomiting
and diarrhea appear within a few days of milk ingestion.
Even in untreated
infants, however, the disability is usually not as severe as
that seen in PKU.
Hemolysis and
coagulopathy in the newborn period can occur as well.
Newborn screening tests are widely utilized in the United
States.
They depend on fluorometric assay of GALT enzyme
activity on a dried blood spot.
A positive screening test
must be confirmed by assay of GALT levels in red cells.
Deficiency of
PAH or dihydropteridine reductase (DHPR) can give rise to
phenylketonuria.
excreted in large amounts in the urine and sweat.
These
impart a strong musty or mousy odor to affected infants.
It is believed that excess phenylalanine or its metabolites
contribute to the brain damage in PKU.
Concomitant lack
of tyrosine (see Fig.
10.14), a precursor of melanin, is
responsible for the light color of hair and skin.
At the molecular level, over 500 mutant alleles of the
PAH gene have been identified.
Mutations in both PAH
alleles are required to develop the disease.
Once a biochemical diagnosis is established, the
specific mutation causing PKU can be determined.
10.14).
It affects 1 in 60,000 live-born infants.
Galactose is then converted to glucose
in several steps catalyzed by distinct enzymes.
Two variants
of galactosemia have been identified.
The rare variant arises from a deficiency
of galactokinase.
10.15).
The two trans-
membrane domains form a channel through which chloride
passes.
Bottom, Normal cystic
fibrosis transmembrane conductance regulator (CFTR) structure and
activation.
This results in
opening of the chloride ion channel.
discussed later in the context of pulmonary and
gastrointestinal pathology in cystic fibrosis.
This is the basis
for the “salty” sweat that mothers can often detect in
their affected infants.
10.16).
CFTR, Cystic fibrosis transmembrane conductance regulator; ENaC,
epithelial sodium channel.
layer coating mucosal cells.
• CFTR regulates transport of bicarbonate ions.
The mutations can be grouped
into six classes based on their effect on the CFTR protein
(Fig.
10.17).
Class I mutations result in no protein production.
Class III mutations affect channel regulation, impairing
channel opening (e.g., Gly551Asp).
Class IV mutants show reduced conduction—i.e., decreased flow of ions (e.g., Arg117His).
Class V mutations cause
substantial reduction in mRNA or protein, or both.
Class VI mutations cause substantial plasma membrane instability.
• Class I: Defective protein synthesis (null mutations).
• Class II: Abnormal protein folding, processing, and trafficking
(processing mutations).
Worldwide, this mutation can be found in
approximately 70% of Caucasian cystic fibrosis patients.
• Class III: Defective regulation (gating mutations).
Thus, there is a normal amount
of CFTR on the apical surface, but it is nonfunctional.
• Class IV: Decreased conductance (conduction mutations).
There is a normal amount of CFTR at the apical
membrane, but with reduced chloride conduction.
• Class V: Reduced abundance (production mutations).
• Class VI: Decreased membrane CFTR stability (instability
mutations).
10.18).
Concurrent viral infections predispose
to such colonization.
Figure 10.19 End-stage pancreatic disease in cystic fibrosis.
The ducts are
markedly dilated, and exocrine glands are destroyed and replaced by
fibrous tissue.
proliferation and portal inflammation.
Hepatic steatosis is not
an uncommon finding in liver biopsies.
Such severe hepatic involvement is
encountered in less than 10% of patients.
The pulmonary changes are the most serious complications
of this disease (Fig.
10.20).
Superimposed infections give rise to severe chronic bronchitis
and bronchiectasis (Chapter 15).
In many instances, lung abscesses
develop.
As mentioned earlier, a mucoid
form of P.
aeruginosa (alginate-producing) is particularly frequent
and causes chronic inflammation.
cenocepacia are the
most common in cystic fibrosis patients.
MORPHOLOGY
The anatomic changes are highly variable in distribution and severity.
In all variants, the sweat glands are mor-
phologically unaffected.
Pancreatic abnormalities are present in approximately 85%
to 90% of patients with cystic fibrosis.
Sometimes
these cause small-bowel obstruction, known as meconium ileus.
Liver involvement follows the same basic pattern.
These patients have other features of classic cystic
fibrosis, such as pulmonary disease.
Chronic sinopulmonary disease manifested by
a.
Chronic cough and sputum production
c.
Airway obstruction manifested by wheezing and air trapping
e.
Nasal polyps; radiographic or computed tomographic
abnormalities of paranasal sinuses
f.
Digital clubbing
2.
Gastrointestinal and nutritional abnormalities, including
a.
Intestinal: meconium ileus, distal intestinal obstruction
syndrome, rectal prolapse
b.
Pancreatic: pancreatic insufficiency, recurrent acute pancreatitis,
chronic pancreatitis
c.
Salt-loss syndromes: acute salt depletion, chronic metabolic
alkalosis
4.
Figure 10.20 Lungs of a patient who died of cystic fibrosis.
There is
extensive mucus plugging and dilation of the tracheobronchial tree.
10.18).
Pancreatic insufficiency is
associated with protein and fat malabsorption and increased
fecal loss.
Hypoproteinemia may be severe enough to cause
generalized edema.
Persistent diarrhea may result in rectal
prolapse in up to 10% of children with this disease.
By 18 years of age, 80% of
patients with classic cystic fibrosis harbor P.
aeruginosa, and
3.5% harbor B.
cepacia.
Patients with mild pulmonary disease usually
have little or no pancreatic disease.
Adult-onset “idiopathic”
bronchiectasis has been linked to CFTR mutations in a subset
of cases.
However, asymptomatic hepa-
tomegaly may be present in up to one-third of individuals.
Sequencing the
CFTR gene is the gold standard for diagnosis of cystic
fibrosis.
New
treatment modalities for restoring mutant CFTR function
are being tested in clinical trials.
Based on the molecular
defect, three classes of agents are being developed:
• Potentiators.
These agents keep the “gate” of the CFTR
channel open.
Hence they are most useful in gating (class
III) and conduction (class IV) mutations.
• Correctors.
Hence they have the potential to help patients
with processing (class II) mutations.
These include patients
with ΔF508, the most common CFTR mutation.
• Amplifiers.
This number translates to about 1360 deaths due to SIDS
in the United States.
Most infants who
die of SIDS die at home, usually during the night after a
period of sleep.
The CNS demonstrates astrogliosis
of the brainstem and cerebellum.
Male sex is
associated with a slightly greater incidence of SIDS.
Benign tumors are even more
common than cancers.
(Courtesy Dr.
Hemangioma
Hemangiomas are the most common tumors of infancy
(Chapter 11).
Architecturally, they do not differ from those
occurring in adults.
10.21).
Teratomas
Teratomas illustrate the relationship of histologic maturity
to biologic behavior.
10.22).
They occur with a frequency of 1 in 20,000 to 40,000 live
Figure 10.22 Sacrococcygeal teratoma.
Histologically, many of the malignant nonhematopoietic
pediatric neoplasms are unique.
If the anatomic site of origin
is known, diagnosis is usually possible on histologic grounds
alone.
The
remaining tumors are discussed in their respective organ-
specific chapters.
Neuroblastoma is the most important member of this family.
The median age at diagnosis is 18 months; approxi-
mately 40% of cases are diagnosed in infancy.
On transection, they are composed
of soft, gray-tan tissue.
Larger tumors have areas of necrosis,
cystic softening, and hemorrhage.
Occasionally, foci of punctate
intratumoral calcification can be palpated.
Mitotic activity, nuclear breakdown
(“karyorrhexis”), and pleomorphism may be prominent.
10.23).
Some neoplasms show signs of maturation that can be
spontaneous or therapy-induced.
Spindle-shaped
Schwann cells are present in the background stroma.
10.24).
Metastases, when they develop, appear early and widely.
Staging.
The staging system is of paramount
importance in determining prognosis.
This tumor is composed of small
cells embedded in a finely fibrillar matrix (neuropil).
complaints.
The clinical course of neuroblastomas is extremely
variable.
The biologic basis of this welcome behavior is not
clear.
The age of 18 months has emerged as a critical
point of dichotomy in terms of prognosis.
• Tumor morphology.
The specific morphologic features that bear on prognosis
are listed in Table 10.7.
• MYCN amplification status.
MYCN is located on the distal short arm of chromosome
2 (2p23-p24).
10.25).
Whole-genome sequencing has uncovered alterations in
a variety of genes.
Some of these alterations have prognostic
implications.
The impact of these changes on prognosis is under
investigation.
(A, Courtesy Dr.
Their lifetime risk of developing
Wilms tumor is approximately 33%.
Individuals with
WAGR syndrome carry constitutional (germline)
deletions of 11p13.
The characteristic glomerular
lesion in these patients is diffuse mesangial sclerosis
(Chapter 20).
As in patients with WAGR, these patients
also demonstrate germline abnormalities in WT1.
The WT1 protein is
critical for normal renal and gonadal development.
BWS has served as a model
for tumorigenesis associated with genomic imprinting
(Chapter 5).
Some of them are
associated with specific histologic features described
later.
MORPHOLOGY
Grossly, Wilms tumor tends to present as a large, solitary, well-
circumscribed mass.
Approximately 10% are either bilateral or
multicentric at the time of diagnosis.
10.26).
10.27A).
Sheets of small blue cells with few distinctive features
characterize the blastemal component.
Epithelial differentiation
is usually in the form of abortive tubules or glomeruli.
10.27B).
Although
multiple mitotic figures are seen, none are atypical in this field.
As stated, most patients with Wilms tumor can expect
to be cured of their malignancy.
Anaplastic histology is
perhaps the most critical determinant of adverse prognosis.
Elborn JS: Cystic fibrosis, Lancet 388:2519–2531, 2016.
[An excellent
overview including clinical and molecular features of cystic fibrosis].
http://ommbid.mhmedical.com/
content.aspx?bookid=971&sectionid=62673211.
(Accessed December
11, 2017).
[An in-depth online resource that reviews this prototypical
Mendelian disorder].
[Updated consensus guidelines for the diagnosis of cystic fibrosis].
[A concise review
of pathogenesis, diagnosis, and treatment of this condition].
[A review of clinical, histologic, and molecular determinants
of prognosis for Wilms tumor].
Matthay KK, Maris JM, Schleiermacher G et al: Neuroblastoma, Nat
Rev Dis Primers 2:16078, 2016.
[An excellent recent review of the clinical,
pathologic, and molecular features of neuroblastoma].
PubMed PMID: 28814547.
Mitchell • Marc K.
veins at the same level of branching to accommodate pulsatile
flow and higher blood pressures.
11.1).
layer of ECM; the intima is demarcated from the media
by the internal elastic lamina.
• In muscular arteries, the media is composed predomi-
nantly of circumferentially oriented SMCs.
• Arterioles are the principal points of physiologic resistance
to blood flow.
The adventitia consists of loose
connective tissue and can also contain nerve fibers.
11.1).
Reverse flow (due to gravity) is prevented in the
extremities by venous valves.
Surgically generated arteriovenous fistulas
provide vascular access for chronic hemodialysis.
Like
berry aneurysms, arteriovenous fistulas can rupture.
The cause is
unknown.
In the renal
arteries, it can be a cause of renovascular hypertension
(Chapter 20).
ECs form a specialized simple squamous epithelium lining
for blood vessels.
capillaries,
arteries vs.
veins) have distinct gene expression profiles,
behaviors, and morphologic appearances.
ECs are versatile multifunctional cells with a wealth of
synthetic and metabolic properties.
11.2).
Viruses,
complement components, and hypoxia also activate ECs.
Normal EC function is characterized by a balance
of these responses.
VEGF, Vascular
endothelial growth factor.Hypertensive vascular disease 489
1.
Recruitment of smooth muscle
cells or smooth muscle precursor
cells to the intima
3.
Elaboration of
2.
circulating precursors.
11.3).
The resulting neointima
is typically completely covered by ECs.
Thus intimal thickening
is the stereotypical response of the vessel wall to any insult.
Neointimal SMCs have a phenotype that is distinct from
that of medial SMCs.
Like height and weight, blood pressure is a continuously
distributed variable.
Table 11.2 lists the major causes of hypertension.
However, approximately 90% of hyperten-
sion is idiopathic—so-called essential hypertension.
anticoagulative, proinflammatory
vs.
antiinflammatory, and nonadhesive vs.
adhesive).
11.4).
• Cardiac output is a function of stroke volume and heart
rate.
Americans.
11.5).
The kidneys filter 170 liters of plasma containing 23 moles
of salt daily.
About 98% of the filtered
sodium is reabsorbed by several constitutively active
transporters.
The kidneys and heart contain cells that sense changes
in blood pressure or volume.
Mechanisms of Essential Hypertension.
They also induce systemic
vasodilation.
Blood volume in
turn is regulated mainly by renal sodium excretion or resorption.
11.5).
Infrequently, hypertension has an underly-
ing endocrine basis.
Mechanisms of Secondary Hypertension.
11.5).
It may
be idiopathic or less commonly caused by aldosterone-
secreting adrenal adenomas.
• Single-gene disorders cause severe but rare forms of
hypertension.
• Mutations affecting proteins that influence sodium reabsorp-
tion.
Three forms of small vessel
disease are hypertension-related (Fig.
11.6).
MORPHOLOGY
Hyaline arteriolosclerosis.
Arterioles show homogeneous, pink
hyaline thickening with associated luminal narrowing (Fig.
11.6A).
(A) Hyaline arteriolosclerosis.
Hyperplastic arteriolosclerosis.
11.6B).
These are described in greater detail in Chapter 15.
There are four general patterns, with different
clinical and pathologic consequences.
Adults older than
age 50 are most commonly affected.
The calcifications
do not encroach on the vessel lumen and are usually not
clinically significant.
• Fibromuscular intimal hyperplasia occurs in muscular arteries
larger than arterioles.
States.
11.7).
Epidemiology.
11.8).
Constitutional Risk Factors
• Genetics.
Family history is the most important independent
risk factor for atherosclerosis.
• Age is a dominant influence.
Thus between ages 40 and 60, the incidence of
myocardial infarction increases fivefold.
Death rates from
ischemic heart disease rise with each decade even into
advanced age.
• Gender.
Higher levels of HDL (“good
cholesterol”) correlate with reduced risk.
Interestingly, approaches that
exclusively raise HDL are not effective.
Smoking cessation reduces that risk substantially.
Clearly, other factors
are contributory.
Among those that are proven or suspected
are the following:
• Inflammation.
Relative
risk (y-axis) refers to the risk of a cardiovascular event (e.g., myocardial
infarction).
In
each risk group, C-reactive protein values further stratify the patients.
11.9).
Accordingly, CRP levels are now incorporated
into risk stratification algorithms.
• Hyperhomocysteinemia.
• Metabolic syndrome.
• Factors affecting hemostasis.
1, Normal.
2, Endothelial injury with monocyte and platelet
adhesion.
3, Monocyte and smooth muscle cell migration into the intima,
with macrophage activation.
4, Macrophage and smooth muscle cell uptake
of modified lipids, with further activation.
Endothelium
Intima
Media
Adventitia
1.
• Other factors.
11.10).
• Accumulation of lipoproteins (mainly LDL and its oxidized
forms) in the vessel wall.
• Platelet adhesion.
• SMC proliferation, ECM production, and recruitment of T
cells.
• Lipid accumulation both extracellularly and within cells
(macrophages and SMCs).
• Calcification of ECM and necrotic debris late in the
pathogenesis.
Endothelial Injury.
EC injury is the cornerstone of the
response-to-injury hypothesis.
Macrophage
activation,
smooth muscle recruitment
Smooth
muscle cell
Fatty streak
4.
Macrophages and
smooth muscle cells
engulf lipid
T lymphocyte
Fibrofatty atheroma
5.
• Modified LDL.
The early lesions containing lipid-
filled macrophages are called fatty streaks.
Inflammation.
Chronic inflammation contributes to the
initiation and progression of atherosclerotic lesions.
11.11).
Infection.
Smooth Muscle Proliferation and Matrix Synthe-
sis.
11.10).
Hemodynamic Disturbances.
Hypercholesterolemia.
All of these abnormalities are associated
with an increased risk of atherosclerosis.
Fig.
All four cell
types are capable of liberating mediators that can influence
atherogenesis.
MORPHOLOGY
Fatty streaks.
Fatty streaks are composed primarily of lipid-filled
foamy macrophages.
The lesions are not particularly raised and do not cause any
significant flow disturbance (Fig.
11.13).
Although fatty streaks
can evolve into plaques, not all are destined to become advanced
lesions.
Atherosclerotic plaque.
The key processes in atherosclerosis
are intimal thickening and lipid accumulation (see Figs.
11.7, 11.10,
and 11.12).
Plaques vary in size
but can coalesce to form larger masses (Fig.
11.14).
11.15A).
Hyperlipidemia, hyperglycemia, hypertension, and other influences cause endothelial
dysfunction.
IL-1, Interleukin-1; MCP-1, monocyte chemoattractant protein-1.
B
A
Figure 11.13 Fatty streak, a collection of foamy macrophages in the intima.
(A) Aorta with fatty streaks (arrows), associated largely with the ostia of
branch vessels.
(B, Courtesy Myron I.
(A) Mild atherosclerosis composed of fibrous plaques, one of which is denoted by the arrow.
of vascular hemodynamics.
Moreover, in any given vessel, lesions at
various stages often coexist.
The lumen (L) has been moderately compromised.
(A) Plaque rupture without superimposed thrombus
in a patient who died suddenly.
In both (A) and (B), an arrow
points to the site of plaque rupture.
11.15C).
11.15C).
Atherosclerotic plaques are susceptible to clinically important
pathologic changes.
11.16).
If the patient
survives, the thrombus may organize and become incorporated
into the growing plaque.
• Hemorrhage into a plaque.
• Atheroembolism.
Plaque rupture can discharge atherosclerotic
debris into the blood stream, producing microemboli.
• Aneurysm formation.
Atherosclerotic Stenosis.
11.17).
Acute Plaque Change.
11.16), resulting in acute tissue infarction
(e.g., myocardial or cerebral infarction) (see Fig.
11.17).
Compensatory enlargement initially prevents a reduction of blood flow through the vessel.
Thin cap plaques are the most prone to plaque
rupture, generally leading to sudden cardiac death.
This event can lead to sudden cardiac death.
syndromes are often asymptomatic before undergoing a
sudden, typically unpredictable change.
Thus a large number of asymptomatic adults may be at risk
for a catastrophic coronary event.
11.18).
Vulnerable plaques have
thin fibrous caps, large lipid cores, and increased inflammation.
Influences extrinsic to plaques also contribute to acute
plaque changes.
and 12 noon).
In
its most serious form, thrombus leads to total occlusion of
the affected vessel.
Mural thrombi in a coronary artery can also embolize.
• Atherosclerotic plaques develop and generally grow slowly over
decades.
11.19).
True aneurysm
A.
Normal vessel D.
False aneurysm E.
Dissection
(fusiform)
B.
True aneurysm
(saccular)
Figure 11.19 Aneurysms.
(A) Normal vessel.
(B) True aneurysm, saccular type.
The wall focally bulges outward and may be attenuated but is otherwise
intact.
(C) True aneurysm, fusiform type.
There is circumferential dilation of the vessel, without rupture.
(D) False aneurysm.
(E) Dissection.
Blood has entered (dissected) the wall of
the vessel and separated the layers.
Dissections are often, but not always, aneurysmal (see later).
Descriptively, aneurysms are classified by macroscopic
shape and size (see Fig.
11.19).
These types are
not specific for any disease or clinical manifestations.
• Abnormal transforming growth factor- β (TGF- β) signaling.
Both processes result in
a loss of elastic fibers necessary for recoil in diastole.
11.20).
Although adventitial lymphoplasmacytic
A
B
Figure 11.20 Cystic medial degeneration.
(B) Normal media for comparison showing the regular layered
pattern of elastic tissue.
AAAs occur more frequently in men and in smokers,
rarely developing before age 50.
be retroperitoneal fibrosis with bilateral hydronephrosis.
In such cases,
suppuration further destroys the media, potentiating rapid dilation
and rupture.
Most aneurysms expand at a rate of 0.2 to
0.3 cm/year, but 20% expand more rapidly.
11.21).
Not infrequently,AAAs
will be accompanied by smaller aneurysms of the iliac arteries.
There may
A B
Figure 11.21 Abdominal aortic aneurysm.
(B) Opened view, with the location of the rupture
tract indicated by a probe.
11.22).
Pathogenesis
Hypertension is the major risk factor for aortic dissection.
11.20); inflam-
mation is characteristically absent.
Thus the relationship
of the structural changes to the pathogenesis of dissection is
uncertain.
A B
Figure 11.22 Aortic dissection.
(B) Histologic view of dissection demonstrating an aortic intramural hematoma (asterisk).
11.22A).
11.22B).
Type A Type B
Figure 11.23 Classification of dissections.
Type B (distal or Debakey III) dissections arise
after the take-off of the great vessels.
Type A dissections typically have the
most serious complications and greatest mortality.
Accordingly, aortic dissec-
tions are generally classified into two types (Fig.
11.23):
• Type A dissections.
• Type B dissections.
Retrograde dissection into the aortic root can also
disrupt the aortic valve annulus.
Common clinical manifesta-
tions include cardiac tamponade and aortic insufficiency.
Com-
plications are related to rupture, thrombosis, and embolization.
Complications arise due to rupture or obstruction of vessels
branching off the aorta.
heart vs.
small bowel).
ANCA, Antineutrophil cytoplasmic antibody.
Nevertheless, several vasculitides
tend to affect only vessels of a particular size or location.
11.24).
As we will see,
there is considerable clinical and pathologic overlap among
many of them.
Often,
however, this type of vasculitis presents a number of
diagnostic challenges.
Only rarely is the specific antigen
responsible for immune complex formation identified.
Note that there is a
substantial overlap in distributions.
ANCA, Antineutrophil cytoplasmic antibody; SLE, systemic lupus erythematosus.
deposits are scarce.
• Vasculitis secondary to infections.
Although a number of
ANCAs have been described, two are most important.
• Anti-proteinase-3 (PR3-ANCA, previously c-ANCA).
PR3-ANCAs are associated with granulo-
matosis with polyangiitis (see later).
• Anti-myeloperoxidase (MPO-ANCA, previously p-ANCA).
MPO-ANCAs are associated with microscopic
polyangiitis and Churg-Strauss syndrome (see later).
A plausible mechanism for ANCA vasculitis is the
following.
Thus ANCA-
associated vasculitides are often described as pauci-immune.
It is
the most common form of vasculitis among elderly adults
in the United States and Europe.
Proinflammatory cytokines (especially TNF) and
anti-EC antibodies also contribute.
11.25),
granulomas and giant cells can be rare or absent.
Inflammatory
IT
A B C
Figure 11.25 Giant cell (temporal) arteritis.
(C, From Salvarani C, et al.
Clinical Features
Temporal arteritis is rare before age 50.
Diagnosis depends on biopsy and histologic
confirmation.
Corticosteroids or anti-TNF
therapies are typically effective.
11.26).
An
autoimmune etiology is likely.
Figure 11.26 Takayasu arteritis.
MORPHOLOGY
Takayasu arteritis classically involves the aortic arch.
11.26A and B).
Such narrowing explains the weakness of the peripheral pulses.
Granulomatous inflam-
mation, replete with giant cells and patchy medial necrosis, is also
seen.
The histology (Fig.
11.26C) is essentially indistinguishable
from giant cell (temporal) arteritis.
Occasion-
ally, aortic root involvement causes dilation and aortic valve
insufficiency.
The course of the disease is variable.
The cause remains unknown in the majority of cases.
Clinical
manifestations result from ischemia and infarction of affected
tissues and organs.
Renal involvement is often
a major cause of mortality.
Its clinical significance stems
from the involvement of coronary arteries.
Originally described in Japan,
the disease is now recognized in the United States and
elsewhere.
11.27).
Older lesions
show fibrous thickening of the vessel wall extending into the
adventitia.
MORPHOLOGY
Kawasaki disease vasculitis resembles that seen in PAN.
As with
other arteritides, healed lesions can also exhibit obstructive intimal
thickening.
Pathologic changes outside the cardiovascular system
are rarely significant.
Clinical Features
PAN is primarily a disease of young adults but can occur
in all age groups.
The course is frequently remitting and
episodic, with long symptom-free intervals.
It is also called hypersensitivity vasculitis or leukocy-
toclastic vasculitis.
There is segmental fibrinoid necrosis
and thrombotic occlusion of the lumen of this small artery.
Note that part
of the vessel wall at the upper right (arrow) is uninvolved.
Indeed, most cases are associ-
ated with MPO-ANCA.
11.28A).
11.28B).
(B and C) Granulomatosis with polyangiitis.
(A, Courtesy Michael A.
11.28C), and
alveolar hemorrhage may be prominent.
Lesions may ultimately
undergo progressive fibrosis and organization.
Clinical Features
Males are affected more often than females, at an average
age of about 40 years.
Rashes, myalgias, articular
involvement, neuritis, and fever can also occur.
Left
untreated, the disease is usually rapidly fatal with 80%
mortality within 1 year.
It occurs almost exclusively in heavy
cigarette smokers, usually before the age of 35.
Identifying the underlying pathology
has therapeutic significance.
11.30).
Raynaud phenomenon can be a primary
entity or secondary to other disorders.
It results from intrinsic hyperreactivity of
medial SMCs.
Ulceration and ischemic gan-
grene are rare.
Less commonly it is caused by infections.
11.24 and
Table 11.4).
A B
Figure 11.30 Raynaud phenomenon.
(A) Sharply demarcated pallor of the distal fingers resulting from the closure of digital arteries.
(B) Cyanosis of the
fingertips.
Of these, some 10% will
eventually manifest an underlying disorder.
Thrombi in the legs tend to produce few, if any, reliable
signs or symptoms.
In many cases the first
manifestation of thrombophlebitis is a pulmonary embolus.
Depending on the size and number of emboli, the outcome
can range from no symptoms to death.
Up to 20% of men and a third of women
develop lower extremity varicose veins.
A familial predilection to varicose veins
reflects defective venous wall development.
Varicosities in two other sites also deserve mention:
• Esophageal varices.
Pulmonary vessels can also
be compressed, inducing respiratory distress.
Eventually inadequate tissue perfusion can lead to skin
ulceration.
Primary tumors of large vessels (aorta, pulmonary
artery, and vena cava) are mostly sarcomas.
In general, benign and malignant
vascular neoplasms can be distinguished by the following
features.
Benign Tumors and Tumor-Like Conditions
Vascular Ectasias.
Most ultimately regress spontaneously.
• Spider telangiectasias are nonneoplastic vascular malforma-
tions grossly resembling a spider.
Hemangiomas.
Hemangiomas are very common tumors
composed of blood-filled vessels (Fig.
11.31); they constitute
7% of all benign tumors of infancy and childhood.
Nearly one-third of internal lesions
occur in the liver.
Malignant transformation is rare.
Several
histologic and clinical variants have been described.
(A) Hemangioma of the tongue.
(B) Histology of juvenile capillary hemangioma.
(C) Histology of cavernous hemangioma.
(D) Pyogenic granuloma of the lip.
(A and D, Courtesy John Sexton, MD, Beth Israel Hospital, Boston, Mass.; B, courtesy Christopher D.
M.
11.31A).
Histologically,
they are composed of thin-walled capillaries with scant
stroma (Fig.
11.31B).
• Cavernous hemangiomas are composed of large, dilated
vascular channels.
11.31C).
Intravascular thrombosis with associated dystrophic
calcification is common.
They bleed easily and are often
ulcerated (Fig.
11.31D).
Roughly a quarter of lesions develop
after trauma, reaching a size of 1 to 2 cm within a few
weeks.
Curettage and cautery is usually curative.
Lymphangiomas.
Lymphangiomas are the benign lymphatic
counterparts of hemangiomas.
The tumor margins are indistinct and
unencapsulated, making resection difficult.
Glomus Tumor (Glomangioma).
Although they may superficially resemble
hemangiomas, glomangiomas arise from SMCs rather than
ECs.
They are most commonly found in the distal portion
of the digits, especially under the fingernails.
Excision is
curative.
Bacillary Angiomatosis.
Lesions can
involve the skin, bone, brain, and other organs.
Two species
are implicated.
11.32).
The infections (and lesions) are cleared
by antibiotics.
Intermediate-Grade (Borderline) Tumors
Kaposi Sarcoma.
(A) Characteristic cutaneous lesion.
Inset, Modified silver (Warthin-Starry) stain demonstrates clusters of tangled bacilli (black).
Lesions can
regress as immunosuppression is reduced, but at the risk
of organ rejection.
Pathogenesis
Virtually all KS lesions are infected by HHV8.
Like Epstein-
Barr virus, HHV8 is a γ-herpesvirus.
HHV8 causes lytic and latent infections in ECs, both of
which contribute to KS pathogenesis.
Molecular
pathogenesis is discussed in more detail in Chapter 6 along
with HIV infections.
11.33A).
• With time, lesions become larger, violaceous, raised plaques
(see Fig.
11.33B), containing small vessels and slitlike spaces with
red cells.
Most primary HHV8 infections are
asymptomatic.
(A) Gross photograph illustrating coalescent red-purple macules and plaques of the skin.
(B, Courtesy Christopher D.
M.
Fletcher, MD, Brigham and
Women’s Hospital, Boston, Mass.)
including nodal involvement.
Hemangioendothelioma.
Malignant Tumors
Angiosarcoma.
Angiosarcomas are malignant endothelial
neoplasms (Fig.
All of these agents have long latencies between initial
exposure and eventual tumor development.
11.34A).
Necrosis and hemorrhage are common.
11.34B)
to wildly undifferentiated tumors with no discernible blood vessels.
11.34C).
• Benign tumors typically form obvious vascular channels lined
by normal-appearing ECs.
(A) Angiosarcoma involving the right ventricle.
11.35).
11.36).
Coronary stents are expandable tubes of metallic mesh.
[Overview of physiologic and developmental blood vessel
formation and remodeling].
Bikfalvi A: The situation is more complex than anticipated.
In A Brief
History of Blood and Lymphatic Vessels, Cham, Switzerland, 2017,
Springer.
[Well-written scholarly
review of the etiology and outcomes of endothelial injury].
Hansson GK, Libby P, Tabas I: Inflammation and plaque vulnerability,
J Intern Med 278:483, 2015.
[Nice review of the current concepts linking
inflammation and plaque vulnerability].
[Epub ahead of print].
[Solid review of the different macrophage activities
in the atherosclerotic plaque].
(A) Angiogram demonstrating constriction (arrow).
(A, Courtesy Anthony D.
[Good overview
of the molecular and cellular basis for thoracic aneurysms].
[Good discussion
of the molecular pathways underlying human abdominal aortic aneurysm
formation].
Vasculitis
Jennette J, Falk R: Nosology of primary vasculitis, Curr Opin Rheumatol
19:10, 2007.
[Good clinical overview of
coronary spasm and its sequelae].
[Solid and thorough
review].
Goss JA, Greene AK: Congenital vascular tumors, Otolaryngol Clin
North Am 51:89, 2018.
[Good overview of vascular tumors and
malformations].
Mitchell • Andrew J.
When the heart fails postnatally, the
results are equally catastrophic.
Thus, dilation of the aortic root can result in valvular
regurgitation.
Increasing evidence,
however, indicates that cardiomyocyte proliferation can be
augmented in mice.
Unfortunately, results thus far have been less than
exciting.
• Obstruction to flow.
• Regurgitant flow.
• Shunted flow.
• Disorders of cardiac conduction.
• Rupture of the heart or major vessel.
12.1).
The pattern of hypertrophy reflects the nature of the
stimulus.
Heart disease can lead to dramatic levels of cardiac
hypertrophy.
Important changes at the tissue and cell level occur with
cardiac hypertrophy.
VentricularHeart failure 531
A B
C D
Figure 12.1 Left ventricular hypertrophy.
(A) Pressure hypertrophy due to left ventricular outflow obstruction.
The left ventricle is on the lower right in
this apical four-chamber view of the heart.
(B) Left ventricular hypertrophy with and without dilation, viewed in transverse heart sections.
(C) Normal myocardium.
(D) Hypertrophied myocardium (C and D are
photomicrographs at the same magnification).
12.2.
As illustrated, heart failure eventu-
ally supervenes.
In valvular heart
disease, the increased pressure or volume overloads the
myocardium globally.
Lungs.
The cardiovascular system is a closed circuit.
Early left-sided heart failure symptoms are related to
pulmonary congestion and edema.
Initially, cough and
dyspnea (breathlessness) may occur only with exertion.
Dyspnea at rest may follow.
• In diastolic failure, the left ventricle is abnormally stiff
and cannot relax during diastole.
MORPHOLOGY
Heart.
As in left-heart failure, the cardiac morphology varies
with cause.
Liver and Portal System.
Pleural, Pericardial, and Peritoneal Spaces.
Subcutaneous Tissues.
In chronically
bedridden patients, presacral edema may predominate.
Generalized
massive edema (anasarca) can also occur.
The kidney and the brain are also prominently affected
in right-sided heart failure.
Incidence
The incidence of CHD depends on what is counted as a
defect.
Twelve disorders account for about
85% of cases; their frequencies are listed in Table 12.2.
Percentages do not add up
to 100% because of rounding.
Does not include bicuspid aortic valves.
Many of these congenital
lesions also can occur sporadically, without specific genetic mutation.
This provides the rationale for early intervention
to close significant left-to-right shunts.
A complete obstruction is called
an atresia.
The altered hemodynamics of CHD usually cause cardiac
dilation or hypertrophy (or both).
be sufficient to derange cardiac development.
Even relatively
minor decrements in activity of particular genes can result
in significant defects.
Other single-gene mutations can alter structural proteins
or affect signaling pathway molecules.
12.3).
12.3A).
Ao
LA
PT
LA
RA
RV
LV
A
MORPHOLOGY
ASDs are classified according to their location.
Although
VSDs are more common, most close spontaneously.
The resulting pulmonary flow volumes may
be two to eight times normal.
Mortality is low, and postoperative survival is comparable
to that for an unaffected population.
However, in the remaining
20%, the unsealed flap can open if right-sided pressures
become elevated.
12.3B).
(A) Atrial septal defect (ASD).
(B) Ventricular
septal defect (VSD).
With VSD, the shunt is left-to-right, and the pressures
are the same in both ventricles.
(C) Patent ductus arteriosus (PDA).
failure to close a foramen (channel) that is part of normal
development.
PDAs account for about 7%
of cases of CHD (see Table 12.2 and Fig.
12.3C), and 90%
of these are isolated defects.
PDA produces a characteristic, continuous, harsh
“machinery-like” murmur.
Because the shunt is initially left-to-right,
there is no cyanosis.
Figure 12.4 A membranous type ventricular septal defect (arrow) just
proximal to the aortic valve.
(Courtesy William D.
About 90% occur in the region of the membranous interventricular
septum (membranous VSD; Fig.
12.4), and the majority are 2 to
3 cm in diameter.
The remaining 10% occur below the pulmonary
valve (infundibular VSD) or within the muscular septum.
Although most VSDs are single, those in the muscular septum may
be multiple.
Conversely, if a VSD
is first detected only in an adult, it is usually an isolated
defect.
Moreover, approximately 50% of small muscular
VSDs close spontaneously.
TOF, the most common in this group,
and TGA are illustrated schematically in Fig.
12.5.
Note that
the names of all of these conditions start with a T.
12.5A).
12.5B and Fig.
12.6).
Patients with d-TGA and a VSD (approximately
35%) often have a stable shunt.
(A) Tetralogy of Fallot.
(B) Dextro-
transposition of the great arteries with and without VSD.
by pulmonary valvular stenosis.
Most infants with TOF are cyanotic at birth
or soon thereafter.
The more severe the subpulmonic stenosis,
Fi e 12.6 Dextro-transposition of the great arteries.
(Courtesy William
the more hypoplastic are the pulmonary arteries (i.e., smaller gur
D.
Obstruction can also occur within
a chamber, as with subpulmonic stenosis in TOF.
12.8).
Without
surgery, most patients die within months.
12.7).
Tricuspid Atresia
Tricuspid atresia represents complete occlusion of the tri-
cuspid valve orifice.
Cyanosis is present virtually
from birth, and there is a high early mortality.
(B) Coarctation of the aorta, postductal type.
The coarctation is a segmental narrowing of the aorta (arrow).
Such
lesions typically manifest later in life than preductal coarctations.
The
dilated ascending aorta and major branch vessels are to the left of the
coarctation.
The lower extremities are perfused predominantly by way of
dilated, tortuous collateral channels.
(A, Courtesy William D.
Edwards, MD, Mayo
Clinic, Rochester, Minn.
isolated or part of a more complex anomaly—either TOF
or TGA.
Congenital aortic valve stenosis is an isolated
lesion in 80% of cases.
Subaortic stenosis is usually
associated with a prominent systolic murmur and sometimes
a thrill.
Most
children are asymptomatic, and the disease may go unrec-
ognized until well into adult life.
The long-standing pressure overload leads to
concentric left ventricular hypertrophy.
Lesions range from relatively asymptomatic to rapidly fatal.
• Right-to-left shunts are most commonly caused by TOF or
TGA.
year.
• Diagnostic and therapeutic advances, allowing earlier and
more effective treatments.
Even a
simple daily prophylactic aspirin can have therapeutic
benefit.
The individual elements and their interactions are dis-
cussed next.
Some conditions can
have multiple deleterious effects.
Thus, most atherosclerotic stenoses can be
accessed by coronary catheterization.
In some cases, microinfarcts can occur distal to
disrupted plaques due to thromboemboli.
This
can result from a fixed stenosis or acute plaque change.
Prinzmetal angina
generally responds promptly to vasodilators.
Myocardial Response.
The
anatomic region supplied by that artery is referred to as
the area at risk.
The outcome depends predominantly on
the severity and duration of flow deprivation (Fig.
12.9).
12.9A).
Such loss of function contributes to
decreased systolic function long before myocyte death occurs.
Pathogenesis
Coronary Arterial Occlusion.
• Activation of coagulation by tissue factor and other
mechanisms adds to the growing thrombus.
• Within minutes, the thrombus can evolve to completely
occlude the coronary artery lumen.
In approximately 10% of cases, MI occurs in the absence
of the typical coronary atherothrombosis.
(A)
Early changes include loss of adenosine triphosphate (ATP) and accumulation of lactate.
Thereafter, progressive loss of viability occurs that becomes complete by 6 to 12 hours.
(Originally modified with
permission from Antman E: Acute myocardial infarction.
Nevertheless, these early manifesta-
tions of ischemic injury are potentially reversible.
The temporal
progression of these events is summarized in Table 12.4.
The progression of ischemic necrosis in the myocardium
is summarized in Fig.
12.10.
Irreversible injury of ischemic
myocytes first occurs in the subendocardial zone.
The area that depends on the occluded vessel for perfusion is the “at risk” myocardium (shaded).
Thus, RCA occlusions can potentially
lead to left ventricular damage.
Patterns of Infarction.
12.11).
12.12).
Thereafter, the
infarct becomes progressively more sharply defined, yellow-tan,
and soft.
Over the succeeding weeks, the injured region evolves
to a fibrous scar.
The histopathologic changes also proceed in a fairly predictable
sequence (Fig.
12.13).The typical changes of coagulative necrosis
“
become detectable in the first 6 to 12 hours.
The specimen is oriented with the posterior wall at the top.
A B C
D E
Figure 12.13 Microscopic features of myocardial infarction and its repair.
Widened spaces between the dead fibers contain edema fluid and scattered neutrophils.
(C) Removal of necrotic myocytes by phagocytosis
(approximately 7 to 10 days).
(D) Granulation tissue characterized by loose collagen and abundant capillaries.
The residual cardiac muscle cells show evidence of compensatory hypertrophy.
The effects of reperfusion on myocardial viability and
function are summarized in Fig.
12.14.
Further, leukocytes elaborate proteases and elastases that
cause cell death.
• Platelet and complement activation also contribute to
microvascular injury.
Infarct Modification by Reperfusion.
If perfusion is not restored (A), then nearly all myocardium in the affected region suffers death.
The earlier reperfusion occurs, the
greater the degree of salvage.
Gross (A) and microscopic (B) appearance of myocardium modified by
reperfusion.
12.12).
Specimen oriented with posterior wall at top.
The typical appearance of reperfused myocardium in
the setting of an acute MI is shown in Fig.
12.15.
Such infarcts
typically are hemorrhagic as a consequence of vascular injury
and leakiness.
In the absence of ATP, the sarcomeres
cannot relax and get stuck in an agonal tetanic state.
12.16).
Cardiac troponins begin to rise in 2 to 4 hours and
peak at 24 to 48 hours after an acute infarct.
Plasma membrane of necrotic
3.
Troponin leaks
out of cell into
myocytes becomes leaky
circulation
Days after onset of acute MI
1.
Onset of myocardial
infarction
4.
Troponin I or troponin T are now most routinely used as diagnostic biomarkers of
myocyte injury.
12.17):
• Contractile dysfunction.
In general, MIs affect left ventricular
pump function in proportion to the volume of damage.
• Papillary muscle dysfunction.
• Right ventricular infarction.
• Myocardial rupture.
Rupture complicates only 1% to 5%
of MIs, but is frequently fatal when it occurs.
12.17A).
Ventricular septal rupture
creates a VSD with left-to-right shunting (see Fig.
12.17B),
and papillary muscle rupture leads to severe mitral
regurgitation (see Fig.
12.17C).
• Arrhythmias.
MIs lead to myocardial irritability and
conduction disturbances that can cause sudden death.
(A) Anterior myocardial rupture in an acute infarct (arrow).
(B) Rupture of the ventricular septum
(arrow).
(C) Complete rupture of a necrotic papillary muscle.
E, Early expansion of anteroapical infarct with wall thinning (arrow) and mural thrombus.
F, Large apical left ventricular aneurysm (arrow).
The left
ventricle is on the right in this apical four-chamber view of the heart.
• Pericarditis.
12.17D).
• Chamber dilation.
• Mural thrombus.
12.17E),
potentially leading to left-sided thromboembolism.
• Ventricular aneurysm.
12.17F).
• Progressive heart failure.
This is discussed in the Chronic
Ischemic Heart Disease section later in this chapter.
With subendocardial infarcts,
only rarely do pericarditis, rupture, and aneurysm occur.
The
compensatory hypertrophy of noninfarcted myocardium is
initially hemodynamically beneficial.
The relationship of the causes, pathophysiology, and
consequences of MI are summarized in Fig.
12.18, including
the possible outcomes of chronic IHD and sudden death,
discussed later.
Patients with chronic IHD
account for almost 50% of cardiac transplant recipients.
Chest pain may occur, even at
rest or with minimal exertion.
Gross and histologic
changes of infarction require hours to days to develop.
Invariably there is some degree of stenotic
coronary atherosclerosis.
Discrete scars representing healed
infarcts are usually present.
Channelopathies are caused by
mutations in genes that are required for normal ion channel
function.
ARRHYTHMIAS
Abnormalities in myocardial conduction can be sustained
or sporadic (paroxysmal).
• Sick sinus syndrome.
• Atrial fibrillation.
• Heart block.
• SCD typically results from ventricular fibrillation and is most
frequently a consequence of CAD.
On that basis, almost one-half of individuals in the
general population (!!) are hypertensive.
The pathogenesis
of hypertension is discussed in Chapter 11.
(A) Systemic (left-sided) hypertensive heart disease.
There is marked concentric
thickening of the left ventricular wall causing reduction in lumen size.
A pacemaker is present in the right ventricle (arrow).
(B) Pulmonary (right-sided) hypertensive heart disease (cor pulmonale).
The
shape of the left ventricle (to the right) has been distorted by the enlarged right ventricle.
Isolated pulmonary HHD, or cor pulmonale, stems from
right ventricular pressure overload.
Acute cor pulmonale can follow massive pulmonary embo-
lism.
12.19B).
Valvular abnormalities can be congenital (discussed
earlier) or acquired.
The causes of acquired heart valve diseases are sum-
marized in Table 12.8.
Persistently elevated pressure overload can cause ventricular
failure with dilation.
• Stenosis is the failure of a valve to open completely,
obstructing forward flow.
Stenosis or insufficiency can occur alone or together in
the same valve.
The free edges of the cusps are usually
not involved (Fig.
12.20A).
Microscopically, the layered architecture
of the valve is largely preserved.
Inflammation is variable, and metaplastic bone can be seen.
In contrast with
rheumatic (and congenital) aortic stenosis (see Fig.
12.22E),
commissural fusion is not usually seen.
Fen-phen, Fenfluramine-phentermine.
Most notably, the abnormal
A B C D
Figure 12.20 Calcific valvular degeneration.
(A) Calcific aortic stenosis of a previously normal valve (viewed from aortic aspect).
Nodular masses of
calcium are heaped up within the sinuses of Valsalva (arrow).
12.22E).
(B) Calcific aortic stenosis of a congenitally bicuspid valve.
One cusp has a partial fusion at its center, called a raphe (arrow).
(C) Left atrial view.
The
raphe is frequently a major site of calcific deposits (see
Fig.
12.20B).
Other
bicuspid valve complications include aortic regurgitation
and infective endocarditis.
12.20C, D).
Mitral annular calcification
usually does not affect valvular function.
12.21A–C).The affected
leaflets are often enlarged, redundant, thick, and rubbery.
The tricuspid, aortic,
or pulmonary valves may also be affected.
12.21B); and (5)
focal calcifications at the base of the posterior mitral leaflet (Fig.
12.21C).
The diagnosis is confirmed
by echocardiography.
(C) Opened valve with pronounced hooding (double arrows) in a patient who died suddenly.
Note also mitral
annular calcification on the left side (arrowhead).
Normal heart valve (D) and myxomatous mitral valve (E).
(A, Courtesy William D.
In
keeping with an immunologic basis of RHD, streptococci
are completely absent from the lesions.
MORPHOLOGY
Key pathologic features of acute RF and chronic RHD are shown
in Fig.
12.22.
During acute RF, focal inflammatory lesions are found
in various tissues.
(A) Acute rheumatic mitral valvulitis superimposed on chronic rheumatic heart disease.
(B) Microscopic appearance of an Aschoff body in a patient with acute rheumatic carditis.
Note the neovascularization
of the anterior mitral leaflet (arrow, D).
(E, Reproduced from Schoen FJ, St.
12.24A).
One or many may be present (see Fig.
12.25).
Approximately 1% of affected
individuals die of fulminant RF involvement of the heart.
Damage to the valves is cumula-
tive.
Turbulence induced by ongoing valvular deformities
leads to additional fibrosis.
12.23).
The long-term prognosis is highly variable.
The aorta, aneurysms, other blood vessels, and prosthetic
devices can also become infected.
In contrast, more virulent S.
aureus is the major offender
in IE among intravenous drug abusers.
More rarely,
Gram-negative bacilli and fungi can be involved.
aureus and S.
aureus
(see later discussion of prosthetic valves).
(A) Endocarditis of mitral valve (subacute, caused by Streptococcus viridans).
The large, friable vegetations are
denoted by arrows.
“Possible”
infective endocarditis diagnosis requires either 1 major +1 minor, or 3 minor.
d Roth spots are oval retinal hemorrhages with pale centers.
In Mann D, et al.,
editors: Braunwald’s Heart Disease.
a Textbook of Cardiovascular Medicine, ed 10,
Philadelphia, 2015, WB Saunders, p 1524.
12.24B).
Left untreated, IE
generally is fatal.
For infections involving low-virulence
organisms (e.g., S.
viridans), the cure rate is 98%, and for
enterococci and S.
12.23 and 12.25).
The thrombus is only loosely attached to the cusp (arrow).
12.23).
Similar lesions can occur
in the antiphospholipid antibody syndrome (Chapter 4).
12.26).
Underlying structures are intact.
With
right-sided involvement, typical findings are tricuspid insufficiency
and pulmonary stenosis.
• Tissue valves (bioprostheses).
(A) Characteristic endocardial fibrotic lesion involving the right ventricle and tricuspid valve.
(B) Microscopic
appearance of carcinoid heart disease with endocardial thickening.
The underlying myocardium is unaffected.
(called cryopreserved “homografts”) can also be used.
Tissue valves are flexible and function similarly to
natural semilunar valves.
Similarly, the freezing and thawing of human homografts
may also render them largely nonviable.
The complications that occur depend on which
type of valve has been implanted (Table 12.10 and Fig.
12.27).
• Thromboembolism is the major consideration with mechani-
cal valves (see Fig.
(A) Thrombosis of a
mechanical prosthetic valve.
Structural deterioration rarely causes failure of any of the
mechanical valves in current use.
12.27B).
• Infective endocarditis is a potentially serious complication
of any valve replacement.
In addition, vegetations may
directly involve the tissue of bioprosthetic valvular cusps.
Both types of valves have an
increased risk of developing endocarditis relative to native valves.
They may be genetic or acquired (e.g., viral myocarditis,
anthracycline cardiotoxic).
hemochromatosis, amyloidosis).
• Valve calcification is a degenerative process that typically results
in stenosis.
• Abnormal matrix synthesis and turnover result in myxomatous
degeneration and insufficiency.
• Inflammatory valve diseases lead to postinflammatory scarring.
Systemic embolization can produce
septic infarcts.
Pathogenesis
Several different pathways can lead to DCM (Fig.
12.29).
Note the changes in atrial and/or ventricular wall thickness.
12.30).
X-linked, autosomal recessive, and mitochondrial
inheritance of DCM are less common.
• Myocarditis.
Sequential endomyocardial biopsies have
documented progression from myocarditis to DCM.
• Alcohol and other toxins.
Alcohol or
its metabolites (especially acetaldehyde) have a direct
toxic effect on the myocardium.
The genetic causes of dilated cardiomyopathy involve mutations in any of a wide range of genes.
LV, left ventricle.
which can lead to beriberi heart disease (a form of DCM).
Cardiotoxic drugs used for
chemotherapy (discussed later) are also important causes
of DCM.
• Childbirth.
• Supraphysiologic stress can also result in DCM.
(A) Four-chamber dilatation and hypertrophy are evident.
The coronary arteries were patent.
12.31).
12.31B).
Clinical Features
The fundamental defect in DCM is ineffective contraction.
Death usually results from progres-
sive cardiac failure or arrhythmia, and it can occur suddenly.
HCM causes primarily diastolic
dysfunction; systolic function is usually preserved.
Occasion-
ally, valvular or congenital subvalvular aortic stenosis can
also mimic HCM.
The prognosis of HCM varies widely and
correlates strongly with specific mutations.
As mentioned earlier, HCM is a disease caused by muta-
tions in proteins of the sarcomere.
Left-sided involve-
ment with left-sided heart failure can also occur.
12.32).
A B
Figure 12.32 Arrhythmogenic cardiomyopathy.
In contrast, DCM is mostly associated
with abnormalities of cytoskeletal proteins (see Fig.
To
complicate matters, mutations in certain genes (highlighted
in Fig.
12.30) can give rise to either HCM or DCM, depending
on the site and nature of the mutation.
12.33B).
In about 10% of cases, the
hypertrophy is concentric and symmetrical.
12.33A).
A B
Figure 12.33 Hypertrophic cardiomyopathy with asymmetric septal hypertrophy.
These rearrangements produce fusion genes that
encode constitutively active PDGFR tyrosine kinases.
Diffuse involvement may be responsible for
rapid and progressive cardiac decompensation and death.
The natural history of HCM is highly variable.
Three other restrictive conditions merit brief mention.
12.34).
12.34B).
Pathogenesis
In the United States, viral infections are the most common
cause of myocarditis.
Coxsackie viruses A and B and other
enteroviruses probably account for most of the cases.
Other
less common etiologic agents include cytomegalovirus, HIV,
and influenza (Table 12.13).
There are also noninfectious causes of myocarditis.
(A) Lymphocytic myocarditis, associated with myocyte injury.
(D) The myocarditis of Chagas disease.
MORPHOLOGY
with lymphocytes, eosinophils, plasma cells, and macrophages.
Focal
to frequently extensive myocyte damage is present (see Fig.
12.35C).
12.35D).
Mural
thrombi may be present.
12.35A).
12.35B).
The clinical features of myocarditis can mimic those
of acute MI.
Discontinuing
the offending agent often leads to prompt resolution, without
apparent sequelae.
Occasionally, however, more extensive
damage produces myocyte death that can evolve to a DCM.
The major
causes of pericarditis are listed in Table 12.14.
• DCM results in systolic (contractile) dysfunction.
Causes include
myocarditis, toxic exposures (e.g., alcohol), and pregnancy.
• HCM results in diastolic (relaxation) dysfunction.
Viral
infections are the most common causes in the United States.
Clinically, myocarditis can be asymptomatic, give rise to acute
heart failure, or evolve into DCM.
Organization
into fibrous adhesions rarely occurs.
Common
causes include acute MI (see Fig.
A fibrinous reaction also follows routine cardiac
surgery.
A loud peri-
cardial friction rub is the most striking clinical finding.
The serosal surfaces are red-
dened, granular, and coated with the exudate (Fig.
12.36).
Complete resolution is infrequent,
and organization by scarring is the usual outcome.
Extensive purulent exudate is evident.
The clinical significance is similar to that of fibrinous
or suppurative pericarditis.
Two forms are worthy of some
discussion.
Systolic retraction of the rib cage
and diaphragm and pulsus paradoxus may be observed.
The increased workload occasionally causes significant
cardiac hypertrophy and dilation.
A prior history of pericarditis may
or may not be present.
MORPHOLOGY
The tumors are usually single, but can rarely be multiple.
The
region of the fossa ovalis in the atrial septum is the favored site
of origin.
12.37B).
Peculiar vessel-like
or glandlike structures are characteristic.
Hemorrhage and
mononuclear inflammation are usually present.
Myxomas are the most common primary tumor of the
adult heart (Fig.
12.37).
These are benign neoplasms arising
from primitive multipotent mesenchymal cells.
About 90% of myxomas arise in the atria, with
a left-to-right ratio of approximately 4:1.
Some-
times fragmentation and systemic embolization calls attention
to these lesions.
Echocardiography provides the opportunity to identify these
masses noninvasively.
12.38B and C).
12.38D), leading to ischemic injury.
Although
impressive, these various devices are not without (somewhat
predictable) risk.
12.38A).
ThereSuggested readings 581
A B
C D
Figure 12.38 Complications of heart transplantation.
B and C,Antibody-mediated rejection.
(C, Courtesy Dr.
Fortunately, the manifest benefits significantly
outweigh the potential risks.
[A balanced
review of research in cardiovascular regeneration].
[A review of cardiomyocyte regenerative biology with
a focus on basic science].
Eschenhagen T et al: Cardiomyocyte regeneration: a consensus statement,
Circulation 136:680, 2017.
[A brief outline consensus overview of the current
evidence for cardiomyocyte regeneration].
Lee RT, Walsh K: The future of cardiovascular regenerative medicine,
Circulation 133:2618, 2016.
[An overview of trends in cardiovascular
regenerative medicine].
[An excellent review of the pathophysiology of heart
failure].
[An overview of the relationships between cardiac development and congenital
heart disease].
[A comprehensive review
of the genes and pathways underlying congenital heart disease].
[An excellent
treatise on classification of congenital heart disease].
[A review of trends in congenital
heart disease medical science and clinical management].
[An
excellent, well-written review on plaque erosion and rupture in acute coronary
syndromes].
Thygesen K et al: Fourth universal definition of myocardial infarction,
Circulation 138:e618, 2018.
[Good study
and discussion of sudden death in the young, an area of much recent
investigation].
Bezzina CR, Lahrouchi N, Priori SG: Genetics of sudden cardiac death,
Circ Res 116:1919, 2015.
[A nice review of the cardiac consequences of systemic
hypertension].
[An excellent review of right-sided
hypertension-associated pathology and pathobiology].
Li C, Xu S, Gotlieb AI et al: The response to valve injury.
A paradigm to
understand the pathogenesis of heart valve disease, Cardiovasc Pathol
20:183, 2011.
[A nice overview of pathologic concepts in valvular disease].
[A good overview of the mechanisms leading to degenerative calcifica-
tion on valves and vessels].
[A nice review
of pathogenesis, clinical features, and clinical management].
[An excellent review on mechanisms of valve disease
and therapeutic approaches].
Cardiomyopathies
Arany Z, Elkayam U: Peripartum cardiomyopathy, Circulation 133:1397,
2016.
[A review of pathophysiology and clinical management].
Braunwald E: Cardiomyopathies: an overview, Circ Res 121:711, 2017.
Buggey J, ElAmm CA: Myocarditis and cardiomyopathy, Curr Opin
Cardiol 33:341, 2018.
[A nice review of etiology, pathogenesis, and clinical
features].
[A nice review of etiology,
pathogenesis, and clinical features].
[An excellent review of the genetic defects underlying many of the
cardiomyopathies].
[An interesting
report of a cardiovascular disease arising from a new therapy].
[A review of cardiovascular
toxicity with current cancer therapies].
[A good review of cardiac
amyloidosis].
[The most recent consensus
classification scheme for tumors of the heart and pericardium].
Sawyer DB: Anthracyclines and heart failure, N Engl J Med 38:1154,
2013.
[A succinct overview of chemotherapeutic cardiotoxicity].
In
this chapter we discuss white cell diseases and disorders
affecting the spleen and thymus.
In Chapter 14 we consider
diseases of red cells and those affecting hemostasis.
By the fourth month
of development, HSCs shift in location yet again to the bone
marrow.
After puberty, hematopoiesis ceases
in distal bones and becomes restricted to the axial skeleton.
Thus in normal adults, only about half of the marrow space
is hematopoietically active.
13.1).
The origins of lymphoid cells are
revisited when tumors derived from these cells are discussed.
Some of these cells are referred to as colony-forming units
(see Fig.
Pluripotency refers to the
ability of a single HSC to generate all mature blood cells.
When an HSC divides, at least one daughter cell must self-
renew to avoid stem cell depletion.
13.1).
Many diseases alter the production of blood cells.
CFU, Colony forming unit; LIN−, negative for lineage-specific markers; NK, natural killer.
and cytokines.
The normal marrow is organized in subtle, but important, ways.
Marrow aspirate smears provide the best assessment of the
morphology of hematopoietic cells.
The most mature marrow
precursors can be identified based on their morphology alone.
Bone marrow biopsies are a
good means for estimating marrow activity.
In normal adults the
ratio of fat cells to hematopoietic elements is about 1:1.
Other
disorders (e.g., metastatic cancers and granulomatous diseases)
induce local marrow fibrosis.
In such cases the marrow usually
cannot be aspirated and the lesions are best seen in biopsies.
Proliferations of
white cells can be reactive or neoplastic.
Neoplastic disorders,
though less frequent, are much more important clinically.
LEUKOPENIA
The number of circulating white cells may be decreased in
a variety of disorders.
• Suppression of committed granulocytic precursors by exposure
to certain drugs (discussed later).
The most common cause of agranulocytosis is drug
toxicity.
It is a common reaction to a variety of
inflammatory states.
• The rate of release of cells from the storage pools into
the circulation.
• The proportion of cells that are adherent to blood vessel
walls at any time (the marginal pool).
• The rate of extravasation of cells from the blood into
tissues.
Some growth factors preferentially stimulate the produc-
tion of a single type of leukocyte.
Infections are a common consequence of agranulocytosis.
Sites
of infection often show a massive growth of organisms with little
leukocytic response.
With agranulocytosis,
infections are often overwhelming and may cause death
within hours to days.
Serious infections are most likely when the neutrophil
count falls below 500/mm3.
13.2).
6.8, Chapter 6).
The activation of resident immune cells leads to mor-
phologic changes in lymph nodes.
Paracortical
T-cell zones may also undergo hyperplasia.
Some that produce distinctive morphologic patterns are
described in other chapters.
Systemic viral infections (particularly in
Figure 13.2 Reactive changes in neutrophils.
MORPHOLOGY
The nodes are swollen, gray-red, and engorged.
Nodes involved by acute lymphadenitis are swollen and
painful.
When abscess formation is extensive the nodes
become fluctuant.
The overlying skin is red.
Healing of such lesions is associated with scarring.
Several different patterns of
morphologic change are seen, often within the same lymph
node.
MORPHOLOGY
Follicular hyperplasia is caused by stimuli that activate humoral
immune responses.
13.3).
This form of hyperplasia
is morphologically similar to follicular lymphoma (discussed later).
Figure 13.3 Follicular hyperplasia.
(A) Low-power view showing a
reactive follicle and surrounding mantle zone.
The right half of the follicle consists of the dark
zone.
These collections are sometimes called tertiary
lymphoid organs.
• Myeloid neoplasms arise from early hematopoietic progeni-
tors.
• The histiocytoses are uncommon proliferative lesions of
macrophages and dendritic cells.
Chromosomal Translocations and Other Acquired Muta-
tions.
For this reason, it is also sometimes referred to as macrophage
activation syndrome.
How these defects lead
to HLH is not known.
Coagulation studies may show evidence of
disseminated intravascular coagulation.
The resulting overexpression of the
involved proto-oncogene converts it to an oncogene.
Inherited Genetic Factors.
Viruses.
The possible mechanisms of transformation by viruses are
discussed in Chapter 7.
HTLV-1 is associated with adult
T-cell leukemia/lymphoma.
Chronic Inflammation.
Examples include the associations between H.
counterpart of the malignant cell.
Fig.
• Finally, mutations that inhibit apoptosis are prevalent
in certain hematologic malignancies.
These relationships are discussed in more detail in
Chapter 6.
Iatrogenic Factors.
Smoking.
Hodgkin lymphoma has distinc-
tive pathologic features and is treated in a unique fashion.
Another special group of tumors includes plasma cell neo-
plasms.
)
3.
Precursor B-Cell Neoplasms
B-cell acute lymphoblastic leukemia/lymphoma (B-ALL)
II.
Precursor T-Cell Neoplasms
T-cell acute lymphoblastic leukemia/lymphoma (T-ALL)
IV.
Peripheral T-cell and NK-cell neoplasms (neoplasms of
mature T cells and NK cells)
5.
of B- or T-cell differentiation (Fig.
13.5), a feature that is
used in their classification.
• Lymphoid neoplasms are often associated with immune
abnormalities.
• Neoplastic B and T cells tend to recapitulate the behavior of
their normal counterparts.
Stages of B- and T-cell differentiation from which specific lymphoid tumors emerge are shown.
About 85%
are B-ALLs, which typically manifest as childhood acute
leukemias.
The less common T-ALLs tend to present in
adolescent males as thymic lymphomas.
ALL is the most common cancer of children.
Hispanics have the highest incidence
of any ethnic group.
B-ALL
and T-ALL also occur less frequently in adults of all ages.
Similar themes are
relevant in the genesis of AML (discussed later).
b Most common tumors in adults.
Approximately 90% of ALLs have numerical or structural
chromosomal changes.
13.6A).
The nuclear membrane is often deeply subdivided,
imparting a convoluted appearance.
In keeping with the aggressive
clinical behavior, the mitotic rate is high.
13.15).
13.6B and C).
A
CD22
CD19
Intracellular TdT C CD10
B
Figure 13.6 (A) Acute lymphoblastic leukemia/lymphoma (ALL).
Lymphoblasts with condensed nuclear chromatin, small nucleoli, and scant
agranular cytoplasm.
(B and C) Phenotype of ALL shown in (A) analyzed
by flow cytometry.
Thus this is a B-ALL.
(A, Courtesy Dr.
Robert W.
Louis Picker, Oregon Health Science Center, Portland, Ore.)
Immunophenotype.
13.6B).
In very
immature B-ALLs, CD10 is negative.
Similarly, T-ALLs
are arrested at various stages of pre–T-cell development.
In most cases the cells are positive for CD1, CD2, CD5, and
CD7.
Treatment of pediatric ALL is one of the great success
stories of oncology.
only 4% of NHLs.
CLL/SLL is much less common in Japan
and other Asian countries than in the West.
The most common
genetic anomalies are deletions of 13q14.3, 11q, and 17p
and trisomy 12q.
13.7).
When present,
proliferation centers are pathognomonic for CLL/SLL.
The blood contains variable numbers of small round lymphocytes
with scant cytoplasm (Fig.
13.8).
In almost all cases, the bone marrow, spleen, and
liver (Fig.
13.9) also are involved, albeit to widely varying degrees.
CLL is the most
common leukemia of adults in the Western world.
There
are about 15,000 new cases of CLL each year in the United
States.
The median age at diagnosis is 60 years, and there
is a 2:1 male predominance.
In contrast, SLL constitutes
Immunophenotype.
CLL/SLL has a distinctive immuno-
phenotype.
Low-power view of a typical periportal lymphocytic
infiltrate.
(Courtesy Dr.
A small monoclonal Ig “spike” is present in the blood of
some patients.
CLL/SLL disrupts normal immune function through
uncertain mechanisms.
The course and prognosis are extremely variable and
depend primarily on the clinical stage.
B
Figure 13.7 Small lymphocytic lymphoma/chronic lymphocytic leukemia
(lymph node).
(A) Low-power view shows diffuse effacement of nodal
architecture.
(B) At high power the majority of the tumor cells are small
round lymphocytes.
(A, Courtesy Dr.
A nucleated erythroid
cell is present in the lower left-hand corner of the field.
It affects 15,000 to 20,000 individuals per year.
It usually
presents in middle age and afflicts males and females equally.
It is less common in Europe and rare in Asian populations.
13.12).
A
B
Figure 13.10 Follicular lymphoma (lymph node).
(A) Nodular aggregates
of lymphoma cells are present throughout lymph node.
(A, Courtesy Dr.
Robert W.
13.10A).
13.10B).
In most
follicular lymphomas, centrocytes are in the majority.
13.11) and hepatic portal triads are also frequently
involved.
Figure 13.11 Follicular lymphoma (spleen).
Prominent nodules represent
white pulp follicles expanded by follicular lymphoma cells.
(Courtesy Dr.
AB
Figure 13.12 BCL2 expression in reactive and neoplastic follicles.
BCL2
protein was detected by using an immunohistochemical technique that
produces a brown stain.
(Courtesy Dr.
Unlike CLL/SLL and mantle
cell lymphoma, CD5 is not expressed.
13.12).
Although incurable, it
usually follows an indolent waxing and waning course.
Histologic transformation occurs in 30% to 50% of fol-
licular lymphomas, most commonly to DLBCL.
The
median survival is less than 1 year after transformation.
Diffuse Large B-Cell Lymphoma
Diffuse large B-cell lymphoma (DLBCL) is the most
common form of NHL.
Each year in the United States there
are about 25,000 new cases.
There is a slight male predomi-
nance.
The median patient age is about 60 years, but DLBCL
also occurs in young adults and children.
13.13).
Other morphologic
features show substantial variation.
Most commonly, the tumor
Figure 13.13 Diffuse large B-cell lymphoma.
Tumor cells have large nuclei,
open chromatin, and prominent nucleoli.
(Courtesy Dr.
Robert W.
Bone marrow involvement is rela-
tively uncommon and usually occurs late in the course.
Rarely, a leukemic picture emerges.
DLBCLs are aggressive tumors that are rapidly fatal
without treatment.
The
cytoplasm is usually moderately abundant and may be pale or
basophilic.
Immunophenotype.
Most have
surface Ig.
Special Subtypes.
Several subtypes of DLBCL are suffi-
ciently distinctive to merit brief discussion.
The neoplastic B cells are usually infected with
EBV, which plays a critical pathogenic role.
Restoration
of T-cell immunity may lead to regression of these
proliferations.
In all cases the tumor cells are infected
with HHV-8, which appears to have a causal role.
It can arise virtually anywhere in
the body.
13.14).
Figure 13.14 Diffuse large B-cell lymphoma involving the spleen.
The
isolated large mass is typical.
In contrast, indolent B-cell lymphomas usually
produce multifocal expansion of white pulp (see Fig.
13.11).
(Courtesy
Dr.
macrophages.
These phagocytes have abundant clear cytoplasm,
creating a characteristic “starry sky” pattern.
Immunophenotype.
Most tumors manifest at extranodal sites.
Involvement of the bone marrow
and peripheral blood is uncommon, especially in endemic
cases.
Burkitt lymphoma is very aggressive but responds well
to intensive chemotherapy.
Most children and young adults
can be cured.
The outcome is more guarded in older adults.
It usually presents in the fifth
to sixth decades of life and shows a male predominance.
13.15).
Frequent sites of extranodal involvement include the bone marrow,
spleen, liver, and gut.
(B) At high power, tumor cells have multiple small nucleoli and
high mitotic index.
The lack of significant variation in nuclear shape and
size lends a monotonous appearance.
(B, Courtesy Dr.
• They remain localized for prolonged periods, spreading
systemically only late in their course.
• They may regress if the inciting agent (e.g., H.
pylori) is
eradicated.
The disease begins
as a polyclonal immune reaction.
At this stage, withdrawal of
the responsible antigen causes tumor involution.
pylori often leads to
tumor regression (Chapter 17).
With further clonal evolution, spread
to distant sites and transformation to DLBCL may occur.
to occasionally deeply clefted (cleaved) nuclear contours
(Fig.
13.16).
Immunophenotype.
This tumor is usually CD5+ and CD23−, which help
to distinguish it from CLL/SLL.
The IGH genes lack somatic
hypermutation, supporting an origin from a naive B cell.
Clinical Features
The most common presentation is painless lymphadenopathy.
Immunophenotype.
Splenomegaly, often massive,
is the most common and sometimes the only abnormal
physical finding.
Hepatomegaly is less common and not as
marked; lymphadenopathy is rare.
About
one-third of those affected present with infections.
Hairy cell leukemia follows an indolent course.
The overall prognosis
is excellent.
13.17).
Hepatic portal
triads are also involved frequently.
• Tumor of mature B cells that usually manifests with bone marrow
and lymph node involvement.
Follicular Lymphoma
• Most common indolent lymphoma of adults.
Diffuse Large B-Cell Lymphoma
• Most common lymphoma of adults.
Burkitt Lymphoma
• Very aggressive tumor of mature B cells that usually arises at
extranodal sites.
A
B
Figure 13.17 Hairy cell leukemia (peripheral blood smear).
(A)
Phase-contrast microscopy shows tumor cells with fine hairlike
cytoplasmic projections.
• Tumor cells often are latently infected by EBV.
Mantle Cell Lymphoma
• Tumor of naive B cells that pursues a moderately aggressive
course.
• Highly associated with translocations involving the cyclin D1
gene.
• Often remain localized for long periods of time.
• Highly associated with mutations in the BRAF serine/threonine
kinase.
Figure 13.18 Peripheral T-cell lymphoma, unspecified (lymph node).
13.19A).
ALK is not expressed in normal
lymphocytes; thus the detection of ALK protein in tumor
cells (Fig.
13.19B) is a reliable indicator of an ALK gene
rearrangement.
The cure rate
with chemotherapy is 75% to 80%.
Both ALK+ and ALK− tumors
usually express CD30, a member of the TNF receptor family.
By contrast, for unknown reasons both T- and NK-cell
tumors occur more frequently in the Far East.
Only the most
common diagnoses and those of particular pathogenetic
interest will be discussed.
13.18).
Brisk neoangiogenesis may also be seen.
By definition, all peripheral T-cell lymphomas are derived
from mature T cells.
They usually express CD2, CD3, CD5,
and either αβ or γδ T-cell receptors.
However, many tumors have
phenotypes that do not resemble any known normal T cell.
Neverthe-
less, these are indolent tumors, with a median survival of
roughly 10 years.
Transformation to aggressive T-cell
lymphoma occurs occasionally as a terminal event.
Lymphadenopathy and hepatomegaly
are usually absent.
Infiltrates
also are usually present in the spleen and liver.
Neutropenia may be accompanied by a striking decrease
in late myeloid forms in the marrow.
Rarely, pure red cell
aplasia is seen.
There is also an increased incidence of
rheumatologic disorders.
A
B
Figure 13.19 Anaplastic large-cell lymphoma.
(B) Immunohistochemical stain demonstrating the
presence of ALK fusion protein.
(Courtesy Dr.
Extranodal NK/T-cell lymphoma is highly associated
with Epstein-Barr virus (EBV).
No consistent chromosome
aberration has been described.
Thus, the prognosis is gener-
ally poor in patients with advanced disease.
is multiple myeloma, of which there are about 15,000 new
cases per year in the United States.
A monoclonal Ig identified in the blood is referred to as
an M component, in reference to myeloma.
However, neoplastic plasma cells often synthesize excess
light chains along with complete Igs.
Occasionally only
light chains are produced, and rare tumors secrete only
heavy chains.
The common feature is the synthesis and
secretion of free heavy-chain fragments.
Its incidence is
higher in men and people of African descent.
It is chiefly
a disease of older adults, with a peak age of incidence of
65 to 70 years.
It is produced
by the tumor cells themselves and by resident marrow
stromal cells.
Figure 13.20 Multiple myeloma of the skull (radiograph, lateral view).
The
sharply punched-out bone lesions are most obvious in the calvaria.
13.20), and consist of soft, gelatinous,
red tumor masses.
and an eccentrically placed nucleus (Fig.
13.21).
Rarely, tumor cells flood the peripheral blood,
giving rise to plasma cell leukemia.
This important
complication is discussed in detail in Chapter 20.
GA M κλ
+
Patient serum –
SP GA M κλ
Immunophenotype.
Bone resorption often leads to pathologic fractures and
chronic pain.
Decreased production of normal Igs sets the
stage for recurrent bacterial infections.
Cellular immunity
is relatively unaffected.
Of great significance is renal insuf-
ficiency, which trails only infections as a cause of death.
13.22).
Myelomas
expressing IgM, IgD, or IgE occur but are rare.
Both free light chains and a serum
M protein are observed together in 60% to 70% of patients.
(Courtesy Dr.
The prognosis is variable.
The median survival is 4 to 7
years, and cures have yet to be achieved.
While still incurable, outcomes have improved over the
past decade with advances in therapy.
If these misfolded proteins are not degraded in proteasomes,
they trigger apoptosis.
Thalidomide
and related compounds such as lenalidomide also have
activity against myeloma.
HSC transplantation prolongs life but has not been
proven to be curative.
Smoldering Myeloma
This entity defines a middle ground between multiple
myeloma and MGUS.
About
75% of patients progress to multiple myeloma over a 15-year
period.
The bone lesions tend to occur
in the same locations as in multiple myeloma.
Extraosseous
lesions are often located in the lungs, oronasopharynx, or
nasal sinuses.
Modest elevations of M proteins in the blood
or urine may be found in some patients.
By
definition, patients are asymptomatic and the serum M
protein level is less than 3 g/dL.
13.23).
Immunophenotype.
Approximately
half the patients have lymphadenopathy, hepatomegaly,
and splenomegaly.
Anemia caused by marrow infiltration is
common.
Lymphoplasmacytic lymphoma is an indolent disorder.
Transformation to large-cell lymphoma occurs but is uncom-
mon.
The average age at diagnosis is 32 years.
It is one of the
most common cancers of young adults and adolescents, but
also occurs in the aged.
Classification.
The WHO classification recognizes five
subtypes of Hodgkin lymphoma:
1.
Nodular sclerosis
2.
Mixed cellularity
3.
Lymphocyte-rich
4.
Lymphocyte depletion
5.
These subtypes are often lumped together as classic
forms of Hodgkin lymphoma.
• May be associated withAL amyloidosis (as may other neoplasms
later).
• Smoldering myeloma: disseminated disease that pursues an
unusually indolent course.
Reed-Sternberg cells are aneuploid and possess diverse
clonal chromosomal aberrations.
Most notably among these factors are PD-L1 and PD-L2,
which antagonize cytotoxic T-cell responses.
13.28.
abundant.
Several Reed-Sternberg cell variants are also recognized.
Mononuclear variants contain a single nucleus with a large
inclusion-like nucleolus (Fig.
13.24B).
13.24C).
13.24D).
The clinical
manifestations common to all are presented later.
Nodular Sclerosis Type.
This is the most common form of Hodgkin
lymphoma, constituting 65% to 70% of cases.
13.25).
This subtype is uncommonly associated with EBV.
The nodular sclerosis type occurs with equal frequency in
males and females.
The prognosis is excellent.
Mixed-Cellularity Type.
This form of Hodgkin lymphoma consti-
tutes about 20% to 25% of cases.
13.26).
The immunophenotype is identical to
that observed in the nodular sclerosis type.
Mixed-cellularity Hodgkin lymphoma is more common in males.
Nonetheless, the overall prognosis is
very good.
(B) Reed-Sternberg cell, mononuclear variant.
(C) Reed-Sternberg cell, lacunar
variant.
(D) Reed-Sternberg cell, lymphohistiocytic variant.
(A, Courtesy Dr.
Robert W.
(Courtesy Dr.
Robert W.
(Courtesy Dr.
Robert W.
The Reed-Sternberg cells are infected with
EBV in over 90% of cases.
Nodular Lymphocyte Predominance Type.
This uncommon “nonclas-
sic” variant of Hodgkin lymphoma accounts for about 5% of cases.
13.27).
“Classic” Reed-Sternberg cells are usually difficult to find.
Eosinophils and plasma
cells are usually scant or absent.
In 3% to 5% of cases, this
type transforms into a tumor resembling diffuse large B-cell
lymphoma.
EBV is rarely associated with this subtype.
Mediastinal and bone marrow involvement is rare.
Figure 13.26 Hodgkin lymphoma, mixed-cellularity type.
(Courtesy Dr.
Robert W.
It is associated with EBV in about 40% of cases and has
a very good to excellent prognosis.
Lymphocyte Depletion Type.
This is the least common form of
Hodgkin lymphoma, amounting to less than 5% of cases.
more likely to have constitutional symptoms such as fever,
night sweats, and weight loss.
13.28).
The cure rate of patients with stages I
and IIA is close to 90%.
Even with advanced disease (stages
IVA and IVB), disease-free survival at 5 years is 60% to 70%.
See text for details.
Some of the best characterized pathogenic mecha-
nisms are summarized in Fig.
• Lymphocyte predominance type expresses B-cell markers and
is not associated with EBV.
13.1).
AML occurs at all ages, but the incidence rises
throughout life, peaking after 60 years of age.
There are
about 13,000 new cases each year in the United States.
Classification.
AML is quite heterogeneous, reflecting the
complexities of myeloid cell differentiation.
The current
WHO classification subdivides AML into four categories
(Table 13.10).
AMLs in these categories have
distinct genetic features and respond poorly to therapy.
A
fourth “wastebasket” category includes AMLs lacking any
of these features.
These are classified based on the degree
of differentiation and the lineage of the leukemic blasts.
IDH inhibitors are effective in treating IDH-mutated
forms of AML.
• Mutation of TP53 or genes that regulate p53.
The cytoplasm often contains fine, peroxidase-positive azurophilic
granules.
13.31A).
Monoblasts (Fig.
13.31B) have folded or lobulated nuclei, lack Auer
rods, and are nonspecific esterase-positive.
Rarely, the blasts of AML show erythroid differentiation.
The number of leukemic cells in the blood is highly variable.
Blasts may be more than 100,000/mm3, but are under 10,000/
mm3 in about 50% of patients.
Occasionally, blasts are entirely
absent from the blood (aleukemic leukemia).
13.30A).
Immunophenotype.
(A, Courtesy Dr.
Robert W.
(A) Acute promyelocytic
leukemia with the t(15;17) (FAB M3 subtype).
(B) Acute myeloid leukemia with
monocytic differentiation (FAB M5b subtype).
Peripheral smear shows one
monoblast and five promonocytes with folded nuclear membranes.
(Courtesy Dr.
Robert W.
Cytogenetic analysis has a central role in the
classification of AML.
Particular chromosomal abnormalities correlate with
certain clinical features.
You will remember that these findings are very similar to
those produced by ALL.
Thrombocytopenia results in
abnormal bleeding, which often is prominent.
Central nervous system spread is
less common than in ALL.
Without systemic
treatment, such tumors inevitably progress to full-blown
AML over time.
However, the outcome varies
markedly among different molecular subtypes.
AMLs with t(8;21) or inv(16) also have a relatively
good prognosis with conventional chemotherapy.
t-MDS usually appears from 2 to 8 years after the genotoxic
exposure.
• RNA splicing factors.
A subset of tumors has mutations
involving components of the 3′ end of the RNA splicing
machinery.
Precisely how these mutations contribute to
the development of MDS has yet to be determined.
• Transcription factors.
Pseudo–Pelger-HüetDisorders of white cells 621
A B
C D
Figure 13.32 Myelodysplasia.
Characteristic forms of dysplasia are shown.
(A) Nucleated red cell progenitors with multilobated or multiple nuclei.
(D) Megakaryocytes
with multiple nuclei instead of the normal single multilobated nucleus.
Treatment options are fairly limited.
Older
patients with MDS are treated supportively with antibiotics
and blood product transfusions.
Myeloid blasts may be increased but
make up less than 20% of the overall marrow cellularity.
Myeloid blasts usually make up less than 10% of the
leukocytes in the blood.
In up to half of the cases,
it is discovered incidentally on routine blood testing.
When
symptomatic, it presents with weakness, infections, and
hemorrhages, all due to pancytopenia.
Several prog-
nostic scoring systems have been developed.
The cell of origin is a pluripotent HSC.
13.33).
Megakaryocytes are also increased and usually include small,
dysplastic forms.
Peripheral blood smear shows
many mature neutrophils, some metamyelocytes, and a myelocyte.
(Courtesy Dr.
Robert W.
der, Derivative chromosome.
Figure 13.35 Chronic myeloid leukemia (spleen).
(Courtesy Dr.
In the other 50% of patients, blast
crises occur abruptly without an accelerated phase.
Blasts usually make up less than 10% of the circulating
cells.
Platelets are also usually increased, sometimes markedly.
The spleen is often greatly enlarged as a result of extensive
extramedullary hematopoiesis (Fig.
13.35), and often contains
infarcts of varying age.
Extramedullary hematopoiesis can also
produce mild hepatomegaly and lymphadenopathy.
Clinical Features
CML is primarily a disease of adults but also occurs in
children and adolescents.
The peak incidence is in the fifth
to sixth decades of life.
There are about 4500 new cases per
year in the United States.
The onset is insidious.
Understanding of the pathogenesis of CML has led to
the use of drugs that target BCR-ABL.
As a result, it is not clear if BCR-ABL
inhibitors are ever truly curative.
The elevated hematocrit leads to increased blood viscosity
and sludging.
13.33).
MORPHOLOGY
The marrow is hypercellular, but some residual fat is usually
present.
At diagnosis, a moderate
to marked increase in reticulin fibers is seen in about 10% of
marrows.
The peripheral blood often contains
increased numbers of basophils and abnormally large platelets.
13.36).Transformation to AML, with its typical
features, occurs in about 1% of patients.
Figure 13.36 Polycythemia vera, spent phase.
(Courtesy Dr.
It appears insidiously, usually in adults of late
middle age.
Most symptoms are related to the increased
red cell mass and hematocrit.
Usually, there is also an
increased total blood volume.
Headache,
dizziness, hypertension, and gastrointestinal symptoms are
common.
High cell turnover gives rise to hyperuricemia;
symptomatic gout is seen in 5% to 10% of cases.
Without treatment, death from bleeding or thrombosis
occurs within months of diagnosis.
The
mechanisms underlying the progression to the spent phase
are not known.
In about 2% of patients, PCV transforms to AML.
The JAK2 mutation is the same as that found in almost all
cases of PCV.
Why some patients with JAK2 mutations
present with PCV and others with ET is not understood.
As mentioned, most cases without JAK2
or MPL mutations have calreticulin mutations instead.
Peripheral smears usually reveal abnormally large platelets
(Fig.
13.37), often accompanied by mild leukocytosis.
Uncommonly, a spent
phase of marrow fibrosis or transformation to AML supervenes.
Clinical Features
The incidence of ET is 1 to 3 per 100,000 per year.
It usually
occurs past the age of 60 but may also be seen in young
adults.
At this stage fibrosis is minimal, and the
blood may show leukocytosis and thrombocytosis.
With progres-
sion, the marrow becomes more hypocellular and diffusely
fibrotic.
Grossly, such spleens are firm and diffusely red to gray.
As in CML, subcapsular infarcts are common (see Fig.
13.41).
The liver may be enlarged
moderately by sinusoidal foci of extramedullary hematopoiesis.
Hematopoiesis may also appear within lymph nodes, but significant
lymphadenopathy is uncommon.
The marrow fibrosis is reflected in several characteristic blood
findings (Fig.
13.38).
Other common, albeit nonspecific, blood findings
include abnormally large platelets and basophilia.
Figure 13.37 Essential thrombocytosis.
Median survival times are 12 to 15 years.
Therapy
consists of “gentle” chemotherapeutic agents that suppress
thrombopoiesis.
As you
recall, platelet-derived growth factor and TGF-β are fibroblast
mitogens.
For
incompletely understood reasons, red cell production at
extramedullary sites is disordered.
This factor and the
concomitant suppression of marrow function result in
moderate to severe anemia.
Figure 13.38 Primary myelofibrosis (peripheral blood smear).
Two
nucleated erythroid precursors and several teardrop-shaped red cells
(dacryocytes) are evident.
Immature myeloid cells were present in other
fields.
Hyperuricemia and secondary gout due
to a high rate of cell turnover can complicate the picture.
These blood findings are not specific; bone marrow biopsy
is essential for diagnosis.
Primary myelofibrosis is a much more difficult disease
to treat than PCV or ET.
The course is variable, but the
median survival is in the range of 3 to 5 years.
MDS
• Myeloid tumors characterized by disordered and ineffective
hematopoiesis and dysmaturation.
• May occur de novo or following genotoxic exposures.
• Manifest with one or more cytopenias and often progress to
AML.
Less common mutations
have also been detected in TP53, RAS, and the receptor
tyrosine kinase MET.
13.39A).The presence
of Birbeck granules in the cytoplasm is characteristic.
13.39B), which
contain the protein langerin.
In addition, the tumor cells also
typically express HLA-DR, S-100, and CD1a.
The course of untreated disease
is rapidly fatal.
With intensive chemotherapy, 50% of
patients survive 5 years.
Eosinophils are usually, but not always, a prominent
component of the infiltrate.
Less commonly, unisystem lesions of
identical histology arise in the skin, lungs, or stomach.
Unifocal lesions most commonly affect the skeletal system
in older children or adults.
A
B
Figure 13.39 Langerhans cell histiocytosis.
(B, Courtesy Dr.
13.40).
As it traverses the red pulp, the blood takes two routesSpleen 629
• Hematopoiesis.
• Sequestration of formed blood elements.
The spleen
also normally harbors approximately 30% to 40% of the
total platelet mass in the body.
Similarly, the enlarged spleen may trap white
cells and thereby induce leukopenia.
It is rarely the primary site of disease.
(Modified from Faller DV:
Diseases of the spleen.
• Antibody production.
Table 13.12 lists major disorders associated with spleno-
megaly.
Splenomegaly in virtually all the conditions
mentioned has been discussed elsewhere.
A few disorders
are left to consider.
Nonspecific Acute Splenitis
Enlargement of the spleen occurs in any blood-borne infec-
tion.
MORPHOLOGY
The spleen is enlarged (200 to 400 g) and soft.
Immunologic-Inflammatory Conditions
Rheumatoid arthritis
Systemic lupus erythematosus
V.
Storage Diseases
Gaucher disease
Niemann-Pick disease
Mucopolysaccharidoses
VI.
Cirrhosis of the liver is the main cause of massive
congestive splenomegaly.
Other forms of cirrhosis are less commonly
implicated.
MORPHOLOGY
Long-standing splenic congestion produces marked enlargement
(1000 to 5000 g).
The organ is firm, and the capsule is usually
thickened and fibrous.
In normal-sized spleens, infarcts are most
often caused by emboli that arise from the heart.
The infarcts
can be small or large, be single or multiple, or even involve
the entire organ.
encroach on and virtually efface the lymphoid follicles.
Rarely, abscess formation
occurs.
MORPHOLOGY
Bland infarcts are characteristically pale, wedge-shaped, and
subcapsular in location.
The overlying capsule is often covered
with fibrin (Fig.
13.41).
In septic infarcts this appearance is modified
by the development of suppurative necrosis.
In the course of
healing, large depressed scars often develop.
All of
these disorders ultimately lead to portal or splenic vein
hypertension.
Hypoplasia is a more common
finding.
They
can be found at any place within the abdominal cavity.
RUPTURE
Figure 13.41 Splenic infarcts.
Splenic rupture is usually precipitated by blunt trauma.
Much less often, it occurs in the apparent absence of a
physical blow.
(discussed earlier).
Benign fibromas, osteomas, chondro-
mas, lymphangiomas, and hemangiomas may arise in the
spleen.
Of these, lymphangiomas and hemangiomas are
most common and often cavernous in type.
Here, our interest
centers on the disorders of the gland itself.
At birth it weighs 10 to 35 g.
The fully developed thymus is composed of two fused,
well-encapsulated lobes.
During adulthood the
thymic production of T cells slowly declines as the organ
atrophies.
Pathologic changes within the thymus are limited and
will be described here.
The changes associated with myas-
thenia gravis are considered in Chapter 27.
The fluid
contents can be serous or mucinous and are often modified
by hemorrhage.
Such B-cell follicles are present in only small
numbers in the normal thymus.
In other instances, a morphologically normal thymus is
simply large for the age of the patient.
Such tumors typically also contain benign
immature T cells (thymocytes).
Males
and females are affected equally.
They
are uncommon in the posterior mediastinum.
The medullary-type epithelial cells
are elongated or spindle-shaped (Fig.
13.42A).
(A) Benign thymoma (medullary type).
Only a few small,
reactive lymphoid cells are interspersed.
(B) Malignant thymoma, type I.
Numerous small, reactive lymphoid
cells are interspersed.
Invasive thymoma refers to a tumor that is cytologically
benign but locally invasive.
These tumors are much more likely
to metastasize.
13.42B), and are usually mixed with numerous thy-
mocytes.
These tumors account for about 20% to 25% of all
thymomas.
By definition, invasive thymomas penetrate
through the capsule into surrounding structures.
Thymic carcinoma represents about 5% of thymomas.
Microscopically, most are squamous cell carcinomas.
[Discussion of
origins of hematopoietic stem cells].
[Discussion of the
nature and biology of the marrow stem cell niche].
[Up-to-date review of the pathogenesis and clinical
features of Langerhans cell histiocytosis].
[Overview of the most recent version of
the classification system used for myeloid neoplasms].
Hunger SP, Mullighan CG: Acute lymphoblastic leukemia in children,
N Engl J Med 373:2015, 1541.
Kumar SJ, Rajkuar V, Kyle RA et al: Multiple myeloma, Nat Rev Dis
Primers 3:17046, 2017.
[Review of the pathogenesis, clinical features, and
treatment of multiple myeloma].
Ogawa S: Genetics of MDS, Blood 133:1049, 2019.
[Comprehensive review
of genetic drivers in myelodysplastic syndromes].
[Recent review of emerging link between myelodysplastic syndromes and
inflammation].
[Review of the molecular pathogenesis Burkitt lymphoma].
[Overview of the most recent version of the classification
system used for lymphoid neoplasms].
[Update on the pathogenesis of the major subtypes of myeloproliferative
neoplasms].
Another 30%
to 45% are detected in the course of evaluating patients
with myasthenia gravis.
The rest are discovered incidentally
during imaging studies or cardiothoracic surgery.
Anemia reduces the
oxygen-carrying capacity of the blood, leading to tissue
hypoxia.
There are many classifications of anemia.
We will follow
one based on underlying mechanisms that is presented in
Table 14.1.
a Most often anemia stems from iron deficiency, not bleeding per se.
Adult reference ranges for red cell indices are shown in
Table 14.2.
Hypoxia can cause fatty change in the
liver, myocardium, and kidney.
Central nervous
system hypoxia can cause headache, dimness of vision, and
faintness.
Extravascular hemolysis is most commonly caused by
alterations that make red cells less deformable.
Extreme
changes in shape are required for red cells to navigate the
splenic sinusoids successfully.
Unlike in extravascular hemolysis,
splenomegaly is not seen.
In all types of uncomplicated hemolytic anemia, the excess
serum bilirubin is unconjugated.
the bleeding is external or internal.
This fluid shift produces hemodilution and
lowers the hematocrit.
13.1).
Initially, red cells appear normal in size and color (normo-
cytic, normochromic).
14.1).
Such iron accumulation is referred to as hemosiderosis.
Figure 14.1 Marrow aspirate smear from a patient with hemolytic
anemia.
There is an increased number of maturing erythroid progenitors
(normoblasts).
(Courtesy Dr.
The prevalence of HS is highest in northern Europe, where
rates of 1 in 5000 are reported.
An autosomal dominant
inheritance pattern is seen in about 75% of cases.
14.2), which lies
closely apposed to the internal surface of the plasma mem-
brane.
HS is caused by diverse mutations that lead to an
insufficiency of membrane skeletal components.
GP, Glycophorin.Anemias 639
that the mutated allele fails to produce any protein.
The travails of spherocytic red cells are fairly
well defined.
In the life of the portly, inflexible spherocyte,
the spleen is the villain.
14.3).
After splenectomy the spherocytes persist, but the anemia
is corrected.
Figure 14.4 Hereditary spherocytosis (peripheral smear).
Note the
anisocytosis and several dark-appearing spherocytes with no central pallor.
(Courtesy Dr.
Robert W.
14.4).
Other features are common to
all hemolytic anemias.
These include reticulocytosis, marrow
erythroid hyperplasia, hemosiderosis, and mild jaundice.
Chole-
lithiasis (pigment stones) occurs in 40% to 50% of affected
adults.
Splenomegaly results from congestion of the
cords of Billroth and increased numbers of phagocytes.
The characteristic clinical features are anemia, spleno-
megaly, and jaundice.
The severity varies greatly.
Thus, older red cells are
much more prone to hemolysis than younger ones.
The other important initiators are drugs
and certain foods.
Some drugs cause
hemolysis only in individuals with the more severe Mediter-
ranean variant.
The most frequently cited food is the fava
bean, which generates oxidants when metabolized.
Oxidants cause both intravascular and extravascular
hemolysis in G6PD-deficient individuals.
These are seen as dark
inclusions within red cells stained with crystal violet
(Fig.
14.6).
Heinz bodies can damage the membrane suffi-
ciently to cause intravascular hemolysis.
Less severe
membrane damage results in decreased red cell deform-
ability.
14.6).
Other less severely damaged
cells become spherocytes due to loss of membrane surface
area.
Both bite cells and spherocytes are trapped in splenic
cords and removed by phagocytes.
The recovery phase is heralded by reticulocytosis.
The
synthesis of NADPH depends on the activity of G6PD.
GSSG, Oxidized
glutathione; NADP, nicotinamide adenine dinucleotide phosphate.
for even short periods leads to sudden worsening of the
anemia.
Transfusions may be necessary to support the patient
during the acute phase of the infection.
Gallstones, found in many
patients, may also produce symptoms.
14.5).
14.5).
In HbSC red cells, the percent-
age of HbS is 50%, as compared with only 40% in HbAS
cells.
• Mean cell hemoglobin concentration (MCHC).
Thus, intracellular dehydration, which
increases the MCHC, facilitates sickling.
(Courtesy Dr.
Robert W.
In affected individuals, almost all the
hemoglobin in the red cell is HbS (α2 βs2).
Although mechanistic details642 CHAPTER 14 Red Blood Cell and Bleeding Disorders
severity.
• Intracellular pH.
• Transit time of red cells through microvascular beds.
As a result, inflamed vascular beds are
prone to sickling and occlusion.
Sickling causes cumulative damage to red cells through
several mechanisms.
As a
result, with repeated sickling episodes, red cells become
dehydrated, dense, and rigid (Fig.
14.7).
Sickled red cells are also mechani-
cally fragile, leading to some intravascular hemolysis as well.
14.7).
Depletion of nitric oxide (NO) also
may play a part in the vascular occlusions.
HbA, Hemoglobin A;
HbS, hemoglobin S; RBC, red blood cell.
14.10).
(B) Higher magnification shows an
irreversibly sickled cell in the center.
(Courtesy Dr.
Robert W.
(B) Under
high power, splenic sinusoids are dilated and filled with sickled red cells.
(Courtesy Dr.
The most commonly involved sites are the
bones, lungs, liver, brain, spleen, and penis.
(Courtesy Drs.
A clinical trial
testing this approach is ongoing and has produced excellent
responses.
Sequestration crises occur in children
with intact spleens.
In addition to these dramatic crises, chronic tissue hypoxia
takes a subtle but important toll.
Increased susceptibility to infection with encapsulated
organisms is another threat.
Some
individuals suffer repeated vaso-occlusive crises, whereas
others have only mild symptoms.
About
90% of patients survive to 20 years of age, and close to 50%
survive beyond the fifth decade.
β-Thalassemia
β-thalassemia is caused by mutations that diminish the
synthesis of β-globin chains.
Its clinical severity varies
widely due to heterogeneity in the causative mutations.
These are the most common cause of
β+-thalassemia.
Others create an “ectopic” splice site within an intron.
• Promoter region mutations.
These mutations reduce
transcription by 75% to 80%.
These are the most common
cause of β0-thalassemia.
Both block translation
and prevent the synthesis of any functional β-globin.
Impaired β-globin synthesis results in anemia by two
mechanisms (Fig.
14.11).
Unpaired α chains precipitate
within red cell precursors, forming insoluble inclusions.
Many red cell precursors succumb to membrane
damage and undergo apoptosis.
In severe β-thalassemia, ineffective erythropoiesis creates
several additional problems.
Injury to parenchymal organs, particu-
larly the heart and liver, often follows (Chapter 18).
This condition is
referred to as β-thalassemia minor or β-thalassemia trait.
A
third genetically heterogeneous variant of moderate severity
is called β-thalassemia intermedia.
β-Thalassemia major is most
common in Mediterranean countries, parts of Africa, and
Southeast Asia.
In the United States, the incidence is highest
in immigrants from these areas.
The anemia manifests 6 to
9 months after birth as hemoglobin synthesis switches from
HbF to HbA.
In untransfused patients, hemoglobin levels
are 3 to 6 g/dL.
The major red cell hemoglobin is HbF, which
is markedly elevated.
HbA2 levels are sometimes high but
more often are normal or low.
β-Thalassemia Minor.
Most patients are heterozy-
gous carriers of a β+ or β0 allele.
These patients are usually
asymptomatic.
Anemia, if present, is mild.
Mild erythroid hyper-
plasia is seen in the bone marrow.
HbF levels
are generally normal or occasionally slightly increased.
Other major alterations involve the bone marrow and spleen.
In untransfused patients, there is a striking expansion of hemato-
poietically active marrow.
14.13).
The clinical course of β-thalassemia major is brief unless
blood transfusions are given.
Hepatosplenomegaly due to extramedullary hematopoiesis
is usually present.
Prenatal diagnosis is possible by molecular analysis
of DNA.
Figure 14.13 β-Thalassemia major.
(Courtesy Dr.
Hematopoietic stem cell
transplantation can be curative.
PNH has an incidence of 2 to 5 per million in the United
States.
Recall that proteins are anchored into the
lipid bilayer in two ways.
This manifests
as intravascular hemolysis, which is caused by the C5b-C9
membrane attack complex.
The anemia is variable but usually
mild to moderate in severity.
Thrombosis is the leading cause of disease-related death
in individuals with PNH.
Each of the
four α-globin genes normally contributes 25% of the total
α-globin chains.
α-Thalassemia syndromes stem from
combinations of deletions that remove one to four α-globin
genes.
The different types of α-thalassemia and their salient
clinical features are listed in Table 14.3.
Silent Carrier State.
These
individuals are completely asymptomatic but have slight
microcytosis.
α-Thalassemia Trait.
The
former genotype is more common in Asian populations,
the latter in regions of Africa.
HbA2 levels are normal or low.
Hemoglobin H (HbH) Disease.
HbH disease is caused by
deletion of three α-globin genes.
It is most common in Asian
populations.
The result is a moderately severe anemia
resembling β-thalassemia intermedia.
Hydrops Fetalis.
Signs of fetal distress usually become evident by
the third trimester of pregnancy.
Quantitative immunologic tests to measure such antibodies
directly also are available.
Warm Antibody Type.
This form constitutes approximately
80% of cases of immunohemolytic anemia.
It is caused by
antibodies that bind stably to red cells at 37°C.
Most causative antibodies are of the IgG class; less
commonly, IgA antibodies are the culprits.
The red cell
hemolysis is mostly extravascular.
Moderate splenomegaly due to hyperplasia of splenic
phagocytes is usually seen.
As with other autoimmune disorders, the cause of primary
immunohemolytic anemia is unknown.
In drug-induced cases, two mechanisms have been described.
• Antigenic drugs.
• Tolerance-breaking drugs.
CD59
CD59
CD55 CD55
B
A
Figure 14.14 Paroxysmal nocturnal hemoglobinuria (PNH).
(Courtesy Dr.
Scott Rodig, Department of Pathology,
Brigham and Women’s Hospital, Boston, Mass.)
cerebral veins.
14.14).
Immunosuppressive
drugs are sometimes beneficial for those with evidence of
marrow aplasia.
The only cure is hematopoietic stem cell
transplantation.
Cold Agglutinin Type.
It
accounts for 15% to 20% of cases.
IgM binding
agglutinates red cells and fixes complement rapidly.
The hemolysis
is of variable severity.
Chronic cold agglutinin
immunohemolytic anemia caused by IgM antibodies may
be difficult to treat.
The best approach, when possible, is
avoidance of cold temperatures.
Cold Hemolysin Type.
14.15).
• Ineffective erythropoesis increases iron absorption and can
lead to systemic iron overload.
(Courtesy Dr.
Robert W.
The causes of megaloblastic anemia
are given in Table 14.5.
Some of the metabolic roles of vitamin B12 and folate are
considered later.
Nucleated
red cell progenitors occasionally appear in the circulating blood
when anemia is severe.
14.16).
Megaloblastic
changes are detected at all stages of erythroid development.
Megakaryocytes
also may be abnormally large and have bizarre, multilobate nuclei.
Figure 14.16 Megaloblastic anemia.
A peripheral blood smear shows a
hypersegmented neutrophil with a six-lobed nucleus.
(Courtesy Dr.
Robert
W.
A to C,
Megaloblasts in various stages of differentiation.
(Courtesy Dr.
The anemia is further exacerbated by a
mild degree of red cell hemolysis of uncertain etiology.
Normal Vitamin B12 Metabolism.
The daily requirement is 2 to 3 µg.
14.18).
Biochemical Functions of Vitamin B12.
Only two reactions
in humans are known to require vitamin B12.
14.19).
In the same reaction, N5-methyl FH4 is converted to tetra-
hydrofolic acid (FH4).
14.20).
A deficiency of vitamin B12 thus leads to increased plasma
and urine levels of methylmalonic acid.
Pernicious Anemia
Incidence.
Three types of autoantibodies are
present in many, but not all, patients.
Type I antibodies are found in both
plasma and gastric juice.
Both type I and type II antibodies are found in
plasma and gastric juice.
In cobalamin (Cbl) deficiency, folate is sequestered
as N5-methyl FH4.
Serum
antibodies to intrinsic factor are highly specific for pernicious
anemia.
Vitamin B12 deficiency also may arise from causes other
than pernicious anemia.
With gastrectomy, intrinsic
factor is lost.
14.20).
Humans depend on dietary sources for folic
acid.
Most normal diets contain ample amounts.
The richest
sources are green vegetables such as lettuce, spinach, aspara-
gus, and broccoli.
The
folic acid in these foods is largely in the form of folylpoly-
glutamates.
The course is progressive unless halted by therapy.Anemias 655
the transport form of folate.
A
normal diet contains folate in excess of the minimal daily
adult requirement.
Importantly, neurologic changes
do not occur.
Iron Metabolism.
The major sites of storage iron are the liver
and mononuclear phagocytes.
Iron in the body is recycled between the functional and
storage pools (Fig.
14.21).
Free iron is highly toxic (Chapter 18), and storage iron
must therefore be sequestered.
This is achieved by the
binding of storage iron to either ferritin or hemosiderin.
Here, it is metabolized to release Fe2+ iron,
which enters a common pool with nonheme Fe2+ iron.
Frequently, less than 5% of dietary
nonheme iron is absorbed.
14.21).
Conversely, with low body stores of iron, hepcidin levels
fall, facilitating iron absorption.
Alterations in hepcidin have a central role in diseases
involving disturbances of iron metabolism.
This is illus-
trated by the following examples.
Here iron is extracted from hemoglobin and recycled to plasma
transferrin.
In iron-overloaded
cells, most iron is stored in hemosiderin.
Iron balance is maintained by regulating the
absorption of dietary iron in the proximal duodenum.
By contrast, as body iron
stores increase, absorption decreases, and vice versa.
14.22)
and differ for nonheme and heme iron.
Duodenal epithelial cell uptake of heme and nonheme iron is described in the text.
DMT1, Divalent metal transporter 1.
Etiology.
To maintain a normal iron balance, about 1 mg
of iron must be absorbed from the diet every day.
The bioavailability of dietary
iron is as important as the overall content.
The absorption
of inorganic iron is influenced by other dietary contents.
Human breast milk provides only about
0.3 mg/L of iron.
Cow’s milk contains about twice as
much iron, but its bioavailability is poor.
Chronic blood loss is the most common cause of iron
deficiency in high income societies.
In this early stage, there is increased erythroid
activity in the bone marrow.
Figure 14.23 Iron deficiency (peripheral blood smear).
Note the
hypochromic microcytic red cells containing a narrow rim of peripheral
hemoglobin.
Scattered fully hemoglobinized cells, present due to recent
blood transfusion, stand in contrast.
(Courtesy Dr.
Robert W.
The diagnosis of iron deficiency anemia ultimately rests
on laboratory studies.
Reduced iron stores inhibit hepcidin synthesis, and its serum
levels fall.
In peripheral blood smears, the red cells are small (microcytic)
and pale (hypochromic).
14.23).
As a result, the erythroid precursors
are starved for iron in the midst of plenty.
What might be the reason for iron sequestration in the
setting of inflammation?
influenzae) that require
iron for pathogenicity.
The anemia is usually mild, and the dominant symptoms
are those of the underlying disease.
Etiology.
The most common circumstances associated with
aplastic anemia are listed in Table 14.7.
Most cases of
“known” etiology follow exposure to chemicals and drugs.
The impli-
cated drugs in these idiosyncratic reactions include chlor-
amphenicol and gold salts.
Why aplastic
anemia develops in certain individuals is not understood.
Whole-body irradiation can destroy hematopoietic stem
cells in a dose-dependent fashion.
• Inherited defects in telomerase are found in 5% to 10% of
adult-onset aplastic anemia.
Telomerase is required for
cellular immortality and limitless replication (Chapters
1 and 7).
Pathogenesis
The pathogenesis of aplastic anemia is not fully understood.
Indeed, it is unlikely that a single mechanism underlies all
cases.
If the damage is
extensive enough, aplastic anemia results.
14.25).
If the anemia necessitates multiple
transfusions, systemic hemosiderosis can appear.
IFNγ
TNF
T-cell response
Marrow
aplasia
Figure 14.24 Pathophysiology of aplastic anemia.
Either pathway could lead to marrow aplasia.
See text for
abbreviations.
14.24).
This scenario is supported by several
observations.
It is proposed that these therapies work
by suppressing or killing autoreactive T-cell clones.
The
antigens recognized by the autoreactive T cells are not
well defined.
Markedly
hypocellular marrow contains mainly fat cells.
(A) Low power.
(B) High
power.
(Courtesy Dr.
Clinical Features
Aplastic anemia can occur at any age and in either sex.
The
onset is usually insidious.
The red cells are usually slightly macrocytic and normo-
chromic.
Reticulocytopenia is the rule.
The diagnosis rests on examination of a bone marrow
biopsy.
The prognosis is variable.
Older patients
or those without suitable donors often respond well to
immunosuppressive therapy.
In severe cases,
red cell progenitors are completely absent from the marrow.
In patients without thymoma, immunosuppressive
therapy is often beneficial.
The following tests are used to evaluate different
aspects of hemostasis:
• Prothrombin time (PT).
This test assesses the extrinsic and
common coagulation pathways.
• Partial thromboplastin time (PTT).
This test assesses the
intrinsic and common clotting pathways.
The clotting
of plasma after addition of kaolin, cephalin, and Ca2+
ions is measured in seconds.
• Platelet counts.
These are obtained on anticoagulated
blood using an electronic particle counter.
The reference
range is 150 × 103 to 350 × 103 platelets/ µL.
Affected individuals are usually
males who are hypertensive, obese, and anxious (“stressed”).
A pathophysiologic
classification of polycythemia divided along these lines is
given in Table 14.8.
Secondary
polycythemia stems from compensatory or pathologic
increases in erythropoietin secretion.
At present, no single test
provides an adequate assessment of the complex func-
tions of platelets.
It is
characterized by dilated, tortuous blood vessels with thin
walls that bleed readily.
• Perivascular amyloidosis can weaken blood vessel walls
and cause bleeding.
A count less
than 150,000 platelets/ µL is generally considered to constitute
thrombocytopenia.
When
thrombocytopenia is isolated, the PT and PTT are normal.
Spontaneous bleeding associated with
thrombocytopenia most often involves small vessels.
The causes of thrombocytopenia fall into four major
categories (Table 14.9).
• Decreased platelet production.
• Decreased platelet survival.
This important mechanism of
thrombocytopenia may have an immunologic or nonim-
munologic basis.
Autoimmune thrombocytopenia
is discussed in the following section.
In the overwhelming majority of cases, the
antiplatelet antibodies are of the IgG class.
The
marrow reveals a modestly increased number of mega-
karyocytes.
Some are apparently immature, with large, nonlobu-
lated, single nuclei.
made in the mother may cause clinically significant
thrombocytopenia in the fetus.
• Sequestration.
• Dilution.
Massive transfusions can produce dilutional
thrombocytopenia.
The diagnosis of primary
chronic ITP is made only after secondary causes are excluded.
The female-to-male ratio is 3 : 1.
It is
often insidious in onset and is characterized by bleeding
into the skin and mucosal surfaces.
Petechiae can become
confluent, giving rise to ecchymoses.
The
disease may manifest first with melena, hematuria, or
excessive menstrual flow.
Typical laboratory findings are reflective of isolated
thrombocytopenia.
The PT and PTT are normal.
Acute ITP is mainly a disease of childhood occurring with
equal frequency in both sexes.
Unlike chronic ITP, acute ITP is
self-limited, usually resolving spontaneously within 6
months.
Glucocorticoids are given only if the thrombocy-
topenia is severe.
Much more rarely, drugs induce true autoantibodies through
unknown mechanisms.
It most likely results from a
direct platelet-aggregating effect of heparin.
• Type II HIT is less common but is often life threatening.
Both decreased platelet
production and increased platelet destruction contribute.
This group of disorders
includes TTP and HUS.
With time, experience, and increased mechanistic insight,
however, these distinctions have blurred.
ADAMTS13 deficiency may be inherited or acquired.
Less commonly,
patients inherit an inactivating mutation in ADAMTS13.
Children and older adults are at highest
risk.
Those affected present with bloody diarrhea, and a
few days later HUS makes its appearance.
Unlike TTP, the basis for the platelet activation in typical
and atypical HUS is unclear.
Immunosuppression
also may be beneficial to patients with inhibitory autoantibod-
ies.
Typical HUS is treated supportively.
The impact of HUS and TTP on the kidneys is discussed
further in Chapter 20.
Affected patients have
a variable, often severe, bleeding tendency.
• Glanzmann thrombasthenia exemplifies bleeding due to
defective platelet aggregation.
It is transmitted as an
autosomal recessive trait.
Among the acquired defects of platelet function, two are
clinically significant.
The first is caused by ingestion of aspirin
and other nonsteroidal anti-inflammatory drugs.
Hereditary deficiencies typically affect a single clotting
factor.
Vitamin K deficiency (Chapter
9) impairs the synthesis of factors II, VII, IX, X and protein
C.
By contrast, in DIC, multiple coagulation factors
are consumed, leading to their deficiency.
Acquired deficien-
cies of single factors occur, but are rare.
These are usually
caused by inhibitory autoantibodies.
Factor VIII is an essential cofactor of factor IX, which
converts factor X to factor Xa (Fig.
14.26; Chapter 4).
The two associate to form a complex in the circulation.
14.26).
Factor VIII and vWF protein levels are measured by
immunologic techniques.
It is inherited as an autosomal
dominant disorder.
The
plasma level of active vWF, measured as the ristocetin
cofactor activity, is reduced.
About 30% of patients have no family history; their disease
is caused by new mutations.
In such cases, factor VIII protein
levels may be normal by immunoassay.
Recurrent bleeding into the joints leads to
progressive deformities that can be crippling.
Petechiae are
characteristically absent.
Factor VIII–specific assays
are required for diagnosis.
Hemophilia A is treated with infusions of recombinant
factor VIII.
Efforts to develop somatic gene
therapy for hemophilia are ongoing.
A wide spectrum
of mutations involving the gene that encodes factor IX is
found in hemophilia B.
In about 15% of these patients, factor IX protein
is present but is nonfunctional.
As with hemophilia A, the
PTT is prolonged and the PT is normal.
The disease is treated with
infusions of recombinant factor IX.
It occurs as a secondary complication
of many disorders.
Sometimes the coagulopathy is local-
ized to a specific organ or tissue.
Clotting in vivo is initiated by exposure of tissue factor,
which activates factor VII.
Activation of factor X leads
to the generation of thrombin, the central player in clotting.
To prevent runaway clotting,
this process must be sharply limited to the site of tissue
injury.
Endothelial injury can initiate DIC in several ways.
However, even subtle endothelial injuries
can unleash procoagulant activity.
One mediator of endo-
thelial injury is TNF, which is implicated in DIC occurring
with sepsis.
The
triggers in these conditions are often multiple and inter-
related.
that secondarily activate platelets and granulocytes.
The possible consequences of DIC are twofold (Fig.
14.27).
• Widespread deposition of fibrin within the microcirculation.
cortical necrosis.
The only definitive treatment is
to remove or treat the inciting cause.
products (packed red blood cells, platelets, and fresh-frozen
plasma) are safer than ever before.
Nevertheless, complications still occur.
Most are minor
and transient.
These reactions are
thought to be caused by inflammatory mediators derived
from donor leukocytes.
Symptoms respond to antipyretics and are short-lived.
These are considerably
more common, occurring in 1% to 3% of transfusions, but
are generally mild.
Fever, shaking chills, and flank pain
appear rapidly.
The direct Coombs test is typically positive,
unless all of the donor red cells have lysed.
Deficiency of ADAMTS 13 results in
abnormally large vWF multimers that activate platelets.
• Hemophilia B:X-linked disorder caused by mutations in coagula-
tion factor IX.
It is clinically identical to hemophilia A.
Over
5 million red cell transfusions are given in US hospitals
each year.
potentially fatal reactions identical to those resulting from
ABO mismatches.
Though its pathogenesis is incompletely understood, current
models favor a “two-hit” hypothesis.
The first is neutrophil
sequestration and priming in the microvasculature of the
lung.
In other cases, donor antibodies to neutrophil-specific
antigens have been implicated as triggers.
Diffuse
bilateral pulmonary infiltrates that do not respond to diuretics
are seen on chest imaging.
Other associated findings include
fever, hypotension, and hypoxemia.
[A review of the molecular pathogenesis of thalassemia syndromes].
Muckenthaler MU, Rivella S, Hentze MW: A red carpet for iron
metabolism, Cell 168:344, 2017.
[A review focused on normal iron
metabolism and disorders that perturb it].
Narla J, Mohandas N: Red cell membrane disorders, Int J Lab Med
39(47):2017.
[An excellent overview of common hemolytic anemias caused
by inherited red cell membrane defects].
[An updated discussion of how
sickle cell disease leads to tissue damage].
Young NS: Aplastic anemia, N Engl J Med 379:2018, 1643.
[A discussion
of the pathophysiology, diagnosis, and treatment of aplastic anemia].
[An overview of the pathophysiology
of disseminated intravascular coagulation].
Leebeek FWG, Eikenboom JCJ: von Willebrand’s disease, N Engl J Med
375:2067, 2016.
Noris M, Remuzzi G: Atypical hemolytic uremic syndrome, N Engl J
Med 361:1676, 2009.
[A current review of basic and clinical aspects of
thrombotic thrombocytopenia purpura].
Developmentally, the respiratory system is
an outgrowth from the ventral wall of the foregut.
The lobar bronchi
allow air to pass in and out of the lung.
The right mainstem bronchus is more
vertical and directly in line with the trachea.
15.35B).
of bronchioles leads to the terminal bronchioles, which are
less than 2 mm in diameter.
The microscopic structure of the alveolar walls (or alveolar
septa) consists of the following (Fig.
15.1):
• An intertwining network of anastomosing capillaries lined
with endothelial cells.
CONGENITAL ANOMALIES
Developmental anomalies of the lung are rare.
Severe hypoplasia is fatal in the early
neonatal period.
A bronchogenic cyst is rarely
connected to the tracheobronchial tree.
It may be associated with other congenital anomalies.
Intralobar sequestration occurs within the lung.
15.2).
Whatever the clinical setting, pulmonary
congestion and edema produce heavy, wet lungs.
Therapy
and outcome depend on the underlying etiology.
Alveolar microhemorrhages
and hemosiderin-laden macrophages (“heart failure” cells) may
be present.
These changes not only impair respiratory
function but also predispose to infection.
Dashed lines indicate
normal lung volume.
• Resorption atelectasis stems from obstruction of an airway.
Over time, air is resorbed from distal alveoli, which
collapse.
Since lung volume is diminished, the media-
stinum shifts toward the atelectatic lung.
With compression atelectasis, the mediastinum shifts
away from the affected lung.
Significant atelectasis reduces oxygenation and predis-
poses to infection.
Except in cases caused by fibrosis, atel-
ectasis is a reversible disorder.
Acute respiratory distress syndrome (ARDS) is a
manifestation of severe ALI.
The histologic manifestation of these diseases is diffuse
alveolar damage.
15.3).
• Endothelial activation is an important early event.
• Adhesion and extravasation of neutrophils.
• Accumulation of intra-alveolar fluid and formation of hyaline
membranes.
IL-1, Interleukin-1; ROS, reactive oxygen species; TNF, tumor necrosis factor.
In most cases the
granulation tissue resolves, leaving minimal functional impairment.
The alveolar walls become lined with waxy hyaline membranes
(Fig.
In the proliferative or
Figure 15.4 Diffuse alveolar damage (acute respiratory distress
syndrome).
Some of the alveoli are collapsed, while others are distended.
The majority of deaths are attributable to sepsis, multiorgan
failure, or severe lung injury.
diseases is based primarily on pulmonary function tests.
An FEV1/FVC ratio of less than 0.7 generally indicates
obstructive disease.
15.5).
Con-
versely, some patients with otherwise typical COPD have
a reversible component.
Clinicians commonly label such
patients as having COPD/asthma.
• Panacinar (panlobular) emphysema.
15.6C and
15.7B).
• Distal acinar (paraseptal) emphysema.
Figure 15.5 Schematic representation of overlap between chronic
obstructive lung diseases.
There is a strong association between
heavy cigarette smoking and COPD.
Women and African
Americans who smoke heavily are more susceptible than
other groups.
We will
finish our discussion by returning to the clinical features
of COPD.
Emphysema is classified according
to its anatomic distribution within the lobule.
Recall that
the lobule is a cluster of acini, the terminal respiratory units.
Of these, only the first two cause clinically significant airflow
obstruction (Fig.
15.6).
• Centriacinar (centrilobular) emphysema.
It occurs pre-
dominantly in heavy smokers with COPD.
15.6B and 15.7A).
(A) Structure of
the normal acinus.
(B) Centriacinar emphysema with dilation that initially
affects the respiratory bronchioles.
Central areas show marked emphysematous damage (E) surrounded by relatively spared alveolar spaces.
(B) Panacinar emphysema involving the entire pulmonary lobule.
• Airspace enlargement with fibrosis (irregular emphysema).
In most instances it occurs in small foci and is
clinically insignificant.
15.8): •
Toxic injury and inflammation.
• Protease-antiprotease imbalance.
• Oxidative stress.
The role of oxidants is supported by
studies of mice in which the NRF2 gene is inactivated.
• Infection.
About 1% of all patients with emphysema have
this defect.
It is encoded by the proteinase inhibitor (Pi)
locus on chromosome 14.
The Pi locus is polymorphic, and
approximately 0.012% of the U.S.
Several other genetic variants have also been linked to
risk of emphysema.
A number of factors contribute to airway obstruction in
emphysema.
Small airways are normally held open by the
elastic recoil of the lung parenchyma.
MORPHOLOGY
Advanced emphysema produces voluminous lungs, often overlapping
the heart anteriorly.
Large alveoli can easily be seen on the cut surface of
fixed lungs (see Fig.
15.7).
There is loss of
attachments between alveoli and the outer wall of small airways.
in the trachea and bronchi.
• Acquired cystic fibrosis transmembrane conductance regulator
(CFTR) dysfunction.
• Inflammation.
• Infection.
Cigarette smoke predisposes to chronic bronchitis in
several ways.
Sometimes, heavy casts of secretions
and pus fill the bronchi and bronchioles.
Several
factors contribute to its pathogenesis.
• Mucus hypersecretion.
• Underlying pulmonary pathology usually includes both chronic
bronchitis and emphysema.
Once COPD appears, symptoms often wax and wane
over time and are generally worse in the morning.
At one extreme end of the
spectrum lie “pink puffers,” patients in whom emphysema
dominates.
Weight loss is common and can
be so severe as to suggest an occult cancer.
Even with intervention, however,
COPD often progresses and frequently proves fatal.
• Compensatory hyperinflation.
• Obstructive overinflation.
In this condition the lung expands
because air is trapped within it.
A common cause is
subtotal obstruction of an airway by a tumor or foreign
object.
• Bullous emphysema.
15.9), often near the apex.
Rupture of the bullae may give rise to pneumothorax.
• Interstitial emphysema.
One biologically
meaningful and clinically useful way to classify asthma is
based on its triggers.
Atopic Asthma.
Non-Atopic Asthma.
A positive family history of
asthma is less common in these patients.
Drug-Induced Asthma.
Several pharmacologic agents
provoke asthma.
Occupational Asthma.
The
Figure 15.9 Bullous emphysema.
Note the large subpleural bullae
(upper left).
tissue produces interstitial emphysema.
Between
the attacks, patients may be virtually asymptomatic.
These
mediators might yet prove important in certain types of
chronic or non-allergic asthma.
It is thus clear that multiple mediators contribute to the
acute asthmatic response.
Genetic Susceptibility.
Genetic polymorphisms linked to asthma and
other allergic disorders were described in Chapter 6.
Th2 Responses, IgE, and Inflammation.
15.10).
Environmental Factors.
Asthma is a disease of industrial-
ized societies where the majority of people live in cities.
Two ideas, neither wholly satisfying, have been proposed
to explain this association.
Infections do not cause asthma by themselves, but may
be important co-factors.
Clinical Features
A classic acute asthmatic attack lasts up to several hours.
Therapy is based on the severity of the disease.
The Th2
cytokines IL-4, IL-5, and IL-13 are important mediators.
widespread damage to airway walls.
Males with this
condition also tend to be infertile as a result of sperm
dysmotility.
It is a hyperimmune response
to the fungus Aspergillus fumigatus.
Pathogenesis
Obstruction and infection are the major conditions associated
with bronchiectasis.
Sometimes this defect stems from airway obstruction, leading
to distal pooling of secretions.
When tumor or aspiration of
foreign bodies leads to bronchiectasis, the involvement is localized.
The airways are dilated, sometimes up to four times
normal size.
15.12).
The histologic findings vary with the activity and chronicity
of the disease.
In some instances, necrosis destroys the bronchial or bronchiolar
walls and forms a lung abscess.
Diffuse restrictive diseases are
categorized based on histology and clinical features (Table
15.5).
In late stages the fungus may infiltrate the bronchial wall.
Obstructive respira-
tory insufficiency can lead to marked dyspnea and cyanosis.
IPF has
characteristic radiologic, pathologic, and clinical features.
15.13).
The implicated factors are as follows:
• Environmental factors.
Most important among these is
cigarette smoking, which increases the risk of IPF several-
fold.
• Genetic factors.
• Age.
IPF is a disease of older individuals, rarely appearing
before the age of 50 years.
Microscopically, the hallmark
is patchy interstitial fibrosis, which varies in intensity
(Fig.
15.14) and age.
The earliest lesions contain an exuberant
proliferation of fibroblasts (fibroblastic foci).
With time these
areas become more fibrotic and less cellular.
Quite typical is the690 CHAPTER 15 The Lung
survival is about 3.8 years after diagnosis.
Fibroblastic
foci, honeycombing, hyaline membranes, and granulomas are absent.
Figure 15.14 Usual interstitial pneumonia.
The fibrosis is more
pronounced in the subpleural region.
(Courtesy Dr.
In acute exacerbations, DAD may be
superimposed on these chronic changes.
Clinical Features
Patients present with dyspnea and cough of several months’
duration.
They are more likely to be female nonsmokers in
their sixth decade of life.
15.16).
The connective
tissue is all of the same age, and the underlying lung
architecture is normal.
There is no interstitial fibrosis or
honeycomb lung.
The long-term prognosis is
dependent on the underlying disorder.
Most patients are 55 to 75 years
old at presentation.
Hypoxemia, cyanosis, and clubbing
occur late in the course.
The course in individual patients
is unpredictable.
The median
Figure 15.15 Usual interstitial pneumonia.
Fibroblastic focus with fibers
running parallel to surface and bluish myxoid extracellular matrix.
(A) Low power.
(B) High power.
dusts encountered in the workplace, now also includes
disease induced by chemical fumes and vapors.
A
simplified classification is presented in Table 15.6.
• Particle size.
• Particle solubility and cytotoxicity, which are influenced
by particle size.
These tend
to evoke fibrosing collagenous pneumoconioses, such as
is characteristic of silicosis.
This innate immune response amplifies the
intensity and the duration of the local reaction.
The ratio of FEV1 to FVC is normal.
• Ididopathic pulmonary fibrosis is prototypic of restrictive
lung diseases.
This histologic pattern is known as usual interstitial fibrosis.
Dust reduction measures in coal mines around the
globe have drastically reduced its incidence.
Contaminating silica in the coal dust favors the development
of progressive disease.
Coal
workers may also develop emphysema and chronic bronchitis
independent of smoking.
Of these, quartz
is most commonly implicated.
A large produce lesions.
amount of black pigment is associated with dense interstitial fibrosis.
As the disease progresses, these nodules coalesce into hard,
collagenous scars (Fig.
15.18).
Microscopically, the
lesions consist of dense collagen and pigment (Fig.
15.17).The center
of the lesion is often necrotic, most likely due to local ischemia.
Currently, silicosis is
the most prevalent chronic occupational disease in the world.
Both dose and race are important in developing silicosis
Figure 15.18 Advanced silicosis.
Scarring has contracted the upper lobe
into a small dark mass (arrow).
Note the dense pleural thickening.
(Courtesy
Dr.
Asbestos occurs in two distinct geometric forms, serpentine
and amphibole.
The serpentine chrysotile form accounts
for 90% of the asbestos used in industry.
Macrophages, both
Figure 15.19 Several coalescent collagenous silicotic nodules.
(Courtesy
Dr.
Fibrotic lesions may also occur in the hilar lymph nodes
and pleura.
15.19).
Examination of the nodules by polarized
microscopy reveals weakly birefringent silicate particles.
Chest radiographs typically show a fine nodularity in the
upper zones of the lung.
The disease may continue to
worsen even if the patient is no longer exposed.
It is slow
to kill, but impaired pulmonary function may severely limit
activity.
15.21).
Figure 15.21 Asbestos-related pleural plaques.
Large, discrete fibrocalcific
plaques are seen on the pleural surface of the diaphragm.
(Courtesy Dr.
Chest x-ray studies
reveal irregular linear densities, particularly in both lower
lobes.
With advancement of the pneumoconiosis, a honey-
comb pattern develops.
The disease may remain static or
progress to respiratory failure, cor pulmonale, and death.
Asbestosis
complicated by lung or pleural cancer is associated with a
particularly grim prognosis.
The lung
disease is progressive even after exposure stops.
Eye and skin
lesions are next in frequency.
Sarcoidosis usually occurs in adults younger than 40 years
of age but can affect any age group.
The prevalence is higher
in women but varies widely in different countries and
populations.
In contrast, the disease is rare among
the Chinese and Southeast Asians.
Patterns of organ involve-
ment also vary with race.
• Impaired dendritic cell function.
Additionally, there are systemic immunologic abnormali-
ties in individuals with sarcoidosis.
There is
twofold increased risk of lung cancer.
Complications of Therapies
Drug-Induced Lung Diseases.
Cough induced by
angiotensin-converting enzyme inhibitors is very common.
Illicit intravenous drug abuse most often causes lung
infections.
Radiation-Induced Lung Diseases.
It most often
involves the lung within the radiation field and occurs in acute
and chronic forms.
Involved tissues
contain well-formed non-necrotizing granulomas (Fig.
Central necrosis is unusual.
Conse-
quently, corneal opacities, glaucoma, and total loss of vision may
occur.
Muscle involvement is underdiagnosed, since it may be
asymptomatic.
Note subepithelial location of granulomas.
Sarcoidosis follows an unpredictable course.
Overall,
65% to 70% of affected patients recover with minimal or no
residual manifestations.
Twenty percent have permanent
loss of some lung function or some permanent visual impair-
ment.
The lung is a common site of involvement.
The bone marrow is involved in about 20% of cases.
Numerous syndromes are described,
depending on the occupation or exposure of the individual.
Humidifier
or air-conditioner lung is caused by thermophilic bacteria in
heated water reservoirs.
Pet birds and moldy basements
are easily missed unless asked about specifically.
• Most patients have specific antibodies against the causative
antigen in their serum.
Figure 15.23 Hypersensitivity pneumonitis.
Loosely formed interstitial
granulomas and chronic inflammation are characteristic.
hours after exposure and may last for 12 hours to several
days.
They recur with re-exposure.
This
is an acute illness of unknown cause.
It has a rapid onset
with fever, dyspnea, and hypoxemic respiratory failure.
Histology shows diffuse alveolar damage
and many eosinophils.
There is a prompt response to
corticosteroids.
Interstitial fibrosis and organizing pneumonia
are often present.
15.23).
Clinical Features
The clinical manifestations are varied.
It is a common histologic lesion in cigarette smokers.
In its mildest form, it is most often an incidental
finding in the lungs of smokers or ex-smokers.
discussed) and restrictive or interstitial diseases.
Mild peribronchiolar fibrosis is also seen, which expands contiguous
alveolar septa.
Centrilobular emphysema is common but not
severe.
Desquamative interstitial pneumonia is often found in
different parts of the same lung.
15.24).
Interstitial fibrosis, when present, is mild.
Emphysema
is often present.
Cessation of smoking usually
results in improvement.
Imaging of the chest shows characteristic cystic and
nodular abnormalities.
Langerhans cells are immature
dendritic cells with grooved, indented nuclei and abundant
cytoplasm.
They are positive for S100, CD1a, and CD207
(langerin) and are negative for CD68.
Virtually all patients are
cigarette smokers.
Figure 15.24 Desquamative interstitial pneumonia.
Whole-lung lavage is the standard of care
and provides benefit regardless of the underlying defect.
PAP is characterized radiologically by bilateral patchy
asymmetric pulmonary opacifications.
• Autoimmune PAP is caused by autoantibodies that bind
and neutralize the function of GM-CSF.
This
form has an autosomal dominant mode of inheritance
and has a highly variable course.
This
form has an autosomal recessive mode of inheritance.
Death ensues
between 3 and 6 months of age unless lung transplantation
is performed.
15.25).
As a consequence there is a
marked increase in the size and weight of the lung.
15.26).
Sudden death often ensues, largely as a result of the blockage
of blood flow through the lungs.
Death may also be caused
by acute right-sided heart failure (acute cor pulmonale).
15.27).
15.28).
Often,
the apposed pleural surface is covered by a fibrinous exudate.
Such lesions are referred
to as septic infarcts, some of which turn into abscesses.
Figure 15.26 Pulmonary alveolar proteinosis associated with mutation of
the ABCA3 gene.
but also in a wide range of conditions that are associated
with hypercoagulability.
Blood clots that occlude the large
pulmonary arteries are almost always embolic in origin.
Pulmonary embolism causes
more than 50,000 deaths in the United States each year.
Patients
with hip fractures are at particularly high risk.
Rarely, pulmo-
nary embolism may consist of fat, air, or tumor.
Figure 15.28 Acute hemorrhagic pulmonary infarct.
Small emboli are silent or induce only transient chest
pain and cough.
Emboli that lead to
pulmonary infarction may additionally produce fever and
hemoptysis.
An overlying fibrinous pleuritis may produce
a pleural friction rub.
Rarely, other
diagnostic methods, such as ventilation-perfusion scanning,
are required.
Deep vein thrombosis can be diagnosed with
duplex ultrasonography.
Perhaps most important is that a small embolus
may presage a larger one.
Prevention of pulmonary embolism is a major clinical
challenge for which there is no easy solution.
• Antecedent congenital or acquired heart disease (group 2).
• Recurrent thromboemboli (group 4).
• Autoimmune diseases (group 1).
15.29).
See text for details.
Clinical signs
and symptoms in all types become evident only in advanced
disease.
Treatment choices depend on the underlying cause.
Lung transplantation provides definitive
treatment for selected patients.
15.30).
In addition, long-term follow-up shows
that some affected patients develop other immune disorders.
The majority of patients are active
smokers.
(A)
Atheroma-like changes, a finding usually limited to large vessels.
(B)
Marked medial hypertrophy.
(C) Plexiform lesion of small arteries that is
characteristic of advanced pulmonary hypertension.
(Fig.
Pneumonia can be
very broadly defined as any infection of the lung
parenchyma.
Pulmonary antimicrobial defense mechanisms are
described in Chapter 8.
• Accumulation of secretions in conditions such as cystic
fibrosis and bronchial obstruction.
• Pulmonary congestion and edema.
Several other points should be emphasized.
MORPHOLOGY
In the classic case, the lungs are heavy, with areas of red-brown
consolidation.
Often the alveoli
contain hemosiderin-laden macrophages (see Fig.
15.31).
Soon, manifestations of glomerulonephritis
appear, leading to rapidly progressive renal failure.
The
most common cause of death is uremia.
The once dismal
prognosis for this disease has been markedly improved by
intensive plasmapheresis.
Its features are discussed in Chapter 11.
Since the
amount of tissue is small, necrosis and granulomatous
vasculitis might not be present.
Often, a bacterial infection follows an upper respiratory
tract viral infection.
Examination of Gram-stained sputum is an important step
in the diagnosis of acute pneumonia.
Antibodies against the
capsule protect the host from H.
influenzae.
With routine use of H.
influenzae vaccines, the incidence of disease caused by the
b serotype has declined significantly.
By contrast, infections
with nonencapsulated forms, also called nontypeable forms,
are increasing.
H.
Before
a vaccine became widely available, H.
Mycoplasma pneumoniae
Chlamydia spp.
(C.
pneumoniae, C.
psittaci, C.
It may be bacterial or viral.
H.
Finally,
H.
influenzae is the most common bacterial cause of acute
exacerbations of COPD.
It is the second most
common bacterial cause of acute exacerbation of COPD.
Along with S.
pneumoniae and H.
influenzae, M.
catarrhalis
is one of the three most common causes of otitis media in
children.
It is also an
important cause of hospital-acquired pneumonia.
It commonly afflicts debilitated
and malnourished people, particularly chronic alcoholics.
Pseudomonas septicemia is a very
fulminant disease.
It also
causes Pontiac fever, a related self-limited upper respiratory
tract infection.
Organ transplant recipients are particularly susceptible.
Bronchopneumonia Lobar pneumonia
Figure 15.32 Comparison of bronchopneumonia and lobar pneumonia.
15.32).
Patchy consolidation of the lung is the dominant characteristic
of bronchopneumonia (Fig.
15.33).
15.35A).
The lower lobe is
uniformly consolidated.
A
pneumonia (Fig.
Moreover, the same organisms may produce either
pattern depending on patient susceptibility.
In the first stage of congestion,
the lung is heavy, boggy, and red.
15.35A).
15.35B), resulting in a color change
to grayish-brown.
15.35C).
More often it undergoes organization, leaving fibrous thickening
or permanent adhesions.
(A) Acute pneumonia.
Fibrin nets have not yet formed.
(C) Advanced organizing
pneumonia.
The viral genome is composed of eight single-stranded
RNAs, each encoding one or more proteins.
A single subtype of
influenza virus A predominates throughout the world at a
given time.
In this instance, essentially all individuals
are susceptible to the new influenza virus.
Of these, secondary
pneumonias caused by S.
aureus are particularly common
and often life-threatening.
Control of the infection relies on several host mechanisms.
When pleuritis is present it is accompanied by
pleuritic pain and pleural friction rub.
The clinical picture is markedly modified by the admin-
istration of effective antibiotics.
These viruses have tropisms that allow
them to attach to and enter respiratory lining cells.
Hemagglutinin has three major subtypes
(H1, H2, H3), while neuraminidase has two (N1, N2).
Both
proteins are embedded in a lipid bilayer, which constitutes
the influenza virus envelope.
Insight into future pandemics has come from studying
past pandemics.
What then might be the source of the next great pandemic?
One such strain,
type H5N1, has spread throughout the world in wild and
domestic birds.
Fortunately, the transmission of the current
H5N1 avian virus is inefficient.
Diagnostic methods include PCR tests for viral RNA.
Treat-
ment generally focuses on supportive measures.
Although
work is ongoing, a clinically effective and safe vaccine has
yet to be developed.
MORPHOLOGY
All viral infections produce similar morphologic changes.
Lung involvement may be quite patchy or may involve whole
lobes bilaterally or unilaterally.
The affected areas are red-blue
and congested.
Pleuritis or pleural effusions are infrequent.
The
histologic pattern depends on the severity of the disease.
Pre-
dominant is an interstitial inflammatory reaction involving
the walls of the alveoli.
15.4).
Eradication of the infection is followed by reconstitution
of the normal lung architecture.
Characteristic viral cytopathic changes are
described in Chapter 8.
Clinical Features
The clinical course of viral pneumonia is extremely varied.
Many cases masquerade as severe upper respiratory tract
infections or as chest colds.
Even individuals with well-
developed atypical pneumonia have few localizing symp-
toms.
Cough may be absent, and the major manifestations
may consist only of fever, headache, and myalgia.
Viral pneumonias are usually mild and resolve spontane-
ously without any lasting sequelae.
The most common organisms isolated are methicillin-resistant
S.
aureus and P.
aeruginosa.
These patients have a higher
mortality than those with community-acquired pneumonia.
Patients on mechanical ventilation are at particularly high
risk.
Gram-positive cocci (mainly S.
aureus, and
a host of gram-negative organisms.
• Antecedent primary lung infection.
Postpneumonic abscess
formations are usually associated with S.
aureus, K.
pneumoniae, and pneumococcus.
Posttransplant or oth-
erwise immunosuppressed individuals are at special risk.
• Septic embolism.
• Neoplasia.
• Miscellaneous.
These are referred to as primary cryptogenic
lung abscesses.
KEY CONCEPTS
ACUTE PNEUMONIA
• S.
• Other common causes of acute bacterial pneumonias in the
community include H.
influenzae and M.
catarrhalis (both associ-
ated with acute exacerbations of COPD), S.
aureus (usually
secondary to viral respiratory infections), K.
pneumoniae
(observed in patients who are chronic alcoholics), P.
aeruginosa
(seen in persons with cystic fibrosis and in those with neutro-
penia), and L.
These patients have abnormal gag and swallowing reflexes
that predispose to aspiration.
In patients who survive, lung
abscess is a common complication.
MORPHOLOGY
Abscesses vary in diameter from a few millimeters to large cavities
of 5 to 6 cm (Fig.
15.36).
They may affect any part of the lung
and may be single or multiple.
Abscesses that712 CHAPTER 15 The Lung
Histoplasmosis
H.
It is endemic along the Ohio and Mississippi
rivers and in the Caribbean.
Like M.
tuberculosis, H.
capsulatum is an intracellular pathogen that is found mainly
in phagocytes.
The pathogenesis of histoplasmosis is incompletely
understood.
The portal of entry is virtually always the lung.
Fever, chest pain, and weight loss are
common.
Clubbing of the fingers and toes may appear.
The course of abscesses is variable.
With antimicrobial
therapy, most resolve, leaving behind a scar.
Tuber-
culosis of the lung and other organs is described in Chapter
8.
Chronic pneumonias caused by fungi are discussed here.
Figure 15.36 Cut surface of lung showing two abscesses.
(Courtesy Dr.
M.
Septic emboli and pyemic
abscesses are multiple and may affect any region of the lungs.
Superimposed saprophytic infections are prone to develop within
the necrotic debris.
In chronic cases considerable fibroblastic
proliferation produces a fibrous wall.
15.37A).
15.37B).
The majority
of cases resolve spontaneously.
Progressive disease or disease
in immunocompromised patients is treated with antifungal
agents.
Blastomycosis
Blastomyces dermatitidis is a soil-inhabiting dimorphic fungus.
There are three clinical forms: pulmonaryPulmonary infections 713
A B
Figure 15.37 Histoplasmosis.
(A) Laminated Histoplasma granuloma of the lung.
One reason for
the infectivity of C.
immitis infection, which frequently involves the skin and
meninges.
MORPHOLOGY
In the normal host, the lung lesions of blastomycosis are suppurative
granulomas.
Macrophages have a limited ability to ingest and kill
B.
dermatitidis, and the persistence of the yeast cells leads to the
recruitment of neutrophils.
In tissue, B.
dermatitidis is a round,
5- to 15-µm yeast cell that divides by broad-based budding.
It
has a thick, double-contoured cell wall, and visible nuclei (Fig.
15.38).
MORPHOLOGY
Within macrophages or giant cells, C.
15.39).
Rare progressive C.
immitis disease involves the lungs, meninges,
skin, bones, adrenals, lymph nodes, spleen, or liver.
At all these
sites, the inflammatory response may be purely granulomatous,
pyogenic, or mixed.
Indeed, more than 80% of people in endemic
A B
Figure 15.38 Blastomycosis.
(A) Rounded budding yeasts, larger than neutrophils, are present.
Note the characteristic thick wall and nuclei (not seen in
other fungi).
The implicated
organisms include S.
pneumoniae, S.
aureus, H.
influenzae,
and gram-negative rods.
• Not all pulmonary infiltrates in HIV-infected individuals are
infectious in etiology.
• The CD4 + T-cell count determines the risk of infection with
specific organisms.
Figure 15.39 Coccidioidomycosis.
Intact and ruptured spherules are seen.
Mortality from these opportunistic
infections is high.
The specific infections
are discussed in Chapter 8.
aeruginosa, Mycobacterium species, L.
jiroveci, Candida species, Aspergillus species, the Phycomycetes,
and Cryptococcus neoformans).
The transplanted lung is subject to two
major complications: infection and rejection.
In the early posttransplant period (the
first few weeks), bacterial infections are most common.
Most infections occur in the third
to twelfth month after transplantation.
P.
Patients present with fever,
dyspnea, cough, and radiologic infiltrates.
An adjacent pulmonary artery is
normal.
(Courtesy Dr.
Globally, in 2018 there were an estimated
2.1 million new cases and 1.8 million lung cancer deaths.
Each year, lung cancer kills more people than colon, breast,
and prostate cancer combined.
Only
2% of all cases occur before the age of 40.
However, the decrease in smoking among
women has lagged behind that of men.
In addition, there are
other genetic and environmental factors.
15.40).
Bronchiolitis obliterans is patchy and
therefore difficult to diagnose via transbronchial biopsy.
Bronchi-
ectasis and pulmonary fibrosis may also develop with long-standing
chronic rejection.
Its pro-
gress may be slowed or even halted for some time, but
it cannot be reversed.
Tobacco Smoking.
For unclear
reasons, it appears that women are more susceptible to
carcinogens in tobacco than men.
Pipe and cigar
smokers also incur an elevated risk, albeit only modestly.
What of heavy smokers who never develop cancer?
Industrial Hazards.
High-dose ionizing radiation is carcinogenic.
Asbestos
exposure also increases the risk for lung cancer development.
The latent period before the development of lung cancer is
10 to 30 years.
Air Pollution.
It may do so through several different mechanisms.
Acquired Mutations.
This subtype is also commonly
associated with amplification of genes of the MYC family.
Lung Cancer in Never-Smokers.
The WHO estimates that
25% of lung cancer worldwide occurs in never-smokers.
This percentage is probably closer to 10% to 15% in Western
countries.
Precursor (Preinvasive) Lesions.
The basis for this
change is unclear.
These have a far better
prognosis than invasive carcinomas of the same size.
Squamous cell carcinoma is more common in men and
is strongly associated with smoking.
Precursor lesions that give
rise to invasive squamous cell carcinoma are well characterized.
15.44).
15.45), but the lesion is asymptomatic and undetect-
able on radiographs.
Eventually, an invasive squamous cell carcinoma
appears.
The tumor may then follow a variety of paths.
15.46) into the adjacent carina or
mediastinum.
As in almost all types of lung
cancer, the neoplastic tissue is gray-white and firm to hard.
Sometimes these necrotic foci cavitate.
Mitotic activity
is higher in poorly differentiated tumors.
15.44).
The epithelium is
cuboidal, and there is mild interstitial fibrosis.
15.41).
It can be single
or multiple and can be in the lung adjacent to invasive tumor or
away from it.
15.42).
They vary histologically from
Figure 15.42 Adenocarcinoma in situ, mucinous subtype.
(B) Well-differentiated squamous cell carcinoma showing keratinization (arrow).
(C) Small cell carcinoma.
There are
islands of small, deeply basophilic cells and areas of necrosis.
(D) Large cell carcinoma.
The tumor cells are pleomorphic and show no evidence of
squamous or glandular differentiation.
chromatin (salt and pepper pattern), and absent or inconspicuous
nucleoli (see Fig.
15.43C).
The cells are round, oval, or spindle-
shaped, and nuclear molding is prominent.
Necrosis is
common and often extensive.
15.43D).
Combined Carcinoma.
Squamous dysplasia may progress through the stages of mild, moderate, and severe dysplasia.
(A–E, Courtesy Dr.
Adi Gazdar, Department of Pathology, University of Texas, Southwestern Medical School, Dallas, Tex.
Note the size of the
tumor cells compared with normal neutrophils (small arrow).
Figure 15.46 Lung carcinoma.
The gray-white tumor infiltrates the lung
parenchyma.
Distant spread of lung carcinoma occurs through both lymphatic
and hematogenous pathways.
Metastasis may be the first
manifestation of an underlying occult pulmonary lesion.
The liver (30% to
50%), brain (20%), and bone (20%) are other favored sites of
metastases.
Secondary Pathology.
Partial obstruction may cause
marked focal emphysema; total obstruction may lead to
atelectasis.
Pulmonary abscesses sometimes call attention
to an otherwise silent carcinoma.
Such tumors
are also referred to as Pancoast tumors.
Staging.
Overall, the outlook is
poor for most patients.
other tyrosine kinases with specific kinase inhibitors prolongs
survival.
Paraneoplastic Syndromes.
• Each of these is clinically and genetically distinct.
The other carcinomas may
be curable by surgery if limited to the lung.
Adenocarcinoma also is the most common
subtype in non-smokers.
• Lung cancers, particularly small cell lung carcinomas,often cause
paraneoplastic syndromes.
Carcinoid Tumors
Carcinoid tumors represent 1% to 5% of all lung tumors.
Approxi-
mately 20% to 40% of patients are nonsmokers.
Approximately,
10% of bronchial carcinoids give rise to this syndrome.
15.47A).
They rarely exceed 3 to 4 cm in diameter.
Most are confined to
the mainstem bronchi.
Peripheral tumors are solid and nodular.
15.47B).Typical carcinoids have fewer
A B
Figure 15.47 Bronchial carcinoid.
(A) Carcinoid growing as a spherical mass (arrow) protruding into the lumen of the bronchus.
(B) The tumor cells have
small, rounded, uniform nuclei and moderate amounts of cytoplasm.
(Courtesy Dr.
Most are solitary, less
than 3 to 4 cm in diameter, and well circumscribed.
Pul-
monary hamartoma consists of nodules of connective tissue
intersected by epithelial clefts.
Cartilage is the most common
connective tissue, but there may also be fibrous tissue and
fat.
The clefts are lined by ciliated or nonciliated epithelium
(Fig.
15.48).
The disease tends
to be slowly progressive over a period of several decades.
Only lung
transplantation is curative.
Presenting symptoms include fever, cough, chest pain,
and hemoptysis.
It may also be asymptomatic.
Imaging
studies usually show a round, well-defined, peripheral mass.
Calcification is present in about a quarter of cases.
Grossly,
the lesion is firm, 3 to 10 cm in diameter, and grayish white.
They often invade or compress the lungs.
Table 15.12 lists
the most common tumors in the various compartments of
the mediastinum.
Specific tumor types are discussed in
appropriate sections of this book.
Metastatic Tumors
The lung is the most common site of metastatic neoplasms.
Esophageal carcinoma and mediastinal
lymphoma may also invade the lung by direct extension.
MORPHOLOGY
The pattern of metastatic spread to the lungs is quite variable.
15.49).
Figure 15.48 Pulmonary hamartoma.
The sanguineous
exudate must be differentiated from hemothorax (discussed
later).
The fluid is clear and
straw colored.
Hydrothorax may be unilateral or bilateral,
depending on the underlying cause.
The escape of blood into the pleural cavity is known as
hemothorax.
Chylothorax is an accumulation of milky fluid, usually of
lymphatic origin, in the pleural cavity.
Chyle is milky white
because it contains finely emulsified fats.
(Courtesy Dr.
Secondary infections and
inflammations are particularly common findings at autopsy.
It may be spontaneous, traumatic, or
therapeutic.
Recurrent attacks are
common and can be quite disabling.
Pneumothorax may cause marked respiratory distress
due to collapse and atelectasis of the lung.
Pleural Tumors
The pleura may be involved by primary or secondary tumors.
Secondary metastatic involvement is far more common than
are primary tumors.
The most frequent metastatic malignan-
cies arise from primary neoplasms of the lung and breast.
For this reason, careful
cytologic examination of the sediment is of considerable
diagnostic value.
The tumor is often attached to the pleural
surface by a pedicle.
15.50).
Figure 15.50 Solitary fibrous tumor.
Cut surface is solid with a whorled
appearance.
(Courtesy Dr.
Justine A.
The solitary
fibrous tumor has no relationship to asbestos exposure.
Thoracic mesothelioma arises from
either the visceral or the parietal pleura.
Asbestos bodies (see Fig.
15.20) are found in increased
numbers in the lungs of patients with mesothelioma.
Another
marker of asbestos exposure, the asbestos plaque, has been
previously discussed (see Fig.
15.21).
15.51).
15.52A).
Immunohistochemi-
cal stains are very helpful in differentiating it from pulmonary
adenocarcinoma.
Most mesotheliomas show strong positivity for
keratin proteins, calretinin (Fig.
The biphasic type of mesothelioma contains
both epithelioid and sarcomatoid patterns (see Fig.
15.52B).
B
Figure 15.52 Histologic variants of malignant mesothelioma.
(A)
Epithelioid type.
(B) Mixed type, stained for calretinin (immunoperoxidase
method).
(Courtesy Dr.
Fifty
percent of patients die within 12 months of diagnosis, and
few survive longer than 2 years.
Figure 15.51 Malignant mesothelioma.
Global Initiative for Asthma.
Global strategy for asthma management and
prevention.
2019.
Available from: www.ginasthma.org.
Pocket guide also available].
Israel E, Reddel HK: Severe and difficult-to-treat asthma in adults, N
Engl J Med 377:965, 2017.
Papi A et al: Asthma, Lancet 391:783, 2018.
Emerging therapies, controversies,
and uncertainties in asthma management are also discussed].
Lederer DJ et al: Idiopathic pulmonary fibrosis, N Engl J Med 378:1811,
2018.
Obstructive Pulmonary Diseases
Global Initiative for Chronic Obstructive Lung Disease.
Global Strategy
for the Diagnosis, Management and Prevention of COPD.
2019.
Available
from: http://goldcopd.org.
A pocket guide is also available].
Rabe KF et al: Chronic obstructive pulmonary disease, Lancet 389:1931,
2017.
[An excellent review of epidemiology, causes, pathophysiology, and
treatment of COPD].
Boucherat O et al: Bridging lung development with chronic obstructive
pulmonary disease.
Jones RL et al: Airway remodelling in COPD: it’s not asthma!, Respirology
21:1347, 2016.
Perret JL et al: Coal mine dust lung disease in the modern era, Respirology
22:662, 2017.
Radiation Pneumonitis
Bledsoe TJ et al: Radiation pneumonitis, Clin Chest Med 38:201, 2017.
Sarcoidosis
Esteves T et al: Is there any association between sarcoidosis and infec-
tious agents?
A systematic review and meta-analysis, BMC Pulm
Med 16:165, 2016.
O’Regan A, Berman JS: Sarcoidosis, Ann Intern Med 156:ITC5-1, 2012.
Eosinophilic Lung Diseases
Cottin V: Eosinophilic lung diseases, Clin Chest Med 37:535, 2016.
[ePub ahead of
print].
[Review of the pathogenesis, classification, and treatment of pulmonary
alveolar proteinosis].
[Review of the most common inflammatory conditions involving
pulmonary vessels].
[Excellent review of salient features
of various bacterial pneumonias].
[Annual report
of registry data including numbers of transplants, indications, and outcomes].
McIntyre A et al: Lung cancer—a global perspective, J Surg Oncol
115:550, 2017.
Thakrar R et al: Preinvasive disease of the airway, Cancer Treat Rev
58:77, 2017.
Lingen • Nicole A.
Caries is the principal cause of tooth
loss before age 35.
The former reflects improved oral hygiene and, in the United
States, drinking water fluoridation.
It may occur at any age but is most prevalent and
severe in adolescence.
If not removed, plaque can become mineralized to form
calculus (tartar).
This leads to loosen-
ing and eventual tooth loss.
Figure 16.1 Aphthous ulcer.
Single ulceration with an erythematous halo
surrounding a yellowish fibrinopurulent membrane.
color and frequently ulcerated (Fig.
16.3).
In some cases, rapid
growth can be alarming and elicit concerns of malignancy.
Complete
surgical excision is the definitive treatment for these lesions.
Peripheral ossifying fibromas
appear as red, ulcerated, nodular lesions of the gingiva.
The peak incidence is in young females.
It is generally covered by intact gingival mucosa,
but may be ulcerated.
Although not encapsulated, the lesions are usually well
delimited and easily excised.
16.1).
16.2).
It is
thought to be a reactive process induced by repetitive trauma.
Treatment is complete surgical excision.
This exophytic inflammatory lesion is red to purple in
Figure 16.2 Irritation fibroma.
Factors that
influence the likelihood of infection include the strain of
C.
albicans, oral microbiome composition, and the individual’s
immune status.
Oral candidiasis can be pseudomembranous,
erythematous, or hyperplastic.
Figure 16.3 Pyogenic granuloma.
Erythematous and hemorrhagic
exophytic mass arising from the gingival mucosa.
In children, primary infections are most
common between 2 and 4 years of age.
These lesions can
be accompanied by lymphadenopathy, fever, and anorexia.
In adults, acute herpes pharyngitis is common and may
recur.
Some of the more common disease associations
and their oral manifestations are cited in Table 16.1.
Only
hairy leukoplakia is considered in more detail here.
in immunocompromised patients.
Unlike
thrush, the lesion cannot be scraped off.
EBV RNA transcripts and proteins can be detected within
the lesional cells.
Superimposed candidal infection can add
to the “hairiness.”
chapters.
16.4).
Head and neck squamous
cell carcinoma (HNSCC) is the sixth most common neoplasm
in the world.
The pathogenesis of SCC is multifactorial.
• In India and Asia, the chewing of betel quid and paan
is a major regional predisposing influence.
HPV-associated SCC of the oropharynx has
increased more than twofold over the past two decades.
Unlike the oropharynx, HPV-associated
SCC of the oral cavity is relatively uncommon.
Prognosis is dependent on a number of factors including
the specific etiology of SCC.
Long-term survival is better in patients with HPV-
positive SCC.
Notably, second primary
A
B
Figure 16.4 Erythroplakia.
(A) Red discoloration of the maxillary gingiva.
(B) Red lesion of the mandibular alveolar ridge.
Biopsy of both lesions
revealed carcinoma in situ.
16.5A).
16.5B).736 CHAPTER 16 Head and Neck
A B
Figure 16.5 Leukoplakia.
(A) Clinical appearance of leukoplakia is highly variable.
In this example, the lesion is relatively smooth and thin with well-
demarcated borders.
tumors occur at 3% to 7% per year, the highest rate of
among all malignancies.
The second primary tumors are commonly
fatal.
Molecular Biology of Squamous Cell Carcinoma.
A number
of important findings have come from these studies.
Finally, the mutations identified
in HPV-positive and HPV-negative tumors were different.
For example, HPV-negative tumors harbored more somatic
mutations than HPV-positive tumors.
Either pattern may be superimposed on a background
of apparent leukoplakia or erythroplakia.
16.6A).
16.7B).
However, further testing, using PCR or in situ hybridization
(ISH) (Fig.
16.7C), may be required in certain cases.
In contrast to the rest of the skeleton,
epithelial-lined cysts are common in the jaws.
Complete surgical
excision is curative.
Treatment requires complete
excision because of locally aggressive behavior.
Recurrence
rates for inadequately removed lesions can be as high as
60%.
lack obvious surface mucosal lesions but are accompanied by
significant cervical lymphadenopathy.
16.6B).
Keratinizing SCCs range from well-differentiated to anaplastic,
and sometimes sarcomatoid, tumors.
SCC tends to infiltrate locally before metastasizing.
The
routes of extension depend on the primary site.
16.7A).
(A) Clinical appearance demonstrating ulceration and induration of the oral mucosa.
Some are true
neoplasms (both benign and malignant), and others are more
likely hamartomas.
The two most common and clinically significant
tumors are odontoma and ameloblastoma.
(A) Histologic
appearance demonstrating nests and cords of basaloid appearing cells.
(B) Immunohistochemistry demonstrating strong nuclear and cytoplasmic
tumor cell staining p16.
(C) In situ hybridization for high-risk human
papillomavirus E6 and E7 mRNA expression.
The radicular cyst is a common inflammatory lesion found
at the tooth apex.
It is
cystic, slow growing, and locally invasive with a typically
indolent course.
Treatment requires wide surgical resec-
tion to prevent recurrence.
is tooth destruction by acid end-products of bacterial sugar
fermentation.
• Gingivitis is a common, reversible inflammation of the mucosa
surrounding the teeth.
It is associated with poor oral hygiene and altered oral
microbiota.
• Aphthous ulcers are painful superficial ulcers of unknown
etiology.
• Fibromas and pyogenic granulomas are common reactive lesions
of the oral mucosa.
• The majority of oral cavity and oropharyngeal cancers are
SCCs.
Nasal Polyps.
16.8).
In
the absence of bacterial infection, the mucosal surface is
intact, but it may become ulcerated.
When multiple or large,
nasal polyps may encroach on the airway and impair sinus
drainage.
Chronic Rhinitis.
Superficial desquama-
tion or ulceration of the mucosal epithelium is common.
Inflammatory infiltrates include variable numbers of neu-
trophils, lymphocytes, and plasma cells.
Infections may
extend into the sinuses.
Sinusitis.
The resulting mucosal edema impairs sinus drainage and
may result in empyema of the sinus.
Outflow obstruction
occurs most often in the frontal and, less commonly, anterior
ethmoid sinuses.
This may occasionally lead to mucus
accumulation, producing a so-called mucocele.
Acute sinusitis may progress to chronic sinusitis, particu-
larly when drainage is disrupted.
These are most often viral in origin, but can be complicated
by superimposed bacterial infections.
Inflammatory Lesions
Infectious Rhinitis.
Infectious rhinitis, also known as the
common cold, is caused by one or more viruses.
These changes may extend, to produce pha-
ryngotonsillitis.
Fortunately, these
infections clear rapidly.
As the saying goes, “in a week if
treated, but in 7 days if ignored.”
Allergic Rhinitis.
It affects 20% of the US population.
The allergic reaction is740 CHAPTER 16 Head and Neck
A B
Figure 16.8 (A) Nasal polyps.
Low-power magnification showing edematous stroma lined by epithelium.
largely composed of normal oral microbiome components,
is present in most cases.
Fungi may cause severe chronic
sinusitis (e.g., in mucormycosis), especially in diabetic
patients.
Spread into the
cranial vault can cause septic thrombophlebitis within a
dural venous sinus.
Nasopharyngeal Angiofibroma.
NUT Midline Carcinoma.
Nasopharyngeal Carcinoma.
of choice.
16.9).
Sinonasal (Schneiderian) Papilloma.
Sinonasal papillomas are most
common in males between 30 and 60 years of age.
The
endophytic form may invaginate into the underlying stroma
(Fig.
16.10).
Malignant transformation occurs in approximately
10% of cases.
Most endophytic sinonasal papillomas have
EGFR gene mutations.
The remaining cases generally harbor
HPV DNA, often low-risk types 6 and 11.
Olfactory Neuroblastoma (Esthesioneuroblastoma).
The age distribution is bimodal, with
peaks at 15 and 50 years.
Patients typically present with nasal
obstruction and/or epistaxis.
16.11).
A fibrillary matrix, representing tangled neu-
ronal cell processes, is often present.
Consistent with their
Figure 16.10 Inverted papilloma.
The cells appear to swirl around a blood-filled vascular channel.
In the United States, nasopharyn-
geal carcinomas are rare in all age groups.
16.12B).
Abundant,
normal-appearing lymphocytes, predominantly T cells, infiltrate
the tumors.
16.12C) or immunohistochemistry,
respectively.
C
Figure 16.12 Nasopharyngeal carcinoma, nonkeratinizing undifferentiated
type.
(B) The syncytial clusters of malignant epithelium are infiltrated by
benign lymphocytes.
(C) In situ hybridization for EBER-1, a small nuclear
RNA encoded by Epstein-Barr virus.
standard treatment and results in an overall 5-year survival
of approximately 60%.
LARYNX
The most common disorders of the larynx are inflammatory.
The larynx may also be affected in
systemic infections, such as tuberculosis and diphtheria.
16.13).
Despite this, the risk of developing cancer in these lesions
is almost nonexistent.
By convention, vocal cord nodules
are bilateral and polyps are unilateral.
Adults are most often
affected.
The latter may be variably fibrotic, fibrinous, or highly
vascularized.
Nodules on opposing vocal cords may impinge
on each other and cause ulceration.
16.13).
The lesions are caused by HPV types
6 and 11 acquired via the maternal birth canal.
They fre-
quently recur but only rarely transform to SCC.
Hyperplasia-Dysplasia-Carcinoma Sequence.
16.13 and 16.14).
Nondysplastic hyperplasias have almost no potential for
malignant transformation.
Histologic evaluation is the only way
to grade dysplasia.
Laryngeal carcinoma is most often related to tobacco
smoke; risk is proportional to exposure.
Prior to malignant
transformation, epithelial changes frequently regress after
smoking cessation.
Alcohol synergizes with tobacco to
increase risk substantially.
MORPHOLOGY
About 95% of laryngeal carcinomas are typical SCCs.
16.14).
Laryngeal carcinoma presents most commonly in men
within the sixth decade of life.
The initial manifestation is
often persistent hoarseness, dysphagia, and dysphonia.
Prognosis is directly related to clinical stage.
Figure 16.14 Laryngeal carcinoma.
Note the large, ulcerated, fungating
lesion involving the right vocal cord and pyriform sinus.
• Laryngeal SCC is linked to smoking and alcohol use and is
most prevalent in older males.
Ears
Although they rarely shorten life, disorders of the ear often
impact its quality.
Paragangliomas are discussed later.
INFLAMMATORY LESIONS
Acute and chronic otitis media occur most often in infants and
children.
The origin is typically viral infection that induces
a serous exudate.
Superimposed bacterial infection, most
frequently by Streptococcus pneumoniae, nontypeable H.
influenzae, or Moraxella catarrhalis, can lead to suppurative
inflammation.
Repeated bouts of acute otitis media with failure of resolu-
tion lead to chronic disease.
The causative agents are usually
Pseudomonas aeruginosa, S.
aureus, fungus, or, in some cases,
a polymicrobial infection.
In individuals with diabetes, otitis media caused by P.
Cholesteatomas are non-neoplastic, cystic lesions asso-
ciated with chronic otitis media.
Cholesterol spicules may be
present.
Both ears are usually affected.
At first, there is fibrous ankylosis of the footplate.
This often
occurs in the early decades of life.
Over time, bony over-
growth anchors the footplate into the oval window.
The
severity of the hearing loss reflects the degree of immobiliza-
tion.
Over time the fibrosis is replaced
by dense new bone anchoring the footplate of the stapes.
These
tend to occur in elderly men and are associated with sun
exposure.
Despite local
invasion, basal cell carcinomas and SCCs involving the pinna
rarely spread.
KEY CONCEPTS
EARS
• Infections of the ear are common in children and typically viral
in etiology.
What remains to be considered here are a few uncommon
lesions unique to the neck.
The fibrous cyst
walls typically contain lymphoid tissue with prominent
germinal centers.
The cysts are readily excised.
Similar
lesions may appear in the parotid gland or oral cavity beneath
the tongue.
Branchial cysts do not undergo malignant
transformation.
Most cystic SCCs in the neck are metastases
from cancers of the upper airways or digestive tract.
Transitional epithelial differentiation patterns also
occur.
The fibrous cyst wall often includes lymphoid
aggregates or thyroid remnants.
Malignant transformation
of the lining epithelium is exceedingly rare.
Adrenal medullary pheochromo-
cytomas are the most common paraganglioma (Chapter 24).
Approximately 70% of extra-adrenal paragangliomas occur
in the head and neck.
Interestingly, the incidence of these
tumors is greater in people living at high altitudes.
These are innervated by
the parasympathetic nervous system and only rarely
produce catecholamines.
MORPHOLOGY
The carotid body tumor is a typical parasympathetic paragan-
glioma.
16.15).
There is little cellular pleomorphism, and mitoses are
scant.
A
B
Figure 16.15 Carotid body tumor.
(A) Low-power view showing tumor
clusters separated by septa (zellballen).
The septae are marked by
capillaries containing bright red blood cells.
(B) Immunohistochemistry
demonstrating positivity for chromogranin in the tumor cells.
dehydrogenase genes) typically involve the head and neck.
About 50% ultimately prove
fatal, largely because of infiltrative growth.
• Seventy percent of extra-adrenal paragangliomas occur in the
head and neck.
They commonly occur singly
and sporadically but also may be familial.
involves other glandular organs such as the pancreas and
testes (Chapter 8).
Mucocele.
Mucoceles are most often found on the lower
lip as the result of trauma (Fig.
16.16B).
Sialolithiasis and Nonspecific Sialadenitis.
aureus and Streptococcus
viridans following ductal obstruction by stones (sialoli-
thiasis).
In
Sjögren syndrome, inflammatory enlargement of the salivary
glands may also occur.
The most prevalent form
of sialadenitis is the mucocele.
(A) Fluctuant fluid-filled lesion on the lower lip subsequent to trauma.
Inflammation causes painful enlargement and,
sometimes, a purulent ductal discharge.
Disease is almost
always unilateral and involves a single gland.
These will be
the focus of the discussion that follows.
Salivary gland neoplasms represent less than 2% of all
tumors in humans.
There is a slight
female predominance overall, but this can vary with histol-
ogy.
Little is known about the origin of pleomorphic adenomas,
but radiation exposure increases risk.
Equally uncertain is
the histogenesis of the various components.
16.17).
These may lead to recurrences if the tumor is merely enucleated.
The dominant histologic feature is morphologic heterogeneity.
16.18).
In other instances, there may be strands or
sheets of myoepithelial cells.
Islands of well-differentiated squamous
epithelium may also be present.
The rate of recurrence following
parotidectomy is about 4%.
Recurrences occur months to
years after surgery.
Cancers are usually adenocarcinomas or undifferentiated
carcinomas.
(A) Slowly enlarging neoplasm in the parotid gland of many years’ duration.
It is unique in that it arises almost exclu-
sively in the parotid gland.
The risk is increased
eightfold in smokers.
Most Warthin tumors are unifocal,
but about 10% are multifocal and 10% bilateral.
(A) Low-power view showing epithelial and lymphoid elements.
Note the lymphoid follicular germinal center beneath the
epithelium (arrow).
the outer layer (Fig.
Secretory cells
dispersed in the inner layer account for secretions within the
dilated lumen.
Foci of squamous metaplasia may be present.
and frequently contain small, mucin-containing cysts.
Accordingly, mucoepidermoid carci-
nomas are subclassified as low, intermediate, or high grade.
A
MORPHOLOGY
B
Mucoepidermoid carcinomas can grow as large as 8 cm in diameter.
(A) Low-power view showing
sheets and microcysts containing cells of varying morphologies.
Low-grade tumors
may invade locally and recur in about 15% of cases, but
they rarely metastasize.
The 5-year survival rate is more
than 90%.
Up to 30% recur and 30% metastasize to distant
sites, yielding a 5-year survival of only 50%.
Adenoid cystic carcinomas.
Among major salivary
glands, parotid and submandibular glands are most com-
monly affected.
16.21A).
Less common histologic patterns are tubular and solid.
Figure 16.21 Adenoid cystic carcinoma.
(A) Three typical growth
patterns including cribriform (left), tubular (center), and solid (right).
(B) Perineural invasion by adenoid cystic carcinoma.
The neoplastic cells are
organized into sheets, microcysts, glands, follicles, or papillae.
16.21B).
Acinic cell carcinomas.
Most develop in the parotid glands,
with the remainder arising in the submandibular glands.
Like
Warthin tumors, acinic cell carcinomas can be bilateral or
multicentric.
The clinical course of acinic cell carcinomas reflects the
degree of cytologic pleomorphism.
Although recurrence is
uncommon after resection, 10% to 15% of tumors metastasize
to lymph nodes.
The survival rate is approximately 90% at
5 years and 60% at 20 years.
(B) High-power image of tumor cells with purple cytoplasmic granules and monotonous round nuclei.
Neville BW, Damm DD, Allen CM et al: Oral and maxillofacial pathology,
ed 4, 2016, Elsevier.
[A comprehensive
TCGA manuscript that defines the mutational landscape of head and neck
cancer].
El-Naggar AK, Chan JKC, Grandis JR et al: Tumors of salivary glands,
Chapter 7.
In WHO classification of head and neck tumors, ed 4, 2017,
WHO, IARC, pp 159–201.
Most of the lesions are incompatible
with survival without prompt surgical repair.
17.1A).
17.1B).
In other cases a fistula can be present without
atresia (Fig.
17.1C).
This results in either partial or
complete obstruction.
Omphalocele is often associated with other birth defects
as well as chromosomal abnormalities.
Surgical repair of omphalocele and
gastroschisis is generally successful.
AB C
Figure 17.1 Esophageal atresia and tracheoesophageal fistula.
(A) Blind
upper and lower esophagus with thin cord of connective tissue linking the
two segments.
(B) Blind upper segment with fistula between lower segment
and trachea.
These are, technically, pseudodiverticula, but are
generally referred to simply as divericula.
They occur most
often in the sigmoid colon (discussed later).
PYLORIC STENOSIS
Pyloric stenosis may be either congenital or acquired.
The
most common congenital form is congenital hypertrophic
pyloric stenosis.
Turner syndrome and trisomy
18 also confer an increased risk.
Diagnosis is primarily by
ultrasonography.
Edema and inflammatory changes in the mucosa and
submucosa may aggravate the narrowing.
Surgical splitting
of the muscularis (myotomy) is curative.
ECTOPIA
Ectopic tissues (developmental rests) are common in the
GI tract.
Ectopic pancreatic tissue occurs less frequently
and is found in the esophagus or stomach.
These nodules
are most often asymptomatic but may produce local damage
and inflammation.
Because rests may be present within any layer
of the gastric wall, they can mimic invasive cancer.
This solitary diverticulum
extends from the antimesenteric side of the bowel (Fig.
17.2).
Hirschsprung disease occurs in approxi-
mately 1 in 5000 live births.
This produces a
Figure 17.2 Meckel diverticulum.
A B
Figure 17.3 Hirschsprung disease.
(Courtesy Dr.
Even after suc-
cessful surgery, it may take years to attain normal bowel
function and continence.
The rectum is always affected, but the length of the additional
involved segments varies widely.
The aganglionic region may have a grossly normal or contracted
appearance.
In contrast, the normally innervated proximal colon
undergoes progressive dilation (Fig.
• Atresia and fistulae are developmental anomalies that typically
present at birth.
• Stenosis may be developmental or acquired.
Both forms are
characterized by a thickened wall and partial or complete luminal
obstruction.
Acquired forms are often due to inflammatory
scarring.
Omphalocele and gas-
troschisis refer to ventral herniation of abdominal organs.
• Ectopia refers to normally formed tissues at an abnormal site.
Obstruc-
tion or constipation follows, often with visible but ineffective
peristalsis.
The major threatsEsophagus 757
involution of the vitelline duct.
It is a frequent site of gastric
ectopia, which may result in peptic injury and occult bleeding.
The
defect, which always involves the rectum, extends proximally
for variable distances.
This can be impeded
by physical or functional obstruction.
The latter results from
disruption of coordinated peristalsis after swallowing.
Esophageal dysmotility falls into three principal patterns.
Manometry is, however, required for diagnosis.
Unlike nutcracker
esophagus, these contractions are of normal amplitude.
In contrast,
malignant strictures are often associated with weight loss.
Esophageal mucosal webs are uncommon ledge-like
mucosal protrusions.
Symptoms
include dysphagia, difficulty in belching, and chest pain.
The cause is unknown;
rare familial cases have been described.
Duodenal, colonic, and ureteric myenteric plexuses can also
be affected in Chagas disease.
transmural tearing and rupture of the distal esophagus.
This
catastrophic event produces severe mediastinitis and generally
requires surgical intervention.
Esophageal infections in otherwise healthy individuals
are most often due to herpes simplex virus.
Among fungi,
candidiasis is most common, although mucormycosis and
aspergillosis also occur.
These do not generally require
surgical intervention, and healing tends to be rapid and
complete.
Infection by fungi or bacteria can either cause injury or
complicate a preexisting ulcer.
The endoscopic appearance frequently indicates the cause of
viral esophagitis.
Herpesviruses typically cause punched-out ulcers
(Fig.
17.4A).
17.4B).
More significant gastric reflux is associated with
erosions (Fig.
17.5A) and influx of eosinophils into the squamous
mucosa (Fig.
17.6A).
Basal zone hyperplasia and elongation of
lamina propria papillae are also common.
B
A C
Figure 17.4 Viral esophagitis.
(A) Postmortem specimen with multiple,
overlapping herpetic ulcers in the distal esophagus.
(B) Multinucleate
squamous cells containing herpesvirus nuclear inclusions.
(C)
Cytomegalovirus-infected endothelial cells with nuclear and cytoplasmic
inclusions.
inclusions within capillary endothelium and stromal cells (Fig.
17.4C).
This relaxation is mediated
via vagal pathways and can be triggered by gastric distention.
Note the
tan islands of metaplastic epithelium within the white squamous mucosa.
(Courtesy Dr.
Linda S.
17.5B).
17.6B).
Esophageal Varices
Esophageal varices are dilated veins within the lower
esophagus.
Although most small varices never bleed, rupture
of large varices can result in exsanguination.
Worldwide, hepatic schistosomia-
sis is the second most common cause of varices.
A more
detailed consideration of portal hypertension is given in
Chapter 18.
A B
Figure 17.6 Esophagitis.
(A) Reflux esophagitis with scattered
intraepithelial eosinophils and mild basal zone expansion.
(B) Eosinophilic
esophagitis is characterized by numerous intraepithelial eosinophils.
Rarely, GERD-
associated chest pain may be mistaken for ischemic heart
disease.
Many patients have atopic dermatitis, allergic
rhinitis, asthma, or modest peripheral eosinophilia.
Con-
sistent with this, recent data suggest that mast cells may
also be important in pathogenesis.
In addition to
GERD-like symptoms, patients experience food impaction,
dysphagia, and vomiting.
Infants may also suffer from
feeding intolerance.
17.7).
DespiteEsophagus 761
white males and typically presents between 40 and 60 years
of age.
The greatest clinical concern is that it confers an
increased risk of esophageal adenocarcinoma.
The vast majority of esophageal adenocarcinomas occur
in association with Barrett esophagus.
Nevertheless, most
individuals with Barrett esophagus do not develop esopha-
geal tumors.
17.5A) and interfaces
with light-brown columnar (gastric) mucosa distally (Fig.
17.8A,
B).
Barrett esophagus can be subclassified as long segment (≥3 cm),
or short segment (<3 cm).
C
Figure 17.7 Esophageal varices.
(C) Dilated varices beneath intact squamous mucosa.
Treatments include beta-blockers to reduce portal blood
flow and endoscopic variceal ligation.
Barrett esophagus is most common in
A B
C
Figure 17.8 Barrett esophagus.
(A) Normal gastroesophageal junction.
(B) Barrett esophagus.
Note the small islands of residual pale squamous
mucosa within the Barrett mucosa.
(C) Histologic appearance of the
gastroesophageal junction in Barrett esophagus.
A B
Figure 17.9 Dysplasia in Barrett esophagus.
(A) Abrupt transition from
metaplasia to low-grade dysplasia (arrow).
Note the nuclear stratification
and hyperchromasia.
Other major risk factors include tobacco use and exposure
to radiation.
Conversely, risk is reduced by diets rich in
fresh fruits and vegetables.
17.8C).
Dysplasia is classified as low grade or high grade.
17.9A).
Dysplastic glands display
budding, irregular shapes, and cellular crowding.
High-grade dysplasia
(Fig.
17.9B) exhibits more severe cytologic and architectural changes
than low-grade dysplasia.
Once diagnosed, the best course of management
is a matter of debate.
Intramucosal or invasive carcinoma requires therapeutic
intervention.
The regions
with highest incidence are Iran, central China, Hong Kong,
Brazil, and South Africa.
A B
Figure 17.10 Esophageal cancer.
(A) Adenocarcinoma usually occurs
distally and, as in this case, often involves the gastric cardia.
17.10A).
Microscopically, tumors typically produce mucin and form
glands (Fig.
Barrett esophagus is frequently present
adjacent to the tumor.
By the
time symptoms appear, the tumor has often spread to
submucosal lymphatic vessels.
As a result, overall 5-year
survival is less than 25%.
(A) Esophageal adenocarcinoma
organized into back-to-back glands.
17.10B).
Early lesions appear
as small, gray-white, plaque-like thickenings.
Most squamous cell carcinomas are moderately to well dif-
ferentiated (Fig.
17.11B).
Regardless of histology,
symptomatic tumors are generally large and invasive at diagnosis.
Clinical Features
The onset of esophageal squamous cell carcinoma is insidious.
Weight loss
and debilitation result from both impaired nutrition and
tumor cachexia.
Lymph node metas-
tases are associated with poor prognosis.
• Esophagitiscan result from chemicalorinfectiousmucosalinjury.
Infection is most common in immunocompromised individuals.
• The most prevalent cause of esophagitis is reflux of gastric
acid into the esophagus (GERD).
• Eosinophilic esophagitis is strongly associated with food allergy,
allergic rhinitis, or asthma.
It is a common cause of GERD-like
symptoms in children living in high income countries.
• Barrett esophagus is a risk factor for development of esophageal
adenocarcinoma.
The stomach is divided into four major anatomic regions:
cardia, fundus, body, and antrum.
The cardia and antrum
are lined mainly with mucin-secreting foveolar cells that
form small glands.
This harsh environment
contributes to digestion but also has the potential to cause
damage.
Multiple mechanisms have evolved to protect the
gastric mucosa (Fig.
17.12).
Gastropathy and gastritis occur when the damaging forces
overwhelm the protective factors (Fig.
17.12).
They also reduce acid secretion.
Although COX-1 plays
a larger role than COX-2, both isoenzymes contribute to
mucosal protection.
pylori.
causes hypersecretion of gastric acid.
Neutrophils may be
found among the epithelial cells or within mucosal gland lumina
in gastritis.
The lamina propria contains only a few lymphocytes
and plasma cells.
Hemorrhage may cause dark puncta
within hyperemic mucosa.
Concurrent erosion and hemorrhage
is termed acute erosive hemorrhagic gastritis.
Other complications, including perforation, can also occur.
NSAID use may enhance bleeding risk.
• Gastric antral vascular ectasia (GAVE) is responsible for 4%
of non-variceal upper GI bleeding.
The erythematous stripes are
created by ectatic mucosal vessels.
While most often
idiopathic, GAVE can be associated with cirrhosis and
systemic sclerosis.
Recurrent bleeding may produce a
positive test for fecal blood and lead to iron deficiency
anemia.
For example:
• Stress ulcers are most common in the setting of shock,
sepsis, or severe trauma.
They
have an elevated risk of perforation.
pylori infection.
Nausea and upper abdominal pain are typical, sometimes
with vomiting, but hematemesis is uncommon.
Helicobacter pylori Gastritis
H.
Acute H.
H.
pylori organisms are
present in the majority of individuals with chronic antral
gastritis.
Epidemiology.
In the United States, H.
Infection is typically
acquired in childhood and persists for life without treatment.
Improved sanitation explains the marked reduction in H.
pylori infection rates among younger people.
In well-
resourced countries, H.
It follows that environment
during childhood is a critical risk factor for H.
pylori
colonization.
Pathogenesis
H.
Alternatively, long-standing H.
pylori
gastritis may progress to involve the gastric body and fundus.
This may result in atrophic gastritis with reduced parietal
cell mass and intestinal metaplasia.
In contrast to autoimmune
gastritis (see later), atrophy induced by H.
pylori is not
associated with autoantibodies and is typically patchy.
Nevertheless, decreased acid secretion in H.
pylori
gastritis with atrophy reduces the risk of gastric and duodenal
ulcers.
H.
pylori organisms have adapted to the ecologic niche
provided by gastric mucus.
For example, the CagA gene is present
in 50% of H.
pylori isolates overall but in 90% of H.
pylori
isolates in populations with an increased prevalence of gastric
cancer.
pylori.
Host factors also play an important role in the outcome
of H.
pylori infection.
The course of H.
MORPHOLOGY
Gastric biopsy specimens generally demonstrate H.
pylori in infected
individuals.
Organisms are most
easily demonstrated with immunostains or histochemical stains
(Fig.
17.13A).
The antrum is the preferred biopsy site for evaluation of H.
pylori gastritis because it is most commonly infected.
H.
pylori–infected antral
mucosa is usually erythematous and has a coarse or even nodular
appearance.
Neutrophils infiltrate across the basement membrane
(Fig.
Lymphoid aggregates, some with
germinal centers, are frequently present (Fig.
Thus, chronic H.
B C
often associated with marked hyper gastrinemia (Table
17.2).
(A) Spiral-shaped H.
pylori are
highlighted in this Warthin-Starry silver stain.
Organisms are abundant
within surface mucus.
(B) Intraepithelial and lamina propria neutrophils are
prominent.
pylori gastritis.
Clinical Features
The changes seen in atrophic H.
pylori DNA.
Effective treatments for H.
pylori infection include com-
binations of antibiotics and proton pump inhibitors.
Individu-
als with H.
Autoimmune Atrophic Gastritis
Autoimmune atrophic gastritis, in contrast to H.
or nodules.
17.14B).
Endocrine
and enterochromaffin-like cell hyperplasia is commonly present.
The median
age at diagnosis is 60.
Uncommon Forms of Gastritis
Eosinophilic Gastritis.
pylori infection.
Lymphocytic Gastritis.
This disease preferentially affects
women and produces nonspecific abdominal symptoms.
Histologically there is a marked
increase in the number of intraepithelial T lymphocytes.
Granulomatous Gastritis.
The antrum and cardia are typically
spared.
In contrast to the superficial lamina propria
inflammation that is typical of H.
17.14A).
Loss of parietal and chief cells can
be extensive.
It encompasses a diverse group of diseases with
widely varying clinical and pathologic features.
Many cases
bacterial strains are involved.
are idiopathic.
pylori).
pylori infection, NSAIDs, or
cigarette smoking.
The most common form of PUD occurs
within the gastric antrum or duodenum as a result of chronic
H.
As mentioned earlier, H.
Epidemiology.
The incidence of PUD is falling along with
reduced prevalence of H.
pylori infection.
However, PUD
in patients older than 60 years has increased due to growing
NSAID use.
This can be amplified by H.
Other risk factors for PUD are listed in Table 17.3.
Thus, PUD generally develops on a background of
chronic gastritis.
However, as with H.
17.15A).
In
contrast, heaped-up margins are more characteristic of
cancers.
B
Figure 17.15 Acute gastric perforation in a patient presenting with free
air under the diaphragm.
(A) Mucosal defect with clean edges.
The risk of adeno-
carcinoma is greatest in autoimmune metaplastic atrophic
gastritis.
Intestinal metaplasia also occurs in
chronic H.
pylori gastritis but may regress after clearance
of the organism.
Preinvasive in situ lesions can be recognized
histologically as dysplasia.
As might be expected, the hypertrophic gastropathies are
linked to excessive growth factor release.
Some cases occur in association with viral or H.
pylori infec-
tion.
The base of peptic ulcers is smooth and clean as a result of
peptic digestion of exudate.
Larger vessels within the scarred
area are typically thickened and are occasionally thrombosed.
Bleeding from these vessels may cause life-threatening hemorrhage.
Others present with
iron deficiency anemia, hemorrhage, or perforation (Table
17.4).
and 2
a.m.), and is relieved by alkali or food.
Nausea, vomiting,
bloating, belching, and significant weight loss are additional
manifestations.
Current therapies for PUD are aimed at H.
pylori eradica-
tion and neutralization of gastric acid, primarily with proton
pump inhibitors.
pylori.
Secondary
symptoms such as weight loss, diarrhea, and peripheral
edema are commonly present.
Risk
of gastric adenocarcinoma is increased in adults with
Ménétrier disease.
A
MORPHOLOGY
Ménétrier disease is characterized by irregular enlargement of
the gastric rugae.
Some areas may appear polypoid.
Enlarged rugae
are present in the body and fundus (Fig.
17.16A), but the antrum
is generally spared.
17.16B).
Inflammation is usually modest, although some cases
show marked intraepithelial lymphocytosis.
In cases associated with herpesvirus, CMV, or H.
pylori,
treatment of the infection may be helpful.
Antibodies that
block epidermal growth factor receptor activation are effec-
tive in many cases.
In severe cases gastrectomy remains a
therapeutic option.
B
Figure 17.16 Ménétrier disease.
(A) Marked hypertrophy of rugal folds.
(B) Foveolar hyperplasia with elongated and focally dilated glands.
(Courtesy Dr.
M.
These gastrinomas are almost
always found in the small intestine or pancreas.
Patients
often present with duodenal ulcers or chronic diarrhea.
Gastrin also induces hyperplasia of mucous
neck and endocrine cells within oxyntic mucosa.
Gastrinomas are sporadic, solitary lesions in 75% of
patients.
The remaining 25% of patients with gastrinomas
have multiple endocrine neoplasia type 1 (MEN1).
These
patients are younger and primarily have duodenal tumors
that commonly metastasize.
MEN1 gene mutations in
sporadic gastrinomas are also associated with aggressive
tumor behavior.
Somatostatin receptor scintigraphy or
endoscopic ultrasonography can help with identification.
Patients with metastatic disease may benefit from treatment
with somatostatin analogues.
Their incidence is correlated with the
regional prevalence of H.
pylori infection.
• The most common cause of chronic gastritis is H.
pylori infection.
Other injurious agents include NSAIDs and alcohol.
• H.
• H.
pylori gastritis induces MALT that can give rise to B-cell
lymphomas (MALTomas).
• After H.
pylori and NSAIDs, autoimmune atrophic gastritis is
the most frequent cause of chronic gastritis.
• Peptic ulcer disease is usually secondary to chronic H.
pylori–
induced gastritis and the resulting hyperchlorhydria.
pylori
eradication.
MORPHOLOGY
The majority of inflammatory or hyperplastic polyps are smaller
than 1 cm in diameter.
Polyps are frequently multiple, particularly
in individuals with atrophic gastritis.
Microscopically, polyps have
irregular, cystically dilated, and elongated foveolar glands
(Fig.
17.17B).
Fundic
gland polyps may be asymptomatic or associated with
nausea, vomiting, or epigastric pain.
They may be774 CHAPTER 17 The Gastrointestinal Tract
A B C D
Figure 17.17 Gastric polyps.
(A) Hyperplastic polyp containing corkscrew-shaped foveolar glands.
(B) Hyperplastic polyp with extensive ulceration.
(D) Gastric adenoma with epithelial nuclear
hyperchromasia and pseudostratification.
Epidemiology.
Gastric cancer incidence varies markedly
with geography.
Metastases are often
present at diagnosis.
Inflammation
is typically absent or minimal (Fig.
17.17C).
Dysplasia may occur
in FAP-associated fundic gland polyps, and rare cancers have been
reported.
They represent up to 10% of all gastric
polyps (see Table 17.5).
MORPHOLOGY
Gastric adenomas are usually solitary antral lesions.
All GI adeno-
mas exhibit dysplasia, which is classified as low- or high-grade
(Fig.
17.17D).
Decreased gastric cancer incidence is
largely attributed to reduced rates of H.
pylori infection and
primarily relates to intestinal-type cancers.
Thus, E-cadherin loss is a key step in the develop-
ment of diffuse gastric cancer.
pylori gastritis.
Thus, both host genetic background
and environmental factors affect risk.
Gastric tumors
with an intestinal morphology form bulky tumors (Fig.
17.18A) and are composed of glandular structures (Fig.
17.19A),
while cancers with a diffuse infiltrative growth pattern (Fig.
17.18B) are typically composed of signet-ring cells (Fig.
17.19B).
Release of extracellular
A
B
Figure 17.18 Gastric adenocarcinoma.
Compare to the peptic ulcer in Fig.
17.15A.
(B) Infiltrative type
(linitis plastica) gastric cancer.
Notably, the
remarkable decrease in gastric cancer incidence applies
only to the intestinal type.
Local invasion into the duo-
denum, pancreas, and retroperitoneum is common.
When possible, surgery
remains the preferred treatment approach.
In
contrast, the 5-year survival rate for advanced gastric cancer
remains less than 20%.
In the gut these tumors are often referred to
as lymphomas of MALT, or MALTomas.
These and other
lymphomas of the gut are discussed in Chapter 13.
H.
This creates a chimeric API2-MLT1 fusion
gene that encodes an API2-MALT1 fusion protein.
Note the absence of gland
formation.
17.18B).
The mean age of presentation is
55 years, and the male-to-female ratio is 2 : 1.
Thus, H.
Removal of this stimulus may explain why these tumors
tend to respond to H.
pylori eradication.
In contrast, tumors
bearing translocations involving MALT1 or BCL10 are
generally insensitive to H.
pylori clearance.
pylori eradication.
17.20A, inset).
17.20B) or infiltrate
the wall diffusely (Fig.
17.20C).
Like other tumors of mature B cells, MALTomas express the
B-cell markers CD19 and CD20.
A B
C
Figure 17.20 Lymphoma.
(A) Gastric mucosa-associated lymphoid tissue
lymphoma replacing much of the gastric epithelium.
(B) Disseminated lymphoma within the small
intestine with numerous small serosal nodules.
(C) Large B-cell lymphoma
infiltrating the small intestinal wall and producing diffuse thickening.
Clinical Features
The most common presenting symptoms are dyspepsia and
epigastric pain.
Hematemesis, melena, and constitutional
symptoms such as weight loss can also be present.
Because
gastric MALTomas and H.
Neuroendocrine Neoplasms
These tumors arise from the diffuse components of the
endocrine system.
Most are found in the GI tract, and more than 40%
occur in the small intestine.
The tracheobronchial tree and
lungs are the next most commonly involved sites.
17.21A).
17.21).
(A) Gross cross section of a submucosal tumor nodule.
(B) Microscopically the nodule is
composed of tumor cells embedded in dense fibrous tissue.
(C) In other areas the tumor has spread extensively within mucosal lymphatic channels.
(D) High magnification shows the characteristically bland cytology.
Despite their innocuous appearance, these tumors can be clinically aggressive.
(E) Electron microscopy reveals cytoplasmic dense
core neurosecretory granules.
Symptoms
reflect hormones released by the tumor cells.
For example,
those that produce gastrin cause Zollinger-Ellison syndrome.
Behavior is also affected by size and location, and staging is
region-specific.
This is particularly true for tumors that arise in
association with atrophic gastritis.
Gastric neuroendocrine
tumors without predisposing factors are often more
aggressive.
Those in the appendix occur at any age and are generally
located at the tip.
These tumors are rarely more than
2 cm in diameter and are almost always benign.
More
than half of these tumors occur in the stomach.
A wide variety of other
mesenchymal neoplasms may arise in the stomach.
These are all uncommon
in the gut and are discussed in Chapter 26.
Epidemiology.
Clinically silent, microscopic proliferations
that may represent precursors to GIST are common.
These
foci have low mitotic rates and extremely low risk of neo-
plastic transformation.
Constitutively active KIT and
PDGFRA trigger the same downstream signaling pathways.
Mutations of the correspondence genes are therefore mutually
exclusive.
Clinical Features
Symptoms of GISTs at presentation are typically related to
mass effects.
Complete
surgical resection is the primary treatment for localized
gastric GIST.
The overlying
mucosa is frequently ulcerated, and the cut tumor surface has a
whorled appearance.
GISTs composed of thin
elongated cells are classified as spindle cell type (Fig.
Nuclear pleomorphism is
uncommon.
These reactive lesions are associated with chronic
gastritis.
• Gastric adenocarcinoma incidence varies markedly with geography.
Individual tumors are classified according to location and gross and
histologic morphology.
Gastric adenocarcinomas are linked to chronic
gastritis.
pylori gastritis.
Finally, the colon is the most common
site of GI neoplasia in Western populations.
obstruction include abdominal pain and distention, vomiting,
and constipation.
Pressure at the neck of the pouch may impair
venous drainage of the entrapped viscus.
17.24).
17.23).
Figure 17.24 Intestinal obstruction.
Portion of bowel incarcerated within
an inguinal hernia.
Sequelae, including obstruction and strangulation, are similar
to external hernias.
Thus, volvulus presents with
features of both obstruction and infarction.
Because it is rare, volvulus can be over-
looked clinically, often with catastrophic results.
Once trapped, the invaginated
segment is propelled by peristalsis and pulls the mesentery
along.
In
idiopathic cases there is no underlying anatomic defect,
and the patient is otherwise healthy.
Surgical intervention is necessary when a mass is
present.
In a large majority of cases, acute obstruction
is caused by thrombosis or embolism.
Less
common causes of thrombosis include systemic vasculitides
(Chapter 11).
Obstructive emboli most commonly originate
from aortic atheromas or cardiac mural thrombi.
Pathogenesis
Intestinal responses to ischemia occur in two phases.
The lesions can be continuous but are
most often segmental and patchy (Fig.
17.25A).
The mucosa is
hemorrhagic and often ulcerated (Fig.
17.25B).
(A) Jejunal resection with dusky serosa of acute ischemia (mesenteric thrombosis).
(B) Mucosa is dark colored
because of hemorrhage.
(C) Characteristic attenuated villous epithelium in this case of acute mesenteric thrombosis.
(D) Chronic colonic ischemia with
atrophic surface epithelium and fibrotic lamina propria.
With appropriate management, mortality in the first 30
days is approximately 10%.
Ischemic bowel injury can take a variety of
subacute or chronic forms.
Serositis,
with purulent exudates and fibrin deposition, may be prominent.
Propagation of the thrombus may lead
to secondary involvement of the splanchnic bed.
17.25C), often with hyperproliferative crypts.
Chronic ischemia is accompanied by fibrous
scarring of the lamina propria (Fig.
17.25D) and, uncommonly,
stricture formation.
Patients may progress to shock and vascular collapse within
hours in severe cases.
Presentation can range
from chronic, intermittent to acute, massive hemorrhage.
carbohydrates, electrolytes and minerals, and water.
Painful, bloody, small-volume
diarrhea is known as dysentery.
Only the malabsorption associated with cystic fibrosis is
considered here.
Some of these differences correlate with varia-
tion in wheat consumption.
17.26).
These lymphocytes express NKG2D, a natural
killer cell marker and receptor for MIC-A.
The right panel depicts a model for the pathogenesis of celiac disease.
While most people eat grain and are exposed to gluten
and gliadin, very few develop celiac disease.
Thus, host
factors determine whether disease develops.
However, the HLA locus accounts for less than half
of the genetic component of celiac disease.
Clinical Features
In adults, celiac disease presents most commonly between
the ages of 30 and 60.
These cases may
present with anemia due to chronic iron and vitamin
malabsorption.
Unfortunately, the only treatment currently available for
celiac disease is a gluten-free diet.
Noninvasive serologic tests are generally performed prior
to biopsy.
The most sensitive test is the measurement of
IgA antibodies against tissue transglutaminase.
IgA anti-
endomysial antibodies can also be present.
IgG anti–tissue
transglutaminase antibodies may be detected in patients with
IgA deficiency.
Individuals with celiac disease have an increased risk
of malignancy.
Small intestinal adenocarci-
noma is also more frequent in individuals with celiac disease.
17.27).
This loss of mucosal
and brush-border surface area contributes to malabsorption.
(A) Advanced cases of celiac disease show
complete loss of villi, or total villous atrophy.
Note the dense plasma cell
infiltrates in the lamina propria.
Affected individuals often suffer from malabsorption,
malnutrition, and stunted growth.
The underlying causes of environmental enteric dysfunc-
tion are unknown.
In
contrast to celiac disease, neutrophils are often seen infiltrat-
ing the intestinal mucosa.
In the absence of lactase, dietary lactose
cannot be broken into glucose and galactose.
Because
the defect is biochemical, histology is generally unremarkable.
Symptoms abate when exposure to milk
and milk products is terminated.
Flatulence also occurs due to
fermentation of the unabsorbed sugars by colonic
bacteria.
The factors responsible
for early or later presentation have not been defined.
Without MTP, lipids accumulate
intracellularly.
Abetalipoproteinemia presents in infancy with failure to
thrive, diarrhea, and steatorrhea.
and severe; the acquired form is common and usually presents
in adulthood.
This
global problem is responsible for over 1 million deaths each
year.
Bacterial
infections, such as enterotoxigenic E.
coli and Salmonella
spp., are frequently responsible for acute diarrheal illnesses.
Mycobacte-
rial infections of the GI tract are considered in detail in
Chapter 8.
This occurs because shell
fish and plankton can be reservoirs of Vibrio cholerae.
Over
half of cases required hospitalization, and 1% were fatal.
Pathogenesis
Severe diarrhea is caused by the toxin released by the
bacteria.
Vibrio organisms are noninvasive and remain within
the intestinal lumen.
Proteins involved in motility and
attachment are necessary for efficient colonization.
Cholera toxin is encoded by a virulence phage.
It is
composed of five B subunits and a single A subunit.
17.28).
• Diarrhea can be characterized as secretory,osmotic,malabsorp-
tive, or exudative.
• Environmental enteric dysfunction is prevalent in areas with
poor sanitation.
• Lactase deficiency causes an osmotic diarrhea due to the inability
to break down lactose.
coli; EIEC, enteroinvasive E.
coli; EHEC, enterohemorrhagic E.
coli; EPEC, enteropathogenic E.
coli; ETEC,
enterotoxigenic E.
coli; GI, gastrointestinal.
Chloride and sodium absorption are also inhibited by cAMP.
that draws water into the lumen and causes massive diarrhea.
Remarkably, mucosal biopsies show only minimal histologic
alterations.
Clinical Features
Most individuals exposed to V.
cholerae are asymptomatic
or develop only mild diarrhea.
The volumi-
nous stools resemble rice water and are sometimes described
as having a fishy odor.
Oral rehydration is often sufficient but is unfor-
tunately underutilized.
Flagella allow Campylobacter to be motile, which
facilitates adherence and colonization.
Some C.
jejuni lipopolysaccharide
cross-react with peripheral and central nervous system
gangliosides.
MORPHOLOGY
Campylobacter are comma-shaped, flagellated, gram-negative
organisms.
Diagnosis is primarily by stool culture, since biopsy
findings are nonspecific.
Importantly, crypt architecture
is preserved (Fig.
(A) Campylobacter jejuni infection produces acute, self-limited colitis.
(D) Enteroinvasive E.
coli infection is similar to other acute, self-limited colitides
such as those caused by C.
jejuni.
Clinical Features
Ingestion of as few as 500 C.
jejuni organisms can cause
disease after an incubation period of up to 8 days.
Patients
may shed bacteria for 1 month or more after clinical resolu-
tion.
Antibiotic therapy is generally not required.
coli.
Although humans are the only known reservoir, Shigella
spp.
Deaths are generally limited to children younger
than 5 years of age.
Pathogenesis
Shigella are resistant to gastric acid, thereby explaining the
low infective dose.
All Shigella spp.
This and other factors lead
to significant potential for confusion with inflammatory bowel
disease.
Duration of symptoms is typically
shorter in children, but severity is often much greater.
Confirmation of Shigella infection
requires stool culture.
S.
coli (EHEC) are more commonly responsible (Chapter 20).
Toxic megacolon and intestinal obstruction are uncommon
complications.
enteritidis.
Centralized food processing can lead to large outbreaks.
Vaccines are available for both humans and farm animals,
e.g., egg-laying hens.
Stool cultures are essential
for diagnosis.
Symptoms range
from loose stools to cholera-like profuse diarrhea to dys-
entery.
The disease
is caused by Salmonella enterica and its two subtypes, typhi
and paratyphi.
The majority of cases in endemic countries
are due to S.
typhi, while infection by S.
paratyphi is more
common among travelers, perhaps because they are often
vaccinated against S.
typhi.
Humans are the sole
reservoir for S.
typhi and S.
paratyphi; transmission occurs
from person to person or via food or contaminated water.
Gallbladder colonization with S.
typhi or S.
paratyphi may
be associated with gallstones and a chronic carrier state.
Pathogenesis
In contrast to S.
enteritidis, S.
Similar
to Shigella, S.
typhi are resistant to gastric acid and, initially,
invade via small intestinal M cells.
Draining mesenteric lymph nodes are
also enlarged.
Mucosal damage
creates oval ulcers, oriented along the axis of the ileum, that may
perforate.
In disseminated S.
Escherichia coli
E.
The latter are classified according to morphology,
pathogenesis, and in vitro behavior.
Subgroups with major
clinical relevance include enterotoxigenic E.
coli (ETEC),
enteropathogenic E.
coli (EPEC), enterohemorrhagic E.
coli
(EHEC), enteroinvasive E.
coli (EIEC), and enteroaggregative
E.
coli (EAEC).
Enterotoxigenic Escherichia coli.
ETEC are the principal
cause of traveler’s diarrhea and spread via contaminated food
or water.
In under-resourced countries, children younger than 2
years of age are particularly susceptible.
ETEC are noninvasive
but produce heat-labile (LT) and heat-stable (ST) toxins.
Enteropathogenic Escherichia coli.
These proteins include Tir, which
is inserted into the intestinal epithelial cell plasma membrane.
EPEC strains do not produce Shiga toxins.
Enterohemorrhagic Escherichia coli.
EHEC are catego-
rized as E.
coli O157:H7 and non-O157:H7 serotypes.
E.
Contaminated milk and vegetables are
also vehicles for infection.
Both O157:H7 and non-O157:H7
serotypes produce Shiga-like toxins, and therefore lesions
(see Fig.
17.29C) and clinical symptoms are similar to those
resulting from S.
dysenteriae infection.
Abdominal tenderness
may mimic appendicitis.
Rose spots, small erythematous
maculopapular lesions, develop on the chest and abdomen.
Symptoms abate after several weeks but relapse can occur.
Patients with sickle cell disease are particularly susceptible
to Salmonella osteomyelitis.
Blood cultures are positive in
more than 90% of affected individuals during the febrile
phase.
Antibiotic treatment can prevent disease progression.
Yersinia
Three Yersinia species are human pathogens.
Y.
enterocolitica
and Y.
pseudotuberculosis cause GI disease and are discussed
here; Y.
pestis, the agent of pulmonic and bubonic plague,
is discussed in Chapter 8.
coli, Klebsiella, Salmonella, and enterobacteria.
17.29B) and granulomas.
As with Shigella, these
factors can cause diagnostic confusion with Crohn disease.
Extraintestinal
symptoms of pharyngitis, arthralgia, and erythema
nodosum occur frequently.
Fever and diarrhea are less
common.
Yersinia can be detected by
stool culture on Yersinia-selective agar.
Enteroinvasive Escherichia coli.
17.29D).
Enteroaggregative Escherichia coli.
EAEC has a unique
“stacked brick” morphology when bound to epithelial
cells.
These organisms cause diarrhea in children and adults
worldwide, including traveler’s diarrhea.
difficile
causes pseudomembranous colitis.
Pathogenesis
Disruption of the normal colonic microbiota by antibiotics
allows C.
difficile overgrowth.
Toxins released by C.
A
B C
Figure 17.30 Clostridioides (formerly Clostridium) difficile colitis.
(B)
Pseudomembranes are easily appreciated on gross examination.
Clinical Features
Risk factors for C.
Individuals with C.
Protein loss can give rise
to hypoalbuminemia.
Fecal leukocytes and occult blood may
be present, but grossly bloody diarrhea is uncommon.
The diagnosis is usually made
by detection of C.
difficile toxin, rather than by culture, and
is supported by the characteristic histopathology.
difficile strains is increasing.
Recurrent C.
difficile–associated
colitis occurs in up to 40% of patients.
Pseudomembranes (Fig.
However, histopathology of C.
difficile–associated
colitis is pathognomonic.
The organism was identified as an actinomycete by PCR in
1992 and named Tropheryma whipplei.
Thus, the malabsorp-
tive diarrhea of Whipple disease is due to impaired lymph
drainage.
17.31B).
Intact rod-shaped bacilli can also be identified by electron
microscopy (Fig.
17.31D), and
the organisms are PAS-positive in both diseases.
The acid-fast
stain can be helpful, since mycobacteria stain positively (Fig.
17.31E),
while T.
whipplei does not.
B
D EC
Figure 17.31 Whipple disease and mycobacterial infection.
(B) Periodic acid–Schiff stain
highlights macrophage lysosomes full of bacilli.
Compare with (A).
(E) Unlike T.
whippelii,
mycobacteria are positive with stains for acid-fast bacteria.
(C, Courtesy
George Kasnic and Dr.
Viral Gastroenteritis
Symptomatic human infection is caused by many viruses.
The most common are discussed here.
Norovirus.
Approximately half of all gastroenteritis outbreaks world-
wide are thought to be due to norovirus.
They cause more
than 200,000 childhood deaths annually in under-resourced
countries.
Fecal-oral transmission is responsible for most sporadic
cases.
In these environments, vehicles
include airborne droplets, environmental surfaces, and
fomites.
The symptoms resolve within
2 to 3 days in most cases.
Norovirus infection in immunocompromised patients is
a significant problem.
As a result, a new pandemic strain
emerges every 2 to 4 years.
Rotavirus.
The WHO recommends that the first dose be
given at 6 weeks of age.
Adenovirus.
A common cause of pediatric diarrhea, adeno-
virus also affects immunocompromised patients.
Viral nuclear inclusions
are uncommon.
Fever and weight loss may
also be present.
Symptoms generally resolve within 10 days.
Ascaris lumbricoides.
This nematode infects 1 billion
individuals worldwide.
Ingested eggs hatch in the intestine,
and larvae penetrate the intestinal mucosa.
Approximately
3 weeks later, the larvae are coughed up and swallowed.
(B) Diffuse eosinophilic infiltrates in parasitic infection.
(C) Schistosomiasis can induce an inflammatory reaction to eggs trapped within the lamina propria.
(D) Entamoeba
histolytica in a colon biopsy specimen.
Note some organisms ingesting red blood cells (arrow).
17.32B) that can cause physical obstruction of
the intestine or biliary tree.
Larvae can also form hepatic
abscesses and cause pneumonitis.
Diagnosis is usually made
by detection of eggs in stool samples.
Strongyloides.
17.32B).
Strongyloides incite a strong
tissue reaction and peripheral eosinophilia.
Necator duodenale and Ancylostoma duodenale.
These
hookworms infect 1 billion people worldwide and cause
significant morbidity.
Infection is initiated by larval penetra-
tion through the skin.
After further development in the
lungs, they migrate up the trachea and are swallowed.
Worms
attach to the duodenal mucosa, suck blood, and reproduce.
Diagnosis can be made by detection of
the eggs in fecal smears.
Trichuris trichiura.
Whipworms primarily infect young
children.
Similar to Enterobius vermicularis, T.
trichiura does
not penetrate the intestinal mucosa and rarely causes serious
disease.
Heavy infections may cause bloody diarrhea and
rectal prolapse.
Enterobius vermicularis and Enterobius gregorii.
E.
Infection is primarily
by the fecal-oral route.
The eggs cause irritation and
rectal and perineal pruritus.
Schistosomiasis.
Eggs are trapped within
the mucosa and submucosa (Fig.
17.32C).
The resulting
immune reaction is often granulomatous and can cause
bleeding and even obstruction.
More details are presented in
Chapter 8.
Intestinal Cestodes.
Release of the larva allows attachment to the intestinal
mucosa through its head, or scolex.
Nevertheless, the parasite burden
can be staggering.
Clinical symptoms include abdominal pain,
diarrhea, and nausea, but most cases are asymptomatic.
Occasionally, D.
Identification of proglottids and eggs in stools is the most
efficient method of diagnosis.
Entamoeba histolytica.
This protozoan causes amebiasis
and is spread by fecal-oral transmission.
E.
E.
17.32D).
Amebae may also spread
to the kidneys and brain via the bloodstream.
Individuals with amebiasis may present with abdominal
pain, bloody diarrhea, or weight loss.
The parasites lack mitochondria
or Krebs cycle enzymes and are thus obligate fermenters
of glucose.
Giardia lamblia.
These organisms, also referred to as G.
duodenalis or G.
G.
Infection may occur
after ingestion of as few as 10 cysts.
Because cysts are resistant
to chlorine, Giardia are endemic in unfiltered public water
supplies.
Secretory
IgA and mucosal IL-6 responses are important for clearance
of Giardia infections.
Immunosuppressed, agammaglobu-
linemic, or malnourished individuals are often severely
affected.
Infection
is usually documented by immunofluorescent detection of
cysts in stool samples.
Oral antimicrobial therapy is effective,
but recurrence is common.
Cryptosporidium.
Like Giardia, cryptosporidia are an
important cause of diarrhea worldwide.
Crypto-
sporidiosis also causes persistent diarrhea in residents of
under-resourced countries.
Oocysts are
resistant to chlorine and may therefore persist in treated,
but unfiltered, water.
Contaminated drinking water continues
to be the most common means of transmission.
Like giardiasis, cryptosporidiosis
is readily spread to water sport participants.
Food-borne
infection occurs less frequently.
Humans are infected by several different Cryptosporidium
species, including C.
hominis and C.
parvum.
Once ingested, as few
as 10 encysted oocytes are sufficient to cause symptomatic
infection.
Sporozoites are released following protease activa-
tion by gastric acid.
17.32F).
Diagnosis is based on finding oocysts
in the stool.
Despite very real symptoms, the endoscopic and
microscopic evaluations are normal in IBS patients.
Thus,
the diagnosis depends on clinical symptoms and functional
testing.
Further, 5-HT3 receptor antagonists are effective
in many cases of diarrhea-predominant IBS.
Other causes, such as
enteric infection or inflammatory bowel disease, must be
excluded.
KEY CONCEPTS
INFECTIOUS ENTEROCOLITIS
• V.
• C.
Most
isolates are noninvasive.
• Salmonella and Shigella spp.
are invasive and associated with
exudative bloody diarrhea (dysentery).
• Salmonella enteritidis infection is a common cause of food
poisoning.
• S.
typhi cause systemic disease (typhoid fever).
• Pseudomembranous colitis is often triggered by antibiotic therapy.
The responsible organism, C.
These spread to form mucopurulent
pseudomembranes.
• Norovirus is a common cause of self-limited diarrhea in adults
and children.
It spreads from person to person in sporadic
cases and via contaminated water in epidemics.
Each
parasite has a distinctive life cycle and tissue reaction.
Those
that invade are typically associated with tissue and systemic
eosinophilia.
The
distinction between Crohn disease and ulcerative colitis is primarily based
on morphology.
Fat/vitamin
Yes No
malabsorption
Malignant
With colonic
involvement
potential
Yes
activation.
The two disorders that comprise IBD are ulcer-
ative colitis and Crohn disease.
17.33) and the morphologic expression of disease
(Table 17.8) at those sites.
Epidemiology.
This is at least partly due to genetic factors, as discussed
later.
inflammation in susceptible hosts.
• Mucosal immunity.
For example, NOD2 polymorphisms have not been associ-
ated with Crohn disease in Asian populations.
• Autophagy and cellular stress responses.
• Host-microbial interactions.
In general, the microbiome is populated by a small
number of species at birth.
Microbial complexity
then declines in old age.
This is one means by which the microbiome
can modulate mucosal immunity.
17.34A).
17.34B).
Edema and loss of the normal mucosal folds are common.
17.34B).
FissuresSmall intestine and colon 801
granulomas (Fig.
17.35C) or uninvolved regions within any layer of
the intestinal wall (Fig.
17.35D).
Granulomas may also be present
in draining mesenteric lymph nodes.
Clinical Features
The clinical manifestations of Crohn disease are extremely
variable.
Unfortunately,
smoking cessation does not result in disease remission.
Perforation and peritoneal abscesses are
common.
Over the
last two decades, anti-TNF antibodies have revolutionized
treatment of Crohn disease.
A B
C D
Figure 17.34 Gross pathology of Crohn disease.
(A) Small intestinal
stricture.
(C) Perforation
and associated serositis.
(D) Creeping fat.
frequently develop and may extend deeply to become fistula
tracts or sites of perforation (Fig.
17.34C).
17.34A).
17.34D).
17.35A).
Epithelial metaplasia is
another consequence of chronic relapsing injury.
One form,
pseudopyloric metaplasia, refers to the presence of gastric
antral-appearing glands.
Paneth cell metaplasia may also occur
in the left colon, where Paneth cells are normally absent.
These
architectural and metaplastic changes may persist even when
active inflammation has resolved.
Mucosal atrophy, with loss of
crypts, may also occur after years of disease.
(A) Haphazard crypt organization results from repeated injury and regeneration.
(B) Noncaseating
granuloma.
(C) Active Crohn disease, with ulceration and purulent exudate.
(D) Transmural Crohn disease with submucosal and serosal granulomas
(arrows).
cases of pancolitis.
There can be an
abrupt transition between diseased and uninvolved colon (Fig.
17.36B).
Isolated islands of regenerating mucosa often bulge into the lumen
to create pseudopolyps (Fig.
17.36C), and the tips of these
polyps may fuse to create mucosal bridges (Fig.
17.36D).
Chronic
disease may lead to mucosal atrophy with a smooth mucosal
surface that lacks normal folds.
Unlike Crohn disease, ulcerative
colitis is not transmural.
17.37A), crypt distortion, and
pseudopyloric epithelial metaplasia (Fig.
17.37B).
Disease of the entire colon is termed pancolitis (Fig.
17.36A).
(B) Sharp demarcation between active ulcerative colitis (right) and normal mucosa (left).
(C) Inflammatory polyps.
(D) Mucosal bridges can join inflammatory polyps.
However,
infectious enteritis precedes disease onset in some cases.
These include
patchy histologic disease, a family history of Crohn disease,
and perianal lesions.
17.37C).
These symptoms may persist for
days, weeks, or months before they subside.
(A) Crypt abscess.
(B) Pseudopyloric metaplasia (right).
(C) Disease is limited to the mucosa (above the
arrow).
Compare to Fig.
17.35D.
often lacking in patients with ulcerative colitis and present
in those with Crohn disease.
Fortunately, overlap in medical management
allows indeterminate colitis to be treated effectively.
Risk increases sharply 8 to 10 years
after disease onset.
• Extent of the disease.
Patients with pancolitis are at greater
risk than those with only left-sided disease.
Crohn
disease patients without colonic involvement are not at
increased risk.
• Nature of the inflammatory response.
Dysplasia can develop in flat areas of mucosa
that are not grossly recognized as abnormal.
IBD-associated
dysplasia is classified histologically as low grade or high
grade (Fig.
17.38A, B) and may be multifocal.
High-grade
dysplasia may be associated with invasive carcinoma at
the same site (Fig.
17.38C) or elsewhere in the colon and
therefore often prompts colectomy.
(A) Dysplasia with extensive
nuclear stratification and marked nuclear hyperchromasia.
(B) Cribriform
glandular arrangement in high-grade dysplasia.
Also
seen are small invasive glands (arrowhead).
B C
Figure 17.39 Uncommon causes of colitis.
(A) Diversion colitis.
Note the
large lymphoid follicles with germinal centers.
(B) Collagenous colitis with
a dense subepithelial collagen band.
(C) Lymphocytic colitis.
Intraepithelial
lymphocytes can be recognized by their densely stained, small nuclei.
Colitis can develop within
the diverted segment.
17.39A).
Such enemas
are, however, used infrequently because of butyrate’s foul
odor.
Diversion colitis resolves after anastomosis and
restoration of fecal flow.
Radiologic and endoscopic studies are typically
normal.
17.39B).
17.39C).
Similar histologic
changes can be induced by NSAIDs and, possibly, proton
pump inhibitors.
The small bowel
and colon are involved in most cases.
Epithelial apoptosis,
particularly of crypt cells, is the most common histologic
finding.
The crypts may be completely destroyed in severe
cases.
The reasons for this dif-
ference in distribution are not well defined.
A
B C
Figure 17.40 Sigmoid diverticular disease.
(A) Stool-filled diverticula are
regularly arranged.
(B) Cross section showing the outpouching of mucosa
through the muscularis propria.
Perforation
can result in pericolonic abscesses, sinus tracts, and, occasionally,
peritonitis.
Patients sometimes experience alternating constipation and
diarrhea that mimics IBS.
Even when diverticulitis
occurs, it most often resolves spontaneously.
Surgical
intervention is generally reserved for those with severe or
recurrent diverticulitis.
17.40A).
These are most common in the
sigmoid colon, but other parts of the colon may be affected.
17.40B, C).
Diverticular obstruction
induces inflammation, termed diverticulitis.
These lesions are without malignant
potential.
the gut microbiome, abnormal GI motility, and increased enteric
sensory responses to GI stimuli.
• IBD is an umbrella term for ulcerative colitis and Crohn disease.
Involvement
is discontinuous, resulting in skip lesions.
In affected areas disease
can be transmural, affecting the full thickness of the entire
bowel wall.
Noncaseating granulomas are common.
• Diverticular disease of the sigmoid colon is common inWestern
populations older than age 60.
The causes include low-fiber
diets, colonic spasm, and the unique anatomy of the colon.
They are smooth,
nodular protrusions of the mucosa, often on the crests of mucosal
folds.
17.41).
Serration is typically restricted
to the upper third of the crypt.
Most, if not all, polyps begin as small eleva-
tions of the mucosa.
Polyps with stalks are termed
pedunculated.
In general, intestinal polyps can be classified
as nonneoplastic or neoplastic.
The most common neoplastic
polyp is the adenoma, which has the potential to progress
to cancer.
Nonneoplastic polyps can be classified as inflam-
matory, hamartomatous, or hyperplastic.
(A) Polyp surface with irregular tufting
of epithelial cells.
(B) Tufting results from epithelial overcrowding.
An inflammatory polyp may
ultimately form as a result of chronic cycles of injury and
healing.
Entrapment of this polyp in the fecal stream leads
to mucosal prolapse.
17.42).
Several
of these syndromes are discussed below and others are
summarized in Table 17.9.
Many juvenile polyps are located in the rectum
and cause rectal bleeding.
Sporadic juvenile polyps, which are also referred to
as retention polyps, are usually solitary.
MORPHOLOGY
Most juvenile polyps are less than 3 cm in diameter.
17.43).
The
muscularis mucosae may be normal or attenuated.
These patients often have both juvenile polyposis
and hereditary hemorrhagic telangiectasia.
Together
these mutations account for fewer than half of patients.
Thus, other genes responsible for autosomal dominant
juvenile polyposis remain to be discovered.
A B C
Figure 17.42 Solitary rectal ulcer syndrome.
(B) Epithelial
hyperplasia.
Dysplasia is rare in sporadic juvenile polyps.
These lesions are similar to
freckles but are distinguished by their presence in the buccal
mucosa.
Peutz-Jeghers polyps can initiate intussusception,
which is occasionally fatal.
Grossly,
the polyps are large and pedunculated with a lobulated contour.
17.44).810 CHAPTER 17 The Gastrointestinal Tract
A
A
B
B
Figure 17.44 Peutz-Jeghers polyp.
Figure 17.43 Juvenile polyposis.
(A) Juvenile polyp.
Note the surface
erosion and cystically dilated crypts.
(B) Inspissated mucus, neutrophils,
and inflammatory debris can accumulate within dilated crypts.
adenocarcinomas.
Adenomas develop in approximately 30% of adults living
in the Western world by age 60.
The preferred approach to surveil-
lance varies, but colonoscopy is the most frequent mode.
As the name implies, tubulovillous adenomas have a mixed
architecture.
17.46D).
These may extend into, but not through, the muscularis mucosae.
17.47A).
17.47B),
constitutes invasive adenocarcinoma and carries a risk of spread
to other sites.
MORPHOLOGY
Colorectal adenomas are characterized by the presence
of epithelial dysplasia.
Typical adenomas range from 0.3 to
10 cm in diameter and can be pedunculated (Fig.
17.45B).
17.46C).
Pedunculated adenomas
have slender fibromuscular stalks (Fig.
17.45C) containing prominent
blood vessels derived from the submucosa.
The stalk is usually
covered by nonneoplastic epithelium, but dysplasia can be present.
Adenomas can be classified as tubular, tubulovillous, or
villous based on their architecture.
17.46A).
Size is the most important characteristic that
correlates with risk of malignancy.
A B C
Figure 17.45 Colonic adenomas.
(A) Pedunculated adenoma (endoscopic view).
(B) Adenoma with a velvety surface.
(A) Tubular adenoma with a smooth surface and rounded glands.
(B) Villous adenoma with long, slender
projections that are reminiscent of small intestinal villi.
(C) Sessile serrated adenoma lined by goblet cells without cytologic features of dysplasia.
Compare to the
hyperplastic polyp in Fig.
17.41.
17.48).
As a result, prophylactic colectomy is
the standard of care.
Colectomy prevents colorectal cancer,
but patients remain at risk for neoplasia at other sites.
The
ampulla of Vater and the stomach are common extracolonic
sites of adenomas in FAP patients.
A
B
Figure 17.47 Adenoma with carcinoma.
(B) Invasive adenocarcinoma
(left) beneath a villous adenoma (right).
Patients with HNPCC inherit
one mutant gene and one normal allele.
A
B
Figure 17.48 Familial adenomatous polyposis.
(A) Hundreds of small
polyps are present throughout this colon with a dominant polyp (right).
(B) Three tubular adenomas are present in this single microscopic field.
This autosomal recessive disorder is
termed MUTYH-associated polyposis, or MAP.
In contrast to
FAP, MAP is characterized by fewer than 100 polyps, which
appear at later ages.
Colon cancer development is also
delayed.
Epidemiology.
Colorectal adenocarcinoma is responsible
for nearly 10% of all cancer deaths worldwide.
In contrast, rates
are lower in South America, India, Africa, and South Central
Asia.
Colorectal cancer incidence peaks at 60 to 70 years of
age.
In addition to dietary modification, pharmacologic
chemoprevention is possible.
Aspirin and other NSAIDs
have a protective effect.
17.49).
Telomerase expression also increases
as lesions become more advanced.
These are referred to as
MSI high, or MSI-H, tumors.
17.50).
Loss of one normal copy of the tumor suppressor gene APC
occurs early.
Individuals born with one mutant allele are therefore at increased risk of developing colon cancer.
Alternatively, inactivation of APC in colonic
epithelium may occur later in life.
This is the “first hit” according to the Knudson hypothesis (Chapter 7).
The loss of the intact second copy of APC
follows (“second hit”).
If these mutations affect genes involved in cell survival and proliferation,
cancer may develop.
Activating mutations in the oncogene
BRAF are common in these cancers.
In contrast, KRAS
and TP53 are not typically mutated.
• A small group of colon cancers display increased CpG island
methylation in the absence of MSI.
Many of these tumors
harbor KRAS mutations, but TP53 and BRAF mutations
are uncommon.
desmoplastic response, which is responsible for their characteristic
firm consistency.
Some poorly differentiated tumors form few
glands (Fig.
17.52B).
Uncommonly, tumors may be composed of signet-
ring cells similar to those in gastric cancer (Fig.
17.52C).
Unfortunately, colorectal cancers develop insidiously and
may go undetected for long periods.
17.53A).
Metastases may involve regional
lymph nodes, lungs (Fig.
17.53C).
The TNM classifica-
tion is used to define tumor stage (Table 17.12).
Five-year survival rates vary widely worldwide.
17.51), sometimes to the point of obstruction.
Both forms
grow into the bowel wall over time.
17.52A).
(A) Circumferential, ulcerated rectal
cancer.
Note the anal mucosa at the bottom of the image.
Areas of chalky necrosis are
present within the colon wall (arrow).
A B C
Figure 17.52 Histologic appearance of colorectal carcinoma.
(A) Well-differentiated adenocarcinoma.
Note the elongated, hyperchromatic nuclei.
Necrotic
debris, present in the gland lumen, is typical.
A B
C
Figure 17.53 Metastatic colorectal carcinoma.
(A) Lymph node
metastasis.
Note the glandular structures within the subcapsular sinus.
(B)
Solitary subpleural nodule of colorectal carcinoma metastatic to the lung.
(C) Liver containing two large and many smaller metastases.
Note the
central necrosis within metastases.
ranges from 90% to 40% depending on stage.
They have no
malignant potential and must be distinguished from sessile
serrated polyps.
• Inflammatory polyps form as a result of chronic cycles of injury
and healing.
• FAP is caused by APC mutations.
• HNPCC is caused by mutations in DNA mismatch repair
enzymes.
17.54B).
Alternatively,
basaloid differentiation may be mixed with mucinous dif-
ferentiation.
17.54C).
The major risk factor for these HPV associated
lesions is anal sex.
Hemorrhoids may
also develop secondary to portal hypertension.
Except
for pregnant women, hemorrhoids are rarely encountered
in persons younger than age 30.
Extensive or severe internal or external hemorrhoids may
be removed surgically by hemorrhoidectomy.
Acute
CpG island hypermethylation underlies most remaining colon
cancers.
TUMORS OF THE ANAL CANAL
The anal canal can be divided into thirds.
17.54A).
A B C
Figure 17.54 Anal tumors.
The
adjacent rectal mucosa is normal.
TUMORS OF THE APPENDIX
Several tumors occur in the appendix.
The most common is
the well-differentiated neuroendocrine (carcinoid) tumor.
Mucinous neoplasms of the appendix occur in adults,
most often in the sixth decade of life.
Mucin can dissect through the wall to the peritoneal
surface, causing appendiceal rupture.
KRAS mutations
are also common.
When confined to the appendix,
prognosis of LAMN is excellent.
Outcomes are more variable
in HAMN.
They also occur in portal hypertension.
• Acute appendicitis is most common in children and adolescents.
It is thought to be initiated by increased intraluminal pressure
and compromised venous outflow.
• Peritoneal dissemination of mucinous neoplasms can cause
pseudomyxoma peritonei.
Diagnosis of acute appendicitis requires neutrophilic infiltration
of the muscularis propria.
In more severe cases a prominent
neutrophilic exudate generates a serosal fibrinopurulent reaction.
Regrettably, classic signs and symptoms of acute appendi-
citis are often absent.
As
with other causes of acute inflammation, there is neutrophilic
leukocytosis.
Damage to the bowel wall may allow bacteria
to spread to the peritoneal cavity.
• Endometriosis, which causes hemorrhage into the peritoneal
cavity, that acts as an irritant.
• Ruptured dermoid cysts, which release keratins and induce
an intense granulomatous reaction.
E.
coli, streptococci, S.
aureus,
enterococci, and C.
perfringens are implicated most often.
Spontaneous bacterial peritonitis develops in the absence
of an obvious source of contamination.
coli, streptococci, and Klebsiella species
are the most frequently involved organisms.
by dense fibrosis that may extend to involve the mesentery.
Peritoneal mesotheliomas are almost always
associated with high levels of asbestos exposure.
The
most common of these is desmoplastic small round cell tumor.
This is an aggressive tumor that occurs in children and young
adults.
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Jacobs D: Clinical practice.
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[Clinically oriented review of hemorrhoid management].
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[Overarching review of peritoneal
mesothelioma and evolving therapies].
The lobule model provides one useful way to consider
the anatomic organization of the liver (Fig.
18.1).
In this
model, the liver is divided into 1- to 2-mm hexagonal lobules
a The contributions of Drs.
BD, Bile duct; HA, hepatic artery; PV,
portal vein.
that are oriented around the terminal tributaries of the hepatic
vein.
Each lobule can be further subdivided into six
triangular acini.
18.1).
Between the trabecular plates
of hepatocytes are vascular sinusoids.
Hepatocytes are thus
bathed on two sides by a mixture of portal venous and
hepatic arterial blood.
The sinusoids are lined by fenestrated
endothelium.
These channels
drain into the canals of Hering that, in turn, connect to bile
ductules.
The ductules empty into the interlobular bile ducts
within portal tracts.
When injury is irreversible, hepatocytes may die by
necrosis or apoptosis.
18.2).
These changes are a result of caspase cascades described in
detail in Chapter 2.
18.3).
This may be seen in acute toxic or ischemic injuries or in
severe viral or autoimmune hepatitis.
Confluent necrosis
may begin with hepatocyte dropout in zone 3 near the central
vein.
In pan-acinar necrosis, the entire lobule is obliterated.
In some cases,
there is scar regression (described in the next section).
When quiescent, the main
function of stellate cells is lipid storage, including vitamin
A.
In Asia, acute hepatitis B and E
are the predominant causes.
An etiology
cannot be established in about 15% of adult and 50% of
pediatric cases.
18.4).Affected
livers are small and shrunken.
Typically, serum liver transaminases
are markedly elevated.
• Coagulopathy.
Thus, with liver
failure, factor deficiencies and coagulopathy develops.
However,
patients with fulminant hepatic failure from any cause
may develop hepatorenal syndrome.
A
B
Figure 18.4 (A) Massive necrosis, cut section of liver.
The liver is small
(700 g), bile-stained, soft, and congested.
(B) Hepatocellular necrosis
caused by acetaminophen overdose.
Confluent necrosis is seen in the
perivenular region (zone 3) (large arrow).
Residual normal tissue is
indicated by an asterisk.
(Courtesy Dr.
Encephalopathy may progress over days, weeks, or
months following acute liver injury.
Associated fluctuat-
ing neurologic signs include rigidity and hyperreflexia.
Figure 18.5 Cirrhosis resulting from chronic viral hepatitis.
Relief may only be found in liver transplantation.
• Impaired estrogen metabolism leads to hyperestrogenemia,
which has several effects.
Each
angioma is a central, pulsating, dilated arteriole from
which small vessels radiate.
In males, hyperestrogenemia
may also produce hypogonadism and gynecomastia.
The dominant intrahepatic cause is
cirrhosis, accounting for most cases of portal hypertension.
18.5).
18.6A).
Morphologic features of regression include
thin incomplete scars (see Fig.
(A) Thick bands of collagen separate rounded cirrhotic
nodules.
(B) After 1 year of abstinence, most scars are gone.
(Masson trichrome stain) (Courtesy Drs.
This is caused
by arterial vasodilation, primarily in the splanchnic circula-
tion.
These
are illustrated in Fig.
18.7 and are described next.
Ascites
usually becomes clinically detectable when at least 500 mL
have accumulated.
The fluid may contain a
scant number of mesothelial cells and mononuclear leukocytes.
These shunts
microcirculation such as nodular regenerative hyperplasia
(discussed later).
Pulmonary Complications of Liver Failure and Portal
Hypertension.
Patients with this
syndrome have a poorer prognosis than patients without
hepatopulmonary syndrome.
• Portopulmonary hypertension refers to pulmonary arterial
hypertension arising in liver disease.
The most common clinical
manifestations are dyspnea on exertion and clubbing of
the fingers.
In such patients, there is often estab-
lished cirrhosis with extensive vascular shunting.
The short-term mortality of patients with
this form of liver failure is around 50%.
Other causes of decompensation are systemic rather than
intrahepatic insults.
In women, oligomenorrhea,
amenorrhea, and sterility as a result of hypogonadism are frequent.
Clinically significant findings are in boldface.
may appear wherever the systemic and portal circulations
share capillary beds (see Fig.
18.7).
Although hemorrhoidal bleeding may occur,
it is rarely massive or life threatening.
Each episode of bleeding is associated with ~30%
mortality.
Splenomegaly
Long-standing portal hypertension may cause congestive
splenomegaly.
and nurseries.
Water-borne epidemics can occur in places
with overcrowded, unsanitary conditions.
Sexual transmission may occur,
but maternal-fetal transmission does not.
Ultrastructurally, HAV is an icosahedral capside
that is 27 nm in diameter.
Clinical Features
The incubation period for HAV is 2 to 6 weeks.
IgM antibody
against HAV appears with the onset of symptoms and
persists for 3 to 6 months (Fig.
18.8).
HAV is shed in the stool for 2 to 3 weeks
before and 1 week after the onset of jaundice.
HAV vaccine is effective in preventing infection.
18.9).
In high-prevalence
regions, transmission during childbirth accounts for 90%
of cases.
• HBV polymerase (Pol), which exhibits both DNA poly-
merase and reverse transcriptase activities.
It has been implicated in the pathogenesis of HBV-related
hepatocellular carcinoma.
HBV replication occurs through reverse transcription via
an RNA intermediate.
The host immune response to the virus is the main
determinant of the outcome of the infection.
Clinical Features
HBV has a prolonged incubation period (4 to 26 weeks).
18.10.
By contrast,
HBsAg persists in cases that progress to chronicity.
18.10A).
18.10B).
In such patients, the HBeAg may be low or undetectable
despite the presence of serum HBV DNA.
In most cases, the infection is self-limited and resolves
without treatment.
The infection persists and becomes
chronic in 5% to 10% of infected individuals.
(A) Acute infection with resolution.
(B) Progression to chronic infection.
Transfusion-related transmission has largely
disappeared in the United States.
Perinatal transmission can
occur in children.
Pathogenesis
HCV, discovered in 1989, is a member of the Flaviviridae
family.
The role of these proteins in the life cycle of HCV is sum-
marized in Fig.
18.11.
Anti-HCV antibodies
emerge 3 to 6 weeks after infection.
18.12).
reason), persistent infection and chronic hepatitis are the usual
outcome.
(A) Acute infection with resolution.
(B) Progression to chronic
infection.
Those who develop cirrhosis
are at risk for development of hepatocellular carcinoma.
18.11).
HCV appears to be cured
in >99% of patients who achieve a sustained viral response.
HDV is uncommon in Southeast Asia
and China.
Pathogenesis
HDV, discovered in 1977, is a 35-nm, double-shelled particle.
Replication of the virus is through RNA-
directed RNA synthesis by host RNA polymerase.
• Co-infection occurs following exposure to serum containing
both HDV and HBV.
Co-infection can result in acute
hepatitis that is indistinguishable from acute hepatitis
B.
It is self -limited and is usually followed by clearance
of both viruses.
However, there is a higher rate of acute
hepatic failure in intravenous drug users.
• Superinfection occurs when a chronic carrier of HBV
is exposed to a new inoculum of HDV.
Co-infection with HDV and HBV increases the risk of
progression to cirrhosis and HCC.
Newer agents targeting viral
entry and replication are in clinical trials.
Vaccination for
HBV also prevents HDV infection.
IgM is replaced with persistent IgG
anti-HEV antibodies during recovery.
Chronic liver disease or persistent viremia in immuno-
competent patients is not observed.
Table 18.3 provides a summary of the salient features of
infection by various hepatitis viruses.
Acute infections by
all of the hepatotropic viruses can either be asymptomatic
or symptomatic.
From Washington K: Inflammatory and infectious diseases of the liver.
In contrast, HCV is notorious for progressing to
chronic infection.
HEV can cause acute liver failure in pregnant
women.
• Acute asymptomatic infection with recovery.
• Acute symptomatic infection with recovery.
The incubation period
for the different viruses is given in Table 18.3.
• Acute liver failure.
Viral hepatitis accounts for approxi-
mately 10% of cases of acute hepatic failure.
• Chronic hepatitis.
• Carrier state.
A “carrier” is an individual who harbors
and can transmit an organism, but has no symptoms.
In both cases, particularly
the latter, affected individuals constitute reservoirs of
infection.
18.11).
For HCV, a state equivalent to the HBV
“healthy carrier” is not recognized.
HIV is an important comorbid factor in hepatotropic
viral infections.
MORPHOLOGY
The general morphologic features of viral hepatitis are depicted
schematically in Fig.
18.4).
18.2 and 18.3), often
with pigmented macrophages scavenging the dead cell debris.
Liver failure can develop with
massive hepatic necrosis.
This may be accompanied by a variable degree of lobular
inflammation.
Fibrous septa
develop and lead to portoportal bridging fibrosis, and eventually
cirrhosis.
Immunostaining for hepatitis B surface and core antigens can
confirm the HBV infection (Fig.
18.14).
18.15).
Steatosis is common in
chronic hepatitis C, and can be marked with genotype 3 infection.
Bridging necrosis can occur in severe acute hepatitis, and
fibrosis is seen in chronic hepatitis.
Ductular reaction is often present in areas of fibrosis in chronic hepatitis.
Hydatid cysts are
usually caused by echinococcal infections (Chapter 8).
Hydatid cysts are uncom-
mon in high income countries.
There
is a female predominance (78%).
A
B
Figure 18.15 Chronic viral hepatitis due to hepatitis C virus.
(A)
Characteristic portal tract expansion by a lymphoid aggregate.
(B) Delicate
bridging fibrosis, seen later in the disease course.
When severe,
this may extend to the liver and produce intrahepatic
abscesses.
Liver abscesses are associated
with fever, right upper quadrant pain, and tender hepato-
megaly.
Jaundice may result from extrahepatic biliary
obstruction.
Numerous
plasma cells in clusters are typical (Fig.
18.16).
Compatible: Chronic hepatitis with lymphocytic infiltration without features
considered typical.
Atypical: Showing signs of another diagnosis like nonalcoholic fatty liver disease.
Figure 18.16 Autoimmune hepatitis.
A focus of lobular hepatitis with
prominent plasma cells typical for this disease is shown.
often at the interface, a curious phenomenon called emperipolesis.
Serum IgG is often elevated
in autoimmune hepatitis and may provide another clue to
the diagnosis.
Other immunosuppressants are used if the
side effects of steroids cannot be tolerated.
Liver transplantation may be
necessary for cirrhotic patients.
Based on U.S.
Pathogenesis
Principles of drug and toxic injury are discussed in Chapter
9.
In most instances, the injury is mediated by reactive
metabolites generated in the liver.
Drug-induced liver injury can be idiosyncratic (unpredict-
able) or dose-dependent (predictable).
It is
thought that there is genetic susceptibility in those who
have idiosyncratic reactions.
Modified from Washington K: Metabolic and toxic conditions of the liver.
While suicide attempts with acet-
aminophen are common, so are accidental overdoses.
• Correlation of temporal profile of drug intake and onset of
disease is necessary for diagnosis.
MORPHOLOGY
Drugs can lead to one or more patterns of injury.
Progression to
chronic hepatitis, and even cirrhosis, can be seen in a small minority
of cases.
Injury caused by intrinsic hepatotoxins is dominated by
necrosis with minimal inflammation.
Some agents produce other patterns of injury.
Pathogenesis
The pharmacokinetics and metabolism of alcohol are
described in Chapter 9.
However,
only 10% to 15% of alcoholics develop cirrhosis.
Thus, other
factors also influence the development and severity of
alcoholic liver disease.
These include:
• Gender.
• Ethnic and genetic differences.
Comorbid conditions.
Several factors appear to contribute to steatosis.
• CYP2E1 induction.
• Methoinine metabolism.
18.17).
Hepatic steatosis (fatty liver)
is an early, predictable effect of alcohol consumption.
After even
moderate intake of alcohol, lipid droplets accumulate in hepatocytes.
18.18).
Steatosis may be separated into microvesicular and macrovesicular
forms.
18.19).
18.19B).
Mallory hyaline may reflect a failed attempt to
sequester and degrade damaged cytoplasmic proteins.
• Inflammation and necrosis.
• Perivenular/pericellular fibrosis.
Steatohepatitis is often accompanied
by fibrosis.
18.18).
18.20).
Complete regression of alcoholic cirrhosis, although reported,
is rare.
Severe hepatic dysfunction is unusual.
Alcohol withdrawal
and consumption of an adequate diet are sufficient treat-
ment.
Some fibrosis (stained blue)
is present in a characteristic perisinusoidal chicken wire pattern.
(Masson
trichrome stain).
(Courtesy Dr.
Elizabeth Brunt, Washington University, St.
Mallory hyaline is present in another
hepatocyte (arrow).
(B) Alcoholic hepatitis with many ballooned hepatocytes (arrowheads).
Elizabeth Brunt, Washington
University, St.
Louis, Mo.)
than serum ALT levels by a ratio of 2 : 1 or greater.
This
finding can be particularly helpful in the setting of occult
alcoholism.
The outlook is unpredictable; each episode of hepatitis
incurs about a 10% to 20% risk of death.
With repeated
bouts, cirrhosis develops in about one-third of patients within
a few years.
Alcoholic hepatitis also may be superimposed
on established cirrhosis.
With proper nutrition and total
cessation of alcohol consumption, alcoholic hepatitis may
clear.
The manifestations of alcoholic cirrhosis are similar to
those of other forms of cirrhosis.
The long-term outlook for alcoholics with liver disease
is variable.
A
B
Figure 18.20 Alcoholic cirrhosis.
The greenish tint is caused by
cholestasis.
increases in mass but also becomes dysfunctional.
The dysfunctional
adipocytes also synthesize pro-inflammatory cytokines
such as TNF- α.
The net effect of these changes is to cause lipid to accu-
mulate in hepatocytes.
Pathogenesis
The precise mechanisms underlying NAFLD are unknown.
18.21).
Determination of the extent of fibrosis is important for clinical
management.
Pediatric NAFLD differs significantly from adult NAFLD.
Clinical Features
The varied clinical course of individuals with NAFLD is
summarized in Fig.
18.22.
Individuals with only steatosis
are generally asymptomatic.
Imaging studies may reveal fat accumulation in the
liver.
Liver biopsy is required for diagnosis of NASH and
aids in assessment of fibrosis.
Serum AST and ALT are elevated in most
patients with NASH.
Despite the enzyme elevations, patients
may be asymptomatic.
(A) Liver with mixed small
and large fat droplets as well as ballooned hepatocytes.
Note the resemblance to alcoholic hepatitis depicted in Fig.
18.18.
None to very minimal
progression to cirrhosis
2.
abnormalities in NASH.
Its histologic features
differ somewhat from those seen in adults.
The disease
typically manifests after 20 g of stored iron has accumulated.
18.23).
Due to these activities, an
increase in hepcidin lowers plasma iron levels.
Conversely,
an abnormal deficiency of hepcidin causes iron overload.
Other proteins involved in iron metabolism do so by regulat-
ing hepcidin levels.
The classification of the
various causes of iron overload is shown in Table 18.7.
Table 18.7 Classification of Iron Overload
I.
Hemochromatosis
TFR2
TFR1 Iron
Enterocyte
Figure 18.24 Hereditary hemochromatosis.
In this Prussian blue–stained
section, hepatocellular iron appears blue.
The parenchymal architecture is
normal.
18.24).
Iron is a direct hepatotoxin, and inflammation
is characteristically absent.
The heart is often
enlarged and exhibits hemosiderosis, producing a striking brown
coloration.
Both organs may develop fibrosis.
The combination of these
pigments imparts a characteristic slate-gray color to the skin.
With hemosiderin deposition in joint linings, an acute synovitis
may develop.
This in turn
reduces efflux of iron from enterocytes.
Through these regulatory
interactions, normal iron absorption is maintained.
hepcidin synthesis.
Death may result
from cirrhosis or cardiac disease.
Fortunately, hemochromatosis is often diagnosed
before irreversible tissue damage has occurred.
Further evaluation
includes exclusion of secondary causes of iron overload.
With treatment, life expectancy is normal.
Ceruloplasmin accounts for 90% to 95% of plasma
copper.
Eventually cirrhosis supervenes.
Histochemical copper staining is not sensitive or specific for
diagnosis of Wilson disease.
Its clinical presentation
is extremely variable.
Some patients present with acute or
chronic liver disease.
Patients may also
have psychiatric symptoms.
Demon-
stration of Kayser-Fleischer rings by slit examination also
is diagnostically helpful.
lead to apoptosis (Chapter 2).
α1 AT is a small 394–amino acid plasma glycoprotein
synthesized predominantly by hepatocytes.
It is a member
of the serine protease inhibitor (serpin) family.
The most common genotype is PiMM, occurring in
90% of individuals (the “wild type”).
These individuals
are at high risk for developing clinical disease.
Among people of northern European descent, the
PiZZ state affects 1 in 1800 live births.
18.26).
(2) Extrahepatic bilirubin
is bound to serum albumin and delivered to the liver.
(5) Gut bacteria deconjugate the bilirubin
and degrade it to colorless urobilinogens.
The urobilinogens and the residue
of intact pigment are largely excreted in feces.
Jaundice becomes evident when the serum bili-
rubin levels rise above 2 to 2.5 mg/dL.
This form
is largely insoluble and cannot be excreted in the urine.
With this as an overview, we next discuss hepatobiliary
disorders that lead to hyperbilirubinemia.
Hence, transient and mild unconjugated
hyperbilirubinemia is nearly universal in the first week.
18.27).
Rupture of canaliculi can lead to extravasation of bile, which is
phagocytosed by Kupffer cells.
Cholangitis
usually presents with fever, chills, abdominal pain, and
jaundice.
Severe cases can result in abscess formation, sepsis,
and death.
18.28).
In ascending
cholangitis, the neutrophils also involve the bile duct epithelium
and lumens (Fig.
18.29).
Persistent obstruction leads to fibrosis,
which can eventually proceed to biliary cirrhosis (Fig.
18.30).
B
C
Figure 18.27 Cholestasis.
(A) Morphologic features of cholestasis (right)
and comparison with normal liver (left).
Cholestatic hepatocytes (1) are
enlarged with dilated canalicular spaces (2).
(B) Intracellular cholestasis showing the bile pigments in the cytoplasm.
(C) Bile plug (arrow) showing the expansion of bile canaliculus by bile.
to conjugated hyperbilirubinemia.
Both are autosomal
recessive disorders and clinically innocuous.
Figure 18.28 Acute large duct obstruction.
Neutrophils are seen within the bile duct epithelial lining and within the
lumen.
Figure 18.31 Ductular cholestasis of sepsis.
(Courtesy Dr.
18.31).
Inflammation and
hepatocellular injury is typically mild.
The disease is highly prevalent in East Asia, but is rare in
other parts of the world.
18.32).The ducts show chronic inflam-
mation, mural fibrosis, and peribiliary gland hyperplasia.
Obstruction
of extrahepatic ducts is not present.
B
Figure 18.30 Biliary cirrhosis.
Other
etiologies of obstructive biliary diseases like cystic fibrosis
also must be excluded.
Liver transplantation is the only option when surgical
intervention is not feasible.
Figure 18.32 Hepatolithiasis.
(Courtesy Dr.
Wilson M.S.
Infections, toxic agents, and
autoimmune injury have been invoked, but the cause is
unknown.
If left uncorrected, cirrhosis can develop by
3 to 6 months of age.
18.33).
Reactive Kupffer cells and extramedullary hematopoiesis
are usually present.
The features of these two conditions are
contrasted in Table 18.10.
Large intrahepatic ducts and the extrahepatic
biliary tree are not involved.
Family members
of PBC patients have an increased risk for development of
the disease.
Other autoantibodies against nuclear pore proteins
and centromeric proteins may also be present.
18.34).
Disease progression leads to
loss of small intrahepatic bile ducts (“ductopenia”).
PSC tends to occur in the
third through fifth decades and has a 2 : 1 male predominance.
Figure 18.34 Primary biliary cholangitis.
accumulation in PBC is not centrizonal, but is seen in periportal/
periseptal regions.
End-stage disease
culminates in cirrhosis.
Hypercholesterolemia is
common.
Splenomegaly and jaundice are seen in advanced
disease.
For uncertain reasons, many
patients also have elevated serum levels of IgM antibody.
Lithiasis can develop
in the dilated ducts.
18.35), eventually
leading to obliteration by a “tombstone” scar.
Progression of cholestasis and fibrosis culminates in biliary cirrhosis.
The endoscope is visible, giving a
sense of scale.
(Courtesy Dr.
M.
Edwyn Harrison, MD, Mayo Clinic,
Scottsdale, Ariz.)
Figure 18.35 Primary sclerosing cholangitis.
A degenerating bile duct is
entrapped in a dense, “onion-skin” concentric scar.
Clinical Features
The most common presenting symptoms are fatigue, pruritus,
and jaundice.
Ascending cholangitis can also be the initial presentation.
Fibrosis and eventually cirrhosis can occur.
18.36).
This is referred to as small-duct PSC and can progress to
typical large-duct PSC.
In 5% to 10% of cases, autoimmune hepa-
titis is present along with PSC.
The disease typically follows a protracted course leading
to cirrhosis over 10 to 15 years.
The lifetime risk of developing
cholangiocarcinoma is 20%.
Liver transplantation is
the treatment of choice for end-stage liver disease.
Ascending cholangitis may develop.
Chronic obstruction can
lead to cirrhosis.
It predisposes to cholangiocarcinoma.
The diagnosis is established by
visualization of the biliary tree.
Patients are at risk for
developing cholangiocarcinoma.
Hepatic etiologies860 CHAPTER 18 Liver and Gallbladder
that are typical of biliary colic.
Approximately 20% of cases
become symptomatic only in adulthood.
The female-to-male ratio is 3 : 1 to 4 : 1.
There
also is an increased risk of developing bile duct carcinoma.
Lesions may be found
incidentally during radiographic studies, surgery, or autopsy.
Persons with fibropolycystic liver disease are at increased
risk for cholangiocarcinoma.
18.37).
Occasional von Meyenburg complexes are
common in otherwise normal individuals.
• Single or multiple intrahepatic or extrahepatic biliary cysts.
When present in isolation, these may be symptomatic
due to ascending cholangitis.
Multifocal cystic dilation
of the large intrahepatic bile ducts is referred to as Caroli
disease.
18.38).
Ducts may be cystically
dilated, but true cysts are also present.
These may be
intrahepatic cysts or choledochal cysts, as described
earlier.
18.39).
Figure 18.38 Congenital hepatic fibrosis with multiple biliary cysts.
Figure 18.37 Von Meyenburg complex (bile duct hamartoma).
Dilated
irregular bile ducts with curvilinear outlines thought to represent ductal
plate formation.
Figure 18.39 Congenital hepatic fibrosis.
Broad bands of fibrosis with
dilated remnants of ductal plates.
18.40).
18.41).
Underlying causes may include neoplasia,
polyarteritis nodosa (Chapter 11), or sepsis.
Figure 18.41 Liver infarct.
Many such patients have an
underlying thrombophilic genotype (e.g., Factor V Leiden,
Chapter 4).
It is
particularly common in India, although the incidence
appears to be declining.
Patients often present with upper
gastrointestinal bleeding.
The pathogenesis is unknown.
Lesions usually disappear after
correction of the underlying cause.
Obstruction of a single main hepatic
vein by thrombosis is clinically silent.
Hepatic damage is
the consequence of increased intrahepatic blood pressure.
18.43).
Pericentral/sinusoidal fibrosis develops in instances in
which thrombosis develops more slowly.
The major veins contain
thrombi showing various degrees of organization.
Clinical Features
The mortality of untreated acute hepatic vein thrombosis
is high.
Prompt surgery to create a portosystemic venous
Figure 18.42 Sickle cell crisis in liver.
The photomicrograph shows
several sinusoids containing “sickled” red cells (arrow).
Figure 18.43 Budd-Chiari syndrome.
The chronic form is far less
lethal, and more than two-thirds of patients are alive after
5 years.
The mortality rate is up to 80% in severe
disease.
Microscopically, there is congestion of dilated
centrilobular sinusoids.
18.45A).
This finding is known as nutmeg liver due to its resemblance
to the cut surface of a nutmeg.
18.44).
• The most common cause of impaired intrahepatic blood flow
is cirrhosis.
Figure 18.44 Sinusoidal obstruction syndrome.
In a
very small subgroup of pregnant women (0.1%), more serious
hepatic complications develop.
In extreme cases,
eclampsia and acute fatty liver of pregnancy may be fatal.
Here we focus on
the hepatic pathology of these entities.
AB hepatic rupture in eclampsia (Fig.
18.46).
Portal tracts and the periportal parenchyma are intact.
Mild cases may be managed
conservatively.
Termination of pregnancy is required in
severe cases.
Women who survive mild or severe preeclamp-
sia recover without sequelae.
Viral hepatitis (HAV, HBV, HCV, or HBV + HDV)
is the most common cause of jaundice in pregnancy.
The liver may also be secondarily
involved by other infections during pregnancy.
Figure 18.46 Eclampsia.
Subcapsular hematoma dissecting under Glisson
capsule in a fatal case.
(Courtesy Dr.
It is a
rare disease affecting approximately 1 in 16,000 pregnant
women.
Thus, this
may be a rare instance of the fetus causing metabolic disease
in the mother.
Cholestasis may also be present.
18.47A).
Most
lesions are 5 cm or less in diameter.
18.47B).
A prominent ductular
reaction is often present, but interlobular bile ducts are absent.
The primary
treatment is termination of pregnancy.
Affected women
present in the latter half of pregnancy, usually in the third
trimester.
In 20% to 40% of cases, the presenting
symptoms may be those of coexistent preeclampsia.
The level of bile salts is increased
greatly.
There
is a modest risk of fetal loss, and the condition may recur in
subsequent pregnancies.
FNH is a benign lesion and does
not need any treatment.
Resection is performed for large
symptomatic lesions.
Histologically, the tumor consists of dilated thin-walled
vascular channels (Fig.
18.48).
Most are asymptomatic and
are detected incidentally by imaging.
• Hepatocyte nuclear factor 1-alpha (HNF1 α)-inactivated
hepatocellular adenoma.
This subtype accounts for 40% to 50% of cases,
A
B
Figure 18.47 Focal nodular hyperplasia.
(A) Resected specimen showing
lobulated contours and a central stellate scar.
syndrome, hemangioma, and vascular malformations.
NRH can lead to portal
hypertension and mimic cirrhosis on imaging.
Both are asymptomatic and generally less than 2 cm.
The latter are thought to be a remnant
of ductal plate malformation.
Figure 18.48 Cavernous hemangioma.
Nearly 40% occur
in men.
18.50B).
18.50C).
Primary Malignant Neoplasms
Malignant tumors in the liver can be primary or metastatic.
Hepatoblastoma is a rare hepatocellular tumor that
occurs in the pediatric setting.
Nonepithelial tumors, such
as angiosarcoma, are exceedingly rare.
Hepatoblastoma
Hepatoblastoma is the most common liver tumor of early
childhood.
It rarely occurs over the age of 3 years, and its
incidence is increasing.
18.49).
18.50A).
A
B
Figure 18.49 Hepatocellular adenoma.
(A) Resected specimen showing a
well-define tan mass in the liver.
(A) HNF1α-inactivated hepatocellular adenoma.
(B) Hepatocellular adenoma with β-catenin
activation.
(C) Inflammatory hepatocellular adenoma.
The tumor is treated with surgical resection and chemo-
therapy, which has improved outcomes.
The overall 5-year
survival rate is approximately 80%.
18.52).
The tumor cells are arranged in sheets
and resemble embryonal and fetal hepatocytes.
MORPHOLOGY
A
Several precursor lesions for HCC have been described.
18.53).
18.53A).
18.53B).
More ominous are nodular lesions
B
Figure 18.52 Hepatocellular carcinoma.
(A) Liver removed at autopsy
showing a unifocal neoplasm replacing most of the right hepatic lobe.
A
such as hereditary hemochromatosis and α1-antitrypsin
deficiency, and alcoholic liver disease.
Nonalcoholic fatty
liver disease also increases the risk of HCC, even in the
absence of cirrhosis.
(A) Large cell change.
(B) Small cell change.
The abnormal cells have a high nuclear-to-cytoplasmic ratio and are
separated by thickened plates.
Normal-appearing hepatocytes are in the
lower-right corner.
(Courtesy Dr.
18.54),
which are often associated with small cell change.
18.54B).
HCC may form a single mass or multiple discrete masses, or
it may diffusely infiltrate the liver.
They may be pale and yellow
due to fatty change or green due to cholestasis.
A
B
Figure 18.55 Fibrolamellar carcinoma.
(A) Resected specimen showing a
well-demarcated nodule.
18.55).
Features of underlying chronic liver disease
can be present.
Ultrasonography is used for
screening high-risk patients such as those with cirrhosis.
Nodule-in-nodule growth suggests an evolving cancer.
(Courtesy Dr.
Masamichi Kojiro, Kurume University, Kurume, Japan.)The liver and bile ducts 871
adequate function.
Liver transplantation is considered for
HCC in the setting of advanced cirrhosis.
Hematogenous metastases,
especially to the lung, tend to occur late in the disease.
Lymph node metastases occur in <5% of cases.
Intrahepatic cholangiocarcinoma
is the most common primary malignant tumor of the liver
after HCC.
Its incidence is rising in the United States.
It
accounts for 7.6% of cancer deaths worldwide and 3% of
cancer deaths in the United States.
KRAS mutations are common in both tumors.
Fusion genes involving
FGFR2 (fibroblast growth factor receptor 2) are also common.
A
B
C
Figure 18.56 Cholangiocarcinoma.
(B) Invasive malignant glands in a reactive, sclerotic stroma.
(A, Courtesy Dr.
Wilson M.S.
18.56) and typically forms a firm gray-white mass.
The liver weight can exceed several
kilograms.
Metastasis may also appear as a single nodule,
in which case it may be resected surgically.
Microscopically, both intrahepatic and extrahepatic tumors
show features of adenocarcinomas.
18.56B).
Lymphovascular and
perineural invasion (see Fig.
Tumor resection with negative margins and
absence of lymph node involvement are favorable factors.
Lymph node metastasis is present in 50% to 60% of patients
at presentation.
Adjuvant chemotherapy is commonly given
after resection, but tumor responses are usually transient.
Other Primary Hepatic Malignant Tumors
A number of other cancers may arise within the liver.
These tumors have the same risk factors
as HCC.
This tumor has become rare with reduced exposures to
these agents.
These tumors have a poor
prognosis.
Gallbladder
As much as 1 L of bile is secreted by the liver per day.
Between meals, bile is stored in the gallbladder, where it
is concentrated.
The adult gallbladder has a capacity of
about 50 mL.
A longitudinal or transverse septum may create
a bilobed gallbladder.
A
folded fundus is the most common anomaly, creating a
phrygian cap (Fig.
18.57).
• Acquired disorders.
• Hereditary factors.
sinensis increases the
Figure 18.57 Phrygian cap of the gallbladder; the fundus is folded inward.
CHOLELITHIASIS (GALLSTONES)
More than 95% of biliary tract disease is attributable to
gallstones.
Gallstones afflict 10% to 20% of adult populations
in high income countries.
Significant associations are
also seen with metabolic syndrome and obesity.
• Environmental factors.
The wall of the gallbladder is
thickened and fibrotic due to chronic cholecystitis.
Figure 18.59 Cholesterolosis.
Gallbladder mucosa demonstrates lamina
propria distended by foamy macrophages.
likelihood of pigment stone formation.
In hemolytic anemias,
the secretion of conjugated bilirubin into bile increases.
salts, while brown stones, which contain calcium soaps, are
radiolucent.
Mucin glycoproteins constitute the scaffolding and
interparticle cement of all types of stones.
Multiple stones are usually present that range up
to several centimeters in diameter.
Rarely, a very large stone may
virtually fill the fundus.
Surfaces of stones may be rounded or
faceted because of tight apposition to adjacent stones.
18.59).
Pigment gallstones are brown to black.
18.60), and are quite friable.
Their contours are
usually spiculated and molded.
Brown stones tend to be laminated
and soft and may have a soaplike or greasy consistency.
Gallstones also are associated with an increased risk of
gallbladder carcinoma (discussed later).
It almost always occurs in
association with gallstones.
In the United States, cholecystitis
is one of the most common indications for abdominal surgery.
Its epidemiology closely parallels that of gallstones.
The action of mucosal phospholipases hydrolyzes luminal
lecithins to toxic lysolecithins.
Acute acalculous cholecystitis is thought to result
from ischemia.
The cystic artery is an end artery without
a collateral circulation.
It usually occurs in acutely ill patients who are
hospitalized for unrelated conditions.
When the
exudate is virtually pure pus, the condition is referred to as
gallbladder empyema.
In mild cases, the gallbladder wall is
thickened, edematous, and hyperemic.
Neutrophils are typically sparse, unless there
is superimposed infection.
It is frequently associated with mild fever,
anorexia, tachycardia, sweating, nausea, and vomiting.
Mild
to moderate leukocytosis may be accompanied by modestly
elevated serum alkaline phosphatase.
Recurrence is common in patients who recover
without surgery.
In rare instances, primary bacterial infection
by agents such as S.
typhi and staphylococci can give rise
to acute acalculous cholecystitis.
Microorganisms, usually E.
coli and enterococci, are cultured
from the bile in about one-third of cases.
Unlike acute
calculous cholecystitis, obstruction of gallbladder outflow
is not a prerequisite.
The serosa is usually smooth
and glistening but may be dulled by subserosal fibrosis.
Dense
fibrous adhesions may be present that represent the sequelae of
prior acute inflammation.
On sectioning, the wall is variably
thickened and has an opaque gray-white appearance.
In uncom-
plicated cases, the lumen contains green-yellow, mucoid bile and
usually stones.
The mucosa itself is generally preserved.
On histologic examination, the degree of inflammation is
variable.
18.61A).
18.61B).
B
Figure 18.61 Chronic cholecystitis.
(A) The gallbladder mucosa is
infiltrated by inflammatory cells.
(B) Outpouching of the mucosa through
the wall forms Rokitansky-Aschoff sinus (contains bile).
recurrent attacks of either steady epigastric or right upper
quadrant pain.
Nausea, vomiting, and intolerance for fatty
foods are frequent accompaniments.
Approximately
6000 new cases of gallbladder cancer are diagnosed each
year in the United States.
As is typical of
TP53-mutated cancers, most gallbladder carcinomas exhibit
aneuploidy.
A
B
Figure 18.62 Gallbladder adenocarcinoma.
(A) The opened gallbladder
contains a large, exophytic tumor that virtually fills the lumen.
(B)
Malignant glands are seen infiltrating a densely fibrotic gallbladder wall.
Gallbladder cancers are mainly adenocarcinomas and are most
often detected in the fundus (Fig.
18.62).
and nausea and vomiting.
• Gallstones are common in Western countries.
The great majority
are cholesterol stones.
Pigmented stones containing bilirubin
and calcium are most common in Asian countries.
Gallstones are also a risk factor for gallbladder
cancer.
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Lefkowitch JH: The pathology of acute liver failure, Adv Anat Pathol
23(3):144–158, 2016.
doi:10.1097/PAP.0000000000000112.
PubMed
PMID: 27058243.
Review, [An excellent review of the pathology of acute
liver failure].
Expert Rev Gastroenterol
Hepatol 12(6):565–573, 2018.
[An excellent perspective on why
and how hepatitis C can be cured].
[Review
of diagnosis, screening and treatment guidelines for hepatitis C].
Joyce MA, Tyrrell DL: The cell biology of hepatitis C virus, Microbes
Infect 12:263, 2010.
[What we understand and do not understand about
hepatitis C virus and the cells it infects].
[Review of
hepatitis B virus infection].
doi:10.1016/j.humpath.
2019.10.003.
pii: S0046-8177(19)30179-0.
[Epub ahead of print], [Review
of hepatitis E virus infection].
[Review of pathogenesis of AIH].
[A still relevant set of criteria for
diagnosing autoimmune hepatitis].
[Review of diagnosis
and treatment guidelines for PBC].
[Review
of all aspects of PSC].
[A comprehensive and
current review].
[Recent review of the pathology of alcoholic liver
disease].
[As authoritative as one can be on the topic].
• Acute calculous cholecystitis is the most common reason for
emergency cholecystectomy.
• Gallbladder cancers are associated with gallstones in the vast
majority of cases.
Typically, they are detected late because of
nonspecific symptoms and hence carry a poor prognosis.
Koyama Y, Brenner DA: Liver inflammation and fibrosis, J Clin Invest
127(1):55–64, 2017.
doi:10.1172/JCI88881.
[Epub 2017 Jan 3].
PubMed
PMID: 28045404.
Quaglia A, Alves VA, Balabaud C et al: International Liver Pathology
Study Group.
doi:10.1111/
his.12957.
[Epub 2016 Apr 28].
PubMed PMID: 26918878.
PubMed PMID: 10573521.
[The meticulous histopathologic identification
of a stem cell niche in liver].
Wanless IR, Nakashima E, Sherman M: Regression of human cirrhosis.
Pathology history happening before your eyes].
[An excellent clinical review].
[About the
most common cause of acute liver failure leading to transplantation].
Khungar V, Poordad F: Hepatic encephalopathy, Clin Liver Dis 16:301,
2012.
[A good overview of the one of the most ominous sequelae of all forms
of liver failure].
[A classic paper in liver pathology].
[A thorough overview of the most common features of liver
disease].
[How bench-top work comes to exert
an impact on clinical medicine, sometimes slowly over decades].
[Provides a review of the spectrum of histologic changes and a unifying
nomenclature].
Adv Anat Pathol 25(4):254–262, 2018.
[Review of epidemiology ad trends in hepatocel-
lular carcinoma and cholangiocarcinoma].
[Review of epidemiology, pathogenesis, and management of
cholangiocarcinoma].
[Review of guidelines for diagnosis and management of HCC].
19.1A).
The exocrine pancreas constitutes 80% to 85% of the
organ and is composed of acinar cells.
Islet cells secrete insulin,
glucagon, somatostatin, and pancreatic polypeptide.
Diseases of the endocrine
pancreas are described in detail in Chapter 24.
The pancreas normally arises from the fusion of dorsal and
ventral outpouchings of the foregut.
Pancreas Divisum.
19.1A).
Annular Pancreas.
Annular pancreas can
produce duodenal obstruction.
Ectopic Pancreas.
The favored sites for ectopia are
aI am grateful for the immense contributions of Ralph H.
Hruban
and Christine A.
Iacobuzio-Donahue, who authored this chapter
in the prior edition of this book.
Many of the photomicrographs
used in this chapter are contributed by Dr.
Hruban.
A.
Acute attacks may range
from mild and self-limited to life-threatening events.
Recur-
rent or persistent pancreatitis may lead to permanent loss
of pancreatic function.
Biliary tract disease
and alcoholism account for approximately 80% of these cases
(Table 19.1).
PANCREAS
DIVISUM
Minor
sphincter
Papilla
of Vater
Figure 19.1 Pancreatic ductal anatomy.
(A) Normal ductal anatomy.
(B) Ductal anatomy in pancreatic divisum.
Agenesis.
Very rarely the pancreas fails to develop (agen-
esis).
Under
normal circumstances, several factors protect the pancreas
from autodigestion.
Acinar
cells can be damaged by a variety of endogenous, exog-
enous, and iatrogenic insults.
Increased calcium flux is another important trigger
for inappropriate enzyme activation.
Calcium has a key
role in trypsin regulation.
Examples
include inherited abnormalities that affect calcium levels
(Table 19.2).
It is not clear if this mecha-
nism is relevant to human acute pancreatitis.
Thus, key aspects of the pathophysiology of alcohol-
induced pancreatitis remain obscure.
• Genetic lesions, as described below.
• Medications.
• Ischemic acinar cell injury due to shock, vascular thrombosis,
embolism, or vasculitis.
Three genes implicated in hereditary pancreatitis deserve
special note: PRSS1, SPINK1, and CFTR.
The extent of each of these depends on the duration and severity
of disease.
19.3).
In acute necrotizing pancreatitis, acini, ducts, and even
islets undergo necrosis.
19.4).
Glycosuria occurs in 10% of cases, and hypocalcemia may
result from saponification of necrotic fat.
Acute
respiratory distress syndrome and acute renal failure are
ominous complications.
Possible sequelae include sterile
pancreatic abscesses and pancreatic pseudocysts.
Systemic organ failure and pancreatic necrosis are
both adverse prognostic indicators.
Clinical Features
Abdominal pain is the cardinal manifestation of acute
pancreatitis.
The severity ranges from mild discomfort
to incapacitating pain.
Anorexia, nausea, and vomiting are
common.
Severe acute pancreatitis is a medical emergency.
19.5).
The most common cause of chronic
pancreatitis is long-term alcohol use.
19.6A).
In this case, an IgG4 stain confirmed abundant IgG4-expressing plasma cells.
(C, Photomicrograph courtesy Aatur D.
Visualization of calcifications within the
pancreas by CT and ultrasonography can be very helpful.
In other patients, severe, chronic pain is a dominant
problem.
Pancreatic pseudocysts (described later) develop in
about 10% of patients.
be atrophic, hyperplastic, or metaplastic (squamous).
19.6B).
19.6C).The last-mentioned may
also be seen in other organs.
Diagnosis of chronic pancreatitis requires a high degree
of suspicion.
During an attack there may be mild fever and
mild-to-moderate elevations of serum amylase.
NONNEOPLASTIC CYSTS
A variety of cysts can arise in the pancreas.
Most are non-
neoplastic pseudocysts, but congenital cysts and neoplastic
cysts also occur.
Cysts
in the kidney, liver, and pancreas frequently coexist in
polycystic kidney disease.
Traumatic
injury to the pancreas can also give rise to pseudocysts.
A
B
Figure 19.7 Pancreatic pseudocyst.
(A) Cross-section revealing a poorly
defined cyst with a necrotic brown-black wall.
(B) The cyst lacks a true
epithelial lining and instead is lined by fibrin and granulation tissue.
malignancies.
Endocrine tumors also occur in the pancreas
and are discussed in Chapter 24.
Serous cystic neoplasms usually occur in the tail of the
pancreas.
19.8).
Surgical resection is curative in the vast majority of
patients.
19.7A).
Pseudocysts are lined by fibrous tissue and granulation
tissue (Fig.
19.7B) and range in size from 2 to 30 cm in diameter.
NEOPLASMS
A broad spectrum of exocrine neoplasms arises in the
pancreas.
(A) Cross-
section through a microcystic serous cystic neoplasm.
Only a thin rim of
normal pancreatic parenchyma remains.
The cysts are relatively small and
contain clear, straw-colored fluid.
(B) The cysts are lined by cuboidal
epithelium without atypia.
B
Figure 19.9 Pancreatic mucinous cystic neoplasm with low-grade
dysplasia.
(A) Cross-section through a mucinous multiloculated cyst in
the tail of the pancreas.
The cysts are large and filled with tenacious
mucin.
(B) The cysts are lined by columnar mucinous epithelium with a
dense “ovarian” stroma.
on chromosome 3p is the most common genetic abnormality
in serous cystic neoplasms.
19.9).
Similar RNF43
mutations also occur in colorectal cancers.
Up to 20% are multifocal.
19.10).
TP53 and SMAD4
mutations typically occur only with transition to invasive
cancer.
The 5-year
survival rate is a dismal 10%.
19.11).
PanIN is often found in pancreatic parenchyma adjacent
to infiltrating carcinoma.
Gs α, are present in approximately two-thirds of IPMNs but
are not found in other pancreatic cysts.
Surgical resection is the treatment of choice and proves
curative in most patients.
KEY CONCEPTS
CYSTIC NEOPLASMS
• Virtually all serous cystic neoplasms are benign.
• Each of the major cystic neoplasms has a relatively specific
mutational profile.
19.12).
• SMAD4 (chromosome 18q) is inactivated in 55% of
pancreatic cancers.
SMAD4 is only
rarely inactivated in other cancer types.
• TP53 (chromosome 17p) is inactivated in 70% to 75% of
pancreatic cancers.
• DNA methylation (epigenetic) abnormalities.
DNA methyla-
tion abnormalities are widespread in pancreatic cancer.
Conversely, promoter hypomethylation leads
to overexpression of oncogenes such as GATA6 and BRD4.
• Transcriptomic profiles and pancreatic cancer subtypes.
How these subtypes respond
differentially to specific therapies is an area of active
investigation.
Epidemiology and Inheritance.
Pancreatic cancer is
primarily a disease of older adults, with 80% of cases
occurring after age 60.
Pancreatic cancer risk is also greater in those
with visceral obesity and high body mass index.
Diabetes
mellitus is also a modest risk factor.
19.13A).
Pancreatic cancers tend to grow along nerves and invade into
blood vessels and the retroperitoneum.
Perineural, lymphatic, and
large vessel invasion are common.
Distant metastases are principally
to the liver and lungs.
Survival after diagnosis of advanced pancreatic carcinoma
is typically short.
A
B
Figure 19.13 Carcinoma of the pancreas.
• Cigarette smoking is a significant cause of pancreatic cancer.
• Cancer-causing germline mutations are present in 10% of patients.
• Ductal adenocarcinomas are highly invasive and elicit an intense
desmoplastic response.
New-onset diabetes is detected in up to half of cases.
(Fig.
19.13B).
The poorly formed malignant glands are lined by
pleomorphic cuboidal-to-columnar epithelial cells.
They are malignant, but survival is better
than with pancreatic ductal adenocarcinomas.
[Discussion of pseudocysts by a leading
expert in pancreatic pathology].
[Guidelines
on the clinical management of cysts].
Kleeff J, Korc M, Apte M et al: Pancreatic cancer, Nat Rev Dis Prim
2:16022, 2016.
[Review of
the normal development of the pancreas and how development explains
anomalies].
Lankisch PG, Apte M, Banks PA: Acute pancreatitis, Lancet 386:85–96,
2015.
Kleef J, Whitcomb DC, Shimosegawa T et al: Chronic pancreatitis, Nat
Rev Dis Primers 3:17060, 2017.
All the authors are world-renowned experts in this area].
Majumder S, Chari ST: Chronic pancreatitis, Lancet 387:1957–1966, 2016.
Azotemia is a consequence of many
renal disorders, but it also arises from extrarenal disorders.
It is a typical feature of both acute and chronic kidney
injury.
Postrenal azotemia is seen
whenever urine flow is obstructed distal to the kidney.
Relief of the obstruction is followed by correction of the
azotemia.
It is the
classic presentation of acute poststreptococcal glomeru-
lonephritis.
The clinical features of
nephritis and the nephrotic syndrome are discussed in
more detail later.
In its most severe forms, it is manifested
by oliguria or anuria (reduced or no urine flow).
It can
result from glomerular, interstitial, vascular, or acute
tubular injury (ATI).
Renal diseases are responsible for a great deal of morbidity
and mortality.
According to the 2015 U.S.
For these reasons, recognizing the
early signs and symptoms is of particular clinical importance.
Some are uniqueGlomerular diseases 897
cases.
It is the end result of all chronic renal parenchymal
diseases.
Chronic kidney
disease causes significant systemic abnormalities, which are
listed in Table 20.1.
It reflects a reduction in GFR.
• Kidney injury that results in azotemia can be either acute or
chronic.
factors and in the course of several systemic diseases.
These are termed secondary glomeru-
lar diseases.
We briefly review
the secondary forms covered in other parts of this book.
Type IV collagen forms a network
suprastructure to which other glycoproteins attach.
20.1).
20.2).
20.1).
Biologically, they are
most akin to vascular smooth muscle cells and pericytes.
They are important in many forms of glomerulonephritis.
20.1).
(B) Schematic representation of a glomerular lobe.
(A, Courtesy Dr.
• Infiltration of leukocytes, including neutrophils, monocytes,
and, in some diseases, lymphocytes.
• Formation of crescents.
Fibrin, amyloid, cryoglobulins, and abnormal fibrillary
proteins may also deposit in the GBM.
When
extensive, these deposits may obliterate the capillary lumens
of the glomerular tuft.
Sclerosis is characterized by deposition of extracellular
collagenous matrix.
Note the filtration slits (arrows) and diaphragm between the
foot processes.
(Courtesy Dr.
20.3.
CD2AP, CD2-associated protein.Glomerular diseases 901
the capillary loops, or both.
Many primary glomerulopathies are classified by their
histology, as seen in Table 20.2.
We begin this
discussion with a review of antibody-instigated injury.
20.4B and E).
Glomerulo-
nephritis can be induced experimentally by antigen-antibody
reactions.
(D, Courtesy Dr.
J.
Kowalewska, Department of Pathology, University of Washington,
Seattle, Washington.
20.4A).
Some tumor antigens are also thought to cause
immune complex–mediated nephritis.
In many cases, the
inciting antigen is unknown.
Here we briefly review the salient features
that relate to glomerular injury.
Deposits
may be located at more than one site in a given case.
20.4D), in the mesangium, or in both locations.
Several factors affect glomerular localization of antigen,
antibody, or immune complexes.
The molecular charge and
size of these reactants are clearly important.
20.5).
This is discussed
later in the sections describing these diseases.
20.6).
• Platelets may aggregate in glomeruli during immune-
mediated injury.
Antiplatelet
agents have beneficial effects in both human and experi-
mental glomerulonephritis.
The
end result is the same as in classical pathway activation.
• Eicosanoids, nitric oxide, angiotensin, and endothelin are
involved in the hemodynamic changes.
• Chemokines such as monocyte chemoattractant protein 1
promote monocyte and lymphocyte influx.
• The coagulation system is also a mediator of glomerular
damage.
20.7).
20.7).
Such mutations are the cause
of rare hereditary forms of the nephrotic syndrome.
Glomerular sclerosis may be seen
even in cases in which the primary disease was nonglo-
merular.
It appears that proteinuria
also can cause direct injury to and activation of tubular cells.
The reduced GFR is mani-
fested clinically by oliguria, fluid retention, and azotemia.
The inciting
antigen may be exogenous or endogenous.
Immune complexes show a granular pattern of deposition
by immunofluorescence.
It usually appears 1
to 4 weeks after a streptococcal infection of the pharynx or
skin (impetigo).
Skin infections are commonly associated
with overcrowding and poor hygiene.
Many lines of evidence support an immunologic basis
for poststreptococcal glomerulonephritis.
against one or more streptococcal antigens are present in a
great majority of patients.
20.8B).
(A) Normal glomerulus.
(C) Typical electron-dense subepithelial “hump” and a neutrophil in the lumen.
(A–C, Courtesy Dr.
H.
Rennke, Brigham and Women’s Hospital, Boston, Mass.
D, Courtesy D.
J.
20.8C),
presumably representing the antigen-antibody complexes at the
subepithelial cell surface.
What triggers the formation of these
autoantibodies is unclear in most patients.
In adults the disease is less benign.
Figure 20.9 Crescentic glomerulonephritis (periodic acid–Schiff stain).
(Courtesy Dr.
M.
A.
20.10).
Segmental glomerular necrosis and distinc-
tive crescents (Fig.
Neutrophils
and lymphocytes may be present.
The crescents may obliterate
the urinary space and compress the glomerular tuft.
Electron
microscopy discloses deposits in those cases due to immune
complex deposition.
Regardless of type, electron microscopy may
Figure 20.10 Crescentic glomerulonephritis.
Other forms of RPGN also respond well to steroids and
cytotoxic agents.
Increased renal catabolism
of filtered albumin also contributes to the hypoalbuminemia.
The generalized edema is a direct consequence of decreased
intravascular colloid osmotic pressure.
There is also sodium and
water retention, which aggravates the edema (Chapter 4).
If severe, it may also lead
to pleural effusions and ascites.
The genesis of the hyperlipidemia is complex.
Most affected children recover; the prognosis is worse in
adults.
Nephrotic Syndrome
Certain glomerular diseases virtually always produce the
nephrotic syndrome.
• Underlying malignant tumors, particularly carcinomas of
the lung and colon, and melanoma.
• SLE.
About 10% to 15% of glomerulonephritis in SLE is
of the membranous type.
Pathogenesis
Membranous nephropathy is a form of chronic immune
complex–mediated disease.
The antigens may
be endogenous or exogenous.
The endogenous antigens
may be renal or nonrenal (described later).
20.4C).
How does the glomerular capillary wall become leaky in
membranous nephropathy?
There is a paucity of neutrophils,
monocytes, or platelets in glomeruli.
How IgG4 may activate the complement system is not
clear.
The
most frequent systemic causes of the nephrotic syndrome
are diabetes, amyloidosis, and SLE.
These
three lesions are discussed individually in the following
sections.
Approximately
75% of cases of membranous nephropathy are primary.
Approximate prevalence of systemic disease = 5% in
children, 40% in adults.
20.11C).
20.11A).
20.11B
and D).
(A) Silver methenamine stain.
Note the effacement of foot processes overlying deposits.
(D) Diagrammatic representation of membranous
nephropathy.
CL, Capillary lumen; End, endothelium; Ep, epithelium; US, urinary space.
(A, Courtesy Dr.
Thus, defects in the charge barrier may contribute
to the proteinuria.
Hematuria and mild hypertension
are present in 15% to 35% of cases.
The course of the disease is variable but generally indolent.
The disease recurs in up to 40% of
patients who undergo transplantation for ESRD.
The peak
incidence is between 2 and 6 years of age.
The disease
sometimes follows a respiratory infection or routine pro-
phylactic immunization.
20.12A).
By
electron microscopy the GBM appears normal, and no electron-
dense material is deposited.
20.12B).
Immunofluorescence
studies show no Ig or complement deposits.
The
proteinuria usually is highly selective, most of the protein
being albumin.
A characteristic feature is its usually
dramatic response to corticosteroid therapy.
Most children
(>90%) with minimal change disease respond rapidly to
this treatment.
Although adults are slower to respond, their
long-term prognosis is also excellent.
It is sometimesGlomerular diseases 915
A B
Figure 20.12 Minimal change disease.
(A) Glomerulus stained with periodic acid–Schiff.
Note normal basement membranes and absence of proliferation.
CL, Capillary lumen; M,
mesangium; P, podocyte cell body.
considered to be a primary disorder of podocytes, like
minimal change disease.
This epithelial
damage is the ultrastructural hallmark of FSGS.
Nephrin is a key component of the slit diaphragm (see
Fig.
20.3), the structure that controls glomerular perme-
ability.
Podocin has also been localized to the slit dia-
phragm.
Mutations in NPHS2 result in a syndrome of
steroid-resistant nephrotic syndrome of childhood onset.
• Mutations in the gene encoding TRPC6 have been found
in some kindreds with adult-onset FSGS.
Particularly
striking examples in which this occurs are reflux nephropathy
and unilateral agenesis.
These may lead to progressive
glomerulosclerosis and renal failure.
Such
a mechanism is suggested by experiments in rats subjected
to subtotal nephrectomy.
The sequence of events (Fig.
20.14A).
Lipid droplets and
foam cells are often present (Fig.
20.14B).
(A) Segmental sclerosis involves the upper half of both glomeruli.
In general, children have a better prognosis than
adults do.
Progression to renal failure occurs at variable
rates.
Recurrences are seen in
25% to 50% of patients receiving allografts.
The latter belong
to a group of disorders called C3 glomerulopathies.
The criteria
that define this group are still evolving.
Silver methenamine stain.
(Courtesy Dr.
In type II, C3 is present
on the GBM but not in the dense deposits.
MPGN accounts for up to 10% of cases of nephrotic
syndrome in children and young adults.
The antigens
involved in idiopathic MPGN are unknown.
Some patients develop numerous
crescents and a clinical picture of RPGN.
About 50% develop
chronic renal failure within 10 years.
The
glomeruli contain deposits of C3 and properdin but not
IgG.
Recall that in the alternative complement pathway, C3
is directly cleaved to C3b (Fig.
20.18; see also Chapter 3,
MORPHOLOGY
The glomeruli are large and hypercellular.
20.16).
Such
interposition also gives rise to the appearance of “split” basement
membranes (Fig.
20.17A).
Crescents are present in many cases.
Type I MPGN is characterized by the presence of discrete
subendothelial electron-dense deposits.
Mesangial and
occasional subepithelial deposits may also be present (see Fig.
20.17A).
There are dense homogeneous deposits within the basement membrane.
In both, the basement membranes appear split when viewed in the light microscope.
CL, Capillary lumen.
(A, Courtesy Dr.
Jolanta
Kowalewska, Cedars-Sinai Medical Center, Los Angeles, Calif.)
Fig.
3.12).
This leads to the generation of C3bBb, the alternative
pathway C3 convertase.
20.18).
This favors persistent C3 activation and hypocomplement-
emia.
Clinically,
patients develop nephrotic syndrome, hematuria, and
progressive renal insufficiency.
The disease recurs in kidney
transplants.
It may be associated
with systemic infections.
It is associated with acquired
or genetic dysregulation of the alternate pathway of complement.
Dense deposit disease affects primarily children and young
adults.
The prognosis is poor, with
over one-half of patients progressing to ESRD.
The precise nature of the dense deposits is unknown.
20.17B).
C3 is also present in the mesangium
in characteristic circular aggregates (mesangial rings).
20.19).
A
B
Figure 20.19 IgA nephropathy.
(A) Light microscopy showing mesangial
proliferation and matrix increase.
may occasionally develop.
Rarely, patients may present with
crescentic GN.
Healing of the focal proliferative lesion may lead to secondary
focal segmental sclerosis.
The characteristic immunofluorescent
picture is of mesangial deposition of IgA (Fig.
20.19B), often
with C3 and properdin and lesser amounts of IgG or IgM.
Early
complement components are usually absent.
The hematuria typically lasts for several
days and then subsides, only to return every few months.
The subsequent course is highly variable.
Many patients
maintain normal renal function for decades.
Slow progression
to chronic renal failure occurs in 15% to 40% of cases over
a period of 20 years.
The disease is inherited
as an X-linked trait in approximately 85% of cases.
Approxi-
mately 90% of affected males progress to ESRD before 40
years of age.
Missense and splice
site mutations, insertions, and deletions have all been identi-
fied.
Figure 20.20 Hereditary nephritis (Alport syndrome).
CL, Capillary lumen;
Ep, epithelium.
basket-weave appearance (Fig.
20.20).
Similar alterations can be
found in the tubular basement membranes.
There is also
absence of α5 staining in skin biopsy specimens from these patients.
Pro-
teinuria may develop later, and rarely, the nephrotic syn-
drome develops.
The auditory defects may be subtle,
requiring sensitive testing.
The abnormality is
estimated to affect 1% of the general population.
The disorder in homozygotes resembles
autosomal recessive Alport syndrome.
Homozygotes or
compound heterozygotes may progress to renal failure.
IgA is deposited in the glomerular mesangium
in a distribution similar to that of IgA nephropathy.
Most
children have an excellent prognosis.
The pathology and patho-
genesis of this disorder are discussed in Chapter 24.
Most of these diseases are
discussed elsewhere in this book.
Here we briefly recall
some of the lesions and discuss only those not considered
in other sections.
Lupus Nephritis
The various types of lupus nephritis are described in Chapter
6.
As discussed, SLE gives rise to a wide variety of renal
lesions and clinical presentations.
It is the most common cause of acute kidney injury.
• Direct toxic injury to the tubules.
ATI accounts for some 50% of cases of acute kidney injury
in hospitalized patients.
Other causes of acute renal failure
are discussed elsewhere in this chapter.
ATI is a reversible process that arises in a variety of
clinical settings.
This pattern is called
ischemic ATI.
In addition to its frequency, the
potential reversibility of ATI adds to its clinical importance.
Proper management can make the difference between
recovery and death.
20.21).
Initially, this response to
the increased sodium lowers the GFR to maintain distal
blood flow.
All of these effects, as shown in Fig.
20.21,
contribute to the decreased GFR.
20.22 and
20.23).
The distinct patterns of tubular injury in ischemic and
toxic ATI are shown in Fig.
20.22.
Figure 20.23 Acute tubular injury.
Tubuloin-
terstitial nephritis can be acute or chronic.
Here we discuss primary causes of
tubulointerstitial injury (Table 20.8).
Glomerular and vascular
abnormalities may also be present in advanced stages of
these diseases.
Toxic ATI is manifested by ATI, most obvious in the proximal
convoluted tubules.
Later, these cells become necrotic, are
desquamated into the lumen, and may undergo calcification.
The only
indication of renal involvement is a slight decline in urine
output with a rise in BUN.
At this point, oliguria could
be explained by a transient decrease in blood flow and
declining GFR.
With appropriate management, the patient
can overcome this oliguric crisis.
• Recovery phase is ushered in by a steady increase in urine
volume that may reach up to 3 L/day.
Hypokalemia,
rather than hyperkalemia, becomes a clinical problem.
There
is a peculiar increased vulnerability to infection at this
stage.
Eventually, renal tubular function is restored and
concentrating ability improves.
At the same time, BUN
and creatinine levels begin to return to normal.
The prognosis of ATI depends on the magnitude and
duration of injury.
With supportive care,
95% of those who do not succumb to the precipitating cause
recover.
This section deals principally
with pyelonephritis and drug-induced tubulointerstitial
nephritis.
It occurs in two forms.
By far the most common is Escherichia
coli, followed by Proteus, Klebsiella, and Enterobacter.
20.24).
Ascending infection is the most common cause of clinical
pyelonephritis.
coli
Proteus
Enterobacter
Figure 20.24 Schematic representation of pathways of renal infection.
Hematogenous infection results from bacteremic spread.
infection.
In
the presence of stasis, bacteria introduced into the bladder
can multiply unhindered.
• Vesicoureteral reflux.
20.26).
In the early stages, the neutrophilic infiltration is limited to
the tubules.
20.27).
Characteristically, glomeruli are relatively resistant to the
infection.
Three complications may be superimposed on acute
pyelonephritis.
Papillary necrosis
is usually bilateral but may be unilateral.
One or all of the pyra-
mids of the affected kidney may be involved.
20.28).
Dye injected into the bladder refluxes into both dilated
ureters, filling the pelvis and calyces.
20.25).
In addition, it may be acquired
by bladder infection itself.
Vesicoureteral reflux is estimated to affect 1%
to 2% of otherwise normal children.
• Intrarenal reflux.
20.25).
Figure 20.26 Acute pyelonephritis.
• Gender and age.
The diagnosis of
infection is established by quantitative urine culture.
coagulative necrosis, with preservation of outlines of tubules.
The leukocytic response is limited to the junctions between
preserved and destroyed tissue.
After the acute phase of pyelonephritis, healing occurs.
A B
Figure 20.28 Papillary necrosis.
Such bacteriuria then either disappears or may
persist, sometimes for years.
The superimposition of papillary necrosis
may lead to acute renal failure.
A viral pathogen causing pyelonephritis in kidney
allografts is polyomavirus.
20.29).
An interstitial
inflammatory response is invariably present.
Treatment
consists of a reduction in immunosuppression.
20.30).
The scars are usually polar and are associated
with underlying blunted calyces.
20.30 and 20.31A).
The kidneys usually
are irregularly scarred; if bilateral, the involvement is asymmetric.
In contrast, both kidneys in chronic glomerulonephritis are diffusely
and symmetrically scarred.
A B
Figure 20.29 Polyomavirus nephropathy.
(B) Intranuclear viral inclusions visualized by electron microscopy.
(Courtesy Dr.
The surface (left) is irregularly scarred.
The cut section (right) reveals blunting and loss of several papillae.
(B) Low-power view shows a corticomedullary renal scar with an underlying dilated deformed calyx.
Note the thyroidization of tubules in the cortex.
Obstructive lesions of the urinary tract are important predispos-
ing factors.
Significant
bacteriuria may be present, but it is often absent in the
late stages.
A rising serum creatinine or acute
kidney injury with oliguria develops in about 50% of cases.
Pathogenesis
Many features of the disease suggest an idiosyncratic immune
mechanism.
These
modified self antigens then become immunogenic.
(Courtesy Dr.
H.
Table 20.9 lists the main features of papillary necrosis in
these conditions.
• Acute hypersensitivity interstitial nephritis, resulting in renal
failure, as described earlier.
• Acute interstitial nephritis and minimal change disease.
Eosinophils and neutrophils may be present
(Fig.
Tubulitis, the infiltration of tubules by
lymphocytes, is common.
Variable degrees of tubular injury and
regeneration are present.
cortical atrophy and scarring.
The earliest functional defect is an inability to concentrate
the urine.
Other tubular defects, such as tubular acidosis and
salt-losing nephritis, may also occur.
With further damage, a
slowly progressive chronic kidney disease develops.
Precipitation of uric acid is favored by the acidic pH in
collecting tubules.
20.33).
The urate
deposits evoke a mononuclear response that contains
foreign-body giant cells.
• Light-chain deposition disease.
• Hypercalcemia and hyperuricemia are often present in these
patients.
The pathogenic mechanisms are unknown.
We limit the discussion
here to the tubulointerstitial lesions in multiple myeloma
patients.
Several factors contribute to renal damage:
• Bence-Jones proteinuria and cast nephropathy.
Two mechanisms seem to account for the renal toxicity
of Bence-Jones proteins.
20.34).The adjacent interstitial
tissue usually shows an inflammatory response and fibrosis.
Clinical Features
Clinically, the renal manifestations are of several types.
Another form occurs suddenly and is
manifested by acute kidney injury with oliguria.
This mechanism of injury is analogous to that with
monoclonal immunoglobulin and myoglobin casts.
VASCULAR DISEASES
Nearly all diseases of the kidney involve the renal blood
vessels secondarily.
Hypertension and diabetes,
however, increase the incidence and severity of the lesions.
20.35).The loss of mass is due mainly to cortical scarring and
shrinking.
20.36).
Figure 20.36 Hyaline arteriolosclerosis.
(Courtesy Dr.
M.
A.
Endothelial injury is a common pathogenic factor
in these disorders.
This occurs more frequently in men, and the incidence
increases with advancing age and diabetes.
The plaque is usually
concentrically placed, and superimposed thrombosis often occurs.
The second most frequent cause of stenosis is fibromuscular
dysplasia of the renal artery.
20.37).
The media shows marked fibrous thickening, and the
lumen is stenotic.
(Courtesy Dr.
On occasion, a bruit can be heard
on auscultation of the affected kidneys.
The cure rate after surgery is 70% to
80% in well-selected cases.
20.38).
Widespread “consumption” of platelets leads
to thrombocytopenia.
Endothelial Injury.
Platelet Aggregation.
However, due to underlying renal
damage, the long-term (15- to 25-year) outlook is more
guarded.
Autoantibodies against complement regulatory proteins
also result in atypical HUS.
The syndrome is described
in detail in Chapter 4.
In this setting, the microangiopathy
tends to follow a chronic course.
• Complications of pregnancy or the postpartum period.
The condition has a grave
prognosis, although recovery can occur in milder cases.
20.39).
most often caused by autoantibodies that inhibit ADAMTS13
function.
Most cases occur
after intestinal infection with strains of E.
However, most cases of typical HUS caused by E.
coli are
sporadic.
Less commonly, infections by other agents, includ-
ing S.
dysenteriae, can give rise to a similar clinical picture.
Typical HUS can occur at any age, but children and older
adults are at highest risk.
Hypertension is
present in about half of patients.
Precisely how Shiga-like toxin exposure causes HUS is
not well understood.
In the
presence of cytokines such as TNF, Shiga-like toxin may
cause endothelial apoptosis.
But other possibilities remain.
(A) Fibrinoid necrosis of afferent arteriole (periodic acid–Schiff stain).
(B) Hyperplastic arteriolitis (onion-skin lesion).
(Courtesy Dr.
H.
• Irradiation of the kidney.
Regardless of the cause, most patients present
as adults younger than 40 years of age.
Less commonly,
patients inherit an inactivating mutation in ADAMTS13.
Figure 20.40 Diffuse cortical necrosis.
The pale ischemic necrotic areas
are confined to the cortex and columns of Bertin.
• In typical HUS, Shiga-like toxin produced by bacteria, most
commonly E.
coli strain O157:H7, is responsible for producing
platelet activation and thrombosis.
The glomerular
capillaries are distended and occluded by thrombi.
Interlobular arteries and arterioles often
show occlusive thrombi.
The renal cortex reveals various
degrees of scarring.
The morphologic lesions are similar to those seen in malignant
hypertension (Fig.
20.39).
The gross
alterations of massive ischemic necrosis are sharply limited to
the cortex (Fig.
20.40).The histologic appearance is that of acute
ischemic infarction.
20.41).
Frequently they are of no significance.
Many renal infarcts are clinically silent.
Figure 20.41 Atheroembolus with typical cholesterol clefts in an
interlobar artery.
The various manifestations are grouped under
sickle cell nephropathy.
The most common abnormalities are hematuria and a
diminished concentrating ability (hyposthenuria).
Proteinuria
is also common in sickle cell disease, occurring in about
30% of patients.
Renal Infarcts
The kidneys are common sites for the development of
infarcts.
About 10% of people are born with significant malformations
of the urinary system.
Renal dysplasias and hypoplasias
account for 20% of chronic kidney disease in children.
Here, we restrict the discussion to
structural anomalies involving primarily the kidney.
All
except horseshoe kidney are uncommon.
Anomalies of the
lower urinary tract are discussed in Chapter 21.
Agenesis of the Kidney.
Bilateral agenesis is incompatible
with life and usually encountered in stillborn infants.
It is
often associated with other congenital disorders (e.g., limb
defects, hypoplastic lungs).
Unilateral agenesis is uncommon
and compatible with normal life if no other abnormalities
exist.
The solitary kidney enlarges as a result of compensatory
hypertrophy.
Hypoplasia.
Hypoplasia refers to failure of the kidneys to
develop to a normal size.
Ectopic Kidneys.
The development of the metanephros into
the kidneys may occur in ectopic foci.
These kidneys lie either
just above the pelvic brim or sometimes within the pelvis.
Horseshoe Kidneys.
This anomaly is found in 1 in 500 to 1000 autopsies.
A useful classification of renal cysts
is summarized in Table 20.12.
The inheritance pattern is
autosomal dominant with high penetrance.
The disease is bilateral; reported unilateral cases probably
represent multicystic dysplasia.
• The PKD1 gene is located on chromosome 16p13.3.
Polycystin-1 is expressed in tubular epithelial cells,
particularly those of the distal nephron.
Mutations in PKD1 account for about 85%
of cases.
Polycystin-2 functions as a
Ca2+-permeable cation channel.
Overall, the disease is
less severe than that associated with PKD1 mutations.
20.42).
The cilia are
part of a system of organelles and cellular structures that
sense mechanical signals.
• Both polycystin-1 and polycystin-2 are localized to the
primary cilium.
On occasion,
papillary epithelial formations and polyps project into the lumen.
In others, hemor-
rhage or progressive dilation of cysts may produce pain.
Excretion of blood clots causes renal colic.
The enlarged
kidneys, usually apparent on abdominal palpation, may
induce a dragging sensation.
Both genetic and environmental factors influence disease
severity.
The kidney is
markedly enlarged and contains numerous dilated cysts.
(D) Liver cysts in adult PKD.
Individuals with polycystic kidney disease also tend
to have extrarenal congenital anomalies.
The cysts are derived from
biliary epithelium.
Cysts occur much less frequently in the
spleen, pancreas, and lungs.
The diagnosis is made by radiologic imaging
techniques.
The gene is highly expressed in adult and fetal kidney and
also in liver and pancreas.
The extracellular region contains
multiple copies of a domain forming an Ig-like fold.
This
complicates molecular diagnosis of the disorder.
MORPHOLOGY
The kidneys are enlarged and have a smooth external appearance.
20.43C).
In almost
all cases, the liver has cysts (Fig.
20.43D) associated with portal
fibrosis and proliferation of portal bile ducts.
In
older children, hepatic disease is the predominant clinical
concern.
Such patients may develop portal hypertension
with splenomegaly.
The
condition occurs in adults and is usually discovered radio-
graphically.
Renal function is usually normal.
The cysts are lined by
cuboidal epithelium or occasionally by transitional epithe-
lium.
Unless there is superimposed pyelonephritis, cortical
scarring is absent.
The pathogenesis is unknown.
Sodium wasting
and tubular acidosis are also prominent.
The expected
course is progression to ESRD in 5 to 10 years.
The NPHP2 gene product has been
Figure 20.44 Medullary cystic disease.
Cut section of kidney showing
cysts at the corticomedullary junction and in the medulla.
identified as inversin, which mediates left-right patterning
during embryogenesis.
20.44).
In general, glomerular
structure is preserved.
The kidney is usually enlarged,
extremely irregular, and multicystic (Fig.
20.45A).
The cysts
vary in size from several millimeters to centimeters in
diameter.
On histologic examination, they are lined by
flattened epithelium.
20.45B).
The main importance of cysts lies in their dif-
ferentiation from kidney tumors.
Fortunately, many causes of obstruction are surgically
correctable or medically treatable.
The common causes
are as follows (Fig.
Even with complete obstruction, glomerular filtration
B
Figure 20.45 Multicystic renal dysplasia.
(A) Gross appearance.
(A, Courtesy Dr.
D.
Schofield, Children’s Hospital, Los Angeles,
Calif.; B, courtesy Dr.
Most
are asymptomatic, but sometimes the cysts bleed, causing
hematuria.
Simple Cysts
Simple cysts may be single or multiple and usually involve
the cortex.
They are commonly 1 to 5 cm but may reach
10 cm or more in size.
They are translucent, lined by a gray,
glistening, smooth membrane, and filled with clear fluid.
Simple cysts are common postmortem findings without
clinical significance.
Progressive blunting of the apices of the pyramids occurs, and
these eventually become cupped.
Only later does the GFR
begin to fall.
20.8).
Most of the early
symptoms are produced by the underlying cause of the
hydronephrosis.
Sometimes its existence
first becomes apparent in the course of imaging studies.
Ultrasonography
is a useful noninvasive technique in the diagnosis of obstruc-
tive uropathy.
Hypertension is common.
20.47).
Curiously, after relief of complete
urinary tract obstruction, postobstructive diuresis occurs.
Men are affected
more often than women, and the peak age at onset is between
20 and 30 years.
Familial and hereditary predisposition to
stone formation has long been known.
A low urine
volume in some metabolically normal patients may also
favor supersaturation.
The resultant alkaline urine causes the precipitation of
magnesium ammonium phosphate salts.
These form some
of the largest stones, as the amount of urea excreted
normally is very large.
In contrast to the radiopaque calcium stones, uric
acid stones are radiolucent.
These stones also form at low urinary pH.
Cells may also
grow as tubules, glands, cords, and sheets of cells.
Figure 20.48 Nephrolithiasis.
A large stone impacted in the renal pelvis.
(Courtesy Dr.
E.
Ultrastructurally the eosinophilic
cells have numerous mitochondria.
There are some familial cases in which these
tumors are multicentric rather than solitary.
There are approximately 65,000
new cases per year and 13,000 deaths from the disease.
Epidemiology
Tobacco is the most significant risk factor.
An international
MORPHOLOGY
Stones are unilateral in about 80% of patients.
The favored sites
for their formation are within the renal calyces and pelves (Fig.
20.48) and in the bladder.
Often many stones are found within one
kidney.
Larger stones often manifest themselves by hema-
turia.
NEOPLASMS OF THE KIDNEY
Both benign and malignant neoplasms occur in the kidney.
Malignant neoplasms are of great importance clinically.
• Von Hippel-Lindau (VHL) syndrome.
• Hereditary leiomyomatosis and renal cell cancer syndrome.
• Hereditary papillary carcinoma.
This autosomal dominant
form is manifested by multiple bilateral tumors with
papillary histology.
• Birt-Hogg-Dubé syndrome.
The major types of
tumor are as follows (Fig.
20.49):
• Clear cell carcinoma.
This is the most common type,
accounting for 70% to 80% of renal cell cancers.
The tumors
are made up of cells with clear or granular cytoplasm
and are nonpapillary.
They can be familial, but in most
cases (95%) are sporadic.
The deleted region harbors the VHL gene (3p25.3).
(Courtesy Dr.
• Papillary carcinoma accounts for 10% to 15% of renal
cancers.
These
tumors are not associated with 3p deletions.
MET is also mutated in a
small proportion of sporadic papillary carcinomas.
Unlike clear cell carcinomas, papillary
carcinomas are frequently multifocal in origin.
On cytogenetic examination, these
tumors show multiple chromosome losses and extreme
hypodiploidy.
Histologic distinction
from oncocytoma can be difficult.
• Xp11 translocation carcinoma is a genetically distinct subtype
of renal cell carcinoma.
The neoplastic cells consist of clear cytoplasm with a
papillary architecture.
They
arise from collecting duct cells in the medulla.
Figure 20.50 Renal cell carcinoma.
Typical cross-section of yellowish,
spherical neoplasm in one pole of the kidney.
Note the tumor in the
dilated thrombosed renal vein.
may show cystic as well as solid areas.
Interstitial foam cells are common in the papillary cores (see Fig.
20.51B).
Psammoma bodies may be present.The stroma is usually
scanty but highly vascularized.
20.51C).
They are bright yellow-gray-white
spherical masses of variable size that distort the renal outline.
The margins are
usually sharply defined and confined within the renal capsule (Fig.
20.50).
The pelvis has
been opened to expose the nodular irregular neoplasm, just proximal to
the ureter.
20.52).
They are almost invariably small when discovered.
These
tumors may block urinary outflow and lead to palpable
hydronephrosis and flank pain.
Urothelial tumors may occasionally be multiple, involving
the pelvis, ureters, and bladder.
(A) Clear cell type.
(B) Papillary type.
Note the papillae and foamy macrophages in the stalk.
(C) Chromophobe
type.
(Courtesy Dr.
A.
Infiltration of the wall of the pelvis and calyces is common.
[A current review of the clinicopathologic manifestations of these diseases].
Roberts IS: Pathology of IgA nephropathy, Nat Rev Nephrol 10:445–454,
2014.
[An excellent review that details emerging concepts of the pathophysiol-
ogy of this disorder].
Zuk A, Bonventre JV: Acute kidney injury, Annu Rev Med 67:293–307,
2016.
[A comprehensive review of acute kidney injury].
[A review of the clinical and pathologic aspects of
pyelonephritis].
[An excellent
review of the pathogenesis and clinical features of various forms of TMA].
Chang A: Thrombotic microangiopathy and the kidney, Diagn Histopathol
23:101–108, 2017.
Hill GS: Hypertensive nephrosclerosis, Curr Opin Nephrol Hypertens
17:266–270, 2008.
[A review of the pathophysiologic underpinning of
hypertensive nephrosclerosis].
Hildebrandt F, Benzing T, Katsanis N: Ciliopathies, N Engl J Med
364:1533–1543, 2011.
[An updated
pathologic classification of renal cell carcinoma].
These tumors
have a poor prognosis.
[An outstanding
and comprehensive review of the immunopathogenesis of glomerular
diseases].
[An excellent synopsis of alternations in podocytes
that underlie glomerular diseases].
This epithelium
rests on a well-developed basement membrane, beneath
which is a lamina propria.
The ureters lie throughout their course in a retro-
peritoneal position.
Retroperitoneal tumors or fibrosis
may entrap and obstruct the ureters.
There is agenesis of the contralateral kidney
in a minority of cases.
In adults, UPJ obstruction is more
common in women and is most often unilateral.
Tumors and Tumor-Like Lesions
Primary tumors of the ureter are rare.
Benign tumors are
generally of mesenchymal origin.
The majority
are urothelial carcinomas (Fig.
21.1).
They commonly
occur concurrently with urothelial carcinomas of bladder
or renal pelvis.
The disorder occurs in middle
to late age and is more common in males than females.
(Courtesy Dr.
Cristina Magi-Galluzzi, The Johns Hopkins Hospital,
Baltimore, Md.)
other organs (Chapter 6).
Most, however, have no obvious cause and are
considered primary or idiopathic (Ormond disease).
• In children, congenital UPJ obstruction is the most common
obstructive lesion.
• Vesicoureteral reflux is the most common and serious
congenital anomaly.
As a result,
the bladder communicates directly with the abdominal
surface (Fig.
21.2).
Exstrophy is associated with an increased risk of
adenocarcinoma in the bladder remnant.
• Urachal anomalies.
Rarely, it remains fully or partially patent.
The
former creates a fistulous urinary tract connection between
the bladder and umbilicus.
The tied
umbilical cord is seen above the hyperemic mucosa of the everted bladder.
Below is an incompletely formed penis with marked epispadias.
(Courtesy
Dr.
Women are more likely to
develop cystitis as a result of their shorter urethras.
Tuberculous
cystitis is almost always a sequel to renal tuberculosis.
Viruses (e.g., adeno-
virus), Chlamydia, and Mycoplasma may also cause cystitis.
Adenovirus and BK virus infections may result in hemorrhagic
cystitis.
MORPHOLOGY
Most cases of cystitis produce nonspecific acute or chronic
inflammation of the bladder.
Other types of non-infectious cystitis include iatrogenic, fol-
licular, and eosinophilic cystitis.
Acute and chronic radiation cystitis may occur
following the irradiation of the bladder region.
These primary lesions must be corrected before
the cystitis can be relieved.
Interstitial Cystitis (Chronic Pelvic Pain Syndrome).
Inter-
stitial cystitis is a disorder of unknown etiology that occurs
most frequently in women.
Typical
cystoscopic findings include mucosal fissures and punctate
hemorrhages (glomerulations).
Treatment is largely empiric.
Late in the course,
transmural fibrosis may lead to a contracted bladder.
Malakoplakia.
It arises in the setting of chronic
bacterial infection, mostly by E.
A
B
Figure 21.3 Malakoplakia.
(A) Bladder involved by malakoplakia showing
the characteristic yellow-orange mucosal lesions.
(B) Periodic acid–Schiff
(PAS) stain.
macrophages with occasional multinucleate giant cells and lym-
phocytes.
21.3B).
21.3A).
His-
tologically, the lesion is composed of aggregates of large foamy
Polypoid Cystitis.
• Cystitis glandularis and cystitis cystica.
Both variants can arise in the setting
of inflammation and metaplasia.
Extensive and multifocal
intestinal metaplasia is a precursor to adenocarcinoma.
• Squamous metaplasia.
• Nephrogenic adenoma.
Nephrogenic adenoma is an unusual
lesion that may not be a form of true metaplasia.
It is the fourth most common cancer in American
men (7% of all new cases).
Many
of these tumors are multifocal at presentation.
21.4).
These tumors have a range of atypical changes
and are graded according to their biologic behavior.
Such lesions are considered to be high grade.
Once muscularis propria invasion
occurs, there is a 30% 5-year mortality rate.
Epidemiology.
About 80% of patients are
between 50 and 80 years of age.
Bladder cancer, with rare
exceptions, is not familial.
Between 50% and
80% of all bladder cancers among men are associated
with the use of cigarettes.
Cigars, pipes, and smokeless
tobacco are associated with a smaller risk.
Cancer appears 15 to 40 years after the first
exposure.
• Schistosoma haematobium infections in endemic areas (Egypt,
Sudan) are an established risk.
• Long-term use of analgesics is implicated, as it is in analgesic
nephropathy (Chapter 20).
21.5).
The majority of muscle-invasive bladder
cancers develop by progression from “flat” CIS.
MORPHOLOGY
The appearance of urothelial tumors varies from purely papillary
to nodular or flat.
21.6).
Multiple discrete tumors are
often present.
Table 21.3 lists the grading system of urothelial tumors.
Papil-
lomas represent 1% or less of bladder tumors and are often seen
in younger patients.
21.7A).
The lower section demonstrates multifocal
smaller papillary neoplasms.
(Courtesy Dr.
Fred Gilkey, Sinai Hospital,
Baltimore, Md.)
A B
C D
Figure 21.7 Papillary urothelial neoplasms.
(A) Papilloma consisting of small papillary fronds lined by normal-appearing urothelium.
(A) Normal urothelium with uniform nuclei and well-developed umbrella cell layer.
may occur.
21.7C).
These low-grade cancers may recur and,
infrequently, may also invade.
Only rarely do these tumors pose
a threat to life.
Some of the tumor cells are
highly anaplastic (Fig.
21.7D).
Mitotic figures, including atypical
ones, are frequent.
Architecturally, there is disarray and loss of
polarity.
21.8).
If untreated, 50% to 75% of CIS pro-
gresses to invasive cancer.
Invasive urothelial carcinoma (Fig.
21.9) may be associated
with papillary urothelial cancer, usually high grade, or adjacent
CIS.
few tumors (<10%) progress to higher-grade lesions.
Clinical Features
Painless hematuria is the most common symptom of bladder
cancer.
Frequency, urgency, and dysuria may accompany
hematuria.
Occasionally, obstruction of the ureteral orifice
may lead to pyelonephritis or hydronephrosis.
Initial treatment of non–muscle-invasive tumors is guided
by the pathologic findings.
Other recurrences are clonally distinct and represent
a second primary tumor.
Lymphoma may involve the bladder as a component of
systemic disease.
Metastatic spread of solid tumors to the
bladder may occur but is very rare.
Once bladder carcinoma metastasizes, treatment options
are limited.
Most are
invasive, fungating tumors or are infiltrative and ulcerative.
Mesenchymal Tumors
Benign Tumors.
Even collectively, they
are rare.
The most common is leiomyoma.
Sarcomas.
True sarcomas are distinctly uncommon in the
bladder.
Their soft, fleshy, gray-white
gross appearance suggests their mesenchymal nature.
The
most common bladder sarcoma in infancy or childhood is
embryonal rhabdomyosarcoma.
In some of these cases they
manifest as a polypoid grape-like mass (sarcoma botryoides).
21.9).
In the course of time,
crypts form and may be converted into diverticula.
The enlarged bladder may reach
the brim of the pelvis or even the level of the umbilicus.
Gonococcal urethritis is one of the earliest
manifestations of this venereal infection.
Nongonococcal
urethritis is common and can be caused by several different
organisms.
Mycoplasma
(Ureaplasma urealyticum) also accounts for symptoms of
urethritis in many cases.
Urethritis is often accompanied
by cystitis in women and by prostatitis in men.
In many
instances of suspected bacterial urethritis, no organism can
be isolated.
Some urethritis is truly noninfectious in origin.
Surgical excision
affords prompt relief and cure.
Primary carcinoma of the urethra is an
uncommon lesion (Fig.
21.10).
Adenocarcinomas are infrequent in the urethra and generally
occur in women.
Neoplasms of the prostatic urethra are
addressed later in the section on the prostate.
Hypospadias, the more common of
the two, occurs in approximately 1 in 300 live male births.
Only the nonspecific infections
causing so-called balanoposthitis are described here.
Balanoposthitis refers to infection of the glans and prepuce
caused by a wide variety of organisms.
Among the more964 CHAPTER 21 The Lower Urinary Tract and Male Genital System
common agents are C.
albicans, anaerobic bacteria, Gardnerella,
and pyogenic bacteria.
Tumors
Tumors of the penis are uncommon.
Figure 21.11 Carcinoma of urethra with typical fungating growth pattern
(arrow).
Treatments include surgery and injection of collagenase to
lyse the fibrous plaques.
These lesions are encompassed by the
umbrella term penile intraepithelial neoplasia (PeIN).
All are
squamous lesions confined to the epidermis by an intact
basement membrane.
PeIN may be HPV-related (undifferenti-
ated PeIN) or non–HPV-related (differentiated).
Penile lesions usually occur in the coronal sulcus
and inner surface of the prepuce.
21.11).
21.12A).
21.12B).
A B
Figure 21.12 Condyloma acuminatum of the penis.
(A) Low magnification reveals the papillary architecture and thickening of the epidermis.
E6 protein also stimulates telomerase expression, leading
to cellular immortalization.
Figure 21.13 Bowen disease (carcinoma in situ) of the penis.
the foreskin of older patients, and as the name implies retains
a degree of squamous maturation.
Both are associated with high-risk
HPV, most commonly HPV 16.
• Bowen disease most commonly affects the penile shaft and
scrotum of older men.
At these sites, it appears as a soli-
tary, thickened, gray-white, opaque plaque.
In less
common cases when it affects the glans, the lesion acquires
a velvety red appearance.
21.13).
Mitoses, some atypical, are
numerous.
In 10% of patients, Bowen disease gives rise
to infiltrating squamous cell carcinoma.
• Bowenoid papulosis occurs in sexually active adults.
Penile
carcinoma affects middle-aged and older patients (40 to
70 years of age).
In the United States, it accounts for less
than 1% of cancers in males.
Low income status and
poor hygiene habits are salient risk factors.
21.14).
• Two pathogenic pathways, one related to HPV and the other
unrelated to HPV.
TESTIS AND EPIDIDYMIS
Distinct pathologic conditions affect the testis and epididy-
mis.
It is found in approximately 1%
of 1-year-old boys.
Testicular descent occurs in two phases.
This phase is controlled by
the hormone müllerian-inhibiting substance.
locally along a broad pushing border, but rarely metastasizes.
The lesions are nonpainful until they undergo secondary
ulceration and infection.
As mentioned above,
prognosis is strongly correlated with tumor stage at diagnosis.
MORPHOLOGY
Cryptorchidism is usually unilateral,being bilateral in 25% of patients.
Cryptorchid testes are small and firm.
The histologic changes in
the malpositioned testis begin as early as 2 years of age.
Early on,
thickening of the basement membrane of the spermatic
tubules is seen (Fig.
21.15).
(A) Normal testis shows tubules with active spermatogenesis.
(B) Testicular atrophy in cryptorchidism.
The tubules show
Sertoli cells but no spermatogenesis.
There is thickening of basement membranes and an apparent increase in interstitial Leydig cells.
The
gross and microscopic alterations follow the pattern already
described for cryptorchidism.
In extreme cases there is
complete regression (“vanishing testis”).
Inflammation and Infections
Inflammatory disorders are distinctly more common in the
epididymis.
The cause of epididymitis varies with the age of the patient.
In
sexually active men younger than age 35 years, the sexually
transmitted pathogens C.
trachomatis and Neisseria gonorrhoeae
are most frequent.
In men older than age 35, common urinary
tract pathogens, such as E.
coli and Pseudomonas, are respon-
sible for most infections.
Current recommenda-
tions are for orchiopexy to be performed at 6 to 12 months
of age.
• The cryptorchid testis carries a three- to fivefold higher risk
for testicular cancer.
• Orchiopexy reduces but does not completely eliminate the
risk of sterility and cancer.
21.16).
There are two settings in which testicular torsion occurs.
Neonatal torsion occurs either in utero or shortly after birth.
It
often occurs without any inciting injury.
Contralateral orchiopexy is performed to prevent
recurrence in the unaffected testis.
Figure 21.16 Acute epididymitis caused by gonococcal infection.
The
epididymis is replaced by an abscess.
Normal testis is seen on the right.
to the testis, where it evokes a similar inflammatory reaction.
Histologically,
the orchitis is distinguished by granulomas restricted to
spermatic tubules.
Although
an autoimmune basis is suspected, the cause of these lesions
remains unknown.
In
severe cases epididymal abscesses may develop, leading to
extensive destruction and scarring.
The infection may also
spread to the testis and produce suppurative orchitis.
Mumps
Mumps is a systemic viral disease that most commonly
affects school-aged children.
Testicular involvement is
extremely uncommon in this age group.
In postpubertal
males, however, orchitis occurs in 20% to 30% of cases.
21.17).
In advanced stages, the swollen
testis consists entirely of soft, necrotic, hemorrhagic tissue.
Figure 21.17 Torsion of testis.
The most common benign paratesticular tumor is adeno-
matoid tumor.
Testicular Tumors
Testicular neoplasms span an amazing gamut of histologic
types.
The lifetime risk is highest in Northern Europe and New
Zealand and is lowest in Africa and Asia.
21.18).
Environmental Factors.
The role of environmental factors
is inferred in part from population migration studies.
Components of this
syndrome include cryptorchidism, hypospadias, and poor
sperm quality.
Genetic Factors.
Interestingly, these genes
are also thought to play a role in gonadal development.
Associations with variants in genes involved in sex hormone
metabolism have also been found.
Steps in the Development of Germ Cell Tumors.
Classification.
A simple classification of the most common
types of testicular tumors is presented in Table 21.7.
Two
broad groups are recognized.
Seminomatous tumors are
composed of cells that resemble primordial germ cells or
early gonocytes.
pale, fleshy, homogeneous mass on cut surface.
Seminoma
Seminoma is the most common type of GCT, making up
about 50% of these tumors overall.
The peak incidence is
in the fourth decade.
MORPHOLOGY
Seminomas produce bulky masses, sometimes ten times the size
of the normal testis.
21.19).
21.20B).
The
cytoplasm contains varying amounts of glycogen.
Approximately 15%
of seminomas contain syncytiotrophoblasts.
In contrast to other
GCTs, affected individuals are generally older (usual more
than 65 years old).
variation in cell and nuclear size and shape (pleomorphism).
Mitotic
figures and tumor giant cells are frequently seen.
Vascular-lymphatic
invasion is common.
In this age group it has
a very good prognosis.
21.21).
Histologically, the cells grow in alveolar or tubular
patterns, sometimes with papillary folds.
More undifferentiated
lesions may display sheets of cells with cleft-like spaces (Fig.
21.22).
In contrast to the seminoma
illustrated in Fig.
They may occur
at any age from infancy to adulthood.
Choriocarcinoma
Choriocarcinoma is a highly malignant type of GCT.
In its
pure form, choriocarcinoma is rare, constituting less than
1% of all GCTs.
Serum hCG is invariably elevated, often
markedly so.
Widespread metastasis, often associated with
hemorrhage at sites of involvement, may be seen.
21.24).
21.25).
Hemorrhage and necrosis are extremely
common.
21.23).
Figure 21.23 Choriocarcinoma.
Testicular tumors have a characteristic mode of spread.
Lymphatic spread is common to all forms.
In general, retro-
peritoneal para-aortic nodes are the first to be involved.
Subsequent spread may occur to mediastinal and supra-
clavicular nodes.
Hematogenous spread is primarily to the
lungs, but liver, brain, and bones may also be involved.
Metastases from seminomas typically involve lymph nodes.
Hematogenous spread occurs later in the course of dis-
semination.
Nonseminomatous GCTs tend to metastasize
earlier and more frequently via a hematogenous route.
The
histology of metastases and distant recurrences may differ
from that of the testicular lesion.
This is a reflection of the
fact that GCTs are derived from pluripotent germ cells.
Serum Biomarkers in Germ Cell Tumors.
Seminoma, which is radiosensitive and chemosensitive,
has the best prognosis.
Pure embryonal carcinoma behaves more aggressively than
mixed GCTs.
Pure choriocarcinoma and mixed GCT with
predominantly choriocarcinoma have a poor prognosis.
Figure 21.24 Teratoma of testis.
The variegated cut surface with cysts
reflects the presence of multiple tissue types.
adenocarcinoma, sarcoma, or other cancers.
Special
types include dermoid cysts, which typically contain hair,
teeth, and skin.
On rare occasions, prepubertal teratoma
may be admixed with yolk sac tumor.
Mixed Tumors
About 60% of GCTs are composed of more than one of the
above types.
Clinical Features of Testicular Germ Cell Tumors.
They
may arise in children or adults.
Approximately
10% of Leydig cell tumors in adults are malignant and can
produce metastases.
Histologically, the tumor cells
resemble their normal counterparts.
testicular neoplasm in men older than 60 years of age.
In
most cases, these are aggressive tumors that are disseminated
at the time of detection.
In contrast to GCTs, tumors are
frequently bilateral and involve the spermatic cord.
• Cryptorchidism, infertility, and prior history of GCT in contra-
lateral testis are risk factors.
• Germ cell neoplasia in situ is a precursor lesion associated
with most GCTs.
Seventy percent of patients with documented
germ cell neoplasia in situ will develop invasive GCTs.
Mixed tumors that contain more than one histologic type account
for 40% of GCTs.
• Clinically, testicular GCTs are divided into two groups: seminomas
and nonseminomatous tumors.
Seminomas spread mainly to
para-aortic nodes and are radiosensitive.
Nonseminomatous
tumors tend to spread earlier via lymphatic and hematogenous
routes.
These
neoplasms appear as firm, small nodules with a homogeneous
gray-white to yellow cut surface.
Most Sertoli cell tumors are
benign, but approximately 10% pursue a malignant course.
In some cases, the germ cell
component becomes malignant, giving rise to seminoma.
Hematocele is a collection of blood in the tunica vaginalis.
Varicocele
is a dilated vein in the spermatic cord.
21.26).
These zones are at risk for different types
of proliferative lesions.
Histologically, the prostate consists of glands separated
by abundant fibromuscular stroma.
21.27), which often contain small papillary infoldings.
We
begin our discussion with consideration of inflammatory
processes.
Figure 21.27 Normal prostate gland, with basal cell and secretory cell
layers.
Thus,
most cases are caused by various strains of E.
coli, other
gram-negative rods, enterococci, and staphylococci.
Clinically, acute bacterial
prostatitis is associated with fever, chills, and dysuria.
On rectal examination the prostate is exquisitely tender
and boggy.
The diagnosis can be established by urine
culture and clinical features.
The implicated
organisms are the same as those that cause acute prostatitis.
Fungal granulomatous prostatitis is typically
seen in immunocompromised hosts.
• Other forms of prostatitis.
Adenoviral and IGg4-associated
(Chapter 6) autoimmune prostatitis have also been
described.
It is not a premalignant lesion.
21.28A).
Estrogens
thus contribute to BPH pathogenesis by tipping the balance
toward proliferation (Fig.
21.28B).
(A) The central role of the stromal cells in generating dihydrotestosterone
(DHT) is depicted.
DHT may also be produced in skin and liver by both type 1 and type 2 5α-reductase.
(A) Well-defined nodules of BPH compress the urethra into a slit-like lumen.
may be seen.
21.29A).
21.29B).
Nodules composed primarily
of fibromuscular stroma are pale gray and firm.
21.29C), and infolding of the glands
may produce a papillary architecture.
DHT, an androgen derived from testosterone,
is the major hormonal stimulus for proliferation.
It is largely a disease of aging.
Epidemiology and Pathogenesis.
Environmental Factors.
21.30).
Inherited Genetic Factors.
Studies of twins and families
support the existence of important genetic predisposing
factors.
See text for details.
Androgens.
Unfortunately, most tumors eventually become resistant to
androgen blockade.
Acquired Genetic and Epigenetic Alterations.
Epigenetic events that modify gene expression are also
common in prostate cancer.
21.30.
Precursor Lesions.
Evidence in favor of stepwise develop-
ment of prostate cancer (as outlined in Fig.
Figure 21.31 Adenocarcinoma of the prostate.
21.31).
The
outer basal cell layer typical of benign glands is absent.
The cytoplasm of the tumor cells ranges from pale-clear to a
distinctive amphophilic appearance.
Nuclei are enlarged and often
contain one or more large nucleoli.
There is some variation in
nuclear size and shape, but in general pleomorphism is not marked.
Mitotic figures are uncommon.
Metastases spread via lymphatics to the obturator
nodes and eventually to the para-aortic nodes.
Hematogenous
spread occurs chiefly to the bones, particularly the axial
skeleton.
21.33).
A few findings are specific,
such as perineural invasion (Fig.
Compare to benign gland (left).
Figure 21.32 Metastatic osteoblastic prostatic carcinoma within vertebral
bodies.
21.33A and benign
hyperplastic glands in Fig.
21.29C with cancerous glands in Fig.
21.33B).
Such markers, while improving diagnostic accuracy,
Grading and Staging.
Grade and stage are the most
important prognostic factors in prostate cancer.
21.35A).
21.35C).
Other grades fall between
A B
Figure 21.33 Prostatic adenocarcinoma.
C
these extremes (Fig.
21.35B).
The two numeric grades
are then added to obtain a combined Gleason score.
Typically, a
transrectal needle biopsy is required to confirm the diagnosis.
PSA is a product of prostatic
epithelium and is normally secreted in the semen.
In normal men, only minute amounts of PSA
circulate in the serum.
Elevated blood levels of PSA occur
in association with localized as well as advanced cancer.
pathologic stage, margin status, and Gleason grade.
Metastatic carcinoma is treated with androgen deprivation
therapy.
KEY CONCEPTS
CARCINOMA OF THE PROSTATE
• Carcinoma of the prostate is very common in older men.
In
the United States, it is the most common malignancy in men.
Bone
metastases, often osteoblastic, typify advanced prostate cancer.
PSA is organ specific, but not cancer specific.
More than 90% of patients who
receive such therapy can expect to live for 15 years.
Currently,
the most common treatment is radical prostatectomy.
Ductal
adenocarcinomas are associated with a relatively poor
prognosis.
Almost
all cases of small-cell carcinoma are rapidly fatal.
The most common tumor to secondarily involve the
prostate is urothelial cancer.
Two distinct patterns of involve-
ment exist.
Large invasive urothelial cancers can directly
invade from the bladder into the prostate.
[Discussion of the pathophysiology of testicular
germ cell tumors and implications for therapy].
[Review of salient
features of germ cell tumor biology and associated biomarkers].
[Update
on the classification of bladder carcinoma].
e25, 2017.
[A first look at the molecular characterization of invasive bladder
carcinoma].
[Current recommendations for prostate cancer
grading].
[Update
on classification of prostate and bladder carcinoma].
[Review of the role of HPV in penile
carcinoma].
[Update of the classification of penile
carcinoma].
[Latest classification system for male urogenital neoplasms].
22.1).
• Germ cells arise in the wall of the yolk sac by the fourth
week of gestation.
22.1A).
Further caudal growth brings these fused
ducts into contact with the urogenital sinus.
22.1B).
In the cervix
and vagina, these rests may be cystic and are termed
Gartner duct cysts.
INFECTIONS
A large variety of organisms can infect the female genital
tract.
HSVs are
DNA viruses that include two serotypes, HSV-1 and HSV-2.
By 40 years of age, approximately 30% of women are
seropositive for antibodies against HSV-2.
About one-third of newly infected individuals are
symptomatic.
Lesions around the urethra may
cause painful urination and urine retention.
As expected, recurrences
are much more common in immunosuppressed individuals.
Figure 22.2 Herpes simplex virus (HSV) infection (cervical smear).
The
cell in the center shows HSV cytopathic effect.
mother.
Cesarean delivery is warranted in such cases to
prevent transmission to the neonate.
The diagnosis is based on typical clinical findings and
HSV detection.
The purulent exudate is aspirated from the
lesions and inoculated into a tissue culture.
The viral
cytopathic effect can be seen after 48 to 72 hours, and the
virus can then be serotyped.
Individuals with primary, acute HSV infection do not have
serum anti-HSV antibodies.
Detection of anti-HSV antibodies
in the serum is indicative of recurrent/latent infection.
The
ultimate solution is an effective vaccine, a tantalizing goal
yet to be realized.
22.3A).
Molluscum may affect
any area of the skin but is most common on the trunk,
arms, and legs.
The average
MORPHOLOGY
By the time an HSV lesion is biopsied, it typically has ulcerated.
The epithelium is desquamated, and marked acute inflammation
is present in the ulcer bed.
22.2).
Condoms and antiviral
therapies reduce the risk of transmission, but do not prevent
it completely.
Previous infection with HSV-1 seems to reduce sus-
ceptibility to HSV-2 infection.
The gravest consequence of
HSV infection is transmission to the neonate during birth.
(A) Low-power appearance of a dome-shaped papule with dimpled center.
(B) High-power magnification
reveals intracytoplasmic viral inclusions.
incubation period is 6 weeks.
22.3B).
Severe
infection may result in mucosal ulcerations.
Patients typically present with thin, green-gray,
malodorous (fishy) vaginal discharge.
Bacterial cultures in such
cases reveal G.
In pregnant patients, bacterial vaginosis has
been implicated in premature labor.
• Chlamydia trachomatis infections mainly take the form of
cervicitis.
Chlamydia
infection is another well-recognized cause of PID.
With gonococcus, inflammatory changes start to appear
approximately 2 to 7 days after inoculation.
Pus fills the
center of the fallopian tube.
Such scarring may cause
infertility or ectopic tubal pregnancy.
channels rather than on the mucosal surfaces.
22.4A).
The infection may then spread to the ovary to create
a salpingo-oophoritis.
22.4B).
Nonspecific vulvitis is
particularly likely to occur in the setting of immunosup-
pression.
(A) Lichen sclerosus.
(B) Squamous cell hyperplasia, displaying thickened epidermis and hyperkeratosis.
These
cysts are usually lined by transitional or squamous epithelium.
They may become large, up to 3 to 5 cm in diameter, and
produce pain and local discomfort.
Bartholin duct cysts are
either excised or opened permanently (marsupialization).
Histologically, the lesion
is characterized by marked thinning of the epidermis (Fig.
The disease occurs in all age groups
but is most common in postmenopausal women.
It may
also be encountered elsewhere on the skin.
22.5B).
Lymphocytic
infiltration of the dermis is sometimes present.
The hyper-
plastic epithelium may show mitotic activity but lacks cellular
atypia.
(A) Low-power view showing exophytic, papillary architecture.
of sexually transmitted infections.
The etiology of
fibroepithelial polyps and squamous papillomas is unknown.
The lesions are
identical to those found on the penis and around the anus
in males (Chapter 21).
22.6A).
Condylomata acuminata are not precan-
cerous lesions.
years of age.
Squamous cell carcinoma is the most common
histologic type of vulvar cancer.
These are less
common (30% of cases) and occur in younger women
(average 60 years of age).
• Keratinizing squamous cell carcinomas are unrelated to HPV
infection.
These are more common (70% of cases) and
occur in older women (average 75 years of age).
Spontaneous regres-
sion of classic VIN has been reported, usually in younger
women.
No invasion is present.
There is a focus of necrosis (red area).
On histologic examination, basaloid
carcinoma (see Fig.
22.8A).
22.8B).
A B
Figure 22.8 Non–human papillomavirus (HPV) vulvar pre-neoplastic and malignant lesions.
No invasion is present.
The initial spread is to ingui-
nal, pelvic, iliac, and periaortic lymph nodes.
Ultimately,
hematogenous dissemination to the lungs, liver, and other
internal organs may occur.
GLANDULAR NEOPLASTIC LESIONS
Like the breast, the vulva contains modified apocrine sweat
glands.
These myoepithelial
elements are characteristic of sweat glands and sweat gland
tumors (Fig.
22.9).
In the vulva, it presents as a pruritic, red, crusted, maplike
area, usually on the labia majora.
In
the rare instances when invasion develops, the prognosis
is poor.
MORPHOLOGY
Paget disease is a distinctive intraepithelial proliferation of malignant
cells.
22.10A).
In addition, unlike squamous epithelium, the
cells express cytokeratin 7 (see Fig.
22.10B).
There is inflammation in the underlying dermis.
(B) Immunostaining for cytokeratin 7 highlights the intraepidermal Paget cells.
This is
normally replaced by squamous epithelium advancing
upward from the urogenital sinus.
They consist of 1- to 2-cm
fluid-filled submucosal cysts.
Infants may develop a unique, rare malignancy—
embryonal rhabdomyosarcoma (sarcoma botryoides).
22.11).
Rarely,
striations (indicative of muscle differentiation) can be seen
within the cytoplasm.
Such lesions can be mistaken for benign
inflammatory polyps.
(Courtesy
Dr.
The endocervix is lined by columnar,
mucus-secreting epithelium.
22.12).
In addition, at low
pH, lactobacilli produce bacteriotoxic hydrogen peroxide
(H2 O2).
Antibiotic therapy that suppresses lactobacilli
can also cause the pH to rise.
8 months, respectively).
Productive, persistent HPV infection requires viral entry
into immature basal epithelial cells.
22.12).
Although HPV infects immature squamous
cells, viral replication occurs in maturing squamous cells.
of other microorganisms, which may result in cervicitis or
vaginitis.
22.13).
Simple curettage
or surgical excision is curative.
The viral
DNA is integrated into the host cell genome in most cancers.
Hence a brief review
of the terminology is warranted.
Because the decision with regard to patient
management is two-tiered (observation vs.
replication, but only mild alterations in the growth of host
cells.
For these reasons, LSIL is not treated like a premalignant
lesion.
LSIL is approximately ten times more common
than HSIL.
By contrast to LSIL, HSIL is considered to be at high
risk for progression to carcinoma.
Nuclear alterations associated with perinuclear halos are termed
koilocytic atypia.
22.15).
The highest viral loads (assessed by in situ hybridization for HPV
DNA; see Fig.
22.15B) are found in maturing keratinocytes in the
upper half of the epithelium.
HPV E6 and E7 proteins prevent
cell cycle arrest.
22.15C), that are normally confined to the basal layer
of the epithelium.
22.15D).
common HPV type in both lesions.
Table 22.2 shows
rates of regression and progression of SILs within a 2-year
follow-up.
Progression
to invasive carcinoma, when it occurs, on average takes
place over several decades.
All of the aforementioned tumor
types are caused by high-risk HPVs.
The dark granular staining denotes HPV
DNA, which is most abundant in the superficial koilocytes.
a Progression within 2 to 10 years.
22.16A–B).
(B) Invasive adenocarcinoma.
(Fig.
22.17A–B).
Adenosquamous carcinoma is composed of
intermixed malignant glandular and squamous epithelium.
Lymphovascular invasion results in local and distant lymph
nodes metastases.
Distant metastases may also be found in the
liver, lungs, bone marrow, and other organs.
Carcinoma involves the vagina but not the lower
third.
Stage III—Carcinoma has extended to the pelvic wall.
These lesions shed abnormal cells that can be
detected on cytologic examination.
22.18.
The cytoplasmic staining of desquamated cells may be
either red or blue.
(A) Normal exfoliated superficial squamous cells.
(B) Low-grade squamous intraepithelial lesion—koilocytes.
(C) High-grade squamous
intraepithelial lesion (HSIL; cervical intraepithelial neoplasia [CIN] II).
(D) HSIL (CIN III).
(Courtesy Dr.
Edmund S.
HPV testing has a higher sensitivity but lower specificity,
as compared to the Pap test.
HPV DNA testing may be
added to cervical cytology for screening in women 30 years
of age or older.
Cervical cancer screening and preventive measures are
carried out in a stepwise fashion.
Abnormal appearing areas are biopsied.
Women with
biopsy-confirmed LSIL can be followed in a conservative
fashion.
HSIL is treated with
cervical conization (superficial excision).
Two HPV vaccines are now FDA-licensed.
The vaccines offer protection for up to 10 years; longer
follow-up studies are still pending.
HSIL may progress to invasive
carcinoma.
Mitotic figures are
numerous, and there is no evidence of mucus secretion
or vacuolation.
22.19A).
22.19B).
By the fourth week, the glands are tortuous,
producing a serrated appearance.
22.19).
(A) Proliferative phase with mitoses (arrow).
(B) Early secretory phase with subnuclear vacuoles (arrow).
(C) Late secretory exhaustion and predecidual changes (arrow).
(D) Menstrual endometrium with stromal breakdown (arrow) (see text).
22.19C).
22.19D).
They may also contribute to
the development of ectopic endometrial tissue and endo-
metrial cancer.
22.20C), submucosal
leiomyomas (see Fig.
This is a
clinical term for uterine bleeding that lacks an underlying
structural abnormality.
Note breakdown associated with proliferative glands.
(B) Chronic endometritis with plasma cells (arrow).
(C) Endometrial polyp.
(D) Submucosal leiomyoma with attenuation of the endometrial lining (arrow).
22.20A).
The inflammatory response
is chiefly limited to the stroma and is entirely nonspecific.
Endometrial
tuberculosis is rare in high income countries.
22.20B),
which are not seen in normal endometrium.
In about 15%
of cases, no cause is apparent.
The responsible organisms may not be detected by culture.
22.21).
A B
Figure 22.21 Endometriosis.
(A) Endometriosis involving the mucosa of the colon.
Molecular analyses have provided additional insights.
22.22).
These
factors may also contribute to avoidance of immune
clearance.
E, Estrogen.
inhibitors of aromatase are beneficial in the treatment of
endometriosis.
Deeply infiltrating endometriosis
can invade tissues and also cause fibrosis and adhesions.
22.21B), with or without the presence of
hemosiderin.
In rare cases only stroma is identified.
• It commonly results in dysmenorrhea, pelvic pain, and infertility.
Polyps may be asymptomatic or
may cause abnormal bleeding and infertility.
Polyps are responsive to
estrogen but show little or no response to progesterone (see
Fig.
22.20C).
However, tamoxifen has weak pro-estrogenic
effects in the endometrium.
Rarely,
adenocarcinoma arises within endometrial polyps.
Adenomyosis occurs in up to 20% of uteri.
It can
coexist with endometriosis.
When PTEN
function is lost, the PI3K/AKT pathway becomes overactive.
The glands show variation in size and shape and
may be dilated (Fig.
22.23B).
Hyperplasia may evolve into cystic atrophy when
estrogen is withdrawn.
A B
C D
Figure 22.23 Endometrial hyperplasia.
(A) Typical hyperplasia.
The glands are commonly back-
to-back and often have complex outlines due to branching
structures.
In addition,
the nuclei have open (vesicular) chromatin and conspicuous nucleoli.
22.23C–D).
• The PTEN tumor suppressor gene is mutated in approximately
20% of endometrial hyperplasias.
serous carcinomas, the most common morphologies of type
1 and type 2 tumors, respectively.
The
majority of these tumors fall in to the type I category.
It accounts for 7% of all invasive
cancer in women, excluding skin cancer.
In 2019 in the United States, 61,880 new
endometrial cancers and 12,160 deaths were predicted.
Worldwide there were over 380,000 new cases diagnosed
in 2018.
Most notable of these is obesity,
a rapidly increasing problem in high income countries.
22.24A).
22.25B), composed almost entirely of well-formed
glands; moderately differentiated (grade 2) (Fig.
22.25D),
characterized by greater than 50% solid growth pattern.
Up to 20% of endometrioid carcinomas contain foci of
squamous differentiation.
22.25A).
Invasion of the
broad ligaments may create a palpable mass.
Eventually,
A B
C D
Figure 22.25 Type I endometrial carcinoma.
(A) Endometrial adenocarcinoma presenting as a fungating mass in the fundus of the uterus.
22.26B and D).
All serous carcinomas belong to the copy number
high/serous-like molecular category.
As a result, they
have often spread outside of the uterus at the time of
diagnosis.
adenocarcinomas.
22.24B).
Serous tumors are considered type II tumors
and are by definition poorly differentiated (grade 3).
They
account for approximately 15% of cases of endometrial
carcinoma.
This subtype shows significant morphologic and
biologic overlap with ovarian serous carcinoma.
A B
C D
Figure 22.26 Type II endometrial carcinoma.
Treatment varies according to tumor type.
22.26C–D).
There is no
currently available screening test.
Stage II—Carcinoma involves the corpus and the cervix.
Stage III—Carcinoma extends outside the uterus but not
outside the true pelvis.
As mentioned, serous carcinoma has a propensity for
extrauterine (lymphatic or transtubal) spread.
Metastases usually
contain only epithelial components (see Fig.
22.27B).
Carcinosarcomas occur in postmenopausal women and
present with bleeding.
Outcome is determined primarily
by depth of invasion and stage.
(A) Micrograph showing both malignant epithelial and stromal components.
• There are two major types of endometrial carcinoma: type I
and type II.
• Four molecular subtypes of endometrioid and serous carcinoma
are currently recognized.
TP53 mutations are also found in precursor lesions.
malignant-appearing stroma, which coexists with benign
but abnormally shaped endometrial glands.
The principal diagnostic
dilemma is distinguishing these tumors from large benign
polyps.
The 5-year
survival rates average 50% for low-grade tumors and are
lower for high-grade tumors.
beneath the serosa (subserosal) (Fig.
22.28A).
Large tumors may develop
areas of yellow-brown to red softening.
22.28B).
Mitotic figures are scarce.
Both have a low mitotic index,
helping to distinguish these benign tumors from leiomyosarcoma.
Both
are considered benign despite their unusual behavior.
They are benign smooth
muscle neoplasms that may occur singly, but more often are
multiple.
Both genes encode closely related DNA-binding factors that
regulate chromatin structure.
Additionally, mutations in the
gene MED12 occur in roughly 70% of uterine leiomyomas.
Uterine leiomyomas, even when large or numerous, may
be asymptomatic.
Malignant transformation to leiomyosarcoma is
extremely rare.
Except in rare instances,
they are found within the myometrium of the corpus.
Only
infrequently do they involve the uterine ligaments, lower uterine
segment, or cervix.
(A) A large hemorrhagic tumor mass distends the lower corpus and is flanked by two leiomyomas.
(B) The tumor cells
are irregular in size and have hyperchromatic nuclei.
Numerous mitotic figures are present (arrows).
22.29A).
22.29B).
• High-grade stromal sarcoma shows marked atypia and is
associated with other gene fusions.
• Both low- and high-grade stromal sarcoma are prone to late
recurrences.
Dissemination throughout
the abdominal cavity is also encountered.
• Stromal nodules are benign, well-circumscribed tumors.
Historically, fallopian tube carcinoma was considered to
be a rare entity.
We will return to this issue when discussing ovarian
cancer in the next section.
abnormalities, polycystic ovaries, chronic anovulation, and
decreased fertility.
The etiology of PCOS
remains incompletely understood.
As the follicles
regress, the concentric theca-lutein hyperplasia may appear
nodular.
This change is not to be confused with true luteomas
of pregnancy (see later).
OVARIAN TUMORS
There are numerous types of ovarian tumors.
About 80%
are benign, and these occur mostly in young women between
20 and 45 years of age.
MORPHOLOGY
These cysts are usually multiple.
Malignant tumors are more common in women between 45
and 65 years of age.
Some, principally epithelial tumors, are often bilateral.
Table
22.6 lists the tumors and their subtypes.
Epithelial Tumors
Most primary ovarian neoplasms arise from müllerian
epithelium.
These epithelial
proliferations are classified as benign, borderline, and
malignant.
The most intriguing risk factors are genetic.
Historically, the source
of these tumors was hypothesized to be cortical inclusion
cysts (Fig.
22.30).
These include
low-grade serous, endometrioid, and mucinous carcinomas.
They demonstrate high-grade
features and are most commonly of serous histology.
STIC, Serous tubal
intraepithelial carcinoma.
22.30).
About 70% are benign or
borderline, and 30% are malignant.
Benign and borderline
tumors are most common between 20 and 45 years of age.
Pathogenesis
Little is known about the risk factors for benign and bor-
derline tumors.
There is a higher frequency
of carcinoma in women with low parity.
Curiously, BRCA1 and BRCA2 mutations are rare in
sporadic high-grade serous carcinoma.
of the stroma is not seen (Fig.
22.33C).
22.33D).
22.32A) or as a mass projecting from the ovarian surface.
Borderline
tumors contain an increased number of papillary projections (Fig.
22.32A and C).
22.32B).
22.32C).
Microscopically, the cysts are lined by columnar epithelium.
In
benign tumors (Fig.
22.33A), the epithelial cells retain abundant
cilia, and microscopic papillae may be found.
(B) Carcinoma.
The cyst is opened to reveal a large, bulky tumor mass.
(A) Serous cystadenoma revealing stromal papillae with a columnar epithelium.
(C) Complex micropapillary growth defines a
low-grade “micropapillary” serous carcinoma.
(D) High-grade serous carcinoma of the ovary with invasion of underlying stroma.
of presentation, a picture associated with rapid clinical
deterioration.
Mucinous Tumors
Mucinous tumors account for about 20% to 25% of all ovarian
neoplasms.
They occur principally in middle adult life and
are rare before puberty and after menopause.
The vast
majority are benign or borderline tumors.
Thus, KRAS mutations may initiate
the development of these neoplasms.
22.34A).
22.34B).
(B) Columnar cells lining the cysts.
22.35).
Pseudomyxoma peritonei,
if extensive, may result in intestinal obstruction and death.
Pathogenesis
In about 15% to 20% of cases, endometrioid carcinoma
coexists with endometriosis.
Endometrioid carcinomas typically present
with solid and cystic areas of growth.
(A) View at laparotomy revealing
massive overgrowth of a gelatinous metastatic tumor.
(A, Courtesy Dr.
Paul H.
Clear cell tumors
of the ovary can be predominantly solid or cystic.
Clear cell carcinoma is treated like other types of ovarian
carcinoma.
They may contain
mucinous, serous, endometrioid, or transitional (Brenner
tumor) epithelium.
Uncommon transitional cell
carcinomas also occur in the ovary.
22.36B).
Most Brenner tumors are
benign, but borderline and malignant counterparts have been
reported.
Brenner tumors are often detected incidentally and even
when large behave in a benign fashion.
Benign lesions are easily resected and cured.
The
malignant tumors tend to cause progressive weakness, weight
loss, and cachexia.
Characteristically,
the ascitic fluid is filled with exfoliated tumor cells.
22.36A).
(B) Histologic detail of characteristic epithelial
nests within the ovarian stroma.
(Courtesy Dr.
M.
For these reasons, development
of new assays that permit early diagnosis is a top priority.
Prevention of ovarian cancer also remains an elusive goal.
Cystic teratomas are usually found in
young women.
KEY CONCEPTS
• Epithelial ovarian tumors are classified into benign, borderline,
or malignant.
• Benign tumors are composed of well-differentiated epithelial
cells with minimal proliferation.
Borderline tumors show
increased cell proliferation, but lack stromal invasion.
• Ovarian carcinomas are currently divided into type I (low-grade)
and type II (high-grade) tumors.
MORPHOLOGY
Benign teratoma is bilateral in 10% to 15% of cases.
Characteristi-
cally it consists of a unilocular cyst containing hair and sebaceous
material (Fig.
22.38).
22.39).
Dermoid cysts are sometimes incorporated
within the wall of a mucinous cystadenoma.
22.37).
Figure 22.38 Opened mature cystic teratoma (dermoid cyst) of the
ovary.
Grading is based on the proportion of the tumor that is comprised
of immature neuroepithelium (Fig.
22.40).
Figure 22.39 Benign cystic teratoma.
Low-power view of skin (right edge),
beneath which there is brain tissue (left edge).
Stage I
tumors, particularly those with low-grade (grade 1) histology,
have an excellent prognosis.
Higher-grade tumors confined
to the ovary are generally treated with adjuvant chemo-
therapy.
Dysgerminoma
Dysgerminoma is the ovarian counterpart of testicular
seminoma.
They may occur in childhood, but 75% occur in the
second and third decades of life.
Some occur in patients
with gonadal dysgenesis, including pseudohermaphroditism.
Most of these tumors have no endocrine function.
The origin of teratomas has been a matter of fascination
for centuries.
Some common beliefs blamed witches, night-
mares, or adultery with the devil.
The karyotype of almost
all benign ovarian teratomas is 46,XX.
They are always unilateral, although a contralateral
teratoma may be present.
Even rarer is strumal car-
cinoid, a combination of struma ovarii and carcinoid in the
same ovary.
Only about 2% of carcinoids in teratomas
metastasize.
The
tumor cells grow in sheets or cords separated by scant fibrous
stroma (Fig.
22.41), which is infiltrated by lymphocytes and may
contain noncaseating granulomas.
Figure 22.42 A Schiller-Duval body in a yolk sac carcinoma.
Overall survival exceeds 80%.
22.37).
Similar to
the normal yolk sac, the tumor cells elaborate α-fetoprotein.
22.42).
With combination chemotherapy,
there is greater than 80% survival, independent of disease
stage.
They
are histologically identical to the more common placental
lesions (described later).
KEY CONCEPTS
GERM CELL TUMORS
• Germ cell tumors constitute 15% to 20% of ovarian tumors.
• The majority are mature cystic teratomas (dermoid cysts) in
women of reproductive age.
• The remainder occur in young women and children; in these
age groups, malignant tumors dominate.
grow in anastomosing cords, sheets, or strands (Fig.
22.43A).
When these structures are evident, the diagnosis is
straightforward.
Although
they may be discovered at any age, approximately two-thirds
occur in postmenopausal women.
Occasionally, granulosa cell tumors produce androgens,
masculinizing the patient.
All granulosa cell tumors are potentially malignant.
It
is difficult to predict their biologic behavior from histology.
The likelihood of malignant behavior (recurrence, extension)
ranges from 5% to 25%.
The 10-year survival rate is approximately
85%.
Tumors composed predominantly of theca cells are
almost never malignant.
22.43B), and for monitoring patients being treated for these
neoplasms.
The granulosa cell component of these tumors has many
histologic patterns.
The small, cuboidal to polygonal cells may
A B
Figure 22.43 Granulosa cell tumor.
(A) Thecoma-fibroma composed of plump, differentiated stromal cells with thecal appearance.
(B) Large bisected fibroma
of the ovary apparent as a white, firm mass (right).
The fallopian tube is attached.
common in juvenile granulosa tumor, suggesting that it is
genetically distinct from the adult type.
22.44A).
Many
tumors contain a mixture of these cells and are termed
fibrothecomas.
Fibrothecomas and pure thecomas (a rare
subtype) may be hormonally active.
By contrast, pure
fibromas as a rule are hormonally inactive.
22.44B).
Focal areas of
thecal differentiation may be identified.
Uncommonly there is also a hydrothorax, usually only on
the right side.
Its
genesis is unknown.
The second association is with the basal
cell nevus syndrome, described in Chapter 25.
The vast
majority of fibromas, fibrothecomas, and thecomas are
benign.
They occur in women of all ages, although
the peak incidence is in the second and third decades.
MORPHOLOGY
These tumors are unilateral and may resemble granulosa cell
tumors grossly.
The cut surface is usually solid and varies from
gray to golden brown in appearance (Fig.
22.45A).
Microscopically,
A B
Figure 22.45 Sertoli cell tumor.
(A) Gross photograph illustrating characteristic golden-yellow appearance of the tumor.
(B) Photomicrograph showing
well-differentiated Sertoli cell tubules.
(Courtesy Dr.
It occurs in individu-
als with abnormal sexual development and in gonads
of indeterminate nature.
A coexistent dysgerminoma occurs in 50% of the
cases.
The prognosis is excellent if the tumor is completely
excised.
22.45B).
Leydig cells may be absent.
Heterologous elements, such as mucinous glands, bone, and
cartilage, may be present in some tumors.
The incidence of recurrence or metastasis by Sertoli-Leydig
cell tumors is less than 5%.
The tumors produce predomi-
nantly testosterone.
Treatment consists of surgical excision.
True hilus cell tumors are almost always benign.
• Pregnancy luteoma refers to a rare tumor that closely
resembles the corpus luteum of pregnancy.
These tumors
may produce virilization in pregnant patients and their
female infants.
• Pure thecomas are rare but may be hormonally active.
These
include selected disorders of early pregnancy, late pregnancy,
and trophoblastic neoplasia.
Understanding placental disorders requires a working
knowledge of normal placental anatomy.
The placenta is
composed of chorionic villi (Fig.
22.47).
Chorionic arteries branch further as they enter the villi.
Ascending infection is
particularly common in second-trimester losses.
Ectopic pregnancies account for
2% of confirmed pregnancies.
In some cases, however, the
fallopian tubes are apparently normal.
The host implantation site may also develop
decidual changes.
A
B
Figure 22.46 Normal placenta.
Rupture frequently results in massive intraperitoneal
hemorrhage, which sometimes is fatal.
Most of these
occur before 12 weeks.
Ten to fifteen percent of clinically
recognized pregnancies terminate in spontaneous abortion.
In most individual instances,
the mechanisms leading to early loss of pregnancy are
unknown.
However, multiple fetal and maternal causes of
spontaneous abortion have been identified.
Clinical Features
Rupture of a tubal pregnancy is a medical emergency.
Umbilical vessels branch and terminate in placental villi, where nutrient exchange takes place.
correlating with distention and then rupture of the fallopian
tube.
In such cases, the patient may rapidly develop hemor-
rhagic shock and signs of an acute abdomen.
There are three types of twin placentas (Fig.
(Modified from Gersell D,
et al: Diseases of the placenta.
Acute chorioamnionitis.
(A) On gross examination, the placenta
contains greenish opaque membranes.
(C) Acute
necrotizing intervillositis from Listeria infection.
The space between the villi is filled with blood and acute inflammatory cells (neutrophils).
The villi appear
necrotic.
Dichorionic placentation may occur with either
monozygotic or dizygotic twins and is not specific.
One complication of monochorionic twin pregnancy is
twin-to-twin transfusion syndrome.
If severe, it may result in the death of
one or both fetuses.
It is an
important cause of severe, potentially life-threatening
postpartum bleeding.
22.49A–B).
22.49C).
22.50).
• Endothelial dysfunction and imbalance of angiogenic and
antiangiogenic factors.
The result is defective vascular
development in the placenta.
Antihypertensive therapy does not affect
the disease course or improve outcome.
They are usually diagnosed during early pregnancy (average
9 weeks) by pelvic sonography.
For unknown reasons, the incidence varies considerably in
different parts of the world.
22.52A–B).
Partial Mole
Partial moles result from fertilization of an egg with two
sperm (see Fig.
22.52C).
In these moles, the karyotype is
triploid (e.g., 69,XXY) or occasionally tetraploid (92,XXXY).
Fetal tissues are typically present.
Figure 22.51 Acute atherosis of uterine vessels in eclampsia.
Note
fibrinoid necrosis of the vessel wall and subendothelial macrophages.
(Courtesy Dr.
Drucilla J.
22.51).
The kidney lesions are variable.
Immunofluorescent studies show abundant fibrin
deposition in glomeruli.
In advanced cases, fibrin thrombi are
present in the glomeruli and capillaries of the cortex.
Similar changes are
often found in the heart and the anterior pituitary gland.
Management of preeclampsia differs depending on the
gestational age and severity of disease.
For term pregnancies,
delivery is the treatment of choice regardless of disease
severity.
However, eclampsia, severe preeclampsia with1034 CHAPTER 22 The Female Genital Tract
A.
Complete mole
Chromosome
duplication
46XX
23X
Homozygous
Empty ovum
complete mole
B.
Note marked distention of
the uterus by enlarged, vesicular chorionic villi.
Adnexa (ovaries and
fallopian tubes) are visible on the left and right side of the uterus.
C.
The tumor manifests clinically with
vaginal bleeding and irregular uterine enlargement.
It is
always associated with a persistently elevated serum hCG.
(B) Less commonly, complete moles arise from dispermy in which two
sperm fertilize an empty ovum.
(C) Partial moles arise from two sperm
fertilizing a single ovum.
22.53 and 22.54).
Most moles are successfully removed by curettage.
Continuous
elevation of hCG may be indicative of persistent or invasive
mole (described next).
(A) Choriocarcinoma presenting as a bulky hemorrhagic mass invading the uterine wall.
(Courtesy Dr.
David R.
Genest, Brigham and Women’s Hospital, Boston, Mass.)
United States.
Rarely, nongestational choriocarcinoma develops
from germ cells in the ovaries or the mediastinum.
Many of the cured patients
have had normal subsequent pregnancies and deliveries.
The malignant trophoblastic cells typically
diffusely infiltrate the endomyometrium.
22.55A).
22.55B); chorionic villi
are absent.
Mitoses are abundant and sometimes abnormal.
Sometimes the tumor
does not appear until months after these events.
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mendations for HPV testing].
Uterus and Endometrium
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of endometriosis pathogenesis].
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of the pathogenesis of leiomyomas].
Giudice LC: Endometriosis, N Engl J Med 362:2389, 2010.
[A review of
the pathophysiology of endometriosis].
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[A
comprehensive genomic study of endometrioid and serous endometrial
carcinoma].
Ovary
Azzia R et al: Polycystic ovary syndrome, Nat Rev Dis Primers 11:16057,
2016.
[A comprehensive review of PCOS].
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study of mutations in non-epithelial ovarian tumors].
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review of the molecular genetics of ovarian germ cell tumors].
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pregnancies].
All of these features impact the origin,
presentation, and treatment of breast disease.
Each of
these elements is the source of both benign and malignant
lesions (Fig.
23.1).
23.1).
Changes in the female breast are most dynamic and
profound during the reproductive years.
Just as the endometrium grows and ebbs with each menstrual
cycle, so does the breast.
In the first half of the menstrual
cycle the lobules are relatively quiescent.
Upon menstruation, the fall in hormone
levels induces regression of the lobules.
Only with pregnancy does the breast completely mature
and become fully functional.
Lobules increase progressively
in number and size.
DCIS, Ductal carcinoma in situ.
and calories) over the next 10 days as progesterone levels
drop.
23.2A).
Greater than 90% of symptomatic breast
lesions are benign.
23.2B).
(B) Presentations of breast cancer.
cyclic pain may be due to premenstrual edema.
• Inflammation causes erythema and edema involving all
or part of a breast.
An impor-
tant mimic of reactive inflammation is inflammatory
breast carcinoma (discussed later).
• Nipple discharge may be normal when small in quantity
and bilateral.
Repeated nipple stimulation also may
induce lactation.
Galactorrhea is not a feature of malig-
nancy.
Bloody or serous discharges are most commonly
due to large duct papillomas and cysts.
During pregnancy,
rapid growth and remodeling of the breast may produce
a bloody discharge.
When pro-
nounced, imaging studies may be needed to exclude the
presence of a discrete mass.
The most common benign
masses are fibroadenomas and cysts.
23.2B).
The sensitivity and specificity of mammography increase
with age.
The principal mammographic
signs of breast carcinoma are densities and calcifications:
• Densities.
Breast lesions that replace adipose tissue with
radiodense tissue form mammographic densities.
• Calcifications.
Calcifications
associated with malignancy are usually small, irregular,
numerous, and clustered.
By the time
of detection, most (70% to 80%) cancers are invasive and
some have metastasized.
when the breast is most vulnerable due to cracks and fissures
in the nipples.
The breast is erythematous and painful, and fever is often
present.
At the outset only one duct system or sector of the
breast is involved.
If not treated, the infection may spread
to the entire breast.
Only rarely is surgical drainage required.
In
many affected women the nipple inverts due to traction
produced by inflammation and scarring.
More than 90% of
afflicted individuals are smokers.
23.3).
When squamous
metaplasia extends deep into a nipple duct, keratin becomes trapped and
accumulates.
dilation and eventually rupture of the duct.
Fat Necrosis
The presentations of fat necrosis are protean and may closely
mimic cancer.
About half of affected women have a history
of breast trauma or surgery.
If
secondary bacterial infection is present, antibiotics also have
a therapeutic role.
Pain and erythema are
uncommon.
This disorder tends to occur in the fifth or sixth
decade of life, usually in multiparous women.
Unlike
squamous metaplasia of lactiferous ducts, it is not associated
with cigarette smoking.
Ill-defined, firm, gray-white nodules containing small chalky-white
foci are seen grossly.
23.4).
Granulomas may form around cholesterol
deposits and secretions.
Subsequent fibrosis produces an irregular
mass with skin and nipple retraction.
Its only clinical
significance is that it must be distinguished from breast
cancer.
Granulomatous lobular mastitis is an uncommon
disease that occurs only in parous women.
These
histologic patterns may be manifestations of the same disease.
Treatment includes antibiotics and sometimes steroids.
Figure 23.4 Duct ectasia.
Chronic inflammation and fibrosis surround an
ectatic duct filled with inspissated debris.
C
Figure 23.5 Apocrine cysts.
(A) Clustered, rounded calcifications are
seen in a specimen radiograph.
(B) Gross appearance of typical cysts filled
with dark, turbid fluid contents.
(C) Cysts are lined by apocrine cells with
round nuclei and abundant granular cytoplasm.
Note the luminal
calcifications, which form on secretory debris.
Several other morphologic alterations fall into the category
of “nonproliferative” changes.
• Cysts.
Small cysts form by the dilation of lobules and in turn
may coalesce to form larger cysts.
Unopened cysts contain
turbid, semitranslucent brown- or blue-colored fluid (blue-dome
cysts) (Fig.
23.5B).
23.5C).
Calcifications are common (Fig.
23.5A).
• Fibrosis.
Cysts frequently rupture, releasing secretory material
into the adjacent stroma.
The resulting chronic inflammation
and fibrosis contribute to palpable nodularity of the breast.
• Adenosis.
Adenosis is defined as an increase in the number
of acini per lobule.
It is a normal feature of pregnancy.
(B) Epithelial hyperplasia.
The lumen is filled with a
heterogeneous, mixed population of luminal and myoepithelial cell types.
Irregular slit-like fenestrations are prominent at the periphery.
incidental findings in biopsies performed for other reasons.
These lesions are considered predictors of risk, rather than
direct precursors, of carcinoma.
23.6A).
Irregular lumens can often be discerned at the periphery
of the cellular masses (Fig.
23.6B).
Epithelial hyperplasia is usually
an incidental finding.
• Sclerosing adenosis.
23.7).
• Complex sclerosing lesion.
These lesions have components
of sclerosing adenosis, papilloma, and epithelial hyperplasia.
• Papilloma.
23.9).
Epithelial hyperplasia and apocrine metaplasia are frequently
present.
Large duct papillomas are situated in the lactiferous
Figure 23.7 Sclerosing adenosis.
Calcifications are present within some of the lumens.
sinuses of the nipple and are usually solitary.
Small duct papillomas
are commonly multiple and located deeper within the ductal
system.
Lobule formation is absent.
It presents as a button-like subareolar enlargement and may
be unilateral or bilateral.
23.10).
Lobule
formation is almost never observed.
Atypical lobular hyperplasia
Figure 23.9 Intraductal papilloma.
The papillae arborize within the lumen and are
biopsies.
lined by myoepithelial and luminal cells.
C
Figure 23.8 Radial sclerosing lesion.
(A) Radiograph shows an irregular
central mass with long radiodense projections.
These
features are highly atypical, but fall short of a diagnosis of ductal carcinoma in situ.
(B) Atypical lobular hyperplasia.
A population of monomorphic small,
round, loosely cohesive cells partially fills a lobule.
It is distinguished from DCIS in that it only partially fills
involved ducts (Fig.
23.11A).
23.11B).
Both breasts are at
increased risk.
• The majority are not precursors of cancer.
• These lesions are classified according to the subsequent risk
of cancer in either breast.
The lifetime risk of breast cancer is 1 in 8 for women
living to age 90 in the United States.
In this chapter, “luminal” cancers
are defined as being positive for ER and negative for HER2.
“Triple negative
breast cancers” (TNBCs) are cancers that are negative for
ER and HER2.
23.12).
Rates are per 100,000 women.
In contrast, luminal cancers show a marked
increase in incidence with age.
TNBC,
Triple negative breast cancer.
Breast cancer incidence and biology vary with ethnicity.
For Hispanic
women, the average age at diagnosis is 56, and 20% are
diagnosed at ages below 50.
The “excess” cancers in women
of European descent are mostly of luminal type (Fig.
23.12).
Surgical and medical interventions also can decrease risk.
Bilateral prophylactic mastectomy decreases risk by about
90%.
Chemoprevention using ER antagonists decreases
the incidence of ER-positive cancers.
These interventions
are mainly offered to women at very high risk for breast
cancer.
Gene expression (mRNA) profiling measures
relative levels of mRNA expression.
Red indicates a relative increase; green, a relative decrease; and black, no change in levels.
Genes are arrayed from top
to bottom and tumors from left to right.
All of these cancers express ER (an
estrogen-dependent transcription factor).
Biallelic
mutations cause a form
of Fanconi anemia.
ER, Estrogen receptor; TNBC, triple negative breast cancer.
Most of these genes play complex and interrelated roles
in maintaining genomic integrity.
BRCA1, BRCA2, and CHEK2 all have important functions
in repair of double-stranded DNA breaks.
23.14 and Table 23.4 and are described next.
DCIS
Figure 23.14 Major pathways of breast cancer development.
Three main pathways have been identified.
The most common pathway (yellow arrow) leads to
luminal (ER-positive) carcinomas.
The third pathway (green arrow) consists of
HER2-positive cancers.
Amplification of HER2 can occur in either ER-positive or ER-negative lesions.
A definite HER2-positive precursor lesion has not
been identified.
See text for other details.
DCIS, Ductal carcinoma in situ.
ER, Estrogen receptor; mRNA, messenger RNA; TNBC, triple negative breast cancer.
23.12).
These
are considered the earliest recognizable precursors of luminal
breast cancers.
23.13).
Recurrences after this time are rare.
HER2-positive cancers show a mixed pattern with both early and late
peaks.
or longer by treatment with antiestrogens (Fig.
23.15).
23.16).
23.15).
TNBC also shares other genetic features with serous
ovarian carcinoma.
In
familial breast cancer, this defect is often related to germline
BRCA1 and BRCA2 mutations.
The cancers that recur usually do so in the
first 8 years after diagnosis (see Fig.
23.15).
Metastases are
often to visceral sites and brain and frequently result in
death.
Patients who survive 10 years are likely cured, as
late recurrences are unusual.
Such
changes may set the stage for stromal invasion by breast
cancer cells.
With this as background, we next turn to discussion of
the pathology of breast cancer.
• The most important risk factors for sporadic cancers in women
are estrogenic stimulation and age.
duct lobular unit.
Ductal Carcinoma in Situ.
DCIS is almost always detected by mammography.
23.17).
Some
cases of DCIS have a single growth pattern, but most are comprised
of a mixture of patterns.
23.17A).
23.17B).
23.17C).
Micropapillary DCIS
produces complex bulbous protrusions without fibrovascular
cores (Fig.
23.17D).
Pruritus is common,
and the lesion may be mistaken for eczema.
(A and B) Comedo type.
(A) Specimen radiograph reveals linear and branching calcifications within the
ductal system.
(C) Cribriform DCIS.
Note
the round, regular (“cookie cutter”) spaces containing calcifying secretory material.
(D) Micropapillary DCIS.
The papillary projections lack fibrovascular
cores.
Paget cells are readily detected by nipple biopsy or cytologic
preparations of the exudate.
In contrast, the majority of women without a palpable
mass have only DCIS.
23.19A).
23.19B).
Necrosis and secretory activity are not seen, and thus calcifica-
tions are absent.
LCIS almost always expresses ER and PR and is
HER2-negative.
Duct involved
by DCIS
Figure 23.18 Paget disease of the nipple.
Death from
metastatic breast cancer after a diagnosis of DCIS occurs in
1% to 3% of women.
Mastectomy is curative in greater than 95% of women.
Trials
to identify patients who can safely undergo observation
rather than treatment are ongoing.
Lobular Carcinoma in Situ.
However, unlike DCIS, it is unclear if surgical removal of
the identified lesion lowers risk.
Invasive (Infiltrating) Carcinoma
Breast carcinoma has a wide variety of morphologic appear-
ances.
23.20).
They most commonly present
as a hard, irregular radiodense mass (Fig.
23.20A, B) associated
with a desmoplastic stromal reaction (Fig.
The underlying lobular architecture can still be recognized.
The cells extend into the adjacent duct by pagetoid spread.
Lobular carcinoma is the subtype with the clearest associa-
tion of phenotype and genotype.
Like LCIS, most cases show
biallelic loss of expression of CDH1, the gene that encodes
E-cadherin.
Of interest, this subtype
has a better prognosis than other poorly differentiated
carcinomas.
Many other special histologic types of breast cancer (too
numerous to list) have been described.
occasional foci of calcification.
Less commonly, tumors present as
deceptively well-circumscribed (Fig.
23.20D, E) masses composed
of sheets of tumor cells with scant stromal reaction (Fig.
23.20F)
or may be almost imperceptible (Fig.
23.20I).
Invasive carcinoma is graded using the Nottingham Histologic
Score.
Carcinomas are scored for tubule formation, nuclear
pleomorphism, and mitotic rate.
23.21A).
23.21B).
A high proliferative rate and areas of tumor necrosis are
common in high-grade tumors (Fig.
23.21C).
These include
lobular carcinoma, mucinous carcinoma, tubular carcinoma, and
papillary carcinoma.
Microscopically, such tumors are marked by an exuberant desmoplastic stromal
response (C).
Rarely, invasive cancers produce little or no stromal response.
Microscopically, tumor cells are found
scattered within normal-appearing fibroadipose tissue (I).
(B, Courtesy Dr.
23.22A).
Tubule formation
is absent.
The borders are pushing or circumscribed.
23.22B).
23.22C).
A cribriform pattern may also be
present.
Apocrine snouts are typical, and calcifications may be
present within the lumens.
Only rare mitoses are present.
Occasional mitotic figures are seen.
implies, produces true papillae, fronds of fibrovascular tissue lined
by tumor cells (Fig.
23.22D).
Two special histologic types frequently overexpress HER2.
The tumor cells of apocrine carcinoma resemble the cells that
line sweat glands.
23.22E).
23.22F).
TNBC (ER-negative, HER2-negative) often corresponds to one
of several special histologic types.
Chief among these is carcinoma
with medullary pattern.
23.22G).
DCIS is minimal or not seen.
23.22H).
These carcinomas rarely metastasize.
Another special subtype that merits mention is inflammatory
carcinoma.
It
presents as breast erythema, swelling, and skin thickening.
The presentation can be confused with a breast
infection, leading to delayed diagnosis.
These tumors are usually
of high grade but do not belong to any particular molecular
subtype.
The major prognostic factors are as follows (Table 23.5):
• Lymph node metastases.
(A) Lobular carcinoma.
(B) Mucinous carcinoma.
(C) Tubular carcinoma.
(D) Papillary carcinoma.
(E) Apocrine carcinoma.
(F) Micropapillary carcinoma.
(G) Carcinoma with medullary pattern.
(H) Secretory carcinoma.
See text for morphologic descriptions.
Histologic grade Survival diminishes with higher histologic grade.
Expression of
ER, PR, and
HER2
in the absence of distant metastases.
Therefore, biopsy is necessary for accurate
assessment.
In these patients, metastasis
may occur via the internal mammary lymph nodes or
hematogenously.
• Distant metastases.
• Tumor size.
• Locally advanced disease.
• Lymphovascular invasion.
This finding is
strongly associated with the presence of lymph node
metastases.
• Inflammatory carcinoma.
The
3-year survival rate is only 3% to 10%.
Additional prognostic factors are related to tumor biology
(see Table 23.5).
A few other prognostic factors are clinically
useful and merit brief mention.
• Gene expression profiling.
Most are heavily weighted toward
inclusion of genes that are involved in proliferation.
• Response to neoadjuvant chemotherapy.
In
contrast, very few luminal cancers respond completely
to chemotherapy.
For many
luminal cancers, endocrine therapy is the best and most
effective therapeutic option.
Chemotherapy is used for highly
proliferative carcinomas, regardless of molecular subtype.
For
HER2 cancers, targeted therapy with HER2 antagonists has
markedly improved prognosis.
A multigene assay, when available, can be used to assign stage in this setting.
The survival estimates include the average survival for patients
with all biologic types of cancer.
disease, Klinefelter syndrome, and residency in Western
countries.
Approximately 6%
of male carriers develop breast cancer.
Dissemination follows
the same pattern as in women.
Most cancers are treated locally with
mastectomy and axillary node dissection.
• Effective treatment requires both local and systemic control
of disease.
There
are about 2670 cases and 500 deaths in the United States each
year.
Fibroadenoma
Fibroadenoma is the most common benign tumor of the
female breast.
Two-thirds of fibroadenomas harbor driver
mutations in MED12.
The pathogenesis of the remainder
is uncertain.
23.23B).
The delicate and often myxoid stroma
resembles normal intralobular stroma.
23.23C).
In older
women, the stroma typically becomes densely hyalinized and the
epithelium atrophic.
Figure 23.23 Fibroadenoma.
(A) Radiograph shows a characteristically
well-circumscribed mass.
The absence of adipose tissue accounts for the radiodensity of the lesion.
The border is sharply delimited from
the surrounding tissue.
Like fibroadenomas, the majority of phyllodes
tumors have MED12 mutations.
Rapid growth and
infarction during pregnancy may raise a false suspicion of
carcinoma.
Whether these lesions are true neoplasms or reactive
hyperplasias is unclear.
23.24).
Malignant Tumors of Interlobular Stroma
Malignant stromal tumors of the breast are rare.
Angiosarcoma of the breast may be
sporadic or arise as a complication of therapy.
Metastases to the breast are rare and most commonly arise
from melanomas and ovarian cancers.
Figure 23.24 Phyllodes tumor.
Low-grade (benign) lesions resemble fibroadenomas but
are more cellular and are mitotically active.
High-grade (malignant)
lesions may be difficult to distinguish from sarcomas.
Only the
stromal component metastasizes.
These include benign as well as malignant tumors,
all uncommon and hence considered briefly.
Lipomas
are often palpable and can also be detected mammographi-
cally as fat-containing lesions.
The only importance of these
lesions is to distinguish them from malignancies.
Fibromatosis is a clonal proliferation of fibroblasts and
myofibroblasts.
It presents as an irregular, infiltrating mass
that can involve muscle.
Though locally aggressive, this
lesion does not metastasize.
Some cases are associated with
prior trauma or surgery.
• Fibroadenomas are the most common benign tumor of the
breast.
[From Queen Atossa in Babylonia in 490
BCE to Dr.
Yalom M: History of the breast, 1998, Ballantine Books.
Available
at https://www.cancer.org.
[Excellent resource for up-to-date information
about breast cancer.].
International Association of Cancer Registries (IACR): GLOBOCAN,
2012.
Available at http://globocan.iarc.fr.
Large Internet Breast Cancer Datasets
The Cancer Genome Atlas project.
https://cancergenome.nih.gov.
(Accessed
1 January 2018).
https://icgc.org.
(Accessed
1 January 2018).
www.cbioportal.org.
(Accessed 1 January 2018).
This site also provides links to other databases].a
National Cancer Database (NCDB).
https://www.facs.org.
(Accessed 1
January 2018).
http://
seer.cancer.gov.
(Accessed 1 January 2018).
[Single-cell sequencing has shown
that every cell in a breast cancer may be genetically unique.
For example, tubule formation correlates
strongly with genes expressed by luminal cancers].
[DNA sequencing and messenger RNA profiling provide only part of the
profile of a cancer cell.
Hortobagyi GN, Connolly JL, D’Orsi CJ et al: Breast.
(Accessed 23 December 2017).
[The American Joint Commission on
Cancer issues guidelines on cancer staging.
After publication of the book,
a significantly revised Breast Chapter was provided online.
Current
CAP protocols are available at www.cap.org].
National Comprehensive Cancer Network (NCCN).
https://www
.nccn.org.
a The largest datasets with molecular information on breast cancer
include these.
An endocrine hormone is
frequently carried by the blood from its site of release to
its target.
24.1).
• Mammosomatotrophs produce GH and prolactin (PRL).
• Lactotrophs produce PRL.
• Thyrotrophs produce thyroid-stimulating hormone (TSH).
• Gonadotrophs produce follicle-stimulating hormone (FSH)
and luteinizing hormone (LH).
The same two hormones also regulate sper-
matogenesis and testosterone production in males.
24.2), which are carried to the anterior
pituitary by the portal venous plexus.
A
B
Figure 24.1 (A) Photomicrograph of a normal pituitary.
Synthetic oxytocin can be given to
pregnant women to induce labor.
An increase in plasma osmotic pressure detected
by osmoreceptors also triggers ADH secretion.
• Hyperpituitarism arises from excess secretion of trophic
hormones.
The symptoms of
hyperpituitarism are discussed later in the context of
individual tumors.
• Hypopituitarism results from deficiency of trophic hor-
mones.
• Symptoms related to local mass effects.
Null cell adenomas, by definition, only present with mass effects.
some hypothalamic disorders.
Pituitary adenomas are usually found in adults; the peak
incidence is from 35 to 60 years of age.
24.3), and β- and γ-subunits that noncovalently
bind α-subunits.
The α-subunit of Gs (Gs α)
is encoded by the GNAS gene, located on chromosome
20q13.
degradation.
MORPHOLOGY
The typical pituitary adenoma is soft and well-circumscribed.
24.4).
Such
lesions are termed aggressive adenomas.
GDP, Guanosine
diphosphate; GTP, guanosine triphosphate; Pi, inorganic phosphate.
See
Fig.
24.2 for other abbreviations.
Figure 24.4 Pituitary adenoma.
Acute
hemorrhage into an adenoma is sometimes associated with
pituitary apoplexy, as noted earlier.
The following is a description of the individual types of
tumors.
Figure 24.5 Pituitary adenoma.
Note also the absence of reticulin network.
24.5).
24.6A).
24.6B).
Local mass effects may be produced by any
type of pituitary tumor.
As mentioned earlier, these effects
AB
Figure 24.6 Ultrastructural features of prolactinoma.
(A) Electron micrograph of a sparsely granulated prolactinoma.
(B) Electron micrograph of
a densely granulated growth hormone–secreting adenoma.
The tumor cells are filled with numerous large, electron-dense secretory granules.
(Courtesy Dr.
Eva Horvath, St.
Lactotroph adenoma is the cause of almost one-fourth of
cases of amenorrhea.
Hyperprolactinemia may result from causes other than
prolactin-secreting pituitary adenomas.
Physiologic hyper-
prolactinemia occurs in pregnancy.
Other causes of hyperprolactinemia include renal failure
and hypothyroidism.
• If the levels of GH are increased after closure of the
epiphyses, acromegaly develops.
Bone density may increase (hyper-
ostosis) in both the spine and the hips.
Enlargement of
the jaw results in its protrusion (prognathism) and broaden-
ing of the lower face.
The feet and hands are enlarged,
and the fingers become thickened and sausage-like.
In
most instances, gigantism is also accompanied by evidence
of acromegaly.
The diagnosis relies on documenting elevated serum GH
and IGF-1 levels.
The causative pituitary
adenoma can be removed surgically or treated by pharma-
cologic means.
Thus,
accurate subtyping of somatotroph adenomas is of prognostic
importance.
MORPHOLOGY
Corticotroph adenomas are usually microadenomas at the time
of diagnosis.
Pituitary carcinoma is rare, accounting for less than 1%
of pituitary tumors.
The presence of craniospinal or systemic
metastases is a sine qua non of a pituitary carcinoma.
Metastases
usually appear late in the course, following multiple local
recurrences.
Pituitary blastoma presents with signs and
symptoms of Cushing disease.
granulated).
Nuclear TPIT is also
positive in the neoplastic cells, consistent with corticotroph lineage.
Because the adrenals are absent in persons with Nelson
syndrome, hypercortisolism does not develop.
They are a rare cause of hyperthyroidism.
Most are derived from cells of PIT-1–expressing lineage.
• Null cell adenomas do not express any markers of hormonal
or lineage differentiation.
• Pituitary adenomas can be macroadenomas (greater than 1 cm
in diameter) or microadenomas.
• Corticotroph adenomas secreteACTH and present with Cushing
syndrome and hyperpigmentation.
During
pregnancy, the anterior pituitary enlarges to almost twice
its normal size.
Classically, this occurs
in obese women with a history of multiple pregnancies.
Sometimes the loss of functioning
parenchyma is sufficient to produce hypopituitarism.
Hypothalamic insuf-
ficiency may also appear following irradiation of the
brain.
• Children can develop growth failure ituitary dwarfism)
(p
due to growth hormone deficiency.
• Prolactin deficiency results in failure of postpartum
lactation.
• Diabetes insipidus.
• Syndrome of inappropriate ADH (SIADH) secretion.
ADH
excess causes over-resorption of free water, resulting in
hyponatremia.
(Courtesy Dr.
“Palisading” of the squamous epithelium is frequently observed
at the periphery.
Compact, lamellar keratin formation (“wet
keratin”) is a diagnostic feature of this tumor (Fig.
24.7).
As
mentioned earlier, dystrophic calcification is a frequent finding.
Larger lesions are more invasive, but this does not impact
on the prognosis.
Cranio-
pharyngioma is thought to arise from vestigial remnants
of Rathke pouch.
These slow-growing tumors account for
1% to 5% of intracranial tumors.
24.8).
24.8).
The net
result is an increase in the basal metabolic rate.
Elevated T3 and T4 levels, in turn,
feed back to suppress the secretion of both TRH and TSH.
Figure 24.9 A person with hyperthyroidism.
most commonly by hyperfunction of the thyroid gland, it
is often referred to as hyperthyroidism.
• Excessive levels of thyroid hormone result in an increase
in the basal metabolic rate.
Heat intolerance is common.
Sweating is increased because of higher levels of calori-
genesis.
Heightened catabolic metabolism results in weight
loss despite increased appetite.
• Cardiac manifestations are among the earliest and most
consistent features.
Tachycardia, palpitations, and cardiomegaly are common.
Arrhythmias such as atrial fibrillation occur frequently,
particularly in older patients.
Congestive heart failure
may develop, especially in older adults with preexisting
cardiac disease.
Proximal muscle weak-
ness and decreased muscle mass are common (thyroid
myopathy).
Most patients
also develop some degree of fat malabsorption.
• Ocular changes often call attention to hyperthyroidism.
24.9).
• The skeletal system is also affected.
The net
effect is osteoporosis and an increased risk of fractures.
• Thyroid storm refers to the abrupt onset of severe hyper-
thyroidism.
Patients
are often febrile and present with tachycardia out of
proportion to the fever.
Thyroid storm is a medical
emergency.
A significant number of untreated patients
die of cardiac arrhythmias.
In these
cases, free T4 levels may be decreased, and direct measure-
ment of serum T3 is useful.
A
normal rise in TSH after administration of TRH excludes
secondary hyperthyroidism.
Hypothyroidism is a common disorder.
The prevalence increases with age, and
it is nearly 10-fold more common in women than in men.
Hypothyroidism can result from a defect anywhere in the
hypothalamic-pituitary-thyroid axis.
FOXE1, Forkhead box E1; PAX8, paired
box 8; THRB, thyroid hormone receptor β.
or as a result of pituitary and hypothalamic disease (Table
24.4).
Primary hypothyroidism can be congenital, autoimmune,
or iatrogenic.
• Congenital hypothyroidism.
• Autoimmune hypothyroidism.
The vast majority of cases
of autoimmune hypothyroidism are due to Hashimoto
thyroiditis.
• Iatrogenic hypothyroidism.
This can be caused by either
surgical or radiation-induced ablation.
Cretinism
Cretinism refers to hypothyroidism that develops in infancy
or early childhood.
It is now much less prevalent as a result of the
widespread supplementation of foods with iodine.
Normally, maternal T3 and T4
cross the placenta and are critical for fetal brain development.
Myxedema
The term myxedema is applied to hypothyroidism develop-
ing in the older child or adult.
The clinical findings vary with age of onset.
Myxedema is marked by a slowing of physical and mental
activity.
Decreased sympathetic activity results in constipation and
decreased sweating.
The skin is cool and pale because of
decreased blood flow.
Measurement of the serum
TSH level is the most sensitive screening test for this
disorder.
T4 levels are decreased in individuals with hypo-
thyroidism of any origin.
Multiple immunologic mechanisms
may contribute to thyroid cell death, including (Fig.
The cut
surface is pale, yellow-tan, firm, and somewhat nodular.
There is
Figure 24.11 Hashimoto thyroiditis.
The thyroid parenchyma contains a
dense lymphocytic infiltrate with germinal centers.
Residual thyroid
follicles lined by deeply eosinophilic Hürthle cells are also seen.
24.11).
Pathogenesis
Granulomatous thyroiditis is believed to be triggered by a
viral infection.
In the typical case,
hypothyroidism develops gradually.
Histologic changes are patchy and depend on the stage of the
disease.
Multinucleate giant cells enclose pools of colloid (Fig.
24.12),
hence the designation granulomatous thyroiditis.
MORPHOLOGY
Except for possible mild symmetric enlargement, the thyroid
appears grossly normal.
Unlike Hashimoto thyroiditis, however, fibrosis and Hürthle cell
metaplasia are not prominent.
Clinical Features
Granulomatous thyroiditis is the most common cause of
thyroid pain.
There is variable enlargement of the gland.
Some
patients transition from hyperthyroidism to hypothyroidism
before recovery.
The disorder is most common between 40 and 50 years of
Figure 24.12 Granulomatous thyroiditis.
Nearly all patients have high serum
T4 and T3 levels and low serum TSH levels during this
phase.
After recovery, generally in 6 to 8 weeks, normal thyroid
function returns.
The
presence of a hard and fixed thyroid mass clinically simulates
a thyroid carcinoma.
It is another type
of autoimmune thyroiditis.
24.13A).
Increases in weight to over 80 g are not uncommon.
On cut section, the parenchyma has a soft, meaty appearance resem-
bling muscle.
24.13B).
Such papillae lack fibrovascular cores, in contrast to
those of papillary carcinoma (see later).
The colloid within the
follicle lumen is pale, with scalloped margins.
Germinal centers are common.
The
Graves disease is the most common cause of endogenous
hyperthyroidism.
Women are affected as much as 10 times more
frequently than men.
This disorder is said to affect 1.5% to
2% of women in the United States.
The most common1082 CHAPTER 24 The Endocrine System
A B
Figure 24.13 Graves disease.
(A) There is diffuse symmetric enlargement of the gland and a beefy deep red parenchyma.
Compare with gross photograph
of multinodular goiter in Fig.
24.15.
(B) Diffusely hyperplastic thyroid in a case of Graves disease.
The follicles are lined by tall, columnar epithelium.
The
crowded, enlarged epithelial cells project into the lumens of the follicles.
In addition, there is infiltration by lymphocytes and fibrosis.
Orbital muscles are edematous initially but may undergo fibrosis
late in the course of the disease.
Diffuse enlargement of the thyroid is present in all cases.
The extraocular muscles are often weak.
The basis of such localization is not clear,
and it is present only in a minority of patients.
Sometimes
individuals spontaneously develop thyroid hypofunction.
• Laboratory features include elevations in serum free T3 and T4
and decreased serum TSH.
Goiters
can broadly be divided into two types: diffuse nontoxic and
multinodular.
This disorder occurs
in both an endemic and a sporadic distribution.
Native populations
subsisting on cassava root are particularly at risk.
• Sporadic goiter occurs less frequently than does endemic
goiter.
There is a striking female preponderance and a
peak incidence at puberty or in young adult life.
In most cases, however, the cause of sporadic
goiter is not apparent.
In these cases, the cut surface
of the thyroid is usually brown, somewhat glassy, and translucent.
Clinical Features
As stated earlier, most persons with simple goiters are clini-
cally euthyroid.
24.14).
Virtually all long-standing
simple goiters convert into multinodular goiters.
Single nodules are about four times more common in women
than in men.
The incidence of thyroid nodules increases
throughout life.
In fact, benign
neoplasms outnumber thyroid carcinomas by a ratio of
nearly 10 : 1.
24.15A).
24.15B).
A B
Figure 24.15 Multinodular goiter.
Note the absence of a prominent capsule, a
distinguishing feature from follicular neoplasms.
(B, Courtesy Dr.
The following sections consider the major
thyroid neoplasms.
This leads to
hyperthyroidism and produces a functional “hot” nodule
on imaging.
Overall, such mutations are present in 50% to
80% of toxic thyroid adenomas.
These are
discussed in further detail later in this chapter.
24.16A).
Follicular adenomas average about 3 cm
in diameter, but some are much larger (≥10 cm in diameter).
24.17).
(A) A solitary, well-
circumscribed nodule is seen.
We begin with a discussion of the molecular pathogenesis
of thyroid neoplasms.
Pathogenesis
Driver Mutations.
• Conventional papillary thyroid carcinomas.
24.18).
Figure 24.17 Hürthle cell (oxyphil) adenoma.
(Courtesy Dr.
Mary Sunday, Duke University,
Durham, NC.)
intact, well-formed capsule encircling the tumor.
Larger
masses may produce local symptoms, such as difficulty in
swallowing.
Suspected
adenomas of the thyroid are therefore removed surgically
to exclude malignancy.
Follicular adenomas do not recur
or metastasize and have an excellent prognosis.
• Follicular neoplasms.
24.18).
24.18).
• Poorly differentiated and anaplastic (undifferentiated) carcino-
mas.
• Medullary thyroid carcinomas.
Environmental Factors.
These rearrange-
ments also produce constitutively active NTRK1 fusion
proteins.
adjacent parenchyma and have ill-defined margins.
The tumors
may contain areas of fibrosis and calcification and are often cystic.
The cut surface sometimes reveals papillary foci that point to
the diagnosis.
The microscopic hallmarks of papillary neoplasms include the
following (Fig.
These
MORPHOLOGY
Conventional papillary carcinomas may be solitary or multifocal.
(B) This particular example contains well-formed papillae.
(D) Cells obtained by fine-needle aspiration of a papillary carcinoma.
Metastases to adjacent cervical lymph nodes occur in
up to one-half of cases.
The tall
cell variant has tall columnar cells with intensely eosinophilic
cytoplasm.
Lymph node metastases are present in
almost all cases.
24.20A).
Larger lesions may penetrate
the capsule and infiltrate into the adjacent neck.
Degenerative changes,
such as central fibrosis and foci of calcification, may be present.
24.20B).
24.21).
Unlike in papillary
cancers, lymphatic spread is uncommon in follicular cancers.
Hoarseness, dysphagia,
cough, or dyspnea suggests advanced disease.
Papillary
carcinomas are cold masses on scintigraphy.
The presence of vascular invasion is another feature of
follicular carcinomas.
Figure 24.20 Follicular carcinoma.
(A) Cut surface of a follicular
carcinoma with substantial replacement of the lobe of the thyroid.
The
tumor has a light-tan appearance and contains small foci of hemorrhage.
(B) A few of the glandular lumens contain recognizable colloid.
Clinical Features
Follicular carcinomas present as slowly enlarging painless
nodules.
The prognosis depends largely on the extent of inva-
sion and stage at presentation.
MORPHOLOGY
Sporadic medullary thyroid carcinomas present as a solitary nodule
(Fig.
24.22A).
In contrast, bilaterality and multicentricity are
common in familial cases.
There may be foci of hemorrhage and necrosis in larger lesions.
Small, more anaplastic cells are present in some
tumors and may be the predominant cell type.
Amyloid deposits
derived from calcitonin polypeptides are present in the stroma
in many cases (Fig.
24.22B).
24.23).
They account for approximately 5% of thyroid neoplasms.
Calcitonin
is a regulator of calcium metabolism.
About 70% of tumors
arise sporadically.
The remainder occur in the setting of
MEN-2A or MEN-2B syndromes.
A
B
Figure 24.22 Medullary carcinoma of the thyroid.
(A, Courtesy Dr.
• Multiple genetic pathways are involved in thyroid carcinogenesis.
Conventional papillary carcinomas harbor either fusions (RET/
PTC, NTRK) or BRAF point mutations.
Progression to aggressive neoplasms is
associated with TP53, CTNNB1, and TERT mutations.
They are
highly aggressive, often lethal cancers.
Multicentricity and C cell hyperplasia are features of
familial cases.
Amyloid deposits are a characteristic histologic
finding.
Figure 24.23 Electron micrograph of medullary thyroid carcinoma.
Notably, hypocalcemia is not a
prominent feature, despite the presence of raised calcitonin
levels.
A sinus tract may persist
as a vestige of the tubular development of the thyroid gland.
Parts of this tube may be obliterated, leaving small segments
that form cysts.
These occur at any age and might not become
evident until adult life.
Characteristically,
subjacent to the lining epithelium, there is an intense
lymphocytic infiltrate.
The
four parathyroid glands are composed of two cell types:
chief cells and oxyphil cells.
Chief cells have secretory granules containing parathyroid
hormone (PTH).
Glycogen granules are also present in
these cells, but secretory granules are sparse or absent.
The function of the parathyroid glands is to regulate
calcium homeostasis.
Normally, decreased levels of free calcium stimulate
the synthesis and secretion of PTH.
Most
cases occur in the 50s or later in life.
24.24).
Between 10% and 20% of sporadic
parathyroid adenomas have this clonal rearrangement.
A
B
Figure 24.25 Parathyroid adenoma.
(B) High-power detail of a chief cell parathyroid
adenoma.
There is slight variation in nuclear size but no anaplasia and a
tendency for follicle formation.
capsule, is often visible at the edge of the adenoma.
In contrast to the normal
parathyroid parenchyma, adipose tissue is inconspicuous.
The combined weight of all glands rarely
exceeds 1 g and is often less.
As
in the case of adenomas, stromal fat is inconspicuous within
hyperplastic glands.
24.25).
These may resemble
Hürthle cell tumors in the thyroid.
24.26).The marrow spaces around the affected surfaces are
replaced by fibrovascular tissue.
26.13, Chapter 26).
• Asymptomatic hyperparathyroidism.
In fact,
primary hyperparathyroidism is the most common cause
of asymptomatic hypercalcemia.
• Symptomatic primary hyperparathyroidism.
a Primary hyperparathyroidism is the most common cause of hypercalcemia
overall.
Malignancy is the most common cause of symptomatic hypercalcemia.
Primary hyperparathyroidism and malignancy account for nearly 90% of cases of
hypercalcemia.
MORPHOLOGY
The parathyroid glands in secondary hyperparathyroidism are
hyperplastic.
As in primary hyperparathyroidism, the degree of
glandular enlargement may be asymmetric.
Fat cells
are decreased in number.
tend to be milder.
Parathyroidec-
tomy may be necessary to control the hyperparathyroidism
in such patients.
• Parathyroid adenomas are solitary, while hyperplasia typically
is a multiglandular process.
Renal
changes include nephrolithiasis (stones) and nephrocalcinosis.
HYPOPARATHYROIDISM
Hypoparathyroidism is far less common than is hyperpara-
thyroidism.
APS-1 is discussed further later in
this chapter.
Recall that loss-of-
function CASR mutations are a rare cause of familial
parathyroid adenomas.
The
classic findings on physical examination are Chvostek sign
and Trousseau sign.
• Ocular disease takes the form of calcification of the lens
and cataract formation.
• Dental abnormalities occur when hypocalcemia is present
during early development.
Indeed,
serum PTH levels are normal or elevated.
PTH resistance
is the most obvious clinical manifestation.
It presents as
hypocalcemia, hyperphosphatemia, and elevated circulat-
ing PTH.
The four main types are β, α, δ,
and PP (pancreatic polypeptide) cells.
24.27).
• The δ cells secrete somatostatin, which suppresses both
insulin and glucagon release.
These cells not only are present in
islets but also are scattered throughout the exocrine
pancreas.
• There are also two rare cell types, D1 cells and entero-
chromaffin cells.
The
α-cell granule shows a dense, round center.
(Electron micrographs courtesy Dr.
Arthur Like, University of Massachusetts Medical School, Worcester, Mass.)
commonly, both.
Diabetes and related disorders of glucose metabolism
are common.
Approximately 1.5 million
new cases of adult diabetes are diagnosed each year in the
United States.
Nonetheless,
diabetes remains in the top 10 “killers” in the United States.
Diagnosis
Blood glucose is normally maintained in a very narrow
range of 70 to 120 mg/dL.
According to the ADA and WHO,
diagnostic criteria for diabetes include the following:
1.
A fasting plasma glucose ≥126 mg/dL
2.
A fasting plasma glucose between 100 and 125 mg/dL
(“impaired fasting glucose”),
2.
Regulation of Insulin Release
Insulin is produced in the β cells of the pancreatic islets
(see Fig.
The most important stimulus for insulin synthesis and
release is glucose.
24.28).
The important similarities and differences between
T1D and T2D are summarized in Table 24.7.
Insulin and glucagon have opposing effects
on glucose homeostasis.
Thus,
fasting plasma glucose levels are determined primarily by
hepatic glucose output.
Insulin promotes glucose uptake and utilization in
tissues (discussed later).
This is one reason why exercise is beneficial
and obesity detrimental to glucose control.
In muscle cells,
glucose is either stored as glycogen or oxidized to generate
ATP.
24.30.
The insulin receptor is a tetrameric protein
composed of two α-subunits and two β-subunits.
The β-
subunit cytosolic domain possesses tyrosine kinase activity.
T1D most commonly
develops in childhood, becomes manifest at puberty, and
progresses with age.
Indeed, GLP-1 receptor agonists are also now
approved for treatment of obesity.
24.29).
The nature of these
environmental influences remains an enigma.
On the other hand, certain infections are
also thought to be protective against T1D.
Three
distinct stages of T1D are now recognized (Fig.
24.31).
Thus, autoreactive T cells not only
survive, but are poised to respond to self antigens.
The activated T cells
then traffic to the pancreas, where they cause β-cell injury.
IRS, Insulin receptor substrate; PI3K,
phosphoinositide 3-kinase.
(Modified from Brendan Manning, Harvard T.H.
Several non-HLA genes also confer susceptibility to T1D.
The mechanism
underlying this association is unknown.
Unlike T1D, there is no evidence of an autoimmune
basis.
subcutaneous]), islet β-cell function, and obesity.
In addition, GWAS
have shown an association between circadian-controlled
genes and T2D.
A variety of functional defects in the insulin-signaling
pathway underlie insulin resistance.
24.30).
The risk for
diabetes rises as the BMI increases.
Studies of
these so-called “metabolically healthy obese” individuals
is an emerging field.
Obesity can adversely impact insulin sensitivity in numer-
ous ways (see Fig.
24.32):
• Free fatty acids (FFAs).
Attenuated insulin signaling allows
phosphoenolpyruvate carboxykinase to “ramp up”
gluconeogenesis.
• Adipokines.
24.32).
Pancreatic β cells compensate
for insulin resistance by hypersecretion of insulin.
However, at some point,
β-cell compensation is followed by β-cell failure, and diabetes ensues.
Adiponectin levels are reduced in obesity, thus contribut-
ing to insulin resistance.
IL-1 and other cytokines act
on the major sites of insulin action to promote insulin
resistance.
This form of monogenic
diabetes is caused by a heterogeneous group of genetic
defects.
24.28).
Such patients often show a velvety
hyperpigmentation of the skin known as acanthosis nigricans.
T1D may arise at any age.
The assimilation of glucose into
muscle and adipose tissue is sharply diminished or abolished.
24.33).
Thus, intense thirst (polydipsia) appears.
A second major effect of insulin deficiency is increased
synthesis of ketone bodies.
When
these FFAs reach the liver, they are esterified to fatty acyl
coenzyme A.
Release of ketogenic amino acids by
protein catabolism aggravates the ketotic state.
Persistence of the ketotic state
eventually leads to depressed consciousness and coma.
hypoglycemia.
It is recommended
that HbA1c be maintained below 7% in patients with dia-
betes.
• Formation of advanced glycation end products.
The rate of AGE formation is accelerated by
hyperglycemia.
Proteins
cross-linked by AGEs are resistant to proteolytic digestion.
Thus, cross-linking decreases protein removal, enhancing
protein accumulation.
AGE-modified matrix components
also trap nonglycated plasma or interstitial proteins.
• Activation of protein kinase C.
• Oxidative stress and disturbances in polyol pathways.
Sorbitol accumulation in the lens contributes to cataract
formation.
• Hexosamine pathways and generation of fructose-6-phosphate.
As dis-
cussed earlier, these changes are seen in both T1D and T2D
(Fig.
24.34).
MORPHOLOGY
PANCREAS
Alterations in the pancreas are inconstant and often subtle.
Distinc-
tive changes are more commonly associated with T1D than with
T2D.
This is most
often seen in T1D, particularly with rapidly advancing disease.
Most of the islets are small and inconspicuous.
24.35A).
Lymphocytic infiltrates
may be present in T1D at the time of clinical presentation.
• Amyloid deposition within islets in T2D begins in and
around capillaries and between cells.
24.36).
The microangiopathy underlies the development of
islets may be virtually obliterated (see Fig.
24.35B); fibrosis may
also be observed.
Presumably, fetal islets undergo hyperplasia in response to the
maternal hyperglycemia.
Diabetic Macrovascular Disease
Diabetes exacts a heavy toll on the vascular system.
L,
Glomerular capillary lumen; U, urinary space.
(Courtesy Dr.
(B) Amyloidosis
of a pancreatic islet in type 2 diabetes.
(A, Courtesy Dr.
from this disease.
Capillary Basement Membrane Thickening.
Capillary
basement membrane thickening is best appreciated by
electron microscopy (Fig.
24.37).
24.38).
Figure 24.36 Severe renal hyaline arteriolosclerosis.
Note a markedly
thickened, tortuous afferent arteriole.
The amorphous nature of the
thickened vascular wall is evident (periodic acid–Schiff stain).
Diabetic Nephropathy
The kidneys are prime targets of diabetes.
Note the diffuse increase in mesangial matrix and
characteristic acellular PAS-positive nodules.
Diffuse Mesangial Sclerosis.
This lesion consists of diffuse
increase in mesangial matrix.
The matrix depositions are
PAS-positive (Fig.
24.39).
As the disease progresses, the
mesangial matrix deposits may take on a nodular appearance.
Nodular Glomerulosclerosis.
This is also known as
intercapillary glomerulosclerosis or Kimmelstiel-Wilson disease.
24.39)
or loops that are markedly dilated.
The loss of these support structures may lead to the formation
of capillary microaneurysms.
Both afferent and efferent
glomerular hilar arterioles show hyalinosis.
24.40).
Hyaline
arteriolosclerosis affects not only the afferent but also the
efferent arteriole.
in patients with diabetes than in the general population.
Diabetic Ocular Complications
The eye is profoundly affected by diabetes mellitus.
The
architecture and microanatomy of the eye are discussed in
Chapter 29.
The most profound ocular changes of diabetes are seen
in the retina.
This is discussed further in
Chapter 27.
Such infections cause
the deaths of about 5% of these patients.
The staggering societal and economic impact of diabetes
has already been discussed.
An elevated risk for cardiovascular
disease is even observed in patients with prediabetes.
Significantly, myocardial infarction is almost as common
in women with diabetes as in men.
In contrast, myocardial
infarction is uncommon in women of reproductive age
without diabetes.
• Diabetic nephropathy is a leading cause of end-stage
renal disease in the United States.
Approximately 30% to
40% of all patients with diabetes develop clinical evidence
of nephropathy.
maintained in noeplastic cells that do not express telom-
erase (Chapter 7).
Clinical manifestations include confusion,
stupor, and loss of consciousness.
PanNETs can occur anywhere within the pancreas
or in the immediate peripancreatic tissues.
These tumors may be
single or multiple and benign or malignant.
Unequivocal
criteria for malignancy include metastases, vascular invasion,
and local infiltration.
Fortunately, insulinomas are the
most common subtype of pancreatic endocrine neoplasms.
Most are solitary, although multiple tumors may
be encountered.
On rare occasions an insulinoma may arise in ectopic
pancreatic tissue.
In such cases, electron microscopy reveals the
distinctive granules of β cells (see Fig.
24.27).
Malignant
tumors are also well-differentiated, and they may be deceptively
encapsulated.
Deposition of amyloid is a characteristic feature
of many insulinomas (Fig.
24.41).
Hyperinsulinism may also be caused by focal or diffuse
hyperplasia of the islets.
This phenomenon is usually transient.
Total resection of the neoplasm,
when possible, eliminates the syndrome.
Figure 24.41 Pancreatic endocrine neoplasm (“islet cell tumor”).
The
neoplastic cells are monotonous and demonstrate minimal pleomorphism
or mitotic activity.
There is abundant amyloid deposition, characteristic of
an insulinoma.
Clinically, the patient had episodic hypoglycemia.
They may be very difficult to localize preoperatively.
High
plasma somatostatin levels are required for diagnosis.
Some of these tumors are locally invasive
and metastatic.
A VIP assay should be performed on
all patients with severe secretory diarrhea.
• Some pancreatic and extrapancreatic endocrine tumors
produce two or more hormones.
It is important to note that there are many other causes of
hypoglycemia besides insulinoma.
Adrenal Glands
structure, and function.
Beneath the capsule is the narrow layer of
zona glomerulosa.
An equally narrow zona reticularis abuts
the medulla.
Intervening is the broad zona fasciculata, which
makes up about 75% of the total cortex.
Catecholamines have many effects that allow
rapid adaptations to changes in the environment.
This variant of Cushing syndrome is
more common in men and usually occurs in the 40s and 50s.
Cortical carcinomas tend
to produce more marked hypercortisolism than adenomas
or hyperplasias.
Cushing syndrome can be broadly
divided into exogenous and endogenous causes.
ACTH-secreting pituitary adenomas account for 60%
to 70% of cases of endogenous hypercortisolism.
The
pituitary form of this syndrome is referred to as Cushing
disease.
In the vast majority of cases, it is caused by an
ACTH-producing pituitary microadenoma.
..
..
Cushing disease 60–70 ..
..
..
..
..
Ectopic ACTHa 5–10 ..
..
..
May respond to dexamethasone, CRH,
desmopressin
Occult neuroendocrine tumours ~2 ..
..
..
Ectopic CRH Very rare ..
..
Causes pituitary corticotroph
hyperplasia
ACTH-Independent 20–30 ..
..
..
Unilateral adrenal ..
..
..
..
..
..
..
Autocrine ACTH production ..
..
..
..
Sporadic or familial (ARMC5) ..
..
..
..
Bilateral micronodular adrenal hyperplasias <2 ..
..
..
Isolated micronodular adrenocortical
disease
Very rare Infants ..
Nonpigmented adrenal micronodules
Primary bimorphic adrenocortical
disease
Very rare Infants ..
..
MORPHOLOGY
The main lesions of Cushing syndrome are found in the pituitary
and adrenal glands.
24.42).
Both glands are enlarged, either
subtly or markedly, weighing up to 30 g.
24.43).
The
pigment is believed to be lipofuscin, a wear-and-tear pigment
(Chapter 2).
Primary adrenocortical neoplasms causing Cushing
syndrome may be malignant or benign.
Both the benign and malignant
lesions are more common in women in their 30s to 50s.
The carcinomas
associated with Cushing syndrome, by contrast, tend to be larger
than the adenomas.
Clinical Features
Cushing syndrome develops slowly and its onset may be
subtle.
Early stages may present with hypertension and
weight gain (Table 24.9).
The catabolic effects cause loss of collagen and resorption
of bones.
24.44).
24.43) in this gland from a patient with ACTH dependent
Cushing syndrome.
(Photographs courtesy Dr.
of cortisol secretion.
Hence, there is no reduction in urinary excretion of
17-hydroxycorticosteroids.
Hyperaldosteronism may be primary, or it may
be secondary to an extra-adrenal cause.
Primary hyperaldosteronism is caused by one of
three conditions (Fig.
ACTH
thus stimulates the synthesis of aldosterone synthase
from the chimeric gene.
They tend to occur in the
30s and 40s, and in women more often than in men.
24.51).
Therefore, the adjacent adrenal cortex and that of the contralateral
gland are not atrophic.
• Familial hyperaldosteronism accounts for ~5% of cases.
In primary hyperaldosteronism, the therapy varies
according to cause.
Adenomas are amenable to surgical
excision.
These patients are best
managed medically with an aldosterone antagonist such as
spironolactone.
Unlike gonadal androgens,
ACTH regulates adrenal androgen formation (Fig.
Such tumors are often also associated with
hypercortisolism (“mixed syndrome”).
They are morphologi-
cally identical to other cortical neoplasms and are discussed
later.
24.46).
Fig.
Thus, the level of testosterone is
increased, with resultant progressive virilization.
There
is only a partial deficiency of 21-hydroxylase, which
accounts for the later onset.
CAH also affects the function
of the adrenal medulla.
CAH should be suspected in any neonate with ambigu-
ous genitalia.
Mineralocorticoid
supplementation is required in the salt-wasting variants of
CAH.
Figure 24.47 Diffuse purpuric rash in a patient with Waterhouse-
Friderichsen syndrome.
APS-1
is caused by mutations in the autoimmune regulator
(AIRE) gene on chromosome 21q22.
Self-reactive T cells
that recognize these antigens are eliminated (Chapter
6).
Overall, APS-2 is more prevalent than
APS-1.
The pathogenesis of
these other autoimmune polyendocrinopathies is not
understood.
• Metastatic neoplasms involving the adrenals are another
cause of adrenal insufficiency.
The adrenals are a fairly
common site for metastases in patients with disseminated
carcinomas.
Although adrenal function is preserved in
Figure 24.48 Waterhouse-Friderichsen syndrome.
underlying detail.
24.48).
The causes of
chronic adrenocortical insufficiency are listed in Table 24.10.
Death occurs rapidly unless
corticosteroid therapy begins immediately.
MORPHOLOGY
The anatomic changes in the adrenal glands depend on the underly-
ing disease.
24.49).
• Patients typically present with fatigue, weakness, and gastro-
intestinal disturbances.
Secondary
Figure 24.49 Autoimmune adrenalitis.
The
cortex may be reduced to a thin ribbon composed largely of
zona glomerulosa.
The medulla is not affected.
Adenomas and
carcinomas are about equally common in adults; in children,
carcinomas predominate.
However,
not all adrenocortical neoplasms elaborate steroid hormones.
24.50).
On cut surface, adenomas are
usually yellow to yellow-brown because of the presence of lipid.
24.51).
The adenoma is distinguished
from nodular hyperplasia by its solitary, circumscribed nature.
Figure 24.51 Histologic features of an adrenal cortical adenoma.
The
neoplastic cells are vacuolated because of the presence of intracytoplasmic
lipid.
There is mild nuclear pleomorphism.
Mitotic activity and necrosis are
not seen.
(in contrast to adrenocortical carcinomas).
24.52).
Larger
cysts may produce an abdominal mass and flank pain.
Figure 24.52 Adrenal carcinoma.
The hemorrhagic and necrotic tumor
dwarfs the kidney and compresses the upper pole.
a strong tendency to invade the adrenal vein, vena cava, and
lymphatics.
The median patient survival is about 2 years.
24.53), whichAdrenal glands 1127
include the carotid bodies (Chapter 16).
The intravagal
paraganglia, as the term implies, are distributed along
the vagus nerve.
The organs of Zuckerkandl, close to the
aortic bifurcation, belong to this group.
Neuroblastomas and other neuroblastic tumors are
discussed in Chapter 10.
Traditionally, the features
of pheochromocytomas have been summarized by the “rule
of 10s”.
• Ten percent of adrenal pheochromocytomas are not associated
with hypertension.
One “traditional” 10% rule that has now been modified
pertains to familial cases.
VHL syndrome is associated with
a number of tumors, including pheochromocytomas and
paragangliomas.
Granules containing
catecholamine are not visible in this preparation.
It is not uncommon to
find bizarre cells, even in pheochromocytomas that are biologically benign.
(Courtesy Dr.
Jerrold R.
The tumor is enclosed within an
attenuated cortex and demonstrates areas of hemorrhage.
The comma-
shaped residual adrenal is seen below.
(Courtesy Dr.
Jerrold R.
Richly vascularized fibrous trabeculae within the tumor produce
a lobular pattern.
On section, the cut surfaces of smaller pheochromocytomas are
yellow-tan.
Larger lesions tend to be hemorrhagic, necrotic, and
cystic and typically efface the adrenal gland.
The histologic pattern in pheochromocytoma is quite variable.
24.55).
24.56).
Figure 24.56 Electron micrograph of pheochromocytoma.
This tumor
contains membrane-bound secretory granules in which catecholamines are
stored (30,000×).
Determining malignancy in pheochromocytomas can be vexing.
Even capsular and vascular invasion may be encountered in benign
lesions.
These episodes may also be associated with
pain in the abdomen or chest, nausea, and vomiting.
Multifocal lesions require long-term medical treatment for
hypertension.
• Tumors occur at a younger age than sporadic tumors.
• Even in one organ, the tumors are often multifocal.
• It is now recognized that the spectrum of this disease
extends beyond the three P’s.
Parathyroid abnormalities include both
hyperplasia and adenomas.
These tumors are usually aggressive and often present
with metastatic disease.
Medullary car-
cinomas of the thyroid occur in almost 100% of patients.
• MEN-2B has significant clinical overlap with MEN-2A.
However, unlike in
MEN-2A, primary hyperparathyroidism is not present.
• MEN-4 has emerged as a new entity in the past decade.
Smith TJ, Hegedus L: Graves’ disease, N Engl J Med 375:1552–1565,
2016.
Your one-stop shop for
this topic].
Lee YS, Wollam J, Olefsky JM: An integrated view of immunometabo-
lism, Cell 172:22–40, 2018.
This review ties together how inflammation
eventually leads to metabolic deregulation].
Pugliese A: Autoreactive T cells in type 1 diabetes, J Clin Invest
127:2881–2891, 2017.
These
tumors are rare and are described in specialized texts.
SUGGESTED READINGS
Pituitary
Asa SL, Mete O: What’s new in pituitary pathology?
Histopathology
72:133–141, 2018.
[A review on the updated WHO classification of pituitary
tumors and other non-neoplastic entities].
[An updated review on the molecular mechanisms underlying diabetes
insipidus].
Cabanillas ME, McFadden DG, Durante C: Thyroid cancer, Lancet
388:2783–2795, 2016.
[A clinically oriented review on diagnosis and
management of thyroid neoplasms].
DeLeo S, Lee SY, Braverman LE: Hyperthyroidism, Lancet 388:906–918,
2016.
[A clinically oriented review on the causes and main therapeutic
avenues in hyperthyroidism].
[A classic publication describing
the index case of the disease named after the author].
[The original description of myxedema,
hence also known as “Gull disease”].
[Dr.
A couple are included in the bibliography.
Take your pick!].
[The original description of
Addison disease].
Charmandari E, Nicolaides NC, Chrousos GP: Adrenal insufficiency,
Lancet 383:2152–2167, 2014.
This review is a great place to get started].
Rushworth RL, Torpy DJ, Falhammar H: Adrenal crisis, N Engl J Med
381:852–861, 2019.
[A review on the causes, pathophysiology, and treatment
of acute adrenal crises].
Waterhouse R: A case of suprarenal apoplexy, Lancet 1:577–578, 1911.
Potential therapeutic
approaches are also discussed].
25.1).
• Dendritic cells.
cells.
• Lymphocytes.
• Adnexal components.
Ingested
agents, such as therapeutic drugs, can cause an enormous
number of rashes or exanthems.
Skin conditions are very common, affecting about one-
third of the US population each year.
Thousands of diseases affect the skin.
Only those that
are common or that illustrate important pathologic mecha-
nisms are described here.
Macule, Patch Circumscribed, flat lesion distinguished from
surrounding skin by color.
Macules are 5 mm in
diameter or less; patches are greater than
5 mm.
Onycholysis Separation of nail plate from nail bed.
Papule, Nodule Elevated dome-shaped or flat-topped lesion.
Papules are 5 mm or less across; nodules are
greater than 5 mm in size.
Pustule Discrete, pus-filled, raised lesion.
Scale Dry, horny, plate-like excrescence; usually the
result of imperfect cornification.
Blister is the common term for either lesion.
Microscopic Lesions
Acanthosis Diffuse epidermal hyperplasia.
Dyskeratosis Abnormal, premature keratinization within cells
below the stratum granulosum.
Erosion Discontinuity of the skin showing incomplete loss
of the epidermis.
Exocytosis Infiltration of the epidermis by inflammatory cells.
Hypergranulosis Hyperplasia of the stratum granulosum, often due
to intense rubbing.
Lentiginous Linear pattern of melanocyte proliferation within
the epidermal basal cell layer.
Parakeratosis Keratinization with retained nuclei in the stratum
corneum.
On mucous membranes,
parakeratosis is normal.
Spongiosis Intercellular edema of the epidermis.
One answer appears to
lie in the phenomenon referred to as oncogene-induced
senescence.
Once present, freckles fade and darken in a cyclic fashion during
winter and summer, respectively.
This is not because of changes
in the number of melanocytes, but in the degree of pigmentation.
It occurs at
all ages, but most commonly appears in infants and children.
There is no sex or racial predilection, and the cause and
pathogenesis are unknown.
Unlike freckles, lentigines do not darken when
exposed to sunlight.
Melanocytic
nevi are thought to progress through a series of morphologic
changes over time.
25.2B).
25.3B).
In older lesions the epidermal nests may be lost entirely to form
pure intradermal nevi.
Compound and dermal nevi are often
more elevated than junctional nevi.
25.4).
25.4E).
Most of us have at least a few “moles”
and probably regard them as mundane and uninteresting.
Acquired melanocytic nevi are the most
common type and are found in virtually all individuals.
Several
lines of evidence support the concept that some dysplastic
nevi are precursors of melanoma.
(A) In contrast to the
junctional nevus, the compound nevus is raised and dome-shaped.
The
symmetry and uniform pigment distribution suggest a benign process.
Figure 25.2 Melanocytic nevus, junctional type.
(A) Grossly, lesions are
small, relatively flat, symmetric, and uniform.
AB CD E
Time
Figure 25.4 Maturation sequence of nondysplastic melanocytic nevi.
(A) Normal skin shows only scattered dendritic melanocytes within the epidermal
basal cell layer.
(B) Junctional nevus.
(C) Compound nevus.
(D) Dermal nevus.
(E) Dermal nevus with neurotization, a change that is also referred to as
maturation.
(A) Lentiginous melanocytic hyperplasia.
(B) Lentiginous junctional nevus.
(D) Early melanoma, or melanoma in radial growth
phase (large dark cells in epidermis).
(E) Advanced melanoma (vertical growth phase) with malignant spread into the dermis and vessels.
age 60, and at-risk individuals sometimes develop melanomas
at multiple sites.
What then distinguishes dysplastic
nevi from typical melanocytic nevi?
An important clue comes
from individuals with dysplastic nevus syndrome.
Such
individuals often have inherited loss-of-function mutations
in CDKN2A.
25.6A).
Most seem to be acquired rather than congenital.
Unlike
ordinary moles, dysplastic nevi occur on both sun-exposed and
protected body surfaces.
25.6A, B).
(A) Numerous atypical nevi on the back.
The dermis underlying the atypical cells characteristically shows linear, or lamellar, fibrosis.
related to a single predisposing environmental factor: UV
radiation exposure from sunlight.
CDKN2A is a
complex locus that encodes three different tumor sup-
pressors, p15, p16, and ARF.
contours; and hyperchromasia (Fig.
The
following comments apply to cutaneous melanomas.
Proteins indicated by asterisks are mutated in
melanoma.
Components of these pathways that are being targeted by drugs are indicated.
• Mutations that activate pro-growth signaling pathways.
25.7), which promote cell growth
and survival (Chapter 7).
PTEN is also silenced in
20% of melanomas arising in non–sun-exposed sites.
• Mutations that activate telomerase.
Rare melanoma-prone families have also been identified
that have germline TERT promoter mutations.
25.8A).
(A) Typical lesions are irregular in contour and pigmentation.
(C) Vertical growth phase demonstrating nodular
aggregates of infiltrating cells.
(D) High-power view of melanoma cells.
Even small numbers of malignant cells in a draining lymph node may confer a worse prognosis.
often notched, unlike the smooth, round, and uniform borders
of melanocytic nevi.
25.8B).
During this initial stage the
tumor cells seem to lack the capacity to metastasize.
25.8C).
25.8D).
The appearance of the
tumor cells is similar in the radial and vertical phases of growth.
25.8D, inset) confers a worse prognosis.
They often recapitulate the
structures from which they arise.
The majority of lesions
are greater than 10 mm in diameter at diagnosis.
The most
consistent clinical signs are changes in the color, size, or
shape of a pigmented lesion.
25.7).
25.9, inset).
It is uniformly tan to dark
brown and usually has a velvety to granular surface.
MORPHOLOGY
All forms of acanthosis nigricans have similar histologic features.
Figure 25.9 Seborrheic keratosis.
cells of the normal epidermis (Fig.
It is divided into two types based on
the underlying condition.
The most
common associations are with obesity and diabetes.
The lay term, wen, derives from
the Anglo-Saxon wenn, meaning a lump or tumor.
• Other appendage tumors are associated with germline mutations
in tumor suppressor genes.
In some such instances, the
disorder presents with multiple adnexal tumors that may
be disfiguring.
Some
have a predisposition to occur on specific body surfaces.
• Eccrine poroma occurs predominantly on the palms and
soles where sweat glands are numerous.
(A) Sebaceous adenoma; inset demonstrates sebaceous differentiation.
these tumors have a particularly high incidence in lightly
pigmented individuals.
Exposure to ionizing radiation,
industrial hydrocarbons, and arsenicals may induce similar
lesions.
dermal matrix (Fig.
25.10B).
25.10C, D).
25.11A).
25.11B).
Some lesions produce so much keratin
that a “cutaneous horn” develops (Fig.
Sun-exposed sites (face, arms, dorsum of hands)
are most frequently affected.
The lips may also develop similar
lesions (termed actinic cheilitis).
25.12B)
or, alternatively, with atrophy that results in thinning of the epi-
dermis.
The atypical basal cells usually have pink or reddish
cytoplasm due to dyskeratosis.
Although most appendage tumors are benign, malignant
variants exist.
Apocrine tumors are unusual in that malignant
forms appear to be more common than benign forms.
freezing, or topical application of chemotherapeutic agents.
susceptibility to cutaneous squamous cell carcinomas.
Except for lesions on the lower
legs, these tumors have a higher incidence in men than
in women.
Invasive squamous cell carcinomas are usually
discovered while they are small and resectable.
Tumor incidence is proportional to the degree of
lifetime sun exposure.
These are slow-growing tumors that rarely metas-
tasize.
The vast majority are recognized at an early stage
and cured by local excision.
Basal cell carcinoma occurs at sun-exposed sites in lightly
pigmented elderly adults.
Pathogenesis
Most basal cell carcinomas have mutations that lead to
unbridled Hedgehog signaling.
NBCCS is one of a number of cancer syndromes associated
with skin manifestations (Table 25.3).
25.13A).
25.12C).
Invasive squamous cell
carcinoma (Fig.
Basal cell
A B C
Figure 25.13 Invasive squamous cell carcinoma.
(A) Lesions are often nodular and ulcerated, as seen in this scalp tumor.
From Tsai KY, Tsao H: The genetics of skin cancer, Am J Med Genet C Semin Med Genet 131C:82, 2004.
mutation, usually caused by exposure to mutagens (par-
ticularly UV light).
Binding of SHH to PTCH releases SMO, which in turn
activates the transcription factor GLI1 (Fig.
25.14), thus
turning on the expression of genes that support tumor cell
growth and survival.
Mutations that activate Hedgehog signaling are also
prevalent in sporadic basal cell carcinomas.
tumors, explaining the archaic designation rodent ulcers.
Histologically, the tumor cells resemble those in the normal
basal cell layer of the epidermis.
They arise from the epidermis
or follicular epithelium and do not occur on mucosal surfaces.
25.15B).
In sections, the stroma retracts away from the carcinoma (Fig.
25.15A).
Left, Normally, PTCH and SMO form a receptor complex that can bind sonic hedgehog (SHH).
In the absence of SHH, PTCH blocks SMO activity.
burn sites, or in association with HPV infection in the setting
of immunosuppression.
Metastasis is very rare.
usually seen in adults and often occur on the legs of young
and middle-aged women.
Lesions are asymptomatic or
tender and may increase and decrease slightly in size over
time.
Their biologic behavior is indolent.
The cause of fibrous histiocytomas remains a mystery.
These tumors appear
to be composed at least partially of dermal dendritic cells.
These tumors are
MORPHOLOGY
These neoplasms appear as firm, tan to brown papules (Fig.
25.16A).
The most common form of fibrous histiocytoma is referred
to as a dermatofibroma.
25.16B, C).
A B C
Figure 25.16 Benign fibrous histiocytoma (dermatofibroma).
aggressive and can recur, they rarely metastasize.
Metastasis
most often is seen with tumors that exhibit greater cytologic
atypia.
While the primary mode of treatment is wide local
observed.
(A) The tumor consists of a flesh-colored fibrotic nodule on sectioning.
(C) Characteristic storiform (swirling) alignment of the spindled cells is apparent.
Mitoses are rare.
In contrast to dermatofibroma, the
overlying epidermis is generally thinned.
25.17B, C).
Raised, indurated, irregularly outlined erythe-
matous plaques may then supervene.
Development of
multiple tumor nodules correlates with systemic spread.
Sometimes the plaques and nodules ulcerate (Fig.
25.18A).
25.18B) and invade the
epidermis as single cells and small clusters (Pautrier microab-
scesses).
(A) Several erythematous plaques with scaling and ulceration are evident.
The resulting increase in KIT
signaling drives mast cell growth and survival.
MORPHOLOGY
The pathologic findings are highly variable.
25.19B).
Fibrosis, edema,
and eosinophils may also be present.
25.19C).
25.20A).
Most ichthyoses
become apparent either at or around the time of birth.
(A) Solitary mastocytoma in a 1-year-old child.
(C) Giemsa staining reveals purple “metachromatic” granules within the cytoplasm of the mast cells.
25.20B).There is generally little or no inflammation.
Discussed
here are examples of the more commonly encountered acute
dermatoses.
Figure 25.20 Ichthyosis.
Note prominent fish-like scales (A) and
compacted, thickened stratum corneum (B).
ichthyosis vulgaris, may be associated with lymphoid and
visceral malignancies.
This combination of effects produces pruritic
edematous plaques called wheals.
Angioedema is closely1154 CHAPTER 25 The Skin
Figure 25.21 Urticaria.
(A) Erythematous, edematous, often circular plaques are characteristic.
related to urticaria and is characterized by edema of the
deeper dermis and the subcutaneous fat.
Urticaria most often occurs between ages 20 and 40, but
all age groups are susceptible.
• Mast cell–dependent, IgE-independent.
• Mast cell–independent, IgE-independent.
These forms of
urticaria are triggered by local factors that increase
vascular permeability.
The precise
mechanism of aspirin-induced urticaria is unknown.
MORPHOLOGY
Lesions vary from small, pruritic papules to large edematous
plaques (Fig.
25.21A).
Eosinophils may also be present.
Collagen bundles
are more widely spaced than in normal skin, a result of dermal
edema (Fig.
25.21B).
Treatment involves a search for
offending substances that can be removed from the environ-
ment.
Topical steroids can be used to block the inflammatory
response.
acanthosis and hyperkeratosis and take on the appearance
of raised scaling plaques (Fig.
25.23A).
25.23B).
(B) Edema within the epidermis creates fluid-filled intraepidermal vesicles.
B
Figure 25.24 Erythema multiforme.
With
time, necrotic/apoptotic keratinocytes appear in the overlying epithelium (double arrow).
25.24A).The
lesions may occur in a variety of distributions.
25.24B).With time there is upward migration of lymphocytes
into the epidermis.
Discrete and confluent zones of epidermal
necrosis occur with concomitant blister formation.
Epidermal
sloughing leads to shallow erosions.
Psoriasis
Psoriasis is a chronic inflammatory dermatosis that appears
to have an autoimmune basis.
It is a common disorder,
affecting as many as 1% to 2% of people in the United States.
Persons of all ages develop the disease.
It can affect
any joint in the body and may be symmetric or asymmetric.
Psoriasis is one cause
of total body erythema and scaling known as erythroderma.
A B
Figure 25.25 Psoriasis.
25.25B).
The stratum granulosum is thinned
or absent, and extensive overlying parakeratotic scale
is seen.
scaling and crusting.
Fissures may also be present, particularly
behind the ears.
Dandruff is the common clinical expression of
seborrheic dermatitis of the scalp.
Resolution often leaves a residuum of postinflam-
matory hyperpigmentation.
Oral lesions, however, may
persist for years.
As in psoriasis, the Koebner phenomenon
may be seen in lichen planus.
Pathogenesis
The pathogenesis of lichen planus is not known.
Pathogenesis
The precise etiology of seborrheic dermatitis is unknown.
Increased sebum production, often in response to androgens,
is one possible contributory factor.
The glans penis is another common site of involvement.
insight into the pathogenic mechanisms.
25.28).
These disorders are usually benign, but in extreme
cases can be fatal without treatment.
Blisters in the various disorders occur
at different levels within the skin (Fig.
The major structural proteins of desmosomes and hemidesmosomes are
shown in the right panel.
A B C
Figure 25.29 Pemphigus vulgaris.
(A) Eroded plaques are formed following the rupture of confluent, thin-roofed bullae.
(C) Ulcerated blisters in the oral mucosa are also
common, as seen here on the lip.
mucosa and skin, especially on the scalp, face, axilla,
groin, trunk, and points of pressure.
It may present as oral
ulcers that may persist for months before skin involve-
ment appears.
25.29A).
(B)
Subcorneal separation of the epithelium is seen.
erythema and crusting; these represent superficial erosions
at sites of blister rupture (Fig.
25.30A).
25.31).
25.28).
(B) In pemphigus
foliaceus the immunoglobulin deposits and acantholysis are more
superficial.
In pemphigus vulgaris (see Fig.
In the vegetans
variant, there is also overlying epidermal hyperplasia.
Some patients
present with urticarial plaques and severe pruritus.
25.32B).
Most antibody deposition occurs
in a continuous linear pattern at the dermoepidermal junction
(Fig.
25.33B).
Ulcers form if
the blisters rupture.
(B) Electron micrograph showing the
ultrastructural features of the dermoepidermal junction.
AF, Anchoring fibrils; LD, lamina
densa.
(See also Fig.
25.31.)Blistering (bullous) diseases 1163
Figure 25.34 Dermatitis herpetiformis.
(B) Selective deposition of IgA autoantibody at the tips of dermal papillae
is characteristic.
(B, Courtesy
Dr.Victor G.
Prieto, Houston, Tex.)
(see Fig.
25.29).
Antibodies against one such component
called BPAG2 are proven to cause blistering.
The disease affects
predominantly males, most often in the third and fourth
decades of life.
In some cases it occurs in association with
intestinal celiac disease (Chapter 17).
The plaques and vesicles
are extremely pruritic.
The resultant injury and inflammation produce a
subepidermal blister.
25.34C).
25.34A).
25.34B).
Two such disorders are epidermolysis bullosa and
porphyria.
Epidermolysis Bullosa.
(A) Junctional epidermolysis bullosa showing typical erosions in flexural creases.
(B) Subepidermal blister at the level
of the lamina lucida.
There is no associated inflammation.
in structural proteins that lend mechanical stability to the
skin.
This is the most common type of epider-
molysis bullosa, encompassing 75% to 85% of cases.
25.35; see Fig.
25.28).
• Mixed types, marked by defects at several levels, are also
recognized.
Porphyria.
Porphyria refers to a group of uncommon inborn
or acquired disturbances of porphyrin metabolism.
Porphy-
rins are pigments that are normally present in hemoglobin,
myoglobin, and cytochromes.
The classification of porphyria
is based on both clinical and biochemical features.
porphyria, (4) porphyria cutanea tarda, and (5) mixed
porphyria.
25.36).
The pathogenesis
of these alterations is not understood.
Elimination of P.
acnes is the rationale
for administration of antibiotics to individuals with inflam-
matory acne.
MORPHOLOGY
Inflammatory acne is marked by erythematous papules, nodules,
and pustules (Fig.
25.37A).
Severe variants (e.g., acne conglobata)
result in sinus tract formation and dermal scarring.
25.37B, C).
Dermal abscesses may
form in association with rupture (Fig.
25.37B) and lead to
scarring.
Acne is seen in all races but is
usually milder in people of Asian descent.
Some
families seem to be particularly prone to acne, suggesting
a hereditary component.
Acne is divided into noninflammatory and inflammatory
types, although both types may coexist.
Noninflammatory
acne may take the form of open and closed comedones.
• Open comedones are small follicular papules containing
a central black keratin plug.
This color is the result of
oxidation of melanin pigment (not dirt).
• Closed comedones are follicular papules without a visible
central plug.
Pathogenesis
The pathogenesis of acne is incompletely understood and
is likely multifactorial.
population, with a predilection
for females.
Several microbial triggers
have been proposed, but none are proven.
(A) Inflammatory acne associated with erythematous papules and pustules.
(B) A hair shaft pierces the follicular epithelium, eliciting
inflammation and fibrosis.
(C) An open comedone.
Panniculitis often involves the lower legs.
Erythema
nodosum is the most common form and usually has a subacute
presentation.
A second somewhat distinctive form, erythema
induratum, also merits brief discussion.
Fever and malaise may accompany the
cutaneous signs.
MORPHOLOGY
The histopathology of erythema nodosum is distinctive.
Verrucae (Warts)
Verrucae are squamoproliferative lesions caused by human
papillomaviruses (HPVs).
They are common lesions of
children and adolescents, although they may be encountered
at any age.
Transmission of disease usually involves direct
contact between individuals or autoinoculation.
Verrucae
are generally self-limited, regressing spontaneously within
6 months to 2 years.
The
clinical variants of warts are often associated with distinct
HPV subtypes.
For example, anogenital warts are caused
predominantly by HPV types 6 and 11.
Viral typing can be accomplished
by either in situ hybridization (Fig.
25.38D) or polymerase
chain reaction.
MORPHOLOGY
The classification of verrucae is based largely on appearance and
location.
Verruca vulgaris is the most common type of wart.
(A) Multiple papules with rough pebble-like surfaces.
25.38A).
Verruca plana, or flat wart, is common on the
face or the dorsal surfaces of the hands.
Verruca plantaris and verruca palmaris occur
on the soles and palms, respectively.
Electron microscopy of these zones
reveals numerous HPV virions within nuclei.
25.38C).
Figure 25.39 Molluscum contagiosum.
Impetigo
Impetigo is a common superficial bacterial infection of skin.
The infection usually involves exposed skin, par-
ticularly that of the face and hands.
Over the past several decades a remarkable
shift in etiology has been observed.
aureus.
25.28).
Infection is usually
spread by direct contact, particularly among children and
young adults.
25.39).
Numerous virions are present within molluscum
bodies.
As pustules break, shallow erosionsSuggested readings 1169
A B
Figure 25.40 Tinea.
(A) Characteristic plaque of tinea corporis.
Periodic acid–Schiff stain (inset) reveals deep red hyphae within the stratum corneum.
usually first appears on the upper inner thighs as moist,
red patches with raised scaly borders.
• Tinea pedis (athlete’s foot) affects 30% to 40% of the popula-
tion at some time in their lives.
There is diffuse erythema
and scaling, often initially localized to the web spaces.
Spread to (or
primary infection of the nails) is referred to as onycho-
mycosis.
This produces discoloration, thickening, and
deformity of the nail plate.
• Tinea versicolor usually occurs on the upper trunk and is
highly distinctive in appearance.
25.40A).
• Tinea cruris occurs most frequently in the inguinal areas
of obese men during warm weather.
Heat, friction, and
maceration all predispose to its development.
Special stains reveal the presence of bacteria
in these foci.
25.40B).
25.40B,
inset).
Cancer Genome Atlas Network: Genomic classification of melanoma,
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syndrome.”, Arch Dermatol 114:732, 1978.
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discussion of the causes and management of a common form of eczema].
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Bone consists of extracellular matrix and several cell
types.
The latter,
The adult human skeleton is composed of 206 bones that
account for ~12% of body weight.
(B) Lamellar bone contrasts with the more cellular, disorganized appearance of woven bone.
Osteoid consists of type I collagen and smaller amounts
of glycosaminoglycans and other proteins.
Serum
osteopontin levels are used as a specific marker of osteoblast
activity.
Bone matrix can be woven or lamellar (Fig.
26.1).
Long bones are composed of a dense
outer cortex and a central medulla.
A
Cells
The cellular components of bone include osteoblasts,
osteocytes, and osteoclasts.
26.2A).
Osteoblast activity is tightly regulated
by hormonal and local mediators.
B
Figure 26.2 (A) Active osteoblasts synthesizing bone matrix.
The
surrounding spindle cells represent osteoprogenitor cells.
(B) Two
osteoclasts resorbing bone.
26.2B).
• Fibroblast growth factors (FGFs) are secreted by a variety
of mesenchymal cells.
26.4).
26.5).
The
cartilage mold (anlagen) is synthesized by mesenchymal
precursor cells.
This forms a primary center of ossification
resulting in radial bone growth.
26.3).
Chondrocytes within the growth plates undergo sequential
proliferation, hypertrophy, and apoptosis.
26.3).
Over time, this process produces
longitudinal bone growth.
1
2
3
4
5
Figure 26.3 Active growth plate with ongoing endochondral ossification.
1, Reserve zone.
2, Zone of proliferation.
3, Zone of hypertrophy.
4, Zone
of mineralization.
26.5).
In contrast, acquired diseases
usually appear in adulthood.
Here we will categorize the
major diseases according to their pathogenesis.
More than 350 skeletal dysostoses and dysplasias are
recognized, most of which are extremely rare.
Osteoclasts are derived from the same
mononuclear cells that differentiate into macrophages.
RANK activation induces
precursor cells to become functional osteoclasts.
Consequently, OPG prevents bone resorption by inhibiting
osteoclast differentiation.
The balance between bone formation and resorption is
modulated by RANK and WNT signaling.
Each of these acts
by altering RANK/NF-κB and WNT/ β-catenin signaling.
BMP, Bone morphogenic protein; LRP5/6,
LDL receptor–related proteins 5 and 6.
FGF-mediated FGFR3
activation normally inhibits endochondral growth.
This
effect is exaggerated by FGFR3 gain-of-function mutations.
Thanatophoric dysplasia is the most common lethal
form of dwarfism.
It is caused by mutations in
genes encoding the α1 and α2 chains of type I collagen.
The fundamental abnormality in OI is too little bone,
resulting in extreme skeletal fragility.
OI is separated into four major clinical subtypes of varying
severity (Table 26.2).
26.6).
Osteopetrosis due to CA2
mutations is, therefore, accompanied by renal tubular aci-
dosis.
26.8).
Deposited bone is not remodeled and tends to be woven
rather than lamellar.
Figure 26.6 Skeletal radiograph of a fetus with lethal type 2 osteogenesis
imperfecta.
The compensa-
tory extramedullary hematopoiesis can lead to prominent
hepatosplenomegaly.
The normal osteoclasts produced from donor
stem cells reverse many of the skeletal abnormalities.
Mesenchymal
cells, particularly chondrocytes, degrade extracellular matrix
mucopolysaccharides.
In these diseases, mucopolysaccharides
accumulate within chondrocytes and induce apoptosis.
Extracellular mucopolysaccharide accumulation leads to
structural defects in articular cartilage.
Figure 26.7 Radiograph of the upper extremity in an individual with
osteopetrosis.
They manifest as absent, supernumerary, or
abnormally fused bones.
Global disorganization of bone and/or
cartilage is termed dysplasia.
Developmental abnormalities can
be categorized by the associated genetic defect.
Depending on the gene mutated, extraskeletal manifesta-
tions may also be present.
Figure 26.8 Section of proximal tibial diaphysis from a fetus with
osteopetrosis.
Fracture, anemia, and hydrocephaly are often seen,
resulting in postpartum mortality.
Osteopenia is
1 to 2.5 standard deviations below the mean.
Generalized
osteoporosis may be primary or secondary to a variety of
conditions (Table 26.3).
The following
discussion relates largely to these forms of osteoporosis.
Pathogenesis
Peak bone mass is achieved during young adulthood.
26.9).
Physical activity, muscle strength,
diet, and hormonal state also make important contributions.
This form of osteoporosis, known as senile
osteoporosis, is categorized as a low-turnover variant.
• Genetic factors such as single-gene defects are rare causes
of osteoporosis.
• Calcium nutritional state contributes to peak bone mass.
Adolescent girls (more than boys) tend to have insufficient
calcium intake in the diet.
• Hormonal influences.
26.10),
but certain bones tend to be more severely impacted.
26.11), leading
to microfractures and eventually to vertebral collapse.
Hyperparathyroidism
Hyperparathyroidism causes increased bone resorption.
PTH mediates the effect indirectly
by increasing RANKL expression on osteoblasts.
Inadequate vitamin D ultimately limits intestinal calcium
absorption.
Figure 26.13 Resected rib, harboring an expansile brown tumor adjacent
to the costal cartilage.
26.12).
Radiographically, dissecting osteitis is seen as decreased bone
density or osteoporosis.
26.13).The brown color reflects vascularity, hemor-
rhage, and hemosiderin deposition.
Bony changes regress or disappear completely when
hyperparathyroidism is controlled.
• Mixed pattern disease with areas of high turnover and low
turnover.
Pathogenesis
Kidney disease causes skeletal abnormalities through three
mechanisms (Fig.
26.14):
• Tubular dysfunction most commonly leading to renal
tubular acidosis.
26.15).
An intriguing aspect is the striking geographic variation in
its prevalence.
This results in hypocalcemia that contributes to second-
ary hyperparathyroidism.
Chronic renal failure disrupts this signaling
axis and contributes to osteopenia and osteomalacia.
• Osteomalacia is defined by the presence of bone that is insuf-
ficiently mineralized.
In the developing skeleton, this results in
rickets.
In high income
countries, where early diagnosis is the norm, these manifestations
are rare.
The bone changes stem from decreased tubular,
glomerular, and hormonal renal functions.
The prevalence in England is 2.5% for men and 1.6% for
women 55 years of age or older.
A decrease in new cases
has been observed in some countries over the past 30 years.
MORPHOLOGY
Paget disease shows remarkable histologic variation over time
and across sites.
Paget disease is monostotic
in about 15% of cases and polyostotic in the remainder.
The
axial skeleton or proximal femur is involved in up to 80%
of cases.
Most cases are asymptomatic and are discovered
as an incidental radiographic finding.
Chalk
stick–type fractures are common and usually involve the
long bones of the lower extremities.
Vertebral compression
fractures can result in spinal cord injury and kyphosis.
The diagnosis of Paget disease can be made radiographi-
cally.
Pagetic bone is typically enlarged with thick, coarsened
cortices and medulla (Fig.
26.17).
FRACTURES
Fractures are defined as loss of bone integrity.
They are
some of the most common pathologic conditions affecting
bone.
• Compound: the bone communicates with the skin surface.
• Comminuted: the bone is fragmented.
• Displaced: the ends of the bone at the fracture site are not
aligned.
• Greenstick: extending only partially through the bone,
common in infants when bones are soft.
The tibia is bowed.
• Pathologic: involving bone weakened by an underlying
disease process, such as a tumor.
Healing of Fractures
Bone has a remarkable capacity for repair.
26.18).
The healing process is
completed by restoration of the medullary cavity.
In such
settings, surgical immobilization is often needed for adequate
repair.
Other factors may also interfere with healing.
OSTEONECROSIS
(AVASCULAR NECROSIS)
Infarction of bone and marrow is relatively common.
It can
be limited to the medullary cavity or involve both the
medulla and cortex.
Figure 26.19 Femoral head with a subchondral, wedge-shaped pale area
of osteonecrosis.
changes supervene.
Subchondral infarcts often collapse,
resulting in secondary osteoarthritis.
Medullary infarcts are
usually small and clinically silent.
Pyogenic Osteomyelitis
Pyogenic osteomyelitis is almost always caused by bacterial
infection.
Staphylococcus aureus is responsible for 80% to 90% of
culture-positive pyogenic osteomyelitis.
Collateral blood flow usually limits
cortical involvement.
The slow pace of substitution in subchondral infarcts
(Fig.
Clinical Features
Symptoms depend on location and extent of infarction.
No specific organism is identified in nearly 50%
of patients.
In older children, involvement of the metaphysis is typical.
The combination of antibiotics and surgical
drainage is usually curative.
Acute osteomyelitis fails to resolve and persists as a
chronic infection in 5% to 25% of cases.
Forty percent of mycobacterial osteomyelitis cases involve
the spine (Pott disease).
Skeletal Syphilis
Syphilis (Treponema pallidum) and yaws (Treponema pertenue)
can involve bone.
MORPHOLOGY
Changes associated with osteomyelitis vary temporally and by
location.
In the acute phase, bacteria proliferate and recruit
neutrophils to the site.
Necrosis of bone cells and marrow ensues
within 48 hours.
Associated periosteal lifting further
impairs blood supply and contributes to the necrosis.
Dead bone, or seques-
trum, can crumble and release fragments into the sinus tract.
This new bone can form a living shell, or
involucrum, around the devitalized, infected bone (Fig.
26.20).
Figure 26.20 Resected femur in a person with draining osteomyelitis.
Most bone neoplasms have a propensity for the long
bones of the extremities.
The age groups and anatomic sites
affected are typical of specific tumor types.
For example,
osteosarcoma incidence peaks during adolescence and most
frequently involves the knee.
In contrast, chondrosarcoma
affects the pelvis and proximal extremities of older adults.
Benign bone tumors are often asymptomatic and identified
incidentally.
Others, however, produce pain, cause a slow-
growing mass, or produce a pathologic fracture.
Bone tumors are classified according to the normal cell
types recapitulated or matrix produced.
MORPHOLOGY
Spirochetes can be detected with silver stains or by immunohis-
tochemistry.
Primary bone tumors are rare and are vastly outnumbered
by metastases and hematopoietic tumors.
By definition, osteoid osteomas are
less than 2 cm in diameter.
A thick rim of reactive cortical bone
may be the only radiographic clue.
Figure 26.22 Specimen radiograph of intracortical osteoid osteoma.
26.21) and surrounded by loose connective tissue with many
dilated and congested capillaries.
26.22).
infarcts, and prior radiation (sometimes called secondary
osteosarcomas).
Men are affected slightly more often than
women (1.6 :1).
Osteosarcomas often present with pain, sometimes due
to pathologic fractures.
26.23).
Pathogenesis
The peak incidence of osteosarcoma is during the adolescent
growth spurt.
Abnormalities that interfere
with p53 function are common in sporadic osteosarcomas.
The age distribution of osteosarcoma is bimodal,
with 75% occurring before 20 years of age.
The tan-white tumor
fills most of the medullary cavity of the metaphysis and proximal diaphysis.
in individuals without overt metastases at initial diagnosis.
Osteosarcoma metastasizes hematogenously to the lungs,
bones, brain, and other sites.
Benign cartilage tumors are
much more common than malignant lesions.
Osteochondroma
Osteochondroma, or exostosis, is the most common benign
bone tumor.
26.24).
Extensive necrosis and
intravascular invasion are also common.
Men are affected three
times more often than women.
Osteochondromas develop
only in bones of endochondral origin.
In many cases, they are detected incidentally.
Reduced expression of
EXT1 or EXT2 has also been observed in sporadic osteo-
chondromas.
These genes encode enzymes that synthesize
heparan sulfate glycosaminoglycans.
(Fig.
26.26) and is covered by perichondrium.
26.27).
Enchondromas are most often diagnosed between 20 and
50 years of age.
When they involve large bones, enchon-
dromas are usually asymptomatic and detected incidentally.
(A) Radiograph of an osteochondroma arising from the distal femur (arrow).
Clinical Features
The growth potential of chondromas is limited.
Treatment
depends on the clinical situation and is usually observation or
curettage.
Chondrosarcoma
Chondrosarcomas are malignant cartilage-producing
tumors.
The clear cell and mesenchymal
variants occur in younger people, in their teens or 20s.
On
imaging, the calcified matrix of chondrosarcomas appears
as foci of flocculent densities.
The clear cell variant is unique in that it
originates in the epiphyses of long tubular bones.
Silencing of the CDKN2A tumor suppressor
Figure 26.27 Enchondroma of the proximal phalanx.
Occasionally, they can be painful or cause pathologic
fractures.
In enchondromatosis, the tumors may be numerous
and large, producing severe deformities.
Pathogenesis
Heterozygous mutations in the IDH1 and IDH2 genes are
present within enchondromas.
This “oncometabolite”
interferes with regulation of DNA methylation (Chapter
7).
26.28).
Approximately 80% of patients are younger
than 20 years of age.
26.29A).
Spotty calcifications are typically present,
and central necrosis may create cystic spaces.
Tumor spreads
through the cortex and into surrounding muscle and fat.
26.29B).
26.29C).
Clinical Features
Chondrosarcomas present as painful, progressively enlarging
masses.
The histologic grade correlates directly with biologic
behavior.
A B C
Figure 26.29 Chondrosarcoma.
26.30).
Fibrous septae may also be present, but there is
little stroma.
Geographic necrosis may be prominent.
A pathologic fracture is
also present.
joints, giant cell tumors may cause arthritis-like symptoms.
They can also present with pathologic fractures.
Chemotherapy-
induced necrosis is a positive prognostic indicator.
Although giant cell tumors are benign,
they can be locally aggressive.
This uncommon tumor usually
arises in the third through fifth decades of life.
Giant cell tumors develop within the epiphysis and may
extend into the metaphysis.
26.31).
Grossly, the tumors are large, red-brown masses
that frequently undergo cystic degeneration.
26.32).
The soft tissue component is
delineated by a thin rim of reactive subperiosteal bone.
(B) Axial magnetic resonance image demonstrating characteristic fluid levels (arrows).
Clinical Features
Giant cell tumors are treated by curettage, but 40% to 60%
recur locally.
Although up to 4% metastasize to the lungs,
these can regress spontaneously and are seldom fatal.
The
RANKL inhibitor denosumab has shown promise as an
adjuvant therapy.
All age groups are affected, but
most cases present in adolescence.
ABC develops most
frequently in the femur, tibia, and vertebral body posterior
elements.
26.33A).
Most show central lysis and a thin sclerotic
“eggshell” of reactive bone at the periphery.
26.33B).
26.34).
Bone deposition typically
follows the contours of fibrous septa.
Treatment
of ABC is by curettage or excision.
Recurrence occurs in
10% to 50% of cases.
The radiographic
findings are sufficiently specific that biopsy is rarely neces-
sary.
They are treated with curettage and may
require bone-grafting for proper healing.
These mutations occur early in embryogen-
esis, and affected individuals are genetic mosaics.
At one extreme, a mutation during early
embryogenesis produces McCune-Albright syndrome.
26.36).
Hemosiderin is commonly present.
Skeletal metastases are typically multifocal.
However,
carcinomas of the kidney and thyroid may present with
solitary lesions.
Some cancers are associated with predominantly
one pattern.
Goals of therapy are symptomatic relief and prevention of
further spread.
Periosteal
reaction usually is absent.
26.37).
Cystic
degeneration, hemorrhage, and foamy macrophages are also
common.
The femur, tibia, ribs, jawbones, and calvarium are most
commonly affected.
Growth
of the lesions may be reactivated during pregnancy.
Symp-
tomatic lesions are treated by curettage, but recurrence is
common.
The femur, skull, and tibia are
most frequently affected.
Bisphosphonates can be used to reduce
the severity of the bone pain.
Most primary bone
tumors are benign.
Metastases, especially adenocarcinomas, are
more common than primary bone neoplasms.
• Cartilage forming: Osteochondroma is a polypoid exostosis
with a cartilage cap.
Syndromic forms are most often associated
with mutations in EXT genes.
Chondrosarcomas are malignant tumors of cartilage
involving the axial skeleton in adults.
• Ewing sarcoma is an aggressive malignant small round cell tumor
associated with t(11;22).
Joints
Joints allow movement while providing mechanical stability.
They are classified as solid (nonsynovial) and cavitated
(synovial).
Immobile cartilaginous joints, or synchondroses, include
symphyses (manubriosternalis and pubic).
Synovial joints,
in contrast, have a joint space that allows for a wide range
of motion.
Synovial membranes are lined
by two types of cells arranged in one to four cell deep layers.
Type A synoviocytes are specialized macrophages with
phagocytic activity.
Type B synoviocytes are similar to
fibroblasts and synthesize hyaluronic acid and various
proteins.
Hyaline cartilage lacks blood
vessels, lymphatics, and nerves.
ARTHRITIS
Arthritis refers to inflammation of joints.
It is
the most common type of joint disease.
In these cases, the disease usually affects
few joints (oligoarticular) but may be generalized.
In these settings, the disease is
called secondary OA.
Gender has some influence on distribu-
tion.
The knees and hands are more commonly affected in
women and the hips in men.
26.38).
This leads to changes in proteoglycan
composition as the disease progresses.
Chondrocytes also
secrete matrix metalloproteases (MMPs) that degrade the type
II collagen network.
Advanced disease is characterized by chondrocyte loss and
severe matrix degradation.
synovial fluid to be forced into the subchondral regions.
As the
loculated fluid collection increases in size, fibrous-walled cysts form.
1.
CHONDROCYTE INJURY
Genetic
Biomechanical
Synovium
Chondrocytes
2.
(3) Late OA is evidenced by loss of both matrix and
chondrocytes with subchondral bone damage.
MORPHOLOGY
Chondrocytes proliferate and form clusters in early stages of
OA.
26.39B).
(A) Histologic demonstration of the characteristic fibrillation of articular cartilage.
Typically, only one or a few joints are involved,
except in the uncommon generalized variant.
The joints
commonly involved include the hips (Fig.
Heberden nodes,
prominent osteophytes at the distal interphalangeal joints,
are common in women.
Wrists, elbows, and shoulders are
usually spared.
26.41).
The prevalence of RA in the United States is
approximately 1%.
The incidence peaks in the second to
fourth decades.
RA is three times more common in women
than in men.
Pathogenesis
The autoimmune response in RA is initiated by CD4+
helper T cells.
26.42).
• IL-17 from Th17 cells that recruits neutrophils and
monocytes.
• RANKL, which is expressed on activated T cells and
stimulates bone resorption.
Figure 26.40 Severe osteoarthritis of the hip.
Some
of these plasma cells secrete antibodies that recognize
self antigens.
IgM and IgA autoantibodies that bind
to IgG Fc regions are present in 80% of individuals.
The HLA-DR4
allele is associated with ACPA-positive RA.
(A) Schematic view of the joint lesion.
(B) Low magnification reveals marked synovial hypertrophy with formation of
villi.
(C) At higher magnification, subsynovial tissue containing a dense lymphoid aggregate.
These small masses are
firm, nontender, and round to oval.
26.44).
Leukocytoclastic vasculitis produces purpura,
cutaneous ulcers, and nail bed infarction.
tuberculosis.
Involved joints are swollen, warm, and painful.
Unlike
OA, morning joint stiffness does not subside with activity.
26.45).
Unfortunately, individuals must
be maintained on anti-TNF therapy to avoid disease flares.
In
the United States, 30,000 to 50,000 individuals are affected.
Antinuclear antibody (ANA) seropositivity is typical,
but rheumatoid nodules are usually absent.
Approxi-
mately 90% of patients are HLA-B27 positive.
HLA-B27 is common in patients with reactive arthritis.
When active disease persists for
more than 6 months, the term chronic reactive arthritis is
used.
Inflammatory low back pain is a common accom-
panying symptom but is rarely the only symptom.
Synovitis of a digital tendon sheath produces “sausage”
finger or toe.
Fever, leukocytosis, and elevated sedimentation
rate are common.
Axial joint
involvement is most frequent in drug users.
Prompt recognition and effective
antimicrobial therapy can prevent joint destruction.
tuberculosis.
Onset is insidious and associated
with gradually increasing pain.
Systemic symptoms may
or may not be present.
Mycobacterial seeding of the joint
induces formation of confluent granulomas with caseous
necrosis.
Chronic disease results in fibrous ankylosis and obliteration
of the joint space.
Viral Arthritis
Arthritis can occur with a variety of viral infections.
The
manifestations range from acute to subacute arthritis.
It is the leading arthropod-borne disease
in the United States.
If left
untreated, arthritis (late disseminated stage) occurs months
after infection.
In neonates, contiguous spread from underlying
epiphyseal osteomyelitis is relatively common.
H.
influenzae
arthritis predominates in children younger than 2 years of
age.
S.
Arthritis may subsequently develop
at new sites.
In severe cases, the histopathology
mimics rheumatoid arthritis.
Elevated uric
acid can result from overproduction, reduced excretion, or
both (Table 26.6).
Uric acid levels are determined by several
factors:
• Uric acid production.
Urate synthesis is the end product of
purine catabolism.
• Uric acid excretion.
Asymptomatic hyperuricemia appears around puberty
in males and after menopause in females.
In primary gout,
hyperuricemia is usually due to reduced excretion.
26.46).
Macrophages
and neutrophils phagocytose the urate crystals.
Comple-
ment activation by the alternative pathway may also con-
tribute to leukocyte recruitment.
The resulting
acute arthritis typically remits spontaneously in days to
weeks.
26.47A).
The resulting pannus destroys the underlying cartilage and
leads to juxta-articular bone erosions.
In severe cases, fibrous or
bony ankylosis ensues, resulting in loss of joint function.
Tophi are the pathognomonic hallmark of gout.
(Fig.
26.47B–C).Tophi may appear in the articular cartilage, ligaments,
tendons, and bursae.
Less frequently they occur in soft tissues
(earlobes, fingertips) or kidneys.
Superficial tophi can ulcerate
through the overlying skin.
Generally, gout does not shorten the life
span, but it does impact quality of life.
Note that IL-1 stimulates the production of chemokines and other
cytokines from a variety of cells.
LTB4, Leukotriene B4.
and periarticular tissue as well as severe cartilage damage
that compromises joint function.
Only about 10% of individuals with hyperuricemia
develop gout.
There is no sex or racial predisposition.
CPPD is divided into sporadic (idiopathic), hereditary, and
secondary types.
These mutations are
distinct from those associated with craniometaphyseal dys-
plasia.
As in gout, inflammation is caused
by activation of the inflammasome in macrophages (see
Fig.
26.46).
26.48A).
Individual crystals are rhomboid, 0.5
to 5 µm in greatest dimension (Fig.
26.48B), and birefringent.
Inflammation is usually milder than in gout.
A
Clinical Features
CPPD is frequently asymptomatic.
Ultimately, approximately
50% of affected individuals experience significant joint
damage.
Therapy is supportive to minimize symptoms.
There is no known treatment that prevents or slows crystal
formation.
The rare malignant
tumors are discussed with soft tissue tumors.
Despite
the name, the lesion is unrelated to ganglia of the nervous
system.
The cyst lining
resembles the synovium, and both cyst and synovium may
be hyperplastic.
Cyst fluid often contains inflammatory cells
and fibrin.
Both
variants are most often diagnosed in the 20s to 40s and
affect the sexes equally.
A
B
Figure 26.48 Pseudogout.
(A) Deposits are present in cartilage and
consist of amorphous basophilic material.
(B) Smear preparation of
calcium pyrophosphate crystals.
sacroiliac, vertebral joints and entheses and are associated with
HLA-B27.
• Suppurative arthritis describes direct infection of a joint space
by bacterial organisms.
• Lyme disease is a systemic infection by B.
MORPHOLOGY
Tenosynovial giant cell tumors are red-brown to orange-yellow.
26.49A); localized tumors are well circumscribed.
26.49B).
Older lesions
may become fibrotic.
They usually result from trauma
or degenerative processes and are much more common than
neoplasms.
(A) Excised synovium with fronds and nodules typical of diffuse tenosynovial giant cell tumor.
The
color and texture explain the old name of pigmented villonodular synovitis.
(B) Sheets of proliferating cells in tenosynovial giant cell tumor bulging the
synovial lining.
Clinical Features
Diffuse tenosynovial giant cell tumors present in the knee
in 80% of cases.
Sometimes a palpable mass is appreciated.
Recurrence
is common.
Bone erosion and recurrence are less common than in the
diffuse type.
Surgical excision is the mainstay of treatment.
Clinical trials using antagonists of M-CSF signaling have
had promising results.
Most soft tissue
tumors arise in the extremities, particularly the thigh.
Approximately 15% arise in children; the incidence increases
with age.
Pathogenesis
Most sarcomas are sporadic and have no known predispos-
ing cause.
Others are linked to known environmental
exposures such as radiation, burns, or toxins.
Some sarcomas reca-
pitulate a recognizable mesenchymal lineage (e.g.
Examples include Ewing sarcoma (discussed earlier) and
synovial sarcoma.
In others, the mechanisms are
unknown.
Oncogenic tumor-specific fusion proteins
represent potential targets for therapy.
Examples include leiomyosarcomas and undifferentiated
pleomorphic sarcoma.
The next section will consider representative soft
tissue tumors.
Pleomorphic liposarcomas have complex karyotypes
without reproducible genetic abnormalities.
26.50A).
26.50B).
MORPHOLOGY
The conventional lipoma is a well-encapsulated mass of mature
adipocytes.
It usually arises in the subcutis of the proximal extremi-
ties and trunk during middle adulthood.
Infrequently, lipomas are
large, intramuscular, and poorly circumscribed.
Lipomatosis
occurs when multifocal lipomas involve a limb.
Most lipomas are
soft, mobile, painless, and cured by simple excision.
Clinical Features
Liposarcomas recur locally, and often repeatedly, unless
adequately excised.
Clinical
subtypes include Dupuytren contracture, Ledderhose disease,
and Peyronie disease.
Incidence increases with age.
Eventually, it may cause abnormal curvature of the shaft
and constriction of the urethra.
Palmar and plantar fibromatoses progress in about 50%
of cases.
The remainder stabilize and do not progress; some
resolve spontaneously.
Nevertheless, recurrence is common,
even after excision.
They arise most frequently in the teens to 30s, pre-
dominantly in women.
The defect that prevents
neoplastic cells from becoming malignant has not been
defined.
Nodular fasciitis typically regresses spontaneously
and, if excised, rarely recurs.
MORPHOLOGY
Nodular fasciitis arises in the deep dermis, subcutis, fascia, or
muscle.
Mitoses are frequent, but atypical forms are
notably absent (Fig.
Storiform or fascicular patterns are
common in cellular areas.
It
affects males more frequently than females.
26.52).
The resulting histologic appearance can
resemble a scar.
Because they are infiltra-
tive, complete excision of deep fibromatosis can be difficult.
Recent efforts have concentrated on medical or radiation
therapy as alternatives to surgery.
A
rhabdomyoma, is frequently associated with tuberous
sclerosis (Chapter 28).
The remaining subtypes
of rhabdomyosarcoma are genetically heterogeneous.
B
Figure 26.53 Rhabdomyosarcoma.
(B) Alveolar rhabdomyosarcoma with
numerous spaces lined by discohesive, uniform round tumor cells.
at the periphery adhere to the septae.
Tumor cells are uniform
and round with little cytoplasm.
Cross-striations are uncommon
(Fig.
26.53B).
Rhabdomyoblasts are occasionally present.
Dense, collagenous, sclerotic stroma may be more common in
adults.
MORPHOLOGY
Embryonal rhabdomyosarcoma is a soft, gray, infiltrative mass.
26.53A).
Rhabdomyoblasts with visible
cross-striations may be present.
Individuals often present
with a deep-seated mass that has been present for several
years.
Tumor cells
have blunt-ended, elongated nuclei with minimal atypia
and few mitotic figures.
Solitary lesions are easily cured.
However, multiple tumors may be so numerous that surgical
removal is impractical.
It accounts for 10% to 20%
of soft tissue sarcomas.
They occur in adults and afflict
women more frequently than men.
A particularly deadly
form arises from the great vessels, often the inferior vena
cava.
Leiomyosarcomas have underlying defects in genomic
stability leading to complex genotypes.
MORPHOLOGY
Synovial sarcomas can be monophasic or biphasic.
26.54).
The 5-year survival varies from
25% to 62% and is related to tumor stage and patient age.
Common sites of metastases are the lung and, unusually
for sarcomas, regional lymph nodes.
MORPHOLOGY
Leiomyosarcomas present as painless firm masses.
Retroperitoneal
tumors may be large and bulky and cause abdominal symptoms.
Clinical Features
Leiomyosarcoma treatment depends on tumor size, loca-
tion, and grade.
Necrosis and hemorrhage common.
26.55).
Mitotic figures, including
atypical asymmetric forms, are abundant.
ACKNOWLEDGMENT
We thank Dr.
Andrew Rosenberg for his outstanding
contribution to previous editions of this chapter.
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5:81–86, 2007.
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osteoporosis].
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Paget Disease
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update on the genetic contribution to Paget disease].
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[A summary of recent developments regarding the
pathophysiology of femoral head osteonecrosis].
Despite this, prognosis is
generally poor.
Metastases occur in 30% to 50% of cases.
• Soft tissue tumors likely arise from pluripotent mesenchymal
stem cells rather than mature cells.
[A concise review of the biology of
osteosarcoma].
[A recent update on the classification
of osteosarcoma].
[A good review of the known
genetic abnormalities in cartilage tumors].
[A seminal article identifying IDH mutations in
inherited cartilage tumors].
[A discussion
of the genetic basis of multiple osteochondroma syndrome].
[A review
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[A recent review of RANK-RANKL interactions in the pathogenesis
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376:1094–1108, 2011.
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[A recent
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[A description of the
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They
can be grouped according to anatomy, disease course,
and pathogenesis.
A discussion of neoplasms that arise from
peripheral nerves ends the chapter.
Injury to either of these components may
result in a peripheral neuropathy.
Myelin basic protein (MBP) is an intracellular protein
that has a role in myelin compaction.
the slowest conduction speeds due to their lack of myelin
and small axonal diameter.
27.1).
27.2).
27.3) and disintegrate into spherical structures (myelin
ovoids).
Macrophages are recruited and participate in the
removal of axonal and myelin debris.
Continuous pruning of the sprouting axons removes mis-
guided branches.
The regeneration is successful only if the two transected
ends remain closely approximated.
27.4).
As a result, degenerating and
regenerating axons coexist in a single biopsy.
With time,
damage tends to outpace repair, resulting in progressive
loss of axons.
(C) Regeneration of axons after injury (left axon) allows reinnervation of myofibers.
See Fig.
27.7 for comparison with reinnervation.
AB
Figure 27.3 Electron micrographs illustrating features of axonal degeneration.
Vasculitis is a common
cause of this pattern of injury.
27.2), whereas
axons are relatively preserved.
This definition is similar to
that of demyelinating diseases that affect the CNS (Chapter
28).
The overall annual
incidence is approximately 1 case per 100,000 persons.
Circulating
antibodies that cross-react with components of peripheral
nerves may also play a role.
Electron
microscopy has identified an early effect on myelin sheaths.
Ultimately, the remnants of the
myelin sheath are engulfed by the macrophages.
A B
Figure 27.5 Onion bulb neuropathy.
(B, Courtesy G.
Pathogenesis
T cells as well as antibodies are implicated in the inflamma-
tory process.
27.5).
Clinical Features
The clinical picture is dominated by ascending paralysis
and areflexia.
Deep tendon reflexes disappear early in
the process.
Many patients spend weeks in the
intensive care unit (ICU) before recovering normal function.
Perivascular
inflammatory infiltrates are often present.
Infectious Neuropathies
Many infectious processes affect peripheral nerves.
Each of these disorders is also discussed in more
detail in Chapter 8.
Thus, large traumatic ulcers may develop.
• Tuberculoid leprosy is characterized by an active cell-
mediated immune response to M.
leprae that usually
manifests as dermal nodules containing granulomatous
inflammation.
In tuberculoid leprosy, affected individuals have much
more localized nerve involvement.
These include
polyradiculoneuropathy and unilateral or bilateral facial
nerve palsies.
Diphtheria
Peripheral nerve dysfunction results from the effects of
the diphtheria exotoxin.
The mechanism of action of diphtheria toxin is
described in Chapter 8.
Following chickenpox, a
latent infection persists within neurons of sensory ganglia.
Most common is the involvement
of thoracic or trigeminal nerve dermatomes.
In a small proportion of patients, weakness
is also apparent in the same distributions.
Peripheral nerves show
degeneration of the axons that belong to the dead sensory
neurons.
Intranuclear inclusions
generally are not found in the peripheral nervous system.
Patients with both type 1 and type
2 diabetes are affected (Chapter 24).
Hyperglycemia causes the nonenzymatic
glycosylation of proteins, lipids, and nucleic acids.
cranial neuropathy, and radiculoplexus neuropathy.
It is often monophasic and can improve over
several months.
These asymmetric manifestations may be
caused by microvascular disease.
Most individuals with renal failure
have a peripheral neuropathy.
Regeneration and
recovery are common after dialysis.
• Thyroid dysfunction.
In rare cases, hyperthyroidism is associated
with a neuropathy resembling Guillain-Barré syndrome.
• Paraneoplastic neuropathies.
Nerve
biopsies show reduced numbers of axons.
27.6).
Paraneoplastic sensory neuronopathy
is most commonly associated with small cell lung cancer.
Sensory symptoms usually start distally
in an asymmetric and multifocal pattern.
• Neuropathies associated with monoclonal gammopathies.
Deposition of IgM can be seen ultrastructur-
ally between the membrane layers of the myelin sheath.
IgG or IgA paraproteins may also be associated with
peripheral neuropathy.
• Avulsion of a nerve may occur when tension is applied,
often to one of the limbs.
Women are
more commonly affected than men, and the problem
is frequently bilateral.
Now there is a
continuously growing list of altered genes that are linked
to these diseases.
27.1.
CMT1A accounts for some 55% of genetically defined
CMT.
• CMTX encompasses X-linked forms of CMT disease.
CMT1X is the most common of these, accounting for
15% of genetically defined cases of CMT.
CMT2A
is the most common subtype, accounting for 4% of all
CMT disease.
It is caused by mutations in the MFN2
gene, which is required for normal mitochondrial fusion.
The phenotype is typically severe, with disease onset in
early childhood.
Loss of pain and temperature sensation is
the most common symptom.
The inability to sense pain
leads to traumatic injury of the hands and feet.
These are
typically axonal neuropathies.
Most are caused by
germline mutations of the transthyretin gene.
The clinical presentation is similar to
that of hereditary sensory and autonomic neuropathies.
Neuromuscular junctions are found midway along the
length of myofibers.
These receptors are responsible
for the initiation of signals leading to muscle contraction.
It has a prevalence of 150 to 200 per 1 million
and shows a bimodal age distribution.
In young adults, the
female-to-male ratio is 2:1, but in older adults there is a
male predominance.
The mechanism of action of the various autoantibodies
appears to differ.
This limits the ability of myofibers to respond
to ACh.
Autoantibodies directed against muscle-specific
receptor tyrosine kinase do not fix complement.
This peculiar condition is marked by
the appearance of B-cell follicles in the thymus.
Overall mortality has dropped from over
30% in the 1950s to less than 5% with current therapies.
Acetylcholinesterase inhibitors that increase the half-life of
ACh are the first line of treatment.
In contrast to
myasthenia gravis, rapid repetitive stimulation increases
muscle response.
Muscle strength is augmented after a few
seconds of muscle activity.
Patients typically present with
weakness of their extremities.
Symptoms may precede the diagnosis
of cancer, sometimes by years.
Patients without cancer often have other autoimmune
diseases, such as vitiligo or thyroid disease.
Botox acts by blocking the release of ACh from presynaptic
neurons (Chapter 8).
• Genetic defects in neuromuscular junction proteins give rise
to congenital myasthenic syndromes.
Skeletal Muscle Atrophy
Skeletal muscle atrophy is a common feature of many
disorders.
27.7).
• Perifascicular atrophy is seen in dermatomyositis (see later).
(B) Damage to innervating axons
leads to loss of trophic input and atrophy of myofibers.
Each type is
described next.
Neurogenic injuries lead to fiber type grouping and grouped
atrophy (see Fig.
27.7), both of which stem from the disruption
of muscle innervation.
Following
denervation, myofibers undergo atrophy, often assuming
a flattened, angulated shape.
These large motor units are also
susceptible to grouped atrophy if the innervating axon is
damaged.
Removal of the degenerated debris sets
the stage for regeneration.
Fusion of activated satellite
cells to damaged myofibers is an important step for
regeneration.
Eventually, new sarcomeres are generated,
and the continuity of the original myofiber is restored.
Depending on the nature of the primary insult,
atrophic myofibers may also be seen.
The histologic hallmark, discussed below,
is perifascicular atrophy.
With that,
polymyositis is a less common diagnosis than in the past.
Rarely certain
infectious agents can cause inflammation of skeletal muscle
(Chapter 8).
The prominence of this signature appears
to correlate with disease activity.
Direct immunologic injury
to the muscle fibers may also play a role.
A direct link between these autoantibodies and disease
pathogenesis has not yet been established.
27.8B).
Segmental fiber necrosis and regeneration may also be seen.
Clinical Features
Muscle weakness is slow in onset, symmetric, and often
accompanied by myalgias.
It typically affects the proximal
muscles first.
Note the heliotrope rash affecting the eyelids.
(B) Dermatomyositis.
The histologic appearance of muscle shows
perifascicular atrophy of muscle fibers and inflammation.
(Courtesy Dr.
Fine
movements controlled by distal muscles are affected only
late in the disease.
Cardiac involvement is common, but
rarely leads to cardiac failure.
Dermatomyositis may occur in adults or in children.
Dermatomyositis is the most common
inflammatory myopathy in children.
In many
patients, IMNM is associated with autoantibodies against
HMG-CoA reductase.
Descriptions of
other entities have made cases of polymyositis less common
as outlined above.
Dysphagia from esophageal and pharyngeal muscle
involvement is not uncommon.
It is present in about half of the patients and is
a useful marker of the disease.
Modified Gomori trichrome stain.
MORPHOLOGY
cases intravenous immunoglobulins (IVIG).
Among
prescription drugs, statins are among the leading culprits.
Myopathy is the most common complication of
statins (e.g., atorvastatin, simvastatin, pravastatin).
Cardiac muscle can also be affected by these drugs and can
exhibit similar pathologic changes.
It has
certain features in common with polymyositis, as discussed
earlier.
Thyroid dysfunction can lead to several types of myopa-
thy.
Hypothyroidism can cause cramping or aching
of muscles, and decreased movement.
Reflexes may be
slowed.
Alcohol can also be myopathic.
These categories should
largely be understood as illustrative of key concepts.
Included in the
group of inherited muscular disorders are the following.
They are often associated with distinct
structural abnormalities of the muscle.
These are exemplified by Ullrich congenital
muscular dystrophy (UCMD) and merosin deficiency.
UCMD
is characterized by hypotonia, proximal contractures,
and distal hyperextensibility.
• Conditions with abnormalities in receptors for extracellular
matrix.
27.10) by O-linked glycosylation.
Alpha-dystroglycan expression
is important for CNS and eye development.
Milder
forms may only cause skeletal muscle disease.
The following section focuses on the most common and
best understood forms of inherited myopathies.
As a result, these
diseases are sometimes referred to as dystrophinopathies.
The most common early-onset form is referred to as Duch-
enne muscular dystrophy.
It has an incidence of 1 per 3500
live male births and has a severe progressive phenotype.
27.10).
Mutations in genes that encode these
glycosylation enzymes can cause myopathy as discussed below.
These
moieties are depicted as light blue branching structure.
The diagnosis is based on the history, physical examina-
tion, and laboratory studies.
The detection of a dystrophin mutation
offers definitive diagnosis.
Treatment of patients with dystrophinopathies is chal-
lenging.
Current treatment consists primarily of supportive
care.
Definitive therapy requires restoration of dystrophin
levels in skeletal and cardiac muscle fibers.
27.11).
Clinical Features
Boys with Duchenne muscular dystrophy appear normal at
birth.
Very early motor milestones are met, but walking is
often delayed.
The first indications of muscle weakness are
clumsiness and inability to keep up with peers.
Weakness
begins in the pelvic girdle muscles and then extends to the
shoulder girdle.
The mean age of wheelchair dependence is
around 9.5 years.
Dystrophin is also expressed in the heart and the CNS.
Histologic images of muscle biopsy specimens from two brothers.
(A and B) Specimens from a 3-year-old
boy.
(C) Specimen from his 9-year-old brother.
Their overall incidence is 1 in 25,000 to
50,000 individuals.
Both age of onset and
disease severity are highly variable.
It affects about
1 in 10,000 individuals.
Myotonia, a sustained involuntary
contraction of muscles, is a key feature of the disease.
Rarely,
patients present with “congenital myotonia,” marked by severe
manifestations in infancy.
They may also
influence gene expression by affecting chromatin organization
in the nucleus.
How defects in these proteins produce the
observed phenotypes is unknown.
It is an autosomal dominant disease affecting
about 1 in 20,000 individuals.
In others, there
is slowly progressive damage of muscle, without episodic
manifestations.
The defect in
this disorder impairs the transport of free fatty acids into
mitochondria.
Severe deficiency
results in the generalized glycogenosis of infancy,
Pompe disease (Chapter 5).
27.12).
By electron microscopy, morphologically abnormal mitochondria
may be seen.
• Myopathic disorders are often marked by degeneration and
regeneration of myofibers.
Immune damage to
small blood vessels and perifascicular atrophy are common
features.
• Polymyositis is an adult-onset myopathy caused by CD8+ T
cells.
Some of these diseases present in infancy,
others in adulthood.
They may be relentlessly progressive or
cause relatively static deficits.
The larger
fibers are those that are innervated and have undergone compensatory
hypertrophy.
27.13).
Most channelopathies are autosomal dominant disorders
with variable penetrance.
• CLC1: Mutations affecting this chloride channel cause
myotonia congenita.
As already discussed, CLC1 expres-
sion is decreased in myotonic dystrophy.
Other
rare tumors arising from nerves may show evidence of
perineurial cell differentiation.
Peripheral nerve sheath tumors have several unique
features.
Tumors with skeletal muscle differentiation
are discussed in Chapter 26.
Loss of
expression of the NF2 gene product, merlin, is a consistent
finding in all schwannomas.
As a result they can often be resected without sacrificing nerve
function.
Grossly, these tumors form firm, gray masses.
Palisading
of nuclei is common.
27.14B).
Electron microscopy shows basement
membrane deposits encasing single cells and collagen fibers.
Some large mitotically
active schwannomas lacking Antoni B areas can mimic a sarcoma.
from the acoustic portion of the nerve nor is it a neuroma.
Surgical removal is
curative.
Neurofibromas may be either sporadic or NF1-associated.
Different types of neurofibroma can be distinguished depend-
ing on their growth pattern.
Loss of the GTPase activity
causes RAS to be trapped in GTP bound active state.
Adnexal structures are sometimes entrapped at the edges of the
lesion.
(A and B) Schwannoma.
(C and D) Plexiform neurofibroma.
(C) Multiple nerve fascicles
are expanded by infiltrating tumor cells.
Diffuse neurofibroma.
Some of these neurofibromas can grow to large sizes.
Plexiform neurofibroma.
These tumors grow within and
expand nerve fascicles (Fig.
27.14C), entrapping associated axons.
The
tumor has cellular composition similar to that of other neurofi-
bromas.
The extracellular matrix varies from loose and myxoid
to more collagenous and fibrous.
Often the collagen is seen in
bundles likened to “shredded carrot” (Fig.
27.14D).
Sporadic cases
may arise de novo.
A wide range of histologic appearance can be
encountered.
spindle cells.
At low power the tumor often appears “marbleized”
due to variations in cellularity.
Mitoses, necrosis, and nuclear
anaplasia are common.
• Schwannomas are encapsulated benign tumors that can be
associated with NF2.
As
has been mentioned earlier, NF-1 protein has GTPase activity
that restrains RAS function.
In the absence of NF-1, RAS
remains trapped in its active state.
The disease has a high penetrance but variable expres-
sivity.
An
unfortunate subset has severe disease.
This disorder
is much less common than NF1, having a frequency of 1
in 40,000 to 50,000.
Collins MP, Hadden RD: The nonsystemic vasculitic neuropathies, Nat
Rev Neurol 13:301, 2017.
Willison HJ, Jacobs BC, van Doorn PA: Guillain-Barré syndrome, Lancet
388:717, 2016.
[Review of the histomorphologic classification of inflammatory
myopathies].
[Committee communication on classification and
diagnosis of congenital muscular dystrophies].
Dalakas MC: Inflammatory muscle diseases, N Engl J Med 372(18):
1734–1747, 2015.
[Review on classification and clinical features of inflam-
matory myopathies].
[Review
of the biologic mechanisms of facioscapulohumeral dystrophy].
Dubowitz V, Sewry CA, Oldfors A: Muscle biopsy: a practical approach,
ed 4, Oxford, 2013, Elsevier.
[Overview of disorders affecting muscle].
[Summary of the different
categories of limb-girdle muscular dystrophies].
[Committee communication on classification and diagnosis of congenital
myopathies].
[Review of possible
treatment strategies for myotonic dystrophy].
Thornton CA: Myotonic dystrophy, Neurol Clin 32(3):705–719, 2014.
[Review of myotonic dystrophy].
[Review of the pathologic
classification and features of peripheral nerve sheath tumors].
In many
of these diseases, the predominant mechanism of cell death appears
to be apoptosis.
28.15A).“Red neurons” are evident
by 6 to 12 hours after an irreversible hypoxic/ischemic insult.
The astrocyte
derives its name from its star-shaped appearance.
Astrocytes act as metabolic buffers
and detoxifiers within the brain.
Figure 28.1 Reactive astrocytes.
Other types of astrocyte injury lead to the formation of
cytoplasmic inclusion bodies.
28.49C).
Figure 28.2 Hydrocephalus.
Dilated lateral ventricles seen in a coronal
CEREBRAL EDEMA,
section through the midthalamus.
28.2).
When hydrocephalus develops in infancy before closure
of the cranial sutures, the head enlarges.
There are two main
pathways of edema formation in the brain.
The
paucity of lymphatics greatly impairs the resorption of
excess extracellular fluid.
28.4).
due to distortion or tearing of penetrating veins and arteries
supplying the upper brainstem.
Hydrocephalus is an increase in CSF volume
within all or part of the ventricular system.
Myelomeningoceles occur most commonly in the
lumbosacral region (Fig.
28.5).
A range of different anatomic malformation patterns has
been defined.
Nodular
subcortical heterotopias may also be encountered.
Intrauterine
diagnosis of severe forms by ultrasonography is now
possible.
Holoprosencephaly is associated with trisomy
13 as well as other genetic syndromes.
28.6).
”
bundles of anteroposteriorly oriented white matter can
be demonstrated.
These may be accompanied by morphologic
changes in other regions of the brain.
28.7), and, almost invariably, hydrocephalus and a
lumbar myelomeningocele.
Disruption
of these processes can alter the size, shape, and organization
of the brain.
Different patterns of injury may occur.
Ultimately, the
infarcted areas develop into large cystic lesions (Fig.
Figure 28.7 Arnold-Chiari malformation.
The disease generally becomes manifest
in the second or third decade of life.
Although neurologic recovery is usually complete,
amnesia for the event often persists.
Hemorrhage can extend into the subarachnoid
space from these lesions.
The crests of gyri are most sus-
ceptible because this is where the direct force is greatest.
In general, if the
head is immobile at the time of trauma, only a coup injury
is found.
Figure 28.8 Chronic stage of periventricular leukomalacia.
A blow to the
head may be penetrating or blunt; it may cause either an
open or a closed injury.
The thickness of the cranial bones
varies; therefore, their resistance to fracture differs greatly.
Also, the relative incidence of fractures among skull bones
is related to the pattern of falls.
28.9A).The appearance of contusions is similar regardless of the
source of the trauma.
In the earliest stages, there is edema and
hemorrhage, which is often pericapillary.
Old traumatic lesions on the surface of the brain have a
characteristic gross appearance.
28.9B), can become epileptic foci.
In old
contusions, gliosis and residual hemosiderin-laden macrophages
predominate.
Axons are injured directly by mechanical
forces, with subsequent alterations in axoplasmic flow.
Traumatic Vascular Injury
Vascular injury is a frequent component of CNS trauma.
28.10).
These arteries, most notably the
middle meningeal artery, are vulnerable to traumatic injury.
28.11).
The expanding
hematoma compresses the underlying brain.
The
extravasated blood dissects through the two layers of the
dura, producing a subdural hematoma.
28.12).The underlying brain is flattened,
and the subarachnoid space is often clear.
Figure 28.11 Epidural hematoma covering a portion of the dura.
Also
present are multiple small contusions in the temporal lobe.
(Courtesy the
late Dr.
Raymond D.
A
Spinal Cord Injury
The spinal cord is vulnerable to trauma from its skeletal
encasement.
B
Figure 28.12 (A) Large organizing subdural hematoma attached to the
dura.
Clinical Features
Symptomatic subdural hematomas most often manifest
within 48 hours of injury.
Neurologic signs are attributable to the
pressure exerted on the adjacent brain.
Slowly progressive
neurologic deterioration is typical, but acute decompensation
may also occur.
The treatment of subdural hematomas is
to remove the blood and associated organizing tissue.
The
risk of repeat bleeding is greatest in the first few months
after the initial hemorrhage.
The general biochemical changes in cells resulting from
ischemia are discussed in Chapter 2.
When the ischemia is
sustained, infarction follows in the territory of the compro-
mised vessel.
• Embolism to the brain occurs from a variety of sources.
Emboli tend to lodge where
blood vessels branch or in areas of preexisting luminal
stenosis.
• Traumatic tearing of blood vessels leads to epidural or subdural
hematoma.
In the brain,
embolism is a more common cause of vascular occlusion
than thrombosis.
• Hemorrhage resulting from rupture of CNS vessels.
Primary angiitis of the CNS can also
develop in the absence of systemic vasculitis.
Brain infarcts are subdivided into two broad groups based
on the presence of secondary hemorrhage.
28.13B).
MORPHOLOGY
Both the gross and microscopic appearance of a nonhemorrhagic
infarct changes over time.
Grossly, there is little change in
appearance during the first 6 hours of irreversible injury.
28.14).
Microscopically, the tissue reaction evolves along the following
sequence:
• Acute infarct (Fig.
28.15A).
There is loss of the usual
tinctorial characteristics of white- and gray-matter structures.
Endothelial and glial cells, mainly astrocytes, swell, and myelinated
fibers begin to disintegrate.
• Subacute (evolving) infarct (Fig.
28.15B).
28.16).
On microscopic
Figure 28.14 Old cystic infarct showing cavitation from loss of brain
parenchyma.
A B C
Figure 28.15 Cerebral infarcts.
(A) Acute ischemic injury causes diffuse eosinophilia of neurons, which are beginning to shrink.
28.17) and is
often bilateral.
Figure 28.16 Lacunar infarcts in the caudate and putamen (arrows).
examination, there is tissue loss surrounded by gliosis.
In general, there is often slow improvement during
a period of months.
The clinical outcome varies with the severity and
length of the insult.
Other forms of hereditary small-vessel diseases of the
CNS have been identified.
28.18A).
Arteriolar walls affected by hyaline change (Fig.
28.18C).
(C, Courtesy Dr.
28.19); multiple aneurysms exist in 20% to
30% of cases based on autopsy series.
The neck of the aneurysm may be wide or
narrow.
Repeat
bleeding is common in survivors and unpredictable in timing.
With each episode of bleeding, the prognosis is worse.
(B) Dissected circle of Willis to show large aneurysm.
Foci of old hemorrhage, infarction, and
calcification frequently surround the abnormal vessels.
Males are affected twice
as frequently as females.
There are four principal routes by which
microbes enter the nervous system.
Meningoencephalitis refers to inflammation
of the meninges and brain parenchyma.
It occurs most often
with meningococcal and pneumococcal meningitis.
Particularly in untreated meningitis, Gram stain reveals variable
numbers of bacteria.
Leptomeningeal fibrosis may follow pyogenic meningitis and
cause hydrocephalus.
The viral aseptic meningitides are usually self-limited and
are treated symptomatically.
The spectrum of pathogens varies seasonally and
geographically.
28.22).
From
Figure 28.22 Pyogenic meningitis.
If untreated, focal neurologic signs, lethargy, and
coma may develop.
It
may involve the meninges or the brain.
28.23).
There may be discrete, white areas of inflammation scattered over
the leptomeninges.
Organisms can often be seen with acid-fast
stains.
Hydrocephalus may
result.
When the
process involves the spinal cord subarachnoid space, nerve
roots may also be affected.
MORPHOLOGY
Neurosyphilis presents in several distinct forms.
• Paretic neurosyphilis is caused by invasion of the brain by
T.
The spirochetes can, at times, be demonstrated in tissue
sections.
• Tabes dorsalis is the result of damage to the sensory axons
in the dorsal roots.
Organisms are not demonstrable in the cord lesions.
Involvement of the nervous system is referred to as
neuroborreliosis.
Some viruses have a propensity to infect the nervous
system.
All of these viruses have animal hosts and insect vectors.
neutrophils) (Fig.
28.24A).
Microglial cells form small aggregates, called microglial
nodules (see Fig.
28.24B).
In severe cases, there may be a necrotiz-
ing vasculitis with associated focal hemorrhages.
effective treatment in many cases, with a significant reduction
in the mortality rate.
28.25A).
The infection is necrotizing and
often hemorrhagic in the most severely affected regions.
28.25B).
The typical presenting symptoms are alterations in
mood, memory, and behavior.
(A, Courtesy Dr.
T.W.
Vaccination is now available to prevent these complications
of varicella-zoster virus reactivation.
The virus can also attack the lower spinal cord and roots, producing
a painful radiculoneuritis.
Any cell in the CNS (neurons, glia,
ependyma, or endothelium) may be infected.
A myocarditis sometimes com-
plicates the acute infection.
Postpolio syndrome can develop in
patients 25 to 35 years after resolution of the initial illness.
Exposure to certain species of
bats, even without a known bite, can also lead to rabies.
MORPHOLOGY
External examination of the brain shows intense edema and
vascular congestion.
28.26).
HIV can
be detected in CD4+ microglia and mononuclear or multinucleated
macrophages.
There are signs of meningeal
irritation and, as the disease progresses, flaccid paralysis.
Figure 28.27 HIV encephalitis.
28.28A).
28.28B).
Greatly enlarged oligodendrocyte
nuclei containing glassy amphophilic viral inclusions (Fig.
Infection of granule cell neurons in
the cerebellum has been demonstrated in rare instances.
The resultant vascular thrombosis produces
infarction that is often strikingly hemorrhagic.
The most commonly encountered
fungi that invade the brain are Candida and Cryptococcus.
The CSF may contain few cells but usually has
a high concentration of protein.
8.43).
Most cases of cryptococcal infection in immunosuppressed
individuals are caused by C.
neoformans.
Recently, a second
species, C.
Some case studies suggest that C.
(B) Microscopically, the lesions consists of areas of demyelination.
• Cerebral amebiasis.
The amebae may be
difficult to distinguish morphologically from activated
macrophages (Fig.
28.29).
• Cerebral malaria.
28.30B).
KEY CONCEPTS
INFECTIONS
• Pathogens from viruses through parasites can infect the brain.
Different pathogens use distinct routes to reach the brain and
cause different patterns of disease.
• Viral infections can cause meningitis or meningoencephalitis.
Several pathologic processes can cause loss of myelin.
separated in time and are attributable to patchy white
matter lesions that are separated in space.
Women are affected twice
as often as are men.
There is a strong association with a
DR haplotype of the major histocompatibility complex.
Environmental factors are also important.
Immune mechanisms that underlie the destruction of
myelin are the focus of much investigation.
The demyelination is caused by these
activated leukocytes and their injurious products.
Plaques can extend into gray
matter because myelinated fibers are present there as well.
28.32B), but axons are relatively preserved (Fig.
28.32C).
In
time, astrocytes undergo reactive changes.
Axons in old gliotic
plaques are usually greatly diminished in number.
(C) Relative preservation of axons is seen on the
neurofilament immunostain (brown).
agents, which may slow the progression of the disease but
are not curative.
Once considered a variant of MS, it is
clearly a distinct disorder.
Areas of demyelination in NMO show
loss of aquaporin-4, the major water channel of astrocytes.
White cells (often including neutrophils) are common in
the CSF.
The disease is fatal in many patients, with significant
deficits present in most survivors.
It appears that rapid increases in osmolality
damage oligodendrocytes through uncertain mechanisms.
Inflammation is absent from the lesions, and neurons and
axons are well preserved.
Secondary injury to axons typically emerges over
time.
However, only classic prion diseases
have been shown to be truly transmissible.
The basis
for aggregation varies from one disease to another.
Normal PrP
is a 30-kD cytoplasmic protein of unknown function.
The disease
has a peak incidence in the seventh decade.
The disease is uniformly
fatal; the average survival is only 7 months after the onset
of symptoms.
28.34A).
Inflammation is notably
absent.
Kuru plaques are extracellular deposits of aggregated abnormal
PrP.
They are Congo red– and PAS-positive and usually occur in
the cerebellum (Fig.
28.34B), but are abundant in the cerebral
cortex in cases of vCJD (Fig.
28.34C).
28.35).
(A) Spongiform change in the cerebral cortex.
Inset, High magnification of neuron with vacuoles.
(C) Cortical kuru plaques surrounded by spongiform change in variant
Creutzfeldt-Jakob disease.
abnormal deposits of tau in the brain is not a sufficient
stimulus to elicit deposition of Aβ.
28.35).
Point mutations in APP
are another cause of familial AD.
• Role of tau.
the course of the illness eventually appears to become
independent of the Aβ.
• Other genetic risk factors.
Three alleles
exist (ε2, ε3, and ε4) based on two amino acid polymor-
phisms.
• Role of inflammation.
• Basis for cognitive impairment.
• Biomarkers.
Neurofibrillary tangles are visible as basophilic fibrillary structures
with H&E staining (Fig.
28.37C) but are demonstrated much more
clearly by silver (Bielschowsky) staining (Fig.
28.37D) and with
tau immunohistochemistry (Fig.
Cerebral amyloid angiopathy (CAA) (Fig.
28.36).
28.37A).
(Courtesy the late Dr.
E.P.
(A) Plaques with dystrophic neurites
surrounding amyloid cores are visible (arrows).
(B) Plaque core and
surrounding neuropil are immunoreactive for Aβ.
(D) Silver stain highlights a neurofibrillary
tangle (black) within the neuronal cytoplasm.
Tau,
particularly when phosphorylated, has a propensity to
aggregate.
Two different types of tau mutations have been described.
Within each of these groups, there are heritable and
sporadic forms.
28.38A).These tangles may contain a
variety of tau isoforms.
Nigral degeneration may occur.
Inclusions
can also be found in glial cells in some forms of the disease.
28.38B).
Pathogenesis
Mutations in three different genes have been found in the
inherited forms of FTLD-TDP.
(A) FTLD-tau.
A tangle is present along with numerous tau-containing neurites.
(B) Pick
disease.
(C) FTLD-TDP.
(D) FLTD-TDP.
With progranulin mutations, the TDP-43–
containing inclusions are commonly intranuclear.
(discussed later).
How the repeat expansion results in
formation of aggregates of TDP-43 is a mystery at present.
Both loss of function and toxic gain of function
may contribute to this form of FTD.
There are forms of FTLD in which there are neither
tau- nor TDP-containing inclusions.
In the inclusions, TDP-43 is phos-
phorylated and ubiquitinated.
28.38D).
replacement therapy with L-DOPA (the immediate precursor
of dopamine).
Deep brain stimulation
has emerged over the past decade as a therapy for the motor
symptoms of PD.
This toxin has been used to generate animal
models of PD, which are used to test new therapies.
This protein is a major component
of the Lewy body, which is the diagnostic hallmark of PD.
This clinical impression is confirmed by symptomatic
response to L-DOPA replacement therapy.
A
MORPHOLOGY
A characteristic gross finding in PD is pallor of the substantia
nigra (compare Fig.
Lewy bodies (Fig.
Areas of neuronal loss also typically show gliosis.
Lewy neurites
are dystrophic processes that contain aggregated α-synuclein.
(A) Normal substantia nigra.
(B)
Depigmented substantia nigra in idiopathic Parkinson disease.
(C) Lewy
body in a substantia nigra neuron, staining bright pink (arrow).
Other
common symptoms include nuchal dystonia, pseudobulbar
palsy, and a mild progressive dementia.
The disease
is often fatal within 5 to 7 years of onset.
As with
PSP, cognitive decline may occur, typically later in the illness.
The same tau variant linked to PSP is also highly associated
with CBD.
In affected regions
of cortex, there is severe loss of neurons, gliosis, and “ballooned”
neurons.
Pathogenesis
As in PD, α-synuclein is the major component of the inclu-
sions.
Pathogenesis
HD is a prototypic polyglutamine trinucleotide repeat
expansion disease (Chapter 5).
The gene for HD, HTT,
located on chromosome 4p16.3, encodes a 348-kD protein
known as huntingtin.
In contrast to many other
degenerative diseases, there is no sporadic form of HD.
28.40B).
A B
Figure 28.40 Multiple system atrophy (MSA).
(A) Severe atrophy of the basis pontis in a case of MSA-C.
Motor symptoms often precede
the cognitive impairment.
Here we focus on the common varieties
of pathogenic mutations that are found in SCA.
Pathogenesis
The genes responsible for over half of the numerous SCAs
have been identified.
28.41A).
28.41, inset).
Figure 28.41 Huntington disease.
(Courtesy Dr.
• Expansion of noncoding repeats, similar to myotonic dys-
trophy.
The pathogenic
connection between expansion of these repeats and disease
is obscure.
• Other mutations.
Deep tendon reflexes are depressed or
absent, but an extensor plantar reflex is typically present.
Concomitant diabetes is found
in up to 25% of patients.
Clinical Features
The disease is relentlessly progressive, with death early in
the second decade.
Many affected individuals
develop lymphoid neoplasms, which are most often T-cell
leukemias.
Sporadic
ALS is more common than familial ALS, which may account
for up to 20% of cases.
A
MORPHOLOGY
The anterior roots of the spinal cord are thin (Fig.
Similar findings are seen in the hypoglossal, ambiguus, and
motor trigeminal cranial nerve nuclei.
Skeletal muscles innervated by the degenerated
lower motor neurons show neurogenic atrophy.
28.42B).
B
Figure 28.42 Amyotrophic lateral sclerosis.
of affected individuals are alive 2 years after diagnosis.
The
disease eventually involves the respiratory muscles, leading
to recurrent bouts of pneumonia.
Life span is normal.
Most SMN protein comes from mRNA transcripts derived
from the SMN1 gene on chromosome 5q.
• Prion diseases may be sporadic, familial, or transmissible.
The most common clinical presentation
is that of rapidly progressive dementia.
These disorders may be
caused by mutations in the mitochondrial or the nuclear
genomes.
The
following examples are representative of this spectrum of
disorders.
The
brain shows loss of myelin and oligodendrocytes (Fig.
28.43); a similar process affects peripheral nerves.
Neurons
and axons are relatively spared.
28.43, inset).
The most striking histologic finding is
demyelination with resulting gliosis.
Macrophages with
vacuolated cytoplasm are scattered throughout the white
matter.
In the typical form, young boys present with behavioral
changes and adrenal insufficiency.
Much of the white matter is gray/yellow
because of the loss of myelin.
Inset, “Globoid” cells are the hallmark of the
disease.
acids within peroxisomes, resulting in elevated serum
levels of these lipids.
The symptoms result from progres-
sive CNS, peripheral nerve, and adrenal disease.
In the
white matter, myelin loss is accompanied by gliosis and
extensive lymphocytic infiltration.
Adrenal cortical
atrophy explains the hypocortisolism.
A wide range of other leukodystrophies are recognized,
some with defects in lipid metabolism.
Ataxia, associated with neuronal loss from
the cerebellar system, is also common.
Most cases of
MERRF are associated with mutations in mitochondrial
tRNA genes.
A wide spectrum of nuclear and mitochondrial DNA
mutations has been identified.
Wernicke encephalopathy
is characterized by acute psychosis and ophthalmoplegia.
These symptoms are reversible when treated with thiamine.
The lesions
result from a defect in myelin formation; the mechanism
of this defect is not known.
Demy-
elination of white matter tracts may be a later event.
28.44).
The fetal alcohol syndrome is discussed in
Chapter 10.
Complete paraplegia may occur, usually only
later in the course.
Some regions of the brain are more sensitive to hypoglycemia
than others.
The affected individual
becomes dehydrated and develops confusion, stupor, and
eventually coma.
The fluid depletion must be corrected
gradually; otherwise, severe cerebral edema may follow.
Toxic Disorders
Cellular and tissue injury from toxic agents is discussed in
Chapter 9.
A unique pattern
Figure 28.44 Alcoholic cerebellar degeneration.
embryonal tumors, and a few less common categories.
In
addition, meningeal tumors and familial tumor syndromes
will be covered.
• Metabolic disturbances may disrupt brain function, often without
detectable morphologic changes.
Tumors of the CNS account
for nearly 20% of all cancers of childhood.
Even the
most highly malignant gliomas rarely metastasize outside
the CNS.
(Fig.
Individual tumor
cells infiltrate brain tissue some distance away from the main
lesion.
28.46).
28.47).
(B) Glioblastoma appearing as a necrotic, hemorrhagic, infiltrating mass.
grade.
28.46A).
These tumors constitute 5% to 15% of gliomas and are most
common in the fourth and fifth decades.
Patients may have
had several years of neurologic complaints, often includ-
ing seizures.
The lesions are found mostly in the cerebral
hemispheres and have a predilection for white matter.
WHO grade II astrocytomas may remain stable or
progress slowly; mean survival exceeds 5 years.
Inset,
Microvascular proliferation.1296 CHAPTER 28 The Central Nervous System
of 1p and 19q.
In contrast to high-grade astrocytic tumors, EGFR gene
amplification is not seen.
Pilocytic astrocytomas grow very slowly and can
often be treated by resection alone.
28.48).
Mitotic activity
and proliferation indices are low in low-grade (WHO grade II)
oligodendroglioma.
Such cases may arise de novo,
but more often progress from WHO grade II oligodendrogliomas.
28.49A), with a contrast-enhancing
mural nodule.
28.49B).
28.49C).
Progression
from low- to higher-grade lesions occurs, typically over a
period of 5 or more years.
Ependymomas do not share the
genetic alterations that are found in infiltrating gliomas.
MORPHOLOGY
Grossly and on MRI, ependymomas are solid (i.e., noninfiltrative)
masses.
In the posterior fossa, they typically arise from the floor of
Figure 28.48 Oligodendroglioma.
Similar to diffuse astrocytoma (see Fig.
(A) Grossly, this cerebellar tumor forms a mural nodule within a cyst.
the fourth ventricle (Fig.
28.50B);
more frequently present are perivascular pseudorosettes (Fig.
Two other variants of ependymoma merit brief mention.
Prognosis depends on completeness
of surgical resection.
A B
Figure 28.50 Ependymoma.
There are also “floating neurons” that sit in basophilic,
mucin-rich pools.
Rapid growth may occlude the flow of
CSF, leading to hydrocephalus.
They are usually asymptomatic and are incidental findings
at autopsy or imaging.
Despite the relationship of ependymomas to the
ventricular system, CSF dissemination is uncommon.
In general, neuronal tumors are
more often seen in children and young adults with epilepsy.
• Gangliogliomas (WHO grade I) are tumors composed of
a mixture of mature neuronal and glial cells.
Most
of these tumors are slow growing.
Gangliogliomas are most commonly found in the
temporal lobe and often have a cystic component.
The glial compo-
nent of these lesions most often resembles a pilocytic
astrocytoma.
28.51A).
In the classic subtype, tumor cells form Homer Wright
rosettes (Fig.
28.51C).The large cell/anaplastic variantTumors 1299
AB
CD
Figure 28.51 Medulloblastoma.
28.51D).
Medulloblastomas have a propensity to spread to the sub-
arachnoid space.
Similarly, targeted therapies are being explored for
those with actionable molecular alterations.
28.52A).
28.52B).
Mitotic rates are often markedly elevated.
Clinical Features
Meningiomas are usually slow-growing tumors.
It is marked by
loss of sensory neurons and lymphocytic inflammation
in the dorsal root ganglia.
This
syndrome can also be seen in the absence of malignancy.
These disorders
are discussed in greater detail in Chapter 27.
Cysts may be found at various sites, including
the liver, kidneys, and pancreas.
Mutations in
TSC1 or TSC2 disrupt this control and lead to increased
and unregulated mTOR activity.
The disease frequency is 1 in 30,000 to 40,000.
VEGF leads
to excessive vessel growth, contributing to the development
of hemangioblastomas.
Ru W, Tang SJ: HIV-associated synaptic degeneration, Mol Brain 10:40,
2017.
Venkatesan A: Epidemiology and outcomes of acute encephalitis, Curr
Opin Neurol 28:277, 2015.
• Glial tumors are broadly classified into astrocytomas, oligoden-
drogliomas, and ependymomas.
Carcinomas are most common.
ACKNOWLEDGMENT
The contributions of Dr.
Matt Frosch to previous versions
of this chapter are gratefully acknowledged.
Epub ahead of print.
Lane CA, Hardy J, Schott JM: Alzheimer’s disease, Eur J Neurol 25:59,
2018.
Vision is a major quality-of-life issue.
Most individu-
als with AMD do not suffer from a total loss of vision—an
immersion into darkness.
The histopathology is unimpres-
sive: small scars develop in the macula.
But consider the
effect of these tiny scars in a retired schoolteacher with
AMD.
The central portion of her or his vision is lost.
The
faces of spouse or grandchildren are not visible.
He or she
cannot read a book or newspaper.
In short, this person is robbed
of the common joys that most of us take for granted.
To study the eye, one needs to comprehend all that has
come before.
However, the study of ocular pathology
does not merely repeat what has been presented thus far.
29.1).
forms of age-related neovascularization, result from patho-
logic angiogenesis.
This chapter is organized on the basis of ocular anatomy.
The orbital
contents are subject to the same disease processes that affect
other tissues.
Representative inflammatory conditions and
neoplasms of the orbit are discussed briefly next.
29.2).
Proptosis may be axial (directly forward) or positional.
These are described
in other chapters.
Neoplasms
may also invade from the sinuses into the orbit.
Note that the tendons of the muscles are spared.
(Courtesy Dr.
Ralph C.
Idiopathic orbital inflammation, also known as orbital
inflammatory pseudotumor (Fig.
29.3), is another inflam-
matory condition affecting the orbit.
29.4).
It may also
extend into the lacrimal gland ductules and thereby into the main
lacrimal gland.
the eyelid generate critical components of the tear film.
Figure 29.4 Anatomy of the conjunctiva and eyelids.
CONJUNCTIVA
Functional Anatomy
The conjunctiva is divided into zones (see Fig.
29.4), each
with distinctive histologic features and responses to disease.
The conjunctiva in the fornix is a pseudostratified
columnar epithelium rich in goblet cells.
Surprisingly, primary melanomas of the eyelid
skin are extremely rare.
Basal cell
carcinoma has a distinct predilection for the lower eyelid
and the medial canthus.
Sebaceous carcinoma
tends to spread first to the parotid and submandibular nodes.
The overall mortality rate can be as high as 22%.
Pagetoid
spread (Fig.
Neoplastic cells
with foamy cytoplasm are present within the epidermis (arrow).
29.1).
The conjunctiva, like the eyelid, is richly invested with
lymphatic channels.
Pterygium typically originates in the conjunctiva
astride the limbus.
29.6A, B).
The resultant
inflamed juvenile nevus is completely benign.
29.6C, D).
BRAF
V600 mutations may be identified in nearly 40% of conjunc-
tival melanomas.
The lesions tend to spread first to the parotid or
submandibular lymph nodes.
Approximately 25% of con-
junctival melanomas prove to be fatal.
(C, D) Conjunctival malignant melanoma.
29.7).
Anteriorly, the cornea is covered by epithelium that rests
on a basement membrane.
The sclera may appear “blue” in a variety of conditions.
• The sclera may appear blue in osteogenesis imperfecta.
The cornea is thin and
scarred (note the increased number of fibroblast nuclei).
Figure 29.7 Normal corneal microarchitecture.
The corneal tissue is
stained by periodic acid–Schiff (PAS) to highlight basement membranes.
A very thin
PAS-positive basement membrane separates the epithelium from the
Bowman layer.
Note that the Bowman layer is acellular.
The “holes” in the stroma are
artifactitious spaces between parallel collagenous stromal lamellae.
The specific forms
of keratitis may have certain distinctive features.
29.8).
Corneal
degenerations may be either unilateral or bilateral and are
typically nonfamilial.
By contrast, corneal dystrophies are
typically bilateral and are hereditary.
Band Keratopathies
Two types of band keratopathy serve as examples of corneal
degenerations.
Calcific band keratopathy is characterized by
deposition of calcium in the Bowman layer.
Such thinning results in a cornea that has a conical
rather than spherical shape.
This abnormal shape generates
irregular astigmatism that is difficult to correct with spec-
tacles.
The risk of corneal graft rejection increases
with stromal vascularization and inflammation.
A precise
alignment of collagen in the corneal stroma also contributes
to transparency.
Corneal vascularization may accompany chronic corneal
edema, inflammation, and scarring.
Scars may result from trauma or
inflammation.
The corneal endothelium is derived from neural crest and
is not related to vascular endothelium.
It rests on its basement
membrane, Descemet membrane.
Descemet membrane
increases in thickness with age.
It is the site of copper
deposition in the Kayser-Fleischer ring of Wilson disease
(Chapter 18).
Exudate1312 CHAPTER 29 The Eye
Figure 29.9 Keratoconus.
Figure 29.10 Fuchs dystrophy.
Numerous
drop-like excrescences—guttata—protrude downward from the Descemet
membrane.
Endothelial cell nuclei are not seen.
Epithelial bullae, not shown
in this micrograph, were present, reflecting corneal edema.
related to a primary loss of endothelial cells.
29.10).
Because of chronic edema, the stroma
may eventually become vascularized.
surface to the cornea and may provide refractive relief for
individuals with keratoconus.
Unlike many types of
degeneration, keratoconus is typically bilateral.
Keratoconus
is associated with Down syndrome, Marfan syndrome, and
atopic disorders.
29.9).
KEY CONCEPTS
• The cornea—not the lens—is the major refractive surface of
the eye.
• Corneal dystrophies are generally inherited and degenerations
are typically not inherited.
It is one of the principal
indications for corneal transplantation in the United States.
Neo-
plasms of the lens have not been described.
Cataract
The term cataract describes lenticular opacities that may be
congenital or acquired.
Age-related cataract typically results from opacification
of the lens nucleus (nuclear sclerosis).
Other physical changes in the lens may generate
opacities.
For example, the lens cortex may liquefy.
29.11).
The posterior chamber lies
behind the iris and in front of the lens.
Thus, the lens epithelium does not
exfoliate like the epidermis or a mucosal epithelium.
Note that the surface of the iris is highly textured with crypts and folds.
Lower left, Primary angle-closure glaucoma.
A prosthetic
intraocular lens is typically inserted into the eye.
As Fig.
With this background, glaucoma can be
classified into two major categories.
Both open-angle and angle-closure glaucoma can be
subclassified into primary and secondary types.
There are multiple causes of secondary open-angle glaucoma.
These anatomic changes provoke a marked elevation in
intraocular pressure (see Fig.
29.11).
This leads to minute anterior subcapsular
opacities that are visible by slit-lamp examination.
There are many causes of secondary angle-closure glaucoma.
29.11).
Necrotic tumors, especially
retinoblastomas, can also induce iris neovascularization and
glaucoma.
An anterior subcapsular
cataract (asc) has formed.
The radial folds in the lens are artifacts.
anterior subcapsular cataract (Fig.
29.12).
29.13).
• Glaucoma may develop in the context of either an open or
closed angle.
Open-angle and angle-closure glaucomas are further
subclassified into primary and secondary types.
Figure 29.13 Exogenous panophthalmitis.
This eye was removed after a
foreign body injury.
The central portion of the vitreous humor was extracted surgically
(by vitrectomy).
(From Folberg R: The
eye.
As will be described briefly,
uveitis is frequently accompanied by retinal pathology.
Examples
are described later.
Granulomatous uveitis is a common complication of sar-
coidosis (Chapter 15).
In the posterior segment, sarcoid
may involve the choroid and retina.
Thus, granulomas may
be seen in the choroid.
Numerous infectious processes can affect the choroid or
the retina.
Inflammation in one compartment is typically
associated with inflammation in the other.
Retinal toxoplas-
mosis is usually accompanied by uveitis and even scleritis.
Sympathetic ophthalmia is an example of noninfectious
uveitis limited to the eye.
The condition may develop from 2 weeks to many
years after injury.
Plasma cells are typically absent, but
eosinophils may be identified in the infiltrate (Fig.
29.14).
Sympathetic ophthalmia is treated by the administration of
systemic immunosuppressive agents.
The
Figure 29.14 Sympathetic ophthalmia.
The granulomatous inflammation
depicted here was identified diffusely throughout the uvea.
The uveal
granulomas may contain melanin pigment and may be accompanied by
eosinophils.
(C) Gross photograph
of a choroidal melanoma that has ruptured the Bruch membrane.
The overlying retina is detached.
(D) Epithelioid melanoma cells associated with an
adverse outcome.
29.15).
• The most common intraocular tumor of adults is metastasis
to the eye.
• The most common primary intraocular tumor of adults is uveal
melanoma.
The retina therefore
responds to injury by means of gliosis.
As in the brain, there
are no lymphatics.
29.16).
The location of the hemorrhage within the retina determines its
appearance by ophthalmoscopy.
Note that the outer segments of the photoreceptors
are missing (see Fig.
29.16 for orientation of layers).
The
photoreceptor outer segments are intact, illustrating an acute detachment.
Separation of the neurosensory
retina from the RPE defines a retinal detachment.
The RPE
has an important role in the maintenance of the outer seg-
ments of the photoreceptors.
The adult vitreous humor is avascular.
The vitreous humor can be
opacified by hemorrhage from trauma or retinal neovascu-
larization.
Rheg-
matogenous retinal detachment is associated with a full-thickness
retinal defect.
29.17).
29.18A).
Retinal arterioles and veins share a common
adventitial sheath.
29.18B).
In malignant hypertension, vessels in the retina and
choroid may be damaged.
29.18A).
29.19).
Diabetes Mellitus
The eye is profoundly affected by diabetes mellitus.
(A) The wall of the retinal arteriole (arrow) is thick.
Note the exudate (e) in the retinal outer plexiform layer.
(B)
The fundus in hypertension.
(B, Courtesy Dr.
Thomas A.
In addition, the number of pericytes relative to
endothelial cells diminishes.
Recall that VEGF was
initially called vascular permeability factor.
29.21C).
The web of
newly formed vessels is referred to as a neovascular membrane.
29.21B).
Figure 29.19 Nerve fiber layer infarct.
(Fundus
photograph, Courtesy Dr.
Thomas A.
29.20) and is reminiscent of similar changes in the glomerular
mesangium.
Figure 29.20 The ciliary body in chronic diabetes mellitus, periodic
acid–Schiff stain.
29.16 for a
schematic of retinal structure).
This is an example of intraretinal
angiogenesis known as intraretinal microangiopathy (IRMA).
Note the
retinal hemorrhage in the outer plexiform layer in the left half.
Absence of the ganglion cell and nerve fiber layers is a
hallmark of glaucoma.
The thin-walled
vessel to the right of the thin arrow is not invested with connective tissue.
Neovascular membrane contraction may create
sufficient force to cause retinal detachment.
The use of VEGF
inhibition in this condition is under investigation.
The final common
pathway in both types is vascular occlusion.
(A) Fundus photograph of the cherry-red spot in Tay-Sachs disease.
(A, Courtesy Dr.
Thomas A.
Total occlusion of a branch of retinal artery can produce a
segmental infarct of the retina.
Total occlusion of the central retinal artery can produce
a diffuse infarct of the retina.
Following an acute occlusion,
the retina appears relatively opaque by ophthalmoscopy.
29.22).
Retinal vein occlusion may occur with or without ischemia.
From the
name of this disorder, it is clear that advancing age is a risk
factor.
Loss of vision
may be severe in these individuals.
29.23).
Typically, both
rods and cones are lost to apoptosis, though in varying propor-
tions.
Loss of rods may lead to early night blindness and
constricted visual fields.
As cones are lost, central visual
acuity may be affected.
The
electroretinogram reveals abnormalities characteristic of this
disease.
RPE
BM
Figure 29.23 “Wet” age-related macular degeneration.
Note the blue discoloration of BM to the right of
the label, indicating focal calcification.
become situated directly beneath the neurosensory retina.
Photodynamic therapy
is also being evaluated for effectiveness.
The molecular genetics of retino-
blastoma are discussed in detail in Chapter 7.
In the sporadic cases, both RB alleles are lost
by somatic mutations.
Retinoblastomas arising in those
with germline mutations are often bilateral.
(A) Gross photograph of retinoblastoma.
Dystrophic calcification (black arrow) is present in the zones of tumor necrosis.
Focal zones
of dystrophic calcification are characteristic of retinoblastoma.
VEGF antagonists may prevent visual
loss in many of these conditions.
• Retinoblastoma is the most common primary intraocular tumor
of children.
• Primary retinal lymphoma is an aggressive tumor that often
involves the brain as well.
Retinoblastoma
tends to spread to the brain and bone marrow and seldom
disseminates to the lungs.
Primary
intraocular lymphoma tends to occur in older individuals
and may mimic uveitis clinically.
Most are diffuse large B-cell
lymphomas (Chapter 13).
Spread to the brain commonly
occurs via the optic nerve.
The diagnosis depends on a
demonstration of lymphoma cells in vitreous aspirates.
The pathology of the optic nerve
is similar to the pathology of the brain.
Zones of relative ischemia may
surround segmental infarcts of the optic nerve.
Optic nerve
function in these poorly perfused but not infarcted zones
may recover.
The optic nerve does not regenerate, and visual
loss from infarction is permanent.
29.25).
A B
C
Figure 29.25 The optic nerve in anterior ischemic optic neuropathy
(AION) and papilledema.
(A and B,
Courtesy Dr.
Sohan S.
Individuals may suffer severe visual compromise.
Leber optic neuropathy shows
maternal inheritance pattern typical of mitochondrial gene
mutations.
29.26), which can be
measured by optical coherence tomography.
See Fig.
29.16 for
orientation.
(C) The arrows point to the dura of the optic nerve.
Notice the wide
subdural space, a result of atrophy of the optic nerve.
NFL
GC IPL
IPL
females.
The usual age of onset is between 10 and 30 years.
It begins with clouding of vision that may progress to total
loss of vision.
One of the most important causes of optic
neuritis is multiple sclerosis (Chapter 28).
Indeed, optic
neuritis may be the first manifestation of this disease.
[This is an outstanding and
comprehensive review of the pathogenesis of diabetic retinopathy].
Dimaras H, Kimani K, Dimba EOA et al: Retinoblastoma, Lancet 379:1436,
2012.
Dimras H, Corson TW, Cobrinik D et al: Retinoblastoma, Nat Rev Dis
Primers 2015.
Lim LS, Mitchell P, Seddon JM et al: Age-related macular degeneration,
Lancet 379:1728, 2012.
Rivera JC, Sapieha P, Joyal JS et al: Neonatology 100:343, 2011.
[This is
a comprehensive review of the pathogenesis of retinopathy of prematurity].
Newman NJ: Treatment of hereditary optic neuropathies, Nat Rev Neurol
8:545, 2012.
Pau D, Al Dubidi N, Yalamanchili S et al: Optic neuritis, Eye (Lond)
25:833, 2011.
Smith DJ, Hagedüs L: Graves’ disease, N Engl J Med 375:1552, 2016.
[Another well-illustrated, concise, and com-
prehensive review].
Pe’er J: Pathology of eyelid tumors, Indian J Ophthalmol 65:177, 2016.
[Well-illustrated, concise, and comprehensive review].
[Keratoconus is a common indication for corneal transplant].
[Fuchs endothelial
dystrophy is a major indication for corneal transplant.
This article reviews
the clinical features, genetics, and pathophysiology of this condition].
Glaucoma
Jonas JB, Aung T, Bourne RR et al: Glaucoma, Lancet 390:2183, 2017.
Therapy 
then becomes logical in this schema and the necessity 
to regurgitate facts is minimized.
Cardiovascular surgery is presented in keeping with the 
exponential strides recently achieved.
There are two major subdivisions to the text.
In the 
first twelve chapters, subjects that transcend several organ 
systems are presented.
The need for a 
text such as we have envisioned is great and the goal 
admittedly high.
It is our hope that this effort fulfills the 
expressed demands.
Seymour I.
Hill, James Wu, Mark D.
Girgis, Danielle Hsu, 
Areti Tillou, James Macho, Vishad Nabili, and 
F.
DEFINITIONS OF LEADERSHIP
Many different definitions of leadership have been described.
.
.
1-1).
The great surgical pioneers, such as Hunter, Lister (Fig.
1-2), Halsted, von Langenbeck, Billroth, Kocher (Fig.
1-4), each possessed visions that revolutionized the field of 
surgery.
The boy recov-
ered, and Lister gathered nine more patients.
Michael E.
7 Different leadership styles are tools to use based on the 
team dynamic.
4 Surgical leaders have the willingness to commit to lifelong 
learning.
5 Surgical leaders have the willingness to communicate  
effectively and resolve conflict.
artery for arterial bypass operations, Dr.
Dr.
Leaders must learn to develop visions to provide direction 
for their team.
Apollo 11 Lunar Module moon walk.
Astronaut Edwin 
“Buzz” Aldrin walks by the footpad of the Apollo 11 Lunar Mod-
ule, July 1969.
(Reproduced with permission from AP Photo/NASA.
© 2014 The Associated Press.)
Figure 1-2.
(Copy-
right Bettmann/Corbis/AP Images.)
Figure 1-3.
Emil Theodor Kocher.
(Courtesy of the National 
Library of Medicine.)
Figure 1-4.
Michael E.
DeBakey.
(Reproduced with permission 
from AP Photo/David J.
Phillip.
To Lead.
A key characteristic of all great leaders is the will-
ingness to serve as the leader.
Dr.
1-5).
He 
described this experience as “.
.
.
rough, really rough, the worst 
time in my life .
.
.
.
I would go to work at 7 a.m.
and I’d get back 
at 9 at night, and the kids would be in bed.
And I couldn’t 
speak, I literally couldn’t, I was so exhausted .
.
.
.
Willingness to lead is a necessity in any individual who 
desires to become a surgeon.
They do 
so, believing fully in the improved quality of life that can be 
achieved.
A tremendous 
sacrifice is required for the opportunity to learn patient care.
To Learn.
Basic and translational science relating to surgical care 
is growing at an exponential rate.
Dr.
Martin Luther King, Jr.
(Reproduced with 
permission from AP Photo.
© 2014 The Associated Press.)
in new techniques using new skills and equipment.
To Communicate Effectively.
Effective communication 
directly impacts patient care.
In 2000, the U.S.
One model to ensure open communication is through 
standardization of established protocols.
A commonly accepted 
protocol is the “Time Out” that is now required in the modern 
operating room.
This 
same standardization can be taught outside the operating room.
To Resolve Conflict.
Great leaders are able to achieve their 
vision through their ability to resolve conflict.
Therefore, the tech-
niques for conflict resolution are essential for surgical leaders.
Introspection 
allows the surgeon to understand the impact of his or her actions 
and biases.
(3) A “differential diagnosis” is formed of possible root 
causes of the conflict.
(4) The “assessment/plan” is developed 
in the best interest of all involved parties.
(6) The 
“operation” is the actual implementation of the agreed-upon 
plan, including a time-out.
This seven-step method is an example of an objective, respect-
ful method of conflict resolution.
Time Management
It is important for leaders to practice effective time manage-
ment.
Time is the most precious resource, as it cannot be 
bought, saved, or stored.
The effi-
cient use of one’s time helps to improve both productivity and 
quality of life.
It is therefore critical that time be used wisely on effectively 
achieving one’s goals.
Parkinson’s law, proposed in 1955 by the U.K.
Individuals list and assign relative 
values to their tasks.
1-7).
Too often, surgeons spend a majority of their time attending to 
Figure 1-6.
Surgery resident time-motion study.
H & 
P = history and physical examination.
Figure 1-7.
Time management.
(From Covey S.
The Seven Habits 
of Highly Effective People.
New York: Simon & Schuster; 1989.)
quadrant I (important and urgent) tasks.
A formal time management program is essential for 
modern leadership.
Just as there are many definitions of leadership, many 
classifications of styles exist as well.
Furthermore, it teaches when the situation may demand change 
in style for the best outcome.
The Coercive leader demands immediate compliance.
This style reflects the command and control style that has 
historically dominated surgery.
However, it is effective in times of crisis to deliver 
clear, concise instruction.
This style should be used sparingly 
and is best suited for emergencies.
This type of leader allows the team freedom to inno-
vate, experiment, and devise its own means.
Goleman’s research 
indicates this style is often the most effective.
This is best 
used when a shift in paradigm is needed.
The Affiliative leader creates harmony and builds emo-
tional bonds.
This requires employment of empathy, building 
relationships, and emphasis on communication.
An affiliative 
leader frequently gives positive feedback.
The Coaching style of leadership focuses on developing 
people for the future.
Coaching is leadership through mentor-
ship.
The coach gives team members challenging tasks, coun-
sels, encourages, and delegates.
This leader-
ship style builds team capabilities by helping motivated learners 
improve.
The Democratic leader forges consensus through partici-
pation.
This leadership style listens to and values each mem-
ber’s input.
It can also be exasperating if a 
clear vision does not arise from the collaborative process.
The Pacesetter leader sets high standards for performance 
and exemplifies them.
These leaders identify poor performers 
and demand more from them.
Each of the above styles of leadership has strengths and 
weakness.
Importantly, leaders who are the most successful do 
not rely only on one leadership style alone.
They use several of 
them seamlessly depending on the situation and the team 
members at hand.
Physician leadership is a new mandate in surgical training.
Am J 
Surg.
2004;187:328-331.
© Copyright Elsevier.
* P<0.001 by Student t test between mean importance and mean compe-
tence scores.
be taught to surgical trainees, and there are many validated tools 
to measure outcomes.
Mentoring
A formal leadership training program for surgical trainees 
should include mentoring.
A greater level 
of trust and commitment distinguishes the mentor from the 
teacher.
More than a teacher, a mentor is a coach.
The underlying prem-
ise is a limited level of advancement for the student.
Modern mentorship implies a partnership 
between the mentor and the mentee.
Emeritus Chair of University of California, Los Ange-
les Head and Neck Surgery, Dr.
.
.
Ward embod-
ied the role as a surgeon’s coach.
Highly successful surgeons most often have had excellent sur-
gical mentors.
Effective leadership can 
change surgical departments and improve patient care through 
innovation.
Surgical leadership is bred through its training programs.
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Systemic Response to Injury and 
Metabolic Support
Siobhan A.
Corbett* 2
*This chapter is dedicated to its previous author, Dr.
Stephen Lowry, my mentor and friend.
Fur-
ther, trauma is the leading cause of mortality and morbidity for 
individuals under age 45.
The resulting neuroendocrine reflex 
plays an important modulatory role in the immune response.
We will also discuss how these events are 
monitored and regulated by the central nervous system.
2-1).
Although the mechanisms for the sterile response are 
Figure 2-1.
(Adapted with 
permission from Guirao X, Lowry SF.
Biologic control of injury 
and inflammation: Much more than too little or too late.
World J 
Surg.
1996;20:437.
Trauma DAMPs are structurally diverse endogenous mol-
ecules that are immunologically active.
High-Mobility Group Protein B1.
HMGB1 
is highly evolutionarily conserved across species.
A Role for Mitochondrial DAMPs in the Injury-Mediated 
Inflammatory Response.
How is it possible for biglycan to provide both sig-
nals?
The best-described ligands for these 
receptors are microbial components, the PAMPs.
The best 
described of these, the TLRs, NLRs, and CLRs, are discussed 
in the following sections.
Toll-Like Receptors.
The first human TLR, TLR4, was identified 
shortly thereafter.
TLRs are expressed on both immune and 
nonimmune cells.
TLR expression is significantly 
increased following blunt traumatic injury.
Nucleotide-Binding Oligomerization Domain-Like Recep-
tor Family.
The protein can then oligomerize and recruit 
other complex members.
The net result is the autoactivation of 
pro-caspase 1 to caspase 1.
C-Type Lectin Receptors.
In 
this way, Mincle may contribute to local inflammation at sites 
of tissue injury.
Soluble Pattern Recognition Molecules: The Pentraxins.
The best described 
of the PRMs are the pentraxins.
The short pentraxin, C-reactive protein (CRP), was the 
first PRM to be identified.
CRP and SAP plasma levels are 
low (≤3 mg/L) under normal circumstances.
Thus, CRP is considered part of the 
acute-phase protein response in humans.
Both molecules also participate in the activation and reg-
ulation of complement pathways.
PTX3 
plasma concentrations increase rapidly in various inflammatory 
conditions, including sepsis.
This event is pivotal to all known inflamma-
some signaling pathways.
2-2).
How does 
the CNS sense inflammation?
DAMPs and inflammatory 
molecules convey stimulatory signals to the CNS via multiples 
routes.
The Hypothalamic-Pituitary-Adrenal Axis.
This 
action is mediated in part by circulating cytokines produced as 
Figure 2-2.
Neural circuit relaying messages of localized injury to the brain (nucleus tractus solitarius).
This vagal response occurs in real time and is site specific.
EPI = epinephrine; IL-1 = interleukin-1; NOREPI = norepinephrine; TNF = 
tumor necrosis factor.
(Adapted and re-created with permission from Macmillan Publishers Ltd.
Tracey KJ.
The inflammatory reflex.
Nature.
2002;420:853.
These include 
TNF-α, IL-1β, IL-6, and the type I IFNs (IFN-α/β).
2-3).
Cortisol elicits its many actions through a cytosolic recep-
tor, the glucocorticoid receptor (GR).
2-4).
Steroid synthesis from 
cholesterol.
Adrenocorticotropic hor-
mone (ACTH) is a principal regulator 
of steroid synthesis.
The end products 
are mineralocorticoids, glucocorti-
coids, and sex steroids.
These include IL-10 and IL-1 receptor 
antagonist.
Growth Hormone, Insulin-Like Growth Factor, and Ghrelin.
GH promotes protein synthesis and insulin 
resistance and enhances the mobilization of fat stores.
It also increases the 
Figure 2-4.
Simplified schematic of 
steroid transport into the nucleus.
Ste-
roid molecules (S) diffuse readily across 
cytoplasmic membranes.
mRNA = messenger 
RNA.
The Role of Catecholamines in Postinjury Inflammation.
Aldosterone.
Aldosterone is a mineralocorticoid released 
by the zona glomerulosa of the adrenal cortex.
MRs have 
also been shown to have effects on cell metabolism and immu-
nity.
Insulin.
RNS include 
NO and nitrite.
Host cells are protected from the dam-
aging effects of ROS through a number of mechanisms.
Prolongation of the UPR, indicative of 
irreversible cellular damage, can result in cell death.
For example, autopha-
gosomes can sequester and degrade pro-IL-1β and inflamma-
some components.
2-5).
Apoptosis during sepsis may influence the ultimate com-
petency of the acquired immune response.
Optimal signaling activity requires receptor trimerization.
(Adapted with permission from Lin E, Calvano SE, Lowry SF.
Tumor necrosis factor recep-
tors in systemic inflammation.
In: Vincent J-L (series ed), Marshall JC, Cohen J, eds.
Update in Intensive Care and Emergency Medicine: Vol.
31: 
Immune Response in Critical Illness.
Berlin: Springer-Verlag; 2002:365.
The net result is 
programmed necrosis (necroptosis).
The effect of cell death by 
necroptosis on the immune response is not yet known.
A brief 
discussion of the important cytokine molecules is included.
Tumor Necrosis Factor-α.
In particular, TNF elicits 
many metabolic and immunomodulatory activities.
IL-1α and IL-1β share similar 
biologic functions, but have limited sequence homology.
Thus, 
IL-1Rα serves as a competitive antagonist for the receptor.
Both the precursor and mature forms of IL-1α 
are active.
It can also be released directly from injured cells.
(TNF, IL-18) and foreign pathogens.
IL-1α or IL-1β itself can 
also induce IL-1β transcription.
In contrast to IL-1α, IL-1β is 
synthesized as an inactive precursor molecule.
Mature IL-1β 
is then released from the cell via an unconventional secretory 
pathway.
High doses of 
either IL-1β or TNF are associated with profound hemodynamic 
compromise.
There are two primary receptor types for IL-1: IL-1R1 
and IL-1R2.
IL-1R1 is widely expressed and mediates inflam-
matory signaling on ligand binding.
IL-1α or IL-1β binds first to 
IL-1R1.
A complex is formed of IL-1R1 plus IL-1 plus the coreceptor.
These events culminate in the activation of NF-κB and 
its nuclear translocation.70
Interleukin-2.
Further, plasma levels of IL-6 are proportional to the degree of 
injury.
The IL-10 family currently has six members including 
IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26.
IL-10 is produced 
by a variety of immune cells of both myeloid and lymphoid 
origin.
Once receptor 
ligation occurs, signaling proceeds by the activation of JAK1 
and STAT3.
IL-12 is unique among the cytokines in being 
the only heterodimeric cytokine.
The individual 
IL-12 family members are formed from various combinations of 
the α and β subunits.
Ligation of the IL-12 receptors 
initiates signaling events mediated by the JAK-STAT pathway.
IL-12 release is inhibited by IL-10.
IL-12 deficiency inhibits 
phagocytosis in neutrophils.
In addition, IL-12 
enhances coagulation as well as fibrinolysis.
Interleukin-18.
IL-18 is a member of the IL-1 superfamily of 
cytokines.
However, activated macrophages and Kupffer cells produce 
large amounts of mature IL-18.
It then exits the cell through a nontra-
ditional secretory pathway.
Interferons are 
categorized into three types based on receptor specificity and 
sequence homology.
The two major types, type I and type II, 
are discussed here.
IFN-γ stimulates the release of IL-12 
and IL-18.
Negative regulators of IFN-γ include IL-4, IL-10, 
and glucocorticoids.
Granulocyte-Macrophage Colony-Stimulating Factor/
Interleukin-3/Interleukin-5.
In this way, GM-CSF, IL-3, and IL-5 are able to 
link the innate and acquired immune responses.
Eicosanoids
Omega-6 Polyunsaturated Fat Metabolites: Arachidonic 
Acid.
2-6A).
Glucocor-
ticoids, nonsteroidal anti-inflammatory drugs, and leukotriene  
Figure 2-6.
Schematic diagram of (A) arachidonic acid and (B) eicosapentaenoic acid metabolism.
The pro-
duction of eicosanoids is cell- and stimulus-specific.
Activation of BLT1 results in inhibition of adenyl-
ate cyclase and reduced production of cAMP.
The major direct dietary source of ara-
chidonic acid is from meat.
The second 
major family of PUFAs is the ω-3 fatty acid.
2-6B).
In fact, key derivatives of ω-3 
PUFAs, termed resolvins, have been identified and synthesized.
Resolvins are now categorized as either E-series (from EPA) or 
D-series (from DHA).
Many 
lipid preparations are soy-based and thus primarily composed of 
ω-6 fatty acids.
Complement activation proceeds via three different path-
ways.
C3a and C5a are 
potent anaphylatoxins.
C3b acts as an opsonin, whereas C5b 
initiates the formation of the membrane attack complex.
The latter rec-
ognizes several PAMPs and DAMPs on foreign and apoptotic 
cells.
Kallikrein-Kinin System.
HK, produced by the liver, is cleaved by kalli-
krein to form bradykinin (BK).
They also increase renal vasodilation and consequently 
reduce renal perfusion pressure.
Serotonin 
is released at sites of injury, primarily by platelets.
Finally, survival 
of lipopolysaccharide-induced endotoxic shock was reduced in 
Tph1–/– mice.
H2R binding is 
best described for its stimulation of gastric parietal cell acid 
secretion.
Several of these receptors 
have characteristic signaling pathways that are associated with 
them.
These will be reviewed in the following sections.
2-7).
STAT molecules possess “docking” 
sites that allow for STAT dimerization.
The STAT complexes 
translocate into the nucleus and serve as gene transcription factors.
P = phosphate.
The 
molecular implications for this in terms of cytokine signaling 
are still being unraveled.
Interestingly, STAT-DNA binding can 
be observed within minutes of cytokine binding.
STATs have 
also been shown to modulate gene transcription via epigenetic 
mechanisms.
PRRs, including both TLR and C-type lectin receptors, have also 
been shown to activate SOCS.
The KIR domain binds with high affinity to the JAK 
kinase domain to inhibit its activity.
2-8).
G-protein–coupled receptors are transmembrane proteins.
The G-protein receptors respond to ligands such as adrenaline and sero-
tonin.
The E component subsequently activates second messengers.
cAMP = cyclic adenosine triphosphate.
Finally, Gα12/13 appears to act through Rho- and 
Ras-mediated signaling.
Optimal signaling activity 
requires receptor trimerization.
An additional “common” Smad is 
then recruited.
How does TGF-β inhibit immune responses?
One 
of the most important effects is the suppression of IL-2 pro-
duction by T cells.
Moreover, 
they occurred rapidly (within 4 to 12 hours) and were prolonged 
for days and weeks.
2-9).
Gene expression and protein synthesis can occur 
within a 24-hour period.
Rapid resynthesis of 
I-κB is one method of inactivating the p50-p65 complex.
IL-1 = interleukin-1; P = phosphate; TNF = tumor necrosis factor.
2-10).
NF-κB 
is composed of two smaller polypeptides, p50 and p65.
On release, NF-κB travels to the nucleus and promotes 
gene expression.
NF-κB also stimulates the gene expression for 
I-κB, which results in negative feedback regulation.
Additionally, I-BET conferred protection against 
bacteria-induced sepsis.
2-11).
A healthy immune response depends on a balanced Th1/
Th2 response.
As a consequence, both macrophage activation and 
proinflammatory cytokine synthesis are inhibited.
What are the systemic mechanisms responsible for this 
shift?
DCs are specialized antigen-presenting cells (APCs) 
that have three major functions.
Eosinophils
Eosinophils are immunocytes whose primary functions are 
antihelminthic.
Mast cells are also known to play an impor-
tant role in the anaphylactic response to allergens.
Interferon-γ (IFN-γ) 
is a known inhibitor of the TH2 response.
(Adapted with permission from Lin E, Calvano SE, 
Lowry SF.
Inflammatory cytokines and cell response in surgery.
Surgery.
2000;127:117.
In tissues, mononuclear phagocytes are quiescent.
M1 macrophages 
promote a strong Th1 response.
Neutrophils are 
circulating immunocytes with short half-lives (4 to 10 hours).
Neutrophils do facilitate the recruitment of monocytes into 
inflamed tissues.
2-12).
There are more 
than 50 different chemokines and 20 chemokine receptors that 
have been identified.
The CXC chemokines are particu-
larly important for neutrophil (PMN) proinflammatory function.
NO can also 
reduce microthrombosis by reducing platelet adhesion and 
aggregation (Fig.
2-13) and interfering with leukocyte adhesion 
to the endothelium.
There are two additional isoforms 
of NOS: neuronal NOS (NOS1) and inducible NOS (iNOS/
NOS2).
Prostacyclin
The immune effects of prostacyclin (PGI2) were discussed 
earlier.
Prostacyclin is a potent vasodilator that also 
inhibits platelet aggregation.
In the kidneys, PGI2 modulates renal blood flow and 
glomerular filtration rate.
ETs are 
21-amino-acid peptides derived from a 38-amino-acid precursor 
molecule.
Atrial ETA receptor activation has 
been associated with increased inotropy and chronotropy.
At low levels, in conjunction with 
NO, ETs regulate vascular tone.
SLOW ROLLING  
(10 to 20 μm/s) is predominantly mediated by P-selectins.
(Adapted with permission 
from Lin E, Calvano SE, Lowry SF.
Selectin neutralization: does it 
make biological sense?
Crit Care Med.
One of these is arachi-
donic acid, the precursor molecule for eicosanoids.
Another is 
platelet-activating factor (PAF).
During acute inflammation, 
PAF is released by immune cells following the activation of 
PLA2.
Endothelial inter-
action with smooth muscle cells 
and with intraluminal platelets.
2-14).
Figure 2-14.
RBC = red blood cell; WBC = white 
blood cell.
(Adapted from Cahill GF: 
Starvation in man.
N Engl J Med.
Body fuel reserves in a 70-kg man and 
B.
Energy equivalent of substrate oxidation
A.
2-15).
2-16).
Alanine 
within skeletal muscles can also be 
used as a precursor for hepatic glu-
coneogenesis.
During starvation, 
such fatty acid provides fuel sources 
for basal hepatic enzymatic function.
RBC = red blood cell; WBC = white 
blood cell.
Fuel utilization in extended starvation.
The brain uses ketones for fuel.
The kidneys become important participants in gluconeogenesis.
RBC = red blood cell; 
WBC = white blood cell.
(Adapted from Cahill GF: Starvation in man.
N Engl J Med.
1970;282:668.)
46
BASIC CONSIDERATIONS
PART
 
I
ammonium ions.
Lipid stores within adipose tissue provide 40% or more of 
caloric expenditure during starvation.
2-17).
2-18).
Oxidation of 
1 g of fat yields approximately 9 kcal of energy.
Although the liver 
is capable of synthesizing triglycerides from carbohydrates and 
Figure 2-17.
Acute injury is asso-
ciated with significant alterations 
in substrate utilization.
There is 
enhanced nitrogen loss, indicative 
of catabolism.
Fat remains the pri-
mary fuel source under these circum-
stances.
RBC = red blood cell; WBC = 
white blood cell.
Figure 2-18.
Influence of injury severity on resting metabolism 
(resting energy expenditure, or REE).
The shaded area indicates 
normal REE.
(From Long CL, Schaffel N, Geiger J, et al.
JPEN J Par-
enter Enteral Nutr.
1979;3(6):452.
Copyright © 1979 by A.S.P.E.N.
2-19).
Lipolysis and Fatty Acid Oxidation.
Periods of energy 
demand are accompanied by free fatty acid mobilization from 
adipose stores.
2-20).
Free fatty acids absorbed by cells conjugate with acyl-
CoA within the cytoplasm.
2-21).
This accounts in part for the fact 
that MCTs are more efficiently oxidized than LCTs.
Excess acetyl-
CoA molecules serve as precursors for ketogenesis.
An RQ of 0.85 suggests 
the oxidation of equal amounts of fatty acids and glucose.
CoA = coenzyme A.
The rate of ketogenesis appears to be inversely related to the 
severity of injury.
However, in minor stress states 
ketogenesis does not exceed that in nonstressed starvation.
Fructose absorp-
tion, however, occurs by concentration-dependent facilitated 
diffusion.
Discussion of carbohydrate metabolism primarily refers to 
the utilization of glucose.
In starvation, glucose production occurs at the expense 
of protein stores (i.e., skeletal muscle).
In cells, glucose is phosphorylated to form glucose-6-
phosphate.
Glucose-6-phosphate can be polymerized during gly-
cogenesis or catabolized in glycogenolysis.
2-22).
Fat mobilization in adipose tissue.
Triglycerides are serially hydrolyzed with resultant free fatty acid (FFA) release at 
every step.
The FFAs diffuse readily into the capillary bed for transport.
Tissues with glycerokinase can use glycerol for fuel by forming 
glycerol-3-phosphate.
Skeletal muscle and adipose cells have little glycerokinase and thus do not use glycerol for fuel.
Free fatty acids (FFAs) in the cells form fatty acyl-
coenzyme A (CoA) with CoA.
Once inside the mitochondria, carnitine 
dissociates and fatty acyl-CoA is re-formed.
The carnitine molecule 
is transported back into the cytosol for reuse.
“R” represents a part of the acyl group of 
acyl-CoA.
Glucose-
6-phosphate becomes an important 
“crossroad” for glucose metabolism.
50
BASIC CONSIDERATIONS
PART
 
I
peripheral insulin resistance.
Hydrophobic cell mem-
branes are relatively impermeable to hydrophilic glucose mol-
ecules.
There are two distinct classes of membrane glucose 
transporters in human systems.
Numerous functional human GLUTs have been cloned 
since 1985.
It is expressed on several other tis-
sues, but little is found in the liver and skeletal muscle.
GLUT2 is the major glucose 
transporter of hepatocytes.
GLUT2 is important for 
glucose uptake and release in the fed and fasted states.
GLUT4 
therefore plays a critical role in the regulation of whole-body 
glucose homeostasis.
GLUT5 has been identified in several tis-
sues but is primarily expressed in the jejunum.
SGLT1 and SGLT2 are both associated with glucose reab-
sorption at proximal renal tubules.
2-23).
Severe trauma, burns, and 
sepsis are associated with increased protein catabolism.
This state of pro-
tein catabolism may persist for as long as 3 to 7 weeks.
The effect of injury sever-
ity on nitrogen wasting.
(From Long CL, 
Schaffel N, Geiger J, et al.
JPEN 
J Parenter Enteral Nutr.
1979;3(6):452.
Copyright © 1979 by A.S.P.E.N.
Therefore, vitamins usu-
ally are not given in the absence of preoperative deficiencies.
Commercial enteral diets contain varying amounts of 
essential minerals and vitamins.
Supplemental trace minerals may be given intravenously 
via commercial preparations.
Adjusted lean body weight also can be cal-
culated.
A recent study 
examined the use of trophic feedings in patients with acute lung 
injury.
Guidelines have not yet been made with 
regard to the fiber content of enteral formulas.
At present, the best-studied immunonutrients are glu-
tamine, arginine, and ω-3 PUFAs.
Of this, 75% is found within the 
skeletal muscles.
Some of these studies 
also provide in vitro evidence of enhanced immunocyte func-
tion.
Hence, there has been significant interest in reduc-
ing the ratio of ω-6 to ω-3 fatty acids.
Low-Residue Isotonic Formulas.
These contain no 
fiber bulk and therefore leave minimum residue.
Isotonic Formulas with Fiber.
Isotonic formulas with fiber 
contain soluble and insoluble fiber, which is most often soy 
based.
Immune-Enhancing Formulas.
Calorie-Dense Formulas.
The primary distinction of calorie-
dense formulas is a greater caloric value for the same volume.
High-Protein Formulas.
These 
formulas have nonprotein-calorie:nitrogen ratios between 80:1 
and 120:1.
Elemental Formulas.
Complex carbohydrates are limited, and fat content, in the form 
of MCTs and LCTs, is minimal.
To date, there has been no evidence of their 
benefit in routine use.
Renal Failure Formulas.
Pulmonary Failure Formulas.
Hepatic Failure Formulas.
Even in intubated patients, naso-
gastric feedings often can be recovered from tracheal suction.
Small-bowel feeding is more reliable for delivering nutri-
tion than nasogastric feeding.
It is also appropriate 
for patients requiring passive gastric decompression.
Most tubes are 18F to 28F in size and may be 
used for 12 to 24 months.
A 14-gauge angiocatheter is passed through the abdominal 
wall into the fully insufflated stomach.
Percutaneous Endoscopic Gastrostomy-Jejunostomy and 
Direct Percutaneous Endoscopic Jejunostomy.
This can be achieved by 
endoscopic or fluoroscopic guidance.
Surgical Gastrostomy and Jejunostomy.
The only absolute contra-
indication to feeding jejunostomy is distal intestinal obstruction.
Needle-catheter 
jejunostomies also can be done with a minimal learning curve.
In some instances, intravenous nutrition may 
be used to supplement inadequate oral intake.
Patients with good nutritional status
5.
Early enteral feeding, compared with parenteral, reduces postop-
erative septic complications.
Ann Surg.
1992;216(2):172-183.
58
BASIC CONSIDERATIONS
PART
 
I
via peripheral veins.
Some nutrients cannot be supplemented 
because they cannot be concentrated into small volumes.
There-
fore, PPN is not appropriate for repleting patients with severe 
malnutrition.
Typi-
cally, PPN is used for short periods (<2 weeks).
Beyond this 
time, TPN should be instituted.
Intravenous vitamin preparations also should be added to 
parenteral formulas.
Vitamin deficiencies are rare occurrences 
if such preparations are used.
Insulin may be supplemented 
as necessary to ensure glucose tolerance.
In patients with diabetes mellitus, additional 
insulin may be required.
In some cases as much as 240 mEq of 
potassium ion daily may be required.
Hypokalemia may cause 
glycosuria, which would be treated with potassium, not insulin.
This may require protocol-driven intrave-
nous insulin therapy.
The delivery of parenteral nutrition requires central intra-
venous access.
Complications of Parenteral Nutrition
Technical Complications.
Other causes of fever 
should also be investigated.
If fever persists, the infusion cath-
eter should be removed and submitted for culture.
Some centers are now 
replacing catheters considered at low risk for infection over a 
guidewire.
This is most likely asso-
ciated with greater catheter manipulation and intensive use.
When catheters are indwelling for 
<3 days, infection risks are negligible.
If indwelling time is 3 to 
7 days, the infection risk is 3% to 5%.
Indwelling times of  
>7 days are associated with a catheter infection risk of 5% to 
10%.
All of these complications may be avoided by 
strict adherence to proper techniques.
Intestinal Atrophy.
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This page intentionally left blank 
Fluid and Electrolyte Management 
of the Surgical Patient
G.
BODY FLUIDS
Total Body Water
Water constitutes approximately 50% to 60% of total body 
weight.
Lean tissues such as muscle 
and solid organs have higher water content than fat and bone.
This decreases 
to approximately 65% by 1 year of age and thereafter remains 
fairly constant.
3-1).
ECF 
is measured using indicator dilution methods.
3-2.
The composition of 
the plasma and interstitial fluid differs only slightly in ionic  
composition.
Functional body fluid 
compartments.
TBW = total body 
water.
6 Most acute surgical illnesses are accompanied by some 
degree of volume loss or redistribution.
For divalent ions such as magnesium, 1 mmol equals 
2 mEq.
The movement of water across a cell membrane depends 
primarily on osmosis.
This movement is determined by 
the concentration of the solutes on each side of the membrane.
Chemical composition of 
body fluid compartments.
active particles.
Conversely, 
if the ECF concentration of sodium decreases, water will move 
into the cells.
Sweat is hypotonic, and sweating usually results in only a small 
sodium loss.
Both plasma and interstitial volumes usually are increased.
Symptoms are primarily pulmonary and cardiovascular (see 
Table 3-2).
In fit patients, edema and hyperdynamic circula-
tion are common and well tolerated.
Volume Control
Volume changes are sensed by both osmoreceptors and baro-
receptors.
Concentration Changes
Changes in serum sodium concentration are inversely pro-
portional to TBW.
Therefore, abnormalities in TBW are 
reflected by abnormalities in serum sodium levels.
Hyponatremia.
A low serum sodium level occurs when there 
is an excess of extracellular water relative to sodium.
Extracel-
lular volume can be high, normal, or low (Fig.
3-3).
The elderly are particularly susceptible to drug-
induced hyponatremia.
A concomitant ECF volume deficit is common.
Oliguric renal failure also can be a rapid complication in the 
setting of severe hyponatremia.
A systematic review of the etiology of hyponatremia 
should reveal its cause in a given instance.
Next, depletional 
versus dilutional causes of hyponatremia are evaluated.
Dilutional causes 
of hyponatremia usually are associated with hypervolemic cir-
culation.
Hypernatremia.
Hypernatremia results from either a loss of 
free water or a gain of sodium in excess of water.
3-3).
Urine 
sodium concentration is typically >20 mEq/L, and urine osmo-
larity is >300 mOsm/L.
This can put traction on the cerebral vessels and lead to 
subarachnoid hemorrhage.
Central nervous system symptoms 
Figure 3-3.
Evaluation of sodium 
abnormalities.
can range from restlessness and irritability to seizures, coma, 
and death.
Composition Changes: Etiology and Diagnosis
Potassium Abnormalities.
Acute and chronic renal insufficiency also 
impairs potassium excretion.
Symptoms of hyperkalemia are primarily GI, neuromus-
cular, and cardiovascular (Table 3-6).
GI symptoms include 
nausea, vomiting, intestinal colic, and diarrhea.
Neuromuscu-
lar symptoms range from weakness to ascending paralysis to 
respiratory failure.
Hypokalemia Hypokalemia is much more common than 
hyperkalemia in the surgical patient.
Unlike changes in albumin, changes in pH will affect the 
ionized calcium concentration.
Acidosis decreases protein bind-
ing, thereby increasing the ionized fraction of calcium.
Daily calcium intake is 1 to 3 g/d.
Most of this is excreted 
via the bowel, with urinary excretion relatively low.
Pancreatitis 
may sequester calcium via chelation with free fatty acids.
Hypocalcemia may lead to decreased 
cardiac contractility and heart failure.
Serum phosphate levels are tightly 
controlled by renal excretion.
Most cases of hyperphosphatemia 
are seen in patients with impaired renal function.
Clinical manifestations of hypophosphatemia usually 
are absent until levels fall significantly.
Magnesium Abnormalities.
Of the fraction found in the 
extracellular space, one third is bound to serum albumin.
Mag-
nesium should be replaced until levels are in the upper limit of 
normal.
The normal dietary intake is approximately 20 mEq/d 
and is excreted in both the feces and urine.
The magnesium ion is essential for proper 
function of many enzyme systems.
Depletion is characterized by 
neuromuscular and central nervous system hyperactivity.
Severe deficiencies can 
lead to delirium and seizures.
Acid-Base Balance
Acid-Base Homeostasis.
Significant compensation may not begin for 6 hours 
and then may continue for several days.
↑
aMeasured as standard bicarbonate, whole blood buffer base, CO2 content, or CO2 combining power.
N = normal; Pco2 = partial pressure of carbon dioxide.
increased loss of bicarbonate (Table 3-9).
Initially the urinary bicarbonate level is high in compensa-
tion for the alkalosis.
Hydrogen ion reabsorption also ensues, 
with an accompanied potassium ion excretion.
Respiratory Derangements.
The principal causes are listed in Table 3-11.
Because 
compensation is primarily a renal mechanism, it is a delayed 
response.
Treatment of acute respiratory acidosis is directed 
at the underlying cause.
Measures to ensure adequate ventila-
tion are also initiated.
Decreased glomerular filtration
2.
The most commonly 
used solutions are listed in Table 3-12.
Lactated Ringer’s is slightly hypotonic in that 
it contains 130 mEq of lactate.
Lactate is used rather than bicar-
bonate because it is more stable in IV fluids during storage.
A trial of 853 patients 
receiving hypertonic saline versus hypertonic saline/dextran 
70 vs.
Albumin (molecular weight 70,000) is prepared from 
heat-sterilized pooled human plasma.
Because it is a 
derivative of blood, it can be associated with allergic reactions.
Thus dextrans are used primar-
ily to lower blood viscosity rather than as volume expanders.
The molecular weights can range from 1000 to 3,000,000.
The 
type of fluid used depends on the severity and ease of correc-
tion.
Caution also should be exercised when using 5% dextrose 
in water to avoid overly rapid correction.
orally, in alert patients, or rectally.
Nebulized albuterol (10 to 
20 mg) may also be used.
All of the aforementioned mea-
sures are temporary, lasting from 1 to approximately 4 hours.
Dialysis should be considered in severe hyperkalemia when 
conservative measures fail.
Oral repletion is adequate for mild, asymptomatic 
hypokalemia.
If IV repletion is required, usually no more than 
10 mEq/h is advisable in an unmonitored setting.
Caution should be exercised when oliguria or impaired 
renal function is coexistent.
Treatment 
of hypercalcemia associated with malignancies is discussed 
later in this chapter.
Hypocalcemia Asymptomatic hypocalcemia can be treated 
with oral or IV calcium (see Table 3-15).
Associated 
deficits in magnesium, potassium, and pH must also be corrected.
Hypocalcemia will be refractory to treatment if coexisting hypo-
magnesemia is not corrected first.
Calcium acetate tablets also are useful when 
hypocalcemia is simultaneously present.
Dialysis usually is 
reserved for patients with renal failure.
If elevated levels or symptoms persist, hemodialy-
sis may be necessary.
Hypomagnesemia Correction of magnesium depletion can 
be oral if asymptomatic and mild.
This does not, however, include replenishment 
of a pre-existing deficit or ongoing fluid losses.
Acute volume deficits should be corrected as much as 
possible before the time of operation.
Close monitoring during this period is imperative.
Until the 1960s saline solutions were withheld during sur-
gery.
In the initial postoperative period, an 
isotonic solution should be administered.
How-
ever, postoperative diuresis may require attention to replace-
ment of urinary potassium loss.
The earliest sign of volume 
overload is weight gain.
Additional 
signs of volume excess may also be present as listed in Table 3-2.
Hemoconcentration also may be present.
Treat-
ment will depend on the amount and composition of fluid lost.
In most cases, restriction of free water will improve 
the hyponatremia.
Furosemide also can be used to induce free water loss.
Diabetes Insipidus.
However, volume 
depletion can occur rapidly in patients incapable of oral intake.
In mild cases, free water replacement may be 
adequate therapy.
In more severe cases, vasopressin can be 
added.
The usual dosage of vasopressin is 5 U subcutaneously 
every 6 to 8 hours.
Cerebral Salt Wasting.
However, severe 
hyperglycemia may result from blunted basal insulin secretion.
Additionally, thiamine should be administered before the initia-
tion of feeding.
With the onset of renal fail-
ure, an accurate assessment of volume status must be made.
Oli-
guric renal failure requires close monitoring of serum potas-
sium levels.
Dialy-
sis may be required for severe hyponatremia.
Bicar-
bonate can be useful, but dialysis often is needed.
Cerebral salt 
wasting also can occur in patients with intracerebral lesions.
Central 
DI also can lead to hypernatremia in patients with central ner-
vous system lesions.
Tumor lysis syn-
drome can precipitate severe hyperkalemia from massive tumor 
cell destruction.
Hypomagnesemia is a side effect of ifosfamide and 
cisplatin therapy.
Humoral hypercalcemia 
of malignancy is a common cause of hypercalcemia in cancer 
patients.
Once an adequate volume status has been 
achieved, a loop diuretic may be added.
Unfortunately, these 
measures are only temporary, and additional treatment is often 
necessary.
They have a slow onset of action, but 
effects can last for 2 weeks.
It acts quickly, within 2 to 4 hours, but its use is limited by the 
development of tachyphylaxis.
Gallium nitrates are potent inhibitors of 
bone resorption.
They display a long duration of action but can 
cause nephrotoxicity.
Tumor lysis syndrome most commonly develops during treat-
ment with chemotherapy or radiotherapy.
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49.
Boateng AA, Sriram K, Mequid MM, et al.
Nutrition.
2010;26(2):156.
50.
Glassford NJ, Bellomo R.
Acute kidney injury: how can we 
facilitate recovery?
Curr Opin Crit Care.
2011;17(6):562.
51.
Kapoor M, Chan GZ.
Fluid and electrolyte abnormalities.
Crit 
Care Clin.
2002;17:503.
52.
Clines GA.
Mechanisms and treatment of hypercalcemia of 
malignancy.
Curr Opin Endocrinol Diabetes Obes.
2011; 
18(6)339.
Holcomb, Matthew Pommerening, 
Kenneth Jastrow, and Rosemary A.
The process is shown schematically in 
Fig.
4-1.
Vascular Constriction
Vascular constriction is the initial response to vessel injury.
Vasoconstric-
tion is subsequently linked to platelet plug formation.
The extent of vasoconstriction varies with the degree of 
vessel injury.
Platelet Function
Platelets are anucleate fragments of megakaryocytes.
The nor-
mal circulating number of platelets ranges between 150,000 and 
400,000/μL.
Up to 30% of circulating platelets may be seques-
tered in the spleen.
4-2).
vWF binds to glycopro-
tein (GP) I/IX/V on the platelet membrane.
Up to 
this point, this process is known as primary hemostasis.
Platelet 
aggregation is reversible and is not associated with secretion.
Adenosine 
diphosphate (ADP) and serotonin are the principal mediators in 
platelet aggregation.
TXA2 has potent vasoconstriction and platelet aggrega-
tion effects.
Platelet factor 4 (PF4) and α-thromboglobulin are 
also secreted during the release reaction.
PF4 is a potent heparin 
antagonist.
Biology of hemostasis.
Key Points
1 The life span of platelets ranges from 7 to 10 days.
Common pathway
Intrinsic pathway
Clotting factors
VIII, IX, X, XI, XII
Fibrin
1.
Vascular phase
(Vasoconstriction)
2.
Platelet phase
(Platelets aggregate)
3.
Coagulation phase (Clot formation)
(Clot retraction) 4.
Platelets may also play a role in the initial 
activation of factors XI and XII.
4-3).
Schematic of platelet activation and thrombus function.
Figure 4-3.
Schematic of the 
coagulation system.
HMW = high 
molecular weight.
TF binds to 
VIIa, and this complex catalyzes the activation of factor X to Xa.
Factor IXa is responsible for the bulk 
of the conversion of factor X to Xa.
The most potent mechanism 
of thrombin inhibition involves the APC system.
APC forms a 
complex with its cofactor, protein S, on a phospholipid surface.
This is of interest clinically in the form 
of a genetic mutation, called factor V Leiden.
Patients with factor V Leiden are predisposed 
to venous thromboembolic events.
Plas-
min formation occurs as a result of one of several plasminogen 
activators.
Of note, the thrombin-TM complex 
activates TAFI, leading to a mixed effect on clot stability.
Plasminogen is converted to plasmin by 
one of several plasminogen activators, including tPA.
4-4).
tPA is synthesized by endothelial cells and released by the cells 
on thrombin stimulation.
After plasmin is 
generated, however, it cleaves fibrin somewhat less efficiently.
Figure 4-4.
Formation of fibrin degradation products (FDPs).
tPA = 
tissue plasminogen activator.
Any circulating plasmin is also inhibited by α2-antiplasmin and 
circulating tPA or urokinase.
Clot lysis yields FDPs including 
E-nodules and D-dimers.
For factor IX replacement, the preferred products 
are recombinant or high-purity factor IX.
For patients 
with low titers, inhibitors can be overcome with higher doses of 
factor VIII.
Menorrhagia is common in women.
vWD is classified into 
three types.
For 
bleeding, type I patients usually respond well to desmopressin 
(DDAVP).
Type II patients may respond, depending on the par-
ticular defect.
Type III patients are usually unresponsive.
These 
patients may require vWF concentrates.3
Factor XI Deficiency.
Antifibrinolytics may 
be useful in patients with menorrhagia.
Inher-
ited deficiencies of factors II, V, and X are rare.
These deficien-
cies are inherited as autosomal recessive.
Significant bleeding 
in homozygotes with less than 1% of normal activity is encoun-
tered.
Bleeding with any of these deficiencies is treated with 
FFP.
Similar to factor XI, FFP contains one unit of activity 
of each per milliliter.
However, factor V activity is decreased 
because of its inherent instability.
Prothrombin 
complex concentrates can be used to treat deficiencies of pro-
thrombin or factor X.
Factor V deficiency may be coinherited with factor 
VIII deficiency.
Factor VII Deficiency.
Inherited factor VII deficiency is a 
rare autosomal recessive disorder.
Bleeding is uncommon unless the 
level is less than 3%.
The half-life of factor VII in FFP is up to 4 hours.
Factor XIII Deficiency.
Umbilical stump bleeding is characteristic, and there is a high 
risk of intracranial bleeding.
Replacement can be accomplished with FFP, 
cryoprecipitate, or a factor XIII concentrate.
Levels of 1% to 
2% are usually adequate for hemostasis.
The major surface protein abnormalities are 
thrombasthenia and Bernard-Soulier syndrome.
This defect leads to faulty 
platelet aggregation and subsequent bleeding.
The disorder was 
first described by Dr.
Transfusion of normal 
platelets is required for bleeding in these patients.
The most common intrinsic platelet defect is storage pool 
disease.
Dense granule deficiency is the most 
prevalent of these.
Bleed-
ing is variable, depending on the severity of the granule defect.
Bleeding is caused by the decreased release of ADP from these 
platelets.
A few patients have been reported who have decreased 
numbers of both dense and α-granules.
They have a more severe 
bleeding disorder.
With 
more severe bleeding, platelet transfusion is required.
The etiologies of both 
qualitative and quantitative defects are reviewed in Table 4-1.
Table 4-1 
Etiology of platelet disorders
A.
Quantitative Disorders
1.
Failure of production: related to impairment in bone 
marrow function
a.
Leukemia
b.
Myeloproliferative disorders
c.
B12 or folate deficiencies
d.
Chemotherapy or radiation therapy
e.
Acute alcohol intoxication
f.
Viral infections
2.
Decreased survival
a.
Disseminated intravascular coagulation (DIC)
c.
Related to platelet thrombi
1) Thrombocytopenic purpura (TTP)
2) Hemolytic uremic syndrome (HS)
3.
Sequestration
a.
Portal hypertension
b.
Sarcoid
c.
Lymphoma
d.
Gaucher’s Disease
B.
Qualitative Disorders
1.
Massive  transfusion
2.
Therapeutic platelet inhibitors
3.
Disease  states
a.
Myeloproliferative disorders
b.
Monoclonal gammopathies
c.
Corticosteroids: The majority of patients respond but 
only a few long term
 b.
Required in most patients
 a.
Splenectomy: open or laparoscopic.
Criteria include 
severe thrombocytopenia, high risk of bleeding, and 
continued need for steroids.
Failure may be due to 
retained accessory splenic tissue.
b.
Rituximab, an anti-CD 20 monoclonal antibody
 c.
Thrombopoietin (TPO) receptor agonists such as 
romiplostim and eltrombopag
Third Line.
To be used after failure of splenectomy and 
rituximab
 a.
TPO receptor agonists
 b.
Immunosuppressive agents.
For failure of TPO receptor 
agonists
quantitative Defects.
Large platelets are seen on peripheral smear.
Both gamma globulin and anti-D immunoglobulin are rapid 
in onset.
Survival of the transfused platelets is usually short.
Primary immune thrombocytopenia is also known as 
idiopathic thrombocytopenic purpura (ITP).
In children, it is 
usually acute in onset, short lived, and typically follows a viral 
illness.
In contrast, ITP in adults is gradual in onset, chronic 
in nature, and has no identifiable cause.
Heparin-induced thrombo-
cytopenia (HIT) is a form of drug-induced immune thrombo-
cytopenia.
A negative ELISA, however, essentially rules out HIT.
The initial treatment of suspected HIT is to stop heparin 
and begin an alternative anticoagulant.
Alternative anticoagulants are pri-
marily thrombin inhibitors.
The finding of schistocytes on a peripheral blood 
smear aids in the diagnosis.
The metalloproteinase is normal in 
these cases.
Neurologic symptoms are less frequent.
A number of patients 
develop features of both TTP and HUS.
Discontinuation 
of the involved drug is the mainstay of therapy.
Platelet 
survival is mildly decreased.
A count of greater than 50,000/μL 
generally requires no specific therapy.
qualitative Platelet Defects.
Impairment of ADP-stimulated aggregation occurs with 
massive transfusion of blood products.
Uremia may be 
associated with increased bleeding time and impaired aggrega-
tion.
If possible, surgery should be delayed until the 
count has been decreased.
These patients are at risk for both 
bleeding and thrombosis.
Acquired Hypofibrinogenemia
Disseminated Intravascular Coagulation (DIC).
As of yet, scoring systems for organ 
failure do not routinely incorporate DIC.
Given the formation of microthrombi 
in DIC, heparin therapy has also been proposed.
Primary Fibrinolysis.
In general, correction based solely on a low platelet count 
should be discouraged.
Most often, treatment should be with-
held for invasive procedures and surgery.
Results are 
mixed following insertion of a transjugular intrahepatic porto-
systemic shunt (TIPS).
Additionally, laboratory abnormalities may mimic those of 
DIC.
Elevated D-dimers have been reported to increase the risk 
of variceal bleeding.
The absorption of vitamin K is dependent 
on bile production.
If the fibrinogen is less than 200 mg/dL, administration of cryo-
precipitate may be helpful.
Cryoprecipitate is also a source of 
factor VIII for the rare patient with a low factor VIII level.
4-5, hypoperfusion causes activa-
tion of TM on the surface of endothelial cells.
These antibodies 
may be associated with either venous or arterial thrombosis, 
or both.
In fact, patients presenting with recurrent thrombosis 
should be evaluated for APLS.
Therapeutic 
anticoagulation is more reliably achieved with a low molecu-
lar weight heparin.
Medications that can alter warfarin requirements are 
shown in Table 4-4.
Illustration of the pathophysiologic mechanism 
responsible for the acute coagulopathy of trauma.
PAI-1 = plas-
minogen activator inhibitor 1; TAFI = thrombin-activatable fibri-
nolysis inhibitor.
More concerning is the absence of any 
available reversal agent.
In most of these cases, reversal of 
anticoagulation is the only treatment that is necessary.
Surgical intervention may prove necessary in patients 
receiving anticoagulation therapy.
Certain surgical procedures should not be performed in 
concert with anticoagulation.
Emergency 
operations are occasionally necessary in patients who have been 
heparinized.
The first step in these patients is to discontinue 
heparin.
For more rapid reversal, protamine sulfate is effective.
The primary indication for this level of aggressiveness is 
patients with mechanical heart valves.
Cardiopulmonary Bypass.
Significant surgical bleeding is usually 
caused by ineffective local hemostasis.
Mechanical Procedures.
When a small vessel is transected, a simple ligature is usu-
ally sufficient.
However, for larger pulsating arteries, a transfix-
ion suture to prevent slipping is indicated.
Packing bone wax on the raw 
surface to effect pressure can control bleeding from cut bone.
Thermal Agents.
A direct current also can result in hemostasis.
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Topical Hemostatic Agents.
Levine and Stetson in 1939 followed with 
the concept of Rh grouping.
Replacement Therapy
Typing and Cross-Matching.
Serologic compatibility for A, 
B, O, and Rh groups is established routinely.
Rh-negative recipients should 
be transfused only with Rh-negative blood.
However, this group 
represents only 15% of the population.
In emergency situations, type O-negative blood may be 
transfused to all recipients.
O-negative and type-specific red 
blood cells are equally safe for emergency transfusion.
If these antibodies are present in high titer, hypother-
mia is contraindicated.
The use of autologous transfusion is growing.
Up to 5 units 
can be collected for subsequent use during elective procedures.
Donations can be scheduled at intervals 
of 3 to 4 days.
Banked Whole Blood.
Once the gold standard, whole 
blood is rarely available in Western countries.
With sequen-
tial changes in storage solutions, the shelf life of red blood 
cells is now 42 days.
Red Blood Cells and Frozen Red Blood Cells.
Red blood 
cells are the product of choice for most clinical situations requir-
ing resuscitation.
The preparation reduces but does not elimi-
nate reactions caused by plasma components.
They are 
used for patients who are known to have been previously sensi-
tized.
The red blood cell viability is improved, and the ATP and 
2,3-DPG concentrations are maintained.
Leukocyte-Reduced and Leukocyte-Reduced/Washed Red 
Blood Cells.
In most 
Western nations, it is the standard red blood cell transfusion 
product.
The shelf life of platelets is 120 hours from time of donation.
One unit of platelet concentrate has a volume of approximately 
50 mL.
Fresh Frozen Plasma.
FFP car-
ries similar infectious risks as other component therapies.
FFP 
can be thawed and stored for up to 5 days, greatly increasing 
its immediate availability.
Tranexamic Acid.
16.0%, RR 0.91, confidence interval 
[CI] 0.85–0.97; P = .0035).
184/2996 [6.1%], RR 0.79, CI 0.64–0.97; 
P = .03).
Treatment given after 3 hours increased the risk of 
death due to bleeding (144/3272 [4.4%] vs.
103/3362 [3.1%], 
RR 1.44, CI 1.12–1.84; P = .004).
TXA is an inhibitor 
of plasminogen activation and an inhibitor of plasmin activity.
This reduces 
plasminogen activation to plasmin.
TXA is 10 times 
more potent in vitro than aminocaproic acid.
It is excreted largely 
unchanged in urine and has a half-life of about 2 hours in cir-
culation.
No adjustment is needed 
for hepatic impairment.
Oxygen-
carrying capacity is primarily a function of the red blood cells.
Thus, transfusion of red blood cells should augment oxygen-
carrying capacity.
Measurements of hemoglobin 
or hematocrit levels are frequently used to assess blood loss.
These measurements can be occasionally misleading in the face 
of acute loss.
No quality clinical data supported this concept.
This definition is admittedly arbitrary.
This varia-
tion correlated with blood product ratios.
Source: Reproduced with permission from Salzman EW: Hemorrhagic disorders.
In: Kinney JM, Egdahl RH, Zuidema GD, eds.
Manual of Preoperative and Postoperative Care.
2nd ed.
Philadelphia: WB Saunders; 
1971:157.
Copyright Elsevier.
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Table 4-6 
Adult Transfusion Clinical Practice Guideline
A.
Initial Transfusion of Red Blood Cells (RBCs):
1.
Notify blood bank immediately of urgent need for RBCs.
O negative uncross-matched (available immediately).
As soon as possible, switch to O negative for females and O positive for males.
Type-specific uncross-matched (available in approximately 5–10 min).
Completely cross-matched (available in approximately 40 min).
2.
A blood sample must be sent to blood bank for a type and cross.
3.
The Emergency Release of Blood form must be completed.
If the blood type is not known and blood is needed immediately, 
O-negative RBCs should be issued.
4.
RBCs will be transfused in the standard fashion.
All patients must be identified (name and number) prior to transfusion.
5.
B.
Adult Massive Transfusion Guideline:
1.
The Blood Bank should strive to deliver plasma, platelets, and RBCs in a 1:1:1 ratio.
Crystalloid infusion should be minimized.
2.
Every attempt should be made to obtain a 1:1:1 ratio of 
plasma:platelets:RBCs.
3.
Once initiated, the MT will continue until stopped by the attending physician.
MT should be terminated once the patient is 
no longer actively bleeding.
4.
5.
Pretreatment 
with acetaminophen reduces the severity of the reaction.
Bacterial contamination of infused blood is rare.
Gram-
negative organisms, which are capable of growth at 4°C, are the 
most common cause.
If the diagnosis is suspected, the trans-
fusion should be discontinued and the blood cultured.
Emer-
gency treatment includes oxygen, adrenergic blocking agents, 
and antibiotics.
Allergic Reactions.
Allergic reactions are relatively frequent, 
occurring in about 1% of all transfusions.
Reactions are usu-
ally mild and consist of rash, urticaria, and flushing.
In rare 
instances, anaphylactic shock develops.
For every 6 red blood cells (RBCs), give  
6 FFP (1:1 ratio).
Platelets For every 6 RBCs and plasma, give one  
6 pack of platelets.
6 random-donor platelet 
packs = 1 apheresis platelet unit.
Platelets are in every cooler.
Keep platelet counts >100,000.
Cryoprecipitate After first 6 RBCs, check fibrinogen 
level.
If ≤200 mg/dL, give 20 units 
cryoprecipitate (2 g fibrinogen).
Treatment and prophylaxis consist of the 
administration of antihistamines.
In more serious cases, epi-
nephrine or steroids may be indicated.
Respiratory Complications.
Overload is manifest 
by a rise in venous pressure, dyspnea, and cough.
Rales can gen-
erally be heard at the lung bases.
Symptoms are similar to circulatory overload with dyspnea 
and associated hypoxemia.
Hemolytic Reactions.
Hemolytic reactions can be classified 
as either acute of delayed.
Associated symptoms 
include fever, respiratory distress, hypotension, and tachycardia.
In anesthetized patients, diffuse bleeding and hypotension are the 
hallmarks.
A high index of suspicion is needed to make the diag-
nosis.
A positive Coombs’ test indicates 
transfused cells coated with patient antibody and is diagnostic.
Delayed hemolytic transfusions may also be manifest by fever 
and recurrent anemia.
Delayed hemolytic transfusion reac-
tions do not usually require specific intervention.
Transmission of Disease.
Malaria can be transmitted by 
all blood components.
The species most commonly implicated 
is Plasmodium malariae.
Cytomegalovirus (CMV) infection resembling 
infectious mononucleosis also has occurred.
Improved donor selection and testing are responsible for 
the decreased rates of transmission.
Common screening laboratory testing includes platelet 
count, PT or INR, and aPTT.
The normal platelet count 
ranges from 150,000 to 400,000/μL.
The 
PT test measures the function of factors I, II, V, VII, and X.
To account for these variations, the INR is 
now the method of choice for reporting PT values.
A template aids in administering a uniform test and 
adds to the reproducibility of the results.
The normal clot goes through accel-
eration and strengthening phase.
The clot forming in the cuvette trans-
mits its movement onto the suspended piston.
4-6).
Coagulation
LY
Fibrinolysis
R MA K
Angle
Figure 4-6.
Illustration of a thromboelastogram (TEG) tracing.
K = 
clot kinetics; LY = lysis; MA = maximal amplitude; R = reaction time.
104
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Several parameters are generated from the TEG tracing.
As 
such, the k-time is prolonged with hypofibrinogenemia and sig-
nificant factor deficiency.
Prolonged r-value and k-time are com-
monly addressed with plasma transfusions.
The alpha or angle 
(∝) is the slope of the tracing and reflects clot acceleration.
The 
angle reflects the interactions of clotting factors and platelets.
The slope is decreased with hypofibrinogenemia and platelet 
dysfunction.
Decreased angles are treated with cryoprecipitate 
transfusion or fibrinogen administration.
The maximal ampli-
tude (mA) is the greatest height of the tracing and represents clot 
strength.
Its height is reduced with dysfunction or deficiencies in 
platelets or fibrinogen.
The LY30 represents clot 
stability and when increased fibrinolysis is present.
Massive blood transfusion is a well-known cause of throm-
bocytopenia.
The first sign of a transfusion reaction may be 
diffuse bleeding.
Transfusion purpura occurs when the donor platelets are 
of the uncommon PlA1 group.
This is an uncommon cause of 
thrombocytopenia and associated bleeding after transfusion.
The platelets sensitize the recipient, who makes antibody to the 
foreign platelet antigen.
The antibody then destroys the 
recipient’s own platelets.
The resultant thrombocytopenia and 
bleeding may continue for several weeks.
Corticosteroids may be of some help 
in reducing the bleeding tendency.
Hemolysis appears to be one mechanism in sepsis leading 
to defibrination.
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This page intentionally left blank 
Shock
Brian S.
Zuckerbraun, Andrew B.
Peitzman, and 
Timothy R.
Hypovolemic 
shock, the most common type, results from loss of circulating 
blood volume.
This categorization of shock based on etiology persists 
today (Table 5-1).
This includes 
etiologies such as pulmonary embolism or tension pneumo-
thorax.
2 A central component of shock is decreased tissue perfusion.
This led to new methods of prolonged 
mechanical ventilation.
Our current concept of ARDS is a com-
ponent in the spectrum of multiple organ system failure.
Thus both 
inadequate and uncontrolled volume resuscitation is harmful.
5-1).
Furthermore, the pathophysiologic responses vary with 
time and in response to resuscitation.
This represents the compensated phase of shock.
Ischemia/reperfusion injury will often exacerbate the 
initial insult.
5-2).
Persistent 
hypoperfusion results in further hemodynamic derangements 
and cardiovascular collapse.
5-3).
Pathways leading to 
decreased tissue perfusion and shock.
3
112
BASIC CONSIDERATIONS
PART
 
I
Figure 5-2.
Figure 5-3.
The percentages shown above the curve 
represent survival rates.
Shock.
1998;10:343-
346.
Peripheral vasoconstriction occurs, and 
fluid excretion is inhibited.
The initial stimulus is loss of circulat-
ing blood volume in hemorrhagic shock.
The initial inciting event usually is loss of 
circulating blood volume.
Baroreceptors also are an important afferent pathway in 
initiation of adaptive responses to shock.
They become activated 
with low volume hemorrhage or mild reductions in right atrial 
pressure.
These receptors normally inhibit induction of the ANS.
Hemorrhage results in 
diminished venous return to the heart and decreased cardiac 
output.
These are compared 
in Table 5-2.
The arte-
rial vasoconstriction is not uniform; marked redistribution of 
blood flow results.
Increased sympathetic output induces catecholamine 
release from the adrenal medulla.
Catecholamine levels peak 
within 24 to 48 hours of injury and then return to baseline.
Hormonal Response.
ACTH subsequently 
stimulates the adrenal cortex to release cortisol.
Cortisol acts 
synergistically with epinephrine and glucagon to induce a 
catabolic state.
Cortisol causes retention of sodium 
and water by the nephrons of the kidney.
The renin-angiotensin system is activated in shock.
Potassium 
and hydrogen ions are lost in the urine in exchange for sodium.
Epinephrine, angiotensin II, pain, and hyperglycemia 
increase production of ADH.
Vasopressin also increases hepatic gluconeo-
genesis and increases hepatic glycolysis.
Proinflammatory cytokines 
also contribute to arginine vasopressin release.
At rest, the majority of the blood volume is within the 
venous system.
This increases venous return to the heart, thus maintain-
ing ventricular filling.
Most alterations in cardiac output in the normal heart are 
related to changes in preload.
These relatively slow responses maintain preload by 
altering circulating blood volume.
Ventricular Contraction.
This relationship is based on force of contraction being deter-
mined by initial muscle length.
Afterload.
Afterload is the force that resists myocardial work 
during contraction.
Arterial pressure is the major component 
of afterload influencing the ejection fraction.
This vascular 
resistance is determined by precapillary smooth muscle sphinc-
ters.
Blood viscosity also will increase vascular resistance.
Microcirculation.
The result is a loss of extracellular fluid volume.
This occurs via the breakdown of cellular glyco-
gen stores to pyruvate.
This is compared to complete 
oxidation of 1 mol of glucose that produces 38 mol of ATP.
There are numerous consequences secondary to these met-
abolic changes.
The depletion of ATP potentially influences all 
ATP-dependent cellular processes.
Furthermore, acido-
sis leads to changes in calcium metabolism and calcium signal-
ing.
Compounded, these changes may lead to irreversible cell 
injury and death.
Epinephrine and norepinephrine have a profound impact 
on cellular metabolism.
Cortisol, 
glucagon, and ADH also contribute to the catabolism during 
shock.
Under normal circumstances, cells can 
“repay” the O2 debt during reperfusion.
The magnitude of 
the O2 debt correlates with the severity and duration of hypo-
perfusion.
5-1).
5-4).
5-5).
Together these signals amplify the immune response 
Figure 5-4.
Cells require multiple inputs and stimuli before activation of a 
full response.
Multiple mediators have been implicated in the host 
immune response to shock.
A more comprehensive review can be 
found in Chap.
2.
Monocytes, macro-
phages, and T cells release this potent proinflammatory cyto-
kine.
During the stress response, TNF-α contributes to the 
muscle protein breakdown and cachexia.
Interleukin-1 (IL-1) has actions similar to those of 
TNF-α.
This cytokine 
also augments the secretion of ACTH, glucocorticoids, and 
β-endorphins.
Signaling via the pattern recognition receptor TLR4.
LPS signaling via TLR4 requires the cofactors LPS binding protein (LBP), 
MD-2, and CD14.
Shock.
IL-6 is elevated in response to hemorrhagic shock, major 
operative procedures, or trauma.
Elevated IL-6 levels correlate 
with mortality in shock states.
Chemokines bind to specific chemokine 
receptors and transduce chemotactic signals to leukocytes.
Activation of the comple-
ment cascade can contribute to the development of organ 
dysfunction.
Activated complement acts synergistically 
with endotoxin to induce the release of TNF-α and IL-1.
However, activated PMNs and their products 
may also produce cell injury and organ dysfunction.
Ischemia-reperfusion activates PMNs and causes PMN-induced 
organ injury.
Interactions between endothelial cells and leukocytes are 
important in the inflammatory process.
Cell Signaling
A host of cellular changes occur following shock.
119
S
HOCK
CHAPTER 5
intracellular energy metabolism.
Intracellular calcium (Ca2+) 
homeostasis and regulation represent one such pathway.
5-6).
These changes increase vaso-
constriction and peripheral arterial resistance.
Diagnosis.
Treatment of shock is initially empiric.
Such apparent clinical shock results 
from at least 25% to 30% loss of the blood volume.
(Reproduced with 
permission from Xiao W, Mindrinos MN, Seok J, et al.
A genomic 
storm in critically injured humans.
J Exp Med.
2011;208:2581–
2590.
© 2011 Xiao et al.
doi: 10.1084/jem.20111354.)
120
BASIC CONSIDERATIONS
PART
 
I
to bleeding (e.g., β-blockers).
However, only 59% of patients achieved a heart rate 
greater than 120 bpm.
The relationship between systolic blood pressure and mortality in trauma patients with hemorrhage.
Base deficit (BD) is also shown on this graph.
ED = emergency department.
J Trauma.
2007;63:291–297.)
with hemorrhage following trauma (Fig.
Patients with penetrating 
injuries who are in shock usually require operative intervention.
In the nontrauma patient, the GI tract must always be considered 
as a site for blood loss.
Direct pressure must be applied and 
Figure 5-8.
(From 
Peitzman et al,7 with permission.
The relationship between base deficit (negative base excess) and mortality in trauma patients.
BEA = base excess arterial; 
ECF = extracellular fluid.
(Reproduced with permission from Siegel JH, Rivkind AI, Dalal S, et al.
Early physiologic predictors of injury 
severity and death in blunt multiple trauma.
Arch Surg.
1990;125:498.
Copyright © 1990 American Medical Association.
All rights reserved.)
sustained to minimize ongoing blood loss.
In 
a more stable patient, a chest radiograph may be obtained to 
look for evidence of hemothorax.
Intraperitoneal hemorrhage is probably the most com-
mon source of blood loss inducing shock.
Treatment.
This probability increased approximately 1% for each 3 
minutes in the emergency department.
Initial resuscitation 
is limited to keep SBP around 80 to 90 mmHg.
This prevents 
renewed bleeding from recently clotted vessels.
In this setting, an SBP of 110 mmHg would seem to be more 
appropriate.
Mortality is inevitable once the patient manifests 
shock in its terminal stages.
Unfortunately, this is often diag-
nosed in retrospect.
5-11).
Figure 5-10.
RBC = red blood cell.
J 
Trauma.
Treatment of 
OR (95% CI) of tranexamic acid
Ti
me 
to
 tr
eatment (h)
0.5
8
7
6
5
4
3
2
1
0
1.
01 .5 2.0 2.5 3.0
Figure 5-11.
Early treatment (within 3 hours) of trauma patients with 
tranexamic acid reduces mortality.
However, later treatment exacer-
bated outcome.
OR = odds ratio.
The Lancet.
2011;377:1096-
1101.
This is not the characteristic response in vasodila-
tory shock.
The most frequently encoun-
tered form of vasodilatory shock is septic shock.
iNOS produces large quan-
tities of nitric oxide for sustained periods of time.
Diagnosis.
Hypoperfusion with signs of 
organ dysfunction is termed severe sepsis.
Treatment.
This resuscitation should be at 
least 30 mL/kg within the first 4 to 6 hours.
These situ-
ations may require multiple operations to ensure proper wound 
hygiene and healing.
Occasionally, patients 
with septic shock will develop arterial resistance to catechol-
amines.
Mortality in this group is high.
33.3%) compared to the 
standard therapy group.
10.3%).
103 mg/dL).
Surviving Sepsis Campaign Bundles
Figure 5-12.
Updated bundles of care 
from the Surviving Sepsis Campaign 
2012.
(From Dellinger RP, Levy MM, 
Rhodes A, et al.
Intensive Care Med.
2013;39:165-
228, Figure 1.
10 ± 11 days; P = .007).
Cardiogenic shock complicates 5% to 10% of acute MIs.
Although shock 
may develop early after MI, it typically is not found on admis-
sion.
Prevention of infarct extension is a critical component.
Myocardial diastolic function is 
impaired in cardiogenic shock as well.
Diagnosis.
Cardiac 
exam may include dysrhythmia, precordial heave, or distal heart 
tones.
Rela-
tively few patients with blunt cardiac injury will develop cardiac 
pump dysfunction.
Those who do generally exhibit cardiogenic 
shock early in their evaluation.
Treatment.
Electrolyte 
abnormalities, commonly hypokalemia and hypomagnesemia, 
should be corrected.
Pain is treated with IV morphine sulfate 
or fentanyl.
Titration of both dopamine and dobutamine infusions 
may be required in some patients.
Inva-
sive monitoring generally is necessary in these unstable patients.
Anticoagulation and aspirin are given for acute MI.
The major determinant of the 
degree of hypotension is the pericardial pressure.
Diagnosis and Treatment.
The diagnosis of tension pneu-
mothorax should be made on clinical examination.
Immediate return of air should be encountered with 
rapid resolution of hypotension.
Hyperresonance may be diffi-
cult to appreciate in a noisy resuscitation area.
Jugular venous 
distention may be absent in a hypovolemic patient.
Tracheal 
deviation is a late finding and often is not apparent on clinical 
examination.
A high index of suspicion is warranted to 
make a rapid diagnosis.
The indi-
cations for this maneuver are discussed in Chap.
7.
Beck’s triad consists of hypotension, muffled heart 
tones, and neck vein distention.
Echocardiogra-
phy has become the preferred test for the diagnosis of cardiac 
tamponade.
Pericardiocentesis to diagnose pericardial blood and potentially 
relieve tamponade may be used.
The procedure is best performed in the operating room 
under general anesthesia.
It can be performed through either the 
subxiphoid or transdiaphragmatic approach.
Diagnosis.
Treatment.
With prolonged anaerobic metabolism, tissue 
acidosis and O2 debt accumulate.
Clinical confirmation of this endpoint remains 
a challenge.
In addi-
tion, mortality was fourfold higher in patients who developed 
infections.
Direct measure-
ment of the O2 debt in the resuscitation of patients is difficult.
Lactate.
Base Deficit.
Gastric Tonometry.
Lactate and base deficit indicate global 
tissue acidosis.
With heterogeneity of blood flow, regional tissue 
beds may be hypoperfused.
Gastric tonometry has been used 
to assess perfusion of the GI tract.
The NIR probe 
emits multiple wavelengths of light in the NIR spectrum (650 
to 1100 nm).
Photons are then either absorbed by the tissue or 
reflected back to the probe.
13%).111,112
Tissue PH, Oxygen, and Carbon Dioxide Concentra-
tion.
Right Ventricular End-Diastolic Volume Index.
RVEDVI is a param-
eter that seems to correlate with preload-related increases in 
cardiac output.
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Surgical Infections
Greg J.
Beilman and David L.
In 1846, Ignaz Semmelweis, a Magyar physician, 
took a post at the Allgemein Krankenhaus in Vienna.
In 1861, he published his classic 
work on childbed fever based on records from his practice.
He died 
shortly thereafter.
His achievements were only recognized after 
Pasteur’s description of the germ theory of disease.
In spite of initial resis-
tance, his methods were quickly adopted throughout Europe.
He used 
these same techniques to identify the organisms responsible for 
cholera and tuberculosis.
2 Source control is a key concept in the treatment of most surgi-
cally relevant infections.
Delays in adequate source control are associated with wors-
ened outcomes.
Barrier function, however, is not solely limited 
to physical characteristics.
Host barrier cells may secrete sub-
stances that limit microbial proliferation or prevent invasion.
In the upper 
respiratory tract, respiratory mucus traps larger particles, includ-
ing microbes.
This results in recruitment 
and proliferation of inflammatory cells.
Macrophage cytokine 
synthesis is upregulated.
A chronic abscess also may 
intermittently drain and/or be associated with bacteremia.
Infection is defined by the presence of microorganisms 
in host tissue or the bloodstream.
6-1).
1
139
S
URGICAL
 I
N
fe
CTIONS
CHAPT
e
R 6
figure 6-1.
Relationship between infection and 
systemic inflammatory response syndrome (SIRS).
Other conditions 
may cause SIRS as well (trauma, aspiration, etc.).
Severe sepsis (and septic shock) are both subsets 
of sepsis.
above normal value
Plasma procalcitonin >2 s.d.
= standard deviations; Svo2 = venous oxygen 
saturation; WBC = white blood cell count.
Bacteria
Bacteria are responsible for the majority of surgical infections.
Specific species are identified using Gram’s stain and growth 
characteristics on specific media.
tetani, C.
septicum
Peptostreptococcus spp.
Gram-negative
Bacteroides fragilis
Fusobacterium spp.
niger, A.
terreus, A.
flavus
Blastomyces dermatitidis
Candida albicans
Candida glabrata, C.
paropsilosis, C.
Other acid-fast bacilli 
include Nocardia spp.
37°C).
Agents currently available for antifungal therapy are 
described in Table 6-3.
Prophylactic and therapeutic use of antiviral 
agents is discussed in Chap.
11.
Guidelines for prophylaxis are provided in Table 6-5.
Initial drug 
selection must be based on initial evidence (Gram-positive vs.
This is safe, and may facilitate earlier discharge.
PYOGeNeS mSSA mrSA S.
ePIDermIDIS eNTerOCOCCUS Vre e.
COlI P.
PYOGeNeS mSSA mrSA S.
ePIDermIDIS eNTerOCOCCUS Vre e.
COlI P.
1 = Reliable activity; +/– = variable activity; 0 = no activity.
The sensitivities presented are generalizations.
Allergy to antimicrobial agents must be considered prior 
to prescribing them.
Penicillin allergy is quite common, the reported inci-
dence ranging from 0.7% to 10%.
Each of these factors has been directly correlated 
with overall drug administration.
Prolonged 
treatment associated with drains and tubes has not been shown 
to be beneficial.
Table 6-6 lists risk factors for development of 
SSIs.
Class I D wounds are similar except that a prosthetic device 
(e.g., mesh or valve) is inserted.
Several of these 
organizations are noted in Table 6-8.
However, the effect of 
this approach on the incidence of SSIs is not known at this time.
figure 6-2.
6-2).
The treatment of organ/space infections is 
discussed in the following section.
These infections invariably are monomi-
crobial and rarely require surgical intervention.
In 
patients without this risk factor organisms can include E.
coli, 
K.
pneumoniae, pneumococci, and others, although many 
different pathogens can be causative.
Candida albicans and other related yeast cause the majority 
of fungal hepatic abscesses.
Splenic 
abscesses are extremely rare and are treated in a similar fashion.
6-3).
Mortal-
ity in 65 patients in 9 case series reported was 6% overall.
Debridement of necrosis through a lumbar approach has 
been advocated by a number of authors.
Patients receive 
transgastric or preferably retroperitoneal drainage of the seques-
trum.
6-4).
69%), with comparable mortality rate, 
hospital, and ICU lengths of stay.
Furuncles 
or boils may drain spontaneously or require surgical incision and 
drainage.
Infected pancreatic necrosis.
(A) Open necrosectomy 
specimen with pancreatic stent in situ.
(C) Retroperitoneal cavity seen through endoscope during VARD.
exogenous microbes, the result can be devastating.
Not surprisingly, patients often develop sepsis syndrome 
or septic shock without an obvious cause.
The extremities, 
perineum, trunk, and torso are most commonly affected, in that 
order.
6-5).
During the procedure a Gram’s stain should be performed 
on tissue fluid.
If so, additional resection of infected tis-
sue and debridement should take place.
The patient succumbed to his disease after 16 hours despite aggressive debridement.
Cellulitis on right anterior thigh is 
outlined.
(C) Classic dishwater edema of tissues with necrotic fascia.
(D) Right lower extremity after debridement of fascia to viable muscle.
or >105 CFU/mL in asymptomatic individuals.
Coli, K.
pneumonia) that achieves 
high levels in the urine is appropriate.
Prolonged mechanical ventilation is associated with nos-
ocomial pneumonia.
This rate is expected to increase as the 
population of aged in the United States increases.
As discussed earlier, one exception is that of 
infected pancreatic necrosis.
The current 
first-line agent for treatment of hypotension is norepinephrine.
However, a recent randomized trial 
failed to show survival benefit.
Resistant Organisms: In the 1940s, penicillin was first pro-
duced for widespread clinical use.
There are two major components that are responsible 
for antibiotic resistance.
Target resuscitation to normalize lactate in patients with elevated lactate levels.
Diagnosis: Obtain appropriate cultures prior to antibiotics but do not delay antibiotic therapy.
Use rapid antigen assays in patients 
with suspected fungal infection.
Imaging studies should be performed promptly to confirm a source of infection.
Discontinue antibiotics in 7–10 d for most infections, stop antibiotics for noninfectious issues.
Remove intravascular access devices if potentially infected.
Infection prevention: Selective oral and digestive tract decontamination.
Phenylephrine is 
not recommended in treatment of septic shock.
Dobutamine infusion can be used in setting of myocardial dysfunction.
Do not use 
strategy of targeting supranormal cardiac index.
Use positive end-expiratory pressure to avoid lung collapse.
Use a weaning protocol to evaluate the 
potential for discontinuing mechanical ventilation.
Pulmonary artery catheter is not indicated for routine monitoring.
Sedation: Minimize sedation using specific titration endpoints.
Adapted from Dellinger et.
al13
the antibiotic will not be effective against this organism.
The second com-
ponent driving resistance is that related to antibiotic selection.
This has led to antibiotic resistance described 
in all classes of antibiotics in common use today.
Resistance mechanisms are varied, and include one of 
three routes.
There are several drug resistant organisms of interest to 
the surgeon.
The 
appropriate antibiotic choice in this setting is a carbepenem.
Hepatitis B virus (HBV) is a DNA virus that affects only 
humans.
This virus is confined to humans and 
chimpanzees.
Several potential 
agents are discussed in the following sections.
A key aspect 
in establishing the diagnosis is eliciting an exposure history.
Rapid antigen tests are currently under development for iden-
tification of this gram-positive rod.
Yersinia pestis (Plague)
Plague is caused by the Gram-negative organism Yersinia pes-
tis.
The naturally occurring disease in humans is transmitted via 
flea bites from rodents.
Postexposure prophylaxis for 
patients exposed to plague consists of doxycycline.
The fatality rate may reach 30%.
After inoculation, this organism proliferates within 
macrophages.
Enlarged 
lymph nodes occur in approximately 85% of patients.
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Homicides, suicides, and other causes are responsible for 
another 50,000 deaths each year.
However, death rate under-
estimates the magnitude of the societal toll.
For these reasons, trauma must be considered 
a major public health issue.
The ATLS 
format and basic tenets are followed throughout this chapter, 
with some modifications.
Soft collars do not effectively immo-
bilize the cervical spine.
7  The abdomen is a diagnostic black box.
Altered 
mental status is the most common indication for intubation.
Options for endotracheal intubation include nasotracheal, 
orotracheal, or operative routes.
Nasotracheal intubation can 
be accomplished only in patients who are breathing spontane-
ously.
Orotracheal 
intubation is the preferred technique used to establish a defini-
tive airway.
13).
Crico-
thyroidotomy (Fig.
The 
cricothyroid membrane is verified by digital palpation and 
opened in a horizontal direction.
Cricothyroidotomy is recommended for emergent 
surgical establishment of a patent airway.
Hemorrhage from these vessels obscures 
vision and prolongs the procedure.
A.
Use of 
a tracheostomy hook stabilizes the thyroid cartilage and facilitates 
tube insertion.
B.
A 6.0 endotracheal tube is inserted after digital 
confirmation of airway access.
of the airway.
7-2).
All 
injured patients should receive supplemental oxygen and be 
monitored by pulse oximetry.
All of these diag-
noses should be made during the initial physical examination.
7-3).
A
B
164
BASIC CONSIDERATIONS
PART
 
I
accumulate in the pleural space.
7-4).
Flail chest occurs when three or more contiguous ribs are 
fractured in at least two locations.
However, the additional work of breathing 
Figure 7-3.
A.
B.
Heavy scissors 
are used to cut through the intercostal muscle into the pleural space.
C.
D.
A 28F chest tube is directed superiorly and posteriorly with the aid 
of a large clamp.
Figure 7-4.
A.
Full-thickness loss of the chest wall results in an 
open pneumothorax.
B.
and chest wall pain caused by the flail segment is rarely suf-
ficient to compromise ventilation.
Pulmonary contusion often progresses during the first 
12 hours.
Resultant hypoventilation and hypoxemia may require 
intubation and mechanical ventilation.
7-5); close monitoring and frequent 
clinical re-evaluation are warranted.
Massive air leak occurs from major tracheobronchial 
injuries.
Bronchoscopy confirms diagnosis 
and directs management.
An initial approximation of the patient’s cardiovascular 
165
T
RAUMA
CHAPTER 7
Figure 7-5.
A.
Admission chest film may not show the full extent 
of the patient’s pulmonary parenchymal injury.
B.
Figure 7-6.
A.
The proximal tibia is the preferred location.
Alterna-
tively, the distal femur can be used if the tibia is fractured.
B.
The 
needle should be directed away from the epiphyseal plate to avoid 
injury.
Figure 7-7.
Saphenous vein cutdowns are excellent sites for fluid 
resuscitation access.
A.
The vein is consistently found 1 cm ante-
rior and 1 cm superior to the medial malleolus.
B.
Proximal and 
distal traction sutures are placed with the distal suture ligated.
C.
A 14-gauge IV catheter is introduced and secured with sutures and 
tape to prevent dislodgment.
status can be obtained by palpating peripheral pulses.
Saphenous 
vein cutdowns at the ankle provide excellent access (Fig.
7-7).
The saphenous vein is reliably found 1 cm anterior and 1 cm 
superior to the medial malleolus.
Figure 7-8.
More than 1500 mL of blood in the pleural space is considered a massive hemothorax.
Chest film findings reflect the positioning 
of the patient.
A.
B.
In the upright position, blood is visible dependently in the right pleural space.
7-8).
After pen-
etrating trauma, a great vessel or pulmonary hilar vessel injury 
should be presumed.
This ultimately leads to decreased right ventricular out-
put.
Diagnosis of hemopericardium is best achieved by bedside 
ultrasound of the pericardium (Fig.
7-9).
7-10).
Subxiphoid pericardial ultrasound reveals a large peri-
cardial fluid collection.
Figure 7-10.
Pericardiocentesis is indicated for patients with evidence of pericardial tamponade.
A.
B.
Seldinger technique 
is used to place a pigtail catheter.
Blood can be repeatedly aspirated with a syringe or the tubing may be attached to a gravity drain.
The utility of RT has been debated for decades.
For all 
penetrating wounds, survival rate is 15%.
7-11).
7-12).
7-13).
Scores range 
from 3 (the lowest) to 15 (normal).
Scores of 13 to 15 indicate 
mild head injury, 9 to 12 moderate injury, and ≤8 severe injury.
No
Tamponade?
ECG = electrocardiogram; OR = operating room; SBP = systolic blood pressure.
Neurologic evaluation is critical before administration of 
neuromuscular blockade for intubation.
Deterioration in mental status may be subtle and may 
not progress in a predictable fashion.
The goal of fluid 
resuscitation is to re-establish tissue perfusion.
The details of a MTP are discussed later.
A.
B and C.
D.
Figure 7-13.
Urine output is a quantitative, reliable indicator of organ per-
fusion.
There are several caveats to be considered when evaluating 
the injured patient for shock.
Scores range from 3 (the lowest) to 15 (normal).
This group of patients can be challenging to triage for definitive 
management.
Evaluation of the CVP may further assist in distinguish-
ing between these two categories.
A patient with distended neck 
veins and a CVP of >15 cm H2O is likely to be in cardiogenic 
shock.
Air embolism is a frequently overlooked lethal complica-
tion of pulmonary injury.
7-14).
Persistent hypotension due to uncontrolled hemorrhage is 
associated with high mortality.
Type-specific RBCs should be 
administered as soon as available.
A.
B.
patient transported to the OR immediately.
7-15).
Fracture-related blood loss, when additive, may 
Figure 7-15.
This dilemma is becoming less common in 
many trauma centers where CT scanning is done in the ED.
Gross hematuria demands evaluation of the genitourinary sys-
tem for injury.
For patients with 
severe blunt trauma, chest and pelvic radiographs should be 
obtained.
Limited one-shot extremity radio-
graphs also may be taken.
For 
less severely injured patients only a complete blood count and 
urinalysis may be required.
Repeat FAST is performed if there are any signs of 
abdominal injury or unexplained blood loss.
Many trauma patients cannot provide specific information 
about the mechanism of their injury.
For patients with stab wounds, the length and type 
of object is helpful.
Finally, some patients experience a com-
bination of blunt and penetrating trauma.
High-velocity gun-
shot wounds (bullet speed >2000 ft/s) are infrequent in the 
civilian setting.
Shotgun injuries are divided into close-range 
(<20 feet) and long-range wounds.
Hemodynamic, respiratory, and men-
tal status will determine the most appropriate course of action.
With these issues in mind, additional diagnostic tests are dis-
cussed on an anatomic basis.
A lateral canthotomy may be needed to relieve 
periorbital pressure.
Anterior facial structures should be examined to rule out 
fractures.
Nasal packing or balloon tamponade may 
be necessary to control bleeding.
7-16).
Hemorrhage into the subarachnoid space may cause vasospasm 
and further reduce cerebral blood flow.
Intraparenchymal hema-
tomas and contusions can occur anywhere within the brain.
7-17).
During cervi-
cal examination one must maintain cervical spine precautions 
Figure 7-16.
Figure 7-17.
A.
A right middle 
cerebral infarct noted on a computed 
tomographic scan of the head.
B.
An inter-
nal carotid artery pseudoaneurysm 
documented by angiography.
BA
and in-line stabilization.
Spinal cord injuries can vary in severity.
Complete injuries 
cause either quadriplegia or paraplegia, depending on the level 
of injury.
Significant 
neurologic recovery is rare.
Central cord syndrome typically occurs in older persons 
who experience hyperextension injuries.
Some functional recov-
ery usually occurs, but is often not a return to normal.
Prognosis for recovery is poor.
A more sub-
tle injury that may not be identified is a fracture of the larynx 
due to blunt trauma.
Signs and symptoms include hoarseness, 
subcutaneous emphysema (Fig.
7-18), and a palpable fracture.
The management 
Figure 7-18.
Figure 7-19.
Algorithm for the management of penetrating neck injuries.
CT = computed tomography; CTA = computed tomographic 
angiography; GSW = gunshot wound.
7-20).
Figure 7-21.
I
II
III
Figure 7-20.
For the purpose of evaluating penetrating injuries, 
the neck is divided into three zones.
Zone I is to the level of the 
clavicular heads and is also known as the thoracic outlet.
Zone II is 
located between the clavicles and the angle of the mandible.
Zone 
III is above the angle of the mandible.
7-21).
7-22).
Other chest radiographic findings suggestive of an 
aortic tear are summarized in Table 7-5 (Fig.
7-23).
7-24).
Injuries of the 
esophagus and trachea are exceptions.
Widened mediastinum
2.
Abnormal aortic contour
3.
Tracheal shift
4.
Nasogastric tube shift
5.
Left apical cap
6.
Left or right paraspinal stripe thickening
7.
Depression of the left main bronchus
8.
Obliteration of the aorticopulmonary window
9.
Left pulmonary hilar hematoma
Figure 7-22.
Figure 7-23.
179
T
RAUMA
CHAPTER 7
and directs angiography or endoscopy as appropriate.
Abdomen The abdomen is a diagnostic black box.
Fortunately, 
with few exceptions, it is not necessary to determine in the 
Figure 7-24.
The diagnostic approach differs for penetrating trauma 
and blunt abdominal trauma.
As a rule, minimal evaluation is 
7
180
BASIC CONSIDERATIONS
PART
 
I
Figure 7-25.
Algorithm for the evaluation of penetrating abdominal injuries.
7-25).
Laparoscopy is another option to assess peritoneal 
penetration for tangential wounds.
If there is doubt, however, 
it is always safer to explore the abdomen.
** A positive local wound exploration is defined as violation of the posterior fascia.
CT
Scan
Left-sided thoracoabdominal DPL vs.
Penetrating thoracoabdominal wounds may cause occult 
injury to the diaphragm.
7-26).
7-27) in Morrison’s pouch, 
the left upper quadrant, and the pelvis.
7-28).
Algorithm for the initial evaluation of a patient with suspected blunt abdominal trauma.
stable patients for whom the physical examination is unreliable.
If DPL is 
pursued, an infraumbilical approach is used (Fig.
7-29).
The aspirate is considered to show positive find-
ings if >10 mL of blood is aspirated.
If <10 mL is withdrawn, a 
liter of normal saline is instilled.
Values representing positive find-
ings are summarized in Table 7-6.
Pelvis Blunt injury to the pelvis may produce complex frac-
tures with major hemorrhage (Fig.
7-30).
Sharp spicules of bone can lac-
erate the bladder, rectum, or vagina.
CT cystography is performed if the urinalysis findings are 
positive for RBCs.
Bony fractures or 
knee dislocations should be realigned before definitive vascular 
examination.
7-31).
It is known that some of these patients 
will have arterial injuries that require repair.
The most common 
Figure 7-27.
Focused abdominal sonography for trauma imaging detects intra-abdominal hemorrhage.
If the difference is >10%, 
CT angiography or arteriography is indicated.
If hemorrhage occurs from 
these injuries, compartment syndrome and limb loss may occur.
partial nephrectomy.
Specific transfusion triggers 
Figure 7-29.
A.
The linea alba is sharply incised, and the catheter is directed into the pelvis.
B.
The abdominal contents should initially be aspirated 
using a 10-mL syringe.
for individual blood components exist.
However, these guidelines have 
been replaced by TEG and ROTEM criteria in many trauma 
centers.
7-32).
Massive transfusion 
185
T
RAUMA
CHAPTER 7
Figure 7-30.
This concept has been termed .
Extended postoperative antibiotic therapy is adminis-
tered only for contaminated open fractures.
Tetanus prophylaxis 
is administered to all patients according to published guidelines.
Trauma patients are at risk for venous thromboembolism 
and its associated morbidity and mortality.
Morbidly obese patients and those over 55 years of age are at 
additional risk.
A final prophylactic measure that is usually not consid-
ered is thermal protection.
Each shipment’s quantity 
can be doubled at the request of Surgery or Anesthesia.
Shipments > 4 are determined by patient’s clinical course 
and lab values.
Shipment     PRBCs FFP Platelets Cryo
14
2
3 4
44
4 2
2
2
2
1
1
10
10
Figure 7-32.
Denver Health Medical Center’s Massive Transfusion Protocol.
187
T
RAUMA
CHAPTER 7
problem.
Hypothermia aggravates coagulopathy and provokes myocar-
dial irritability.
7-33).
Figure 7-33.
A.
B.
C.
Further exposure is facilitated by resection of the posterior belly of the 
digastric muscle.
7-33).
The glossopharyngeal and vagus 
nerves are also mobilized and retracted as necessary.
If acces-
sible, the styloid process and attached muscles are removed.
At 
this point anterior displacement of the mandible (subluxation) 
may be helpful.
In desperate situations, the vertical ramus of the 
mandible may be divided.
The location of the incision is in the 
fifth interspace, in the inframammary line (Fig.
7-34).
7-35).
If the sternum is divided, the 
internal mammary arteries should be ligated to prevent blood 
loss.
Emergent median sternotomy is 
limited to anterior stab wounds to the heart.
Patients in extremis, however, should undergo 
anterolateral thoracotomy.
1
2
3
B
Figure 7-34.
Figure 7-35.
A.
A “clamshell” thoracotomy provides exposure to 
bilateral thoracic cavities.
B.
For children under the age of 6, a transverse 
incision may be advantageous.
7-36).
7-37).
Similarly, clamping 
the splenic hilum may more effectively control bleeding than 
packing alone.
7-38).
The first decision is whether the patient 
has a supracolic or an infracolic vascular injury.
7-39).
The left 
Figure 7-36.
A sagittal view of packs placed to control hepatic 
hemorrhage.
Lap = laparotomy.
Figure 7-37.
Figure 7-38.
With complete mobilization, the spleen can reach the 
level of the abdominal incision.
The operative approach for 
SMA injuries is based on the level of injury.
More distal SMA injuries, Fullen zones III and IV, 
are approached directly within the mesentery.
Inferior vena cava injuries are approached by 
a right medial visceral rotation (Fig.
7-40).
A Satinsky 
clamp can be used to control anterior caval wounds.
Tamponade with a folded laparotomy pad 
Figure 7-39.
A left medial visceral rotation is used to expose the 
abdominal aorta.
Figure 7-40.
A right medial visceral rotation is used to expose the 
infrahepatic vena cava.
Figure 7-41.
Pelvic vascular isolation.
A.
B.
Alter-
natively, complete pelvic vascular isolation (Fig.
7-42).
Associated hematomas 
should be unroofed to rule out adjacent bowel injury.
Duodenal injuries should be evaluated with a wide Kocher 
maneuver.
The skin is closed selectively based on 
the amount of intra-abdominal contamination.
Ragged 
edges of the injury site should be débrided using sharp dissec-
tion.
Figure 7-42.
Options for the treatment of vascular injuries are listed 
in Table 7-9.
In the lower extremities, 
at least one artery with distal runoff should be salvaged.
Follow-up imag-
ing is performed 1 to 2 weeks after injury to confirm healing.
The SMV should be repaired optimally, but 
>80% of patients will survive following ligation.
The type of operative repair for a vascular injury is based 
on the extent and location of injury.
Lateral suture repair is pre-
ferred for arterial injuries with minimal loss of tissue.
7-43).
7-44).
Larger arteries (e.g., subclavian, innomi-
nate, aorta, common iliac) are bridged by PTFE grafts.
Figure 7-44.
Traction 
must be maintained on both ends of the suture to prevent loosening 
and leakage of blood.
Six stitches should be placed before the graft 
is pulled down to the artery.
Figure 7-43.
Small arteries repaired with an end-to-end anastomo-
sis are prone to stricture.
A curved 
hemostat is a useful adjunct to create the curve.
7-45).
Injuries of the common and external 
iliac arteries can be handled in a similar fashion (Fig.
7-46), 
while maintaining flow in at least one internal iliac artery.
Venous injuries are inherently more difficult to reconstruct 
due to their propensity to thrombose.
Small injuries without loss 
of tissue can be treated with lateral suture repair.
In the remainder of venous 
injuries the vein may be ligated.
Controlling surgical bleeding while 
preventing ischemia is of utmost importance during DCS.
Aor-
tic injuries must be repaired using an interposition PTFE graft.
Venous injuries are Figure 7-45.
Figure 7-46.
A.
Right common iliac artery transposed to left common iliac artery.
B.
Left 
internal iliac artery transposed to the distal right common iliac artery.
C.
Right internal iliac artery transposed to the right external iliac artery.
The bloody vicious cycle.
FFP = fresh-frozen plasma; RBC = red blood cell.
tamponade bleeding (see Fig.
7-36).
7-48).
For thoracic injuries requiring DCS several options exist.
For 
Figure 7-48.
A.
B.
Once placed inside the injury tract, the balloon is inflated 
with saline until hemorrhage stops.
C.
In penetrating injuries, pulmonary trac-
totomy is used to divide the parenchyma (Fig.
Pledgeted repair should be 
performed for the relatively thin right ventricle.
The second key component of DCS is limiting enteric 
content spillage.
Alternatively, open ends of 
the bowel may be ligated using umbilical tapes to limit spill-
age.
Urologic injuries 
may require catheter diversion.
Before the patient is returned 
to the SICU, the abdomen must be temporarily closed.
7-50).
Figure 7-49.
The opened track permits direct 
access to injured vessels or bronchi for individual ligation.
The burr 
hole is made on the side of the dilated pupil to decompress the 
intracranial space.
Resuscitation efforts aim for a euvolemic state and an SBP of 
>100 mm Hg.
A burr hole is made for decompression of an epidural 
hematoma as a life-saving maneuver.
No attempt should be made to control intracranial hemor-
rhage through the burr hole.
Figure 7-52.
(Image used with permission from Vincent D.
Eusterman, 
MD, DDS.)
posterior nasal bleeding, and oropharyngeal packing.
Prompt 
angioembolization will halt exsanguinating hemorrhage.
7-52).
Urgent decompression in acute cervical spinal cord 
injury is safe.
Prompt revascularization of the internal carotid artery, using a 
Figure 7-53.
The Denver grading scale for blunt cerebrovascular injuries.
Grade III: pseudoaneurysm.
Grade IV: vessel occlusion.
Grade V: vessel transection.
CAI = carotid 
artery injury; VAI = vertebral artery injury.
temporary Pruitt-Inahara shunt, should be considered in patients 
arriving in profound shock.
Currently, we 
administer heparin with an ACT target of 250 sec.
Screening and treatment algorithm for blunt cerebrovascular injuries (BCVIs).
(aspirin 325 mg/d or clopidogrel 75 mg/d).
Aerodigestive Subclinical fractures of the larynx and trachea 
may manifest as cervical emphysema.
Fractures documented by 
CT scan are usually repaired.
More than 
85% of patients can be definitively treated with a chest tube.
One caveat concerns 
the patient who presents after a delay.
7-55).
Descending thoracic aortic injuries may require urgent 
if not emergent intervention.
A.
Angiography reveals a 1-cm pseudoaneurysm of the innominate artery origin.
B.
C.
The origin of the innominate is then oversewn at its base to exclude the pseudoaneurysm.
While 
endograft sizing has improved, the major question is long-term 
outcome in younger patients.
7-56).
However, primary arterial repair should be done when possible.
LA
Figure 7-56.
Figure 7-57.
A variety of techniques 
may be necessary to repair cardiac 
wounds.
Generally, pledget support 
is used for the relatively thin-walled 
right ventricle.
Principles of repair are similar to those 
for repair of cervical tracheal injuries.
The most common complication after thoracic injury is 
development of an empyema.
While fibrinolytics 
are often used for empyema there is a paucity of data to support 
their use.
Operative options are 
based on the extent and location of esophageal injury.
Early institution of effective pain control 
is essential.
The current role of opera-
tive rib fixation remains controversial.
7-58).
1 polypropylene 
suture.
The only absolute contraindication to nonopera-
tive management is hemodynamic instability.
With extensive injuries and 
major hemorrhage a Pringle maneuver should be done immedi-
ately.
Intermittent release of the Pringle is helpful to attenuate 
hepatic cellular loss.
Hemorrhage from most major hepatic injuries can be controlled 
with effective perihepatic packing.
7-36).
A Pringle maneuver can help delineate the source of hemor-
rhage.
Injuries of the portal triad vasculature should be addressed 
immediately.
In general, ligation from the celiac axis to the 
Figure 7-58.
If the right hepatic artery is 
ligated, cholecystectomy also should be performed.
Place-
ment of a hepatic vein stent by interventional radiology may 
be considered.
Minor lac-
erations may be controlled with manual compression applied 
directly to the injury site.
Caution must be used to prevent hepatic 
necrosis.
Omen-
tum can be used to fill large defects in the liver.
Additionally, the omentum can provide buttressing support for 
parenchymal sutures.
Injuries 
of the extrahepatic bile ducts are a challenge due to their small 
size and thin walls.
These factors may preclude primary repair.
Venovenous bypass permits hepatic vascular isola-
tion with continued venous return to the heart.
IMV = inferior mes-
enteric vein; IVC = inferior vena cava; SMV = superior mesenteric 
vein.
Alternatively, the duct can be ligated 
if the opposite lobe is normal and uninjured.
Earlier exploration may be indi-
cated in patients with evidence of ongoing hemorrhage.
Alternatively, angioembolization is appropri-
ate for complex injuries.
Although febrile patients should be 
Figure 7-60.
7-60).
Bilomas are loculated collections of bile, which may or may not 
be infected.
If infected, they should be treated like an abscess 
via percutaneous drainage.
Primary 
repair of the injured intrahepatic duct is unlikely to be success-
ful.
Pseudoaneurysms and biliary fistulas are rare complica-
tions in patients with hepatic injuries.
Spleen Until the 1970s, splenectomy was considered manda-
tory for all splenic injuries.
The authors use autotrans-
plantation of splenic implants (Fig.
Drains are not used.
Hemorrhage from the raw splenic 
Figure 7-61.
Figure 7-62.
Interrupted pledgeted sutures may effectively control 
hemorrhage from the cut edge of the spleen.
7-62).
Gastric wounds can be oversewn 
with a running single-layer suture line or closed with a stapler.
The most commonly missed gastric injury is the poste-
rior wound of a totally penetrating injury.
Alternatively, air can be introduced via the NG 
tube with the abdomen filled with saline.
26).
Following repair of GI tract injuries, there is an obligatory 
postoperative ileus.
Return of bowel function is indicated by a 
decrease in gastrostomy or nasogastric tube output.
The topic of 
nutrition is well covered in other chapters, but a few issues war-
rant mention.
The wound should be closed in a direc-
tion that results in the largest residual lumen.
Challenges arise 
when there is a substantial loss of duodenal tissue.
7-63).
Otherwise, 
208
BASIC CONSIDERATIONS
PART
 
I
Figure 7-64.
Figure 7-63.
cholangiography, optimally via the cystic duct, is diagnostic.
7-64).
In these cases of extensive injuries, damage 
control principles are often employed.
Several options exist for treating injuries of the 
pancreatic body and tail.
In stable patients, spleen-preserving 
distal pancreatectomy should be performed.
An alternative, 
209
T
RAUMA
CHAPTER 7
Figure 7-65.
A.
B and C.
The authors frequently use needle-catheter jejunostomy tube feedings for these patients.
Application of fibrin glue over the stump may be advantageous.
A gastrojejunos-
tomy restores GI tract continuity.
Vagotomy is not necessary 
because a risk of marginal ulceration has not been documented.
Perhaps surprisingly, the sutures maintain diversion for only 3 
to 4 weeks.
Complications should be expected after major pancreati-
coduodenal injuries.
33).
33).
Intra-abdominal abscesses are common and routinely managed 
with percutaneous drainage.
All sutur-
ing and anastomoses are performed using a running single-layer 
technique (Fig.
Diverting ileostomy with colocolostomy, however, 
is used for most other high-risk patients.
Therefore, indirect 
treatment with intestinal diversion usually is required.
The cur-
rent options are loop ileostomy and sigmoid loop colostomy.
7-67).
7-67).
29).
Due to lack 
of mobility of the abdominal aorta, few injuries are amenable 
to primary repair.
Figure 7-66.
Technique for bowel repair and anas-
tomosis.
A.
The running, single-layer suture is started 
at the mesenteric border.
B.
C.
The continuous suture is tied near the antimesenteric 
border.
Patients requiring 
Figure 7-67.
Loop colostomy will completely divert 
the fecal flow, allowing the low rectal injury to heal.
ligation of an inferior vena cava injury often develop marked 
bilateral lower extremity edema.
Consequently, long-term administration of antiplatelet 
agents or antithrombotics is not routine.
7-68).
Arterial reconstruction using 
graft interposition should be attempted for renal preservation.
Over 90% of blunt renal injuries are treated nonopera-
tively.
Vascular occlusion con-
trols bleeding and permits adequate 
visualization.
B.
The renal capsule is 
carefully preserved.
C.
The collect-
ing system is closed separately with 
absorbable suture.
D.
The preserved 
capsule is closed over the collecting 
system repair.
irrigation to dispel blood clots is warranted.
The renal arteries 
and veins are uniquely susceptible to traction injury caused 
by blunt trauma.
The renal vein may be torn or completely 
avulsed from the vena cava due to blunt trauma.
Typically, the 
large hematoma causes hypotension, which leads to operative 
intervention.
Techniques of repair and hemostasis are similar to 
those described earlier.
An 
injury may not be identified until a complication (i.e., a uri-
noma) becomes apparent.
Laparoscopic repair is becoming common in 
patients not requiring laparotomy for other injuries.
Extraperito-
neal ruptures are treated nonoperatively with bladder decompres-
sion for 2 weeks.
Strictures are not uncommon but can be managed electively.
Female Reproductive Tract Gynecologic injuries are rare.
Occasionally the vaginal wall will be lacerated by a bone frag-
ment from a pelvic fracture.
Although repair is not mandated, 
it should be performed if physiologically feasible.
7-69).
In high risk patients, (e.g.
7-70).
Pelvic packing also eliminates the often 
difficult decision by the trauma surgeon: OR vs.
interventional 
radiology?
Currently, angiography is reserved for patients with evidence of 
Figure 7-69.
Management algorithm for patients with pelvic fractures with hemodynamic instability.
Another clinical challenge is the open pelvic fracture.
To reduce 
the risk of infection, performance of a diverting sigmoid colos-
tomy is recommended.
Vascular injuries, either isolated or in combination with 
fractures, require emergent repair.
Controversy exists regarding which 
should be done first, fracture fixation or arterial repair.
For subclavian or axillary artery repairs, 6-mm PTFE 
Figure 7-70.
A.
B.
C.
215
T
RAUMA
CHAPTER 7
graft and RSVG are used.
The injured vessel segment is excised, and 
an end-to-end interposition RSVG graft is performed.
Close monitoring for calf compartment syndrome 
is mandatory.
7-71).
Rarely, with 
open wounds a straight posterior approach with an S-shaped 
incision can be used.
For an isolated popliteal 
artery injury, RSVG is performed with an end-to-end anastomosis.
Paresthesias may 
also be described.
Progression to paralysis can 
occur, and loss of pulses is a late sign.
In comatose or obtunded 
patients, the diagnosis is more difficult to secure.
7-72).
Step 2:   Intra-arterial nitroglycerin 200 μg/20 mL bolus
Repeat same dose once as needed.
If spasm continues, proceed to step 3.
Step 3:   Inter-arterial verapamil 10 mg/10 mL bolus
If spasm continues, proceed to step 4.
Step 4:   Inter-arterial papaverine drip 60 mg/50 mL given 
 over 15 min
Figure 7-71.
A.
B.
Alternatively, a medial approach with two incisions may be used.
216
BASIC CONSIDERATIONS
PART
 
I
and priorities.
In fact, optimizing crystalloid administra-
Figure 7-72.
A.
Care must be 
taken to avoid the superficial pero-
neal nerve running along the raphe.
B.
The role of rela-
tive adrenal insufficiency is another controversial area.
The goal is to normalize lactate within 24 hours.
The most common intra-abdominal complica-
tions are anastomotic failure and abscess.
The most 
common technique is to measure the patient’s bladder pressure.
Increased abdominal pressure affects multiple organ sys-
tems (Fig.
7-73).
Organ failure can occur over a wide range 
of recorded bladder pressures.
This method is particularly applicable for 
nonoperative management of major liver injuries.
7-50).
Several management points deserve attention.
Patients with an open abdomen lose between 
500 and 2500 mL per day of abdominal effluent.
colloid).
The advent of VAC 
technology has revolutionized fascial closure.
7-74).
128 The 
authors’ success rate with this approach exceeds 95%.
These include intra-abdominal abscess, enteric fistula, 
and bowel perforations (Fig.
7-75).
SPECIAL POPULATIONS
Pregnant Patients
During pregnancy, 7% of women are injured.
Pregnancy results in physiologic changes that may impact 
postinjury evaluation (Table 7-13).
Consequently 
a pregnant woman may lose 35% of her blood volume before 
exhibiting signs of shock.
Other physiologic changes during pregnancy affect the GI, 
renal, and hematologic systems.
Liver function test values increase, with the alkaline phos-
phatase level nearly doubling.
The authors’ sequential closure technique for the open abdomen.
A.
Interrupted No.
B.
C and 
D.
E.
F.
Plasma albumin level decreases from a normal 
of around 4.3 g/dL to an average of 3.0 g/dL.
The uterus 
may also compress the ureters and bladder, causing hydrone-
phrosis and hydroureter.
Assessment of the fetal heart rate is 
the most valuable information regarding fetal viability.
Amniotic sac rupture can result 
in prolapse of the umbilical cord with fetal compromise.
Determin-
ing fetal age is key for considerations of viability.
Discrepancy in dates and size may be due to uter-
ine rupture or hemorrhage.
DPL can be performed in pregnant women via 
a supraumbilical, open technique.
Trauma radiography of preg-
nant patients presents a conundrum.
If clinically warranted, however, a 
radiograph should be obtained.
The vast majority of injuries are treated similarly whether 
the patient is pregnant or not.
A particular challenge in the 
pregnant trauma patient is a major pelvic fracture.
Fetal 
loss may be related to both maternal shock and direct injury 
to the uterus or fetal head.
Penetrating injuries in this patient 
population also carry a high risk.
On the other hand, stab wounds do not often 
penetrate the thick wall of the uterus.
They should be counseled regarding warning signs that 
mandate prompt return to the ED.
Early monitoring of arterial blood gas values will identify occult 
shock.
First, outcomes 
are worse in this age group than in their younger counterparts.
One of the most common sequelae of blunt thoracic 
trauma is rib fractures.
In the aging population, perhaps due to 
osteoporosis, less force is required to cause a fracture.
Upon the pediatric 
patient’s arrival, the basic tenets of the ABCs apply, with some 
caveats.
Additionally, the child’s tongue is much larger in 
relation to the oropharynx.
Administration 
of atropine before rapid-sequence intubation will prevent bra-
dycardia.
In children older than 11 years, standard cricothy-
roidotomy is performed.
Alternatively, tracheostomy may be performed.
As is true in adults, the vast majority of thoracic trauma 
is also blunt.
However, because a child’s skeleton is not com-
pletely calcified, it is more pliable.
Significant internal organ 
damage may occur without overlying bony fractures.
The evaluation for abdominal trauma in the pediatric 
patient is similar to that in the adult.
44%).139
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gelatin-coated Dacron vs.
Surgery.
2001;130(3):408-414.
63.
Mattox KL.
Red River anthology.
J Trauma.
1997;42(3): 
353-368.
64.
Richardson JD, Bergamini TM, Spain DA, et al.
Opera-
tive strategies for management of abdominal aortic gunshot 
wounds.
Surgery.
1996;120(4):667-671.
65.
Cosgriff N, Moore EE, Sauaia A, Kenny-Moynihan M, Burch 
JM, Galloway B.
J Trauma.
1997;42(5):857-861.
66.
Maegele M, Spinella PC, Schöchl H.
The acute coagulopathy 
of trauma: mechanisms and tools for risk stratification.
Shock.
2012;38(5):450-458.
67.
Nirula R, Millar D, Greene T, et al.
J 
Trauma, in press.
68.
Cooper DJ, Rosenfeld JV, Murray L, et al.
Decompressive craniectomy in diffuse 
traumatic brain injury.
N Engl J Med.
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69.
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Emergency cra-
niotomy in a rural level III trauma center.
J Trauma.
1998; 
44:984-989.
70.
Hutchison JS, Ward RE, Lacroix J, et al.
Hypothermia therapy after traumatic brain 
injury in children.
N Engl J Med.
2008;358(23):2447-2456.
71.
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Therapeu-
tic hypothermia for severe traumatic brain injury: a critically 
appraised topic.
Neurologist.
2012;18(3):173-177.
225
T
RAUMA
CHAPTER 7
 72.
Pieracci FM, Moore EE, Beauchamp K, et al.
A cost- 
minimization analysis of phenytoin vs.
levetiracetam for early 
seizure pharmacoprophylaxis after traumatic brain injury.
J Trauma Acute Care Surg.
2012;72(1):276-281.
73.
Cogbill T, Cothren CC, Ahearn MK, et al.
J Trauma.
2008; 64:250.
74.
Bracken MB, Shepard MJ, Holford TR, et al.
Results of the Third National Acute Spinal Cord Injury Ran-
domized Controlled Trial.
National Acute Spinal Cord Injury 
Study.
JAMA.
1997;277:1597-1604.
75.
Stahel PF, Vanderheiden T, Finn MA.
Management strategies 
for acute spinal cord injury: current options and future per-
spectives.
Curr Opin Crit Care.
2012;18(6):651-660.
76.
Spine.
2006; 31:S28,-S35.
77.
Biffl WL, Moore EE, Offner PJ, et al.
Blunt carotid arterial 
injuries: implications of a new grading scale.
J Trauma.
1999; 
47:845-853.
78.
Burlew CC, Biffl WL, Moore EE, Barnett CC, Johnson JL, 
Bensard DD.
J Trauma 
Acute Care Surg.
2012;72(2):330-335.
79.
Cothren CC, Moore EE, Biffl WL, et al.
Anticoagulation is 
the gold standard therapy for blunt carotid injuries to reduce 
stroke rate.
Arch Surg.
2004; 139:540-545.
80.
Edwards NM, Fabian TC, Claridge JA, et al.
J Am 
Coll Surg.
2007; 204:1007-1013.
81.
Bladergroen M, Brockman R, Luna G, et al.
A twelve-
year study of cervicothoracic vascular injuries.
Am J Surg.
1989;157:483-486.
82.
Johnston RH, Wall MJ, Mattox KL.
Innominate artery trauma: 
a thirty-year experience.
J Vasc Surg.
1993; 17:134-139.
83.
Fabian TC, Davis KA, Gavant ML, et al.
Ann Surg.
1998;227:666.
84.
Karmy-Jones R, Nicholls S, Gleason TG.
The endovascular 
approach to acute aortic trauma.
Thorac Surg Clin.
2007; 
17:109-128.
85.
Demetriades D, Velmahos GC, Scalea TM, et al.
Diagnosis 
and treatment of blunt thoracic aortic injuries: changing per-
spectives.
J Trauma.
2008;64(6):1415-1418.
86.
Moore EE, Burch JM, Moore JB.
Ann Surg.
2004; 240:38-43.
87.
Wall MJ, Tsai P, Mattox KL.
Heart and Thoracic Vascular 
Injury.
Mattox KL, Moore EE, Feliciano DV (eds): Trauma, 
7th ed.
New York: McGraw-Hill, 2013.
88.
Jones EL, Burlew CC, Moore EE.
J Trauma Acute Care Surg.
2012;72(3):796-798.
89.
Cothren CC, Moore EE.
Traumatic ventricular septal defect.
Surgery.
2007;142:776-777.
90.
Wall MJ Jr., Hirshberg A, Mattox KL.
Pulmonary tractotomy 
with selective vascular ligation for penetrating injuries to the 
lung.
Am J Surg.
1994; 168:665-669.
91.
Cothren C, Moore EE, Biffl WL, et al.
J Trauma 
2002;53:483-487.
92.
Cryer HG, Mavroudis C, Yu J, et al.
Shock, transfusion, 
and pneumonectomy.
Death is due to right heart failure 
and increased pulmonary vascular resistance.
Ann Surg.
1990;212:197-201.
93.
Luo L, Yin L, Liu Z, Xiang Z.
Posttraumatic pulmonary pseu-
docyst: Computed tomography findings and management in 
33 patients.
J Trauma and Acute Care Surg.
2012;73(5): 
1225-1228.
94.
Moore HB, Moore EE, Burlew CC, et al.
J Trauma Acute Care 
Surg.
2012;73: 1372-1379.
95.
de Souza A, Offner PJ, Moore EE, et al.
Optimal management 
of complicated empyema.
Am J Surg.
2000; 180:507-511.
96.
Truitt MS, Murry J, Amos J, et al.
Continuous intercos-
tal nerve blockade for rib fractures: ready for primetime?
J 
Trauma.
2011;71(6):1548-1552.
97.
Kozar RA, Moore FA, Cothren CC, et al.
Risk factors for 
hepatic morbidity following nonoperative management: mul-
ticenter study.
Arch Surg.
2006; 141:451-458.
98.
Malhotra AK, Fabian TC, Croce MA, et al.
Blunt hepatic 
injury: a paradigm shift from operative to nonoperative man-
agement in the 1990s.
Ann Surg .
2000;231:804-813.
99.
Peitzman AB, Marsh JW.
Advanced operative techniques 
in the management of complex liver injury.
J Trauma Acute 
Care Surg.
2012;73(3):765-770.
100.
Biffl WL, Moore EE, Franciose RJ.
J Trauma.
1998; 45:400-403.
101.
Poggetti RS, Moore EE, Moore FA, et al.
Balloon tamponade 
for bilobar transfixing hepatic gunshot wounds.
J Trauma.
1992; 33:694-697.
102.
Delis SG, Bakoyiannis A, Selvaggi G, et al.
Liver transplanta-
tion for severe hepatic trauma: experience from a single cen-
ter.
World J Gastroenterol.
2009;15(13):1641-1644.
103.
Lillemoe KD, Melton GB, Cameron JL, et al.
Postoperative 
bile duct strictures: management and outcome in the 1990s.
Ann Surg.
2000;232:430-441.
104.
Pickhardt B, Moore EE, Moore FA, et al.
Operative splenic 
salvage in adults: a decade perspective.
J Trauma.
1989; 29: 
1386-1391.
105.
Feliciano DV, Spjut-Patrinely V, Burch JM, et al.
Splenor-
rhaphy: the alternative.
Ann Surg.
1990; 211:569-580.
106.
Stassen NA, Bhullar I, Cheng JD, et al.
J Trauma and Acute Care Surg.
2012;73(5):S294-S300.
107.
McIntyre LK, Schiff M, Jurkovich GJ.
Failure of nonoperative 
management of splenic injuries: Causes and consequences.
Arch Surg.
2005;140:563-568.
108.
Smith HE, Biffl WL, Majercik SD, et al.
Splenic artery embo-
lization: have we gone too far?
J Trauma.
2006; 61:541-546.
109.
Toutouzas KG, Velmahos GC, Kaminski A, et al.
Leukocy-
tosis after posttraumatic splenectomy: a physiologic event or 
sign of sepsis?
Arch Surg.
2002; 137:924-928.
110.
Howdieshell TR, Heffernan D, Dipiro JT.
Therapeutic Agents 
Committee of the Surgical Infection Society.
Surgical infec-
tion society guidelines for vaccination after traumatic injury.
Surg Infect (Larchmt).
2006;7(3):275-303.
111.
Burch JM, Franciose RJ, Moore EE, et al.
Single-layer con-
tinuous vs.
two-layer interrupted intestinal anastomosis: 
a prospective randomized trial.
Ann Surg Surg.
2000;231: 
832-837.
112.
Todd SR, Kozar RA, Moore FA.
Nutrition support in adult 
trauma patients.
Nutr Clin Pract.
2006; 21:421-429.
113.
Burlew CC, Moore EE, Cuschieri J, et al; the WTA Study Group.
Who should we feed?
J Trauma Acute Care Surg.
2012;73:1380-1387.
226
BASIC CONSIDERATIONS
PART
 
I
114.
Sharpe JP, Magnotti LJ, Weinberg JA, et al.
Impact of a 
defined management algorithm on outcome after traumatic 
pancreatic injury.
J Trauma Acute Care Surg.
2012;72: 
100-105.
115.
Vaughn GD, Frazier OH, Graham D, et al.
The use of pyloric 
exclusion in the management of severe duodenal injuries.
Am 
J Surg.
1977;134:785.
116.
Nelson R, Singer M.
Primary repair for penetrating colon inju-
ries.
Cochrane Database Syst Rev 3:CD002247, 2003.
117.
Asensio JA, Britt LD, Borzotta A, et al.
Multi-institutional 
experience with the management of superior mesenteric artery 
injuries.
J Am Coll Surg.
2001;193:354-356.
118.
Burch JM, Richardson RJ, Martin RR, et al.
Penetrating iliac 
vascular injuries: experience with 233 consecutive patients.
J Trauma.
1990; 30:1450-1459.
119.
Mullins RJ, Lucas CE, Ledgerwood AM.
The natural his-
tory following venous ligation for civilian injuries.
J Trauma.
1980;20:737-743.
120.
Roth SM, Wheeler JR, Gregory RT, et al.
Blunt injury of the 
abdominal aorta: a review.
J Trauma.
1997; 42:748-755.
121.
Jurkovich GJ, Hoyt DB, Moore FA, et al.
Portal triad injuries.
J Trauma.
1995;39:426-434.
122.
Voelzke BB, McAninch JW.
Renal gunshot wounds: clinical 
management and outcome.
J Trauma.
2009;66(3):593-600.
123.
Knudson MM, Harrison PB, Hoyt DB, et al.
Outcome after 
major renovascular injuries: A Western trauma association 
multicenter report.
J Trauma.
2000; 49:1116-1122.
124.
J Trauma.
62:834-839.
125.
Burlew CC, Moore EE, Smith WR, et al.
J Am Coll Surg.
2011;212(4):628-635.
126.
Bosse MJ, MacKenzie EJ, Kellam JF, et al.
An analysis of 
outcomes of reconstruction or amputation of leg-threatening 
injuries.
N Engl J Med .
2002;347:1924-1931.
127.
Moore FA, McKinley BA, Moore EE, et al.
III.
Guidelines for shock resuscitation.
J Trauma, 2006;61:82-89.
128.
Burlew CC, Moore EE, Biffl WL, Bensard DD, Johnson JL, 
Barnett CC.
J Trauma Acute Care Surg.
2012;72(1):235-241.
129.
Sela HY, Weiniger CF, Hersch M, Smueloff A, Laufer N, 
Einav S.
The pregnant motor vehicle accident casualty: adher-
ence to basic workup and admission guidelines.
Ann Surg.
2011;254(2):346-352.
130.
ACOG Committee on Obstetric Practice: ACOG Commit-
tee Opinion.
Number 299, September 2004.
Guidelines 
for diagnostic imaging during pregnancy.
Obstet Gynecol 
2004;104:647-651.
131.
Morris JA, Rosenbower TJ, Jurkovich GJ, et al: .
Infant sur-
vival after cesarean section for trauma.
Ann Surg.
1996;223: 
481-488.
132.
Curet MJ, Schermer CR, Demarest GB, et al.
J Trauma.
2000;49:18-24.
133.
Davis JW, Kaups KL.
Base deficit in the elderly: a marker of 
severe injury and death.
J Trauma.
1998; 45:873-877.
134.
Reynolds FD, Dietz PA, Higgins D, et al.
J Trauma.
2003;54:492-496.
135.
Bulger EM, Arneson MA, Mock CN, et al.
Rib fractures in the 
elderly.
J Trauma 2000;48:1040-1046.
136.
Bergeron E, Lavoie A, Clas D, et al.
Elderly trauma patients 
with rib fractures are at greater risk of death and pneumonia.
J Trauma.
2003;54:478-485.
137.
Tepas JJ.
The national pediatric trauma registry: a legacy of 
commitment to control childhood injury.
Semin Pediatr Surg.
2004;13:126-132.
138.
Partrick DA, Bensard DD, Moore EE, et al.
J Trauma.
1998;45:57-63.
139.
Partrick DA, Bensard DD, Moore EE, et al.
J Pediatr Surg.
1999;34: 
1695-1699.
Burns
Jonathan Friedstat, Fred W.
Endorf,  
and Nicole S.
BACKGROUND
Burn injury historically carried a poor prognosis.
Anticipating the need for intubation and establishing an 
early airway are critical.
A primary sur-
vey should be conducted in accordance with Advanced Trauma 
Life Support guidelines.
Hypothermia is a common pre-
hospital complication that contributes to resuscitation failure.
Patients should be wrapped with clean blankets in transport.
Cooling blankets should be avoided in patients with moderate 
or large (>20% TBSA) burns.
A tetanus 
booster should be administered in the emergency room.
However, we 
must also consider treatment of long-term anxiety.
The “rule of nines” is a crude but quick and effective method 
of estimating burn size (Fig.
8-1).
The importance of an accurate burn size assessment cannot 
be overemphasized.
2 Never administer prophylactic antibiotics other than tetanus 
vaccination.
3 Early excision and grafting of full-thickness and deep partial-
thickness burns improve outcomes.
soiled skin with burns.
Hydrofluoric acid is a particu-
larly common offender due to its widespread industrial uses.
The concept behind continuous fluid requirements is 
simple.
As in any critically ill patient, a target 
MAP of 60 mmHg ensures optimal end-organ perfusion.
Goals for urine output should be 30 mL/h in adults and 
1 to 1.5 mL/kg/h in pediatric patients.
The use of colloid as part of the burn resuscitation has gen-
erated much interest over the years.
Determining patient 
cardiac function and volume status may guide fluid resuscita-
tion.
a traditional transfusion trig-
ger of 10 g/dL.
The physiologic effects of smoke inhalation are numer-
ous.
Silver sulfadiazine is one of the most widely used in 
clinical practice.
It has the 
added benefits of being inexpensive and easily applied and has 
soothing qualities.
It is not significantly absorbed systemically 
and thus has minimal metabolic derangements.
Also, silver sulfadiazine may retard epithelial migration 
in healing partial-thickness wounds.
Mafenide acetate, either in cream or solution form, is an 
effective topical antimicrobial.
Use of mafenide acetate may 
be limited by pain with application to partial-thickness burns.
Silver nitrate has broad-spectrum antimicrobial activity as 
a topical solution.
A rare complication is methemo-
globinemia.
All three have been reported to 
cause nephrotoxicity and should be used sparingly in large 
burns.
This formula estimates caloric needs to be 
25 kcal/kg/d plus 40 kcal/%TBSA/d.
One study of HIT in burn patients showed 
an incidence of 1.6% in heparinized burn patients.
Excision to 
fat or fascia may be necessary in deeper burns.
In larger burns, meshed 
 autografted skin provides a larger area of wound coverage.
The search for a perfect permanent synthetic skin substi-
tute remains elusive.
Immediate 
and ongoing physical and occupational therapy is mandatory to 
prevent functional loss.
This includes patients with burns over joints, such as with 
hand burns.
Patients should be taught exercises they can do them-
selves to maintain full range of motion.
Whether they prevent hypertrophic scar 
formation has been long debated.
However, they do provide vas-
cular support that many patients find more comfortable.
Laser-based therapies provide addition treatment options 
for symptomatic hypertrophic scars.
Lasers are believed to help with scar remodel-
ing and collagen reorganization.
Outpatient and office-based 
treatment sessions are tolerated well by most patients.
Psychological rehabilitation is equally important in the 
burn patient.
First, the proximity to the 
detonated bomb directly impacted mortality.
Of the survivors, 79,130 
people were injured and 118,613 remain uninjured.
A 20-kiloton nuclear device generates 
180 mph winds 0.8 miles from the epicenter.
The explosion 
results in a direct pressure wave and an indirect wind drag.
Decontamination and triage are vital to maximize the num-
ber of survivors.
Initial decontamination requires removal of 
clothing and washing wounds with water.
Irrigation fluid should 
be collected to prevent radiation spread into the water supply.
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This page intentionally left blank 
Wound Healing
Adrian Barbul, David T.
Efron, and 
Sandra L.
The 1650 
b.c.
These 
same properties are still considered essential in contemporary 
daily wound management.
He emphasized the importance of maintaining a 
moist environment to ensure adequate healing.
Joseph Lister probably 
made one of the most significant contributions to wound healing.
The 1960s and 1970s led to the development of polymeric 
dressings.
semiocclusive), varying degrees of absorbency, and differ-
ent physical forms.
It is the combination of all these modali-
ties that enables optimal wound healing.
.
.
An approximate timeline of these events is 
depicted in Fig.
9-1.
The cellular, biochemical, and 
mechanical phases of wound healing.
9-2A).
Cellular infiltration after injury follows a characteristic, 
predetermined sequence (see Fig.
9-1).
PMNs are the first infil-
trating cells to enter the wound site, peaking at 24 to 48 hours.
The postulated primary role of neutrophils is phagocytosis 
of bacteria and tissue debris.
The phases of wound healing viewed histologically.
A.
The hemostatic/inflammatory phase.
B.
Latter inflammatory phases 
reflecting infiltration by mononuclear cells and lymphocytes.
C.
The 
proliferative phase, with associated angiogenesis and collagen synthesis.
9-2B).
9-2B,C).
244
BASIC CONSIDERATIONS
PART
 
I
Figure 9-3.
The steps of collagen synthesis.
mRNA = messenger RNA.
9-2C).
It is dur-
ing this phase that tissue continuity is re-established.
Endothelial cells migrate from intact venules 
close to the wound.
Type I collagen is the major component of extracellular matrix 
in skin.
Biochemically, each chain of collagen is composed of a 
glycine residue in every third position.
9-3).
At both ends, this struc-
ture contains nonhelical peptide domains called registration 
peptides.
Proteoglycan Synthesis.
Rarely found free, they couple with proteins to form proteoglycans.
The major glycosaminoglycans present in wounds are der-
matan and chondroitin sulfate.
The interaction between collagen and proteo-
glycans is being actively studied.
The mechanical strength of the scar never achieves that of 
the uninjured tissue.
Collagenolysis is the result of collagenase activity, 
a class of MMPs that require activation.
Both collagen synthesis 
and lysis are strictly controlled by cytokines and growth factors.
Some factors affect both aspects of collagen remodeling.
9-4).
The healing by epithelialization of superficial cutane-
ous wounds.
Growth factors act on cells via surface receptor binding.
Wound Contraction
All wounds undergo some degree of contraction.
Small blood vessels are 
fragile, making suturing difficult during surgery.
Inguinal her-
nias in these children resemble those seen in adults.
Great care 
should be taken to avoid tearing the skin and fascia.
The trans-
versalis fascia is thin, and the internal ring is greatly dilated.
248
BASIC CONSIDERATIONS
PART
 
I
of the ascending aorta.
Patients who suffer from this syndrome also 
are prone to hernias.
OI is a result of a mutation in type I collagen.
There 
are four major OI subtypes with mild to lethal manifestations.
Patients experience dermal thinning and increased bruisability.
Scarring is normal, and the skin is not hyperextensible.
Source: Reproduced and updated with permission from Phillips et al.31 Copyright © Elsevier.
skin layers; the last can present as multiple blisters throughout 
different layers of skin.
Characteristic features of EB are blistering and ulceration.
Surgical interventions include esophageal dilata-
tion and gastrostomy tube placement.
Diagnosis is con-
firmed by the presence of an abnormally low blood zinc level 
(>100 mg/dL).
The gross anatomic features of the GI tract are remarkably 
constant throughout most of its length.
Injuries to all parts of the GI tract undergo the same 
sequence of healing as cutaneous wounds.
However, there are 
some significant differences (Table 9-5).
Mesothelial (serosal) 
and mucosal healing can occur without scarring.
9-5).
Collagen synthesis in the GI tract is carried out by 
both fibroblasts and smooth muscle cells.
stapled, continuous vs.
interrupted sutures, absorbable 
vs.
nonabsorbable sutures, or single- vs.
two-layer closure).
(Reproduced with permission from Hunt 
TK, Van Winkle W Jr.
Wound healing: normal repair.
In: Dunphy 
JE, ed.
Fundamentals of Wound Management in Surgery.
This 
is similar to the formation of granulation tissue in soft tissue.
The soft callus is formed externally along the bone shaft 
and internally within the marrow cavity.
Clinically, this phase is 
characterized by the end of pain and inflammatory signs.
This may take up to 
2 to 3 months and leads to complete bony union.
The healing response of cartilage depends on the depth of 
injury.
In contrast to superficial injuries, deep injuries involve 
the underlying bone and soft tissue.
They consist 
of parallel bundles of collagen interspersed with spindle cells.
Due to the mobility 
of the underlying bone or muscles, the damaged ends usually 
separate.
As the collagen fibers are organized, 
transmission of forces across the damaged portion can occur.
Restoration of the mechanical integrity may never be equal to 
that of the undamaged tendon.
Tendon vasculature has a clear effect on healing.
Schwann 
cells ensheathe and help in remyelinating the regenerating axons.
Functional units are formed when the regenerating axons connect 
with the appropriate end targets.
This complex interplay of growth factors 
and adhesion molecules helps in nerve regeneration.
Wound Environment.
Different clinical approaches to the closure and heal-
ing of acute wounds.
Figure 9-7.
The acquisition of wound mechanical strength over 
time in normal, delayed, and impaired healing.
Growth Factors.
Fetal wounds are notable for the absence of 
TGF-β, which may have a significant role in scarring.
Wound Matrix.
Acute wounds 
heal in a predictable manner and time frame.
The process occurs 
with few, if any, complications, and the end result is a well-healed 
wound.
Surgical wounds can heal in several ways.
An incised 
wound that is clean and closed by sutures is said to heal by pri-
mary intention.
9-6).
The healing spectrum of acute wounds is broad (Fig.
9-7).
Normal healing is affected by both systemic and local factors 
(Table 9-6).
Factors Affecting Wound Healing
Advanced Age.
Clinical experience with elderly patients tends 
to support this belief.
Hypoxia, Anemia, and Hypoperfusion.
Low oxygen tension 
has a profoundly deleterious effect on all aspects of wound heal-
ing.
Uremia also has been associated with disordered 
wound healing.
Obesity is the largest growing public health problem in 
the United States and the world.
Over 60% of Americans are 
overweight or obese.
Many of these molecules have 
effects on cells participating in the healing response.
The mechanism by which obesity 
impairs wound healing awaits complete delineation.
Nutrition.
9-8).
Effect of malnutrition on collagen deposition in exper-
imental human wounds.
OHP = hydroxyproline.
following diverse surgical procedures.
Arginine appears most active in terms of enhancing wound 
fibroplasia.
The vitamins most closely involved with wound healing 
are vitamin C and vitamin A.
The recommended dietary allowance is 
60 mg daily.
This provides a considerable safety margin for most 
Figure 9-9.
*P < .05.
(Reproduced with 
permission from Williams JZ, Abumrad NN, Barbul A.
Effect of a 
specialized amino acid mixture on human collagen deposition.
Ann 
Surg.
2002;236:369.)
5
4
3
2
1
ASP LYSO HP
Experimental
Control
αAN
healthy nonsmokers.
Serious injury or stress leads to increased vitamin A 
requirements.
In the severely injured patient, supplemental doses 
of vitamin A have been recommended.
Doses ranging from 
25,000 to 100,000 IU per day have been advocated.
Frequently, 
deficiencies are multiple and include macronutrient deficien-
cies.
Clinically, 
preventing deficiencies is often easier to accomplish than diag-
nosing them.
It is essential for wound healing in animals and humans.
These defects are reversed by zinc supplementation.
Cosmetically, infections can lead to disfig-
uring, unsightly, or delayed closures.
Many factors 
contribute to the development of postoperative wound infec-
tions.
There has been much debate about the actual definition 
of wound infection.
This causes minimal if any discomfort to 
the patient.
Most intra-abdominal infections do not, 
however, communicate with the wound.
Deep infections present 
with fever and leukocytosis.
Sometimes wound dehiscence will occur.
The most dangerous of the deep infections is necrotizing 
fasciitis.
It results in high mortality, particularly in the elderly.
This is an invasive process that involves the fascia and leads 
to secondary skin necrosis.
The aim of surgical treatment 
is thorough removal of all necrosed skin and fascia.
aureus, S.
epidermidis Cefazolin 1–2 g IV2
Ophthalmic S.
epidermidis, S.
aureus, streptococci, 
enteric gram-negative bacilli,  
Pseudomonas spp.
epidermidis Cefazolin16 or Vancomycin2,16 1–2 g IV2, 1 g IV
Thoracic (noncardiac) S.
aureus, S.
There seems to be 
confusion as to what exactly constitutes wound infection.
aureus, S.
aureus, S.
2The recommended dose of cefazolin is 1 g for patients who weigh 80 kg and 2 g for those >80 kg.
Morbidly obese patients may need higher doses.
Fluoroquinolones should not be used for prophylaxis in cesarean section.
8Cefotetan, cefoxitin, and ampicillin/sulbactam are reasonable alternatives.
or 2 g of neomycin plus 2 g of metro-
nidazole at 7 p.m.
and 11 p.m.
the day before an 8 a.m.
operation.
10Due to increasing resistance of E.
11For a ruptured viscous, therapy is often continued for about 5 d.
13Shock wave lithotripsy, ureteroscopy.
If manipulation of 
bowel is involved, prophylaxis is given according to colorectal guidelines.
15Divided into 100 mg before procedure and 200 mg after.
10(122):73.
www.medicalletter.org.
As discussed previously, neutrophils play a major role in 
preventing wound infections.
Surgeons become involved when 
the patient develops infectious or obstructive complications.
The nitroblue tetrazolium (NBT) reduction test is used to 
diagnose CGD.
Wound 
complications, mainly infection, are common.
Sutures should 
be removed as late as possible since the wounds heal slowly.
Thomas K.
The majority of wounds that have not healed 
in 3 months are considered chronic.
9-10).
Cancers arising de novo in chronic 
wounds include both squamous and basal cell carcinomas.
Ischemic Arterial Ulcers.
These wounds occur due to a lack 
of blood supply and are painful at presentation.
After establishing adequate blood 
supply, most such wounds progress to heal satisfactorily.
A strategy of prevention is extremely important in the 
approach to patients with limb ischemia.
Venous 
hypertension and capillary damage lead to extravasation of hemo-
globin.
The products of this breakdown are irritating and cause 
pruritus and skin damage.
Venous stasis occurs due to the incompetence of either the 
superficial or deep venous systems.
The wound usually is shal-
low with irregular margins and pigmented surrounding skin.
Compression can be accomplished via rigid or 
flexible means.
The most commonly used method is the rigid, 
zinc oxide–impregnated, nonelastic bandage.
Ten percent to 25% of diabetic patients 
run the risk of developing ulcers.
The neuropathy is both sensory and motor and is secondary 
to persistently elevated glucose levels.
There is also severe micro- and 
macrovascular circulatory impairment.
Once ulceration occurs, the chances of healing are poor.
Wide débridement of all necrotic or infected 
tissue is another cornerstone of treatment.
Pressure 
ulcer formation is accelerated in the presence of friction, shear 
forces, and moisture.
Typical appearance of the malignant transformation of a long-standing chronic wound.
(Photos used with permission by 
Dr.
Robert S.
9-11).
Men and women are equally affected.
They vary in size from a few millimeters to large, 
Figure 9-11.
Recurrent keloid on the neck of a 17-year-old patient 
that had been revised several times.
(Reproduced with permission 
from Murray JC, Pinnell SR.
Keloids and excessive dermal scar-
ring.
In: Cohen IK, Diegelmann RF, Lindblad WJ, eds.
Wound 
Healing: Biochemical and Clinical Aspects.
Philadelphia: WB 
Saunders; 1993.
Copyright Elsevier.)
pedunculated lesions with a soft to rubbery or hard consistency.
They rarely occur on eyelids, genitalia, palms, soles, 
or across joints.
There is an abundance of collagen and glycoprotein depo-
sition.
In HTS, the collagen 
bundles are flatter and more random, and the fibers are in a wavy 
pattern.
This perturbed synthetic activity is mediated by altered 
growth factor expression.
The underlying mechanisms that cause HTSs and keloids 
are not known.
Much is inferred from the presence of various 
immune cells in HTSs and keloids.
HTSs have higher T lymphocyte and Langerhans 
cell contents.
It may 
be secured with tape or worn beneath a pressure garment.
Intralesional injections are more effective on 
younger scars.
Success is enhanced when used 
in combination with surgical excision.
Serial injections every 
2 to 3 weeks are required.
Complications include skin atrophy, 
hypopigmentation, telangiectasias, necrosis, and ulceration.
It is more effective when combined 
with surgical excision.
Pressure aids collagen maturation, flattens scars, and 
improves thinning and pliability.
External 
compression is used to treat HTSs, especially after burns.
Scars older than 6 to 12 months respond poorly.
Peritoneal Scarring.
Operations in the lower abdomen have 
a higher chance of producing small bowel obstruction.
Fibrin deposition occurs between the damaged but 
opposed serosal surfaces.
9-12).
Fewer adhesions 
form with laparoscopic surgical techniques due to reduced tis-
sue trauma.
Fibrin formation and degradation in peritoneal tis-
sue repair and adhesion formation.
264
BASIC CONSIDERATIONS
PART
 
I
TREATMENT OF WOUNDS
Local Care (Fig.
The history is fol-
lowed by a meticulous examination of the wound.
Figure 9-13.
Algorithm for management of acute 
wounds.
Management of acute wounds
1.
Examination
a) Depth?
Underlying structures injured
b) Configuration?
c) Nonviable tissue?
4.
Follow-up
a) Cellulitis/drainage?
b) Suture removal
 -4–5 days for face
 -7–10 days other skin
3.
This 
is particularly important for wounds that cross the vermilion 
border, eyebrow, or hairline.
Drains may be placed in areas at risk of 
forming fluid collections.
Intradermal 
absorbable sutures do not require removal.
Use of skin tapes 
alone is only recommended for closure of the smallest superfi-
cial wounds.
These new glues are less prone 
to brittleness and have superior burst-strength characteristics.
Antibiotics
Antibiotics should be used only when there is an obvious wound 
infection.
Most wounds are contaminated or colonized with bac-
teria.
The presence of a host response constitutes an infection 
and justifies the use of antibiotics.
Signs of infection to look for 
include erythema, cellulitis, swelling, and purulent discharge.
In addition, appli-
cation of compression provides hemostasis and limits edema.
It also allows transfer of gases and water vapor from 
the wound surface to the atmosphere.
Dressings can be classified as primary or secondary.
Many types of dress-
ings exist and are designed to achieve certain clinically desired 
endpoints.
Absorbent Dressings.
Accumulation of wound fluid can lead 
to maceration and bacterial overgrowth.
Nonadherent Dressings.
Occlusive and Semiocclusive Dressings.
Hydrophilic and Hydrophobic Dressings.
These dressings 
are components of a composite dressing.
Hydrocolloid and Hydrogel Dressings.
Hydrocolloid and 
hydrogel dressings attempt to combine the benefits of occlusion 
and absorbency.
Hydrogel is a cross-linked polymer that has 
high water content.
Alginates.
The ratios of these sugars vary with the species 
of algae used, as well as the season of harvest.
The 
polymers gel, swell, and absorb a great deal of fluid.
Absorbable Materials.
Medicated Dressings.
Medicated dressings have long been 
used as a drug-delivery system.
These agents have been shown to increase epi-
thelialization by 28%.
The type of dressing to be used depends on the amount 
of wound drainage.
A nondraining wound can be covered with 
semiocclusive dressing.
Drainage of less than 1 to 2 mL/d may 
require a semiocclusive or absorbent nonadherent dressing.
Mechanical Devices.
The continuous nega-
tive pressure is very effective in removing exudates from the 
wound.
Conventional Skin Grafts.
Skin grafts have long been used to 
treat both acute and chronic wounds.
Split-thickness grafts require less 
blood supply to restore skin function.
Tem-
porary placement of allografts or xenografts may be used to 
prepare the wound bed.
Skin Substitutes.
Cultured epithelial autografts (CEAs) represent expanded 
autologous or homologous keratinocytes.
CEAs are available from cadavers, unrelated adult donors, 
or neonatal foreskins.
Cost
Short shelf life
True engraftment questionable
Growth Factor Therapy.
Growth factors for clinical use may be either recombi-
nant or homologous/autologous.
Gene or Cell Therapy.
Elaborate systems have been created for topical use as on/off 
switches for genes.
What, if any, are the deficiencies in gene expression or 
activity in failed wounds is unknown.
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Autol-
ogous platelet-rich plasma for treating chronic wounds.
Cochrane Database Syst Rev.
2012;10:CD006899.
The surgeon often is responsible for the 
initial diagnosis and management of solid tumors.
The primary goal of surgical and radiation therapy is 
local and regional control.
Recent advances in molecular biology are revolutionizing 
medicine.
2 Understanding cancer biology is essential to successfully 
implement personalized cancer therapy.
Incidence is usually expressed as the number of new cases 
per 100,000 persons per year.
Incidence and mortality data are 
usually available through cancer registries.
The incidence of cancer varies by geography.
nonsmokers).
The results are expressed in terms of an odds ratio, or 
relative risk.
Prostate cancer rates rapidly increased and 
decreased between 1995 and 1998.
Reprogramming of energy metabolism and evading 
immune destruction.
Source: Modified with permission from John Wiley and Sons: Siegel R et al.
Cancer statistics, 2013.
CA: a cancer journal for clinicians.
2013;63:11.
© 2013 
American Cancer Society, Inc.
male lung cancer and more than 40% for prostate cancer.
10-3).
The mortality rates for different cancers 
also vary significantly among countries.
The incidence of stomach cancer varies significantly among dif-
ferent regions of the world.
Cancer statistics, 2013.
CA: a cancer journal for clinicians.
2013;63:11.
Stomach cancer is the second 
leading cause of cancer death in both sexes worldwide.
Overall, the incidence of breast cancer is rising in most 
countries.
Low rates are estimated in developed 
regions, with the exception of Southern Europe.
The geographical distribution of the mortality rates is similar to 
that observed for incidence.
This is due in part to genetic differ-
ences, including racial and ethnic differences.
Human cells require several genetic changes for neo-
plastic transformation.
Cell type–specific differences also exist 
for tumorigenic transformation.
Rates are age adjusted to the 2000 U.S.
standard population.
(Modified with permission from John Wiley and Sons: Siegel 
R et al.
Cancer statistics, 2013.
CA: a cancer journal for clinicians.
2013;63:11.
Cancer statistics, 2013.
CA: a cancer 
journal for clinicians.
2013;63:11.
© 2013 American Cancer Society, Inc.
Thus, many normal-appearing 
cells may have an increased malignant potential.
This is referred 
to as a field effect.
Subsequent events can lead to accumula-
tions of additional deleterious mutations in the clone.
Fearon and Vogelstein proposed the model for colorec-
tal tumorigenesis presented in Fig.
There are several controls at each level.
The cell cycle is divided into four phases (Fig.
Oncogenes
Normal cellular genes that contribute to cancer when abnor-
mal are called oncogenes.
The normal counterpart of such a 
gene is referred to as a proto-oncogene.
Oncogenes are usu-
ally designated by three-letter abbreviations, such as myc or ras.
More than 100 oncogenes have 
been identified.
Persistent overexpression 
Figure 10-3.
Estimated cancer incidence worldwide in 2008.
(Modified with permission from Ferlay, IARC)4
All cancers
< 11.2
< 0.3 < 0.5 < 0.7 < 1.
0< 11.2 < 0.4 < 0.7< 1.
0< 1.
Protein tyrosine kinases account for a large por-
tion of known oncogenes.
One of the best-studied oncogenes, 
HER2 is discussed as an example later.
Hallmarks of cancer and their therapeutic implications.
The drugs 
listed are illustrative examples.(Modified with permission from  Hanahan et al.
A genetic model for colorectal tumorigenesis.
Individuals with familial adenomatous polyposis (FAP) inherit a mutation on chromosome arm 5q.
The chromosome 
arms most frequently deleted include 5q, 17p, and 18q.
DCC = deleted in 
colorectal cancer gene.
(Modified with permission from Fearon et al.
Unlike other recep-
tor tyrosine kinases, HER2/neu does not have a direct soluble 
ligand.
10-7).
Schematic representation of the phases of the cell 
cycle.
Mitogenic growth factors can drive a quiescent cell from G0 
into the cell cycle.
The DNA is replicated in S phase, and the 
chromosomes are condensed and segregated in mitosis.
Cell-cycle checkpoints have been identified in 
G1, S, G2, and M phases.
CDK = cyclin-dependent kinase.
In animal models, HER2 increases tumorigenic-
ity, angiogenesis, and metastasis.
These results all suggest that 
HER2 plays a key role in cancer biology.
More recently HER2 
mutations have also been reported in human cancer.
All of these mutations were sensitive to the irreversible kinase 
inhibitor, neratinib.
Cancer cells must avoid apoptosis if tumors are to arise.
Apoptosis is distinguished from necrosis because 
it leads to several characteristic changes.
Apoptotic cells are then engulfed and 
degraded by phagocytic cells.
Another regulatory group is the FADD-like 
interleukin-1 protease-inhibitory proteins (FLIPs).
FLIPs have 
homology to caspase 8; they bind to the DISC and inhibit the 
activation of caspase 8.
The HER2 signaling pathway.
Cell-to-cell adhesion in normal cells involves interactions 
between cell-surface proteins.
Integrins are a family of glycoproteins that form heterodi-
meric receptors for ECM molecules.
Serine, cysteine, and aspartic proteinases and MMPs have 
all been implicated in cancer invasion.
Plasmin, in return, can 
degrade several ECM components.
Plasmin also may activate 
MMPs.
uPA has been more closely correlated with tissue inva-
sion and metastasis than tPA.
MMPs comprise a family of metal-dependent endopepti-
dases.
Upon activation, MMPs degrade a variety of ECM com-
ponents.
For example, collagenase-1 is now referred to 
as MMP-1.
The MMPs are further classified as secreted and 
membrane-type MMPs.
MMPs are upregulated in almost every type of cancer.
This neovascularization is essential 
for tumor growth and metastasis.
Finally, sprouting tips anastomose to 
form a vascular network surrounded by a basement membrane.
A schematic representation of the metastatic process.
A.
The metastatic process begins with an in situ cancer surrounded by an 
intact basement membrane.
B.
C.
Metastasizing cells can enter the circulation via the lymphatics.
D.
They can also directly enter 
the circulation.
E.
Intravascular survival of the tumor cells and extravasation of the circulatory system follow.
F.
Metastatic single cells can 
colonize sites and remain dormant for years as occult micrometastases.
G.
(Adapted by permission from Macmillan Publishers Ltd.
Steeg PS.
Metastasis suppressors alter the signal transduction of cancer cells.
Nat Rev Cancer.
2003;3:55.
Ang-1, via the Tie-2 
receptor, induces remodeling and stabilization of blood vessels.
Therefore the balance between these factors determines the 
angiogenetic capacity of a tumor.
Tumor angiogenesis is regulated by several factors in a 
coordinated fashion.
Such inhibitors of 
angiogenesis include thrombospondin 1 and angiostatin.
Angio-
genesis is a prerequisite not only for primary tumor growth 
but also for metastasis.
Expression of angiogenic factors 
such as VEGFs has had prognostic value in many studies.
These 
findings further emphasize the importance of angiogenesis in 
cancer biology.
The 
metastatic process consists of a series of steps that need to be 
completed successfully (Fig.
After the cancer 
cells are shed into the circulation, they must survive.
Metastases can sometimes arise several years after the 
treatment of primary tumors.
Several types of tumors metastasize in an organ-specific 
pattern.
Metastasis also may involve the loss 
of metastasis-suppressor genes.
Currently available drugs can 
shrink metastatic tumors but often cannot eradicate them.
Therapeutic approaches 
targeting stem cells specifically are under study.
Accumulation of somatic mutations acquired by the cancer cell.
Other processes 
such as example DNA repair defects may contribute to the mutational burden.
Stratton MR, Campbell PJ, Futreal PA.
The cancer genome.
Nature.
2009;458:719.
Copyright © 2009.)37
or to a loss of function by tumor-suppressor genes.
Somatic mutations in a 
cancer genome may consist of several classes of DNA sequence 
changes.
Somatic mutations in a cancer cell genome have accumu-
lated over the lifetime of the patient (Fig.
10-9).37 DNA in normal 
cells is continuously damaged by internal and external mutagens.
Most of this damage is repaired; however, a small fraction may 
remain as fixed mutations.
This is clearly the case for some cancers.
The most common cancer genes are protein kinases.
The remainder of mutations are “bystanders” or “pas-
sengers” that do not confer growth advantage.
It is likely that 
most somatic mutations are passenger mutations.
10-10).
287
ONCOLOGY
CHAPTER 10
Hereditary:N onhereditary:
Tumor Tumor
Figure 10-11.
“Two-hit” tumor formation in both hereditary 
and nonhereditary cancers.
(Adapted by permission from Macmillan  
Publishers Ltd.
Knudson AG.
Two genetic hits (more or less) to 
cancer.
Nat Rev Cancer.
2001;1:157.
Molecular subsets of lung adenocarcinoma.
Pao W, Hutchinson KE.
Chipping away at the lung cancer 
genome.
Nat Med.
2012;18:349.
The following factors may suggest the presence of a 
hereditary cancer49:
1.
Tumor development at a much younger age than usual
2.
Presence of bilateral disease
3.
Presence of multiple primary malignancies
4.
Presentation of a cancer in the less affected sex (e.g., male 
breast cancer)
5.
Clustering of the same cancer type in relatives
6.
Some of the more commonly encountered 
hereditary cancer syndromes are discussed here.
rb1Gene.
The retinoblastoma gene rb1 was the first tumor 
suppressor to be cloned.
These findings led to the theory that a single 
mutation is not sufficient for tumorigenesis.
p53 and Li-Fraumeni Syndrome.
Tumor heterogeneity.
A.
Cells within the primary tumor can acquire or lose genomic alterations in metastatic sites.
C.
Futreal PA et al.
A census of human cancer genes.
Nat Rev Cancer.
2004;4:177.
Copyright © 2004.
Of the known genes in human cancer, p53 is the most com-
monly mutated.
It is estimated that 5% to 10% of breast cancers are 
hereditary.
BRCA2, mapped to 
13q12.3, was reported shortly afterward.
The polyps usually appear in adoles-
cence and, if left untreated, progress to colorectal cancer.
Mismatch Repair Genes and Hereditary Nonpolyposis 
Colorectal Cancer.
These errors are corrected through a process 
referred to as mismatch repair.
The “hot spot” for PTEN mutations has been identified in 
exon 5.
This suggests that the PTEN catalytic activity is vital 
for its biologic function.
Breast cancer develops in 25% to 50% of 
affected women.78
p16 and Hereditary Malignant Melanoma.
E-cadherin and Hereditary Diffuse Gastric Cancer.
Mutations in the RET gene have also been 
identified in half of sporadic medullary thyroid cancers.
Genetic Modifiers of Risk.
Chemicals are clas-
sified into three groups based on how they contribute to tumor 
formation.
Group 3 agents are not classifiable, 
and Group 4 agents are probably not carcinogenic to humans.
H.
The long fibers support cell proliferation and 
have been shown to preferentially induce tumors.
Therefore, physical car-
cinogens may be synergistic with chemical carcinogens.
Within the next 20 years, a large number of radiation-related 
skin cancers were reported.
It is thought that 
radiation may initiate cancer by inactivating tumor-suppressor 
genes.
Activation of oncogenes appears to play a lesser role in 
radiation carcinogenesis.
Strong*
4,4’-Methylenebis(2-chloroaniline) ..
See text*§
3,3’,4,4’,5-Pentachlorobiphenyl (PCB-126) ..
See text*§
Ethylene oxide ..
*Agents classified in Group 1 on the basis of mechanistic information.
†Weak evidence in workers, but strong evidence for some chemicals in this industry.
‡Due to the diversity and complexity of these exposures, other mechanisms may also be relevant.
§Strong evidence for an aryl hydrocarbon receptor (AhR)-mediated mechanism.
¶Particularly myeloid leukemia.
||After maternal exposure (before or  during pregnancy, or both).
**New epidemiological findings.
Source: Adapted from Baan et al 2009.
Patients with ataxia telangiectasia mutated syndrome also have 
a radiation-sensitive phenotype.
Oncogenic viruses 
may be RNA or DNA viruses.
Oncogenic RNA viruses are ret-
roviruses and contain a reverse transcriptase.
Oncogenic transforming retroviruses 
carry oncogenes derived from cellular genes.
These genes 
are required for viral replication using the host cell machinery.
Like other types of carcinogenesis, viral carcinogenesis 
is a multistep process.
Furthermore, some viruses encode genes that suppress or delay 
apoptosis.
When cancer does develop, it usually occurs 
several years after the viral infection.
Source: Modified from Butel JS.
Viral carcinogenesis: revelation of molecular mechanisms and etiology of human disease.
Carcinogenesis.
2000;21:405.
By permission of Oxford University Press.
297
ONCOLOGY
CHAPTER 10
and over her  lifetime (to age 90 years).
Similar models are in development or are 
being validated for other cancers.
CANCER SCREENING
Early detection is the key to success in cancer therapy.
The consequences of a false-positive screen-
ing test result also need to be considered.
Among women 
for whom biopsy specimen is recommended, 25% to 40% will 
have a breast cancer.
Beginning in 
their early 20s, women should be told about the benefits 
and limitations of BSE.
Women at any age should not be 
screened annually by any screening method.
Guaiac-based toilet bowl FOBT tests also are 
not recommended.
There is no justification for 
repeating FOBT in response to an initial positive finding.
Stool DNA testb, or Interval uncertain, starting at age 50 y.
FSIG, or Every 5 y, starting at age 50 y.
DCBE, or Every 5 y, starting at age 50 y.
Colonoscopy Every 10 y, starting at age 50 y.
CT colonography Every 5 yr, starting at age 50 y.
These guidelines need to be modified for patients 
who are at high risk.
Screening should not be 
viewed as an alternative to smoking cessation.
Prostate cancer screening should not occur 
without an informed decision-making process.
aBeginning at age 40 y, annual CBE should ideally be performed prior to mammography.
Source: Modified with permission from John Wiley and Sons: Smith RA et al.
CA: a cancer 
journal for clinicians.
2013;63:87.
© 2013 American Cancer Society, Inc.
FDG PET assesses the rate of glycolysis.
The TNM staging applies only to tumors that have been 
microscopically confirmed to be malignant.
Standard TNM 
staging (clinical and pathologic) is completed at initial diag-
nosis.
If even one lymph node is involved by tumor, the N com-
ponent is at least N1.
NX indicates that the lymph nodes cannot 
be fully assessed.
N Engl J Med.
2004;351:281.
Copyright © 2004 Massachusetts Medical Society.
The 
RS was indeed able to stratify patients by freedom from distant 
recurrence (Fig.
Unfor-
tunately, identification of serum markers of clinical value has 
been challenging.
More-
over, tumor marker levels can be elevated in benign conditions.
In spite of these 
many clinical limitations, several serum markers are in clinical 
use.
A few of the commonly measured serum tumor markers are 
discussed in the following sections.
Prostate-Specific Antigen.
PSA is normally present in low concentrations 
in the blood of all adult males.
Carcinoembryonic antigen 
(CEA) is a glycoprotein found in the embryonic endoder-
mal epithelium.
CEA measurement is most commonly used in the man-
agement of colorectal cancer.
However, the appropriate use of 
CEA testing in patients with colorectal cancer has been debated.
Use of CEA level as a screening test for colorectal cancer is 
not recommended.
Preoperative elevation of CEA level is an 
indicator of poor prognosis.
Alpha-fetoprotein (AFP) is a glyco-
protein normally produced by a developing fetus.
AFP levels 
decrease soon after birth in healthy adults.
Rarely, other types of cancer 
such as gastric are associated with an elevated AFP level.
Cancer Antigen 19-9.
The CA 
15-3 epitope is recognized by two monoclonal antibodies in a 
sandwich radioimmunoassay.
CA 15-3 levels are infrequently elevated 
in early-stage breast cancer.
Another methodology used to detect cancer cells in the periph-
eral blood is RT-PCR.
In a prospective 
multicenter trial, the number of CTCs (≥5 CTCs vs.
This 
technology, known as CellSearch, has been approved by the 
FDA for clinical use.
An example 
of this is toilet mastectomies for large ulcerated breast tumors.
The traditional Halsted 
view states that lymphadenectomy is important for staging and 
survival.
The effect of appropriate 
staging on survival is twofold.
Clearly the impact of lymphadenectomy on 
survival will not be easily resolved.
Moreover, the utility of sentinel 
node biopsy specimen in other cancer types is being explored.
The first node to receive drainage from the tumor site is 
termed the sentinel node.
Lymphatic mapping and sen-
tinel lymph node biopsy specimen for breast 
cancer.
A.
Peritumoral injection of blue dye.
B.
Blue dye draining into the sentinel lymph 
node.
(Modified with permission from Meric F, 
Hunt KK.
Careful manual palpation is a crucial part of the 
procedure to minimize the false-negative rate.
Another area of active investigation is the prognostic value 
of minimal nodal involvement.
All 
patients underwent breast-conserving surgery and tangential 
whole-breast irradiation.
The role of completion lymph node 
dissections in melanoma is under investigation.
Patient selection is the key to the success of surgical ther-
apy for distant metastases.
The cancer type is a major deter-
minant in surgical decision making.
The goal 
of therapy in this setting is to decrease the tumor burden, thus 
prolonging survival.
It is rare to achieve cure with chemother-
apy for metastatic disease for most solid tumors.
Preoperative chemotherapy has three potential advantages.
There are some potential disadvantages to preoperative 
chemotherapy, however.
Anticancer Agents
Alkylating Agents.
The damage to the 
DNA prevents cell division and, if severe enough, leads to apopto-
sis.
Antitumor Antibiotics.
Antitumor antibiotics are the prod-
ucts of fermentation of microbial organisms.
Like the alkylat-
ing agents, these agents are cell-cycle nonspecific.
Antimetabolites.
These drugs 
are most effective, therefore, in tumors that have a high growth 
fraction.
The 
antimetabolites include folate antagonists, purine antagonists, 
and pyrimidine antagonists.
Plant Alkaloids.
Combining cell-cycle–specific and cell-cycle–
nonspecific agents may be especially advantageous.
However, it 
increases the drug’s toxicity to a wide range of organs through-
out the body.
Hormonal therapy pro-
vides a highly tumor-specific form of therapy in sensitive tis-
sues.
Androgen 
receptor is also being pursued as a therapeutic target for breast 
cancer treatment.
These drugs 
work by targeting bcr-abland c-kit (imatinib) and HER2 and 
Braf, respectively.
Sequencing of the human genome has revealed approxi-
mately 500 protein kinases.
Some other agents, such as sunitinib, are 
multi-targeted kinase inhibitors.
Selected FDA-approved targeted 
therapies are listed in Table 10-11.
Finally, most biologic 
agents are cytostatic, not cytotoxic.
Several antitumor strategies are under investigation.
An 
alternate strategy is the use of autologous tumor vaccines.
Targeting PI3K/Akt/mTOR signaling.
(Modified with permission from McAuiliffe et al.
Thus 
both anti-PD1 and anti-PD-L1 strategies are actively being pur-
sued for cancer therapy.
Several vector systems are under study for gene ther-
apy; however, none is considered ideal.
Tumor size is 
another important variable.
Because of the larger proportion of cells divid-
ing, smaller tumors may be more chemosensitive.
For 
example, cells in the G0 phase are resistant to drugs active in 
the S phase.
For 
drug-sensitive cancers, another factor limiting optimal killing is 
improper dosing.
One mechanism is 
through the loss of the target.
Gamma rays are photons that are released from the 
nucleus of a radioactive atom.
X-rays are photons that are created 
electronically, such as with a clinical linear accelerator.
Currently, 
high-energy radiation is delivered to tumors primarily with linear 
accelerators.
Gamma rays typically are produced by radioac-
tive sources used in brachytherapy.
The dose of radiation absorbed correlates with the energy 
of the beam.
One gray is equivalent to 100 rads, the unit of radiation mea-
surement used in the past.
The mechanism 
of DNA damage differs by the type of radiation delivered.
Radiation damage is manifested primarily by the loss of 
cellular reproductive integrity.
Some cell types, however, undergo apoptosis.
The extent of DNA damage after radiation exposure is 
dependent on several factors.
The most important of these is cel-
lular oxygen.
Hypoxic cells are significantly less radiosensitive 
than aerated cells.
Conventional fractionation is 1.8 to 2 Gy/d, administered 
5 days each week for 3 to 7 weeks.
In these cases, radiation is 
recommended for symptomatic metastases only.
The goal of adjuvant radiation therapy is to decrease local-
regional recurrence rates.
Preoperative radiation therapy has several advantages.
Further, the 
radiation therapy can be modified on the basis of margin status.
Another mode of postoperative radiation therapy is 
brachytherapy.
The radiation source may be cesium, gold, iridium, 
or radium.
Several additional studies of 
adjuvant IORT also are ongoing internationally.
It is thought that chemotherapy given concurrently with 
radiation improves survival rates.
10-16).160 
A minimum dose of radiation must be given before any response 
is seen.
The response to radiation then increases slowly with 
an increase in dose.
The side effects depend on the tissue included in the target 
 volume.
The probability of tumor control and of complica-
tions at different radiation doses.
A.
At lower doses, the probability 
of complications is low, with a moderate chance of tumor control.
B.
(Modified with 
permission from Eisbruch A, Lichter AS.
In selected circumstances, the risk of cancer is high 
enough to justify surgical prevention.
Further, the conservative options of close surveillance 
and chemoprevention need to be discussed.
One of the critical changes expected is earlier 
detection of cancers.
Another area of rapid development is the identification of 
serum markers.
Surgical Therapy
The current trend in surgery is toward more conservative resec-
tions.
With earlier identification of tumors, more conservative 
operations may be possible.
The goal, however, is always to 
remove the tumor en bloc with wide negative margins.
The debate over how to manage the regional lymph node 
basins for certain cancer types continues.
Systemic Therapy
The current trend in systemic therapy is toward individualized 
therapy.
It is now presumed that all cancers of a certain cell ori-
gin are the same.
Thus all patients are offered the same systemic 
therapy.
It is likely that in the near future all tumors can be 
tested and treatments individualized.
Instead, the latter patients can be offered 
novel therapies.
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Transplantation
Angelika C.
Gruessner, Tun Jie, Klearchos Papas, 
Marian Porubsky, Abbas Rana, M.
Cristy Smith, 
Sarah E.
Yost, David L.
Dunn, and Rainer W.G.
But the success of transplantation has created new chal-
lenges.
11-1).
11-2).
HISTORY
Over the centuries, multiple references to transplantation can 
be found in the literature.
Two major events preceded the rise of 
transplantation.
322
Figure 11-1.
Patients on the waiting list and the 
number of organ transplants performed, 2000 to 
2009.
(U.S.
data from the Scientific Registry of 
Transplant Recipients Annual Report, http://srtr.
Second, the findings of British scientist Sir Peter B.
Other centers performed similar trans-
plants and could reproduce the good results.
Ultimately, attempts were made to perform kidney trans-
plants between nonidentical individuals.
Dramatic changes occurred with the further develop-
ment of immunosuppression.
The gradual increase in the organ shortage led to innova-
tive surgical techniques.
For example, deceased donor split-liver 
Figure 11-2.
Patients on the waiting list and 
the number of organ transplants performed, 
2009.
KP = kidney and pancreas.
(U.S.
Murray Boston, MA
Liver 1963 Thomas E.
Starzl Denver, CO
Lung 1963 James D.
Hardy Jackson, MS
Pancreas 1966 Richard C.
Lillehei Minneapolis, MN
Heart 1967 Christiaan N.
Barnard Cape Town, South Africa
Small intestine 1967 Richard C.
Lillehei Minneapolis, MN
Heart/lung 1981 Bruce Reitz Stanford, CA
Multivisceral 1989 Thomas E.
Similarly, living donor intestine and pan-
creas techniques have been developed.
TRANSPLANT IMMUNOBIOLOGY
The outcomes of early transplants were unsatisfactory.
The 
limiting factor was the lack of understanding of immunologic 
processes.
Irreversible rejection was the reason for graft loss in 
the vast majority of recipients.
In humans, these antigens make up the 
human leukocyte antigen (HLA) system.
The antigen-encoding 
genes are located on chromosome 6.
Two major classes of HLA 
antigens are recognized.
They differ in their structure, function, 
and tissue distribution.
Class I antigens (HLA-A, HLA-B, and 
HLA-C) are expressed by all nucleated cells.
This leads to 
recognition and elimination of the foreign antigen with great 
specificity.
HLA molecules play a crucial role in transplant 
recipients as well.
They can trigger rejection of a graft via two 
different mechanisms.
This process is called 
allorecognition, with T cells playing the crucial role.
This 
interaction causes transmission of the signal into the cell, named 
signal 1.
However, this signal alone is not sufficient to activate 
the T cell.
An additional costimulatory signal is required, named 
signal 2.
Two well-characterized costimulatory interactions are 
the CD40/CD154 and B7/CD28 pathways.
Rejection is a result of an attack of acti-
vated T cells on the transplanted organ.
The end result is graft damage caused by inflam-
matory injury.
It is triggered by preformed antibodies 
against the donor’s HLA or ABO blood group antigens.
Chronic
Chronic rejection is a slow type of rejection.
Immunosuppressive regimens are very 
important to graft and patient survival posttransplant.
Certain regimens may involve withdrawal, 
avoidance, or minimization of certain classes of drugs.
Char-
acteristics of the most common immunosuppressive agents are 
listed in Table 11-3.
One dose 
alone (30 mg) depletes 99% of lymphocytes.
Moreover, they are often the 
first-line agents in the treatment of acute rejection.
AZA decreases T-lymphocyte 
activity and decreases antibody production.
The most significant side effect of AZA, often dose-
related, is bone marrow suppression.
Leukopenia is often 
reversible with dose reduction or temporary cessation of the 
drug.
Mycophenolate is the prodrug of mycophenolate acid, derived 
from Penicillium fungi.
The other important side effects are leukopenia, anemia, and 
thrombocytopenia (Table 11-4).
Sirolimus is a substrate for CYP3A4/4 
and has many significant drug interactions (see Table 11-4).
Sandim-
mune, an older, oil-based formulation, has poor bioavailabil-
ity and variable absorption.
The newer formulations, Gengraf 
and Neoral, are microemulsified with improved bioavailability.
They also can cause hyperkalemia and 
hypomagnesemia.
It is associated 
with a higher incidence of hypertension and hyperlipidemia than 
is tacrolimus.
Tacrolimus causes a higher incidence of new-onset dia-
betes posttransplant than does cyclosporine.
It is a high-
avidity molecule with slower dissociation rates.
Recent trials have compared the use of belatacept vs.
The FDA recommends the use of 
belatacept only in seropositive recipients.
Studies in liver trans-
plant recipients were halted early because of increased mortality 
rates.
The CD20 antigen is expressed early in the B-cell cycle but 
is absent on mature plasma cells.
It can directly target plasma cells.
It blocks the activation of the terminal complement 
cascade.
Infections
Transplant recipients are predisposed to a variety of infec-
tions.
Immunosuppression is the obvious reason.
Posttransplant, they continue to have significant 
comorbid conditions.
Early.
Infections during 
this period can be devastating.
It is imperative to differentiate between medical and 
surgical infections.
Surgical infections are the most common 
and require expedient surgical intervention.
In liver and pancreas recipients, surgical infections are 
most severe.
Furthermore, pretrans-
plant infections can re-emerge or worsen.
Treatment entails a prompt return to the operating room.
Common fungal isolates are Can-
dida albicans, Candida krusei, and Candida glabrata.
Local-
ized infections or abscesses can be treated with percutaneous 
drainage and antibiotics.
Medical infections include respiratory, urinary tract, 
and bloodstream infections.
Late.
Pretransplant exposure to viruses may confer immunity.
Infections 
usually occur 3 to 6 months posttransplant or during treatment 
for rejection.
It results from the 
proliferation of EBV-positive B cells in immunosuppressed 
patients.
Among patients with early lesions, the 
first line of treatment is to reduce immunosuppression.
For those 
with more advanced PTLD, rituximab is used.
Diagnosis is con-
firmed by biopsy; the preferred treatment is IV amphotericin B.
It is 
endemic in the Southwest, Northern Mexico, and various parts 
of Central and South America.
This infection can be resilient 
and difficult to treat.
The first line of treatment is high-dose 
amphotericin B.
Treatment consists of pro-
longed (3 to 13 months) administration of oral itraconazole.
Patients with invasive Candida or Aspergillus infec-
tions have a 20% mortality rate.
The standardized incidence ratio was 2.10 (as 
compared with the general population).
The nation-
wide “Organ Donation Breakthrough Collaborative,” sponsored 
by the U.S.
How-
ever, a severe donor shortage remains.
The number of living 
organ donors peaked in 2007 and has declined since.
Deceased Donors
Most transplants today utilize organs from deceased donors.
Formerly, death was determined by the cessation of both cardiac 
and respiratory function.
Donation after Brain Death.
The medical history and social history are obtained from the 
available family members.
11-3).
Exposure for thoracic and abdominal organ  
procurement.
preserved.
The common bile duct is transected at the superior mar-
gin of the head of the pancreas.
The gallbladder is incised and 
flushed with ice-cold saline to clear the bile and sludge.
If the 
pancreas is to be procured, the duodenum is flushed with anti-
microbial solution.
The tho-
racic organs, liver, pancreas, and kidneys are then removed.
Donation after Cardiac Death.
After the cessation of cardiac and respiratory 
function, organ procurement commences.
The surgical team must be 
familiar with, and respect, the local protocol.
The initial experience with organs procured using ECMO has 
been encouraging.
Surgical Technique.
Alternatively, the NHBD is transported 
to the operating room after declaration of cardiac death.
A midline incision is used to rapidly gain entry into the 
abdominal cavity.
A 
short segment of the distal aorta is dissected out from the retro-
peritoneum.
A moist umbilical tape is passed around the aorta, 
which is used to secure a cannula.
The distal aorta is clamped.
Next, a cannula is passed cephalad through an aortotomy and 
secured.
The portal flush is 
then instituted.
It is the fiduciary duty of 
transplant professionals to explain the risks of organ donation.
Any decision to donate should be uncoerced, and no entice-
ments should be offered.
The use of living donors offers numerous advantages for 
recipients in need.
Receiving an organ from a closely matched 
relative may also have immunologic benefits.
The major disadvantage is the risk to the living donor.
Medically, there is no possibility of benefit to the donor, only 
the potential for harm.
The risk of death associated with dona-
tion depends on the organ being removed.
The risk of surgical and medical 
complications also depends on the procedure being performed.
The guiding prin-
ciple should be minimization of risk to the donor.
The donor’s left kidney is usually 
preferable because of the long vascular pedicle.
11-4).
11-5).
Such solutions help prevent cellular swelling 
and the loss of cellular potassium.
Laparoscopic left donor nephroureterectomy.
A.
Takedown of splenic flexure of colon to expose the left renal hilum.
B.
Dis-
section of left ureter off the psoas muscle.
C.
Dissection of left renal vein and gonadal vein.
Left ureter seen lateral to the dissection.
D.
Dissection of left renal artery.
Lumbar veins clipped and divided.
E.
Endo-TA stapler transection of the left renal artery.
F.
Placement of 
ports and Pfannenstiel incision for the donor kidney extraction.
Figure 11-5.
Donor hepatectomy (right hepatectomy).
A.
The liver parenchymal transection line (c, the Cantlie line) marked with cautery.
Right portal vein (p) and right hepatic artery (a) isolated.
b = bile duct.
Cystic duct was cannulated for intraoperative cholangiography.
B.
Exposure of hepatic veins after transection of the parenchyma.
In the case of heart and lung recipients, ischemic times should 
be under 6 hours.
All of those times assume the use of normal 
donors.
This 
infrastructure later became the blueprint for other countries to 
follow.
As a result, organ transplantation is the most transparent 
field of medicine.
The meeting is coordinated by 
a transplant physician or surgeon.
In an open forum format, 
important decisions such as type of donor (living vs.
deceased) 
are discussed.
4
335
T
RANSPLANTATION
CHAPTER 11
Medical Evaluation
Cardiovascular Disease.
Diabetes and hypertension are the 
leading causes of chronic renal disease.
Concomitant cardiovas-
cular disease (CVD) is a common finding in this population.
The perioperative risk assessment is based on 
patient symptoms and exercise tolerance.
Malignancies.
Transplant candidates should undergo routine tuberculosis 
(TB) screening.
In such 
candidates, obtaining a liver biopsy is essential to assess the 
disease severity.
Transplant candidates with chronic HCV infection often 
have HCV-related glomerulonephritis.
In 
patients with evidence of cirrhosis, a combined liver-kidney trans-
plant should be considered.
In appropriate candidates, pretrans-
plant antiviral treatment with interferon-α may be considered.
Kidney Disease.
Adjuvant therapy with rituximab 
recently has been proposed.80
Hypercoagulopathy.
Surgical Evaluation
Urologic Evaluation.
Vascular Evaluation.
Careful physical examination often reveals significant central 
and/or peripheral vascular disease.
Immunologic Evaluation.
ABO blood typing and HLA typ-
ing (HLA-A, -B, and -DR) are required before a kidney trans-
plant.
Psychosocial Evaluation.
Recipient Operation
Kidney allografts usually are transplanted heterotopically.
The rectus muscle can be easily mobilized medially 
without being divided.
11-6).
The retroperitoneal space of the iliac fossa is entered by 
mobilizing the peritoneum medially.
A self-retained retractor is used to expose 
the surgical field.
The iliac vessels should be dissected with 
great care.
11-7).
Incision and exposure for kidney transplant.
A.
Mark for the skin incision.
B.
Anterior rectus sheath incised obliquely.
The 
abdominal muscle transected lateral to the rectus muscle.
C.
External iliac artery and vein dissected.
Figure 11-7.
Vascular anastomoses of kidney transplant.
A.
B.
AB
the anastomosis.
11-8).
Therefore, reconstruction of the en bloc graft pretransplant is 
key to a successful transplant.
The donor’s suprarenal vena 
cava and aorta are oversewn.
The lumbar branches of the cava 
and aorta are ligated.
Dissection around the renal hilum should 
be avoided.
The orientation of the cava and aorta should be 
AB
Figure 11-8.
Arterial and venous reconstruction.
A.
Two renal arteries combined into a single Carrel patch (arrow).
Right renal vein exten-
sion conduit constructed with stapled caval patch.
IVC = inferior vena cava; R = right renal vein.
B.
Three renal arteries anastomosed to 
external iliac artery separately.
AB
Figure 11-9.
En bloc kidney transplant (3-month-old donor kidneys).
A.
En bloc kidneys benched.
Vascular integrity tested with methylene 
blue (blue hue look of the kidneys).
B.
En bloc kidneys transplanted in to a 62-year-old woman.
clearly marked, in order to avoid torsion of the anastomosis.
11-9).
Electrolyte 
panels should be checked.
The crucial elements include hemodynamic stability 
and fluid and electrolyte balance.
Hypotension is an unusual event immediately posttrans-
plant.
Immediate 
action should be taken to avoid life-threatening complications.
Postoperatively, urine output is used as a surrogate marker 
to monitor graft function.
Suddenly decreased or minimal urine output requires 
immediate attention.
Postoperative bleeding is an uncommon event after a kid-
ney transplant.
Recipients on anticoagulation or antiplatelet 
treatments are at increased risk.
Doppler 
ultrasound is useful to establish the underlying cause.
Surgical 
exploration seldom is required, because the accumulated hema-
toma tamponades the bleed.
One of the most devastating postoperative complications 
in kidney recipients is graft thrombosis.
It is rare, occurring in 
fewer than 1% of recipients.
Graft thrombosis usually occurs 
within the first several days posttransplant.
Doppler ultrasound may help 
confirm the diagnosis.
Urologic complications are seen in up to 5% of recipi-
ents.
Late 
urinary obstruction is often related to ischemia.
The appear-
ance of hydronephrosis on ultrasound is a good initial indicator.
Treatment includes percutaneous placement of a nephrostomy 
and ureteral stenting.
Results
A kidney transplant remains the most common solid organ 
transplant in the world today.
According to a recent analysis of 
more than 250,000 U.S.
An estimated 10% to 15% of the U.S.
population is 
affected by it; of all diabetic patients, 10% have early-onset dis-
ease.
It is one of the most common causes of death, along 
with myocardial infarction and stroke.
Diabetes significantly 
decreases not only the quality of life but also life expectancy.
Almost 80% of pancreas 
transplants are performed in this category.
A successful SPK 
transplant renders the recipient dialysis-free and insulin-
independent.
•    Pancreas after kidney (PAK) transplant in diabetic and 
posturemic patients.
Approximately 15% of all pancreas 
transplants fall into this category.
•    Pancreas transplant alone (PTA) in nonuremic patients 
with brittle diabetes mellitus.
Only about 8% of all pan-
creas transplants are in this category.
11-10).
The splenic artery 
is divided close to its origin and is retained with the pancreas.
The SMA is also procured with an aortic Carrel patch and is 
retained with the pancreas.
Simultaneous pancreas, in situ 
split-liver, and intestine procurement.
(Repro-
duced from Gruessner RWG, Sutherland DER, 
eds.
Transplantation of the Pancreas.
New York: 
Springer, 2004; Color Plate VI, Figure 8.1.3.11.
Back table preparation is carried out in a basin filled 
with chilled preservation solution.
11-11).
11-12 and 11-13).
For venous drainage, systemic 
venous drainage is preferred over portal venous drainage.
Venous and arte-
rial anastomoses are performed end-to-side.
After restoration of 
SA
IIA
EIA
SMA SMA
Figure 11-11.
Posterior view of the pancreas graft with Y-graft 
reconstruction.
(Reproduced from Gruessner RWG, Sutherland DER, eds.
Trans-
plantation of the Pancreas.
New York: Springer, 2004; Color Plate 
VII, Figure 8.1.3.13[B].
With kind permission of Springer Science 
+ Business Media.)
Figure 11-12.
Whole-organ transplant with systemic 
vein and bladder exocrine drainage.
(Reproduced from 
Gruessner RWG, Sutherland DER, eds.
Transplanta-
tion of the Pancreas.
New York: Springer, 2004; Color 
Plate XIV, Figure 8.2.2.2[B].
The pancreas usually is placed with the 
pancreatic head and duodenum pointing caudally.
Bladder drainage has 
two main advantages.
Amylase levels are measured routinely in the recipient’s urine.
In the absence of hyperglycemia, more 
than 90% of pancreas rejection episodes are reversible.
Second, 
bladder drainage avoids the bacterial contamination that occurs 
with enteric drainage.
Enteric drainage is more physiologic and has advantages 
as well.
Whole-organ transplant with systemic vein and 
enteric exocrine drainage.
(Reproduced from Gruessner RWG, 
Sutherland DER, eds.
Transplantation of the Pancreas.
New York: 
Springer, 2004; Color Plate XIV, Figure 8.2.2.2[A].
Bleeding frequently 
requires relaparotomy.
Thrombosis usually occurs within the first week posttrans-
plant.
Surgi-
cal exploration in recipients with thrombosis usually requires a 
graft pancreatectomy.
The most common nonsurgical complication posttrans-
plant is rejection.
The incidence of rejection is about 30% within 
the first year.
In enteric-
drained recipients, one must rely on serum amylase and lipase 
levels only.
The diagnosis of 
rejection should be confirmed by a percutaneous pancreas graft 
biopsy.
Bladder-drained pancreas recipients may experience an 
array of unique urologic complications.
In particular, patients with high PRA levels should be 
considered for a living donor transplant.
11-14).
Ste-
roid avoidance has increased over time in all three recipient 
categories.
These changes have led to improved patient and graft 
survival rates.
Like-
wise, the 1-year immunologic graft loss rate has also decreased, 
ranging from 2% to 6%.
The 1-year patient survival rates now 
exceed 90% in all three recipient categories.
The 1-year pancreas graft sur-
vival rate is 80% in PAK recipients and 78% in PTA recipients.
Figure 11-14.
Segmental transplant with systemic vein and blad-
der exocrine drainage.
The splenic artery anastomosis is lateral and proximal 
to the splenic vein anastomosis.
A two-layer ductocystostomy is 
constructed.
(Reproduced from Gruessner RWG, Sutherland DER, 
eds.
Transplantation of the Pancreas.
New York: Springer, 2004; 
Color Plate XVI, Figure 8.2.2.4.
The quality of the deceased donor 
graft is of paramount importance.
Islet vs.
Islet transplants rarely maintain long-term insulin 
independence.
The full potential of islet transplants remains to be real-
ized, but the future is exciting.
History
The first experimental liver transplants in dogs are often attrib-
uted to C.
Stuart Welch in 1955 and then Jack Cannon in 1956.
The 
advent of better immunosuppressive drugs was instrumental.
In 
1978, cyclosporine was introduced clinically in England.
It was 
soon combined with prednisone to great effect.
The arrival of 
tacrolimus in the 1990s further improved graft survival.
Technical advances were also significant.
Improvements in portosystemic shunting and perioperative criti-
cal care also were contributory.
Chronic alcoholic disease and HCV 
are the most common indications in the United States.
Furthermore, most transplant centers recommend rehabilitation 
and Alcoholics Anonymous programs.
Once recur-
rence occurs, treatment methods are limited.
Posttransplant outcomes for such 
patients have been excellent.
Hemochromatosis, an inherited disorder, 
results in excessive intestinal iron absorption.
Iron deposition 
can cause cirrhosis and severe cardiomyopathy.
Careful cardiac 
evaluation is necessary pretransplant.
Careful pul-
monary evaluation is necessary pretransplant.
Patients can 
develop significant neurologic complications and cirrhosis.
Resection is the first 
line of treatment if possible, but often, cirrhosis is too advanced.
If the tumor meets the Milan criteria, a liver transplant can be 
performed.
A significant 
number of patients will recover with supportive care.
They are 
susceptible to infections, which are frequently overwhelming.
Recipient Selection
The diagnosis of cirrhosis itself is not an indication for a trans-
plant.
The early stages result in sleep disturbances and depression.
Hyperammonemia suggests worsening liver 
function and bypass of portal blood flow around the liver.
GI 
bleeding and infection can exacerbate hepatic encephalopathy.
coli, although Gram stain  
and culture results should be used to guide therapy.
Portal hypertensive bleeding can be a devastating event 
for patients with cirrhosis.
Only 50% of bleeding events cease spontaneously, 
so treatment must be expedient.
The initial medical treatment 
is with vasopressin and octreotide.
The initial intervention is 
endoscopy with sclerotherapy and band ligation of bleeding 
varices.
Hepatorenal syndrome is a form of acute renal failure that 
develops as liver disease worsens.
Candidates should have 
a normal ejection fraction.
If coronary arterial disease is pres-
ent, they should undergo revascularization pretransplant.
Severe 
chronic obstructive pulmonary disease (COPD) with oxygen 
dependence is a contraindication.
Candidates with pulmonary hypertension should be 
evaluated with a right heart catheterization.
Fungal and multidrug-resistant bacterial infections 
are relative contraindications.
Some centers require an extended 
period of treatment and documented eradication pretransplant.
A bilateral subcostal incision with midline extension is used.
Mechanical retraction spreads the rib cage to allow access.
The ligamentous attachments of the liver are dissected free.
11-15).
The bile duct, portal structures, and vena cava are 
divided, completing the hepatectomy (Fig.
After the liver is removed, the anhepatic phase begins.
Significant hemodynamic instability and increased 
variceal bleeding can occur.
The donor liver is placed in the orthotopic position.
Coagulopathy also can worsen because of 
these byproducts as well as fibrinolysis.
Of course, many variations 
are possible.
After arterial reperfusion, the bile duct anastomosis 
Figure 11-15.
Cirrhotic liver immobilized in preparation for com-
plete hepatectomy.
Figure 11-16.
If necessary for technical reasons, 
the recipient common duct can be joined to a Roux-en-Y limb.
The piggyback technique is a common variation of the 
standard technique.
The recipient’s IVC is preserved by care-
fully dissecting off the posterior aspect of the liver.
The recipient’s liver is 
removed by dividing it at the confluence of the hepatic veins.
The most common indication is biliary atresia.
The surgical procedure is similar to the adult procedure.
As a result, surgical 
complications are much more common in pediatric recipients.
Hepatic artery thrombosis is about three times more common.
11-17).
Both techniques have simi-
lar outcomes.
11-18).
Donation 
by an adult living donor to a pediatric recipient requires the left 
lateral lobe (Fig.
11-19).
Donor safety is paramount.
Donor and recipient procedure for living donor liver 
transplant into a pediatric recipient.
A separate donor team should serve as the 
donor advocate and thoroughly explain all risks.
Careful recipient selection is essential.
Postoperative Care
A liver transplant imposes significant trauma on the major 
organ systems.
Immediately posttransplant, the first goal is 
to stabilize those systems.
350
BASIC CONSIDERATIONS
PART
 
I
Figure 11-18.
A.
Hepatic transection completed for right lobe removal.
B.
Implantation of the donor right lobe with the MHV.
CHA = common hepatic artery.
(Reproduced with permission 
from Gruessner RWG, Benedetti E, eds.
Living Donor Organ Transplantation.
New York: McGraw-Hill, 2008.
R.P .A.
RHD
C.A.
C.D.
Careful attention needs to be paid to ongoing 
bleeding.
Appropriate hemoglobin levels should be main-
tained.
Evaluation of Graft Function
Evaluation of the graft begins in the operating room.
A.
Hepatic transection completed for removal of 
left lateral segments (S2 and S3).
Bile ducts to segments 2 and  
3 divided; vascular structures still intact.
B.
Implantation of the 
donor left lobe.
(Reproduced with permission from Gruessner 
RWG, Benedetti E, eds.
Living Donor Organ Transplantation.
New 
York: McGraw-Hill, 2008.
Transaminases usually 
peak by postoperative day 2.
An aspartate transaminase (AST) 
level greater than 2500 IU/L is suggestive of significant injury.
Cholestasis usually peaks from postoperative day 7 to 12.
The 
INR should improve shortly after reperfusion.
The most common vascular complication is hepatic artery 
thrombosis.
Diagnostic imaging with ultrasound has more 
than 90% sensitivity and specificity.
If hepatic artery thrombosis 
is identified, urgent re-exploration is needed.
Thrombosis of the portal vein is very uncommon.
Signs of 
early thrombosis include liver dysfunction, ascites, and variceal 
bleeding.
Upon diagnosis, an operative thrombectomy should 
be attempted.
Signs include fever and abdominal pain, with bilious drainage 
from surgical drains.
Diagnosis is made with cholangiography.
Complications manifest themselves as leaks or stric-
tures.
Two common reconstructions are 
choledochostomy and choledochojejunostomy.
Some centers 
also routinely use T-tube stents or internal stents.
Consensus 
has not been reached as to which reconstruction technique is 
superior.
Intra-
abdominal infections should raise concerns of a possible bile 
leak.
Fungal infections are often associated with poor graft 
function.
Acute rejection occurs in approximately 20% of liver 
recipients.
Maintenance immunosuppression consists of a 
corticosteroid, tacrolimus, and mycophenolate.
Over the first two decades, the results were dismal.
High levels 
of immunosuppression are needed, yet the rejection rate is still 
high.
Intestine failure is typically multifactorial.
Indications for a transplant differ between the adult and 
pediatric population.
The leading causes of intestine failure are 
summarized in Table 11-7.
Liver failure is often seen in patients on long-term 
TPN.
Both vessels are isolated at the root of the 
mesentery.
Figs.
11-20  to 
11-22 show these three main types of transplants.
The vast majority of intestine transplants use a deceased 
donor organ.
11-24).
Similarly, the recipient operation also varies by the organs 
transplanted.
The 
diversion of splanchnic flow into the systemic venous circulation 
Figure 11-20.
Isolated intestine transplant.
Figure 11-21.
Combined liver-intestine transplant.
Figure 11-22.
Multivisceral transplant.
Once the recipient recovers, the ileostomy 
can be taken down.
Broad-spectrum antibiotics are an integral 
component of care.
Of all solid organ transplants, intestine transplants have 
the highest rate of rejection.
Rejection leads to structural damage of the intes-
tinal mucosa.
Translocation of endoluminal pathogens into the 
circulation can cause systemic infections.
Immediately posttransplant, recipients are maintained 
on TPN.
Enteral nutrition is initiated as early as possible, but 
is advanced very cautiously.
Despite all the recent advances, the complication rate 
posttransplant remains high.
A.
Donor operation.
B.
Recipient operation.
(Reproduced with permission from Gruessner RWG, 
Benedetti E, eds.
Living Donor Organ Transplantation.
New York: McGraw-Hill, 2008.
Hardy performed the first human lung transplant in 
1963, although the patient lived only 18 days.
The first suc-
cessful long-term lung transplant was performed in 1983 in 
Toronto.
The 1980s 
marked the start of the modern age of thoracic transplants.
Heart Transplants
Indications.
About 3000 patients are 
added to the waiting list each year.
Evaluation.
Procedure.
Heart transplants are most often performed ortho-
topically (Fig.
11-25).
The recipient’s native heart is removed, 
Figure 11-24.
Recipient operation.
A very short Roux-en-Y loop (10 to 
20 cm) is anastomosed to the donor’s bile duct(s).
(Reproduced with 
permission from Gruessner RWG, Benedetti E, eds.
Living Donor 
Organ Transplantation.
Color Plates, Figure IN-6.
New York: 
McGraw-Hill, 2008.
© 2008 by The McGraw-Hill Companies, Inc.)
Figure 11-25.
A donor’s heart brought forward for anastomosis.
Usually the left atrial cuff 
is anastomosed first, providing left heart inflow.
11-26).
Posttransplant Care.
Patient survival rates for heart recipi-
ents differ slightly after primary transplants vs.
retransplants.
Heart recipients must be monitored for both early and late 
complications.
Both T-cell–mediated (cellular) and 
B-cell–mediated (antibody-mediated) rejection are monitored.
Figure 11-26.
Other immunosuppressive agents can be used, depending on the 
needs of individual recipients.
Coronary artery disease can 
begin to develop as early as 1 year posttransplant.
Its pathogen-
esis is unknown, but it is believed to be immunologic.
Lung Transplants
Indications.
The next most common diagnosis 
among patients on the waiting list is cystic fibrosis.
A lung allo-
cation score (LAS) was instituted in 2005.
Evaluation.
Potential lung donors are also screened for blood type 
and size match.
Living donors 
can donate a single lobe to a smaller recipient, such as a child.
Procedure.
11-27).
The pulmonary veins and 
main pulmonary artery are encircled outside the pericardium.
The bronchial anastomosis 
(Fig.
11-28) is performed first and then covered with peribron-
chial tissue or pericardium.
The pulmonary artery and, finally, 
the vein are anastomosed.
All clamps are removed, and the lung is aerated.
At least 
two chest tubes are left in place.
Posttransplant Care.
Patient survival rates for lung recipients 
vary significantly after primary vs.
redo transplants.
Postoperative care of lung recipients can be very labor- 
intensive.
Most patients are extubated within the first 24 to 
48 hours.
Early complications include technical complications, 
graft dysfunction, infections, and rejection.
In up to 20% of recipi-
ents, primary early graft dysfunction can occur with no obvious 
cause.
Rejec-
tion is monitored by biopsies and treated as needed.
Strictures are treated with bronchoscopic dilation 
and intervention.
All recipients should be 
taught to perform microspirometry at home as a screening 
Figure 11-27.
Clamshell incision.
Bronchial anastomosis with 
ligated pulmonary arteries and veins.
Figure 11-28.
Bronchial anastomosis.
358
BASIC CONSIDERATIONS
PART
 
I
tool posttransplant.
Biopsies are performed to confirm the diag-
nosis of any complication and, if possible, the cause.
Heart-lung candidates are often younger than their single-organ 
counterparts.
The patient survival rates at 1, 3, and 5 years are 
66%, 48%, and 39%, respectively.
Often, lung complications 
ultimately lead to graft failure.
Alternative names for AHXR include acute vascular rejection 
or delayed xenograft rejection.
The future of xenotransplantation is exciting.
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Entries highlighted in bright blue are key references.
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2.
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Yu Yo Voronoy and the first human 
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1984;159(3):289-294.
3.
Medawar PB.
Br J Exp Pathol.
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4.
Merrill JP Murray J, Harrison JH.
Successful homotransplan-
tation of the human kidney between identical twins.
JAMA.
1956;160(4):277-282.
5.
Murray JE, Merrill J, Harrison JH, et al.
Prolonged sur-
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Starzl TE, Waddell WR, Marchioro TL.
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Calne RY, Rolles K, Thiru S, et al.
Lancet.
1979;2(8151):1033-1036.
8.
Hall BM, Dorsch S, Roser B.
Cellular basis of allograft-
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In: Kouchoukos NT, Blackstone EH, Doty DB, et al, eds.
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3rd ed.
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2003:1725.
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The History Channel website.
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transplantation, heart-lung transplantation.
In: Pearson FG, 
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2011;25(4):E415-E421.
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2009;16:196-202.
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2009;16(4):215-222.
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2002;2:695.
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T
RANSPLANTATION
CHAPTER 11
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This page intentionally left blank 
Patient Safety
Catherine L.
Chen, Michol A.
Cooper,  
Mark L.
Shapiro, Peter B.
Angood, and Martin  
A.
A single error can even destroy a surgeon’s 
career.
Other 
high-risk industries have managed to maintain an impeccably 
low error rate.
For example, one of the highest risk systems in 
existence today, the U.S.
Navy’s nuclear submarine program, 
has an unmatched safety record.
•  People trust one another.
•  People have friendly, open relationships emphasizing cred-
ibility and attentiveness.
The IOM report brought much-needed attention to the 
field of patient safety.
7 Patient rapport is the most important determinant of 
 malpractice claims against a surgeon.
Her father, Sidney 
Zion, a lawyer and columnist for the N.Y.
These recommendations 
were adopted by New York State in 1989.
Context: Are we improving the safety culture?
Outcome Process
Structure
Figure 12-1.
Donebedian model for measuring quality.
(From 
Makary et al,6 with permission.)
and evidence-based medicine).
Intimidation of other OR personnel by surgeons 
was historically accepted as the norm.
This can prevent nurses 
and other OR staff from pointing out potential errors or mis-
takes.
Moreover, this culture is not limited to the OR.
The 
hospital was sued by the two women’s families and by one 
of the doctors disciplined.
•  I am encouraged by my colleagues to report any patient safety 
concerns I may have.
•  The culture in this clinical area makes it easy to learn from 
the mistakes of others.
•  Medical errors are handled appropriately in this clinical area.
•  I know the proper channels to direct questions regarding 
patient safety in this clinical area.
•  I receive appropriate feedback about my performance.
•  I would feel safe being treated here as a patient.
•  In this clinical area, it is difficult to discuss mistakes.
Scores can be compared to those of 
other participating institutions to compare safety climates.
Teamwork is dependent on the underlying culture and patterns 
of communication.
12-2).
Root causes of sentinel events 2004 to 
2012.
(From Makary et al,17 with permission from Else-
vier.
It is 
also associated with higher job satisfaction ratings and less sick 
time taken from work.
12-3).
Similar 
discrepancies have been found in ICUs.
Differences in teamwork perceptions between sur-
geons and operating room (OR) nurses.
(From Makary et al,17 with 
permission.
CRNA = certified registered nurse anesthetist.
Source: From Makary et al,17 with permission from Elsevier.
©2006 by the American College of Surgeons.
Table 12-3 
Five-point operating room briefing
What are the names and roles of the team members?
Is the correct patient/procedure confirmed?
(The Joint  
 Commission Universal Protocol [TIME-OUT])
Have antibiotics been given?
(if appropriate)
What are the critical steps of the procedure?
What are the potential problems for the case?
Source: From Makary et al,19 with permission from Elsevier.
©2007 by 
the American College of Surgeons.
Briefings often are locally adapted to the specific needs 
of the specialty.
Figure 12-5.
Incidence of identification errors 
observed per 1000 specimens (n = 21,351).
(From Makary et al,22 with permission.
Copy-
right Elsevier.)
Figure 12-4.
World Health Organization surgical safety checklist.
(Reproduced with permission from World Health Organization Safe Sur-
gery Saves Lives.
Available at: http://www.who.int/patientsafety/safesurgery/en/.
Yes
Is the site marked?
Yes
Not applicable
Yes
Yes
No
Yes
Difficult airway or aspiration risk?
No
Yes, and equipment/assistance available
Risk of >500ml blood loss (7ml/kg in children)?
Confirm the patient’s name, procedure, 
and where the incision will be made.
Has antibiotic prophylaxis been given within 
the last 60 minutes?
How long will the case take?
What is the anticipated blood loss?
To Anaesthetist:
Are there any patient-specific concerns?
To Nursing Team:
Has sterility (including indicator results) 
been confirmed?
Are there equipment issues or any concerns?
This checklist is not intended to be comprehensive.
Additions and modifications to fit local practice are encouraged.
Not applicable
Is the anaesthesia machine and medication
check complete?
Is the pulse oximeter on the patient and
functioning?
Known allergy?
This makes sign outs 
a very vulnerable process of care, which can lead to catastrophic 
events.
Sign outs 
should occur whenever a patient’s care setting or provider is 
changing.
.
12-6).
She spent 10 days in the pediatric intensive care unit and was well on her way to recovery.
Around 1 p.m.
the next day, a nurse came to Josie’s bedside with a syringe of methadone.
Josie’s heart stopped, and her 
eyes became fixed.
She was moved to the pediatric intensive care unit and placed on life support.
Two days later, on February 22, 
2001, she died from severe dehydration.
Figure 12-6.
Impact of operating room briefings on team-
work and communication.
(From Makary et al,19 with per-
mission from Elsevier.
Decision making
utilized input
from relevant
personnel.
Surgery and
anesthesia
worked together
as a well-
coordinated
team.
They can identify potential 
safety problems that merit further investigation.
These process and 
outcome measures are detailed in Table 12-5.
hospitals participate in the program.
Several insights about patient safety have arisen as a result 
of NSQIP.
This survey is conducted in 41 regions that 
cover over half of the U.S.
population and 62% of all hospital 
beds in the country.
In 2011, more than 1200 urban, suburban, 
and rural hospitals participated in the survey.
This 
information can be viewed at hospitalsafetyscore.org.
Coronary artery bypass graft ≥450/100
2.
Percutaneous coronary intervention ≥400/75
3.
Abdominal aortic aneurysm repair ≥50/22
4.
Aortic valve replacement ≥120/22
5.
Pancreatic resection ≥11/2
6.
Esophagectomy ≥13/2
7.
Bariatric surgery >100/20
Source: From The Leapfrog Group,34 with permission.
The second Global Patient Safety Challenge focuses 
on improving the safety of surgical care.
Criteria for inclusion as a “never event” are 
listed below.
Source: From National Quality Forum,36 with permission.
But the program was shut 
down by this event.
Of these, mortality was reported in 6.6%, permanent 
injury in 33%, and temporary injury in 59%.
The cost of the 
never events totaled $1.3 billion.
The decision to remove these retained needles 
depends on symptoms and patient preference.
Retained 
surgical sponges should always be removed.
It is difficult 
to determine the true incidence of wrong-site surgery for several 
reasons.
Another factor is that wrong-site surgery is underreported 
by healthcare providers.
Finally, the total number of potential 
opportunities for each type of wrong-site error is unknown.
The protocol has been endorsed by more 
than 50 professional associations and organizations.
Through this, over the next year, most hospitals 
decreased their mortality rate to below 2%.
Transparency in healthcare is becoming central to the 
healthcare quality discussion.
•    Perform an operating room briefing (checklist) to identify 
and mitigate hazards early.
•    Promote a culture of speaking up about safety concerns.
•    Use a screening x-ray to detect foreign bodies in high-risk 
cases.
•    Begin patient sign-outs with the most likely immediate 
safety hazard.
Source: Reproduced with permission from Michaels RK, et al.
Ann Surg 245:526, 2007.
Most surgical errors occur in 
the OR and are technical in nature.
Physicians’ fear of litigation represents 
a major barrier to error disclosure.
Its average payout in 2005 was $16,000 per  
settlement, vs.
This model also was replicated at 
the University of Michigan Health System with similar results.
In addition, University of 
Michigan doctors, patients, and lawyers are happier with this 
system.
Individual errors can cause minor or major com-
plications during or after a surgical procedure.
Complications in Minor Procedures
Central Venous Access Catheters.
Complications of central 
venous access catheters are common.
•  Experienced personnel should insert the catheter or should 
supervise the insertion.
•  Use proper positioning and sterile technique.
•  Ultrasound is recommended for internal jugular vein  insertion.
•  All central catheters should be removed as soon as possible.
Common complications of central venous access include 
the following.
Prevention 
requires proper positioning of the patient and correct insertion 
technique.
If the patient is symptomatic, a thoracostomy tube should 
be placed.
This  
usually creates sufficient compromise that a tube thoracostomy 
is required.
A prompt chest x-ray and close monitoring of the 
patient until retrieval are indicated.
Treatment may prove 
futile if the air bolus is larger than 50 mL, however.
Nearly 15% of hospital-
ized patients will acquire central venous line sepsis.
The required treatment 
is 4 to 6 weeks of tailored antibiotic therapy.
Arterial Lines.
Arterial lines are placed to facilitate arterial 
blood gas sampling and hemodynamic monitoring.
Although complications occur less than 1% of the time, they 
can be catastrophic.
Pseudoaneurysms and arteriovenous fistulae can also occur.
Endoscopy and Bronchoscopy.
The principal risk of gas-
trointestinal (GI) endoscopy is perforation.
In 
obtunded or elderly patients, a change in clinical status may take 
24 to 48 hours.
When diagnosed in a timely fashion, they are rarely life 
threatening.
If biopsies have been performed, 
the risk for these complications increases.
Tracheostomy.
A recent literature review examining early 
(<3–7 days) vs.
Complications and outcomes between the 
two different methods remain largely equivalent.
The most dramatic complica-
tion of tracheostomy is tracheoinnominate artery fistula (TIAF) 
(Fig.
12-7).58,59 This occurs rarely (~0.3%) but carries a 50% to 
80% mortality rate.
TIAFs can occur as early as 2 days or as 
late as 2 months after tracheostomy.
A sentinel bleed occurs in 
50% of TIAF cases, followed by a large-volume bleed.
This illustration depicts improper positioning of the 
percutaneous needle.
the innominate artery while preparation for a more definitive 
approach is organized.
Percutaneous Endogastrostomy.
Tube Thoracostomy.
Chest tube insertion is performed for 
pneumothorax, hemothorax, pleural effusions, or empyema.
Complications of Angiography.
Invasive or noninvasive 
imaging studies confirm the suspected problem.
Initial management is direct compression at 
the access site and resuscitation as indicated.
Renal complications of angiography occur in 1% to 2% 
of patients.
Nonionic contrast also may be of benefit 
in higher-risk patients.
Complications of Biopsies.
Bleeding at a biopsy 
site usually can be controlled with direct pressure.
Organ System Complications
Neurologic System.
The nerve injury may be a stretch injury or an 
unintentionally severed nerve.
Mental status changes in the postoperative patient can 
have numerous causes (Table 12-12).
Mental status changes 
must be continually assessed.
A noncontrast CT scan should be 
used early to detect new or evolving intracranial causes.
Neurologic consultation should be obtained immediately to 
confirm the diagnosis.
DESs do require systemic 
antiplatelet therapy due to the alternative coagulation path-
way.
Duration of antiplatelet therapy of 1 year is routine.
Eyes, Ears, and Nose.
Corneal abrasions are unusual, but 
are due to inadequate protection of the eyes during anesthesia.
Overlooked contact lenses in patients occasionally may cause 
conjunctivitis.
The use of antibiotics for posterior 
packing is controversial.
External otitis and otitis media occasionally occur post-
operatively.
Thyroid and Parathyroid Glands.
Recurrent laryngeal nerve (RLN) injury occurs in less than 
5% of patients.
Of those with injury, approximately 10% are 
permanent.
Dissection near the inferior thyroid artery is a com-
mon area for RLN injury.
The cord on the affected side will be in the paramedian 
position.
With bilateral RLN injury, the chance of a successful 
extubation is poor.
If paralysis of the cords is not permanent, 
function may return 1 to 2 months after injury.
Respiratory System.
Hypotension, hypoxemia, and tracheal deviation 
away from the affected side may be present.
A tension pneumo-
thorax can cause complete cardiovascular collapse.
Treatment 
is by needle thoracostomy, followed by tube thoracostomy.
The 
chest tube is inserted at the fifth intercostal space in the anterior 
axillary line.
Hemothoraces should be evacuated completely.
Delay in 
evacuation of a hemothorax leaves the patient at risk for empy-
ema and entrapped lung.
Fiberoptic bronchoscopy can be useful to clear 
mucous plugs and secretions.
Aspiration complications include pneumonitis and pneu-
monia.
Antibiotics 
are not indicated.
Not all patients can be weaned easily from mechanical 
ventilation.
o2).
Lipids, carbohydrates, and protein have dif-
fering effects on CO2 production.
Patients consuming a diet of 
mostly carbohydrates have an RQ of 1 or greater.
Ideally, an RQ of 0.75 to 0.85 suggests 
adequate balance and composition of nutrient intake.
The occurrence of PE is probably underdiagnosed.
Its 
 etiology is thought to stem from DVT.
The Greenfield filter has 
been most widely studied, and it has a failure rate of less than 
4%.
Retrievable filters, 
however, must be considered as permanent.
In most studies, the 
actual retrievable rate only reached about 20%.
However, IVC filters do not prevent 
PEs that originate from DVTs of the upper extremities.
Cardiac System.
Ventricular arrhythmias and other tachyarrhythmias may 
occur in surgical patients as well.
Cardiac ischemia is a cause of postoperative mortality.
The workup to rule out an AMI includes an ECG and cardiac 
enzyme measurements.
The patient should be transferred to a 
monitored (telemetry) floor.
Gastrointestinal System.
These have lower leak rates, but leaks result in 
mediastinitis and can be difficult to control.
Postoperative ileus is related to dysfunction of the neural 
reflex axis of the intestine.
Excessive narcotic use may delay 
return of bowel function.
Erythromycin is a motilin 
agonist that works throughout the stomach and bowel.
When it does occur, adhesions are usu-
ally the cause.
Internal and external hernias, technical errors, 
and infections or abscesses are also causative.
GI bleeding can occur perioperatively (Table 12-14).
Errors in surgery that cause hyperbilirubinemia largely 
involve missed or iatrogenic injuries.
The presence of cirrhosis predisposes to postoperative 
complications.
Abdominal or hepatobiliary surgery is problem-
atic in the cirrhotic patient.
Spirono-
lactone with other diuretic agents may be helpful in the post-
operative care.
The treatment is long-term 
antibiotics with percutaneous drainage of large abscesses.
Pancreatitis can occur following injection of contrast dur-
ing cholangiography and ERCP.
A pancreatic fistula may 
respond to antisecretory therapy with a somatostatin analogue.
The majority of pancreatic fistulae 
will eventually heal spontaneously.
Renal System.
The 
most common cause is a misplaced or clogged urinary catheter.
Oliguria is initially evaluated by flushing the urinary cath-
eter using sterile technique.
Urine electrolytes should also be 
measured (Table 12-15).
A hemoglobin and hematocrit level 
should be checked immediately.
Hepatobiliary-Pancreatic System.
Complications involv-
ing the hepatobiliary system are usually due to technical errors.
The recommended treatment 
is a Roux-en-Y hepaticojejunostomy.
These patients may 
present with abdominal pain and hyperbilirubinemia.
The diag-
nosis of a biliary leak can be confirmed by CT scan, ERCP, or 
radionuclide scan.
Intrinsic renal 
failure and subsequent ATN are often the result of direct renal 
toxins.
Contrast-induced nephropathy usually leads to a subtle or 
transient rise in creatinine.
Mannitol and furosemide are not 
recommended.
Patients who do not respond to resuscitation are 
at risk for needing renal replacement therapy.
Fortunately, most 
of these patients eventually recover from their renal dysfunction.
Musculoskeletal System.
A compartment syndrome can 
develop in any compartment of the body.
Compartment syn-
drome of the extremities generally occurs after a closed fracture.
Routine skin care and turning of the patient 
help ensure a reduction in skin ulceration.
This can be labor 
intensive, and special mattresses and beds are available to help.
The treatment of a decubitus ulcer in the noncoagulopathic 
patient is surgical débridement.
Earlier rates were 
erroneously reported higher due to lack of contemporary technology.
bHBV is reported with pre-nucleic acid amplification technology.
HBV = hepatitis B virus; HCV = hepatitis C virus.
dressings with frequent dressing changes is the alternative and is 
labor intensive.
Expensive topical enzyme preparations are also 
available.
If the wounds fail to respond to these measures, soft 
tissue coverage by flap is considered.
Contractures are the result of muscle disuse.
Hematologic System.
Transfusion reactions are common complications of blood 
transfusion.
These can be attenuated with a leukocyte filter, but 
not completely prevented.
Severe transfusion reactions are rare but 
can be fatal.
One unit of platelets will 
increase the platelet count by 5000 to 7500 per mL in adults.
It is important to delineate the cause of the low platelet count.
Rarely, it is due to heparin-induced thrombocytopenia I 
and II.
The treatment is 
anticoagulation with synthetic agents such as argatroban.
Factor VIIa use may also be limited due to its potential throm-
botic complications.
Other blood dyscrasias seen by surgeons include hyper-
coagulopathic patients.
Abdominal Compartment Syndrome.
Wounds, Drains, and Infection
Wound (Surgical Site) Infection.
Prophylactic use of antibiotics should sim-
ply not be continued beyond this time.
Overtreating colonization is just as injurious as  undertreating 
infection.
The strict definition of wound (soft  tissue) infection is 
more than 105 CFU per gram of tissue.
Drain Management.
They prevent premature closure of an abscess cavity 
in a contaminated wound.
The risk of surgery is far greater than the 
placement of an image-guided drain.
Urinary Catheters.
The most frequent nosocomial infection is urinary tract 
infection (UTI).
These infections are classified into compli-
cated and uncomplicated forms.
The uncomplicated type is a 
UTI that can be treated with outpatient antibiotic therapy.
The interpretation of urine culture results of less 
than 100,000 CFU/mL is controversial.
Undertreatment or misdiagnosis 
of a UTI can lead to urosepsis and septic shock.
Recommendations are mixed on the proper way to treat 
Candida albicans fungal bladder infections.
Replacement of 
the urinary catheter and a course of fluconazole are appropriate 
A
B
Figure 12-8.
treatments, but some infectious disease specialists claim that  
C.
albicans in the urine may serve as an indication of  fungal 
infection elsewhere in the body.
Empyema.
One of the most debilitating infections is an 
empyema, or infection of the pleural space.
Once the specific 
organisms are confirmed, anti-infective agents are tailored 
appropriately.
Refractory empyemas require specialized surgical 
approaches.
Abdominal Abscesses.
Necrotizing Fasciitis.
septicum, carry a mortality 
of 30% to 70%.
S.
Systemic Inflammatory Response Syndrome, Sepsis, 
and Multiple-Organ Dysfunction Syndrome.
SIRS is the result of proin-
flammatory cytokines related to tissue malperfusion or injury.
Sepsis is categorized as sepsis, severe sepsis, and septic 
shock.
Sepsis is SIRS plus infection.
Severe sepsis is sepsis 
plus signs of cellular hypoperfusion or end-organ dysfunction.
Septic shock is sepsis plus hypotension after adequate fluid 
resuscitation.
Nutritional and Metabolic Support 
Complications
Nutrition-Related Complications.
Slow progression of the enteral feeding administration rate 
can avoid this complication.
Common TPN problems are mostly related to electrolyte 
abnormalities that may develop.
Glycemic Control.
In addi-
tion, some studies find no relationship between glycemic control 
and improved outcomes.
When 
this is performed, glycemic control is enhanced and hypoglyce-
mia is avoided.
Metabolism-Related Complications.
A rapid provocative 
test with synthetic adrenocorticotropic hormone may confirm 
the diagnosis.
After a baseline serum cortisol level is drawn,  
250 μg of cosyntropin is administered.
Problems with Thermoregulation
Hypothermia.
Bradycardia occurs with temperatures below 30°C 
(86°F).
It is well known that hypothermia may induce CO2 
retention, resulting in respiratory acidosis.
Whether this is a worthwhile practice or not may be contro-
versial.
Hyperthermia.
Aggressive cooling meth-
ods are also implemented, such as an alcohol bath, or packing 
in ice.
In cases of severe malignant hyperthermia, the mortality 
rate is nearly 30%.
Thyrotoxicosis can occur after surgery due to undiag-
nosed Graves’ disease.
As 
the name suggests, these patients are usually toxic and require 
supportive measures as well.
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This page intentionally left blank 
Physiologic Monitoring of the 
Surgical Patient
Louis H.
Alarcon and Mitchell P.
Also presented is a brief look at emerging techniques 
that may soon enter into clinical practice.
Delivery of oxygen 
to mitochondria may be insufficient for several reasons.
These factors include the hor-
monal milieu and mechanical workload of contractile tissues.
Arterial blood pressure is a complex function of 
both cardiac output and vascular input impedance.
Several 
methods exist for this purpose.
Systolic pressure is defined as the pressure in the cuff when tap-
ping sounds are first audible.
Diastolic pressure is the pressure 
in the cuff when audible pulsations first disappear.
Unfortunately, this approach is neither accurate nor reliable.
A number of automated devices are capable of repetitively 
measuring blood pressure noninvasively.
Therefore, the width of the cuff should be approximately 
40% of its circumference.
This could 
result in the use of monitoring data to make inappropriate 
clinical decisions.
Under 
these conditions, the pressure in the cuff reflects the pressure 
in the digital artery.
Digital values for systolic and diastolic pressure 
also are displayed.
Other sites include 
the femoral and axillary artery.
Distal ischemia is an uncommon complication of intra-
arterial catheterization.
Catheter-related 
infections can occur with any intravascular monitoring device.
The limb leads are defined as lead I (LA-RA), 
lead II (LL-RA), and lead III (LL-LA).
To detect 95% 
of the ischemic episodes, two or more precordial leads were 
necessary.
determinants of Cardiac Performance
Preload.
Thus, cardiac preload is determined by end-diastolic vol-
ume (EDV).
The presence of atrioventricular 
valvular stenosis may alter this relationship.
Ventricular compliance 
is altered by various pathologic conditions and pharmacologic 
agents.
Afterload.
Contractility.
Contractility is defined as the inotropic state 
of the myocardium.
These end-systolic points on the pres-
sure vs.
volume diagram describe a straight line, known as the 
end-systolic pressure-volume line.
A steeper slope of this line 
indicates greater contractility.
One channel terminates in a balloon at the tip of 
the catheter.
Prior to insertion of the PAC, the integrity of the 
balloon should be verified by inflating it.
One of these channels terminates at the tip of the catheter.
The 
other terminates 20 cm proximal to the tip.
Placement of a PAC requires access to the central venous 
circulation.
Percutaneous placement through either the jugular or 
subclavian vein generally is preferred.
A small-bore needle is 
inserted through the skin and subcutaneous tissue into the vein.
A dilator/introducer sheath is passed over 
the wire, and the wire and the dilator are removed.
The equations used to calculate the derived 
parameters are summarized in Table 13-2.
Measurements of 
QT using the thermodilution technique are simple and reasonably 
accurate.
The measurements can be performed repetitively and 
the principle is straightforward.
to zero.
In 
clinical practice, the Stewart-Hamilton equation is solved by a 
microprocessor.
Changes in blood tem-
perature and QT during the respiratory cycle can influence the 
measurement.
The Fick equation 
can be rearranged as follows: CVO2 = Cao2 – VO2/QT.
Thus it can be seen that SVO2 is a func-
tion of VO2 (i.e., metabolic rate), QT, Sao2, and Hgb.
Therefore for practical purposes, mea-
surements of SVO2 can be performed only intermittently.
By adding a fifth channel to the PAC, it has become pos-
sible to monitor SVO2 continuously.
There was a significantly higher rate of pul-
monary emboli in the PAC group (0.9% vs.
0%).
There 
was no difference in hospital mortality between the 2 groups 
(with PAC 68% vs.
without PAC 66%, p = 0.39).
Clearly, these were critically ill patients, as noted by the high 
hospital mortality rates.
There was no 
formal treatment protocol, but inotropic support was discouraged.
Substantial reduction in symptoms, jugular venous pressure, and 
edema was noted in both groups.
without PAC 9%).
Adverse events were more common among 
patients in the PAC group (21.9% vs.11.5%; P = 0.04).
There was a 1% rate of crossover from 
CVC-guided therapy to PAC-guided therapy.
Certainly, given the available evidence, routine use 
2 of the PAC cannot be justified.
Defining what constitutes the optimum cardiac output, 
however, has proven to be difficult.
As a 
result, the marginal benefit now available by placing a PAC may 
be quite small.
Less invasive modalities are available that may 
provide clinically useful hemodynamic information.
Several approaches 
have been developed, which have achieved variable degrees of 
success.
doppler ultrasonography.
Therefore, measurements of the 
Doppler shift can be used to calculate red blood cell velocity.
Two approaches have been developed for using Dop-
pler ultrasonography to estimate QT.
A second more promising, albeit more invasive, approach 
has been introduced.
FTc is a function of preload, 
contractility, and vascular input impedance.
This methodology is called impedance cardiog-
raphy.
The vast majority of 
pulsatile flow is related to blood moving within the aorta.
Partial carbon dioxide 
(CO2) rebreathing uses the Fick principle to estimate QT non-
invasively.
TEE requires that the patient 
be sedated and usually intubated for airway protection.
Doppler techniques allow estimation of atrial filling 
pressures.
Assessing Preload Responsiveness.
Thus, if QT 
is low, some other means must be employed to estimate pre-
load.
Many clinicians assess the adequacy of cardiac preload by 
determining CVP or PAOP.
StO2 and BD were 
also comparable in predicting mortality.
Many of 
these patients require mechanical ventilation.
When indicated, carboxyhemoglobin and methemoglobin levels 
also can be measured.
Continuous monitor-
ing, however, is expensive and is not widely employed.
DO2 also is dependent on QT 
and Hgb.
Thus, when Sao2 is low, the clinician has only a limited 
number of ways to improve this parameter.
It is considered one of the most important and 
useful technologic advances in patient monitoring.
Under normal circumstances, the contributions of carboxyhe-
moglobin and methemoglobin are minimal.
Capnometry is most commonly 
measured by infrared light absorption.
CO2 absorbs infrared light 
at a peak wavelength of approximately 4.27 μm.
Capnometers are configured with either an in-line sensor or 
a sidestream sensor.
The in-line devices 
are bulky and heavier, but are less likely to become clogged.
A number of situations can be promptly detected 
with continuous capnography.
Causes of 
an increase in Petco2 include reduced minute ventilation or 
increased metabolic rate.
With a patent Foley catheter, urine output is a gross 
indicator of renal perfusion.
Oligu-
ria is a cardinal sign.
While the diagnosis of ACS is a clinical 
one, measuring IAP is useful to confirm the diagnosis.
CPP is equal to the difference between MAP and ICP: 
CPP = MAP – ICP.
These devices can be placed in the 
intraventricular, parenchymal, subdural, or epidural spaces.
It is especially useful in obtunded and comatose patients.
They also can provide prognostic data 
in posttraumatic coma.
Normal 
values for PbtO2 are 20 to 40 mm Hg, and critical levels are 
8 to 10 mm Hg.
Goals of therapy 
in both groups included maintaining an ICP <20 mm Hg and 
a CPP >60 mm Hg.
Among patients with PbtO2 monitoring, 
therapy also was directed at maintaining PbtO2>25 mm Hg.
The 
groups had similar mean daily ICP and CPP levels.
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Spight, John G.
Hunter, and Blair A.
It is not a discipline unto itself, but more a philosophy of 
surgery, a way of thinking.
As  public awareness has grown, so too has its spread outside of 
larger institutions.
The primary advantage of SILS is the 
reduction to one surgical scar.
Clinically the 
transvaginal approach has been studied the most extensively.
Subsequently,  CO2 and N2O were used for inflating the 
abdomen.
N2O had the advantage of being physiologi-
cally inert and rapidly absorbed.
As such, caution should be exercised when perform-
ing laparoscopic cancer surgery with this agent.
Finally, the 
safety of N2O pneumoperitoneum in pregnancy has yet to be 
elucidated.
14-1).
CO2 is rapidly absorbed across the 
peritoneal membrane into the circulation.
means of performing procedures that previously required a celi-
otomy.
Moreover, MRI magnets 
are bulky and limit the surgeon’s access to the patient.
(Reproduced with 
permission from Hunter JG, ed.
Bailliere’s Clinical Gastroenterol-
ogy Laparoscopic Surgery.
London/Philadelphia: Bailliere Tindall; 
1993:758.
The most common arrhythmia created by laparoscopy is brady-
cardia.
The pathophysiology and management are 
discussed at the end of this section.
Endocrine responses to laparoscopic surgery are not 
always intuitive.
Immune suppression 
also is less after laparoscopy than after open surgery.
Thoracoscopy
The physiology of thoracic MIS (thoracoscopy) is different 
from that of laparoscopy.
By collapsing the ipsilateral lung, working space 
within the thorax is obtained.
14-2).
Balloons are used to create extra-anatomic working 
spaces.
influence cardiovascular performance by reducing or removing 
the CO2 pneumoperitoneum.
MIS procedures 
are often outpatient procedures, so short-acting anesthetic agents 
are preferable.
The video monitor(s) should be set across the operating table 
from the surgeon.
14-3).
Patient Positioning
Patients usually are placed in the supine position for laparo-
scopic surgery.
The legs may be elevated in Allen stirrups 
or abducted on leg boards to achieve this position.
14-4).
Once the robot is docked to the patient, the bed cannot 
be moved without undocking.
Figure 14-3.
An example of a typical minimally invasive surgery 
suite.
All core equipment is located on easily movable consoles.
The nares, mouth, urethra, 
and anus are used to access the respiratory, GI, and urinary sys-
tems.
The advantage of using these points of access is that no 
incision is required.
The disadvantages lie in the long distances 
between the orifice and the region of interest.
Similarly, the peritoneal cavity may be reached through the side 
wall of the stomach or colon.
vessel, usually in the groin.
In these procedures, 
general anesthesia and single lung ventilation are essential.
14-5).
The umbilicus usually is selected as the preferred 
Figure 14-5.
A.
B.
The abdomen is inflated 
with a pressure-limited insufflator.
CO2 gas usually is used, with 
maximal pressures in the range of 14 to 15 mmHg.
14-6).
After peritoneal insufflation, direct access to the abdomen 
is obtained with a 5- or 10-mm trocar.
A fin-
ger is placed into the abdomen to make sure that there is no 
adherent bowel.
14-7).
Rapid insufflation can make up for some of the time lost with 
the initial dissection.
It is essential to be able to interpret the insufflator 
pressure readings and flow rates.
These readings indicate proper 
intraperitoneal placement of the Veress needle.
Figure 14-7.
It is generally agreed that 5-mm trocars need no site sutur-
ing.
For retroperitoneal locations, balloon dissection is effec-
tive.
The balloon is inflated in the extraperitoneal 
space to create a working chamber.
Higher gas pressures force CO2 into the soft tissues and may 
contribute to hypercarbia.
14-8).45,46 Once the saphenous vein is 
A
B
Figure 14-8.
A.
B.
Harvest of muscle, nerve, fascia, and vein.
In: Bostwick J III, Eaves 
FE III, Nahai F, eds.
Endoscopic Plastic Surgery.
St Louis: Qual-
ity Medical Publishing, Inc.: Quality Medical Publishing, Inc.; 
1995:542.
A small incision above the knee also can be 
used to ligate perforating veins in the lower leg.
It is easier to hide several 5-mm incisions than one 
long incision.
Some prefer gas insufflation of these soft tissue planes.
14-9).
Remaining trocars are 8 mm.
The ease of decontamination, 
entry, and closure of these structures create variable challenges.
The esophagus can be traversed to 
enter the mediastinum.
14-10).
Closure has been performed using endo-
scopic clips or sutures with advanced endoscopic platforms.
The advantage of this tech-
nique is that conventional laparoscopic tools can be employed.
This is an example of hand-assisted laparoscopic surgery during left colectomy.
This 
technique is particularly useful in the region of the transverse colon.
Figure 14-10.
Submucosal tunnel technique for transesophageal mediastinoscopy.
(Reproduced with permission from Khashab MA, Kalloo 
AN.
NOTES: current status and new horizons.
Gastroenterology.
2012;142:704-710.
© 2012 by the AGA Institute.)
C
D
E
AB
is needed.
14-11A,B).
The major disad-
vantage is cost.
14-12).
As a result, the surgeon must often work in a crossed hands fash-
ion (Fig.
14-13).
A.
Specialized multilumen trocars can facilitate instrument placement.
B.
(Illustration by Corinne Sandone.
© 2014 JHU.
The distance between the left and the right 
hand is also ideally 10 to 15 cm.
In this “baseball diamond” con-
figuration, the surgical target occupies the second base position.
Figure 14-13.
(Illustration 
by Corinne Sandone.
© 2014 JHU.
Reprinted with permission.)
426
BASIC CONSIDERATIONS
PART
 
I
Figure 14-14.
A.
The laparoscope tips come in a variety of 
angled configurations.
All laparoscopes have a 70° field of view.
Video cameras come in two basic designs.
To enjoy the benefit of the 
clarity of HD video imaging, HD monitors also are necessary.
Without the first 
two attributes, video surgery is unsafe.
Rigid telescopes may have a flat or angled end.
14-14A); rotating an angled telescope changes 
the field of view.
Flexible tip 
laparoscopes offer even greater optical freedom.
Light is delivered to the endoscope through a fiber-optic 
light cable.
14-15).
The larger the number of line pairs per 
millimeter, the sharper and more detailed the image.
Most 
high- resolution monitors have up to 700 horizontal lines.
However, this technology has not yet been widely adopted.
Interest in three-dimensional (3-D) laparoscopy has waxed 
and waned.
Single-incision laparoscopy presents new challenges to 
visualization of the operative field.
In the traditional laparo-
scope, the light source enters the scope at a 90° angle.
That 
position coupled with a bulky scope handle creates crowding in 
an already limited space.
With bipolar electrosurgery, the electrons flow between 
two adjacent electrodes.
The tissue between the two electrodes 
is heated and desiccated.
14-16).
In addition, the integrity of the 
Figure 14-15.
The video 
camera is placed on the eyepiece to provide the working image.
The image is only as clear as the weakest link in the image chain.
CCD = 
charge-coupled device.
An example of bipolar coagulation devices.
insulation must be maintained and assured.
14-17A).
This may result in 
thermal necrosis and a delayed fecal fistula.
14-17B).
Another method of delivering RF electrosurgery is argon 
beam coagulation.
Bipolar electrocoagulation is used primarily for thermal 
hemostasis.
The next 
most popular laser is the neodymium yttrium-aluminum garnet 
(Nd:YAG) laser.
Nd:YAG laser light is 1.064 μm (1064 nm) 
in wavelength.
14-18).
A disadvantage is that the deep tissue heating 
may cause perforation of a hollow viscus.
When it is desirable to coagulate flat lesions in the cecum, 
a different laser should be chosen.
The depth of tissue heating is intermediate, between 
those of the CO2 and the Nd:YAG lasers.
A.
B.
(Reproduced with permission from Odell.58)
Figure 14-18.
(Reproduced with 
permission from Hunter JG, Sackier JM, eds.
Minimally Invasive 
Surgery.
Two days after administration, the drug is 
endoscopically activated using a laser.
The activated porfimer 
sodium generates oxygen free radicals, which kill the tumor 
cells.
The tumor is later endoscopically débrided.
These devices also are inserted through thin probes for  endoscopic 
application.
Methods of producing shock waves or heat with ultrasonic 
energy are also of interest.
Techniques such as mucosotomy, hydrodissection, and 
clip application require specialized training.
14-19).
14-20).
Robotic instruments and hand controls.
Figure 14-20.
Room setup and position of surgeon and assistant for robotic surgery.
(©2013 Intuitive Surgical, Inc.
Female pelvic surgery with the da Vinci robot is also 
reaching wide appeal.
14-21).
14-23).
The deployment of a metal stent across an  isolated 
vessel stenosis is illustrated.
(Reproduced with permission 
from Hunter JG, Sackier JM, eds.
Minimally Invasive Surgery.
New York: McGraw-Hill; 1993:235.)
432
BASIC CONSIDERATIONS
PART
 
I
Figure 14-22.
Figure 14-23.
Covered self-expanding metal stents.
These devices 
can be placed fluoroscopically or endoscopically.
was added to coronary stents several years ago to decrease 
endothelial proliferation.
Endovascular stenting of aortic aneurysms has 
nearly replaced open surgery for this condition.
14-24).
The scope is advanced 
4
433
Minimally Invasive Surgery
CHAPTER 14
Figure 14-24.
(Illustration by Jennifer Fairman.
© 2007 JHU.
The mucosotomy is then closed using endoscopic clips  
(Fig.
14-25).
Over 1000 clinical POEM cases have been per-
formed worldwide.
14-26).
14-11).
Ports typically contain three or four 
channels.
The latter often affords the ability to place a dedicated 
retractor.
There are many challenges faced by the operating surgeon 
in SILS procedures.
5
434
BASIC CONSIDERATIONS
PART
 
I
A
B
Figure 14-25.
A.
Peroral endoscopic esophageal myotomy for the 
treatment of achalasia.
B.
(A.
From Inoue 
H, Minami H, Kobayashi Y, et al.
Peroral endoscopic myotomy 
(POEM) for esophageal achalasia.
Endoscopy.
2010;42:265-
271.
Thieme.
B.
From Rieder E, Dunst CM, Kastenmeier AS, et 
al.
Development and technique of peroral endoscopic myotomy 
(POEM) for achalasia.
Eur Surg.
2011;43/3:140-145.
14-27).
A low-profile HD scope with or without a 
deflectable tip can improve visualization greatly.
Contraindications include those true of traditional lapa-
roscopy.
Relative contraindications include previous surgery 
and high body mass index (BMI).
Patients with a high BMI or 
Figure 14-26.
Transanal endoscopic microsurgery scope.
(Illustration by Corinne Sandone.
© 2014 JHU.
Reprinted with 
permission.)
Figure 14-27.
Example of curved instruments used in single-incision 
laparoscopic surgery.
(©2013 Intuitive Surgical, Inc.
Current status of single-
incision laparoscopic surgery: European experts’ views.
Surg Laparosc 
Endosc Percutan Tech.
2012;22(3):194-199.
Size and morphology of 
the target organ should always be considered when doing SILS.
This is in large part due to the already improved benefits of 
laparoscopic surgery.
14-28).
However, laparoscopy in 
the infant and young child requires specialized instrumenta-
tion.
The instruments are shorter (15–20 cm), and many are 3 
mm in diameter rather than 5 mm.
Current status of single-
incision laparoscopic surgery: European experts’ views.
Surg Laparosc 
Endosc Percutan Tech.
2012;22(3):194-199.
DVT 
is rare in children, so prophylaxis against thrombosis probably 
is unnecessary.
A and B.
Robotic single-incision surgery platform.
(©2013 Intuitive Surgical, Inc.
Reprinted with permission.)
436
BASIC CONSIDERATIONS
PART
 
I
20 weeks.
Fetal acidosis induced by maternal hyper-
carbia also has been raised as a concern.
Protection of the fetus against intraoperative x-rays is impera-
tive.
MIS 
techniques also have been used in the staging of cancer.
All of the major abdominal cancer opera-
tions have been performed with laparoscopy.
The advantage of MIS lies in what happens after the 
operation.
Much of the morbidity of surgery in the elderly is 
a result of impaired mobility.
Additionally, ascitic 
leak from a port site may occur, leading to bacterial peritonitis.
Therefore, a watertight port site closure should be carried out 
in all patients.
This training occurred on patients.
Although such a paradigm 
did not compromise patient safety, learning in the OR is costly.
Clearly, 
there was a need for developing a less invasive approach  
(Fig.
14-29).
The third step is in vivo stud-
ies in the most appropriate animal model.
1880 1900 1920 1940 1960 1980 1985 1990 1995 2000?
?
Open surgery
Laparoscopic surgery
Seamless surgery
Progress in Surgery
Figure 14-29.
The progress of general sur-
gery can be reflected by a series of performance 
curves.
Video 
optics allowed the development of minimally 
invasive surgery over the last 25 years.
These steps often are called the 
preclinical phase of procedure development.
The decision as to when such procedures are ready to 
come out of the lab is a difficult one.
Once these three criteria are reached, 
the time for human application has arrived.
Cer-
tainly if a dying cancer patient has a chance with a new drug, this 
makes sense.
This may take  
10 procedures, or it may take 50 procedures.
This will complete phase 
I of the procedure development.
In phase II, the efficacy of the procedure is tested in a non-
randomized fashion.
These same requirements may be applied to the introduction 
of new technology into the OR.
In phase III, a 
randomized trial pits the new procedure against the old.
If not, further observation and assistance from the 
experts are required.
Although this approach may sound obvi-
ous, it is fraught with difficulties.
Would I consider undergoing this procedure if 
I developed a surgical indication?
Is the procedure as good as 
or better than the procedure it is replacing?
Answering these questions in 
the affirmative should be a professional obligation.
REFERENCES
Entries highlighted in bright blue are key references.
1.
Hopkins HH.
Optical principles of the endoscope.
In: Berci 
G, ed.
Endoscopy.
New York: Appleton-Century-Crofts; 
1976:3.
2.
Katzir A.
Optical fibers in medicine.
Sci Am.
1989;260:120.
3.
Hirschowitz BI.
A personal history of the fiberscope.
Gastro-
enterology.
1979;76:864.
4.
Veritas TF.
Coelioscopy: a synthesis of Georg Kelling’s work 
with insufflation, endoscopy, and luft tamponade.
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Watson and Francis H.
C.
Within cells, DNA is packed tightly into chromosomes.
15-1).
15-2).
The nucleotides are joined together by phosphodiester bonds.
The flow of genetic information from DNA to pro-
tein to cell functions.
Key historical events 
concerning genetics are outlined in Table 15-1.
Figure 15-2.
Schematic representation of a DNA molecule form-
ing a double helix.
DNA is made of four types of nucleotides, 
which are linked covalently into a DNA strand.
The diagram at the bot-
tom left of the figure shows the DNA molecule straightened out.
(Republished with permission of Garland Publishing, 
Inc.
from Alberts B, Johnson A, Lewis J, et al.
Molecular Biology 
of the Cell, 5th ed.
New York: Garland Science; 2008.
446
BASIC CONSIDERATIONS
PART
 
I
Figure 15-4.
Four major steps in the control of eukaryotic gene expression.
Note that posttranscriptional and posttranslational controls consist of several steps.
DNA replication.
In this way, double-helical DNA 
can be copied precisely.
(Republished 
with permission of Garland Publishing, 
Inc.
from Alberts B, Johnson A, Lewis J, 
et al.
Molecular Biology of the Cell,  
5th ed.
New York: Garland Science; 2008.
Before a 
cell divides, DNA must be precisely duplicated.
15-3).
Proofreading mechanisms ensure 
that the replication process occurs in a highly accurate man-
ner.
15-4).
However, gene regulation is far more com-
plex, particularly in eukaryotic organisms.
For example, many 
gene transcripts must be spliced to remove the intervening 
sequences.
Transcription.
A promoter region is the 
DNA region upstream of the transcription initiation site.
Consequently, few 
nucleotides can be base-paired with the DNA template to begin 
transcription.
Once transcription begins, the σ factor is released.
The growing RNA chain may begin to peel off as the chain 
elongates.
In this way, the protein products are synthesized 
in a coordinated manner.
The precursor is 
then modified and/or processed into its final functional form.
(d) 
RNA is made in the nucleus and transported into cytoplasm, 
where translation occurs.
Therefore, unlike bacteria, eukaryotes 
undergo uncoupled transcription and translation.
Translation.
DNA directs the synthesis of RNA; RNA in turn 
directs the synthesis of proteins.
The process of decoding information on mRNA to synthesize 
proteins is called translation (see Fig.
15-1).
Translation takes 
place in ribosomes composed of rRNA and ribosomal proteins.
Because of this 
decoding, the information carried on mRNA relies on tRNA.
Translation involves all three RNAs.
A codon, a triplet of three bases, codes for 
one amino acid.
In this case, random combinations of the four 
bases form 4 × 4 × 4, or 64 codes.
The 
codons on mRNA are sequentially recognized by tRNA adaptor 
proteins.
Specific enzymes termed aminoacyl-tRNA synthetases 
link a specific amino acid to a specific tRNA.
Protein synthesis proceeds in the amino-to-
carboxy-terminus direction.
The biologic versatility of proteins is astounding.
They also 
transport ions and various small molecules across plasma mem-
branes.
The unique functional properties of proteins are largely deter-
mined by their structure (Fig.
15-5).
Regulation of Gene Expression.
For 
example, muscle and bone express different genes or the same 
genes at different times.
15-4).
Each of the steps during transcription is properly regulated in 
eukaryotic cells.
Letter in [ ] indicates single letter code for amino acid.
Figure 15-5.
Maturation of a functional protein.
Transcriptional control by RNA polymerase.
DNA 
is packaged into a chromatin structure.
Coactivator or 
corepressor is a factor linking the TF with the Pol II complex.
TF
Coactivator or
Corepressor
Pol II
Holoenzyme
TBP TBP
TATA
TFBS
dependent.
However, there is a common scheme that applies 
to transcription at the molecular level (Fig.
15-6).
Human Genome
Genome is a collective term for all genes present in one organ-
ism.
15-1).
Although the potential of this field of study is vast, it is in its 
early stages.
Thus, 
the cell cycle is the fundamental mechanism to maintain tissue 
homeostasis.
15-7).
Early G1 cyclin 
D/CDK4/6 or late G1 cyclin E/CDK2 controls the G1-S transi-
tion.
The cell cycle is connected with signal transduction path-
ways as well as gene expression.
Growing cells proliferate only when supplied with 
appropriate mitogenic growth factors.
Cells become committed 
to entry of the cell cycle only toward the end of G1.
Meanwhile, cells also 
receive antiproliferative signals such as those from tumor sup-
pressors.
For example, when DNA is damaged, cells will repair the 
damage before entering the S phase.
Therefore, G1 contains one 
of the most important checkpoints for cell cycle progression.
Accelerated proliferation or improper cell cycle progression with 
damaged DNA would be disastrous.
In addition to cell cycle control, cells use genetically pro-
grammed mechanisms to kill cells.
15-8).
However, recent 
advances in apoptosis research suggest an interconnection of 
the two pathways.
The complex machinery of apoptosis must be tightly controlled.
Perturbations of this process can cause neoplastic transforma-
tion or other diseases.
15-9).
All cells have the ability to sense 
changes in their external environment.
Other substances bind directly 
with a transmembrane protein (cell-surface receptor).
Figure 15-7.
The cell cycle and its control system.
A complex of cyclin and cyclin-
dependent kinase (CDK) controls specific events of each phase.
Without cyclin, CDK is inactive.
Different cyclin/CDK complexes 
are shown around the cell cycle.
A, B, D, and E stand for cyclin A, 
cyclin B, cyclin D, and cyclin E, respectively.
A simplified view of the 
apoptosis pathways.
Cell-surface and intracellular receptor pathways.
The 
receptor serves as the receiver, and in turn activates the downstream 
signals in the cell.
Either extracellular or intracel-
lular signals often reach the nucleus to control gene expression.
In a given cell, many signaling pathways operate 
simultaneously and crosstalk with one another.
Signaling pathways often are grouped according to the 
properties of signaling receptors.
Members of this superfamily share a characteristic 
seven-transmembrane configuration.
Structurally, these receptors usually have only one 
transmembrane-spanning domain.
Insulin is a peptide hormone that 
is secreted by the β-cell of the pancreas.
Insulin 
binding to InsR activates the kinase activity of InsR.
15-10).
Type 2 diabetes 
accounts for about 90% of all cases of diabetes.
Although insulin and many mitogenic 
Figure 15-10.
Insulin-signaling pathway.
Inactivation of the 
insulin pathway can lead to type 2 diabetes.
TGF-β is one of them.
15-11).
The com-
plex consists of transmembrane serine/threonine kinases.
The 
outcome of the altered gene expression leads to the inhibition 
of cell cycle progression.
Resistance to TGF-β’s anticancer action is one hall-
mark of human cancer cells.
TGF-β receptors and SMADs are 
identified as tumor suppressors.
Some lose TGF-β responsiveness through 
downregulation or mutations of their TGF-β receptors.
The locus 
encoding cell cycle inhibitor p15INK4B may be deleted.
Finally, functional pRb, the end target of this pathway, 
may be lost through mutation of its gene.
Cancer is a complex disease, involving uncontrolled 
growth and spread of tumor cells (Fig.
15-12).
TGF-β signaling pathway.
The TGF-β family has 
at least 29 members encoded in the human genome.
They are also 
peptide growth factors.
Meta-
static cancer cells that enter the bloodstream can reach virtu-
ally all tissues of the body.
Bones are one of the most common 
places for these cells to settle and start growing again.
Bone 
metastasis is one of the most frequent causes of pain in people 
with cancer.
It also can cause bones to break and create other 
symptoms and problems for patients.
The progression in the knowledge of cancer biology  
has been accelerating in recent years.
As a result of 
explosive new discoveries, some modern treatments were devel-
oped.
Immunotherapy.
The growth of the body is controlled by 
many natural signals through complex signaling pathways.
Tumor clonal evolution and metastasis.
A tumor 
develops from mutant cells with multiple genetic mutations.
The expanded lymphocyte 
pool enables recognition of the antigen on cancer cells.
Chemotherapy.
In CML, 
STI571 is targeted at the Bcr-Abl kinase, an activated oncogene 
product in CML (Fig.
15-13).
Gene Therapy.
Several problems must be resolved to transform it into a 
clinically relevant form of therapy.
Adju-
vant therapy was first tested and found to be effective in breast 
cancer.
It was later adopted for use in other cancers.
Many of these 
tumors can be cured today by combination chemotherapy.
As 
Figure 15-13.
Mechanism of STI571 as a 
molecular drug.
PO4 = phos-
phate; Tyr = tyrosine.
This can lead to subtle changes in func-
tion or dramatic results that cause pathology.
This results in a shift in the oxygen-
hemoglobin dissociation curve to the left, causing hypoxia.
Stem cells are 
endowed with two remarkable properties (Fig.
15-14).
Second, they have the abil-
ity to differentiate into many specialized cell types.
There are 
two groups of stem cells: embryonic stem (ES) cells and adult 
stem cells.
Adult stem cells are present in and can 
be isolated from adult tissues.
For example, hema-
topoietic stem cells are adult stem cells.
It is believed that dis-
covery of the signals that control self-renewal vs.
Stem cells.
15-15).
The process of molecular cloning 
involves several steps of manipulation of DNA.
The 
vector and the DNA fragment are then joined in vitro by a DNA 
ligase.
Precautions must be taken in 
every step of cloning to generate the desired DNA construct.
The selection of desired recombinant plasmid-bearing 
E.
coli normally is achieved by the property of drug resistance 
conferred by the plasmid vectors.
The resulting plasmid vec-
tor can be amplified in E.
Detection of Nucleic Acids and Proteins
Southern Blot Hybridization.
15-16).26 Southern 
blotting is named after E.
M.
Southern, who in 1975 first 
described the technique of DNA analysis.
Southern blotting is com-
posed of several steps.
The DNA gel is stained with a dye, usually ethidium 
Figure 15-15.
Generation of recombinant DNA.
The vector is a circular DNA molecule that is capable of replicating in Escherichia coli cells.
Ligated 
DNA (i.e., the recombinant plasmid DNA) is then transformed into E.
coli cells, where it replicates to produce recombinant progenies.
E.
coli
E.
coli containing
recombinant plasmid
Propagation
E.
coli containing
recombinant plasmid
Figure 15-16.
Southern blotting.
DNA is digested with
restriction enzymes.
DNA fragments are denatured
and separated by gel
electrophoresis.
DNA fragments are transferred
to a membrane filter.
The filter is hybridized with 
a radioactive DNA probe.
DNA fragment that is hybridized 
to the radioactive DNA is detected 
by autoradiography.
The DNA gel then is treated so the DNA fragments are dena-
tured (i.e., strand separation).
Northern Blot Hybridization.
Polymerase Chain Reaction.
It is simple, yet robust, 
speedy, and most of all, flexible.
As a recombinant DNA tool, 
it underlies almost all of molecular biology.
Immunoblotting and Immunoprecipitation.
Analyses of 
proteins are primarily carried out by antibody-directed immu-
nologic techniques.
Immunoblotting refers to the process of identifying a pro-
tein from a mixture of proteins (Fig.
15-18).
diseased tissues is possible.
15-19).
The purified protein can 
then be analyzed by a number of biochemical methods.
DNA Microarray.
Amplification of DNA using the polymerase chain reaction (PCR) technique.
A.
B.
(Republished with permission of Garland Publishing, Inc.
from Alberts B, Johnson A, Lewis J, et al.
Molecular Biology of the Cell, 
5th ed.
New York: Garland Science; 2008.
Permission conveyed through Copyright Clearance Center, Inc.)
Etc.
Immunoblotting.
The massive scale of micro-
array experiments requires the aid of computers.
For example, analysis 
of genomic DNA detects amplifications and deletions found 
in human tumors.
The fluorescent 
make a human being.
461
MOLECULAR AND GENOMIC SURGERY
CHAPTER 15
Figure 15-19.
Immunoprecipitation.
Proteins 
prepared from cells or tissues can be enriched 
using an antibody directed against them.
The anti-
body is first conjugated to agarose beads and then 
incubated with protein mixture.
The immunoprecipitated protein can then be 
analyzed by immunoblotting.
DNA microarrays.
DNA microarray is used to comparatively analyze gene expression 
in different cells or tissues.
The two fluorescent cDNA 
probes are mixed and hybridized to the same DNA microarrays.
Yellow spots represent 
equal expression of the gene in both cell samples.
BS-seq is commonly used to identify DNA 
methylation on the genome (5-methylcytosine [5mC]).
Thus, 5mC and cytosine are distinguished 
by this way.
Usually, cDNA 
that is reversely transcribed from extracted RNA is used to gen-
erate libraries.
Depending on the needs, mRNA and ncRNA can 
be enriched in different protocols for RNA extraction.
ChIP-seq 
is always used to map the location of a DNA-binding protein in 
the genome.
First, POI 
and DNA are cross-linked before sonication.
Then, a specific 
antibody is used to pull down POI and attached DNA fragments.
Figure 15-21.
Cell culture and 
transfection.
A.
Primary cells can be 
isolated from tissues and cultured in 
medium for a limited period of time.
B.
15-21).
immortalized/transformed cells).
If 
cultured cells grow continuously in suspension, they are split or 
subcultured by dilution.
The common procedure to use is cryo-
preservation.
Cell Transfection.
Cells are cultured for two reasons: to main-
tain and to manipulate them (see Fig.
15-21).
DNA transfec-
tion has become an important tool for studying the regulation 
and function of genes.
These methods have shown variable success when attempting  
to transfect a wide variety of cells.
Transfection can be per-
formed in the presence or absence of serum.
Depending on the transfection method, DNA expression 
can be transient or stable.
Stable cell clones can be selected 
when plasmids carry an antibiotic-resistant marker.
In all cases, the gene to be manipulated must first be 
cloned.
Transgenic Mice.
15-22).
These animals, called transgenic, contain for-
eign DNA within their genomes.
Figure 15-22.
Transgenic mouse tech-
nology.
The 
microinjected egg develops offspring 
mice.
The design of a transgene construct is 
a simple task.
Overexpression of the transgene normally 
represents gain-of-function mutations.
The second application of the trans-
genic expression is to analyze the gene promoter of interest.
Concentration of DNA should be accu-
rately determined.
Mice that develop from injected eggs often 
are termed founder mice.
Depending on the 
promoter and the transgene, phenotypes can be predictable or 
unpredictable.
Gene Knockout in Mice.
The first recorded knockout mouse 
was created by Mario R.
Capecchi, Sir Martin J.
Evans, and 
Oliver Smithies in 1989.
They were awarded the 2007 Nobel 
Prize in Physiology or Medicine.
15-23).
Excellent protocols 
are available in public domains or in mouse facilities in most 
 institutions.
To alter the genome of ES cells, the targeting vector DNA 
then is transfected into ES cells.
Electroporation is the most 
widely used and the most efficient transfection method for ES 
cells.
Similar procedures for stable cell transfection are used for 
Figure 15-23.
Knockout mouse technology.
Summary of the procedures used for making gene replacements in mice.
Some of these mice also will contain germline cells that contain the altered gene.
These defects are carefully analyzed to help decipher the normal function of the missing gene.
(Republished with permission of Garland Publishing, Inc.
from Alberts B, Johnson A, Lewis J, et al.
Molecular Biology of the Cell, 5th ed.
New York: Garland Science; 2008.
Stable ES cells 
are selected in the presence of a positive selectable antibiotic 
drug.
Positive ES colonies are then expanded and used for 
creation of chimeras.
RNA Interference.
15-24).
The antisense siRNA strand is fully complementary to 
the mRNA target sequence.
Target sequences for an siRNA are 
identified visually or by software.
Those sequences that appear 
to be specific to the GOI are the potential siRNA target sites.
A few of these target sites are selected for siRNA design.
The 
antisense siRNA strand is the reverse complement of the target 
sequence.
The sense strand of the siRNA is the same sequence 
as the target mRNA sequence.
There are two ways to introduce siRNA to knock down 
gene expression in human cells:
1.
RNA transfection: siRNA can be made chemically or 
using an in vitro transcription method.
Like DNA oligos, 
chemically synthesized siRNA oligos can be commercially 
ordered.
In vitro transcription provides a more 
economic approach.
Both short and long RNA can be syn-
thesized using bacteriophage RNA polymerase T7, T3, or 
SP6.
Transfection of siRNA directly into primary 
cells may be difficult.
2.
15-24).
There are two advan-
tages of the siRNA expression vectors over siRNA oligos.
First, it is easier to transfect DNA into cells.
Therefore, 
the applications of RNAi to human health are enormous.
Practical applications of RNAi will possibly result in new 
therapeutic interventions.
RNAi 
has been shown to antagonize the effects of hepatitis C virus 
in mouse models.
Finally, siRNA also has potential applications for some 
dominant genetic disorders.
However, this knowledge 
has not been effectively or reproducibly clinically translated.
Figure 15-24.
RNA interference in mammalian cells.
Small interfering RNA (siRNA) can be produced from a polymerase III–driven expres-
sion vector.
siRNA can be chemically 
synthesized and directly introduced into the target cell.
A phase I clinical trial (BB-IND 14205) involving 52 cancer 
patients was recently completed.
No toxic effect was identified.
Expected survival 
of similar patients is historically less than 1 year.
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Accounting for 
approximately 15% of total body weight, it is the largest organ 
in the human body.
Enabled by an array of tissue and cell types, 
intact skin protects the body from external insults.
16-1).
Ninety to ninety-five percent of these 
epithelial cells are ectodermally derived keratinocytes.
16-1).
Transit time (kera-
tinization) is approximately 30 days.
Epidermal Components
Keratinocytes.
Melanosomes are positioned 
over the nucleus.
2 Dermal fibers are predominantly made of type I and III col-
lagen in a 4:1 ratio.
They are responsible for the mechanical 
resistance of skin.
3 Staphylococcus aureus is the most common isolate of all skin 
infections.
Cautery and ablation, cryotherapy, 
drug therapy, and radiation therapy are alternative treatments.
Key Points
conferring mechanical resistance to the epidermis as a whole.
Proliferation occurs at this cell layer.
Spinosum layer keratinocytes are polygonal, with an eosinophilic 
cytoplasm.
Langerhans Cells.
474
Figure 16-1.
Schematic representation of the skin and 
its appendages.
Note that the root of the hair follicle may 
extend beneath the dermis into the subcutis.
Melanocytes express the bcl-2 oncoprotein, S100 protein, and 
vimentin.
Merkel Cells.
Merkel cells display both neuroendocrine and epi-
thelial features.
Lymphocytes.
They express predominantly a T-memory/effector 
 phenotype.3
Toker Cells.
Appendages serve 
functions that include lubrication, sensation, contractility, and 
heat loss.
Sweat Glands.
Sweat glands are tubular exocrine glands, con-
sisting of a secretory coil and an excretory duct.
These glands are found in the axillary, anogenital, 
and nipple regions.
A third type of sweat gland was more recently described 
in the axillary region.
Their size and morphology are 
variable (terminal, vellus, lanugo, and intermediary hair).
Nails.
The nails overlie the dorsal aspect of the distal phalanges 
of the fingers and toes.
Dermis
Architecture.
It consists of cells, fibrous 
molecules, and a ground substance.
The elastic network is 
also thicker in this layer.
Dermal Fibers.
Collagen 
accounts for 98% of the total mass of dry dermis.
This core is surrounded by a varying number of microfibrils 
made of fibrillin.
Cells.
Dermal dendrocytes 
complement the immunologically functional cells of the epider-
mis.
Cutaneous Vasculature.
The skin contains a rich and com-
plex enervation, consisting of an afferent and an efferent limb.
The diagnosis is made clinically without the 
need for imaging or laboratory tests.
Treatment varies depending on disease severity and extent.
Antiandrogens have an equivo-
cal role in therapy.
Skin grafting has a faster heal-
ing rate compared with secondary wound closure.
Secondary infec-
tion is common.
PG is more common in women and peaks in 
the third to sixth decades of life.
Lesion borders are purplish in 
color with erythematous edges.
Five clinical types are identi-
fied: ulcerative, pustular, bullous, vegetative, and peristomal.
Treatment 
of PG combines systemic, topical, and surgical modalities.
16-2).
The process progresses for 7 to 10 days; re-epithelialization 
occurs over 1 to 3 weeks.
Mucosal and ocular surfaces may be 
involved in a similar fashion.
Immunosuppressed patients are 
at higher risk.
Less than 10% of total body surface area is involved 
with this disease.
Blisters on the forearm of a patient several days after 
exposure to vancomycin.
surface area.
Despite drug withdrawal, noxious metabolites 
may persist.
A Wood’s lamp exami-
nation every 1 hour should be performed to look for corneal 
sloughing.
There are mixed reports of 
IVIG treatment efficacy.
Surgeons must be aware of the role radiation plays in 
oncologic multidisciplinary care.
Acute skin changes are the result of injury to the basal 
epithelium in the radiated region.
Within weeks, this manifests 
as erythema, edema, and alopecia.
Histologically, the epidermis appears 
thickened, but the functional integrity is compromised.
UVB radiation reaches the 
earth in relatively low amounts but is highly energetic.
Seasonal, 
temporal, geo-orbital, and environmental parameters affect solar 
irradiance.
UVA rays are more penetrant, with 20% to 30% reach-
ing the deep dermis.
The major chromophores are nucleic acids, 
aromatic amino acids, and melanin.
Short-term solar radiation effects include erythema and 
pigmentation.
Pigmentation occurs as a result of photo-
oxidation of melanin by UVA.
Partial fading occurs rapidly 
within 1 hour after the end of exposure.
For higher UVA doses, 
a stable residual pigmentation is observed after the transient 
effect.
It becomes visible after about 
72 hours.
UVB pigmentation results in a 
homogeneous tan and UVA protection.
Trauma-Induced Injuries
Mechanical Injury.
Clean lacerations may be closed primarily after irrigation, 
debridement, and exploration.
Bite Wounds.
Early pre-
sentation bite wounds yield polymicrobial cultures.
Capnocytophaga canimorsus bacteria after a dog bite 
are rare.
Bacteria colonizing human bites are those present on the 
skin or in the mouth.
Antibiotic 
coverage must cover gram-positive and anaerobic organisms.
Most wounds are amenable to standard wound care protocols.
Larger wounds with signs of infection will 
require pulse irrigation.
Rapid quantitative cultures should be used 
to guide treatment in wounds with suspected infection.
Human 
bites typically are characterized by higher bacteria load (>105).
In devel-
oping countries, dog bites remain the most common source of 
rabies.
Management of this is beyond the scope of this chapter.
This limits subsequent tissue penetration.
16-4).
This permits further penetration of the unattached molecules, 
causing further tissue destruction.
The clinician observes and treats based on the 
degree of presentation.
Surgery is indicated for tissue 
necrosis, uncontrolled pain, or deep-tissue damage.
Antibiot-
ics should not be administered unless signs of infection are   
present.
Topical calcium carbonate gel and quaternary 
AB
Figure 16-3.
A.
Dog bite to the face involving the lip and left oral commissure.
B.
Primary closure following debridement and irrigation.
Closure was performed due to aesthetic and functional considerations.
480
SPECIFIC CONSIDERATIONS
UNIT
 
II
PART II
 ammonium compounds detoxify fluoride ions.
16-5).
Initial presentation may include ery-
thema, blistering, and pain.
Injury to deeper structures should be excluded.
Topical antimicrobial therapy is encouraged until 
surgery is possible.
The depth and extent of injury are dependent on the 
duration and temperature of the exposure.
The pathophysiol-
ogy and management are discussed elsewhere in this book.
16-6).
Self-inflicted alkali burn with cleaner fluid.
481
THE SKIN AND SUBCUTANEOUS TISSUE
CHAPTER 16
AB
C
Figure 16-5.
A.
Potassium chloride intravenous infiltrate in a critically ill patient on multiple vasopressors.
B.
Following operative debride-
ment to paratenon layer.
C.
Temporary coverage with Integra skin substitute.
Frequent or pro-
longed ischemic insults will ultimately result in tissue damage  
(Fig.
16-7).
Stage 2 and 3 ulcers may be left to 
heal secondarily after debridement.
A.
Pressure wound after removal of a poorly padded 
cast.
Stage cannot be determined until debridement but is at least a 
grade 2 lesion.
B.
Decubitus ulcer of the sacral region, stage 4, to 
the tendinous and bone layers.
Figure 16-6.
Scald burn of upper arm, back, and buttock.
Biobrane 
is a silicon and nylon mesh layer bound with porcine collagen.
The more superficial silicon layer 
can be removed, and an autograft can subsequently be applied.
Several other skin substitutes are 
also available.
Folliculitis and furuncles resolve with adequate hygiene and 
warm soaks.
Need 
for empiric coverage for streptococci is unlikely.
Clindamycin, 
trimethoprim-sulfamethoxazole, linezolid, and tetracyclines are 
options.
The infections can be managed on an outpatient basis 
in the vast majority of cases.
Aspirated fluid from suspected infected collection 
should be cultured.
Empiric MRSA coverage is warranted in all other 
complicated skin and subcutaneous infections.
Clindamycin is also approved for 
S.
These signs are late findings and are 
frequently absent.
Common sites of origin are the genitalia, perineum 
(Fournier’s gangrene), and abdominal wall.
16-8).
Necrotizing 
myositis primarily involves the muscle but can spread to sur-
rounding tissue as well.
Three types of necrotizing infections can be distinguished 
based on the organisms involved.
Type 3  
A
B
Figure 16-8.
A.
Initial presentation of necrotizing soft issue infec-
tion in an obese, diabetic patient.
B.
Following operative debride-
ment to muscle layer.
is a rare but fulminant subset resulting from a V.
vulnificus 
infection of traumatized skin in sea divers.
Laboratory findings are nonspecific.
Leukocytosis, low 
calcium, and elevated lactate, creatine kinase, and creatinine 
may be seen.
Advanced illness may bring on coagulopathy and 
acidemia.
Blood cultures may or may not be positive.
If the diagnosis is clear, 
operative exploration and debridement should not be delayed.
Surgery is the definitive treatment.
Necrotic tissue will appear dull, gray, and avas-
cular and should be excised.
Characteristic “murky dishwater”–
like fluid may be encountered at the affected sites.
Borders for 
debridement are where tissue planes cease to readily separate.
Revision surgery should be 
planned (“second look”) within 24 to 48 hours.
Wound closure is performed once 
bacteriologic, metabolic, and nutritional balances are obtained.
Mortality ranges from 25% to 40% and is higher in truncal and 
perineal cases.
Oral infection may spread to the hypopharynx, 
larynx, trachea, salivary glands, and sinuses.
Treatment consists of a 
combination of penicillin therapy and surgical debridement.
[C10]AUTHOR: “infection” okay as added 
here?
Cutaneous manifestations of HPV can vary.
Plane warts occur on the face, dorsum of hands, and shins.
They regress spontaneously.
There is a 30% to 50% risk of squamous cell carcinoma (SCC) 
transformation.
If these fail, cryotherapy may be considered.
Kaposi’s sarcoma may precede the onset of immunosuppression.
Recurrent 
and persistent mucocutaneous candidiasis is common in patients 
with HIV infection.
Bacterial infections such as impetigo and 
folliculitis may be more persistent and widespread.
Approximately 6% of HIV 
patients will develop a cutaneous malignancy over a 7.5-year  
period.
In 
both of these cases, resection is also indicated.
Systemic pred-
nisone and interferon-α can impede tumor progression.
They are most commonly 
acquired, and most involute after migration into the dermis.
All clinically 
appear as a white, creamy substance-containing subcutaneous, 
thin-walled nodule.
The eyebrow is the most frequent site of 
presentation.
After the acute phase subsides, the entire cyst should 
be removed to prevent recurrence.
Keratosis
Actinic Keratosis.
In fact, 60% to 65% of SCCs are 
believed to originate from these precursor lesions.
Seborrheic Keratosis.
Untreated BCC can result in significant morbidity.
This variant tends to develop 
in sun-exposed areas of individuals over the age of 60.
Treatment options include Moh’s microsurgery, exci-
sional surgery, and cautery and destruction.
Lastly, topical photodynamic therapy 
has shown some benefit in treatment as well.
16-9).
In situ disease presents as well-delineated pink 
Figure 16-9.
Squamous cell carcinoma forming in a chronic 
wound.
Bleeding of the lesion with 
minimal trauma is not uncommon, and pain is rare.
Surgical excision is the treatment of choice, when feasi-
ble.
Management of lymph 
node disease involves surgical resection and/or radiation ther-
apy.
6
488
SPECIFIC CONSIDERATIONS
UNIT
 
II
PART II
Melanoma
Background.
A well-known environmental risk factor is exposure to solar 
UV radiation.
The most common 
subtype is superficial spreading, accounting for 70% of cases 
(Fig.
16-10).
These melanomas are found anywhere on the body 
Figure 16-11.
Nodular melanoma seen in the leg of a 55-year-old 
male.
Figure 16-10.
Primary cutaneous melanoma seen in the scalp of 
a 61-year-old male.
with the exception of the hands and feet.
16-11).
Diagnosis and Staging.
Workup should begin with a history 
and physical exam.
Suspicious lymph nodes should undergo fine-needle aspiration 
(FNA).
16-12 and 16-13).
The radioactive tracer-dye combination 
allows the sentinel node to be identified in 98% of cases.
16-14).
Surgical Management of the Primary Tumor and Lymph 
Nodes.
The appropriate excision margin is based on primary 
tumor depth.
A.
B.
C.
ANT = anterior; INJ = injection;  
POST = posterior.
Figure 16-13.
Technique of sentinel lymph 
node biopsy for cutaneous melanoma.
(From Ger-
shenwald JE, Ross MI.
Sentinel-lymph node 
biopsy for cutaneous melanoma.
N Engl J Med.
2011;364:1738-1745.
Copyright © 2011 Mas-
sachusetts Medical Society.
A trial from 
the Swedish Melanoma Study Group supported the WHO trial.
74%; P = .88) 
or overall survival (75% vs.
74%; P = .77) between the groups.
77%; P = .074) or local recur-
rence (2.1% vs.
2.6%) between the two cohorts.
Technically challenging locations should be treated 
in a similar fashion.
when it was delayed until the 
patients presented with clinical findings.
Several studies evaluated the indications and benefit 
for extended lymphadenectomy.
If metastatic workup including PET-CT excludes 
AB
Figure 16-14.
Operation of sentinel lymph node biopsy for cutaneous melanoma.
An incision is made directly overlying the lymph node basin in the posterior axillary space.
The sentinel lymph nodes 
are identified and excised.
Nonmeta-
static, in-transit disease should undergo excision to clear mar-
gins when feasible.
16-15).
Radiotherapy for symptomatic 
bony or brain metastases provides palliation in diffuse disease.
Adjuvant and Palliative Therapies.
Most patients with metastatic melanoma will not be sur-
gical candidates.
Special Circumstances.
The prognosis 
of pregnant patients is similar to women who are not pregnant.
Mela-
noma of the mucous membranes most commonly presents in 
Figure 16-15.
Isolated limb infusion.
Sche-
matic of isolated limb infusion of lower 
extremity.
(From Testori A, Verhoef C, 
Kroon HM, et al.
J Surg Oncol.
2011;104:397-404.
Copyright 2011 John 
Wiley and Sons.
Generally speaking, lymph node 
dissection should be avoided because the benefit is unclear.
16-16).
Risk factors include UV radiation, 
PUVA, and immunosuppression.
A rapidly growing, flesh-colored papule or plaque 
characterizes the disease.
Merkel cell carcinoma seen just above the left knee 
in a 44-year-old female.
Elective lymph 
node dissection may decrease regional nodal recurrence and 
in-transit metastases.
Patients with clinically positive nodes 
should have an FNA to confirm disease.
Moh’s microsurgery may play 
a role to ensure negative margins.
Clinically, Kaposi’s 
sarcoma appears as multifocal, rubbery blue nodules.
Tumor depth is the most important 
prognostic variable.
Recurrent 
tumors should be resected whenever possible.
They present as solitary, soft to firm, skin-colored subcutane-
ous nodules.
Adjuvant radiation therapy can be considered in a multidisci-
plinary fashion.
Cases of extremity disease can be considered 
for amputation.
Improvements in drugs therapies and health-
care practices have helped recovery from skin injuries.
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Ges.
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The Breast
Kelly K.
Hunt, John F.R.
Robertson, and 
Kirby I.
The can-
cer was in a man, but the description encompassed most of the 
common clinical features.
Theories 
espoused by Galen dominated medicine until the Renaissance.
Tulp, Observationes medicae 1652).
However there were no new theories espoused in 
relation to cancer.
The 17th century saw the 
start of the Age of Enlightenment which lasted until the 19th 
century.
Halsted and Meyer advocated complete dissection of axillary 
lymph node levels I to III.
17-1) when normal regression fails.
Each breast develops 
when an ingrowth of ectoderm forms a primary tissue bud in 
the mesenchyme.
The primary bud, in turn, initiates the devel-
opment of 15 to 20 secondary buds.
Epithelial cords develop 
from the secondary buds and extend into the surrounding mes-
enchyme.
Major (lactiferous) ducts develop, which open into a 
shallow mammary pit.
During infancy, a proliferation of mes-
enchyme transforms the mammary pit into a nipple.
If there is 
failure of a pit to elevate above skin level, an inverted nipple 
results.
This congenital malformation occurs in 4% of infants.
These transitory events occur in 
response to maternal hormones that cross the placenta.
However, the breasts remain incom-
pletely developed until pregnancy occurs.
Symmastia is a rare 
anomaly recognized as webbing between the breasts across the 
midline.
Accessory axillary breast tissue is uncommon and 
usually is bilateral.
Functional Anatomy
The breast is composed of 15 to 20 lobes (Fig.
It extends transversely from the lateral 
border of the sternum to the anterior axillary line.
The axillary tail of Spence extends 
laterally across the anterior axillary fold.
The breast has a protuberant conical form.
The 
base of the cone is roughly circular, measuring 10 to 12 cm in 
diameter.
The nulliparous 
breast has a hemispheric configuration with distinct flattening 
above the nipple.
Figure 17-2.
Anatomy of the breast.
Tangential and cross-sectional 
(sagittal) views of the breast and associated chest wall.
(Reproduced 
with permission from Romrell LJ, Bland KI.
Anatomy of the 
breast, axilla, chest wall, and related metastatic sites.
In: Bland 
KI, Copeland EMI, eds.
The Breast: Comprehensive Management 
of Benign and Malignant Diseases.
Philadelphia: Saunders, 2009.
Copyright Elsevier.)
501
T
HE
 B
REAST
CHAPTER 17
Nipple-Areola Complex.
The epidermis of the nipple-areola 
complex is pigmented and is variably corrugated.
During 
puberty, the pigment becomes darker and the nipple assumes 
an elevated configuration.
Throughout pregnancy, the areola 
enlarges and pigmentation is further enhanced.
Inactive and Active Breast.
17-2).
In the inactive breast, the epithelium is 
sparse and consists primarily of ductal epithelium (Fig.
17-3).
In the early phase of the menstrual cycle, minor ducts are cord-
like with small lumina.
When the hormonal stimulation decreases, the alveolar epithe-
lium regresses.
With pregnancy, the breast undergoes proliferative and 
developmental maturation.
Inactive human breast (100x).
The epithelium, which 
is primarily ductal, is embedded in loose connective tissue.
Dense 
connective tissue surrounds the terminal duct lobular units (TDLU).
(Photo used with permission of Dr.
Sindhu Menon, Consultant His-
topathologist & Dr.
Active human breast: pregnancy and lactation (160x).
The alveolar epithelium becomes conspicuous during the early pro-
liferative period.
The alveolus is surrounded by cellular connective 
tissue.
(Photo used with permission of Dr.
Sindhu Menon, Consul-
tant Histopathologist & Dr.
The 
minor ducts branch and alveoli develop.
17-4).
Blood Supply, Innervation, and Lymphatics.
17-5).
It also 
gives rise to lateral mammary branches.
Lymph vessels generally parallel the course of 
blood vessels.
These 
branches exit the intercostal spaces between slips of the serratus 
anterior muscle.
The six axillary lymph node 
groups recognized by surgeons (Figs.
Lymphatic pathways of the breast.
Arrows indicate 
the direction of lymph flow.
(Visual Art: © 2012.
The University 
of Texas MD Anderson Cancer Center.)
Figure 17-7.
Axillary lymph node groups.
(Visual Art: © 2012.The 
University of Texas MD Anderson Cancer Center.)
Figure 17-5.
Arterial supply to the breast, axilla, and chest wall.
(Reproduced with permission from Romrell LJ, Bland KI.
Anat-
omy of the breast, axilla, chest wall, and related metastatic sites.
In: Bland KI, Copeland EMI, eds.
The Breast: Comprehensive 
Management of Benign and Malignant Diseases.
Philadelphia: 
Saunders, 2009.
Overview of the neuroendocrine con-
trol of breast development and function.
(Reproduced with permission from Kass R et al.
Breast physiology: normal and abnormal develop-
ment and function.
In: Bland KI, Copeland EMI, 
eds.
The Breast: Comprehensive Management of 
Benign and Malignant Diseases.
Philadelphia: 
Saunders, 2009.
Copyright Elsevier.)
GRF
LH-RH
Dopamine Oxy/ADH
TRH
CRF
-
group of lymph nodes.
The 
axillary lymph nodes usually receive >75% of the lymph drain-
age from the breast.
It upregulates hormone receptors and stimu-
lates epithelial development.
17-9A).
These physiologic events initiate 
A
B
C
D
Figure 17-9.
The breast at different physi-
ologic stages.
The central column contains 
three-dimensional depictions of microscopic 
structures.
A.
Adolescence.
B.
Pregnancy.
C.
Lactation.
D.
Senescence.
In the first and second trimesters, the minor ducts branch and 
develop.
In late pregnancy, prolactin stimulates the synthesis 
of milk fats and proteins.
After weaning of the infant, 
prolactin and oxytocin release decreases.
17-9C).
17-9D).
In contrast, 
senescent gynecomastia is usually bilateral.
Mammography and ultrasonography are used to differentiate 
breast tissues.
Gynecomastia generally does not 
predispose the male breast to cancer.
Refeeding gynecomastia 
Table 17-1
Pathophysiologic mechanisms of gynecomastia
I.
Estrogen excess states
A.
Gonadal origin
1.
True hermaphroditism
2.
Gonadal stromal (nongerminal) neoplasms of the 
testis
a.
Leydig cell (interstitial)
b.
Sertoli cell
c.
Granulosa-theca cell
3.
Germ cell tumors
a.
Choriocarcinoma
b.
Seminoma, teratoma
c.
Embryonal carcinoma
B.
Nontesticular tumors
1.
Adrenal cortical neoplasms
2.
Lung carcinoma
3.
Hepatocellular carcinoma
C.
Endocrine disorders
D.
Diseases of the liver—nonalcoholic and alcoholic 
cirrhosis
E.
Nutrition alteration states
II.
Androgen deficiency states
A.
Senescence
B.
Hypoandrogenic states (hypogonadism)
1.
Primary testicular failure
a.
Klinefelter’s syndrome (XXY)
b.
Reifenstein’s syndrome
c.
Rosewater-Gwinup-Hamwi  familial 
gynecomastia
d.
Kallmann syndrome
e.
Kennedy’s disease with associated 
gynecomastia
f.
Eunuchoidal state (congenital anorchia)
g.
Hereditary defects of androgen biosynthesis
h.
Adrenocorticotropic hormone deficiency
2.
Secondary testicular failure
a.
Trauma
b.
Orchitis
c.
Cryptorchidism
d.
Irradiation
C.
Renal failure
III.
Pharmacologic causes
IV.
Androgen deficiency may initiate gyne-
comastia.
This senescent gynecomastia usually occurs in men aged 
50 to 70 years.
Hypoandrogenic states can be from primary tes-
ticular failure or secondary testicular failure.
Secondary testicular failure may result 
from trauma, orchitis, and cryptorchidism.
Renal failure, regard-
less of cause, also may initiate gynecomastia.
When it 
is caused by medications, then these are discontinued if possi-
ble.
When endocrine defects are responsible, then these receive 
specific therapy.
Techniques include local excision, liposuction or sub-
cutaneous mastectomy.
Breast infections 
may be chronic, possibly with recurrent abscess formation.
Uncommon organ-
isms may be encountered, and long-term antibiotic therapy may 
be required.
Epidemic puerperal mastitis is initiated 
by highly virulent strains of methicillin-resistant S.
Purulent fluid may 
be expressed from the nipple.
The addition of antibiotic therapy results in a satisfactory out-
come in >95% of cases.
Pus mixed with blood may be 
expressed from sinus tracts.
Antifungal agents can be adminis-
tered for the treatment of systemic (noncutaneous) infections.
Scrapings from the lesions demonstrate fungal 
elements (filaments and binding cells).
Involvement of the axillary skin is often multifo-
cal and contiguous.
Antibiotic therapy with incision and drain-
age of fluctuant areas is appropriate treatment.
Excision of the 
involved areas may be required.
A tender, 
firm cord is found to follow the distribution of one of the major 
superficial veins.
This benign, self-limited disorder is not indicative of a can-
cer.
The process usually resolves within 4 to 6 weeks.
In: Mansel RE, et al, eds.
Hughes, Mansel & Webster’s Benign Disorders and Diseases of the Breast.
London: Saunders, 2009.
Copyright Elsevier.
The vertical component indi-
cates the period during which the condition develops.
Early Reproductive Years.
The precise etiology of adolescent 
breast hypertrophy is unknown.
A spectrum of changes from 
limited to massive stromal hyperplasia (gigantomastia) is seen.
Later Reproductive Years.
Painful nodularity that 
persists for >1 week of the menstrual cycle is considered a disor-
der.
Involution.
Involution of lobular epithelium is dependent 
on the specialized stroma around it.
The macrocysts are com-
mon, often subclinical, and do not require specific treatment.
Periductal fibro-
sis is a sequela of periductal mastitis and may result in nipple 
retraction.
About 60% of women ≥70 years of age exhibit some 
degree of epithelial hyperplasia (Fig.
17-11).
The classification 
Figure 17-11.
A.
Ductal epithelial hyperplasia.
B.
Lobular hyperplasia.
(Photos used with permission of Dr.
R.L.
Hackett.)
Figure 17-10.
Fibroadenoma (40x).
(Photo used with permission of Dr.
Sindhu 
Menon, Consultant Histopathologist & Dr.
N Engl J Med 312:146, 1985.
Calcium deposits are frequently encountered in the breast.
Most are benign and are caused by cellular secretions and 
debris or by trauma and inflammation.
Fibroadenomas have 
abundant stroma with histologically normal cellular elements.
They may be divided into tubular 
adenomas and lactating adenomas.
Arch Pathol Lab Med.
1986;110:171.
diameter, firm, and sharply circumscribed.
Fibrocystic Disease.
The term fibrocystic disease is nonspe-
cific.
Benign calcifications are often associated with 
this disorder.
Florid duc-
tal epithelial hyperplasia occupies at least 70% of a minor duct 
lumen.
Intraductal papillomas arise in the major 
ducts, usually in premenopausal women.
They generally are 
<0.5 cm in diameter but may be as large as 5 cm.
A common 
presenting symptom is nipple discharge, which may be serous 
or bloody.
Lobular carcinoma in situ (100x).
(Photo used with permission of  
Dr.
Sindhu Menon, Consultant Histopathologist & Dr.
17-12).
There is a variant of 
LCIS that has been termed pleomorphic LCIS.
Treatment of Selected Benign Breast  
Disorders and Diseases
Cysts.
The volume of a typical 
cyst is 5 to 10 mL, but it may be 75 mL or more.
After aspiration, the breast is carefully palpated to exclude 
a residual mass.
When cystic fluid is bloodstained, fluid 
can be sent for cytologic examination.
Fibroadenomas.
Careful ultrasound examination with core-needle 
biopsy will provide for an accurate diagnosis.
Larger lesions are often still 
best removed by excision.
Sclerosing Disorders.
The clinical significance of sclerosing 
adenosis lies in its imitation of cancer.
Periductal Mastitis.
Antibiotics are then 
continued based on sensitivity tests.
Ultrasound will accurately delineate its extent.
Recurrent abscess with fistula is a difficult problem.
London: 
WB Saunders, 2000, p 162.
Copyright © Elsevier.
Nipple Inversion.
Finally, there is an association between 
obesity and increased breast cancer risk.
Nonhormonal risk factors include radiation exposure.
Risk Assessment Models
The average lifetime risk of breast cancer for newborn U.S.
There are several risk assessment models 
available to predict the risk of breast cancer.
The output is a 
five-year risk and a lifetime risk of developing breast cancer.
N Engl J Med.
342:564, 2000.
Furthermore, 
these hormone supplements were thought to reduce coronary 
artery disease as well.
benefits of postmenopausal 
hormone replacement therapy.
They found an 
increased risk of breast cancer with ever use of estrogen replace-
ment therapy.
In addition, a clini-
cal breast examination by a health professional is recommended 
annually.
Chemoprevention.
There have been 4 prospective 
studies published evaluating tamoxifen vs.
placebo for reducing 
the incidence of invasive breast cancer for women at increased 
risk.
Cataract surgery is required almost 
twice as often among women taking tamoxifen.
The 
trial randomized 4,560 women to exemestane 25 mg daily vs.
placebo for five years.
Preventive Services Task Force.
Risk-reducing Surgery.
BRCA Mutations
BRCA1.
More 
than 500 sequence variations in BRCA1 have been identified.
Approximately 50% of children of carriers inherit the 
trait.
Several founder mutations have been identified in BRCA1.
BRCA2 is located on chromosome arm 13q and spans 
a genomic region of approximately 70 kb of DNA.
The mutational spec-
trum of BRCA2 is not as well established as that of BRCA1.
To date, >250 mutations have been found.
Approximately 50% of children of carriers inherit 
the trait.
A number of founder mutations 
have been identified in BRCA2.
BRCA Mutation Testing.
This person undergoes complete 
sequence analysis of both the BRCA1 and BRCA2 genes.
If a 
mutation is identified, relatives are usually tested only for that 
specific mutation.
In addition, no BRCA muta-
tion can be passed on to the woman’s children.
Overall, the false-negative rate for BRCA mutation testing is 
<5%.
This is because single base-pair changes do not always result in 
a nonfunctional protein.
Indeterminate genetic 
variance currently accounts for 12% of the test results.
Cancer Prevention for BRCA Mutation Carriers.
Risk man-
agement strategies for BRCA1 and BRCA2 mutation carriers 
include the following:
1.
Risk-reducing mastectomy and reconstruction
2.
Risk-reducing salpingo-oophorectomy
3.
Intensive surveillance for breast and ovarian cancer
4.
Risk-reducing salpingo-
oophorectomy is a reasonable prevention option in mutation car-
riers.
Hormone replacement therapy is dis-
cussed with the patient at the time of oophorectomy.
For 2002 to 2008 rates were 92% and 78%, respectively.
There is a 10-fold variation in breast cancer incidence 
among different countries worldwide.
The incidence rates of breast cancer increased in most 
countries through the 1990s.
It was predicted that there would be approxi-
mately 1.4 million new cases in 2010.
These are features that characterize many 
underdeveloped nations and also many eastern nations.
The 
median survival of this population was 2.7 years after initial 
diagnosis (Fig.
17-13).117 The 5- and 10-year survival rates 
Figure 17-13.
Survival of women with untreated breast cancer 
compared with natural survival.
(Reproduced with permission 
from Bloom HJG, Richardson WW, Harries EJ.
Br Med J.
Only 
0.8% survived for 15 years or longer.
Almost 75% of the women 
developed ulceration of the breast during the course of the 
disease.
The longest surviving patient died in the nineteenth 
year after diagnosis.
Primary Breast Cancer.
Localized edema (peaud’orange) 
develops when drainage of lymph fluid from the skin is dis-
rupted.
With continued growth, cancer cells invade the skin, and 
eventually ulceration occurs.
As new areas of skin are invaded, 
small satellite nodules appear near the primary ulceration.
17-14).
Axillary Lymph Node Metastases.
Eventually the lymph 
nodes adhere to each other and form a conglomerate mass.
17-14A).
Distant Metastases.
These cells are scavenged by natural killer 
lymphocytes and macrophages.
A.
Overall survival for women with breast can-
cer according to axillary lymph node status.
The time periods 
are years after radical mastectomy.
Analysis of 716 consecutive patients.
Cancer.
1978;11:1170.
Copyright © American Cancer Society.
Risk of metastases according to 
breast cancer volume and diameter.
(Reproduced with permission 
from Koscielny S et al.
Br J Cancer.
Before the widespread use 
of mammography, diagnosis of breast cancer was by physical 
examination.
Table 17-8 lists 
the clinical and pathologic characteristics of DCIS and LCIS.
Lobular Carcinoma In Situ.
LCIS originates from the termi-
nal duct lobular units and develops only in the female breast.
Cytoplasmic mucoid globules are 
a distinctive cellular feature.
Invasive 
breast cancer develops in 25% to 35% of women with LCIS.
Philadelphia: WB 
Saunders;1998:1020.
Copyright Elsevier.
Ductal Carcinoma In Situ.
Published series suggest a detection frequency of 7% in all 
biopsy tissue specimens.
Calcium deposition 
occurs in the areas of necrosis and is a common feature seen 
on mammography.
Based 
on multiple consensus meetings, grading of DCIS has been rec-
ommended.
17-15A and B).
bSolid, cribriform, papillary, or focal micropapillary.
PPO Updates 10:1, 1996.
521
T
HE
 B
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CHAPTER 17
invasive ductal carcinoma of no special type (NST).
These can-
cers generally have a worse prognosis than special-type cancers.
Paget’s disease of the nipple
2.
Medullary carcinoma, 4%
4.
Mucinous (colloid) carcinoma, 2%
5.
Papillary carcinoma, 2%
6.
Tubular carcinoma, 2%
7.
Invasive lobular carcinoma, 10%
8.
A palpable mass 
may or may not be present.
Paget’s disease 
may be confused with superficial spreading melanoma.
This cancer occurs most 
frequently in perimenopausal or postmenopausal women in the 
Figure 17-15.
Ductal carcinoma in situ (DCIS).
A.
Craniocaudal mammographic view shows a poorly defined mass containing microcalci-
fications.
(Photo used with permission of Dr.
Anne Turnbull, Consultant Radiologist/Director of Breast Screening.
Royal Derby Hospital.) B.
Sindhu Menon, 
Consultant Histopathologist & Dr.
17-16A 
and B).
Grossly, the can-
cer is soft and hemorrhagic.
A rapid increase in size may occur 
secondary to necrosis and hemorrhage.
On physical examina-
tion, it is bulky and often positioned deep within the breast.
Bilaterality is reported in 20% of cases.
In rare circumstances, 
mesenchymal metaplasia or anaplasia is noted.
The cut 
surface of this cancer is glistening and gelatinous in quality.
Fibrosis is variable, and when abundant it imparts a firm consis-
tency to the cancer.
Typically, papillary car-
cinomas are small and rarely attain a size of 3 cm in diameter.
These cancers are defined by papillae with fibrovascular stalks 
and multilayered epithelium.
Distant metastases are 
rare in tubular carcinoma and invasive cribriform carcinoma.
Long-term survival approaches 100%.
Invasive lobular carcinoma accounts for 10% of breast 
cancers.
17-17).
At presentation, invasive 
Figure 17-17.
Lobular carcinoma (100×).
(Used with permission of Dr.
Sindhu 
Menon, Consultant Histopathologist & Dr.
Invasive ductal carcinoma with productive fibrosis (scirrhous, simplex, no special type) A.
100x and B.
200x.
(Used with 
permission of Dr.
Sindhu Menon, Consultant Histopathologist & Dr.
It is frequently multifocal, multicentric, and bilateral.
Breast pain usually is associated with benign disease.
Examination
Inspection.
The surgeon inspects the woman’s breast with 
her arms by her side (Fig.
17-18A), with her arms straight up 
in the air (Fig.
Palpation.
As part of the physical examination, the breast is 
carefully palpated.
With the patient in the supine position (see 
Fig.
The breast may be cupped or molded in the 
surgeon’s hands to check for retraction.
A systematic search for 
lymphadenopathy then is performed.
Figure 17-18D shows the 
position of the patient for examination of the axilla.
By support-
ing the upper arm and elbow, the surgeon stabilizes the shoul-
der girdle.
Careful palpation 
Figure 17-18.
Examination of the breast.
A.
Inspection of the 
breast with arms at sides.
B.
Inspection of the breast with arms 
raised.
C.
Palpation of the breast with the patient supine.
D.
Palpa-
tion of the axilla.
of supraclavicular and parasternal sites also is performed.
17-19).
Imaging Techniques
Mammography.
By comparison, chest radiography delivers 25% of this 
dose.
Screening mammography is used to detect unexpected 
breast cancer in asymptomatic women.
In this regard, it supple-
ments history taking and physical examination.
17-20A and B) and the mediolat-
eral oblique (MLO) view (Fig.
17-20 C and D).
17-21C).
A breast examination record.
A-D.
Mammogram of a premenopausal 
breast with a dense fibroglandular pattern.
E-H.
Mam-
mogram of a postmenopausal breast with a sparse 
fibroglandular pattern.
(Photos used with permission of 
Dr.
(Continued )
microcalcifications.
Mammogram revealing a small, spiculated mass in the right breast A.
A small, spiculated mass is seen in the right breast with 
skin tethering (CC view).
B.
Mass seen on oblique view of the right breast.
C.
Spot compression mammography view of the cancer seen in  
A and B.
The spiculated margins of the cancer are accentuated by compression.
(Photos used with permission of Dr.
This is especially useful in women with dense breasts 
and women <50 years of age.
Recently, investigators directly 
compared digital vs.
Ductography.
Intraductal papillomas are 
seen as small filling defects surrounded by contrast media  
(Fig.
17-22).
Cancers may appear as irregular masses or as mul-
tiple intraluminal filling defects.
Ultrasonography.
17-23).
Breast cancer 
characteristically has irregular walls (Fig.
17-25) but may have 
smooth margins with acoustic enhancement.
17-26).
There is current interest in the use of MRI to screen the 
Figure 17-22.
Ductogram.
(Photos used with permission of B.
Steinbach.)
BA
breasts of high-risk women and of women with a newly diag-
nosed breast cancer.
17-27).
17-28).
The use of dedicated breast coils is mandatory in the MRI 
imaging of the breast.
Breast cyst.
A.
Simple cyst.
B.
Complex solid and cystic mass.
(C) Complex solid and cystic mass characteristic of intracystic papillary tumor.
(Photos used with 
permission of Dr.
Figure 17-24.
Ultrasonography images of benign breast tumors.
A.
Fibroadenoma.
B.
Intraductal papilloma.
(Photos used with permission 
of Dr.
Breast Biopsy
Nonpalpable Lesions.
The com-
bination of diagnostic mammography, ultrasound or stereotactic 
A
B
CD
Figure 17-25.
Ultrasonography images of malignant breast lesions.
A.
25 mm irregular mass.
B.
Ultrasound 30 mm mass anterior to an 
implant.
C.
Ultrasound breast cancer with calcification.
D.
Ultrasound 9 mm spiculated mass with attenuation.
(Photos used with permission 
of Dr.
Palpable Lesions.
Ultrasonography images of lymph nodes.
A.
Normal axillary lymph node.
B.
Indeterminate axillary lymph node.
C.
Malignant 
appearing axillary lymph node.
(Photos used with permission of Dr.
(Photo used with permission of Dr.
MRI imaging of the breast revealing multifocal tumors not detected with standard breast imaging.
(Photo used with permission 
of Dr.
The cellular material is then expressed onto microscope 
slides.
Both air-dried and 95% ethanol–fixed microscopic sec-
tions are prepared for analysis.
Automated devices also are avail-
able.
Tissue specimens are placed in formalin and then 
processed to paraffin blocks.
The clinical, radiographic, and pathologic findings should be 
in concordance.
17-14B).
Biomarkers
Breast cancer biomarkers are of several types.
Size 
should be measured to the nearest millimeter.
In general, pathologic determination should take precedence over clinical determination of T size.
ITCs may be detected by 
routine histology or by immunohistochemical (IHC) methods.
** RT-PCR: reverse transcriptase/polymerase chain reaction.
New York: Springer; 2010:358-361.
Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois.
–The designation pM0 is not valid; any M0 should be clinical.
–Postneoadjuvant therapy is designated with “yc” or “yp” prefix.
New York: Springer; 
2010:360-361.
Used with permission of the American Joint Committee 
on Cancer (AJCC), Chicago, Illinois.
Steroid Hormone Receptor Pathway.
Hormones play an 
important role in the development and progression of breast 
cancer.
Breast cancer risk is related to estrogen exposure over 
time.
Growth Factor Receptors and Growth Factors.
Patients 
whose tumors overexpress HER-2/neu are candidates for anti–
HER-2/neu therapy.
Trastuzumab (Herceptin) is a recombinant 
humanized monoclonal antibody directed against HER-2/neu.
Indices of Angiogenesis.
Antiangiogenesis breast 
cancer therapy is now being studied in human trials.
Bevaci-
zumab (a monoclonal antibody to VEGF) was approved by the 
U.S.
Indices of Apoptosis.
Coexpression of Biomarkers.
Adjuvant!
Adjuvant!
New York: 
Springer-Verlag;2003:112.
With kind permission of Springer Science + 
Business Media.
Source: Adapted from Carlson RW, et al: Breast cancer, in NCCN Prac-
tice Guidelines in Oncology.
Fort Washington, PA: National Compre-
hensive Cancer Network, 2006.
537
T
HE
 B
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CHAPTER 17
course of treatment.
17-29).
For women with limited 
disease, lumpectomy and radiation therapy are generally rec-
ommended.
Specimen mammography is performed to ensure that all 
visible evidence of cancer is excised.
Adjuvant tamoxifen ther-
apy is considered for DCIS patients with ER-positive disease.
AB
Figure 17-29.
Extensive DCIS seen on mammography.
A.
Extensive calcifications are seen throughout the breast on this CC view.
B.
Mag-
nification view of calcifications.
Due to the extent of the disease the patient is not a good candidate for breast conserving surgery.
(Photos 
used with permission of Dr.
Women treated with 
mastectomy have local recurrence and mortality rates of <2%.
There is no randomized trial comparing mastectomy vs.
About 
45% of these recurrences will be invasive cancer when radia-
tion therapy is not used.
In contrast, patients with high grade 
DCIS had an unacceptably high local recurrence rate.
lumpectomy with whole breast 
irradiation.
The role of axillary staging in patients with DCIS 
is limited.
One consideration is for patients undergoing mastec-
tomy.
13.4%, P = 0.0009).
5.2%, P<0.001).
However it should be noted that 
there were several criteria in the B-06 study.
There was a specific 
lymphadenopathy exclusion criteria.
All patients 
received adjuvant tamoxifen.
Although there were fewer local 
recurrences with radiation (1% vs.
4%, P<0.001), there were no 
differences in DFS and OS.
Mean age was 68 years, and 80% of women had 
ER-positive tumors.
Again, local recurrence rates were lower 
in women who received radiation (0.6% vs.
1.3% with 
EBRT, a 2% increased recurrence risk.
Immediate reconstruction allows for skin-sparing, thus optimiz-
ing cosmetic outcomes.
standard axillary surgery.
A total of 26% of these clini-
cally node-negative patients had a positive SLN.
Patients with 1 or 2 positive SLNs were randomized to 
completion ALND or no further surgery.
Adjuvant systemic 
therapy recommendations were left to the treating clinicians.
The morbidity of SLN dissection alone vs.
those who had no further axillary surgery.
These issues have thus far lim-
ited the uptake of the results of Z0011 by some centers.
Patients with SLN 
micrometastases were randomized to ALND vs.
no further sur-
gery.
Unlike Z0011, the 23-01 trial did not exclude patients 
treated with mastectomy.
Approximately 9% of patients ran-
domized to each study arm underwent mastectomy.
17-31).
Indeed, a previous 
AB
Figure 17-30.
Locally advanced breast cancer.
A.
Mammography of the right breast reveals a large tumor with enlarged axillary lymph 
nodes.
B.
Imaging of the left breast is normal.
(Photos used with permission of Dr.
Treatment pathways for stage IIIA and 
stage IIIB breast cancer.
However, the Oxford overview of all randomized 
studies of neoadjuvant therapy (vs.
adjuvant therapy) reported a 
hazard ratio of 1.5 (i.e., 50% increase) in local recurrence rates.
In both stage IIIA and IIIB disease, sur-
gery is followed by adjuvant radiation therapy.
Symptoms per se (e.g., breathlessness) are not in themselves an 
indication for chemotherapy.
The same approach should be taken to other 
symptoms such as pain.
A randomized trial is currently underway through ECOG to 
address this question.
Chemo-
therapy and antiestrogen therapy are considered.
Data have been collected since 1973 
and is updated at regular intervals.
Today it is 
AB
Figure 17-32.
Lesion to be targeted to excisional 
biopsy.
A.
B.
Oblique 
view demonstrating target lesions.
(Photos used 
with permission of Dr.
mastectomy with or without reconstruction) and the need for 
nodal assessment with SLN dissection.
17-32).
In 
the lower half of the breast, the use of radial incisions typically 
provides the best outcome.
The biopsy tissue specimen is orientated for 
the pathologist using sutures, clips, or dyes.
Electrocautery or 
absorbable ligatures are used to achieve wound hemostasis.
Wound drainage is usually not required.
The lesion can also be 
targeted by sonography in the imaging suite or in the operating 
room.
17-33).
17-34).
Although limited data are available, SLN 
Figure 17-33.
Wire localization procedure.
(Photos used with permission of Dr.
Subdermal 
injections are given in proximity to the cancer site or in the 
subareolar location.
Specimen mammography.
(Photos 
used with permission of Dr.
The use 
of radioactive colloid is safe, and radiation exposure is very low.
A hand-held gamma counter is used to transcutaneously 
identify the location of the SLN.
This can help to guide place-
ment of the incision.
The gamma probe is used to facilitate the dissection and to 
pinpoint the location of the SLN.
Before the SLN is removed, a 10-second in vivo radioactivity 
count is obtained.
A search is made for 
additional SLNs if the counts remain high.
Finally, removal of a larger number 
of SLNs at surgery appears to reduce the false-negative rate.
This was significantly 
influenced by the site of radioisotope injection.
Radial incisions are preferred when 
the tumor is in the lower aspect of the breast.
Specimen orientation is performed by the surgeon.
Requests for determination of 
ER, PR, and HER-2 status are conveyed to the pathologist.
It is the surgeon’s responsibility to ensure complete 
removal of cancer in the breast.
Cancer size and the extent 
of skin excision are not significant factors in this regard.
If clear margins are not obtainable with re-excision, mastectomy 
is required.
SLN is performed before removal of the primary 
breast tumor.
The overall goal is to achieve the best possible aes-
thetic result.
Modified radical mastectomy: eleva-
tion of skin flaps.
Skin flaps are 7 to 8 mm in thick-
ness, inclusive of the skin and telasubcutanea.
(Visual 
Art: © 2012.
The University of Texas MD Anderson 
Cancer Center.)
Figure 17-36.
Modified radical mastectomy after 
resection of breast tissue.
The pectoralis major muscle 
is cleared of its fascia as the overlying breast is elevated.
The latissimus dorsi muscle is the lateral boundary of the 
dissection.
(Visual Art: © 2012.The University of Texas 
MD Anderson Cancer Center.)
pectoral nerve.
17-35).
17-36).
Subsequently, an axillary lymph node dissection is per-
formed.
Care 
is taken to preserve the thoracodorsal neurovascular bundle.
In Patey’s modified radi-
cal mastectomy he removed the pectoralis minor muscle.
The use of closed-system suction drainage reduces 
the incidence of this complication.
Catheters are retained in the 
wound until drainage diminishes to <30 mL per day.
Figure 17-37.
Modified radical mastectomy (Patey): axillary lymph node dissection.
Care is 
taken to preserve the thoracodorsal artery, vein, and nerve in the deep axillary space.
The superomedial limit 
of this dissection is the clavipectoral fascia (Halsted’s ligament).
Inset depicts division of the insertion of the pectoralis minor muscle at the 
coracoid process.
The surgeon’s finger shields the underlying brachial plexus.
(Reproduced with permission from Bland KI, et al.
Modified 
radical mastectomy and total (simple) mastectomy.
In: Bland KI, Copeland EMI, eds.
The Breast: Comprehensive Management of Benign 
and Malignant Diseases.
Philadelphia: Saunders, 2009.
The free TRAM 
flap uses microvascular anastomoses to establish blood supply 
to the flap.
Chemotherapy Adjuvant
Chemotherapy.
Table 17-14 lists the frequently used chemotherapy 
regimens for breast cancer.
Neoadjuvant (Preoperative) Chemotherapy.
Source: Adapted from Carlson RW, et al: Breast cancer, in NCCN Prac-
tice Guidelines in Oncology.
Fort Washington, PA: National Compre-
hensive Cancer Network, 2006.
Neoadjuvant Endocrine Therapy.
Neoadjuvant endocrine 
therapy has not been based on randomized controlled trials.
Antiestrogen Therapy 
Tamoxifen.
The analysis 
also showed a 39% reduction in the risk of cancer in the con-
tralateral breast.
Thrombotic events occur in <3% of treated women.
Cataract surgery is more frequently performed in patients 
receiving tamoxifen.
A long-term risk of tamoxifen use is 
endometrial cancer.
This 
approach has not been universally accepted.
Aromatase inhibitors.
5 years of tamoxifen and this is irrespective of 
absolute risk.
The risk of osteoporosis 
can be averted by treatment with bisphosphonates.
Joint pains 
are a side effect which affects a significant number of patients.
Oopho-
rectomy was used in premenopausal breast cancer patients.
For 
both groups, the response rates were nearly 30%.
Dose-dependent and transient side effects include ataxia, dizziness, 
and lethargy.
Neither permanent adrenal insufficiency nor acute crises have 
been observed.
Patients with HER-2-positive tumors 
benefit if trastuzumab is added to paclitaxel chemotherapy.
It was approved for use with capecitabine in patients 
with HER-2-positive metastatic disease.
In this circumstance, 
mammography and ultrasound are indicated for further evalu-
ation.
Nipple discharge associated with a cancer may be clear, 
bloody, or serous.
A 3.0 lacrimal 
duct probe can be used to identify the duct that requires exci-
sion.
Another approach is to inject methylene blue dye within 
the duct after ductography.
Suspicious findings on mammography, ultra-
sonography, or MRI necessitate breast biopsy.
Chemotherapy and 
endocrine therapy should be considered.
Fewer than 25% of the breast nodules 
developing during pregnancy and lactation will be cancerous.
Ultrasonography and needle biopsy specimens are used in the 
diagnosis of these nodules.
Lactation 
is suppressed.
Jewish and African American males have the 
highest incidence.
Male breast cancer is preceded by gyneco-
mastia in 20% of men.
Breast cancer is rarely seen in young 
males and has a peak incidence in the sixth decade of life.
A 
firm, nontender mass in the male breast requires investigation.
Skin or chest wall fixation is particularly worrisome.
DCIS makes up <15% of male breast cancer, whereas 
infiltrating ductal carcinoma makes up >85%.
Special-type can-
cers, including infiltrating lobular carcinoma, have occasionally 
been reported.
Borderline tumors have a greater 
potential for local recurrence.
Cystic areas represent sites of 
infarction and necrosis.
Most malignant phyllodes tumors (Fig.
Small 
phyllodes tumors are excised with a margin of normal-appearing 
breast tissue.
Large phyllodes tumors may require mastectomy.
Axillary dis-
section is not recommended because axillary lymph node metas-
tases rarely occur.
There may be 
an associated breast mass (Fig.
17-39).
Inflammatory breast cancer also 
may be mistaken for a bacterial infection of the breast.
A positron emission 
A
B
Figure 17-38.
A.
Malignant phyllodes tumor (cystosarcoma-
phyllodes).
B.
Histologic features of a malignant phyllodes tumor 
(hematoxylin and eosin stain, ×100).
Figure 17-39.
Inflammatory breast carcinoma.
Table 17-15 
Inflammatory vs.
Inflammatory changes are 
present without dermal lymph 
vessel invasion.
Cancer is not sharply 
delineated.
Cancer is better delineated.
Erythema and edema 
frequently involve >33% of 
the skin over the breast.
Erythema is usually confined 
to the lesion, and edema is 
less extensive.
Lymph node involvement is 
present in >75% of cases.
Lymph nodes are involved 
in approximately 50% of the 
cases.
Distant metastases are present 
in 25% of cases.
Distant metastases are less 
common at presentation.
Distant metastases are 
more common at initial 
presentation.
Philadelphia: WB Saunders;1998;1281.
Copyright 
Elsevier.
This multimodal 
approach results in 5-year survival rates that approach 30%.
Patients with inflammatory breast cancer should be encouraged 
to participate in clinical trials.
Rare Breast Cancers
Squamous Cell (Epidermoid) Carcinoma.
Adenoid Cystic Carcinoma.
Adenoid cystic carcinoma is very 
rare, accounting for <0.1% of all breast cancers.
It is typically 
indistinguishable from adenoid cystic carcinoma arising in sali-
vary tissues.
These cancers are generally 1 to 3 cm in diameter 
at presentation and are well circumscribed.
Axillary lymph node 
metastases are rare, but deaths from pulmonary metastases have 
been reported.
Apocrine Carcinomas.
There is a very low mitotic rate and little 
variation in cellular features.
However, apocrine carcinomas 
may display an aggressive growth pattern.
Sarcomas.
Sarcomas of the breast are histologically similar 
to soft tissue sarcomas at other anatomic sites.
The 
clinical presentation is typically that of a large, painless breast 
mass with rapid growth.
Diagnosis is by core-needle biopsy or by 
open incisional biopsy.
Primary treatment is wide local excision, which may necessitate 
mastectomy.
Axillary dissection is not indicated unless there is 
biopsy proven lymph node involvement.
Sixty percent of 
women developing this cancer have a history of adjuvant radia-
tion therapy.
Lymphomas.
Primary lymphomas of the breast are rare, and 
there are two distinct clinicopathologic variants.
The second 
type is seen in women ≥40 years of age and is usually of the 
B-cell type.
Breast involvement by Hodgkin’s lymphoma has 
been reported.
An occult breast lymphoma may be diagnosed 
after detection of palpable axillary lymphadenopathy.
Treat-
ment depends on the stage of disease.
Lumpectomy or mas-
tectomy may be required.
Axillary dissection for staging and 
for clearance of palpable disease is appropriate.
The prognosis is favorable, with 
5- and 10-year survival rates of 74% and 51%, respectively.
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Disorders of the Head and Neck
Richard O.
Wein, Rakesh K.
Chandra,  
C.
René Leemans, and Randal S.
Infected, desquamated debris accumulates within the canal.
For this 
reason, the patient should also be instructed to keep the ear dry.
In addition to the previ-
ously mentioned findings, cranial neuropathies may be observed.
Patients who do not respond to medical management require 
surgical debridement.
In its acute phase, otitis media typically implies a bacterial 
infection of the middle ear.
Long-term car-
diovascular problems are a significant concern in these patients.
Most cases occur before 2 years 
of age and are secondary to immaturity of the Eustachian tube.
18-1).
If the process lasts 3 to 8 weeks, it is deemed 
subacute.
Acute otitis media.
Figure 18-2.
Myringotomy and tube.
dysfunction, and other factors.
The exact role of bacteria in the pathophysiol-
ogy is controversial.
The patient experiences otalgia, ear full-
ness, and conductive hearing loss.
Bubbles may be seen behind the 
retracted membrane.
Treatment for uncomplicated otitis media is oral antibiotic 
therapy.
Chronic otitis media is frequently treated with myringotomy 
and tube placement (Fig.
18-2).
7 Disorders of the head and neck can cause significant cos-
metic and functional impairment.
The practitioner must be 
empathetic to the effect of these morbidities on quality of 
life.
567
DISORDERS OF THE HEAD AND NECK
CHAPTER 18
fluid and middle ear ventilation.
Chronic otitis media, however, may be associated with 
nonhealing tympanic membrane perforations.
Patients may have 
persistent otorrhea, which is treated with topical drops.
Squamous epithelium may also migrate into the middle ear via a 
perforation.
The mastoid air cells 
coalesce into one common space filled with pus.
These diagnoses are confirmed by 
computed tomographic (CT) scan.
Labyrinthitis refers to inflam-
mation of the inner ear.
Most cases are idiopathic or are second-
ary to viral infections of the endolymphatic space.
Labyrinthitis associated 
with middle ear infection may be serous or suppurative.
Total recovery is 
eventually possible after the middle ear is adequately treated.
This condition 
may hallmark impending meningitis and must be treated rapidly.
Meningitis is the most common intracranial complica-
tion.
Otologic meningitis in children is most commonly associ-
ated with a H.
influenzae type B infection.
Mastoidectomy and neurosurgical consultation may be 
necessary.
Historically, Bell’s 
palsy was synonymous with “idiopathic” facial paralysis.
Treatment 
includes oral steroids plus antiviral therapy (i.e., valacyclovir).
Traumatic facial nerve injuries may occur secondary to 
accidental trauma or surgical injury.
Complete recovery of nerve 
function is uncommon in these cases.
The classification of sinusitis as acute vs.
This may be accomplished by 
endoscopic or radiologic examination (i.e., CT scan).
This results in stasis of secretions, tis-
sue hypoxia, and ciliary dysfunction.
These conditions promote 
bacterial proliferation and acute inflammation.
pneumoniae,  
H.
influenzae, and M.
catarrhalis.
Nosocomial acute sinusitis 
frequently involves Pseudomonas or S.
aureus, both of which 
may also exhibit significant antibiotic resistance.
Nasal endoscopy is a critical element of the diagnosis of 
chronic sinusitis.
18-3 
and 18-4).
In this setting, purulence 
may represent an acute exacerbation of chronic sinusitis.
Overall, S.
Endoscopic view of purulence within a surgically 
opened maxillary sinus cavity.
Figure 18-4.
Endoscopic image of a nasal polyp.
Figure 18-5.
POC-CT system.
All components can be fit within an 
8' × 10' room in an outpatient office setting.
sinusitis.
Thus, the increased prevalence of community acquired 
methicillin resistant S.
CT scan has excellent negative predictive value when per-
formed in the setting of active symptoms.
18-5).
One theoretical 
shortcoming of this technology is that it does not permit soft tis-
sue imaging.
This is seldom a concern in sinonasal evaluation, as 
this is typically undertaken in bone windows.
18-6 and 18-7).
Inspis-
sated mucin or pus is drained and cultured.
The role of fungi in sinusitis is an area of active investiga-
tion.
Fungal sinusitis may take on both noninvasive and invasive 
forms.
Polyps in the ethmoid cavity are seen on the endoscope image.
570
SPECIFIC CONSIDERATIONS
UNIT
 
II
PART II
subtle and limited to a single sinus.
Fungus balls represent a 
 significant proportion of isolated sphenoid sinus pathology 
(Fig.
18-7).
Oral antifungal 
therapy is sometimes indicated as well.
The mucosa of the 
posterior and lateral pharyngeal walls is also rich with lym-
phoid cells.
In the vast majority of cases, infectious pharyngitis is viral 
rather than bacterial in origin.
Most cases resolve without com-
plication from supportive care and possibly antibiotics.
Patients 
with tonsillitis typically present with sore throat, dysphagia, 
and fever.
The mucosa is inflamed.
Tonsillar exudates and 
cervical adenitis may be seen, especially when the etiology is 
bacterial.
If adenoiditis is present, symptoms may be similar to 
those of sinusitis.
Tonsillitis and adenoiditis may follow acute, recurrent 
acute, and chronic temporal patterns.
When the patient also has hoarseness, rhinorrhea, 
Figure 18-7.
Sphenoid sinus fungal ball.
pneumoniae, and group C and G streptococci.13  
H.
influenzae and anaerobes also have been implicated.
Some experts advocate culture only when these 
are negative.
Complications of S.
The incidence of glomerulonephritis 
is not influenced by antibiotic therapy.
Scarlet fever results from 
production of erythrogenic toxins by streptococci.
The so-called strawberry 
tongue also is seen.
Locoregional complications include peri-
tonsillar abscess and, rarely, deep-neck space abscess.
Candida albicans is the most common fungal organism 
to cause pharyngitis.
Whitish-cheesy or 
creamy mucosal patches are observed with underlying erythema.
Progression of the clinical picture 
reveals lymphadenopathy, splenomegaly, and hepatitis.
Noninfectious causes of pharyngitis must also be consid-
ered.
There is no consensus as to the best 
method.
Adenoidectomy 
is also the first line of surgical management for children with 
chronic sinusitis.
In both procedures, there is risk 
of velopharyngeal insufficiency.
In the latter condition, nasal 
regurgitation of liquids and hypernasal speech are experienced.
In OSA, polysom-
nogram demonstrates at least 10 episodes of apnea or 
hypopnea per hour of sleep.
These episodes occur as a 
result of collapse of the pharyngeal soft tissues during sleep.
This can be accomplished with cold steel, laser, and/or cau-
tery.
Patients with moderate to severe sleep apnea frequently mani-
fest involvement of the tongue base.
Figure 18-8.
Laryngeal granuloma.
These “social snorers” may pursue elective 
procedures that stiffen the uvula and soft palate.
Elec-
tive uvulopharyngoplasty may also be a consideration in this 
population.
The princi-
pal symptom of these disorders, at least when a mass lesion 
is present, is hoarseness.
Other vocal manifestations include 
hypophonia or aphonia, breathiness, and pitch breaks.
Many 
cases resolve after puberty, but the disorder may progress into 
adulthood.
The diagnosis 
can be established with office endoscopy.
Currently, there is no 
“cure” for RRP.
Therefore, surgery has an ongoing role for palliation 
of the disease.
Multiple procedures are typically required over 
the patient’s lifetime.
18-8).
Effective management requires identifica-
tion of the underlying cause(s).
Patients report pain (often with 
swallowing) more commonly than vocal changes.
The 
management of vocal cord paresis/paralysis is discussed later in 
this section.
The 
superficial lamina propria just underlies the vibratory epithelial 
surface.
Patients report progressive development of a rough, low-
pitched voice.
Use 
of anticoagulant or antiplatelet drugs may be a risk factor.
Notably, top-
ical and systemic steroids are ineffective for these conditions.
Focal polyps may be excised superficially under microlaryn-
goscopy.
Postoperative voice therapy is usually 
indicated.
Large cyst of vocal cord.
as the supraglottic larynx.
Cysts may present in a variety of ways 
depending on the size and site of origin (Fig.
18-9).
Cysts observed in children can be quite 
large, thus compromising the airway.
Lesions of the true vocal 
cord usually present with hoarseness.
Treatment again depends 
on the size and site of the cyst.
Lesions exhibiting hyperplasia have a 1% to 3% risk 
of progression to malignancy.
In contrast, that risk is 10% to 
30% for those demonstrating dysplasia.
Features of ulceration and erythropla-
sia are particularly suggestive of possible malignancy.
A history 
of smoking and alcohol abuse should also prompt a malignancy 
work-up.
In the absence of suspected malignancy, conserva-
tive measures are used for 1 month.
Antireflux therapy, including proton 
pump inhibitors, may be prescribed.
Investigational therapies, 
including retinoids, also have been attempted.
Any lesions that 
progress, persist, or recur should be considered for excisional 
biopsy specimen.
The cause remains idiopathic in up to 20% of adults 
and 35% of children.
Some patients do well 
with this modality alone.
This 
technique also is useful for vocal cord atrophy, which may occur 
with aging.
18-10).26 This may be 
combined with procedures to adduct the vocal process of the 
arytenoids.
Figure 18-10.
Cross-section of the larynx demonstrating the prin-
ciple of medialization laryngoplasty.
An implant is used to push the 
paralyzed vocal cord toward the midline.
While 40% of cases will resolve completely, the remainder 
will require intervention.
Subcu-
taneous interferon-α-2a may also be used for this purpose.
Capillary malformations 
usually involve the midline neck or forehead, and may fade 
with age.
Venular malformations are also known as port-wine 
stains.
These lesions often follow facial dermatomes and usu-
ally thicken with age.
Venous malformations are composed of 
ectatic veins within the lips, tongue, or buccal area.
These may 
present as purple masses or subcutaneous/submucosal nodules.
Those 
arising above the hyoid bone tend to be microcystic and have an 
infiltrative quality.
Lymphangiomas may become secondarily 
infected and may rapidly enlarge, causing airway compromise.
These lesions may also be associated with feeding difficulties 
and failure to thrive.
Capillary hemangiomas and superficial port-wine stains 
are effectively treated by FPDL.
The KTP or Nd:YAG laser is 
used for deeper port-wine stains.
Arteriovenous malformations require formal surgical resection 
with negative margins.
Preoperative angiographic embolization 
is frequently used to facilitate surgery.
This often is difficult for microcystic cases 
given the infiltrative nature.
Head and neck soft tissues have the benefit of a robust 
blood supply.
A pressure dressing is also 
applied.
These measures are employed to avoid a pincushion 
deformity (Fig.
18-11).
Sutures are removed after 4 to 5 days, but may be removed 
earlier in thin-skinned areas.
The chosen antibiotic should cover S.
aureus.
The gray line (conjunctival margin; Fig.
18-12) must 
Figure 18-11.
Figure 18-12.
Alignment of the gray line is the key step in the 
repair of eyelid lacerations.
Management of lip injuries follows the same principle.
The orbicularis oris must be closed, and the vermilion bor-
der carefully approximated (Fig.
18-13).
These injuries must be repaired so that the cartilage is 
covered.
A pressure dress-
ing is frequently advocated after closure of an ear laceration.
Soft-
tissue injuries occurring in the midface may involve distal facial 
nerve branches.
If neural segments are missing, cable 
Figure 18-13.
Approximation of the vermilion border is the key 
step in the repair of lip lacerations.
3%
3%
36%
2%
20%
21% 14%
Figure 18-14.
Sites of common mandible fractures.
Injuries to 
the buccal branch should alert the examiner to a possible parotid 
duct injury.
The duct should be repaired 
over a 22-gauge stent or marsupialized into the oral cavity.
Facial bone fractures most commonly involve the man-
dible.
18-14).
Currently, arch bars and IMF are performed to establish occlu-
sion.
The fracture is then exposed and reduced, using transoral 
approaches where possible.
Rigid fixation is then accomplished by the application of plates 
and screws.
Midface fractures are classically described in three pat-
terns: Le Fort I, II, and III.
A full understanding of midface 
structure is first necessary (Fig.
18-15).
Le Fort I fractures occur transversely across the alveolus, 
above the level of the teeth apices.
The 
nasal dorsum, palate, and medial part of the infraorbital rim are 
mobile.
The Le Fort III fracture is also known as craniofacial 
disjunction.
The frontozygomaticomaxillary, frontomaxillary, 
and frontonasal suture lines are disrupted.
The entire face is 
mobile from the cranium.
It is convenient to conceptualize com-
plex midface fractures according to these patterns (Fig.
18-16); 
however, in reality, fractures reflect a combination of these three 
types.
Also, the fracture pattern may vary between the left and 
right sides of the midface.
Lateral blows to the cheek may be 
associated with isolated zygoma fractures.
Major buttresses of the midface.
III
II
I
Figure 18-16.
Classic Le Fort fracture patterns.
Figure 18-17.
18-17).
This may be associated with enophthalmos or entrap-
ment of the inferior oblique muscle.
The latter results in diplopia 
upon upward gaze.
Temporal bone fractures occur in approximately one fifth 
of skull fractures.
Unfortunately, the incidence of temporal bone 
fracture from gunshot wounds to the head is rising.
Fractures are 
divided into two patterns (Fig.
18-18), longitudinal and trans-
verse, based on the clinical picture and CT imaging.
In practice, 
most fractures are oblique.
The facial nerve is injured in approximately 20% of cases.
The facial nerve is injured in 50% of cases.
Hemotympanum may be 
observed.
A cerebrospinal fluid (CSF) leak must be suspected 
in temporal bone trauma.
This resolves with conservative mea-
sures in most cases.
Delayed or partial paralysis will almost always resolve 
with conservative management.
View of cranial surface of skull base.
Longitudinal 
(left) and transverse (right) temporal bone fractures.
for nerve decompression.
This is because the majority of malignancies of 
this region are represented by this pathology.
The selection of treatment protocols varies for each site 
within the upper aerodigestive tract.
The importance of multi-
disciplinary management cannot be underestimated.
The future of the treatment of head and neck 
cancer lies within the field of molecular biology.
This relationship is 
synergistic rather than additive.
This increased 
risk rises to > threefold for heavy drinkers.
Smokers presented more 
frequently with tumors of the larynx, hypopharynx, and floor 
of mouth.
The nut is 
chewed in combination with lime and cured tobacco as a mix-
ture known as a quid.
The risk of hard 
palate carcinoma is 47 times greater in reverse smokers com-
pared to nonsmokers.
Environmental ultraviolet light exposure has been associated 
with the development of lip cancer.
In addition, pipe smoking also has been 
associated with the development of lip carcinoma.
Oral cavity landmarks.
18-19).
The pharynx is divided into three regions: nasopharynx, 
oropharynx, and hypopharynx.
The inferior margin of the nasophar-
ynx is the superior surface of the soft palate.
The adenoids, typi-
cally involuted in adults, are located with the posterior aspect 
of this site.
Retropharyngeal metastatic lymphatic 
spread may occur with oropharyngeal lesions.
The larynx is divided into three regions: the supraglot-
tis, glottis, and subglottis.
Overexpression of mutant p53 is associated with carcino-
genesis at multiple sites within the body.
Point mutations in p53 
have been reported in up to 45% of head and neck carcinomas.
These two events also are known 
as initiation and promotion.
The overall rate of second primary tumors is approxi-
mately 14%.
The prevalence of synchronous tumors is 
approximately 3% to 4%.
Additionally, 
barium swallow has been used instead of esophagoscopy as a 
preoperative evaluation.
Table 18-1 demonstrates TNM 
staging for oral cavity lesions.
The N classification system is 
uniform for all head and neck sites except for the nasopharynx.
Upper Aerodigestive Tract
Lip.
Basal cell carcinoma presents more fre-
quently on the upper lip than lower.
Clinical findings in lip cancer include an ulcerated lesion on 
the vermilion or cutaneous surface.
Careful palpation is impor-
tant in determining the actual size and extent of these lesions.
Lip cancer results in fewer than 200 patient deaths annu-
ally and is stage dependent.
Early diagnosis coupled with ade-
quate treatment results in a high likelihood of disease control.
Lymph node metastasis occurs in 
fewer than 10% of patients with lip cancer (Fig.
18-20).
The 
primary echelon of nodes at risk is in the submandibular and 
submental regions.
In the presence of clinically evident neck 
metastasis, neck dissection is indicated.
The typical lip length is 6 to 7 cm.
Resection with primary closure is possible with 
a defect of up to one third of the lip (Fig.
18-21).
Lymphatics of the lip.
Figure 18-21.
Wedge resection of lower lip squamous cell 
 carcinoma.
18-22).
Microstomia is a potential complication with these 
types of lip reconstruction.
The majority of tumors in the 
oral cavity are squamous cell carcinomas (>90%).
Each site is 
briefly reviewed with emphasis placed on anatomy, diagnosis, 
and treatment options.
Oral Tongue.
The oral tongue is a muscular structure with 
overlying nonkeratinizing squamous epithelium.
The tumors may present as ulcerations or as exophytic 
masses (Fig.
18-24).
18-25).
The CO2 laser may be used for excision 
Figure 18-22.
A-C.
Karapandzic labiaplasty for lower lip carcinoma.
Figure 18-23.
Oral tongue squamous cell carcinoma.
Figure 18-24.
Primary lymphatics for regional 
spread of oral cavity malignancies.
The ostia of the submaxillary and sublingual glands are con-
tained in the anterior floor of mouth.
Invasion into these muscles can result in decreased 
tongue mobility and poor articulation.
18-26).
Figure 18-25.
A and B.
Anatomy of the floor of 
mouth and submandibular space.
a.
= artery; m.
= 
muscle; n.
= nerve.
A
B
Submandibular gland
Digastric m.
(anterior belly)
Myohyoid m.
Stylopharyngeus,
stylohyoid and
styloglossus mm.
Digastric muscle
(posterior belly)
Styloid 
process
Hypoglossal n.
Middle
constrictor m.
External 
carotid a.
Hyoid bone
Hyoglossus m.
Lingual n.
Deep lingual a.
Dorsal lingual a.
Genioglossus m.
Geniohyoid m.
Sublingual a.
Lingual n.
Hyoid bone
Hypoglossal n.
18-27) and immediate recon-
struction.
Composite resection specimen of a T4 floor of 
mouth squamous cell carcinoma.
Figure 18-26.
A and B.
Differences in 
the transoral resection of a floor of mouth 
and alveolar ridge lesion.
AB
Incision
Tissue excised
muscular bed.
Alveolus/Gingiva.
The alveolar mucosa overlies the bone of 
the mandible and maxilla.
It extends from the gingivobuccal 
sulcus to the mucosa of the floor of mouth and hard palate.
Although access for such a procedure can be per-
formed by using an anterior mandibulotomy (Fig.
For radiographic 
evaluation of the mandible, Panorex views demonstrate gross 
cortical invasion.
MRI is the best modality for demonstrating 
invasion of the medullary cavity of the mandible.
Patients with N0 disease had a 5-year survival rate 
of 69%.52
Buccal Mucosa.
Tumors in this area have a propensity to 
spread locally and to metastasize to regional lymphatics.
Lymphatic drainage is to the facial 
and the submandibular nodes (level I).
Anterior mandibulotomy with mandibular swing to 
approach a posterior lesion.
cheek may require through-and-through resection.
Palate.
Most squamous cell 
carcinomas of the hard palate are caused by habitual tobacco 
and alcohol use.
Chronic irritation from ill-fitting dentures 
also may play a causal role.
Treatment is symptomatic and biopsy specimen 
confirms its benign nature.
Mucosal melanoma may occur on the palate and presents 
as a nonulcerated, pigmented plaque.
Kaposi’s sarcoma of the 
palate is the most common intraoral site for this tumor.
Tumors 
may present as either an ulcerative, exophytic, or submucosal 
mass.
Minor salivary gland tumors tend to arise at the junc-
tion of the hard and soft palate.
Squamous cell carcinoma of the hard palate is treated 
surgically.
Adjuvant radiation is indicated for advanced staged 
tumors.
Involvement of the periosteum requires 
removal of a portion of the bony palate.
Oropharynx.
Oropharyngeal cancer may present as an ulcerative lesion 
or an exophytic mass.
Tumor fetor from necrosis is common.
Dysphagia and weight loss are common symptoms.
The incidence of regional metas-
tases from cancers of the oropharynx is high.
The etiology for this rise has been attributed to the HPV-16 
related development of malignancy.
Patients were treated 
with sequential chemoradiation for advanced stage disease.
HPV positivity was found in 57% of all oropharyngeal can-
cers in the study.
HPV-positive cancers demonstrated a higher 
response rate to induction chemotherapy (82% vs.
55%) 
and improved 2-year survival (95% vs.
62%).
Extensive oropharyngeal cancers may require surgical 
resection and postoperative radiotherapy.
Nasal regurgitation of air and liquids can be decreased with use.
Preoperative planning can 
result in the creation of a defect that better tolerates obturation.
Hypopharynx and Cervical Esophagus.
18-29).
Squamous cancers of the hypopharynx frequently 
present at an advanced stage.
Relationship of nasopharynx, oropharynx, and 
hypopharynx.
18-30).
Resection of the primary tumor and surrounding pha-
ryngeal tissue is performed en bloc.
When total laryngopharyngoesoph-
agectomy is necessary, gastric pull-up is performed.
Cervical esophageal cancer may be managed surgically or 
by concomitant chemoradiation.
Larynx.
18-31).
The lateral limits of the larynx are the ary-
epiglottic folds.
The larynx is composed of three regions: the 
supraglottis, the glottis, and the subglottic (Fig.
18-32).
The epi-
glottis and the vocal cords are lined by stratified, nonkeratinizing 
squamous epithelium.
The subglottic mucosa is pseudostratified, 
ciliated respiratory epithelium.
Minor salivary glands are also 
found in the supraglottic and subglottic.
Tumors of the laryngeal framework include synovial 
sarcoma, chondroma, and chondrosarcoma.
Endoscopic view of a laryngeal squamous carcinoma.
Referred 
otalgia or odynophagia is encountered with advanced supraglottic 
cancers.
Bulky tumors of the supraglottic may result in airway 
compromise.
Decreased vocal cord mobility may be caused by direct muscle 
invasion or involvement of the RLN.
Superficial tumors that are bulky may appear 
to cause cord fixation through mass effect.
Lymph node metastasis may be defined more 
readily with the use of imaging studies.
Lymphatic drainage of the larynx is distinct for each sub-
site.
Limited glottic  
cancers typically do not spread to regional lymphatics (1%–4%).
In contrast, more 
advanced tumors may require partial laryngectomy (Fig.
18-33) or 
even total laryngectomy (Fig.
18-34).65 Further complicating the 
Perichondrium
Unilateral
lesion
Thyroid
cartilage
Figure 18-33.
Example of the resection of a vertical partial laryn-
gectomy for an early stage glottic carcinoma.
Figure 18-34.
591
DISORDERS OF THE HEAD AND NECK
CHAPTER 18
Figure 18-35.
resection.
Use 
of an operative microscope aids the precision of such dissec-
tions.
Open laryngofissure and cordectomy may be reserved for 
more invasive tumors.
The risk for aspiration is high following certain partial lar-
yngectomies.
Patient selection is vital to successful application 
of these techniques.
Presurgical pulmonary assessment may be 
necessary.
One simple measurement of functional reserve is to 
have the patient climb two flights of stairs.
Close follow-up 
examinations and smoking cessation are mandatory adjuncts of 
therapy.
18-35) or free flap reconstruction is 
required for lesions with pharyngeal extension.
Speech and Swallowing Rehabilitation.
The sounds produced can be articulated into words.
Unfortunately, less than 20% of postlaryngectomy patients 
develop fluent esophageal speech.
The valve prevents retrograde passage of food or saliva 
into the trachea.
The vibrations create sound waves that the 
patient articulates into words.
A disadvantage of the electro-
larynx is the mechanical quality of the sound produced.
This 
device is most useful in the postoperative period before training 
for esophageal speech.
Unknown Primary Tumors.
Example of the Ohngren’s line and the relationship 
to the maxilla.
patients previously considered to have an unknown primary.
Symptoms associated with sinonasal tumors 
are subtle and insidious.
They include chronic nasal obstruc-
tion, facial pain, headache, epistaxis, and facial numbness.
As 
such, tumors of the paranasal sinuses frequently present at an 
advanced stage.
Orbital invasion can result in proptosis, diplo-
pia, epiphora, and vision loss.
Malignant tumors of the sinuses are predominantly squa-
mous cell carcinomas.
Metasta-
ses from the kidney, breast, lung, and thyroid may also present 
as an intranasal mass.
The site of origin, involved bony structures, and the presence of 
vascularity should be assessed.
A meningocele or encephalocele 
will present as a unilateral pulsatile mass.
Biopsy of a unilat-
eral nasal mass should be deferred until imaging studies are 
obtained.
An untimely biopsy specimen can result in a CSF leak.
Each team member is necessary to facilitate the goal of safe 
and complete tumor removal.
Prognosis is dependent on tumor location and extension to 
the surrounding anatomy.
If there is invasion of the orbital fat, exenteration 
of the orbital contents is required.
The head and neck surgeon and neurosurgeon work in con-
cert to perform this procedure.
Chemotherapy has a limited application and may be used for 
specific indications.
Rhabdomyosarcoma is primarily treated 
with chemotherapy followed by radiation therapy.
Surgery is 
reserved for persistent disease after chemoradiation.
Risk factors for nasopharyngeal carcinoma include area 
of habitation, ethnicity, and tobacco use.
Cra-
nial nerve involvement is indicative of skull base extension and 
advanced disease.
Lymphatic spread occurs to the posterior 
cervical, upper jugular, and retropharyngeal nodes.
Bilateral 
regional metastatic spread is common.
Distant metastasis is 
present in 5% of patients at presentation.
Evaluation with 
imaging studies is important for staging and treatment planning.
The status 
of the cavernous sinus and optic chiasm should also be assessed.
Endoscopic removal is also 
possible in selected cases.
The most 
common histology is squamous cell carcinoma.
In the pediatric population, tumors of the temporal bone 
are most commonly soft-tissue sarcomas.
For extensive, 
pinna-based lesions, procedures such as auriculectomy may  
be required.
advanced skin cancer with positive margins, perineural spread, 
or multiple involved lymph nodes.
Temporal bone resec-
tions are classified as lateral or subtotal (Fig.
18-37).
It is indicated for malignant tumors 
extending into the middle ear.
The differential diagnosis of a neck mass 
is dependent on its location and the patient’s age.
In children, 
most neck masses are inflammatory or congenital.
The use of imaging (CT and/or MRI) is dictated by the patient’s 
clinical presentation.
Patterns of Lymph Node Metastasis.
The regional lym-
phatic drainage of the neck is divided into seven levels.
18-38).
Levels of the neck denoting lymph node bearing 
regions.
Primary tumors within the oral cavity and lip metastasize to the 
nodes in levels I, II, and III.
18-39).
18-40).
18-41).
This may be in the form of elective neck irradiation 
or elective neck dissection.
Figure 18-39.
Shaded region indicates the region included in a 
supraomohyoid neck dissection.
Figure 18-40.
Shaded region indicates the region included in a 
lateral neck dissection.
For clinically N+ necks, frequently the surgical treat-
ment of choice is the MRND or RND.
Surgically debulking 
metastatic disease does not improve survival and is not advo-
cated.
Parapharyngeal Space Masses.
18-42), dysphagia, cranial nerve dysfunction, 
Horner’s syndrome, or vascular compression.
Figure 18-41.
Shaded region indicates the region included in a 
posterolateral neck dissection.
Lymph node metas-
tases and primary lymphoma represent 15% of lesions.
Surgical access to these tumors may require a trans-
mandibular and/or lateral cervical approach.
Benign Neck Masses.
A number of benign masses of the 
neck occur that require surgical management.
Many of these 
masses are seen in the pediatric population.
They present as a midline or paramedian 
cystic mass adjacent to the hyoid bone.
After an upper respira-
tory infection, the cyst may enlarge or become infected.
There are several types, numbered according to their cor-
responding embryologic branchial cleft.
18-43).
The removal of 
Figure 18-43.
CT scan demonstrating a branchial cleft cyst with operative specimen.
They 
typically present as mobile, fluid-filled masses.
Recurrence and re-growth occur with incomplete removal.
Deep Neck Fascial Planes.
The deep cervi-
cal fascia is composed of three layers.
These are the investing 
(superficial deep), pretracheal, and the prevertebral fascias.
This layer surrounds the SCM muscle and cov-
ers the anterior and posterior triangles of the neck.
This fascia blends laterally to the carotid sheath.
The major sali-
vary glands are the parotid, submandibular, and sublingual glands.
About 85% of salivary gland neoplasms arise within 
the parotid gland (Fig.
18-44).
Tumors arising from minor salivary gland tissue carry 
an even higher risk for malignancy (75%).
Salivary gland tumors are usually slow growing and 
well circumscribed.
Additional findings ominous for malignancy include skin inva-
sion and fixation to the mastoid tip.
Anterior facial v.
Temporal
branches
Posterior belly
of digastric m.
Cervical
branch
Masseter m.
Zygomatic branch
Parotid duct
Buccal
branch
Mandibular
branch
Figure 18-44.
Example of a tumor in the parotid with the pattern 
of the facial nerve and associated anatomy.
m.
= muscle; n.
= nerve; 
v.
= vein.
tumor and possible fixation to the mandible or involvement of the 
tongue.
Parotid gland malignancies can metastasize to the 
intra- and periglandular nodes.
The next echelon of lymphat-
ics for the parotid is the upper jugular nodal chain.
Tumors arising in patients of advanced age 
also tend to have more aggressive behavior.
Diagnostic imaging is standard for the evaluation of sali-
vary gland tumors.
Diagnosis of salivary 
gland tumors is frequently aided by the use of FNA.
The final histopathologic diagnosis is confirmed by 
surgical excision.
Nonepithelial benign lesions include 
hemangioma, neural sheath tumor, and lipoma.
Tumor spillage of a 
pleomorphic adenoma during removal can lead to problematic 
recurrences.
Malignant epithelial tumors range in aggressiveness from 
low to high grade.
The most common malignant epithelial neoplasm of the salivary 
glands is mucoepidermoid carcinoma.
The primary treatment of salivary malignancies is surgi-
cal excision.
Radical resection is indicated with tumors that 
invade the mandible, tongue, or floor of mouth.
Tumor surgery frequently 
necessitates removal of structures related to speech and swal-
lowing.
It is important to remember that the most com-
plex procedure is not always the most appropriate.
Full-thickness grafts are used on the face when local rotational 
flaps are not available.
These grafts have less contracture over 
time than split-thickness grafts.
Several myocutaneous flaps exist for head and neck recon-
struction.
This flap is ideal for 
reconstruction of scalp and lateral skull base defects.
The latter vessel may be sacrificed to 
increase the arc of rotation.
The latissimus dorsi flap provides a large source of soft 
tissue and has a wide arc of rotation.
The flap is based on the 
thoracodorsal vasculature.
This flap can be used as a regional 
rotational flap or as a free flap.
The natural shape of this donor 
site bone is similar to the mandibular angle.
However, for lengthy mandibular defects (>10 cm), the fibular 
flap usually is chosen.
The scapular flap can 
provide approximately 12 cm of scapula bone and is based on 
Figure 18-45.
Radial forearm free flap before harvest 
from the arm.
602
SPECIFIC CONSIDERATIONS
UNIT
 
II
PART II
the circumflex scapular artery.
Placement of a tracheostomy does not obligate a patient 
to loss of speech.
Such a patient may require dilatation and/
or placement of a gastrostomy tube for nutrition.
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Also see http://www.headandneckcancer.org/
clinicalresources/docs/oralcavity.php.
Chest Wall, Lung, Mediastinum,  
and Pleura
Katie S.
Nason, Michael A.
Maddaus, and 
James D.
The cricoid cartilage consists 
of an anterior arch and a posterior broad-based plate.
Articulat-
ing with the posterior cricoid plate are the arytenoid cartilages.
The vocal cords originate from the arytenoid cartilages and then 
attach to the thyroid cartilage.
19-2).
8 The assessment of patient risk before thoracic resection 
is based on clinical judgment and data.
11  Treatment of pulmonary aspergilloma is individualized.
Asymptomatic patients can be observed without any 
additional therapy.
High cuff 
pressures can cause ischemia of the contiguous airway wall in 
as short as 4 hours.
Avoidance requires careful cuff management to keep pressures 
Epiglottis
Aryepiglottic m.
Transverse, oblique
arytenoid mm.
Lateral
cricoarytenoid m.
Posterior
cricoarytenoid m.
Thyroid cartilage
            facet
Recurrent
laryngeal n.
Internal
laryngeal n.
Thyroepiglottic m.
Thyroarytenoid m.
Cricothyroid m.
(cut)
Inferior
thyroid a.
Branch from 
internal thoracic a.
Superior bronchial a.
Middle bronchial a.
1
Lateral longitudinal
anastomosis
3
2
Figure 19-1.
Anatomy of the larynx and upper trachea.
m.
= muscle; n.
= nerve.
Figure 19-2.
Arterial blood supply to the larynx and upper trachea.
a.
= artery.
Mild 
ulceration and stenosis are frequently seen after tracheostomy 
removal.
Stridor and dyspnea on exertion are the primary symptoms 
of tracheal stenosis.
19-3).
Acute Management.
A comprehensive bronchoscopic evalua-
tion is critical in the initial phase of evaluation.
Rarely, if ever, is 
tracheostomy necessary.
Resection typically involves 2 to 4 cm of trachea 
for benign stenosis.
It is critical to fully resect all inflamed and 
scarred tissue.
This removes all 
Figure 19-3.
Diagram of the principal postintubation lesions.
A.
A circumferential lesion at the cuff site after the use of an endotracheal 
tube.
B.
Potential lesions after the use of tracheostomy tubes.
Anterolateral stenosis can be seen at the stomal level.
Circumferential stenosis 
can be seen at the cuff level (lower than with an endotracheal tube).
The segment in between is often inflamed and malacotic.
C.
Damage to 
the subglottic larynx.
D.
E.
Tracheoinnominate artery fistula.
(Adapted with permission from Grillo H.
Surgical treatment of postintubation tracheal injuries.
J 
Thorac Cardiovasc Surg.
1979;78:860.
Tracheal Fistulas
Tracheoinnominate Artery Fistula.
Most cuff-induced fistulas will develop 
within 2 weeks after placement of the tracheostomy.
Clinically, tracheoinnominate artery fistulas present with 
bleeding.
With significant 
609
Chest Wall, Lung, Mediastinum, and Pleura
CHAPTER 19
Figure 19-4.
Steps in the emergency 
management of a tracheoinnominate 
artery fistula.
bleeding, the tracheostomy cuff can be hyperinflated to tempo-
rarily occlude the arterial injury.
19-4).
The patient can then be orally intubated, 
and the airway suctioned free of blood.
Tracheoesophageal Fistula.
Clinically, airway suctioning 
reveals saliva, gastric contents, or tube feedings.
Gastric insuf-
flation, secondary to positive pressure ventilation, can occur.
Alternatively, esophagoscopy demonstrates the cuff of 
the endotracheal tube in the esophagus.
The cuff of the endotracheal tube should be placed below the 
fistula, avoiding overinflation.
If aspira-
tion persists, esophageal diversion with cervical esophagostomy 
can be performed.
Their biologic behavior is similar to that of squamous 
cell carcinoma of the lung.
Esophagus
Figure 19-5.
Single-stage operation for clo-
sure of a tracheoesophageal fistula and tra-
cheal resection.
A.
The fistula is divided and 
the trachea is transected below the level of 
damage.
B.
The damaged trachea 
segment is resected.
C.
View of completed 
tracheal anastomosis.
m.
= muscle.
(CT) and rigid bronchoscopy.
19-6).
Up to 50% of the length of the trachea can be 
resected with primary anastomosis.
Nodal positivity does not seem to be associated with worse sur-
vival.
LUNG
Anatomy
Segmental Anatomy.
19-7).
Note the continuity of the pulmonary 
parenchyma between adjacent segments of each lobe.
Lymphatic Drainage.
19-8).
Algorithm for eval-
uation and treatment of tracheal 
neoplasm.
PET = positron emis-
sion tomography.
19-9).
The N2 lymph nodes consist of four main groups.
19-10).
Ciliated cells predominate.
Two cell types, called type I and type II pneumocytes, 
make up the alveolar epithelium.
Apical
2.
Posterior
3.
Anterior
4.
Lateral
5.
Medial
6.
Superior
7.
Medial Basal *
8.
Anterior Basal
9.
Lateral Basal
10.
Segmental anatomy of the lungs and bronchi.
Figure 19-8.
The location of regional lymph node stations for lung cancer.
(Reproduced with permission from Mountain CF, Dresler CM.
Regional lymph node classification for lung cancer staging.
Chest.
1997;111:1718.)
613
Chest Wall, Lung, Mediastinum, and Pleura
CHAPTER 19
Figure 19-9.
Figure 19-10.
Normal lung histology.
A.
Pseudostratified ciliated columnar cells and mucous cells normally line the tracheobronchial tree.
B.
A Kulchitsky cell is depicted (arrow).
B
A
capable of regeneration because they have no mitotic potential.
In addition, 
clusters of neuroendocrine cells are seen in the alveolar spaces.
Three precancerous lesions of the respiratory tract are currently 
recognized.
1.
Squamous dysplasia and carcinoma in situ.
Gradations are considered mild, moderate, or 
severe.
Carcinoma in situ represents carcinoma still con-
fined by the basement membrane.
2.
Atypical adenomatous hyperplasia (AAH).
3.
Diffuse idiopathic pulmonary neuroendocrine cell hyper-
plasia.
Lesions over 5.0 mm in size or that 
breach the basement membrane are carcinoid tumors.
Non–Small Cell Lung Carcinoma.
J Thorac Oncol.
2011;6:244.
aNumbers represent the percentage of cases that are reported to be positive.
including large cell, squamous cell, and adenocarcinoma.
Adenocarcinoma.
It 
occurs more frequently in females than in males.
1
2
3
615
Chest Wall, Lung, Mediastinum, and Pleura
CHAPTER 19
1.
Adenocarcinoma in situ (AIS).
They are very rarely mucinous, consisting of type II pneu-
mocytes or Clara cells.
Mucinous AIS is more likely 
to appear solid or to have the appearance of consolida-
tion.
2.
Minimally invasive adenocarcinoma (MIA).
J Thorac 
Oncol.
2011;6:244.
As with AIS, MIA is very 
rarely mucinous.
3.
Lepidic predominant adenocarcinoma (LPA).
4.
Invasive adenocarcinoma.
19-11).Subtypes include:
a.
Lepidic predominant
b.
Acinar predominant
c.
Papillary predominant
d.
Micropapillary predominant
e.
Pleural retraction is 
also a poor prognostic indicator.
5.
616
SPECIFIC CONSIDERATIONS
UNIT II
PART II
Figure 19-11.
Major histologic patterns of invasive adenocarcinoma.
A.
B.
C.
Area of invasive acinar adenocarcinoma (same tumor as in A and B).
D.
Acinar adenocarcinoma consists 
of round to oval-shaped malignant glands invading a fibrous stroma.
E.
F.
G.
H.
Solid adenocarcinoma 
with mucin.
(Reproduced with 
permission from Travis W, Brambilla E, Noguchi M, et al.
J Thorac Oncol.
2011;6:244.)
Squamous Cell Carcinoma.
Histologically, cells develop a pattern 
of clusters with intracellular bridges and keratin pearls.
Such cavities may 
become infected, with resultant abscess formation.
Large Cell Carcinoma.
Salivary Gland–Type Neoplasms.
The two most common are adenoid cystic 
carcinoma and mucoepidermoid carcinoma.
Both tumors occur 
centrally due to their site of origin.
Neuroendocrine Neoplasms.
It 
occurs primarily in younger patients.
Histologically, tumor cells 
are arranged in cords and clusters with a rich vascular stroma.
Histologic findings may include areas of necrosis, 
nuclear pleomorphism, and higher mitotic rates.
Lymph node 
metastases are found in 30% to 50% of patients.
At diagnosis, 
25% of patients already have remote metastases.
They are often large with central necrosis and a high mitotic 
rate.
These 
cancers also arise primarily in the central airways.
Evaluation includes expert 
pathology review and comprehensive evaluation for metastatic 
disease.
These tumors are the leading pro-
ducer of paraneoplastic syndromes.
19-12).
13.8% 
for men), younger age (5-year survival of 22.8% for those <45 
years vs.
13.7% for those >65 years), and white race (5-year sur-
vival of 16.1% for whites vs.
12.2% for blacks).
According to the U.S.
Note: Due to changes in ICD coding, numerator information has changed over time.
Leading new cancer cases and deaths: 2012 estimates.
*Excludes basal and squamous cell skin cancers and in situ carcinomas 
except urinary bladder.
(Modified with permission from John Wiley and Sons: Siegel R, Naishadham D, Jemal A.
Cancer statistics, 2013.
CA Cancer J Clin.
2012;62:10.
© 2012 American Cancer Society, Inc.)
Figure 19-13.
Age-adjusted cancer death rates.
A.
Males by site, United States, 1930 to 2008.
B.
Females by site, United States, 1930 to 
2008.
*Per 100,000, age adjusted to the 2000 U.S.
standard population.
(Modified with permission from John Wiley and Sons: Siegel R, 
Naishadham D, Jemal A.
Cancer statistics, 2013.
CA Cancer J Clin.
2012;62:10.
†Uterus cancer death rates are for uterine cervix and uterine corpus combined.
Note: Due to changes in ICD coding, numerator information has changed over time.
cancer increases with longer duration and higher level of 
exposure to environmental tobacco.
Source: Reprinted by permission from Macmillan Publishers Ltd.
Sun S, Schiller JH, Gazdar AF.
Lung cancer in never smokers–a different disease.
Nat Rev Cancer.
2007;7:778 Copyright © 2007.
First, there was a 7% false-positive rate in this 
trial.
About 150,000 solitary nodules are found incidentally 
each year.
The clinical significance of such a lesion depends on 
whether or not it represents a malignancy.
It is also more likely to be 
AB
CD
Figure 19-14.
Spiral computed tomography scan showing normal transverse chest anatomy at four levels.
A.
At the level of the tracheal 
bifurcation, the aorticopulmonary window can be seen.
B.
The origin of the left pulmonary artery can be seen at a level 1 cm inferior to A.
C.
The origin and course of the right pulmonary artery can be seen at this next most cephalad level.
The left upper lobe bronchus can be seen at 
its origin from the left main bronchus.
D.
Cardiac chambers and pulmonary veins are seen in the lower thorax.
malignant if it is symptomatic or the patient is older, male, or 
has had occupational exposures.
19-14).
For assessing the trachea and central bronchi, 
collimation of 3 to 5 mm is recommended.
19-15).
Calcification that is stippled, amorphous, or eccentric is usually 
associated with cancer.
Growth over time is an important characteristic for dif-
ferentiating benign and malignant lesions.
One must always entertain the possibility that a 
single new lesion is a primary lung cancer.
The probability of 
a new primary cancer vs.
metastasis in patients presenting with 
solitary lesions depends on the type of initial neoplasm.
The registry 
A
B
C
Figure 19-15.
Computed tomography scan images of solitary 
pulmonary nodules.
A.
The corona radiata sign demonstrated by 
a solitary nodule.
B.
A 
biopsy-proven adenocarcinoma demonstrating spiculation.
C.
About 88% of patients underwent complete 
resection.
When any or all of these optimal charac-
teristics are absent, survival progressively declines.
The general principles of patient selection for metasta-
sectomy are listed in Table 19-6.
The technical aim of pulmo-
nary metastasectomy is complete resection of all macroscopic 
tumors.
Multiple lesions and/or hilar lesions may require lobectomy.
Pneumonectomy is rarely justified or employed.
Pulmonary Symptoms.
Pulmonary symptoms result from the 
direct effect of the tumor on the bronchus or lung tissue.
Nonpulmonary Thoracic Symptoms.
Other specific nonpulmonary thoracic symptoms include:
1.
Pancoast’s syndrome.
2.
Phrenic nerve palsy.
3.
Recurrent laryngeal nerve palsy.
4.
Superior vena cava (SVC) syndrome.
(Reprinted with 
permission from Pastorino, U.
(2010).
The Development of an International Registry.
J Thorac Oncol.
5(6): S196-S197)
625
Chest Wall, Lung, Mediastinum, and Pleura
CHAPTER 19
and conjunctival edema.
It is seen most commonly with 
NEC grade IV (small cell) lung cancer.
5.
Pericardial tamponade.
6.
Back pain.
Results from direct invasion of a vertebral body 
and is often localized and severe.
If the neural foramina are 
involved, radicular pain may also be present.
7.
Other local symptoms.
Primary tumor must already be controlled.
2.
3.
Metastases must be completely resectable based on 
computed tomographic imaging.
4.
There is no evidence of extrapulmonary tumor burden.
5.
Alternative superior therapy must not be available.
Their presence does not influence resectability or 
treatment options.
1.
Hypertrophic pulmonary osteoarthropathy (HPO).
Often severely debilitating, symptoms of HPO may ante-
date the diagnosis of cancer by months.
Clubbing of the digits may 
occur in up to 30% of patients with grade IV NEC (Fig.
19-17).
2.
Hypercalcemia.
Hypertrophic pulmonary osteoarthropathy associated with small cell carcinoma.
A.
Painful clubbing of the fingers.
B.
Painful 
clubbing of the toes (close-up).
C.
The arrows point to new bone formation on the femur.
disease is not present.
Unfortunately, tumor recurrence is extremely 
common and may manifest as recurrent hypercalcemia.
3.
Hyponatremia.
Another cause of 
hyponatremia can be the ectopic secretion of atrial natri-
uretic peptide (ANP).
4.
Cushing’s syndrome.
5.
Peripheral and central neuropathies.
Other metastatic dis-
ease leading to disability must also be excluded.
6.
Lambert-Eaton syndrome.
Therapy is directed at the primary 
tumor with resection, radiation, and/or chemotherapy.
Many patients have dramatic improvement after successful 
therapy.
Unlike with myasthenia gravis 
patients, neostigmine is usually ineffective.
Symptoms Associated with Metastatic Lung Cancer.
Bony metastases are 
identified in 25% of all patients with lung cancer.
Liver metastases are most often an incidental finding on CT 
scan.
Adrenal metastases are also typically asymptomatic and 
are usually discovered by routine CT scan.
They may lead to 
adrenal hypofunction.
Nonspecific Cancer-Related Symptoms.
Lung Cancer Management
Role of Histologic Diagnosis and Molecular Testing.
19-18).
In many cases, tumor morphology differentiates 
adenocarcinoma from the other histologic subtypes.
EGFR, KRAS, and EML4-ALK fusion gene).
Patient Evaluation.
Assessment of the Primary Tumor.
Algorithm for adenocarcinoma diagnosis in small biopsies and/or cytology.
If all markers are negative, the tumor is classified as NSCLC-NOS.
In NSCLC-NOS, if 
EGFR mutation is positive, the tumor is more likely to be ADC than SQCC.
(Reproduced with permission from Travis W, Brambilla E, Noguchi M, et al.
J Thorac Oncol.
2011;6:244.
This is 
especially true if the use of iodine contrast material is contra-
indicated.
Options for Tissue Acquistion.
Diagnostic tissue from 
bronchoscopy can be obtained by one of four methods:
1.
Brushings and washings for cytology
2.
Direct forceps biopsy of a visualized lesion
3.
For central lesions, direct forceps biopsy by bron-
choscopic visualization is often possible.
Surgical risk acceptable?
Consider XRT or monitor
for symptoms and
palliate as necessary.
(Reproduced 
with permission from the American College of Chest Physicians from Gould MK, et al.
(2nd edition) Chest.
Lesions 
most suitable for VATS are those that are located in the outer 
one third of the lung.
A thoracotomy is occasionally necessary to diagnose and 
stage a primary tumor.
Assessment for Metastatic Disease.
Distant metastases are 
found in approximately 40% of patients with newly diagnosed 
lung cancer.
The presence of lymph node or systemic metasta-
ses may imply inoperability.
This is particularly true 
for patients with a significant tobacco history.
The skin should 
be thoroughly examined.
Mediastinal Lymph Nodes.
Any CT finding of metastatic nodal involvement 
must be confirmed histologically.
However, the false-negative rate 
increases to nearly 30% with centrally located and T3 tumors.
Therefore, all such patients should undergo mediastinoscopy.
Mediastinal lymph node staging by PET scanning appears 
to have greater accuracy than CT scanning.
PET staging of 
mediastinal lymph nodes has been evaluated in two meta-analyses.
It understaged the tumor in 12 patients and over-
staged it in 16 patients.
PET correctly identified the nodal stage 
in 59 patients (87%).
It understaged the tumor in five patients 
and overstaged it in four.
CT scan alone yielded 75%, 63%, and 68%, respectively.
There are several options for invasive 
mediastinal staging:
1.
Like mediastinoscopy, EBUS does 
not allow assessment of level 3, 5, or 6 nodal stations.
2.
19-8).
Using FNA or core-needle 
biopsy, samples of lymph nodes or primary lesions can be 
obtained.
3.
19-20).
4.
19-8).
If the index of suspicion is high, the VATS biopsy is per-
formed as a separate procedure.
Pleural Effusion.
The presence of pleural effusion on radio-
graphic imaging should not be assumed to be malignant.
Figure 19-20.
Cervical mediastinoscopy.
Table 19-10
Indications for prethoracotomy biopsy of station 5 and 
6 lymph nodes
1.
Enrollment criteria for induction therapy protocol require 
pathologic confirmation of N2 disease.
2.
3.
Cytology reveals malignant cells in 50% 
of malignant effusions.
Distant Metastases.
Currently, chest CT and PET are rou-
tine in the evaluation of patients with lung cancer.
19-21).
Tumor, Node, and Metastasis: Lung Cancer Staging.
Therapeutic plans are generated based on 
clinical stage.
The staging of solid epithelial tumors is based on the TNM 
staging system.
19-8).
A.
CT of the chest showing a tumor in the left upper lobe.
B.
PET scan of the chest at the identical cross-sectional level.
C.
Coregistered PET-CT scan clearly showing tumor invasion (con-
firmed intraoperatively).
(Reprinted with permission from Lardi-
nois D, Weder W, Hany TF, et al.
N Engl J Med.
2003;348:2504.
Copyright © 
2003 Massachusetts Medical Society.)
sis status.
Although they do not affect 
the stage grouping, they indicate cases 
needing separate analysis.
Source: Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois.
of the TNM descriptors currently used in staging NSCLC and 
the overall stage classifications.
Staging for small cell lung cancer (SCLC) is typically 
based on the extent of disease.
Limited disease must be treatable within a tolerable 
field of radiation.
Using AJCC descriptors, this includes any 
T stage, any N stage, without metastatic disease (M0).
Metastases to brain, bone, bone marrow, and the 
pleural and pericardial spaces are common.
Assessment of Functional Status.
A sequential process of evaluation then 
unfolds.
A patient’s history is the most important tool for gauging 
risk.
Specific questions regarding performance status should be 
routinely asked.
Current smoking status and sputum production are also 
pertinent.
Nevertheless, abstinence for at least 2 
weeks before surgery should be encouraged.
Sputum culture, 
antibiotic administration, and bronchodilators may be warranted 
preoperatively.
It 
must be emphasized that these are guidelines only.
For example, with a planned right upper lobectomy, a total 
of three segments will be removed.
At presentation, the patient was dyspneic 
with ambulation, and the FEV1 was 1.38 L.
Six months prior, 
this patient could walk up two flights of stairs without dyspnea.
Solid line indicates logistic regression model; dashed 
lines indicate 95% confidence limits.
(Adapted with permission from 
Wang J, Olak K, Ferguson M.
J Thorac Cardiovasc Surg.
1999;117:582.
Copyright Elsevier.)
6
637
Chest Wall, Lung, Mediastinum, and Pleura
CHAPTER 19
Figure 19-23.
Chest computed tomography scan of an obstructing right main stem lung tumor.
Arrow indicates location of right main bron-
chus.
The right lung volume is much less than the left lung volume.
postoperative value would be 27%, and pneumonectomy would 
pose a significantly higher risk.
The risk assessment of a patient is an amalgam of clinical 
judgment and data.
Early-Stage Non–Small Cell Lung Cancer.
(2nd edition) Chest.
2007;132:161S.
(2nd edition) Chest.
The latter cir-
cumstance occurs with bulky adenopathy or with extracapsular 
nodal spread.
Management of Early-Stage Lung Cancer in the High-Risk 
Patient.
Rationale for Limited Resection in Early-Stage Lung Cancer.
1.
Radiofrequency ablation.
In lung tumors, the electrodes are typically inserted into 
the tumor mass under CT guidance.
19-24).
OF LIMITED 
RESECTIONS
NO.
bOnly intentional resection.
cIncluding 13 pneumonectomies.
Survival 
following lobectomy vs limited resection for stage I lung cancer: a meta-analysis.
Br J Cancer.
2005;92:1033.
Copyright © 2005.
2.
Stereotactic body radiotherapy.
Failure in regional 
node basins was seen in two patients.
Chemotherapy and surgery versus surgery alone in non-
small cell lung cancer.
Cochrane Database Syst Rev.
2007:CD006157.
John Wiley & Sons, Ltd.
Copyright Cochrane Collaboration.
Evaluation and Management of Locally Advanced 
NSCLC.
This is particularly 
true in regions with high incidence of granulomatous diseases.
Surgery in T4 and Stage IV Disease.
Survival rates remain extremely low 
for these patients.
Simlarly, the treatment of patients with stage 
IV disease is chemotherapy.
Surgery for Management of Pancoast’s Tumor.
Treatment algorithm for Pancoast’s tumors.
Complete resection was achieved in 76%.
Five-year 
survival was 44% overall and 54% when complete resection 
was achieved.
19-25.
Preoperative (Induction) Chemotherapy for NSCLC.
2.
The primary tumor may be downstaged, enhancing resect-
ability.
3.
4.
It functions as an in vivo test of the primary tumor’s sensi-
tivity to chemotherapy.
5.
Response to chemotherapy can be monitored and used to 
guide decisions about additional therapy.
6.
Systemic micrometastases are treated.
7.
Potential disadvantages include:
1.
2.
Postoperative (Adjuvant) Chemotherapy for NSCLC.
In the situa-
tion where the margins of resection are positive, re-resection 
is recommended.
Definitive Nonsurgical Treatment for NSCLC.
Once a treatment plan has been devised, two strategies 
for delivery are available.
5 mo (DFS; P = .006) 22 vs.
10 mo (P = .005) 16% vs.
0%
Roth et al90 60 (60) Cyclophosph
amide
Etoposide
Cisplatin
35 NR 39% vs.
31% Not reached vs.
9 mo  
(P = .006)
64 vs.
11 mo (P = .008) 56% vs.
15%a
Pass et al91 27 (27) Etoposide
Cisplatin
62 8 85% vs.
86% 12.7 vs.
5.8 mo (P = .083) 28.7 vs.
15.6 mo (P = .095) NR
Nagai et al92 62 (62) Cisplatin
Vindesine
28 0 65% vs.
77% NR 17 vs.
16 mo (P = .5274) 10% vs.
22%
Gilligan et al93 519 (80) Platinum basedb 49 4 82% vs.
80% NR 54 vs.
55 mo (P = .86) 44% vs.
45%
Depierre et al94 355 (167) Mitomycin
Ifosfamide
Cisplatin
64 11 92% vs.
86% 26.7 vs.
12.9 mo (P = .033) 37 vs.
26 mo (P = .15) 43.9% vs.
35.3%c
Pisters et al95 354 (113)d Carboplatin
Paclitaxel
41 NR 94% vs.
89% 33 vs.
21 mo (P = .07) 75 vs.
46 mo (P = .19) 50% vs.
43%
Sorensen et al96 90 (NR) Paclitaxel
Carboplatin
46 0 79% vs.
70% NR 34.4 vs.
22.5 mo (NS) 36% vs.
24% (NS)
Mattson et al97 274 (274) Docetaxel 28 NR 77% vs.
76%e 9 vs.
7.6 mo (NS) 14.8 vs.
12.6 mo (NS) NR
a3-year survival.
c4-year survival.
d113 patients (32%) were reported to have stage IIB or IIIA disease.
e22 patients in the chemotherapy arm and 29 patients in the control arm had resectable disease.
Source: Reproduced with permission from JNCCN—Journal of the National Comprehensive Cancer Network.
(Reproduced with 
permission from Demmy TL, Nwogu C.
Is video-assisted thoracic 
surgery lobectomy better?
Quality of life considerations.
Ann Tho-
rac Surg.
2008;85:S719.
Source: Reproduced with permission from Demmy TL, Nwogu C.
Is video-assisted thoracic surgery lobectomy better?
Quality of life considerations.
Ann 
Thorac Surg.
2008;85:S719.
Copyright © Elsevier.
Copyright Elsevier.
and altered fractionation.
Subjective measures of quality 
of life after VATS, such as pain (Fig.
Finally, recovery of respiratory function occurs earlier in VATS 
patients.
Table 19-16 provides a summary of pop-
ulations that may benefit from VATS approaches.
Video-Assisted Thoracoscopic Surgery.
The incision location 
varies according to the procedure.
Selected video-assisted thoracic surgery lobectomy maneuvers.
All the maneuvers are shown with the patient positioned in 
the left lateral decubitus position.
The same maneuvers can be performed in mirror image for left-sided work.
A.
Medial viewing and inferior 
holding of lung to allow dissection through the access incision.
Example shows dissection of the apical hilum.
B.
Medial viewing and access 
holding of lung to allow stapling of hilar structures from below.
C.
Example shows use of stapler to divide pulmonary artery to right lower lobe.
D.
This method is commonly used to dissect the pul-
monary artery in the major fissure.
Example shows inferior pulmonary vein after the pulmonary ligament was divided using this maneuver.
E.
Standard viewing and use of access incision to deliver stapler to divide fissures.
Example shows division of the posterior fissure between 
the right lower lobe and the upper lobe.
19-27).
Open approaches to Thoracic Surgery.
19-28).
The anterolateral thoracotomy has 
traditionally been used in trauma victims.
This approach allows 
quick entry into the chest with the patient supine.
The posterolateral thoracotomy incision.
A.
Skin incision from the anterior axillary line to the lower extent of the scapula 
tip.
B and C.
Division of the latissimus dorsi and shoulder girdle musculature.
D.
centers.
A hypesthetic nipple 
is a frequent complication of this approach.
19-29).
Postoperative Care
Chest Tube Management.
At the conclusion of most thoracic 
operations, the pleural cavity is drained with a chest tube(s).
After chest tube placement, the 
lung is re-expanded with positive-pressure ventilation.
atrial
appendage
R.
ventricle
Preperitoneal
fat Diaphragm
L.
atrial
appendage
Aortic arch
Innominate v.
Pulmonary a.
Figure 19-29.
The median sternotomy incision.
A.
Skin incision 
from the suprasternal notch to the xiphoid process.
B.
Exposure of 
the pleural space.
a.
= artery; v.
= vein.
If the lung is well-
expanded, the chest tube can remain to water seal drainage.
These catheters are also 
prone to kinking at the insertion site into the skin.
If bubbles pass through the water seal cham-
ber, an air leak is presumed.
Pain Control.
The most common techniques of pain management are epidural, 
paravertebral, and intravenous.
Combinations 
of narcotic and topical analgesia are then infused as with the 
epidural catheter.
Motor function, however, remains 
649
Chest Wall, Lung, Mediastinum, and Pleura
CHAPTER 19
intact.
Dosing must be titrated to balance the 
degree of pain relief with the degree of sedation.
Respiratory Care.
Post-
operatively, proper pain control (as outlined earlier) is essential, 
without oversedation.
This 
catheter is well-tolerated by most patients and allows regular 
and convenient suctioning.
Clinically, 
symptoms of respiratory distress manifest hours to days after 
surgery.
Radiographically, diffuse interstitial infiltration or 
frank alveolar edema is seen.
Treatment consists of ventilatory sup-
port, fluid restriction, and diuretics.
Extracorporeal membrane 
oxygenation may be life-saving in centers where this option is 
available.
The syndrome reportedly has a nearly 100% mortality 
rate despite aggressive therapy.
Other postoperative complications include air leak and 
bronchopleural fistula.
Although these are two very differ-
ent problems, distinguishing between them may be difficult.
Patients often have concomitant empyema, and 
open drainage may be necessary.
The most com-
mon cause is rupture of an apical subpleural bleb.
Treatment is 
generally chest tube insertion with water seal.
Pulmonary Infections
Lung Abscess.
Less often, there may be multiple, 
smaller cavities (<2 cm).
In that case, the infection is typically 
referred to as a necrotizing pneumonia.
An abscess that is pres-
ent for more than 6 weeks is considered chronic.
Direct extension from 
a contiguous site is less frequent.
Most primary lung abscesses 
are suppurative bacterial infections secondary to aspiration.
Infected cysts or bullae 
are not considered true abscesses.
Microbiology.
Clinical Features and Diagnosis.
Severe complications 
Table 19-17 
Causes of lung abscess
I.
Primary
A.
Necrotizing pneumonia
1.
Staphylococcus aureus, Klebsiella, Pseudomonas, 
Mycobacterium
2.
Bacteroides, Fusobacterium, Actinomyces
3.
Entamoeba, Echinococcus
B.
Aspiration pneumonia
1.
Anesthesia
2.
Stroke
3.
Drugs or alcohol
C.
Esophageal disease
1.
Achalasia, Zenker’s diverticulum, 
gastroesophageal reflux
D.
Immunodeficiency
1.
Cancer (and chemotherapy)
2.
Diabetes
3.
Organ transplantation
4.
Steroid therapy
5.
Malnutrition
II.
Secondary
A.
Bronchial obstruction
1.
Neoplasm
2.
Foreign body
B.
Systemic sepsis
1.
Septic pulmonary emboli
2.
Seeding of pulmonary infarct
C.
Complication of pulmonary trauma
1.
Infection of hematoma or contusion
2.
Contaminated foreign body or penetrating injury
D.
Direct extension from extraparenchymal infection
1.
Pleural empyema
2.
Mediastinal, hepatic, subphrenic abscess
Source: Adapted with permission from Rusch VW, et al.
Chest wall, 
pleura, and mediastinum.
In: Schwartz SI, et al, eds.
Principles of Sur-
gery.
7th ed.
New York: McGraw-Hill; 1999:735.
The CXR is the primary tool for diagnosing a lung abscess 
(Fig.
19-30).
Its distinguishing characteristic is a density or mass 
with a relatively thin-walled cavity.
A cavi-
tating lung carcinoma is frequently mistaken for a lung abscess.
Ideally, the specific etiologic organism is identified before 
antibiotic administration.
Actinomycosis lung infection typically 
begins as acute pneumonitis after an aspiration.
Actinomyces israelii is the most common 
cause of disease among the Actinomyces species.
In some cases, empyema also develops.
Management of Lung Abscess.
Systemic antibiotics directed 
against the causative organism represent the mainstay of therapy.
Oral therapy can then be used to complete the 
course of therapy.
Clindamycin 
is also a primary therapeutic agent.
Indications for intervention are listed in Table 19-18.
Sur-
gical resection is required in fewer than 10% of lung abscess 
patients.
Lobectomy is the preferred intervention for bleeding 
from a lung abscess or pyopneumothorax.
Surgical treatment has a 90% success rate, with 
an associated mortality of 1% to 13%.
Bronchiectasis.
Pathogenesis.
Development of bronchiectasis can be attributed 
to either congenital or acquired causes.
Congenital causes tend to produce 
a diffuse pattern of bronchial involvement.
Acquired causes 
are categorized broadly as infectious and inflammatory.
Lung abscess resulting from emesis and aspiration after an alcoholic binge.
A.
Chest x-ray showing an abscess cavity in the 
left upper lobe.
B.
A coronal tomogram highlights the thin wall of the abscess.
C.
Healing of the abscess cavity after 4 weeks of antibiotic 
therapy and postural drainage.
Thus chronic airway inflam-
mation is the essential pathologic feature of bronchiectasis.
The saccular type is the most common after bronchial obstruc-
tion or infection (Fig.
19-31).
Clinical Manifestations and Diagnosis.
Other patients 
Table 19-18 
Indications for surgical drainage procedures for lung 
abscesses
1.
Failure of medical therapy
2.
Abscess under tension
3.
Abscess increasing in size during appropriate treatment
4.
Contralateral lung contamination
5.
Abscess >4–6 cm in diameter
6.
Necrotizing infection with multiple abscesses, 
hemoptysis, abscess rupture, or pyopneumothorax
7.
Inability to exclude a cavitating carcinoma
Figure 19-31.
may appear asymptomatic or have a dry nonproductive cough 
(“dry bronchiectasis”).
These patients are prone to have involve-
ment of the upper lobes.
The clinical course is characterized 
by progressive symptoms and respiratory impairment.
Increas-
ing resting and exertional dyspnea are the result of progressive 
airway obstruction.
Acute exacerbations may be triggered by 
viral or bacterial pathogens.
Massive bleeding 
may result from erosion of the hypertrophied bronchial arteries.
Sputum culture may identify 
characteristic pathogens.
Management of Bronchiectasis.
Mycobacterial Infections
Epidemiology.
Tuberculosis is a widespread problem that 
affects nearly one third of the world’s population.
HIV infection is the strongest risk factor 
for developing active tuberculosis.
Microbiology.
Mycobacterial species are obligate aerobes.
They 
are primarily intracellular parasites with slow rates of growth.
It is estimated that 9% of all MDRTB cases are 
extensively drug resistant.
The more important NTM organisms include Mycobacte-
rium kansasii, M.
avium and M.
intracellulare complex (MAC), 
and M.
fortuitum.
The highest incidence of M.
kansasii infec-
tion is in midwestern U.S.
cities among middle-aged males from 
good socioeconomic surroundings.
MAC organisms are impor-
tant infections in elderly and immunocompromised patient 
groups.
M.
fortuitum infections are common complications of 
underlying severe debilitating disease.
None of these organisms 
are as contagious as M.
tuberculosis.
Pathogenesis and Pathology.
The main route of transmission 
is via airborne inhalation of viable mycobacteria.
Three stages 
of primary infection have been described.
In the first stage, 
alveolar macrophages become infected through ingesting the 
bacilli.
Activated macrophages acquire 
an increased capacity for bacterial killing.
Reactivation tuberculosis may occur after hydrolytic 
enzymes liquefy the caseum.
Edema, hemorrhage, and mononuclear 
cell infiltration are also present.
The pathologic changes caused by NTM organisms are 
similar to those produced by M.
tuberculosis.
M.
Cavitary dis-
ease is infrequent, although nodules may be noted.
Clinical Presentation and Diagnosis.
About 
80% to 90% of tuberculosis patients present with clinical dis-
ease in the lungs.
After primary infection, pulmonary tuberculosis is fre-
quently asymptomatic.
Systemic symptoms of low-grade fever, 
malaise, and weight loss are subtle and may go unnoticed.
A 
productive cough may develop, usually after tubercle cavita-
tion.
Extrapulmonary involvement is due to 
hematogenous or lymphatic spread from pulmonary lesions.
The pleura, chest wall, and 
mediastinal organs may all be involved.
For pulmonary tuberculosis, 
sputum examination is inexpensive and has a high diagnostic 
yield.
Chest CT 
scan can delineate the extent of parenchymal disease.
Management.
A 
current treatment algorithm is outlined in Fig.
19-32.
Gener-
ally, therapy lasts about 18 months.
The overall response rate is 
satisfactory in 70% to 80% of patients with M.
kansasii infec-
tion.
In con-
trast, pulmonary M.
Scattered nodular disease may be left intact, given its low 
mycobacterial burden.
Pulmonary Fungal Infections.
Patients receiving high-dose, intensive 
antibiotic therapies are also susceptible.
Serologic testing to identify mycotic-specific antibodies 
may also be useful.
Aspergillosis.
The species most commonly 
responsible for clinical disease include A.
fumigatus, A.
flavus, 
A.
niger, and A.
terreus.
Aspergillus is a saprophytic, filamen-
tous fungus with septate hyphae.
Treatment algorithm for tuberculosis.
A repeat smear and cul-
ture should be performed when 2 months of treatment has been completed.
*EMB may be discontinued when results 
of drug susceptibility testing indicate no drug resistance.
†PZA may be discontinued after it has been taken for 2 months (56 doses).
§Therapy should be extended 
to 9 months if results of 2-month culture are positive.
(Reproduced with permission of the American Thoracic Society.
Copyright © American 
Thoracic Society.
Blumberg HM, et al.
Am J Respir Crit Care Med.
Complications resulting from previous thoracic surgery to 
treat tuberculosis
2.
Need for tissue acquisition for definitive diagnosis
4.
Extrapulmonary thoracic involvement
6.
Pleural  tuberculosis
7.
19-33).
This form is the most common presentation of non-
invasive pulmonary aspergillosis.
The natural history varies greatly between patients and, 
therefore, treatment is individualized.
Asymptomatic patients can be observed without any additional 
therapy.
Antifungals have limited utility due to the poor blood 
supply to the aspergilloma.
Operative intervention may be required for recurrent hemoptysis, 
A
C
B
Figure 19-33.
Pulmonary aspergilloma.
A.
B.
A cut section shows the “fungus ball” occupying an old, fibrotic cavity.
C.
Histologic stain reveals 
characteristic Aspergillus hyphae invading the wall of the cavity.
Long-term follow-up is neces-
sary, given that the recurrence rate after surgery is about 7%.
They may also have pleuritic chest pain, cough, dyspnea, or 
hemoptysis.
Characteristic signs on CT scan include the halo 
sign and cavitary lesions.
In addition, 
the patient should no longer be immunosuppressed.
Cryptococcosis.
Cryptococci are typi-
cally present in soil and dust contaminated by pigeon droppings.
Symptoms 
are nonspecific, as are the radiographic findings.
Multiple antifungal agents are 
effective against C.
neoformans, including amphotericin B and 
the azoles.
The choice of antifungal and duration of treatment 
depend on the severity of disease.
Duration of therapy is longer 
in patients who are immunocompromised.
Candidiasis.
The fungi of this genus are common 
hospital and laboratory contaminants.
Other potentially pathogenic Candida species 
include C.
tropicalis, C.
glabrata, and C.
krusei.
Historically, 
C.
albicans was the most common pathogen to cause invasive 
candidal infection.
However, more recent reports suggest that 
other Candida species, particularly C.
glabrata and C.
krusei, 
are becoming more prevalent and now account for between 40% 
and 50% of all cases.
Pulmonary candidal infections typically result in 
an acute or chronic granulomatous reaction.
Treatment for candidal infection includes both fungicidal 
and fungistatic agents.
For funge-
mia, an eye examination should be performed.
Treatment should 
continue for at least 2 weeks after the last positive blood culture.
Mucormycosis.
Infection occurs via 
inhalation of spores.
Tissue destruction is significant, 
along with cavitation and abscess formation.
Lipid formulations of amphotericin B are recom-
mended at this time.
Primary Fungal Pathogens
Histoplasma capsulatum.
The clinical presentation depends on the inoculum size 
and on host factors.
CXRs may be normal or may 
show mediastinal lymphadenopathy and patchy parenchymal 
infiltrates.
Most patients improve in a few weeks; mild to mod-
erate disease can be treated with itraconazole.
Central and concentric 
calcification may occur; if so, no further treatment is required.
Typical symptoms include 
cough, hemoptysis, and dyspnea.
Life-threatening complica-
tions include massive hemoptysis or bronchoesophageal fistula.
In addition to radiography, bronchoscopy should be performed 
to aid in diagnosis.
Endobronchial debridement is not advised as this 
can result in massive, fatal bleeding.
A trial of itraconazole is 
worthwhile, although it is not proven to be effective.
In the majority of patients, how-
ever, antifungal therapy has not been proven effective.
There 
is no role for corticosteroids at this time or for antifibrotics.
Occasionally, intravascular stents have been helpful for severe 
vascular compromise.
Chest radiography may reveal 
intrapulmonary cavitation and scarring.
Occasionally, partial 
resolution of the inflammatory changes may be observed.
Itra-
conazole provides effective therapy, but must be given for 12 
to 24 months.
Vori-
conazole and posaconazole have been found to be useful for 
salvage therapy.
Serum itraconazole levels should be monitored 
to ensure that the drug is being absorbed.
Occasionally, lipid-
associated amphotericin B is necessary for more severe infec-
tions.
Coccidioides immitis.
Inhalation of the fungus causes pulmonary involvement 
in 95% of patients with symptomatic disease.
Primary pulmonary 
coccidioidomycosis occurs in about 40% of people who inhale 
spores.
The other 60% will remain asymptomatic and develop 
life-long immunity.
Pathologic findings of infection in normal and immunocompromised hosts.
A.
The exudate consists mostly of mononuclear phagocytes, lymphocytes, and occasional plasma cells.
Many of the alveolar walls are 
markedly thickened (hematoxylin and eosin stain [H&E], ×50).
B.
C.
D.
E.
A few multinucleated macrophages are present.
A thin layer of fibroblasts circumscribes the lesion.
Yeasts 
of H.
Lesions of this type often undergo necrosis to become necrotizing granulomas 
(H&E, ×50).
F.
Necrotizing (sometimes referred to as caseating) granuloma from the same lung as in E.
A prominent giant 
cell is present in the lower left of the granuloma (at approximately 8 o’clock).
Microorganisms are usually present only in relatively small 
numbers in these types of lesions.
There are several relative indications for surgery in pulmo-
nary coccidioidomycosis.
Amphotericin B deoxycholate or the triazoles continue to be 
the primary antifungal medications.
Intrathecal amphotericin B 
can also be administered in some cases.
Blastomyces dermatitidis.
It resides in the soil as a nonmotile spore called 
conidia.
Exposure occurs when contaminated soil is disturbed 
and the conidia are aerosolized.
B.
Symptoms are nonspecific and con-
sistent with chronic pneumonia in 60% to 90% of patients.
Pulmonary parenchymal abnormalities in the upper lobe(s) may 
be noted.
Mass lesions similar to carcinoma are frequent, 
and lung biopsy is frequently used.
It is a medi-
cal emergency associated with a mortality rate of 30% to 50%.
First, it is difficult for the 
patient or caregivers to quantify the volume of blood being lost.
Anatomy.
The lungs have two sources of blood supply: the 
pulmonary and bronchial arterial systems.
Causes.
Significant hemoptysis occurs as a result of pulmo-
nary, extrapulmonary, and iatrogenic causes.
Table 19-20 
summarizes the most common causes of hemoptysis.
Most 
are secondary to inflammatory processes.
Hemoptysis due to lung cancer is usually mild, result-
ing in blood-streaked sputum.
Although rare, 
it is often a terminal event.
Management.
Achieve respiratory stabilization and prevent 
asphyxiation.
2.
Localize the bleeding site.
3.
Control the hemorrhage.
4.
Determine the cause.
5.
Definitively prevent recurrence.
Scenario 1: Significant, Persistent, but Nonmassive Bleeding.
A CXR is the first test and often proves to be the most 
revealing.
Chest CT scan provides more 
detail and is nearly always performed if the patient is stable.
Pathologic areas may be obscured by blood soiling.
Flexible bronchoscopy is the next step in evaluating the 
patient’s condition.
Some clinicians argue that rigid bronchos-
copy should always be performed.
Scenario 2: Significant, Persistent, and Massive Bleeding.
Life-threatening bleeding requires emergency airway control 
and preparation for potential surgery.
Such patients are best 
cared for in an operating room equipped with rigid bronchos-
copy.
Immediate orotracheal intubation may be necessary to 
gain control of ventilation and suctioning.
However, rapid trans-
port to the operating room with rigid bronchoscopy should be 
facilitated.
The best option is to 
place a bronchial blocker in the affected bronchus with inflation.
Surgical Intervention.
A chest CT scan and 
pulmonary function studies should be obtained preoperatively.
General indications for urgent 
surgery are presented in Table 19-22.
End-Stage Lung Disease
Lung Volume Reduction Surgery.
Operative mortality in the initial experience was 16.9%, 
with a 1-year mortality of 23%.
surgical management after a 10-week pretreatment pulmonary 
rehabilitation program.
After 2 years, functional improvements began to 
decline toward baseline.
Similar parameters in medically treated 
patients steadily decline below baseline.
The most common indications for 
lung transplant are COPD and idiopathic pulmonary fibrosis 
(IPF).
Most patients with IPF and older patients with COPD are 
offered a single-lung transplant.
Table 19-22 
General indications for urgent operative intervention 
for massive hemoptysis
1.
Presence of a fungus ball
2.
Presence of a lung abscess
3.
Presence of significant cavitary disease
4.
Patients with significant pulmonary 
hypertension should be listed earlier.
19-35 and 19-36.
The mortality of 
patients while waiting for transplants is about 10%.
Recipient outcomes are similar to those with cadaver donors in 
carefully selected patients.
19-37).
Episodes of acute rejection are the major risk factors for develop-
ing BOS.
The overall survival rate after lung transplantation 
at the University of Minnesota.
Survival
123
BOS-free survival
1.0
0.8
0.6
0.4
0.2
Years posttransplant
Figure 19-36.
All chest wall tumors should be consid-
ered malignant until proven otherwise.
Complete resection is imperative if there is any hope for 
cure and/or long-term survival.
A general approach is outlined 
in Figs.
19-38 and 19-39.
With Ewing’s 
sarcoma, fever and malaise may also be present.
Overall, between 50% and 80% 
of chest wall tumors are malignant.
Evaluation and Management.
Laboratory evaluations are 
useful in assessing chest wall masses for the following:
1.
2.
Osteosarcoma: Alkaline phosphatase levels may be elevated.
3.
Ewing’s sarcoma: Erythrocyte sedimentation rates may be 
elevated.
Radiography.
Biopsy.
The first step in the management of all chest wall 
tumors is to obtain a tissue diagnosis.
CT = computed tomography; 
MRI = magnetic resonance imaging.
Figure 19-39.
Systematic approach for evaluating a chest wall 
mass for which the diagnosis is not unequivocal.
A tissue diagno-
sis is critical for effective management of chest wall masses.
CT  
computed tomography; MRI  magnetic resonance imaging; PNET  
primitive neuroectodermal tumor.
1.
2.
3.
Benign Chest Wall Neoplasms
1.
Chondroma.
Chondromas may grow to huge 
sizes if left untreated.
Treatment is surgical resection with a 
2-cm margin.
Fibrous dysplasia.
Radiographically, an expansile mass is present, 
with cortical thinning and no calcification.
Local excision 
with a 2-cm margin is curative.
3.
Osteochondroma.
Osteochondromas in the thorax arise 
from the rib cortex.
When part of this syndrome, osteochondromas 
have a high rate of degeneration into chondrosarcomas.
Local excision of a benign 
osteochondroma is sufficient.
If malignancy is determined, 
wide excision is performed with a 4-cm margin.
4.
Eosinophilic granuloma.
Eosinophilic granulomas are 
benign osteolytic lesions.
The cause is 
unknown.
They are diagnosed primarily in children between the ages 
of 5 and 15 years.
5.
Desmoid tumors.
Desmoid 
tumors possess alterations in the adenomatous polyposis 
coli (APC)/β-catenin pathway.
The tumor is usually fixed to the chest wall, but not to the 
overlying skin.
A 
margin of less than 1 cm results in much higher local recur-
rence rates.
19-40).
All sarcomas have a 
propensity to spread to the lungs.
In fact, patients receiving surgical intervention 
have significantly better overall survival.
Chest computed tomography scan 
showing a right chest wall tumor (arrow).
Tissue 
diagnosis revealed that this mass was a leiomyosar-
coma.
The following is an overview of several chest wall sarcomas.
1.
Chondrosarcoma.
Chondrosarcomas are the most com-
mon primary chest wall malignancy.
As with chondro-
mas, they usually arise anteriorly from the costochondral 
arches.
19-41).
The involved bony structures are also 
destroyed.
Chondrosarcomas 
are not sensitive to radiation or chemotherapy.
Prognosis is 
determined by tumor grade and extent of resection.
2.
Osteosarcoma.
Osteosarcomas 
are potentially sensitive to chemotherapy.
Currently, pre-
operative chemotherapy is common.
Source: Reproduced with permission from Gutierrez et al.152 Copyright Elsevier.
Malignant fibrous histiocytoma.
The typical age at presentation is between 
age 50 and 70 years.
Presentation is pain, with or without a 
palpable mass.
Radiographically, a mass is usually evident, 
with destruction of surrounding tissue and bone.
Treatment 
is wide resection with a margin of 4 cm or more and recon-
struction.
Over two thirds of patients suffer from distant 
metastasis or local recurrence.
4.
Liposarcoma.
Liposarcomas make up 15% of chest wall 
sarcomas.
They typically present as a painless mass.
Treat-
ment is wide resection and reconstruction.
Local recurrence can be treated with re-excision, with 
occasional use of radiotherapy.
5.
Fibrosarcoma.
Local and systemic 
recurrence is frequent.
Patient survival at 5 years is about 
50% to 60%.
6.
Rhabdomyosarcoma.
Rhabdomyosarcomas are rare tumors 
of the chest wall.
Microscopically, they are a spindle cell 
tumor.
The diagnosis often depends on immunohistochemi-
cal staining for muscle markers.
Rhabdomyosarcomas are 
sensitive to chemotherapy.
Treatment consists of preopera-
tive chemotherapy with subsequent surgical resection.
Other Tumors of the Chest Wall
1.
Primitive neuroectodermal tumors (PNETs) and 
Ewing’s sarcoma.
Systemic symptoms of malaise and fever are often 
present.
Evidence of bony destruction is also com-
mon.
The diagnosis can be made by a percutaneous needle 
biopsy or an incisional biopsy.
Figure 19-41.
Chest computed tomography scan showing a right posterior lung tumor.
Increasing tumor size is asso-
ciated with decreasing survival.
2.
Plasmacytoma.
Plain radiographs show an osteolytic 
lesion in the region of the pain.
As with other chest wall 
tumors, a needle biopsy under CT guidance is performed 
for diagnosis.
Histologically, the lesion is identical to mul-
tiple myeloma, with sheets of plasma cells.
It occurs at an 
average age of 55 years.
If the results of these studies are negative, then 
a solitary plasmacytoma is diagnosed.
19-42).
Anteriorly based lesions contiguous with the sternum require 
partial sternectomy.
Primary malignant tumors of the sternum 
may require complete sternectomy.
19-42).
There are 
several properties that make Gore-Tex an excellent material for 
AB
Figure 19-42.
Principles of reconstruction after resection of a chest wall tumor (osteogenic sarcoma) are shown.
A.
The resected 
specimen is shown.
B.
A prosthesis has been sewn in place.
In the lower third of the prosthesis, the line of diaphragm reattachment is seen.
The skin defect was closed with a myocutaneous flap from the ipsilateral rectus muscle.
19-43).
The visceral or middle compartment is located 
between the great vessels and the trachea.
The thymus gland is large dur-
ing childhood, occupying the entire anterior mediastinum (Fig.
19-45).
Numerous pathologic 
variants may be present in the various compartments, with much 
overlap.
Thymoma in child-
hood is rare (Table 19-26).
Anatomic division of the mediastinum.
Thymus
Figure 19-44.
Normal appearance of the thymus 
gland in childhood.
Ao = aorta; PA = pulmonary 
artery; VC = vena cava.
of mediastinal tumors are malignant.
Pediatric tumors will be 
discussed in Chapter 39.
When symptomatic, these 
tumors are significantly more likely to be malignant.
The patient in Fig.
672
SPECIFIC CONSIDERATIONS
UNIT II
PART II
Figure 19-45.
Computed tomography scan showing 
the normal appearance of an involuted thymus gland 
in an adult.
The mediastinum and its compartments.
In: Shields TW, ed.
Mediastinal Surgery.
Philadelphia: 
Lea & Febiger; 1991:5.
If an endocrine origin is suspected, several other imaging 
modalities are available (Table 19-29).
The sestamibi scan may be useful for 
diagnosing and localizing a mediastinal parathyroid gland.
The use of serum markers to evaluate a mediastinal mass can 
be invaluable in some patients.
In over 90% of nonseminomatous germ cell tumors, 
either the AFP or the hCG level will be elevated.
Results are 
close to 100% specific if the level of either AFP or hCG is 
greater than 500 ng/mL.
Mediastinal masses.
Surg Clin North Am.
1980;60:760.
Copyright 
Elsevier.
Primary lesions of the mediastinum 
and their investigation and treatment.
In: Shields TW, ed.
General 
Thoracic Surgery, 4th ed.
Baltimore: Lippincott Williams & Wilkins; 
1994:1731.
Figure 19-46.
Finally, core-needle 
biopsy was better at diagnosis for benign diseases compared 
to FNA.
Recently, core-needle biopsy with EBUS 
became possible with release of a EBUS-core needle device.
At the time of sternotomy, if 
the lesion is easily resectable, it should be completely removed.
Masses in the paratracheal region are eas-
ily biopsied by mediastinoscopy.
Source: Reproduced with permission from McGinnis KM, et al.
Markers of the mediastinum.
In: Pearson FG, et al, eds.
Thoracic Surgery.
2nd ed.
New 
York: Churchill Livingstone; 2002:1675.
Copyright Elsevier.
Other minimally invasive approaches are under study.
Mediastinal Neoplasms
Thymic Hyperplasia.
The role of PET 
scanning is unclear.
Thymoma.
Most patients with thy-
moma are asymptomatic.
The diagnosis may be suspected based on CT scan and 
history, but imaging alone is not diagnostic.
Biopsy should 
be avoided in cases where imaging is highly suggestive of thy-
moma.
Grossly, 
many thymomas remain well encapsulated.
19-47).
The goal for surgical resection should be complete exci-
sion of the mass with total thymectomy.
The role of adjuvant or neoadjuvant therapies for 
advanced-stage tumors remains unclear.
Stage-specific survival for thymomas.
Cisplatin/doxorubicin-based regimens appear to yield the 
best results.
Massive thymolipoma that was asymp-
tomatic in an 18-year-old female.
the surgeon and radiation oncologist can ensure appropriate 
radiation treatment.
Thymic Carcinoma.
Thymic carcinomas are unequivocally 
malignant at the microscopic level.
Malignant pleural and pericardial effu-
sions occur frequently.
Five-year survival rates are between 30% and 50%.
The prognosis of patients with thymic 
cancer remains poor.
Thymolipoma.
Thymolipomas are rare benign tumors that 
may grow to a very large size prior to diagnosis.
19-48).
Resection is recommended for large 
masses.
Neurogenic Tumors.
The 
incidence, cell types, and risk of malignancy strongly correlate 
with patient age.
Tumors of nerve sheath origin predominate in 
adults.
Most present as asymptomatic incidental findings, and 
most are benign.
Nerve sheath tumors account for 20% of 
all mediastinal tumors.
More than 95% of nerve sheath tumors 
are benign neurilemomas or neurofibromas.
Malignant neuro-
sarcomas are much less common.
Neurilemoma.
Neurilemomas, also called schwannomas, arise 
from Schwann cells in intercostal nerves.
They are firm, well-
encapsulated, and generally benign.
Antoni type A regions contain compact spindle 
cells with twisted nuclei and nuclear palisading.
19-49).
Neurofibroma.
Figure 19-49.
Complete surgical resection is the mainstay of treatment.
Ganglion Cell Tumors.
Ganglioneuroma.
Ganglioneuroblastoma.
Ganglioneuroblastomas contain a 
mixture of benign ganglion cells and malignant neuroblasts.
The distribution of these cells within the tumor is predictive of 
the clinical course.
Ganglioneuroblastomas arise most frequently in 
infants and children <3 years old.
The majority are resectable, 
with 80% 5-year survival.
Neuroblastoma.
Highly malignant, neuroblastomas are the 
most common extracranial solid malignancy of childhood.
Paraganglionic Tumors.
Only 10% of all pheochromocytomas are located in 
an extra-adrenal site.
Intrathoracic pheochromocytomas are 
one of the rarest tumors.
Localization 
is by CT scan, aided by MIBG scintigraphy.
These tumors tend to 
be highly vascular and should be approached with care.
They rarely secrete 
catecholamines and are malignant in up to 30% of patients.
Lymphoma.
Overall, lymphomas are the most common malig-
nancy of the mediastinum.
The posterior compartment 
is rarely involved.
Mediastinal Germ Cell Tumors.
Germ cell tumors are 
uncommon neoplasms, with only about 7000 diagnosed each 
year.
However, they are the most common malignancy in young 
men 15 to 35 years of age.
Previously, most 
mediastinal germ cell tumors were thought to be metastatic.
Two thirds are nonseminomatous 
tumors or teratomas.
Treatment and prognosis vary consider-
ably within these two groups.
In 10% of seminomas, hCG levels may be slightly ele-
vated.
FNA findings, along with high hCG and AFP levels, can 
accurately diagnose nonseminomatous tumors.
Thoracoscopy is the most frequent diagnostic 
surgical approach.
Seminoma.
Complete responses 
have been reported in over 75% of patients treated with these 
regimens.
Surgical resection of residual masses after chemo-
therapy may be indicated.
Nonseminomatous germ cell tumors.
Lactate dehydrogenase (LDH), AFP, and hCG levels are 
frequently elevated.
With this regimen, survival is 67% at 2 years and 60% at 
5 years.
Surgical resection of residual masses is indicated, as it 
may guide further therapy.
Therapy for mature, benign teratomas is surgical 
resection, which confers an excellent prognosis.
For most simple, asymptomatic pericardial cysts, 
observation alone is recommended.
Surgical resection or aspira-
tion may be indicated for complex cysts or large symptomatic 
cysts.
Bronchogenic cyst.
Approximately 15% occur within the pulmonary 
parenchyma.
They may 
communicate with the tracheobronchial tree.
Symptoms 
include chest pain, cough, dyspnea, and fever.
Thoracoscopic exploration and resection are possible for 
small cysts with minimal adhesions.
Enteric cyst.
Thus, 
surgical resection is the treatment of choice in both adults and 
children.
Thymic cyst.
Generally asymptomatic, thymic cysts are often 
discovered incidentally.
Simple cysts are of no consequence; 
however, the occasional cystic neoplasm must be ruled out.
Cystic components occasionally are seen in patients with thy-
moma and Hodgkin’s disease.
Ectopic endocrine glands.
Usually nontoxic, over 95% can be completely 
resected through a cervical approach.
True ectopic thyroid tis-
sue of the mediastinum is rare.
Location can generally be pin-
pointed by a combination of CT scan and Sestamibi scans.
Mediastinitis
Acute Mediastinitis.
Antibiotics, fluid resuscitation, and other sup-
portive measures are also important.
Blood cell counts and serial CT 
scans may also be required.
Persistent sepsis or collections on 
CT scan may require further radical surgical debridement.
Chronic Mediastinitis.
There is no defini-
tive treatment.
Infections 
of the mediastinum.
In: Pearson FG, et al, eds.
Thoracic Surgery.
2nd ed.
New York: Churchill Livingstone; 2002:1604.
Copyright Elsevier.
achieve vascular reconstruction.
In one series 
of 22 patients, ketoconazole was effective in controlling progres-
sion.
In another series of 71 patients, 30% died during long-term 
follow-up.
A network of somatic, sympa-
thetic, and parasympathetic fibers innervates the parietal pleura.
Normally, 15 to 20 mL of pleural fluid is present 
at any given time.
Any disturbance in these forces can lead to 
imbalance and accumulation of pleural fluid.
19-50).
Pleural effusion.
N Engl J Med 2002;346:1971.
Copyright © Massachusetts Medical Society.
All rights reserved.
Adapted from Light RW.
Approach to the patient.
In: Light RW, ed.
Pleural Diseases.
5th ed.
Philadelphia: Lippincott Williams & 
Wilkins; 2007:111.
Figure 19-50.
Techniques for aspiration and drainage of a pleural effusion.
A.
Needle aspiration.
Large volumes of fluid can be removed with a little patience 
and a large-bore needle.
B.
Chest tube insertion.
A 28F to 32F tube is adequate for most situations.
A 36F tube is preferred for hemothorax or for a 
viscous empyema.
Many surgeons prefer a very small tube (16F–20F) for drainage of simple pneumothorax.
C.
The tube is connected to a 
water-seal drainage system.
demonstrated to be free-flowing.
If the 
effusion is loculated, CT- or ultrasound-guided drainage may 
be indicated.
Complications of Pleural Drainage.
Sometimes bleeding may be the result 
of an underlying coagulopathy or anticoagulant therapy.
For this reason, it is recom-
mended to drain only up to 1500 mL initially.
Pleural Fluid Analysis.
Pleural fluid collections are generally 
classified as transudates and exudates (Table 19-34).
On gross visual inspection, a transudative effusion 
is generally clear or straw-colored.
Grossly, they are often turbid, 
bloody, or purulent.
Transudates and exudates can be differentiated using 
Light’s criteria.
If criteria suggest an exudate, further diagnostic 
studies may be helpful.
Effusion size and degree of associated dyspnea influ-
ence management.
Patient preference is 
also considered, as is their life expectancy.
The choice of 
sclerosant includes mechanical, talc, bleomycin, or doxycycline.
Success rates range from 60% to 90% and are highest with talc.
Figure.
19-51 presents a decision algorithm for 
the management of malignant pleural effusion.
Empyema
Thoracic empyema is defined by a purulent pleural effusion.
Pathophysiology.
The spectrum of organisms 
involved in pneumonic processes that progress to empyema is 
changing.
Cases 
involving mycobacteria or fungi are rare.
Multiple organisms 
may be found in up to 50% of patients.
Transudative pleural effusions
A.
Congestive heart failure
B.
Cirrhosis
C.
Nephrotic syndrome
D.
Superior vena caval obstruction
E.
Fontan procedure
F.
Urinothorax
G.
Peritoneal dialysis
H.
Glomerulonephritis
I.
Myxedema
J.
Cerebrospinal fluid leaks to pleura
K.
Hypoalbuminemia
L.
Pulmonary emboli
M.
Sarcoidosis
II.
Exudative pleural effusions
A.
Neoplastic diseases
1.
Metastatic disease
2.
Mesothelioma
3.
Body cavity lymphoma
4.
Pyothorax-associated lymphoma
B.
Infectious diseases
1.
Tuberculosis
2.
Other bacterial infections
3.
Fungal infections
4.
Parasitic infections
5.
Viral infections
C.
Pulmonary embolization
D.
Gastrointestinal disease
1.
Pancreatic disease
2.
Subphrenic abscess
3.
Intrahepatic abscess
4.
Intrasplenic abscess
5.
Esophageal perforation
6.
After abdominal surgery
7.
Diaphragmatic hernia
8.
Endoscopic variceal sclerosis
9.
After liver transplantation
E.
Heart diseases
1.
After coronary artery bypass graft surgery
2.
Post-cardiac injury (Dressler’s) syndrome
3.
Pericardial disease
F.
Obstetric and gynecologic diseases
1.
Ovarian hyperstimulation syndrome
2.
Fetal pleural effusion
3.
Postpartum pleural effusion
4.
Megis’ syndrome
5.
Endometriosis
G.
Collagen vascular diseases
1.
Rheumatoid pleuritis
2.
Systemic lupus erythematosus
3.
Drug-induced lupus
4.
Immunoblastic lymphadenopathy
5.
Sjögren’s syndrome
6.
Familial Mediterranean fever
7.
Churg-Strauss syndrome
8.
Wegener’s granulomatosis
H.
Drug-induced pleural disease
1.
Nitrofurantoin
2.
Dantrolene
3.
Methysergide
4.
Ergot alkaloids
5.
Amiodarone
6.
Interleukin-2
7.
Procarbazine
8.
Methotrexate
9.
Clozapine
I.
Miscellaneous diseases and conditions
1.
Asbestos exposure
2.
After lung transplantation
3.
After bone marrow transplantation
4.
Yellow nail syndrome
5.
Sarcoidosis
6.
Uremia
7.
Trapped lung
8.
Therapeutic radiation exposure
9.
Drowning
10.
Amyloidosis
11.
Milk of calcium pleural effusion
12.
Electrical burns
13.
Extramedullary hematopoiesis
14.
Rupture of mediastinal cyst
15.
Acute respiratory distress syndrome
16.
Whipple’s disease
17.
Iatrogenic pleural effusions
J.
Hemothorax
K.
Approach to the patient.
In: Light RW, ed.
Pleural Diseases.
5th ed.
Philadelphia: Lippincott Williams 
& Wilkins; 2007:110.
These 
mechanisms lead to variable degrees of endothelial injury and 
capillary instability.
This process overwhelms the normal 
pleural lymphatic drainage.
This early effusion is watery and 
free-flowing in the pleural cavity.
free-flowing purulent fluid).
Cancer.
1985;56:905.
Cancer.
1985;56:905.
Treatment decision algorithm for the management of malignant pleural effusion (MPE).
CT = computed tomography; VATS = 
video-assisted thoracic surgery.
The chest drain was clamped for 1 hour after 
injection and released.
Management.
If there is a residual space, persistent pleural 
infection is likely to occur.
If the space is small 
and well-drained by a chest tube, a conservative approach may 
be possible.
19-52).
If the mediastinal pleura 
are disrupted on both sides, bilateral chylothoraces may occur.
Pathophysiology.
19-52).
The duct continues superiorly, lying just 
to the right of the vertebral column.
Thoracentesis is usually 
grossly suggestive, revealing milky, nonpurulent pleural fluid.
Empyema and 
bronchopleural fistula.
In: Pearson FG, et al, eds.
Thoracic Surgery.
2nd ed.
New York: Churchill Livingstone; 2002:1177.
Copyright Elsevier.
686
SPECIFIC CONSIDERATIONS
UNIT II
PART II
fluid may not be grossly abnormal.
If the triglyceride level is less than 50 mg/mL, there is 
only a 5% chance of chylothorax.
Management.
19-53).
The pleura.
In: Sabiston DC, et al, eds.
Surgery of the Chest.
6th ed.
Philadelphia: 
Elsevier; 1995.
Copyright Elsevier.
Thoracic d.
Cisterna chyli
Figure 19-52.
Normal thoracic duct anatomy.
Somatostatin has been advocated by some authors, 
with variable results.
Malignant Mesothelioma.
Male predominance is 2:1, and it occurs most commonly 
after the age of 40.
Algorithm for the manage-
ment of chylothorax.
NPO = nothing by mouth.
Other risk factors 
include radiation exposure.
Clinical Presentation.
Most patients present with dyspnea and 
chest pain.
Over 90% have a pleural effusion, but thoracentesis 
is diagnostic in less than 10% of patients.
Sarcomatous and mixed tumors share a more 
aggressive course.
Management.
The treatment of malignant mesotheliomas 
remains controversial.
Whenever 
possible, patients are referred for clinical trials of multimodality 
therapy.
Fibrous Tumors of the Pleura.
Fibrous tumors of the pleura 
are unrelated to asbestos exposure or malignant mesotheliomas.
They can also have an hemangiopericytoma-like 
appearance.
A proposed new international TNM staging system for malignant 
pleural mesothelioma.
Chest.
1995;108:1122.
Less 
common are fever and hemoptysis.
Symptoms resolve with surgical resection.
The 
authors also express appreciation to their spouses, Chris, Lee, 
and Chris.
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PART II
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Congenital Heart Disease
Tara Karamlou, Yasuhiro Kotani, and  
Glen A.
Van Arsdell 20
INTRODUCTION
Congenital heart surgery is a dynamic and evolving field.
Embryology.
The atrial and ventricular septa form between 
the third and sixth weeks of fetal development.
Anatomy.
20-1).1
Pathophysiology.
This shift occurs because the resistance of the downstream 
vascular beds changes after birth.
New monitoring devices and periopera-
tive strategies are currently under investigation.
Figure 20-1.
The anatomy of atrial septal defects.
B.
Secundum 
defects generally occur as isolated lesions.
C.
(Reproduced with permission from 
Greenfield LJ, Mulholland MW, Oldham KT, et al, eds.
Surgery: 
Scientific Principles and Practice.
3rd ed.
Patients at this stage 
have a balanced circulation and may deceptively appear less 
 symptomatic.
Diagnosis.
Patients with ASDs may present with few physi-
cal findings.
The electrocardiogram shows 
right axis deviation with an incomplete bundle-branch block.
In general, ASDs are closed when patients are between 
4 and 5 years of age.
Patients who are symptomatic may 
require repair earlier, even in infancy.
The details of the repair itself are 
generally straightforward.
The caudal end of the transected 
cava is oversewn.
The cranial end of the transected cava is anas-
tomosed to the auricle of the right atrium.
Inside the atrium, a 
patch is used to redirect pulmonary venous blood flow to the 
left atrium.
698
SPECIFIC CONSIDERATIONS
UNIT II
PART II
Results and Complications of Surgical ASD Closure.
New and Future Approaches to Traditional Surgical ASD 
Closure.
Operative precision must be maintained with limited exposure 
in any minimally invasive technique.
Certain approaches have a specific 
patient population in whom they are applicable.
Aortic Stenosis
Anatomy and Classification.
20-2).
Associated left-
sided lesions are often present.
Endocardial fibroelastosis also is common among infants with 
critical aortic  stenosis (AS).
In severe cases, a 
reversal of flow may occur, causing right ventricular volume 
loading.
Those infants with mild-to-moderate AS 
in whom LV function is preserved are asymptomatic at birth.
The anatomy of the types of congenital aortic ste-
nosis.
A.
Valvar aortic stenosis.
B.
Supravalvar aortic stenosis 
and its repair (insert).
C.
Tunnel-type subvalvar aortic stenosis.
D.
Membranous subvalvar aortic stenosis.
(Reproduced with 
 permission from Greenfield LJ, Mulholland MW, Oldham KT, 
et al, eds.
Surgery: Scientific Principles and Practice.
3rd ed.
Diagnosis.
A systolic click 
correlates with a valvular etiology of obstruction.
As LV 
dysfunction progresses, evidence of congestive heart failure 
occurs.
Treatment.
20-3).
The infant 
with severe AS requires urgent intervention.
Exposure is attained with placement of a retractor 
into the right coronary sinus.
20-4).
Induction of 
more than moderate aortic regurgitation is poorly tolerated in 
Figure 20-3.
VSD 
= ventricular septal defect.
(From Alsoufi B, et al.
Eur J Cardiothorac Surg.
2007;31:1013.
Fig 1.
Aortic valvotomy with cardiopulmonary bypass.
Exposure is accomplished with placement of a retrac-
tor into the right coronary sinus.
(Reproduced with permission from Doty DB.
Cardiac 
Surgery: A Looseleaf Workbook and Update Service.
Chicago: 
Year Book; 1986.
In general, catheter-based balloon valvotomy has sup-
planted open surgical valvotomy.
20-5).
The placement of a 
pulmonary conduit, which does not grow and becomes calcified 
Figure 20-5.
A through C.
The pulmonary auto-
graft for aortic valve replacement.
The pulmonary valve and main pulmonary artery 
are excised and transferred to the aortic position.
The coronary buttons are then attached to the 
neoaortic root.
A pulmonary allograft is inserted 
to re-establish the right ventricular outflow tract.
(From Kouchokos NT, Davila-Roman VG, Spray 
TL, et al.
N Engl J Med.
20-6).
20-7).
The signs and symptoms of supravalvular AS are similar 
to other forms of LVOT obstruction.
An asymptomatic murmur 
is the presenting manifestation in approximately half of these 
patients.
Syncope, poor exercise tolerance, and angina may all 
occur with nearly equal frequency.
A gradient of 50 mmHg or greater is an indication 
for operation.
In the normal fetal cardiovascular 
Figure 20-6.
nonautograft) for a hypo-
thetical patient of 3 years undergoing AVR in 1990.
AoV = aortic valve.
(Reproduced with permission from Karam-
lou T, et al.
Circula-
tion.
Natural History.
Clinical Manifestations and Diagnosis.
Unrestrictive ductal flow may lead 
to pulmonary hypertension within the first year of life.
Auscultation demonstrates 
a systolic or continuous murmur, often termed a machinery 
 murmur.
Cyanosis is not present in uncomplicated isolated PDA.
Figure 20-7.
A.
B.
C.
A separate peri-
cardial patch closes the right ventriculotomy.
(Reproduced with permission from Misbach 
GA, Turley K, Ullyot DJ, et al.
Left ventricular 
outflow enlargement by the Konno procedure.
J Thorac Cardiovasc Surg.
1982;84:696.
Cardiac cath-
eterization is necessary only when pulmonary hypertension is 
suspected.
Therapy.
Surgical closure can be achieved via either open or 
video-assisted approaches.
The lung 
is then retracted anteriorly.
In the neonate, the PDA is sin-
gly ligated with a surgical clip or permanent suture.
In older 
patients, the PDA is triply ligated.
Care must be taken to 
avoid the recurrent laryngeal nerve, which courses around 
the PDA.
In this case, division between 
vascular clamps with oversewing of both ends is advisable  
(Fig.
20-8).
In extreme cases, the use of CPB to decompress 
the large ductus during ligation is an option.
A.
Surgeon’s perspective of infant patent ductus arteriosus exposed via a left thoracotomy.
B.
The pleura over the aortic isth-
mus is incised and mobilized.
C and D.
Technique of triple ligation.
a.
= artery; n.
= nerve.
(From Castaneda AR, Jonas RA, Mayer JE, et al.
Cardiac Surgery of the Neonate and Infant.
Philadelphia: W.B.
Saunders; 1994:208, with permission.
Copyright Elsevier.)
A
B
C
D
Pulmonary a.
Aorta
Recurrent
laryngeal n.
Vagus n.
In older 
infants and children, mortality is less than 1%.
Bleeding, chylo-
thorax, vocal cord paralysis, and the need for reoperation occur 
infrequently.
This narrowing is most commonly located distal 
to the left subclavian artery.
The embryologic origin of COA 
is a subject of some controversy.
In addition, detailed information regard-
ing other associated anomalies can be gleaned.
Aortography is 
reserved for those cases in which the echocardiographic find-
ings are equivocal.
Therapy.
Hypertension is also well recognized following repair of 
COA.
Both balloon dilatation and primary stent 
implantation have been used successfully.
These patients 
may be ideal candidates for primary stent placement.
Truncus Arteriosus
Anatomy.
Figure 20-9.
Type I is the 
same as A1.
(Reproduced with permission from Fyler DC.
Truncus arteriosus.
In: 
Fyler DC, ed.
Nadas’ Pediatric Cardiology.
Philadelphia: Hanley & Belfus; 1992:676.
Copyright Elsevier.
As adapted with permission from 
Hernanz-Schulman M, Fellows KE.
Persistent truncus arteriosus: pathologic, diagnostic and therapeutic considerations.
Semin Roentgenol.
1985;20:121.
The ECG is usually nonspecific, demonstrating normal 
sinus rhythm with biventricular hypertrophy.
The presence of truncus is an indication for surgery.
Repair should be undertaken in the neonatal period or as soon as 
the diagnosis is established.
Repair.
The results of complete repair of truncus have steadily 
improved.
Unique to this lesion is the absence of a definitive form of 
palliation.
Anatomy and Embryology.
Accordingly, the pulmonary veins 
drain to the heart through a systemic vein (Fig.
20-10).
This invari-
ably occurs via a nonrestrictive patent foramen ovale.
Therapy.
The ASD can then 
be closed with an autologous pericardial or synthetic patch.
20-11).
20-12).
4
Figure 20-10.
(From Castaneda 
AR, Jonas RA, Mayer JE, et al.
Cardiac 
Surgery of the Neonate and Infant.
Phila-
delphia: W.B.
Saunders; 1994:158, with 
permission.
(From Castaneda 
AR, Jonas RA, Mayer JE, et al.
Cardiac Sur-
gery of the Neonate and Infant.
Philadelphia: 
W.B.
Saunders; 1994:161, with permission.
Results.
In the sutureless techniques, there are no sutures 
placed in the fragile veins themselves.
Early and late extrinsic stenosis are thought to be reduced 
using this latter technique.
Hyde et al80 similarly reported that connec-
tion type was not related to outcome.
20-13).
Cor Triatriatum
Anatomy.
20-14).
Pathophysiology and Diagnosis.
Cor triatriatum results 
in obstruction of pulmonary venous return to the left atrium.
a.
b.
(Reproduced with permission from 
Karamlou T, et al.
Circulation.
Therapy.
Operative treatment for cor triatriatum is fairly 
 simple.
CPB and cardioplegic arrest are used.
20-15).
Pathophysiology and Diagnosis.
Figure 20-14.
A.
Common chamber draining 
to right atrium directly.
B.
Common chamber 
draining into systemic venous circulation via 
anomalous vein.
RA = right atrium.
(Adapted 
with permission from Krabill KA, Lucas RV 
Jr.
Abnormal pulmonary venous connec-
tions.
In: Emmanouilides GC, ed.
Moss and 
Adams’ Heart Disease in Infants, Children, 
and Adolescents.
5th ed.
Echocar-
diography can detect the defect and also provide information 
about associated anomalies.
Retrograde aortography will con-
firm the diagnosis but is rarely necessary.
Therapy.
All infants with APW require surgical correction 
once the diagnosis is made.
Repair is undertaken through 
a median sternotomy and the use of CPB.
The coronary ostia 
must be carefully visualized and included on the aortic side 
of the patch.
A through C.
Classification of aortopulmonary win-
dow.
(Reproduced with permission from Mori K, Ando M, Takao A.
Distal type of aortopulmonary window: report of 4 cases.
Br Heart 
J.
1978;40:681.
20-16).86
Results.
This results 
in discontinuity between the right atrium and RV.
The RV is 
generally hypoplastic, and left-heart filling is dependent on an 
ASD.
Anatomy.
An unrestrictive ASD is usually 
present.
20-17).
Pathophysiology.
As the ductus 
begins to close shortly after birth, infants become intensely 
 cyanotic.
Pulmonary hypertension is unusual in 
tricuspid atresia.
Two-patch repair of aor-
topulmonary window.
A.
The ductus arteriosus (when 
present) can be ligated.
The aorta is 
cross-clamped and the heart arrested 
with cardioplegia.
B.
A piece of previously prepared pul-
monary homograft material is used to 
patch the aortic defect.
In older children, 
polytetrafluoroethylene material can be 
safely used.
C.
D.
Diagnosis.
When 
pulmonary blood flow is provided through a VSD, there may be 
a prominent systolic murmur.
This is often 
related to excessive flow across a VSD.
Chest radiography will 
show decreased pulmonary vascularity.
Two-dimensional 
echocardiography readily confirms the diagnosis and the ana-
tomic subtype.
Treatment.
20-18).
Multiple modifications of this initial repair were per-
formed over the next 20 years.
This repair became known as the modified Fontan 
operation.
20-19).96
Figure 20-17.
Classification of  tricuspid 
atresia.
(Repro-
duced with permission from Tricuspid 
atresia.
In: Mavroudis C, Backer CL, 
eds.
Pediatric Cardiac Surgery.
2nd ed.
St.
Louis: Mosby; 1994:381.)
714
SPECIFIC CONSIDERATIONS
UNIT II
PART II
Figure 20-18.
Superior vena cava–pulmonary artery 
shunts.
A.
Classic Glenn shunt.
B.
C.
D.
(Reproduced with permission from Tricuspid atresia.
In: 
Mavroudis C, Backer CL, eds.
Pediatric Cardiac Surgery.
2nd ed.
St.
Louis: Mosby; 1994:383.)
Figure 20-19.
The fenestrated Fontan proce-
dure.
(Reproduced with 
permission from Kopf GS, Kleinman CS, Hijazi 
ZM, et al.
J 
Thorac Cardiovasc Surg.
1992;103:1039.
Competing risks depiction of events after diagnosis in 150 patients with tricuspid atresia.
At any point in time, the sum of 
proportions of children in each state is 100%.
(From Karamlou et al,99 Fig.
1, with permission.
20-20).
Anatomy.
Closure of the ductus is incompatible with life in 
these neonates.
Neonates with severe HLHS receive all pulmonary, sys-
temic, and coronary blood flow from the RV.
Treatment.
20-21).
Unfortunately, in 
717
C
ONGENITAL
 H
EART
 D
ISEASE
CHAPTER 20
Figure 20-21.
Current techniques for first-stage palliation of the hypoplastic left-heart syndrome.
A.
Incisions used for the procedure, 
incorporating a cuff of arterial wall allograft.
The distal divided main pulmonary artery may be closed by direct suture or with a patch.
B.
Dimensions of the cuff of the arterial wall allograft.
C.
D and E.
The procedure is completed 
by atrial septectomy and a 3- to 5-mm modified right Blalock shunt.
F.
a.
= artery.
(From Castaneda AR, Jonas RA, Mayer JE, et al.
Cardiac Surgery of the Neonate and Infant.
Philadelphia: 
W.B.
Saunders; 1994:371, with permission.
Copyright Elsevier.)
A
B 
C
D
EF
Homograft
Aorta 
Main pulmonary a.
64%, P = .01).
20-22).
Not all patients with HLHS require this three-stage pallia-
tive repair.
In this group, a 
two-ventricle repair can be achieved with reasonable outcome.
Technique of a bidirectional 
Glenn shunt.
(From Castaneda 
AR, Jonas RA, Mayer JE, et al.
Cardiac Surgery 
of the Neonate and Infant.
Philadelphia: W.B.
Saunders; 1994:376, with permission.
Outcomes for HLHS are still significantly worse 
than those for other complex cardiac defects.
DEFECTS THAT MAY BE PALLIATED OR 
REPAIRED
Ebstein’s Anomaly
Anatomy.
This is a rare defect, occurring in less than 1% 
of CHD patients.
The atrialized RV is usually 
thin and dilated.
There is commonly an 
ASD present, which results in a right-to-left shunt at the atrial 
level.
Occasionally, there is true anatomic pulmonary atresia 
or milder forms of RVOT obstruction.
Diagnosis.
The ECG may show right bundle-
branch block and right axis deviation.
A score of greater 
than 1 translates into uniformly fatal outcome.
Treatment.
720
SPECIFIC CONSIDERATIONS
UNIT II
PART II
Neonatal Ebstein’s anomaly is a separate entity.
Results.
Supraventricular 
tachycardia also has been problematic postoperatively.
There are few published reports of outcomes, due to the 
rarity of this defect.
Pathophysiology.
This causes left atrial enlargement and a left-to-right shunt via 
the patent foramen ovale.
Postnatally, the LV does not hypertrophy because it is not 
subjected to systemic afterload.
Clinical Manifestations and Diagnosis.
Surgical Repair.
20-24).
Figure 20-23.
The Senning operation.
A.
B.
C.
D.
(Reproduced with permission from D-Trans-
position of the great arteries.
In: Mavroudis C, Backer CL, eds.
Pediatric Cardiac Surgery.
2nd ed.
St.
Double-Outlet Right Ventricle
Anatomy.
The noncom-
mitted VSD (10%–20%) exists when the VSD is remote from 
the great vessels.
20-25).
Clinical Manifestations and Diagnosis.
Therapy.
In patients without pulmonary stenosis who 
Figure 20-24.
A.
A and B.
(Reproduced with permission from 
Backer CL, Idriss FS, Mavroudis C.
In: Mavroudis C, Backer CL, eds.
Arterial Switch.
Cardiac Surgery: State of the Art 
Review.
Vol.
5, no.
1.
Philadelphia: Hanley & Belfus; 
1991:108.
A.
Subaortic VSD without pulmonary stenosis.
B.
Subaortic VSD 
with pulmonary stenosis.
C.
Subpulmonary VSD (Taussig-Bing 
malformation).
D.
Doubly committed VSD.
E.
Noncommitted 
(remote) VSD.
F.
Intact interventricular septum.
(Adapted with permission from 
Zamora R, Moller JH, Edwards JE.
Double-outlet right ventricle.
Chest.
Tetralogy of Fallot
Anatomy.
20-26).
Pathologic specimen of the heart in a patient with 
tetralogy of Fallot.
(From Van Praagh et al,141 with permission.
© Elsevier Ltd.)
Pathophysiology and Clinical Presentation.
Occasion-
ally, aortography is necessary to delineate the coronary artery 
anatomy.
Treatment.
20-27).
Results.
This may be partly 
explained by a higher chance of postoperative complications in 
neonates.
Figure 20-27.
The free 
edge of the tricuspid leaflets is shown by dashed lines.
A.
B.
The same perspective without the 
outline of the tricuspid valve leaflets.
C.
D.
E.
The repair of the ventricular septal 
defect is completed.
ant.
= anterior;  
ML = mitral leaflet; post.
= posterior; TV = tricuspid 
valve.
4th ed.
Philadelphia: Elsevier, 2013, p 1384.
Copyright Elsevier.)
Parietal
extension Amputation
Transection
TV post.
leaflet
TV ant.
Clinical events were reported in 12% 
of patients at 35 years after repair.
Ventricular Septal Defect
Anatomy.
VSD refers to a hole between the LV and RV.
20-28).
The supracristal or outlet VSD results from a defect within 
the conal septum.
These are surrounded by muscle and can occur anywhere 
Figure 20-28.
Classic anatomic types of ventricular 
septal defect (VSD).
A.
Type I (conal, infundibular, 
supracristal, subarterial) VSD.
B.
Type II or peri-
membranous VSD.
C.
Type III VSD (atrioventricu-
lar canal type or inlet septum type).
D.
Type IV VSD 
(single or multiple).
(Reproduced with permission 
from Ventricular septal defect.
In: Mavroudis C, 
Backer CL, eds.
Pediatric Cardiac Surgery.
2nd ed.
St.
Pathophysiology and Clinical Presentation.
The size of 
the VSD determines the initial pathophysiology of the dis-
ease.
Diagnosis.
Treatment.
Repair of isolated VSDs requires the use of CPB with 
moderate hypothermia and cardioplegic arrest.
20-29).
Atrioventricular Canal Defects
Anatomy.
20-30).156
Pathophysiology and Diagnosis.
Left-to-right shunting predominates as 
long as pulmonary vascular resistance remains low.
(Reproduced from Feldt 
RH, Porter CJ, Edwards WD, et al.
Defects 
of the atrial septum and the atrioventricular 
canal.
In: Adams FH, Emmanouilides GC, 
eds.
Moss’ Heart Disease in Infants, Children, 
and Adolescents.
4th ed.
Baltimore: Lippincott 
Williams & Wilkins; 1989.
© Mayo Clinic ID 
#: CP1214116B-2.
Used with permission of 
Mayo Foundation for Medical Education and 
Research.)
Figure 20-29.
A.
Stay sutures have been placed to slightly evert the atrial wall.
Note that initially, the superior edge of this typical peri-
membranous defect is not visible.
B and C.
(Reproduced with permission 
from Walters HL, Pacifico AD, Kirklin JK: Ventricular septal defects.
In: Sabiston DC, Lyerly HK, eds.
Textbook of Surgery: The Biologic 
Basis of Modern Surgical Practice.
Philadelphia: W.B.
Saunders; 1997:2014.
Physical examination may reveal a right ventricular heave 
and a systolic murmur.
The management of patients with AV canal 
defects can be especially challenging.
Timing of operation is 
individualized.
Results.
IAA is classified based on the location of the interruption  
(Fig.
20-31).
RPA
Ao
IA LC
LS IA LC
LS
MPA
LPA
PDA IA
LC LS
PDA
A B C
Figure 20-31.
Anatomic types of interrupted aortic arch.
A.
Inter-
ruption distal to the left subclavian artery.
B.
Interruption between 
the left subclavian and left carotid arteries.
C.
Interruption between 
the left carotid and innominate arteries.
(Reproduced with permission from Jonas RA.
Interrupted aortic arch.
In: Mavroudis C, Backer CL, eds.
Pediatric 
Cardiac Surgery.
2nd ed.
St.
Louis: Mosby; 1994:184.)
Clinical Manifestations and Diagnosis.
Treatment.
However, complete surgical repair in infants with IAA 
is now preferable.
These infants 
should be managed with a Norwood procedure followed by a 
Fontan repair.
Results.
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C
ONGENITAL
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EART
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ISEASE
CHAPTER 20
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This page intentionally left blank 
Acquired Heart Disease
Shoichi Okada, Jason O.
Robertson,  
Lindsey L.
Saint, and Ralph J.
Damiano, Jr.
This discomfort may radiate to the left 
arm, neck, mandible, or epigastrium.
Left heart 
failure manifests as dyspnea, usually with exertion.
However, 
most cardiac pathologies do result in fatigue or exercise intoler-
ance of some degree.
Recent results 
for destination therapy have approached those of cardiac 
transplantation.
mitral stenosis.
Patients typically describe palpitations as a “skipped beat” 
or “racing heart”.
Clinically significant 
arrhythmias, however, require thorough investigation.
It results in an irregu-
lar, and at times, rapid heartbeat.
Syncope associated with heart disease results from abrupt 
reduction of cerebral perfusion.
Any episode 
of syncope warrants a thorough evaluation and search for the 
root cause.
Functional Disability and Angina.
With regard to heart fail-
ure, functional capacity is strongly correlated with mortality.
The general appearance of a patient is important in the 
clinical assessment.
II Comfortable at rest.
Slight limitation of physical 
activity.
Fatigue, palpitations, or dyspnea with 
ordinary physical activity.
III Comfortable at rest.
Marked limitation of physical 
activity.
Fatigue, palpitations, or dyspnea with 
less than ordinary physical activity.
IV Inability to carry out any physical activity.
Symptoms may be present at rest and increase 
with activity.
Angina occurs with 
strenuous, rapid, or prolonged exertion during 
work or recreation.
II Slight limitation of ordinary activity.
Walking more than 2 blocks or 
climbing one flight of stairs causes angina.
IV Inability to carry out any physical activity without 
discomfort.
Angina may be present at rest.
hypertrophy or parasternal heaves seen in right ventricular over-
load.
Murmurs 
are characterized by their location, timing, quality, and radia-
tion.
A rub 
due to pericardial friction is specific and virtually pathogno-
monic for pericarditis.
Auscultation of the lung fields may reveal rales in 
patients with pulmonary edema.
The work of breathing may also 
be assessed simply by observing the patient.
Jugular venous dis-
tention and hepatosplenomegaly are seen in right heart failure.
3–5 Pursue further testing if it will advance 
management.
Diagnostic Studies
Electrocardiogram and Chest X-ray.
Echocardiography.
Posterior structures such as the mitral 
valve and left atrium are particularly well visualized.
Radionuclide Studies.
In the 
past, planar imaging with three separate two-dimensional views 
of the heart were obtained.
Territories that do not show uptake at rest or during stress 
are likely to be nonviable scar.
This study is also useful in revealing 
hypokinetic segments of the myocardium.
Cardiac Catheterization.
Right-
sided pressures and structures are assessed in a similar fashion 
as in the left heart.
(Fig.
Multislice computed 
tomography (CT) imaging can be used to assess the coronary 
vasculature.
Cardiac catheterization angiography.
A.
Stenosis of 
right coronary artery indicated by the arrow.
B.
Still image of a 
normal left ventriculogram.
asystole and hypothermia.
The early bubble oxygenators have evolved into the modern 
membrane oxygenators.
Once the appropriate cannulations 
and connections are complete, CPB is commenced.
Venous 
return is initiated followed by arterial flow while monitoring 
systemic blood pressures.
Once 
the heart is decompressed and hemodynamics are acceptable, 
ventilation is stopped.
The oxygenator is adjusted to maintain 
a PaO2 of 150 mm Hg and normocarbia.
The venous return to the CPB machine is gradually 
reduced allowing the heart to fill.
Inotropic and vasopressor support may be 
used to augment cardiac function and treat hypotension.
Once 
CPB has been stopped and stable hemodynamics achieved, the 
cannulae are removed.
Generation of thrombin 
plays a major role in both thrombotic and bleeding phenomena 
during CPB.
Platelets are activated by the converging hemostatic pathways 
and are consumed.
This can be a problem particularly with the cerebral, 
renal, and mesenteric circulations.
There are controversies regarding the method (antegrade  
retrograde vs.
both), type (crystalloid vs.
blood), temperature 
(cold vs.
warm vs.
tepid), and interval (continuous vs.
inter-
mittent) of cardioplegia delivery.
The optimal combination is 
beyond the scope of this text.
However, most surgeons in the 
United States favor cold blood potassium cardioplegia.
The use of vein 
patches to repair the arteriotomy sites was described by Sen-
ning in 1961.
Beta-blockers are to be considered in patients 
with LV dysfunction and following MI or ACS.
The variety 
of presentations can make myocardial ischemia difficult to diag-
nose.
Typical angina is relieved by rest and/or use of sublingual 
nitroglycerin.
This 
may be silent and need not be preceded by angina.
The ischemic insults from CAD may lead to congestive 
heart failure.
The initial myocardial damage sets off a cascade 
of responses, both local and systemic.
Heart failure should be suspected in patients who present 
dyspnea, orthopnea, fatigue, and edema.
Arrhythmias may also be a sequela of CAD.
Ischemic eti-
ologies should be investigated in patients who present with new 
arrhythmias.
Coronary angiography is the primary diagnostic tool.
A stress ECG is frequently used as a screening tool 
with a high sensitivity.
The positive predict value is 90% in 
patients with ST-segment depression >1mm.
Some of the representative studies 
are summarized here.
The New York State Study (2005).
Of these, 
37,212 patients received a CABG and the others underwent a 
PCI.
Revascularization strategies, CABG vs.
CABG was performed on 86,244 patients and 103,549 
underwent PCI.
Operative Techniques and Results
Bypass Conduit Selection.
The most important criterion in 
conduit selection is graft patency.
The radial artery is another frequently used conduit.
This artery can also be harvested using an 
endoscopic technique.
745
Acquired Heart Disease
CHAPTER 21
Figure 21-2.
Coronary artery bypass grafting.
A.
B.
Anastomotic site is shown 
by the arrow.
Conventional Coronary Artery Bypass Grafting.
Tradi-
tionally, CABGs are performed with the patient lying supine 
through a median sternotomy.
After the patient is heparinized, 
cardiopulmonary bypass is initiated.
The aorta is cross-clamped 
and cardioplegia is delivered.
(Fig.
Once all grafts are in place, the patient is 
weaned from bypass.
The mortality and morbidity of the procedure itself has 
changed over time.
With OPCAB the heart is left beating.
(Fig.
This occlu-
sion causes temporary ischemia, and if not tolerated, coronary 
shunts can be employed.
Minimally Invasive Direct Coronary Artery Bypass.
Epicardial stabilizing device used during off-pump 
coronary anastomosis.
MIDCAB Results A review of 411 patients undergoing MID-
CAB quotes an operative mortality >1%.
Transmyocardial Laser Revascularization.
New Developments
Regenerative Medicine and Tissue Engineering.
Diastolic 
and continuous murmurs, on the other hand, are frequently 
pathologic in nature.
748
SPECIFIC CONSIDERATIONS
UNIT II
PART II
Table 21-7
Classification of cardiac murmurs.
Table 21-8
Hemodynamic alterations in cardiac murmur intensity.
INTERVENTION EFFECT
Respiration Right-sided murmurs increase with inspiration.
Left-sided murmurs increase with expiration.
Valsalva maneuver Most murmurs decrease in length and intensity.
The murmur of HCM becomes louder, and the 
murmur of MVP becomes louder and longer.
The murmurs of MR, VSD, and AI also increase with isometric exercise.
Systolic murmurs of 
atrioventricular valve regurgitation do not change.
The response in MVP is 
biphasic (softer then louder than control).
tissue valve prosthesis.
Current options for mechanical valve replacement include 
tilting disc valves and bileaflet valves.
Mechanical Valves.
The first bileaflet valve was introduced in 
1977.
21-4).
Tissue Valves.
21-5).
This effect is most pronounced in patients with small prosthetic 
Figure 21-4.
St.
Jude bileaflet mechanical valve.
(Photo repro-
duced with permission of St.
Jude Medical, Inc., St.
Paul, MN.
All 
rights reserved.)
Figure 21-5.
Edwards’ Magna Ease stented porcine bioprosthesis.
Homografts.
Autografts.
Valve Repair.
MITRAL VALVE DISEASE
Mitral Stenosis
Etiology.
Pathology.
21-6).
Mitral stenosis.
The thickened, fused leaflets of the 
diseased mitral valve are viewed through a left atriotomy.
(Image 
courtesy of the Centers for Disease Control and Prevention, Edwin 
P.
Ewing, Jr.)
752
SPECIFIC CONSIDERATIONS
UNIT II
PART II
against a fixed obstruction.
Clinical Manifestations.
The murmur, classically known as the 
auscultatory triad, is best heard at the apex.
Hemoptysis, and pulmonary edema may develop 
as the venous hypertension worsens.
Diagnostic Studies.
In most cases further examinations are not necessary.
Pathophysiology.
Clinical Manifestations.
As mentioned previously, patients may present with AF due to 
dilatation of the left atrium.
Findings consistent with pulmonary 
hypertension frequently indicate late-stage disease.
Diagnostic Studies.
However, TTE 
may underestimate lesion severity due to inadequate views of 
the color flow jet.
Commissurotomy.
Upon opening the left atrium, the MV is 
visualized and the left atrium is examined for thrombus.
The anterior leaflet is grasped with forceps 
and brought through its complete range of motion.
Occasionally, the leaflets can be debrided carefully 
to increase mobility.
Valve replacement may be more appropri-
ate if extensive secondary mobilization is required.
21-7).
Mitral Valve Repair.
Mitral valve replacement.
A St.
Jude bileaflet 
mechanical valve is viewed through a left atriotomy.
5
756
SPECIFIC CONSIDERATIONS
UNIT II
PART II
intraoperative assessment of valvular pathology.
The 
commissures are examined for evidence of prolapse, fusion, 
and malformation.
Leaflet 
perforations are generally repaired primarily, or with a peri-
cardial patch.
The degree of annular dilation is also noted.
Recent trends have been toward leaflet preservation.
One of the mainstays of MV repair is triangular resection 
of the posterior leaflet.
If focal insufficiency 
is identified in other areas, additional procedures are performed.
Chordal shortening 
has generally been abandoned in favor of chordal replacement.
While some groups report excellent late 
results, its use remains controversial.
Mitral valve repair.
AORTIC VALVE DISEASE
Aortic Stenosis
Etiology.
21-9).
Pathology.
Pathophysiology.
Aortic stenosis.
(Image courtesy of the Centers for Disease 
Control and Prevention, Edwin P.
Diagnostic Studies.
Any abrupt change in signs or symptoms in 
a patient with AS is an indication for TTE examination.
Additional preoperative studies may be necessary in some 
patients.
Pathology.
Depending on the severity 
of AI, the left atrium may undergo dilation and hypertrophy as 
well.
There are also many primary valvular diseases that cause 
AI, generally in  association with AS.
Pathophysiology.
115,117
Eventually, left ventricular compensatory mechanisms fail 
and systolic dysfunction ensues.
Clinical Manifestations.
Diagnostic Studies.
Aortic Valve Replacement.
The annulus is thoroughly debrided of calcium deposits.
After 
the calcium has been removed, the ventricle is copiously irri-
gated with saline.
At this point, the annulus is sized and an 
appropriate prosthesis is selected.
21-10).
For 
Figure 21-10.
Aortic valve replacement.
The stented porcine bio-
prosthesis as viewed through an aortotomy.
hemorrhagic complications for biological and mechanical 
valves, respectively.
Aortic Valve Repair.
90%, 
P=0.03; and 100% vs.
77%, P=0.002, respectively) at midterm 
follow-up.
123
Ross Procedure.
Transcatheter Aortic Valve Replacement.
The transaortic approach is usually done through a min-
isternotomy.
30.7%, P = <0.001), 
the rate of death from cardiovascular causes (41.9% vs.
19.6%, 
p = <.001), and the rate of repeat hospitalization (44.1% vs.
4.5%, P = 0.04), major vascular complications (16.8% vs.
2.2%, P = <.001), and major bleeding events (22.3% vs.
5 days, 
P = <0.001), and a shorter index hospitalization (8 vs.
12 days, 
P = <.001).
4.3%, P = 0.04), and major vascular complications (11.3% 
vs.
3.5%, P = <.001) at one year.
TRICUSPID VALVE DISEASE
Tricuspid Stenosis and Insufficiency
Etiology.
This is most commonly caused by MV disease.
Pathology.
Clinical Manifestations.
In the absence of pulmonary hypertension, 
dyspnea is not a prominent feature of tricuspid disease.
Diagnostic Studies.
Indications for Operation.
As an isolated lesion, mild or 
moderate TV disease does not require surgical correction.
Operative Techniques and Results.
Most surgeons favor ring over suture 
annuloplasty.
The choice of 
prosthetic valve is also somewhat controversial.
Etiology and Pathophysiology
Heart failure can be classified as acute vs.
chronic, genetic vs.
acquired, left-sided vs.
right-sided and systolic vs.
diastolic 
dysfunction.
The underlying causes and treatments for each of 
these vary considerably.
It is most successful when treating 
hibernating as opposed to infarcted myocardium.
Entry criteria included an EF ≤35% with 
CAD and anatomy suitable for CABG.
16%, p<0.0001).
77%, P = 0.02).
71%, 
P = NS).
53%, 
p<0.05), as well as worse 5-year freedom from recurrent CHF 
(85% vs.
3% in patients without significant dyssynchrony 
(p<0.001).
with end-stage heart failure who present with low EF and lim-
ited myocardial viability.
Mitral valve repair is the procedure of choice when surgery 
is indicated for secondary MR.
Outcomes from surgery vary between centers and amongst 
patients in this heterogeneous group.
This usually occurs 4 to 8 weeks 
following the infarct.
The rest are inferior in location and the result of circumflex 
or right coronary occlusion.
Clinical Presentation and Diagnosis.
Rupture is extremely uncommon.
Patients generally present for coronary artery bypass or during 
evaluation of CHF or arrhythmias.
21-11A & B).
Figure 21-11.
Surgical ventricular restoration of a ventricular aneurysm using the Dor Procedure.
A.
B.
These patients should also be candidates 
for repair of any other concomitant cardiac disease.
With respect to VT, Dor et al.
Mechanical Circulatory Support
Intra-aortic Balloon Pump.
The 
device is inserted percutaneously through the femoral artery 
into the thoracic aorta.
This is the most serious complication of IABP 
placement.
Ventricular Assist Device Indications and Cannula-
tion.
Left Ventricular Assist Devices.
The first generation 
LVADs were pulsatile devices.
These devices are 
smaller, quieter, and durable enough for long term support.
21-12A & B, 21-13A & 
B).
These devices are com-
monly used in either post-MI or postcardiotomy heart failure.
Bridge to Recovery.
The HeartMate II LVAD viewed from the (A) outside and (B) inside.
The device is an axial flow, rotary pump that produces 
no pulsatile action.
(Images reprinted with the permis-
sion of Thoratec Corporation.)
AB
Figure 21-13.
The HeartWare HVAD system.
A.
B.
Similar to the HeartMate II, it can deliver a flow rate of up to 10 L/min.
At 3 months, 81% of patients were in class I 
or II heart failure.
Destination Therapy.
24%, P=0.008) and adverse event rates were significantly lower.
There is currently no destination 
therapy device for biventricular failure.
Unlike ven-
tricular assist devices, the TAH replaces the entire heart.
Medical Management.
Restoration of normal sinus rhythm has several potential 
benefits over other strategies 198-200.
Indications for Surgical Management.
The Cox-Maze IV Procedure.
In 2002, the Cox-Maze IV, 
was introduced.
21-14).
Results from the Cox-Maze IV procedure have been excel-
lent.
The Cox-Maze IV Lesion Set.
A.
B.
(From Weimar T, Bailey MS, Watanabe Y, et al.
J Interv Card Electrophysiol.
2011;31: 
47-54.
Although, 
there is seldom justification for limited lesion sets in experienced 
hands.
Pulmonary vein isolation is ubiquitously performed, and the 
LAA is often excised.
Pulmonary Vein Isolation.
These include staplers and epicardial clips that 
can be placed without the need for CPB.
However, it may be monophasic or biphasic in up to 
50% of patients.
Table 21-16
Features of acute pericarditis.
Treatment.
The preferred treatment depends on the underly-
ing cause of the pericarditis.
Some patients may require judicious use of 
steroids or IV antibiotics.
More 
commonly, surgical intervention is required to manage recur-
rent disease.
Relapsing 
pericarditis normally responds to a longer course of NSAIDS 
± colchicine.
No perioperative deaths were observed, and 
only 2 patients (3%) had major complications.
Chronic Constrictive Pericarditis
Etiology, Pathology, and Pathophysiology.
In many 
patients, these symptoms develop insidiously over a course 
of years.
Clinical and Diagnostic Findings.
Several findings are characteristic on noninvasive and 
invasive testing.
CVP is often elevated 15 to 20 mm Hg or 
higher.
Pericardial adhesions may also 
be seen on tagged cine MRI studies.
Surgical Treatment.
These patients 
are best treated with medical therapy alone.
Surgical Results.
Despite the risks, many patients experience significant 
benefits from surgical treatment.
Clinical Presentation.
Arrhythmias and pericardial effusions are very rare in 
this population.
Diagnosis and Characterization of Cardiac Masses.
Delayed enhance-
ment cMRI is the best modality to separate these two entities.
Myxoma
Pathology and Genetics.
18%) 
or one of the ventricles (25% vs.
0%), more often multicentric 
(33% vs.
6%) and more likely to recur (20% vs.
3%).238 They 
also present earlier at an average age of 24 years old (range  
4–48 years).
Pathophysiology.
21-15).
Treatment.
In order to prevent 
recurrence, a full thickness excision of the attachment site is 
Figure 21-15.
Massive left atrial myxoma.
A.
B.
The 
resected specimen.
The neck of the mass that was obstructing the mitral orifice is clearly delineated.
Rhabdomyomas are myocardial hamar-
tomas that are often multicentric in the ventricles.
They frequently invade nearby car-
diac structures and are multicentric in 60% of cases.
Workup is simi-
lar to other cardiac tumors.
Treatment is generally with com-
bined chemotherapy and radiation and is rarely effective.
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This page intentionally left blank 
Thoracic Aneurysms and Aortic 
Dissection
Scott A.
LeMaire, Raja R.
Gopaldas, and Joseph S.
22-1).
The proximal aortic segment includes the ascending aorta and 
the transverse aortic arch.
The ascending aorta begins at the aor-
tic valve and ends at the origin of the innominate artery.
The aortic 
root joins the tubular portion of the ascending aorta at the sino-
tubular ridge.
The transverse aortic arch is the area from which 
the brachiocephalic branches arise.
The distal aortic segment 
includes the descending thoracic aorta and the abdominal aorta.
Aneurysms can be localized to a single 
aortic segment, or they can involve multiple segments.
Fusiform 
aneurysms are more common and can be described as symmetri-
cal dilatations of the aorta.
Saccular aneurysms are localized 
outpouchings of the aorta.
These include rupture, which is usually a fatal event.
Therefore, 
aggressive treatment is indicated in all but the poorest surgical 
candidates.
2 The clinical progression of an aortic aneurysm is continued 
expansion and eventual rupture.
5 Ascending aortic aneurysms that are symptomatic or  
>5.5 cm should be repaired.
This threshold is lowered for 
patients with connective tissue disorders.
Figure 22-1.
Illustration of normal thoracic aortic anatomy.
nancy.
An emergency operation is performed for any patient in 
whom a ruptured aneurysm is suspected.
Patients with thoracic aortic aneurysm often have coexist-
ing aneurysms of other aortic segments.
Therefore, staged repair of multiple 
aortic segments often is necessary.
Causes and Pathogenesis
General Considerations.
Any alteration in this delicate 
balance can lead to aortic disease.
Thoracic aortic aneurysms have a variety of causes  
(Table 22-1).
Hemodynamic factors clearly contribute to the process 
of aortic dilatation.
Turbulent blood 
flow is also recognized as a factor.
Hemodynamic 
derangements, however, are only one piece of a complex puzzle.
Atherosclerosis is commonly cited as a cause of thoracic 
aortic aneurysms.
Nonspecific Medial Degeneration.
Nonspecific medial 
degeneration is the most common cause of thoracic aortic dis-
ease.
The underlying causes of medial 
degenerative disease remain unknown.
Aortic Dissection.
This event profoundly weakens the outer wall.
Genetic Disorders.
Loeys-Dietz Syndrome Loeys-Dietz syndrome is phenotypi-
cally distinct from Marfan syndrome.
It is characterized as an 
aneurysmal syndrome with widespread systemic involvement.
The subtypes represent differing defective steps of 
collagen production.
Infection.
Primary infection of the aortic wall resulting in 
aneurysm formation is rare.
The ascend-
ing aorta and arch are the most commonly involved areas.
Aortitis.
The cause of the intense inflammatory reaction is unknown.
Systemic autoimmune disorders also cause thoracic aor-
titis.
Pseudoaneurysms.
As expected, aortic diam-
eter was a strong predictor of rupture, dissection, and mortality.
One common clinical scenario deserves special attention.
The clinical history of these ectatic ascend-
ing aortas has been defined by several studies.
Therefore, patients often are asymptom-
atic at the time of diagnosis.
Local Compression and Erosion.
Initially, aneurysmal 
expansion and impingement on adjacent structures causes mild, 
chronic pain.
Pulmonary or air-
way erosion presents as hemoptysis.
Compression and erosion 
of the esophagus cause dysphagia and hematemesis, respec-
tively.
Jaundice due to compression of the liver or porta 
hepatis is uncommon.
Aortic Valve Regurgitation.
In response 
to the volume overload, the heart remodels and becomes 
increasingly dilated.
Distal Embolization.
Rupture.
Whenever possible, 
all results should be compared to those of prior imaging studies.
Plain Radiography.
Ascending aortic 
aneurysms produce a convex shadow to the right of the cardiac 
silhouette.
Aortic root aneurysms, for 
example, often are hidden within the cardiac silhouette.
22-2).
Echocardiography and Abdominal Ultrasonography.
Computed Tomography.
A.
Anteroposterior 
view.
B.
Lateral view.
Magnetic Resonance Angiography.
Invasive Aortography and Cardiac Catheterization.
Proximal aortography carries a 0.6% to 1.2% 
risk of stroke.
Treatment
Selecting the Appropriate Treatment.
None-
theless, endoluminal stenting is approved by the U.S.
Determination of the Extent and Severity of Disease.
A CT 
scan can reveal detailed information about aortic calcification 
and luminal thrombus.
These details are important in preventing 
embolization during surgical manipulation.
Indications for Operation Thoracic aortic aneurysms are 
repaired to prevent fatal rupture.
In contrast, patients who present 
with symptoms may need urgent operation.
Symptomatic 
patients are at increased risk of rupture and warrant expedi-
tious evaluation.
The majority 
of hybrid approaches involve repairing the aortic arch.
These patients also have a mortal-
ity rate that is significantly higher than normal.
Operative Repair.
The spectrum of operations 
(Fig.
22-4) ranges from simple graft replacement of the tubular 
portion of the ascending aorta (Fig.
Mechanical prosthe-
ses necessitate following a lifelong anticoagulation regimen.
Illustrations of proximal aortic repairs in which the native aortic root is left intact.
A.
Graft replacement of the tubular portion 
of the ascending aorta with the aortic arch left intact.
B.
C.
A modified hemiarch with additional graft replacement of the innominate artery.
D.
Patch repair of the aortic arch.
E.
F.
G.
The elephant 
trunk approach with a concomitant island brachiocephalic artery reattachment.
Contemporary Y-graft arch repairs include H.
the single 
Y-graft approach, I.
the double Y-graft approach, J.
the elephant trunk approach with a single Y-graft, and K.
the elephant trunk approach 
with a double Y-graft.
The aortic wall was then wrapped around the graft 
to establish hemostasis.
22-6).
22-4).
This permits 
the distal anastomosis to be brought forward and aids in hemo-
stasis.
aortic 
root aneurysm.
B.
The diseased aortic tissue (including the sinuses of Valsalva) is excised.
Buttons of surrounding tissue are used to mobi-
lize the origins of the coronary arteries.
C.
A synthetic graft is sewn to the distal ascending aorta with continuous suture.
D.
E.
F.
The annular sutures 
are then tied.
G.
Each of the three commissures is then secured near the top of the graft.
H.
The supra-annular aortic tissue is sewn to the graft 
in continuous fashion.
I.
J.
The 
two aortic grafts are sewn together with continuous suture.
K.
L.
22-7).
Illustration of a modified Bentall procedure for 
replacing the aortic root and ascending aorta.
by using a hybrid endovascular approach (Fig.
22-8) in certain 
settings.
This provides constant perfusion of the brain and 
other vital organs during the repair.
Although its use was 
cumbersome in the past, contemporary ACP techniques (Fig.
Upon initiation, cold blood 
is delivered into the brain via the right common carotid artery.
Illustration of a contemporary Y-graft approach to total arch replacement for aortic arch aneurysm.
A.
The proximal portions 
of the brachiocephalic arteries are exposed.
B.
The proximal ends of the transected brachiocephalic arteries are ligated.
C.
D.
The proximal aspect of the Y-graft is clamped.
This directs 
flow from the axillary artery to all three brachiocephalic arteries.
The arch is then replaced with a collared elephant trunk graft.
E.
The collared 
graft accommodates any discrepancy in aortic diameter.
F.
(Adapted from LeMaire et al,73 Fig.
2.
Used with permission.
Copyright The Society of Thoracic Surgeons.) 
arena, although they remain controversial.
22-10).
The branches 
of the graft are then sewn to the arch vessels.
Once the arch 
is “debranched,” the arch aneurysm can be excluded with 
an endograft.
Commonly, a zone 0 approach (Fig.
Illustration of Borst’s elephant trunk technique using a contemporary Y-graft approach.
A.
A section of the graft is left sus-
pended within the proximal descending thoracic aorta.
B.
Stage 2: The distal repair uses the floating “trunk” for the proximal anastomosis.
C.
An alternate “hybrid” approach may be used in patients with less extensive distal aortic disease.
Endovascular stent grafts are placed within 
the elephant trunk to complete the repair.
(Used with permission of Baylor College of Medicine.)
Figure 22-9.
A.
B.
(Images adapted from Gravlee GP, Davis RF, Stammers AH, et al, eds.
Cardiopulmonary Bypass: Principles 
and Practice, 3rd ed.
Philadelphia: Lippincott Williams & Wilkins; 2008, Chap.
32, Fig.
1A,B.
Illustration of a hybrid arch repair.
A.
B.
C.
The completed repair.
The proximal landing zone of the endograft is within zone 0.
Zone 0 
includes the ascending aorta and the origin of the innominate artery.
Zone 1 includes the origin of the left common carotid artery.
Zone  
2 includes the left subclavian artery origin.
22-12).
Extent IV repairs begin at the 
diaphragmatic hiatus and often involve the entire abdominal aorta.
Descending thoracic aortic aneurysms are repaired through 
a left thoracotomy.
Clamping the descending thoracic aorta causes ischemia 
of the spinal cord and abdominal viscera.
(Reproduced with permission from Coselli et al,232 
Fig.
1.
Copyright The Society of Thoracic Surgeons.)
operations.
A.
Stage 1: The distal aorta is repaired through a left thoracoabdominal approach.
Proximal intercostal arteries are oversewn.
B.
C.
Stage 2: The proximal aorta is repaired through a median sternotomy.
The aortic arch is opened under hypothermic circulatory arrest.
The 
“trunk” is pulled out and used to replace the aortic arch and ascending aorta.
This eliminates the need for a new distal anastomosis and simpli-
fies the procedure.
Circulatory arrest and operative time, along with their attendant risks, are reduced.
D.
The completed two-stage repair of 
the entire thoracic aorta.
Ann Thorac Surg 2005; 80:2166, Figs.
2, 3, 7, and 8.
The most common complication of extensive 
repairs is pulmonary dysfunction.
Injury 
to the esophagus during the proximal anastomosis can have 
catastrophic consequences.
Myo-
cardial perfusion is maintained through the carotid-
subclavian bypass graft.
(Reproduced with permission 
from Jones et al,96 Fig.
2.
If the femoral artery will not accommodate the nec-
essary sheath, then an iliac artery is exposed.
The endograft is then advanced 
into the aorta and suitably positioned.
An aortogram is then 
taken to rule out any endoleak, and protamine is administered.
This allows the distal end of the trunk to be identified via fluo-
roscopy.
Occasionally, the wire must be advanced in an antegrade 
fashion from a brachial artery.
Hybrid Repair As discussed previously, hybrid aortic repairs are 
extremely heterogeneous.
22-16).
805
T
HORACIC
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AND
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ORTIC
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ISSECTION
CHAPTER 22
Figure 22-15.
Illustration of a hybrid repair of the proximal descending thoracic aorta.
A.
B.
After the bypass is completed, the left subclavian artery is ligated proximal to the graft.
C.
(Reproduced with permission from Bozinovski  
et al,103 Figs.
9, 10, and 11.
dure or develop over time.
As the separation of the layers of the media propagates, 
at least two channels form (Fig.
The dissecting mem-
brane separates the true and false lumens.
The extensive disruption of the aortic wall has severe 
anatomic consequences (Fig.
22-18).
Dissection vs.
Aneurysm.
The relationship between dissec-
tion and aneurysmal disease requires clarification.
In most cases, dissection occurs in 
patients without aneurysms.
The subsequent progressive dilata-
tion of the weakened outer aortic wall results in an aneurysm.
The overused term dissecting aneurysm 
should be reserved for this specific situation.
Classification.
Normal aorta Aortic dissection Intramural hematoma Penetrating aortic ulcer
Figure 22-17.
Illustration of longitudinal sections of the aortic wall and lumen.
Blood flows freely downstream in normal aortic tissue.
In each of these conditions, the outer aortic wall is severely 
weakened and prone to rupture.
Dissection is considered 
808
SPECIFIC CONSIDERATIONS
UNIT
 
II
Part II
Figure 22-18.
A.
Ascending aortic rupture and cardiac tam-
ponade.
B.
Disruption of coronary blood flow.
C.
Injury to the aortic valve causing regurgita-
tion.
D, E, and F.
Compromised blood flow to 
branch vessels, causing ischemic complications.
(Images adapted from Creager MA, Dzau VS, 
Loscalzo J, eds.
Vascular Medicine.
Philadelphia: 
WB Saunders; 2006.
Copyright © Saunders/
Elsevier, 2006.
Fig.
Figure 22-20 provides an algorithm 
for the management of acute aortic dissection.
The subacute period 
encompasses days 15 through 60 after the initial tear.
22-17).
Eventually, the ulcer can penetrate the aortic 
wall, which leads to dissection or rupture.
Ultimately, 
any condition that weakens the aortic wall increases the risk of 
aortic dissection.
The location of the pain often indicates which aortic 
segments are involved.
22-18 and  
Table 22-5).
Ascending aortic dissection can directly injure the aortic 
valve, causing regurgitation.
Patients with acute aortic 
valve regurgitation may report worsening dyspnea.
The sudden disruption of 
coronary blood flow can cause a myocardial infarction.
(Repro-
duced with permission from Creager 
MA, Dzau VS, Loscalzo J, eds.
Vascu-
lar Medicine.
Philadelphia: WB Saun-
ders; 2006.
Copyright © Saunders/
Elsevier, 2006, Fig.
35-2).
Free rupture into the pericardial space produces rapid tampon-
ade and is generally fatal.
Ascending aortic
dissection (Stanford A or
DeBakey I or II)?
Anti-impulse therapy
(beta blockers),
blood pressure control
Aortic dissection?
Complicated descending
aortic dissection 
(malperfusion, rupture)?
Management of acute aortic dissection
Ascending aortic
dissection (Stanford A or
DeBakey I or II)?
Figure 22-20.
Algorithm used to facilitate decisions regarding treatment of acute aortic dissection.
For classification purposes (acute vs.
subacute 
vs.
Unfortunately, laboratory studies are of little help in diag-
nosing acute aortic dissection.
22-21).
Treatment
Initial Assessment and Management.
22-20).
The goals of pharmacologic treatment are to stabi-
lize the dissection and prevent rupture.
Patients are monitored closely in an intensive care unit.
Central 
venous catheters ensure reliable IV access for delivering vaso-
active medications.
Pulmonary artery catheters are reserved for 
patients with severe cardiopulmonary dysfunction.
Particular attention is paid to changes in 
neurologic status, peripheral pulses, and urine output.
Reductions in dP/dT are achieved by lowering both car-
diac contractility and blood pressure.
A.
An acute DeBakey type I aortic dissection.
The dissecting membrane appears 
wavy (arrows) in the early phase of dissection.
Here, the true lumen of the proximal aorta can be seen to be extensively compressed.
This may 
lead to malperfusion of the heart.
B.
A chronic DeBakey type III aortic dissection.
Doses of beta antag-
onists are titrated to achieve a heart rate of 60 to 80 bpm.
Nitro-
prusside, a direct vasodilator, can be administered once beta 
blockade is adequate.
These drugs inhibit renin release, which 
may improve renal blood flow.
22-22).
Also, it allows the surgeon to carefully 
inspect the aortic arch for intimal tears.
A polyester tube graft 
is sutured to the distal aortic cuff.
This is probably due to the 
extensive coverage of the intercostal vessels by the stent-graft.
Illustration of proximal aortic repair for acute ascending aortic dissection.
A.
This repair requires a median sternotomy and 
cardiopulmonary bypass.
22-8).
B.
The dissecting membrane is removed to expose the true lumen.
C.
D.
E.
F.
G.
(Reproduced with permission 
from Creager MA, Dzau VS, Loscalzo J, eds.
Vascular Medicine.
Philadelphia: WB Saunders; 2006.
Copyright © Saunders/Elsevier, 2006, 
Fig.
In most 
respects, the operation is similar to that for acute dissection 
repair.
Therefore, patients are continually reassessed for new 
complications.
Long-term pharmacologic therapy is important for patients 
with chronic aortic dissection.
The 
first surveillance scan is obtained approximately 6 weeks after the 
onset of dissection.
Acute malperfusion syndromes also warrant intervention.
In the recent past, visceral and renal malperfusion were consid-
ered indications for operation.
When the endovascular approach is unavailable 
or unsuccessful, surgical options can be used.
However, in 
acute cases, open surgery is associated with poor outcomes.
Therefore, endovascular intervention is the preferred initial 
approach in such cases.
Placement of a stent graft in the true lumen of the aorta 
can resolve a “dynamic” malperfusion.
However, these patients remain at risk of further complication or 
future reintervention.
An aortogram is taken, and the intimal tear is 
identified.
A stent graft approximately 10% wider in diameter than the 
true lumen is selected for these cases.
The 
 distal half also may be replaced if it exceeds 4 cm in diameter.
When an endovascular approach 
is unavailable or unsuccessful, open surgery is necessary.
22-23).
Asymmet-
ric expansion of the false lumen can create wide separation of 
the renal arteries.
Illustration of distal aortic repair of a chronic dissection.
A.
Thoracoabdominal incision.
B.
Extent II thoracoabdominal aortic 
aneurysm resulting from chronic aortic dissection.
C.
The isolated 
segment of aorta is opened by using electrocautery.
D.
The dissecting membrane is excised, and bleeding intercostal arteries are oversewn.
E.
F.
G.
H.
Cold 
crystalloid is delivered to the renal arteries.
The critical intercostal arteries are reattached to an opening cut in the graft.
I.
A second oval opening is fashioned in the graft 
adjacent to the visceral vessels.
Selective perfusion of the visceral arteries continues during their reattachment to the graft.
A separate anas-
tomosis is often required to reattach the left renal artery.
J.
The final anastomosis 
is created between the graft and the distal aorta.
(Reproduced with permission from Creager MA, Dzau VS, Loscalzo J, eds.
Vascular Medicine.
Philadelphia: WB Saunders; 2006.
Copyright © Saunders/Elsevier, 2006, Fig.
35-8A–J.)
rates and acceptable morbidity rates.
A meta-
analysis conducted by Koullias and Wheatley82 of data from  
Figure 22-23.
Open Repair of Descending Thoracic and Thoracoabdomi-
nal Aortic Aneurysms.
For malperfusion of the visceral or 
renal arteries, an endovascular approach is ideal.
Malperfusion was 
present in one patient; this patient had an open fenestration pro-
cedure.
A substantial number of patients (n = 7, 22%) had con-
nective tissue disorders.
Green, MPH, and Stephen 
N.
Palmer, PhD, ELS, for editorial assistance; Scott A.
Weldon, 
MA, CMI, and Carol P.
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HORACIC
 A
NEURYSMS
 
AND
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ORTIC
 D
ISSECTION
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Arterial Disease
Peter H.
Approximately 
30% of vascular patients will be diabetic.
A history of prior and 
current smoking status should be noted.
Only 5% of patients with claudication will need 
intervention because of disabling extremity pain.
The 
5-year mortality of a patient with claudication approaches 
30%.
Symptoms persisting longer than 24 hours constitute 
a stroke.
The patient fears eating because of the pain, avoids 
food, and loses weight.
It should also be examined for 
the presence of bruits.
The differential diagnosis is a transmitted 
murmur from a sclerotic or stenotic aortic valve.
The carotid is 
palpable deep to the sternocleidomastoid muscle in the neck.
Palpation, however, should be gentle and rarely yields clinically 
useful information.
It is usually easily palpable in the axilla and medial upper arm.
The radial artery is 
palpable at the wrist anterior to the radius.
Palpation of the popliteal artery is a bimanual tech-
nique.
The posterior tibial pulse is detected 
by palpation 2 cm posterior to the medial malleolus.
Note should also be made 
of nail changes and loss of hair.
A change in pulse 
quality, aneurysmal enlargement, or a new bruit should be care-
fully noted.
Noninvasive Diagnostic Evaluation of the 
Vascular Patient
Ankle-Brachial Index.
The ABI is determined in the following ways.
23-1).
Normal is more than 1.
Those with gangrene 
have an ABI of less than 0.3.
These ranges can vary depending 
on the degree of compressibility of the vessel.
The test is less 
reliable in patients with heavily calcified vessels.
Segmental Limb Pressures.
This data can then be used to infer the level of the occlu-
sion.
The low thigh pressure should be 
equivalent to brachial pressures.
Subsequent pressures should 
fall by no more than 10 mmHg at each level.
Noncompressible arter-
ies yield ankle systolic pressures ≥250 mmHg and ABIs >1.40.
False-positive results with the TBI are 
unusual.
Figure 23-1.
Calculating the ankle-brachial index (ABI).
23-2).
Radiologic Evaluation of the Vascular Patient
Ultrasound.
B-mode ultrasonography provides black and white, 
real-time images.
Calci-
fication in atherosclerotic plaques will cause acoustic shadow-
ing.
B-mode ultrasound probes cannot be sterilized.
Experience is needed to 
obtain and interpret images accurately.
Computed Tomography Angiography.
It depends on intrave-
nous infusion of iodine-based contrast agents.
femoral
0.75
0.50
0.25
0.25
0.00
149 Brachial
0.66 U.
thigh
L.
832
SPECIFIC CONSIDERATIONS
UNIT II
PART II
slices.
23-3).
This technology has been advanced as a consequence of aortic 
endografting.
23-4).
23-5).
Patients with 
claustrophobia may require sedation to be able to complete the 
test.
Diagnostic Angiography.
Diagnostic angiography is consid-
ered the gold standard in vascular imaging.
Nevertheless, contrast angiography still remains in 
A                 B
Figure 23-3.
A.
B.
A 53-year-old male with occluded right common iliac artery (double arrows).
Figure 23-4.
833
Arterial Disease
CHAPTER 23
widespread use.
The imaging system and the contrast agent are used 
to opacify the target vessel.
There are several considerations 
when relying on angiography for imaging.
DSA also allows for real-time video replay (Fig.
23-6).
Magnetic resonance angiogram of aortic arch and 
carotid arteries.
Figure 23-6.
Needles and Access
Needles are used to achieve percutaneous vascular access.
The 
size of the needle will be dictated by the diameter of the guide-
wire used.
Most often, an 18-gauge needle is used, as it will 
accept a 0.035-inch guidewire.
A 21-gauge micropuncture nee-
dle will accept a 0.018-inch guidewire.
Femoral arterial puncture is the most common site for 
access.
The single-wall puncture technique requires a sharp, 
beveled needle tip and no central stylet.
Retrograde femoral access is the most common arterial 
access technique (Fig.
23-7).
The artery is accessed with a micropuncture needle just 
proximal to the antecubital crease.
Guidewires
Guidewires are used to introduce, position, and exchange cath-
eters.
A guidewire generally has a flexible and stiff end.
In 
general, only the flexible end of the guidewire is placed in the 
vessel.
Guidewires come in different maximum transverse diam-
eters, ranging from 0.011 to 0.038 inches.
The stiffness of the guidewire is also an important charac-
teristic.
Stiff wires allow for passage of large aortic stent graft 
devices without kinking.
They are also useful when trying to 
perform sheath or catheter exchanges around a tortuous artery.
An example of a stiff guidewire is the Amplatz wire.
The 
coating is primed by bathing the guidewire in saline solution.
Figure 23-7.
A.
Antegrade femoral artery access.
B.
Brachial artery approach.
Guidewires also come in various tip configurations.
The Rosen wire has a soft curled end, which makes it 
ideal for renal artery stenting.
The soft curl of this wire prevents 
it from perforating small renal branch vessels.
The sheath acts to protect the vessel 
from injury as wires and catheters are introduced (Fig.
23-8).
Sheaths are sized by their inner diameter.
The multiple shapes permit access to ves-
sels of varying dimensions and angulations.
23-9).
Besides length and diameter, 
Figure 23-8.
Low-compliance balloons are the 
mainstay for peripheral intervention.
Fre-
quently, several inflations are required to achieve a full profile 
of the balloon.
They serve to buttress collapsible vessels and help prevent 
atherosclerotic restenosis.
Self-expanding stents (Fig.
The self-expanding stent is mounted on a central shaft and is 
placed inside an outer sheath.
It relies on a mechanical spring-
like action to achieve expansion.
In this way, self-expanding stents are more difficult to place 
with absolute precision.
There are several advantages related 
to self-expanding stents.
This makes these stents ideal 
for placement in the internal carotid artery.
23-11).
The most exciting area of development in stents is the 
evolution of drug-eluting stents (DES).
Covered stents have been designed 
Figure 23-9.
A.
An artery with luminal 
narrowing caused by plaque.
B.
C.
The plaque is com-
pressed with widened flow lumen as the result 
of balloon angioplasty.
837
Arterial Disease
CHAPTER 23
Figure 23-10.
Figure 23-11.
In a balloon-expandable stent, the stent is pre-
mounted on a balloon catheter.
The balloon stretches the stent 
members beyond their elastic limit.
The stent is deployed by full 
balloon expansion.
23-12).
Stroke due to carotid bifurcation occlusive disease is usu-
ally caused by atheroemboli (Fig.
23-13).
The carotid bifurca-
tion is an area of low flow velocity and low shear stress.
23-14).
Crescendo TIAs refer to a syndrome comprising 
Figure 23-12.
A stent graft is a metal 
stent covered with fabric that is com-
monly used for aneurysm exclusion.
It is implied that these are due to severe 
Figure 23-13.
839
Arterial Disease
CHAPTER 23
extracranial disease and poor intracranial collateral recruitment.
When a neurologic deficit lasts longer than 
3 weeks, it is considered a completed stroke.
This partial blindness usually lasts for a few minutes and then 
resolves.
Monocular blindness progressing over a 20-minute period sug-
gests a migrainous etiology.
In 
BA
Sectional view
Low
shear
region
High shear
region
Figure 23-14.
A.
The carotid bifurcation is an 
area of low flow velocity and low shear stress.
B.
contrast, they represent loss or diminution of neurologic func-
tion.
Characteristically, the peak systolic velocity is 
increased at the site of the vessel stenosis.
The end-diastolic 
velocity is increased with greater degree of stenosis.
A ratio greater than 4 is a great predictor of angiographic ste-
nosis of 70% to 99%.
MRA is noninvasive and does not require iodinated contrast 
agents.
23-15).
The advantages of CTA over MRA include faster 
data acquisition time and better spatial resolution.
23-16).
A.
A carotid 
artery occlusion is noted in the internal 
carotid artery B.
Figure 23-16.
(symptomatic).
It is estimated that 15% of all strokes are pre-
ceded by a TIA.
The main conclusions of the tri-
als remain validated and widely acknowledged.
The dismal outcome reported in the early experience was likely 
related to poor patient selection.
Carotid endarterectomy produced a relative 
risk reduction of 53% over medical management alone.
2.3%) and a higher rate of myocardial infarction 
in the endarterectomy group (2.3% vs.
1.1%).
All available randomized studies have provided some 
answers and raised some questions.
Carotid artery 
stenting is not recommended for asymptomatic patients at this 
time.
Stump pressures have 
been used to determine the need for intra-arterial carotid shunt-
ing.
23-17).
The platysma is divided completely.
Typically tributaries of the anterior jugular vein are ligated and 
Figure 23-17.
844
SPECIFIC CONSIDERATIONS
UNIT II
PART II
divided.
The dissection is carried medial to the sternocleido-
mastoid.
This 
muscle can be divided.
The carotid fascia is incised, and the 
common carotid artery is exposed.
The common carotid artery 
is mobilized cephalad toward the bifurcation.
A useful landmark in the 
dissection of the carotid bifurcation is the common facial vein.
This vein can be ligated and divided.
The external carotid artery is 
mobilized just enough to get a clamp across.
Intravenous heparin sulfate (1 mg/kg) is routinely admin-
istered just prior to carotid clamping.
The external and common carotid 
arteries are clamped subsequently.
Endarterectomy is carried out to 
remove the occlusive plaque (Fig.
23-18).
23-19).
Typically, a plane is teased 
Figure 23-18.
A.
Carotid plaque is elevated from the carotid lumen.
B.
Figure 23-19.
out from the vessel wall, and the entire plaque is elevated and 
removed.
23-20).
The endarterectomized surface is then irrigated 
and any debris removed.
23-21).
845
Arterial Disease
CHAPTER 23
off the vessel wall.
The wound 
is closed in layers.
Complications of Carotid Endarterectomy.
Acute ipsilateral stroke is a dreaded 
complication following carotid endarterectomy.
Cerebral isch-
emia can be due to either intraoperative or postoperative events.
The most 
common cause of postoperative stroke is due to embolization.
Less frequently, acute carotid artery occlusion can cause acute 
postoperative stroke.
Re-exploration is mandated for acute 
carotid artery occlusion.
Cerebral angiography can be useful if 
intracranial revascularization is considered.
Local complications related to surgery include excessive 
bleeding and cranial nerve palsies.
Any expanding hematoma should be evac-
uated and active bleeding stopped.
Often these are traction injuries but can 
also be due to severance of the respective nerves.
BA
Figure 23-21.
A.
B.
A completion closure of carotid endarterectomy incision using a synthetic patch.
23-22).
The patient is placed in the supine position.
The patient’s blood 
pressure and cardiac rhythm are closely monitored.
Using the Seldinger technique, we insert a 
diagnostic 5- or 6-French sheath in the CFA.
A diagnostic arch 
aortogram is obtained.
It is critical not to advance the sheath beyond the occlu-
sive plaque in the carotid bulb.
Several distal EPDs are available (Table 23-6).
The EPD device is carefully deployed beyond the target lesion.
All current 
carotid stents use the rapid-exchange monorail 0.014-inch plat-
form.
The size selection is typically based on the size of com-
mon carotid artery.
The puncture 
site is closed using available closure device or with manual 
compression.
Throughout the procedure, the patient’s neuro-
logic function is closely monitored.
Complications of Carotid Stenting.
BA
Figure 23-22.
A.
Carotid angiogram 
demonstrating a high-grade stenosis of 
the left internal carotid artery.
B.
Com-
pletion angiogram demonstrating a sat-
isfactory result following a carotid stent 
placement.
Acute carotid stent thrombosis is rare.
The incidence of in-stent 
carotid restenosis is not well known but is estimated at 10% to 
30%.
NA = not applicable.
Nonatherosclerotic Disease of  
the Carotid Artery
Carotid Coil and Kink.
23-23).
In children, carotid coils appear to be congenital in 
origin.
Kinking is more common in women 
than men.
Most carotid kinks and coils are found incidentally 
on carotid duplex scan.
Fibromuscular Dysplasia.
23-24).
Women in the fourth or fifth decade 
of life are more commonly affected than men.
Hormonal effects 
on the vessel wall are thought to play a role in the pathogenesis 
of FMD.
Four histologic types of FMD have been described 
in the literature.
Commonly, mural dilations and microaneurysms 
can be seen with this type of FMD.
Intimal fibroplasia accounts for 5% of all 
cases and occurs equally in both sexes.
FMD can also involve the 
renal and external iliac arteries.
The string of beads 
can also be shown noninvasively by CTA or MRA.
Antiplatelet medication is the gener-
ally accepted therapy for asymptomatic lesions.
Endovascular 
treatment is recommended for patients with documented lateral-
izing symptoms.
Surgical correction is rarely indicated.
Carotid Artery Dissection.
Subintimal dissections 
can lead to intramural clot or thrombosis.
Iatrogenic dissections can 
also occur due to catheter manipulation or balloon angioplasty.
Figure 23-24.
The ischemia may cause TIAs or infarctions, 
or both.
23-25).
The dissection typically starts in the internal carotid artery distal 
to the bulb.
The recurrence rate is low.
Carotid Artery Aneurysms.
Carotid artery aneurysms are 
rare, encountered in less than 1% of all carotid operations 
(Fig.
23-26).
The true carotid artery aneurysm is generally due 
to atherosclerosis or medial degeneration.
Patients typically present with a pul-
satile neck mass.
Thrombosis and rupture of the carotid aneurysm are rare.
Pseudoaneurysms of the carotid artery can result from injury 
or infection.
849
Arterial Disease
CHAPTER 23
Carotid Body Tumor.
23-27).
The gland is innervated by the glos-
sopharyngeal nerve.
Carotid body tumor is a rare lesion of the neuroen-
docrine system.
A.
An anteroposterior angiogram of the neck revealing a carotid artery aneurysm.
B.
A lateral projection of the carotid artery 
aneurysm.
C.
Following endovascular placement, the carotid artery aneurysm is successfully excluded.
and adrenal medulla.
Approximately 5% to 7% of carotid body tumors are 
malignant.
The risk of malignancy is 
greatest in young patients with familial tumors.
Symptoms related to the endocrine products of the carotid 
body tumor are rare.
A.
A carotid body 
tumor (arrow) located adjacent to the 
carotid bulb.
B.
Following periad-
ventitial dissection, the carotid body 
tumor is removed.
850
SPECIFIC CONSIDERATIONS
UNIT II
PART II
mass.
The diagnosis of carotid body tumor requires confir-
mation on imaging studies.
Classically, a carotid body tumor will widen 
the carotid bifurcation.
Surgical resection is the rec-
ommended treatment for suspected carotid body tumor.
Carotid Trauma.
Blunt or penetrating trauma to the neck can 
cause injury to the carotid artery.
Spiral CTA has become the modality of choice to detect 
extracranial carotid artery injury.
The most common location of aortic aneurysms is the 
infrarenal aorta.
Advantages and potential complications of these treatments will 
also be addressed.
Rupture risk appears to be directly related to aneurysm 
size as predicted by Laplace’s Law.
In the past, AAA rupture risk has been 
overestimated.
The rupture risk is quite low below 5.5 cm and 
begins to rise exponentially thereafter.
Physical examination is neither sensitive nor specific except 
in thin patients.
Rarely patients present with back pain and/or 
abdominal pain with a tender pulsatile mass.
Patients with these 
symptoms must be treated as a rupture until proven otherwise.
23-28).
Male aortas tend to be larger 
Figure 23-28.
An operative view of an infrarenal aortic aneurysm.
Ninety percent of AAAs are 
infrarenal in location and have a fusiform morphology.
There 
is a higher predilection for juxtarenal and suprarenal AAAs in 
women compared with men.
Distally, the iliac arteries can have severe tortu-
osity with multiple compound turns.
Cross-sectional imaging is required for definitive evalu-
ation of AAA.
Extremely high-resolution images are obtained with submilli-
meter spatial resolution (Fig.
23-29).
The spiral technique further affords the ability for three-
dimensional reconstruction.
Conventional angiography has a minimal role 
in the current management of AAA.
Angiography is invasive 
with an increased risk of complications.
The aneurysm sac is open next, and a prosthetic graft is 
used to reconstruct the aorta.
23-30).
23-31).
Advantages and Risks of Open Abdominal Aortic Aneu-
rysm Repair.
The risk of aneurysm 
Figure 23-29.
853
Arterial Disease
CHAPTER 23
recurrence or delayed rupture no longer exists.
As a result, long-
term imaging surveillance is not needed with these patients.
In 
contrast, the long-term efficacy of endovascular repair remains 
unclear.
A.
Schematic depiction of an aortic tube graft used to repair an aortic aneurysm.
B.
Intraoperative image of an aortic tube 
graft reconstruction.
23-32).
Unlike open surgical repair, the aneurysm sac is not 
Figure 23-31.
Intraoperative view of a bifurcated graft used to 
repair an aortic aneurysm.
resected, which is subjected for potential aneurysm expansion or 
even rupture.
Several techniques have been proposed to overcome 
this limitation.
A.
An aortogram dem-
onstrating a large infrarenal abdominal 
aortic aneurysm.
B.
Following endovas-
cular stent graft implantation, the aortic 
aneurysm is successfully excluded.
All diameter measurements are mid-wall to 
mid-wall of the vessel.
The usual distal landing zone is the common 
iliac artery.
The next step in the preoperative planning is device selec-
tion.
Advantages and Risks of Endovascular Repair.
The obvi-
ous advantage of an endovascular AAA repair is its minimally 
invasive nature.
Despite its many advantages, endovascular repair does 
have potential complications.
Technical Considerations of Endovascular Aortic Aneu-
rysm Repair.
The patient is prepped and draped just as in open AAA repair.
A variety 
of anesthetic options may be used.
Regional anesthesia may 
be appropriate for patients with pulmonary disease.
Special attention is paid to avoid 
the groin crease to decrease the risk of wound complications.
Transfemoral access is obtained using standard Seldinger 
technique.
An angiographic catheter is advanced from 
the contralateral femoral artery to the same level.
A road-mapping aortogram is obtained to localize the 
renal arteries.
23-33).
The patients recover in the recovery room for 2 to 4 hours and 
admitted to the general care floor.
Although in the past, patients 
A
DC
B
Figure 23-33.
A.
B.
The device is deployed in the aorta just below the 
renal arteries.
C.
D.
857
Arterial Disease
CHAPTER 23
were admitted to the intensive care unit, this is rarely needed.
Most patients can be started on a regular diet that evening and 
discharged the next morning.
Surveillance Following Endovascular Aortic Aneurysm 
Repair.
Life-long follow-up is essential to the long-term suc-
cess after endovascular AAA repair.
The abdominal 
x-ray gives a “birds-eye” view of the overall morphology of the 
stent graft.
Early reports on results with endovascular repair were 
often flawed due to selection biases.
There was a 
higher incidence of graft-related complications in the endolu-
minal group.
There was no difference in the nonvascular local 
complication rate among the two groups.
Short-term mortality at 30 days was 
4.7% in the open group and 1.7% in the endoluminal group.
2.1%).
As expected, the secondary intervention rate was higher in the 
endoluminal group (9.8% vs.
5.8%).
Complication rates were 
not reported in the EVAR-1 trial.
Criticisms can be applied to 
both of these trials.
Patients had to be eligible for either type of 
repair in order to be included in the study.
There was no difference in pri-
mary outcome of all-cause mortality.
Endovascular repair and 
open repair resulted in similar long-term survival.
Rupture after endovascular 
repair remains a concern.
A significant interaction was observed 
between age and type of treatment.
Device-Specific Outcome.
There were no deployment failures or early conversions.
There 
was an annual 7% reintervention rate.
Aneurysm growth was 
demonstrated in 14% of patients at 2 years.
The endoleak rates were 7.4% and 5.4% at 
1- and 2-year intervals, respectively.
There was a 5.3% migra-
tion of 5 mm at 1 year.
Freedom from rupture was noted to be 98.4% at 4 years.
Endoleak rate was 10%.
Three deploy-
ment failures were noted, and freedom from rupture was 100%.
Patients with a wide neck (>26 mm) 
had a 3% growth and migration rate.
Narrow-neck patients 
(<26 mm) had a 1% growth rate and a 2% migration neck.
Interestingly, short-neck patients (<15 mm) had no aneurysm 
growths and a 2% migration rate.
Cost Analysis.
23-34).
Figure 23-35.
beyond the first year of follow-up.
Endoleaks can be detected 
using conventional angiography, contrast CT (Fig.
23-35), 
MRA, and color-flow duplex ultrasound.
Four types of endoleaks have been described (Table 23-10).
Persistent type I 
endoleaks, on the other hand, require prompt treatment.
On angi-
ography, they are seen as a late filling of the aneurysm sac from 
a branch vessel(s).
Regardless of the etiology or timing, these 
should be promptly repaired.
Endotension Following Endovascular Aortic Aneurysm 
Repair.
Secondary Interventions Following Endovascular Aortic 
Aneurysm Repair.
The most common cause of mesenteric ischemia is 
atherosclerotic vascular disease.
On the other hand, mesenteric isch-
emia can occur suddenly, as in the case of thromboembolism.
23-36).
In addition, the mesenteric cir-
culation responds to the gastrointestinal contents.
Certain 
intrinsic vasoconstrictors, such as vasopressin, can diminish the 
mesenteric blood flow.
On the other hand, neural regulation is 
provided by the extensive visceral autonomic innervation.
This leads to transient anaerobic 
metabolism and acidosis.
This vessel network provides 
collateral flow between the superior mesenteric artery and IMA.
the splanchnic and systemic circulation.
23-37 and 23-38).
Figure 23-37.
Figure 23-38.
Fever, 
nausea, vomiting, and abdominal distention are some common 
but nonspecific manifestations.
The classical symptoms include postprandial abdominal pain, 
food fear, and weight loss.
Persistent nausea and occasionally 
diarrhea may coexist.
Abdominal pain is only 
present in approximately 70% of these patients.
When present, 
the pain is usually severe but may vary in location, character, 
and intensity.
23-39).
Most patients 
are young females between 20 and 40 years of age.
Metabolic acidosis 
develops as a result of anaerobic metabolism.
Diagnosis of chronic mesenteric ischemia can be more 
challenging.
Rarely, the vascular surgeon is the first to encounter a patient 
with the above symptoms.
In this situation, it is advisable to 
Figure 23-39.
Finally, 
spiral CT with three-dimensional reconstruction (Fig.
23-40) 
and MRA (Fig.
23-41) have been promising in providing clear 
radiographic assessment of the mesenteric vessels.
In most 
Figure 23-40.
23-42).
Figure 23-41.
Figure 23-42.
Mesenteric arteriography can also play a therapeutic role.
Surgical Repair
Acute Embolic Mesenteric Ischemia.
Appropriate antibiotics are given prior 
to surgical exploration.
The operative management of acute 
mesenteric ischemia is dictated by the cause of the occlusion.
Acute Thrombotic Mesenteric Ischemia.
The bypass graft may originate 
from either the aorta or iliac artery.
Patency rates are similar regardless of inflow vessel 
choice.101
Chronic Mesenteric Ischemia.
Transaortic endarterectomy is indicated for 
ostial lesions of patent CA and SMA.
A left medial rota-
tion is performed, and the aorta and the mesenteric branches 
are exposed.
A lateral aortotomy is performed encompassing 
both the CA and SMA orifices.
Otherwise, an intimal flap may develop, 
which can lead to early thrombosis or distal embolization.
Restenosis after PTA is also an indication for stent 
placement.107
Acute Mesenteric Ischemia.
There are two main 
drawbacks with regard to thrombolytic therapy in mesenteric 
ischemia.
Nonocclusive Mesenteric Ischemia.
Once the diagnosis is made on the mesenteric arteriography (see 
Fig.
23-42), intra-arterial papaverine is given at a dose of 30 to 
60 mg/h.
This must be coupled with the cessation of other vaso-
constricting agents.
Techniques of Endovascular Interventions.
These stents can be placed over a low-profile 0.014- 
or 0.018-inch guidewire system.
The balloon is then deflated and carefully 
withdrawn through the guiding sheath.
Complications of Endovascular Treatment.
Complica-
tions are not common and rarely become life threatening.
These 
include access site thrombosis, hematomas, and infection.
Dis-
section can occur during PTA and is managed with placement 
of a stent.
Moreover, both groups had similar 3-year cumu-
lative recurrent stenosis and mortality rates.
Long-term patency rates appear to also 
be superior with the open technique.
The study showed that covered 
stents are associated with less restenosis (18% vs.
47%), symp-
tom recurrence (18% vs.
50%), and reintervention (9% vs.
44%) 
at 24 months and better primary patency at 3 years (92% vs.
23-43).114 Atheroscle-
rotic lesions are bilateral in two thirds of patients.
Individuals 
with this disease commonly present during the sixth decade of 
life.
Men are affected twice as frequently as women.
23-44 and 23-45).
The cause of medial 
fibroplasia remains unclear.
Figure 23-45.
Captopril inhibits the 
secretion of angiotensin II.
Significant parenchymal 
disease limits the reliability of this study.
This value represents the contribution of each kidney 
to renin production.
The RSRI of the affected kidney in patients with 
renovascular hypertension is greater than 0.24.
while using a minimally nephrotoxic agent.
Flow void may be 
inaccurately interpreted as occlusion or stenosis in MRA.
Figure 23-46.
Magnetic resonance angiography of the abdominal 
aorta reveals bilateral normal renal arteries.
Figure 23-47.
Types of Surgical Reconstruction.
Autologous vein is the preferred conduit.
If the vein is not suit-
able, then prosthetic material can be used.
After plaque removal, the arteri-
otomy is closed with a prosthetic patch.
Adequate mobilization of the 
renal arteries is essential for a safe and complete endarterectomy.
Greater 
saphenous vein is the conduit of choice.
A 
redundant renal artery is a prerequisite for the procedure.
Completion angiog-
raphy is usually performed to assess the immediate results.
The 
technical aspect of an endovascular renal artery revasculariza-
tion is discussed below.
Techniques of Renal Artery Angioplasty and Stenting.
Choosing a balloon with diameter 4 mm is a reasonable first 
choice.
43%, respectively).
14%, respectively).
However,  transient  hemodialysis  may  become  necessary  in 
approximately 1% of patients.
Clinical Results of Endovascular Interventions
Percutaneous Transluminal Balloon Angioplasty.
The technical success 
rate of balloon angioplasty for FMD was 95%.
Primary patency 
rates were 81%, 69%, 69%, and 69% at 2, 4, 6, and 8 years, 
respectively.
Assisted primary patency rates were 87%, 87%, 
87%, and 87% at 2, 4, 6, and 8 years, respectively.
The resteno-
sis rate was 25% at 8 years.
Renal Artery Stenting.
Five-year patency 
was 84.5% (mean follow-up, 27 months).
Hypertension was cured or 
improved in 78% of patients.
The authors concluded that primary 
BA
Figure 23-48.
Renal artery stent-
ing.
A.
Focal lesion in the renal artery 
(arrow).
B.
The overall cure rate for hypertension was 20%, 
whereas hypertension was improved in 49%.
Renal function 
improved in 30% of patients and stabilized in 38% of patients.
The restenosis rate at follow-up of 6 to 29 months was 17%.
Various risk factors exist that can lead to the devel-
opment of aortoiliac occlusive disease.
In addition, complaints that are 
experienced upon standing suggest nonvascular causes.
23-49).
23-50).
23-51).
Due to the localized nature of this type of aortic 
Figure 23-49.
23-52).
Aortoiliac disease can be classified into three types.
Type I represents focal disease affecting the distal aorta and proxi-
mal common iliac artery.
Type II represents diffuse aortoiliac dis-
ease above the inguinal ligament.
Figure 23-51.
Symptoms typically consist 
of bilateral thigh or buttock claudication and fatigue.
Men report 
diminished penile tumescence and may have complete loss of 
erectile function.
These symptoms in the absence of femoral 
pulses constitute Leriche’s syndrome.
Rest pain is unusual with 
isolated aortoiliac disease unless distal disease coexists.
23-53).
A.
B.
This is consistent with 
type I aortoiliac occlusive disease.
dominately the abdominal aorta with disease extension into the 
common iliac artery.
This disease pattern affects approximately 
25% patients with aortoiliac occlusive disease.
23-54).
875
Arterial Disease
CHAPTER 23
limb salvage rather than for claudication.
Patients should have hypertension, 
hyperlipidemia, and diabetes mellitus controlled.
They should 
be advised to stop smoking.
Most patients are empirically 
placed on antiplatelet therapy.
A graduated exercise program 
Figure 23-54.
Type A lesions
Type B lesions Type D lesions
Type C lesions
Figure 23-55.
Surgical Reconstruction of Aortoiliac  
Occlusive Disease
Aortobifemoral Bypass.
A retro-
peritoneal approach may be selected as an alternative in certain 
situations.
There are randomized reports, however, that support 
and refute the superiority of this approach.
23-56).
23-57).
Furthermore, the distal aorta often pro-
ceeds to total occlusion after an end-to-side anastomosis.
The limbs of the 
Figure 23-56.
In an end-to-end proximal aortic anastomosis, the 
aorta is divided in half.
Figure 23-57.
Endarterectomy or patch angioplasty of the profunda femo-
ris may be required concurrently.
During this period, the 
patient must be carefully monitored for hypotension.
As a rule, if the profunda femoris can accept a 4-mm probe and 
if a No.
Aortic Endarterectomy.
Axillofemoral Bypass.
It may be performed under 
local anesthesia and is used for limb salvage.
It 
is anastomosed ipsilaterally at the CFA bifurcation into the SFA 
and PFA.
23-58).
BA
Figure 23-58.
A.
Skin markings showing the incisions of an ilio-
femoral bypass.
B.
878
SPECIFIC CONSIDERATIONS
UNIT II
PART II
Obturator Bypass.
Thoracofemoral bypass has long-term patency 
comparable to aortofemoral bypass.
Focal Aortic Stenosis.
Bilateral CFA access is established followed by 
insertion of a 10-French sheath.
Balloon size 
will range from 12 to 18 mm in most cases.
A single stent is 
generally sufficient in most cases.
Newer self-expanding stents have also been 
used.
Occlusive Lesions of the Aortic Bifurcation.
PTA is most use-
ful in the treatment of isolated iliac stenoses of less than 4 cm in 
length.
Technical Considerations for Iliac Interventions.
Crossing a 
high-grade stenosis or occlusion can be challenging in the iliac 
arteries.
Guidewire traversal must be achieved 
for performance of endovascular iliac intervention.
Over 90% 
of iliac occlusions can be passed with simple guidewire tech-
niques.
There are several approaches that can 
be used to achieve re-entry of total chronic occlusions.
Intravascular ultrasound can 
be used for true lumen re-entry under fluoroscopic guidance.
A 4-French Berenstein catheter (Cordis Corp., 
Miami Lakes, FL) is used to probe the occlusion.
The approach to aortoiliac stenting is intui-
tive.
Stent Graft Placement for Aortoiliac Interventions.
The role of stent grafts in aortoiliac occlusive disease 
has not been fully elucidated yet.
Many of these minor complications are related to the arterial 
puncture site.
The most frequent complications relate to access 
site cannulation.
The incidence of 
pseudoaneurysm formation at the puncture site is 0.5%.
Arterial rupture may complicate the procedure in 0.3% of cases.
In 
case of failure, surgical treatment is required.
24.6%).
The open bypass group experienced more complica-
tions (18.0% vs.
13.4%) and greater 30-day mortality (2.6% vs.
0.7%).
86.0%, 86.0% vs.
80.0%, and 82.7% vs.
71.4%, respectively); the same was true 
for secondary patency (95.7% vs.
90.0%, 91.5 vs.
86.5%, and 
91.0% vs.
82.5%, respectively).
Ideal 
iliac angioplasty lesions are nonocclusive and short.
Likewise as vessel diameter and flow rates change, so do suc-
cess rates after angioplasty.
Ninety percent of acute ischemia 
cases are either thrombotic or embolic.
In 
addition, multiple comorbid conditions increase risks of surgical 
procedures.
However, among patients with an ABI ratio 
<0.75, 42% were unknown to the primary physicians.
The bedside 
ABIs using blood pressure cuff also aid in diagnosis.
Noninvasive studies are important in documenting the 
severity of occlusive disease objectively.
Normal ABI is greater than 1.0.
Decrease in segmental pressure between two segments 
indicates significant disease.
23-59 and 23-60).
Contrast angiography remains the gold standard imaging 
study.
Symptom severity varies from mild to severe.
Nocturnal calf muscle spasms or night 
cramps are not indicative of arterial disease.
They are common 
but are difficult to diagnose with certainty.
Foot ulceration is not 
always the result of arterial insufficiency.
Ischemic ulcers occur 
on the toes or lateral side of the foot and are painful.
Ulcers may be the result of more than 
one etiology.
Spinal stenosis causes pain 
that is exacerbated with standing and back extension.
There are two major 
classifications developed based on the clinical presentations.
Asymptomatic patients are classified 
Figure 23-59.
Distal occlusive disease is noted in the left tibial arteries 
(arrow).
Based on the guide-
line, femoropopliteal lesions are divided into four types: A, B, 
C, and D.
23-61).
Type A lesions are single lesions less than 1 cm in length not 
involving the trifurcation.
Most cases of lower extremity 
ALI are the result of thrombosis of a prosthetic conduit.
This 
stems from increased use of prosthetic conduits to address CLI.
Presenting symptoms in ALI are pain and loss of sensory 
or motor function.
Atrial fibrillation is the most common 
source.
Mural thrombi can also develop within a ventricle dilated by 
cardiomyopathy.
Diseased valves are another source of distal 
embolization.
Historically, this occurred as a result of rheumatic 
heart disease.
Currently, subacute endocarditis and acute bacte-
rial endocarditis are the more common causes.
Infected emboli 
can seed the recipient vessel wall, creating mycotic aneurysms.
Type A lesions
Type B lesions
Type C lesions
Type D lesions
Figure 23-61.
The presence of mobile 
plaque on transesophageal echocardiography is suggestive of 
this source.
Arterial Thrombosis.
Thrombosis can occur in native arteries 
and in arterial reconstructions.
The most common location for an embolus to 
lodge in the leg is at the common femoral bifurcation.
Typically 
a patient will complain of foot and calf pain.
Pulses are absent, 
and there may be diminution of sensation.
This will prevent propagation of the clot into unaf-
fected vascular beds.
Intravenous fluid should be started and a 
Foley catheter inserted to monitor urine output.
Baseline labs 
should be obtained and creatinine levels noted.
Skeletal 
muscle tissue appears to be most vulnerable to ischemia.
The more 
severe the cellular damage, the greater are the microvascu-
lar changes.
The groin 
is opened through a vertical incision, exposing the CFA and 
its bifurcation.
The 
artery is clamped and opened transversely over the bifurcation.
Good back-bleeding and antegrade bleeding 
suggest that the entire clot has been removed.
Completion angiography is advisable to 
ascertain the adequacy of clot removal.
The artery is then closed 
and the patient fully anticoagulated.
Use of fluoroscopic imaging and an over-the-wire 
thrombectomy catheter can overcome this problem.
Bypass Graft Thrombectomy.
Bypass thrombectomy is more 
likely to succeed with prosthetic bypasses.
Gastrointestinal bleeding is reported in 5% 
to 10% of cases.
Hematuria following thrombolysis is uncom-
mon and should prompt a search for urinary tumors.
The most feared complication that patients can sustain is 
intracerebral hemorrhage.
Compartment syndrome occurs after prolonged ischemia 
is followed by reperfusion.
23-62).
The most commonly affected compartment is the ante-
rior compartment in the leg.
Although controversial, pressures greater than 20 
mmHg are an indication for fasciotomy.
Compartment pressures 
are relieved in the leg by medial and lateral incisions.
Through 
the lateral incision, the anterior and peroneal compartments are 
opened.
Laboratory 
evidence of rhabdomyolysis is seen in 20% of cases.
Schematic illustration of fascial compartments of 
the lower extremity.
ulceration or gangrene (Table 23-24).
23-63).
Stenoses, which develop here, progress to occlusion of the dis-
tal third of the SFA (Fig.
23-64).
Pain 
from isolated SFA and popliteal occlusion typically manifests as 
calf claudication.
Activities such as climbing stairs or going uphill also exacerbate 
the pain.
It is important to evaluate whether the symptoms are 
progressive or static.
bGrades II and III, categories 4, 5, and 6, are encompassed by the term chronic critical ischemia.
AP = ankle pressure; PVR = pulse volume recording; TM = transmetatarsal; TP = toe pressure.
Patients may report 
that they either sleep in a chair or hang the foot off the side of 
the bed.
The pain is severe and relentless, even with narcot-
ics.
Ischemic ulceration most commonly involves the toes.
Any 
toe can be affected.
Occasionally ulcers develop on the dor-
sum of the foot.
The 
initial development of gangrene commonly involves the digits.
Endovas-
cular intervention provides an attractive alternative.
Proper selection of patients and techniques is critical in 
achieving good long-term outcome.
BA
Figure 23-63.
A.
The foot 
may be warm to touch, and pulses may be present in the distal pedal arteries.
B.
An ischemic ulcer is characterized by a gangrenous skin 
change in the foot or toes.
The foot is usually cold to touch with absent pedal pulses.
The foot is painful to touch with decreased distal capil-
lary refills.
Figure 23-64.
Endovascular intervention for lower extremity occlusive 
disease is continuously evolving.
Endovascular Treatment
Technical Considerations.
The most common and safest access site is CFA 
via either a retrograde or an antegrade approach.
For diagnos-
tic angiography, arterial access should be contralateral to the 
symptomatic sides.
The antegrade approach may be challenging, particularly in 
obese patients.
Traversing the lesion with a wire is the most critical part 
of the procedure.
After the procedure, all patients 
are placed on antiplatelet therapy, such as aspirin.
Percutaneous Transluminal Balloon Angioplasty.
The balloon tends to be approximately 
10% to 20% oversized.
The radiopaque markers of the balloon 
catheter are placed so that they will straddle the lesion.
23-65).
The patient may experience mild pain, which is 
not uncommon.
However, severe pain can be indicative of ves-
sel rupture, dissection, or other complications.
Frequently, several inflations 
are required to achieve a full profile of the balloon (Fig.
23-66).
Low-
compliant balloons are the mainstay for peripheral intervention.
Furthermore, trackability, pushability, and 
Figure 23-65.
A.
Angiogram demonstrating a focal stenosis in the superficial femoral artery (arrow).
B.
C.
Completion angiogram demonstrating satisfactory 
radiographic result.
Figure 23-66.
A.
B.
C.
Completion angiogram demonstrated satisfactory result with no evidence of vessel dissection.
crossability of the balloon should be considered when choosing 
a particular type of balloon.
After PTA, a completion angiogram 
is performed while the wire is still in place.
Subintimal Angioplasty.
The occluded lumen is recanalized through the subintimal plan.
When the wire is advanced, a loop is naturally 
formed at the tip of the guidewire.
Once the subintimal plan is 
entered, the wire tends to move freely in dissection space.
This is followed by a balloon 
angioplasty.
If flow is impaired, repeat balloon 
dilatation may be necessary.
Multiple studies have demonstrated the efficacy of subin-
timal angioplasty.
Limb salvage 
rates reached over 80% at 12 months.
Stent Placement.
There are sev-
eral situations where stent placement is appealing.
The primary 
indication is the potential salvage of an unacceptable angio-
plasty result.
Stent placement is typically used when residual 
stenosis after PTA is 30% or greater.
An endoluminal stent is 
also used for dissection, perforation, and other PTA complica-
tions.
In addition, an endoluminal stent is potentially 
beneficial for early restenosis after PTA.
Additionally, stent 
characteristics may contribute to the patency rate.
The average 
length treated was 60 mm.
Only 12% of patients who 
died had a preceding major amputation.
Target limb revascularization occurred in 15% 
of patients.
Stent Graft.
Stent grafts can be divided into two categories: 
unsupported and fully supported.
The unsupported grafts are flexible 
with a low profile, but prone to external compression.
The sup-
ported stent grafts consist of a metallic skeleton covered with 
graft fabric.
There is no FDA-approved stent graft for peripheral 
intervention.
Fifty limbs were randomized into each group.
Atherectomy.
The basic principle of atherectomy is to remove 
the atheroma from obstructed arterial vessels.
Paul, MN), and 
Rotablator system (Boston Scientific Corporation, Natick, MA).
These devices either cut and remove or pulverize the atheroma 
plaques.
The atheroma protruding into the window is 
excised and pushed into the collection chamber.
The rotating 
cam tip pulverizes the atheromatous lesion into minute particles.
The work-
ing end consists of a hinged housing unit containing a carbide 
cutting blade.
The Rotablator system high-speed rotational 
device uses calcium ablation to achieve larger lumens.
It has 
been used for more than 20 years to treat challenging, calcified 
coronary artery disease.
The diamond-coated burr is designed 
to preferentially engage calcium and modify lesion compliance.
Laser Atherectomy.
This lumen is further dilated by an angioplasty balloon.
Patency rates were 59% and 54% at 6 and 12 months, 
respectively.
Complications of Endovascular Interventions
Angioplasty-Related Complications.
The adductor canal has nonlami-
nar flow dynamics, especially with walking.
The forces exerted 
on the SFA include torsion, compression, extension, and flex-
ion.
These forces exert significant stress on the SFA and stents.
23-67).
Surgical Treatment for Chronic Limb Ischemia 
due to Femoropopliteal Disease
Endarterectomy.
Endarterectomy has a limited, albeit impor-
tant role in lower extremity occlusive disease.
It is most fre-
quently used when there is disease in the CFA or involving the 
PFA.
This permits the inner 
layer containing the atheroma to be excised.
The 
high incidence of restenosis is what limits utility of endarterec-
tomy in this location.
Short-segment stenoses are more appro-
priately treated with balloon angioplasty.
Bypass Grafting.
Bypass grafting remains the primary interven-
tion for lower extremity occlusive disease.
The type of bypass and 
the type of conduit are important variables to consider.
Patients 
with occlusive disease limited to the SFA, who have at least 4 cm 
Figure 23-67.
In patients 
with diabetes, it is frequently the peroneal artery that is spared.
Five-year 
assisted patency rate for infrapopliteal venous bypasses is 60%.
Venous conduits have also been shown to be suitable for bypasses 
to plantar arteries.
End-
to-side anastomoses are then created.
Amputation.
It is rarely necessary in patients who, as 
a result of neglect, present with class III ALI.
Complications of Surgical Reconstruction
Vein Graft Stenoses.
Secondary patency is mark-
edly inferior to primary assisted patency.
Limb swelling tends to worsen with repeat revascularization 
(see Table 23-22).
Wound Infection.
When 
a prosthetic graft has been used, management of graft infection 
is a major undertaking.
Choice of Conduit for Infrainguinal  
Bypass Grafting
Autogenous Vein.
This preference is applicable not only 
for the initial bypass but also for reoperative cases.
The small saphenous vein is of 
particular utility when a posterior approach is used.
Cryopreserved vein grafts are more expensive 
than prosthetic grafts and are more prone to failure.
Cryopreserved grafts are also 
prone to aneurysmal degeneration.
If a 
vein is truly unavailable, PTFE or Dacron is the best option for 
above-knee bypass.
29% for PTFE with no cuff) and also improve limb salvage 
(84% vs.
Distal runoff is 
another powerful predictor of long-term success.
Additionally, 
stent characteristics may contribute to the patency rate.
Patients were treated with Cordis SMART 
self-expanding nitinol stents.
The mean lesion length was 
12.2 cm (range, 4–28 cm).
The technical success was 98%.
Mean 
follow-up was 302 days.
Mean recanalization 
length was 19 cm (range, 3–53 cm).
Mean follow-up time was 
2.4 years (range, 3 days–4.8 years).
The his-
tologic and pathologic changes and laboratory findings are simi-
lar.
Cerebral symptoms occur when the disease process 
extends to the carotid arteries.
Jaw claudication and temporal 
artery tenderness may be experienced.
Symptoms are related to end-organ ischemia.
The acute inflammation can destroy the arterial media and lead 
to aneurysm formation.
However, these associa-
tions have not been seen in North America.
The pathologic changes pro-
duce stenosis, dilation, aneurysm formation, and/or occlusion.
These include fever, anorexia, weight 
loss, general malaise, arthralgias, and malnutrition.
Repair is problematic because the 
vessel wall is soft and sutures pull through the fragile tissue.
Ligation may be the only option in many circumstances.
Ocular manifestations are flattened corneas, 
lens subluxation, and myopia.
Skin, central nervous system, and 
pulmonary features may be present as well.
Aortic root dilata-
tion will generally occur in all patients.
An 
infectious agent may be causative; however, no specific agent 
has been identified.
A classification system of systemic vasculitis by 
vessel size is shown in Table 23-28.
An HLA linkage has been 
found, indicating a genetic component to the etiology.
This disease 
predominantly affects men over women by a 2:1 ratio.
PAN 
develops subacutely, with constitutional symptoms that last 
for weeks to months.
Intermittent, low-grade fevers, malaise, 
weight loss, and myalgias are common presenting symptoms.
Patients may succumb to renal failure, 
intestinal hemorrhage, or perforation.
The mainstay of treatment 
is steroid and cytotoxic agent therapy.
Radiation-induced damage to blood vessels has been well 
studied.
The digital vessels then 
relax, eventually leading to reactive hyperemia.
The majority 
of patients are young women less than 40 years of age.
Different changes 
in digital blood pressure will occur in patients with Raynaud’s 
syndrome.
The majority (90%) of patients will 
respond to avoidance of cold and other stimuli.
Calcium channel–blocking agents 
such as diltiazem and nifedipine are the drugs of choice.
FMD occurs most frequently in women 
(90%) and is recognized at approximately 55 years of age.
Clinically, symptoms are due to encroachment on the ves-
sel lumen and a reduction in flow.
Surgical treatment has been favored 
for symptomatic patients with angiographically proven disease.
PTA has been used effectively in 
patients with FMD-induced hypertension.
Adventitial Cystic Disease of the Popliteal Artery.
Noninvasive studies may suggest arterial stenosis with ele-
vated velocities.
Various therapeutic methods have been described for the 
treatment of adventitial cystic disease.
Popliteal Artery Entrapment Syndrome.
Concomitant popliteal vein impinge-
ment occurs in up to 30% of cases.
Twenty-five percent of cases 
are bilateral.
Although 
CT and MRI have been employed, angiography remains the 
most widely used test.
Lysis will improve distal runoff and may improve 
limb-salvage and bypass patency rates.
End-stage lesions demonstrate organized thrombus and 
blood vessel fibrosis.
Even if symptoms are not yet 
present in a limb, angiographic findings may be demonstrated.
35%).
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913
Arterial Disease
CHAPTER 23
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This page intentionally left blank 
Venous and Lymphatic Disease
Jason P.
Jundt, Timothy K.
Liem, 
and Gregory L.
Alterations in the intricate balance of these 
factors can result in venous pathology.
Structure of Veins
Veins are thin-walled, highly distensible, and collapsible.
In the axial veins, unidirectional blood flow is achieved 
with multiple venous valves.
In the axial veins, valves are more numerous 
distally in the extremities than proximally.
The deep veins follow the course of major arteries in the 
extremities.
Venous bridges 
connect the paired veins in the lower leg.
The popliteal vein 
continues through the adductor hiatus to become the femoral 
vein.
Potentially 
clinically important perforator veins are the Cockett and Boyd 
perforators.
They connect the poste-
rior arch vein (a tributary to the GSV) and the posterior tibial 
vein.
They may become varicose or incompetent in venous 
insufficiency states.
These 
sinuses are valveless and are linked by valved, small venous 
channels that prevent reflux.
A large amount of blood can be 
stored in the venous sinuses.
Deep veins of the upper extremity are 
paired and follow the named arteries in the arm.
It then joins with the deep brachial 
veins to become the axillary vein.
The axillary vein becomes the subclavian vein at the lat-
eral border of the first rib.
The risk is further increased in patients with 
malignancy and a history of venous thromboembolism.
However, prophylaxis should be stratified based on the 
patient's level of risk.
5 The mainstay of treatment for chronic venous insufficiency 
is compression therapy.
6 Lymphedema is categorized as primary (with early or 
delayed onset) or secondary.
The goals of treatment are to 
minimize edema and prevent infection.
Risk factors for acute and chronic 
venous disease are identified.
24-1).
The superficial veins of a 
Figure 24-1.
Varicose vein demonstrating evidence of chronic 
venous insufficiency.
Possible signs of superficial venous abnormal-
ities are listed in Table 24-1.
CVI results from incompetence of venous valves, venous 
obstruction, or both.
The leg may also be indurated and pigmented with eczema 
and dermatitis.
24-2).
24-3).
There 
are two components to this test.
Characteristic hyperpigmentation of chronic venous 
insufficiency.
Figure 24-3.
Venous ulceration located proximal to the medial 
malleolus.
Identifiable risk factors for VTE generally 
relate to one of the conditions described by Virchow.
Often 
more than one risk factor is present.
Specific risk factors for 
VTE are listed in Table 24-2.
Heritable risk factors include male sex, factor V Leiden 
and deep veins.
The GSV valves are incompetent if the second 
component of the test yields a positive result.
Noninvasive Evaluation.
Invasive Evaluation.
Complications of venography include pain, thrombosis, 
or hematoma at the puncture site.
External compression of major veins 
by masses of various types can also lead to venous thrombosis.
Many cases of VTE are potentially preventable.
Diagnosis
Clinical Evaluation.
Isolated 
proximal DVT without tibial vein thrombosis is unusual.
Early 
in the course of a DVT, there may be no or few clinical findings 
such as pain or swelling.
Even extensive DVT may sometimes 
be present without signs or symptoms.
History and physical 
examination are therefore unreliable in the diagnosis of DVT.
Clinical symptoms may worsen as DVT propagates and 
involves the major proximal deep veins.
24-4).
This condition is char-
acterized by pain and pitting edema with associated cyanosis.
Source: Summary of recommendations from Gould MK, Garcia DA, Wren SM, et al.
Chest.
2012;141:227S.
Reproduced with permission from the American College of Chest Physicians.
Normally, in transverse section, 
the vein walls should coapt with pressure.
Lack of coaptation 
indicates thrombus.
Calf vein thrombi are often best detected 
by abnormalities in color flow imaging.
The examination begins at the ankle and continues 
proximally to the groin.
Each vein is visualized, and the 
flow signal is assessed with distal and proximal compres-
sion.
24-6), inability to compress the vein (Fig.
Again, lack of 
venous compression on B-mode imaging is the primary diag-
nostic variable.
In the supine patient, normal lower extremity venous flow 
is phasic (Fig.
Figure 24-4.
Phlegmasia cerulea dolens of the left leg.
Note the 
bluish discoloration.
Figure 24-5.
Duplex ultrasound scan of a normal femoral vein 
with phasic flow signals.
Figure 24-6.
No compressionC ompression
R  FVP R  FVP
Figure 24-7.
B-mode ultrasound of the femoral vein in cross-section.
The femoral vein does not collapse with external compression 
(arrows).
It is still, however, frequently used in research 
studies evaluating DVT prophylaxis.
Antithrombotic Therapy.
A minimum of 5 days of heparin or fondaparinux therapy is rec-
ommended.27 Recently, the U.S.
Unfractionated heparin (UFH) binds to antithrombin via 
a specific 18-saccharide sequence.
This increases antithrombin 
activity over 1000-fold.
UFH therapy is most commonly administered with an ini-
tial IV bolus of 80 units/kg.
The 
half-life of IV UFH ranges from 45 to 90 minutes and is dose 
dependent.
This should correspond with plasma heparin anti-Xa 
activity levels of 0.3 to 0.7 IU/mL.
An increase of 20% or more in one area 
of a limb indicates an area of thrombus.
Venography Venography is the gold standard to which other 
diagnostic modalities are compared.
A small catheter is placed 
in a dorsal foot vein with injection of a radiopaque contrast 
agent.
Radiographs are obtained in at least two projections.
24-8).
A normal 
1
Figure 24-8.
Venogram showing a filling defect in the popliteal 
vein (arrows).
Protamine sulfate binds to 
UFH and forms an inactive salt compound.
Side effects of protamine sulfate include hypotension, pul-
monary edema, and anaphylaxis.
Protamine adminis-
tration should be terminated if any side effects occur.
In addition to hemorrhage, heparin also has unique com-
plications.
Low molecular weight heparins (LMWHs) are derived 
from the depolymerization of porcine UFH.
However, LMWHs have fewer additional saccharide 
units.
This results in less inactivation of thrombin (factor IIa).
Moni-
toring may be performed using anti-Xa activity assays.
The ther-
apeutic anti-Xa goal range depends on the type of LMWH and 
the frequency of dosing.
Treatment dosing for one LMWH therefore 
cannot be extrapolated for use with another.
6.9% for LMWH) or major bleeding complications (2.0% for 
UFH vs.
0.5% for LMWH).
There was, however, a 67% reduc-
tion in mean days in the hospital for the LMWH group.
The half-life of fondaparinux is approximately  
17 hours in patients with normal renal function.
These 
actions are independent of antithrombin.
Commercially available hirudin is manufactured using 
recombinant DNA technology.
It is indicated for the prophy-
laxis and treatment of patients with HIT.
The half-life ranges from 30 to  
60 minutes.
The less commonly used ecarin clotting time is an alter-
native method of monitoring.
Argatroban is indicated for the prophylaxis and treatment 
of thrombosis in HIT.
In these patients, therapy is monitored 
using the activated clotting time.
There is no reversal agent 
for argatroban.
Factors X and II have the longest half-lives, in the 
range of 36 and 72 hours, respectively.
A steady-state concen-
tration of warfarin is usually not reached for 4 to 5 days.
Current ACCP recommendations 
for duration of warfarin therapy are summarized in Table 24-4.
Source: Summary of recommendations from Kearon C, Akl EA, Com-
erota AJ, et al.
Chest.
2012;141:e495S.
Reproduced with permission from the American 
College of Chest Physicians.
warfarin (0.7 events per 100 person-years vs.
secondary) than by the actual presence 
or absence of the more common thrombophilic conditions.
Fevers and shivering occur in 1% to 4% 
of patients.
Urokinase is derived from human neonatal kidney cells 
grown in tissue culture.
However, it often is used for CDT 
of DVT.
Reteplase and tenecteplase are indicated only for the 
treatment of acute myocardial infarction.
However, 
venous function was not significantly improved.
In addition, 
more bleeding complications occurred (RR 1.73).
At 6 months, iliac 
vein patency was significantly improved in the thrombolysis 
group (65.9% vs.
47.4%).
Early filters 
were placed surgically through the femoral vein.
When possible, therapy should be continued in patients 
with vena cava filters.
IVC filters are associated with acute and late complica-
tions.
24-9).
Such patients can be treated with so-called removable 
IVC filters.
Operative Venous Thrombectomy.
More 
than 90% of patients had minimal or no symptoms of PTS.
There were 12 (16%) early thrombectomy failures.
Emergency pulmonary embolectomy for 
acute PE is rarely indicated.
Patients with preterminal massive 
PE (Fig.
Mechanical clot frag-
mentation is followed by CDT.
Results of catheter-based 
fragmentation are based on small case series.
The first manifestation of VTE may be a 
life-threatening PE (Fig.
24-11), and as indicated earlier, clinical 
evaluation to detect DVT before PE is unreliable.
The distal thrombus in the 
leg is removed by manual pressure beginning in the foot.
If the thrombus 
in the femoral vein is old and cannot be extracted, the vein may 
be ligated.
The IVC is opened and the thrombus is removed by gentle mas-
sage.
An intraoperative completion venogram determines if any 
residual thrombus or stenosis is present.
Heparin is administered postoperatively for several days.
Warfarin anticoagulation is maintained for at least 6 months 
after thrombectomy.
In limbs with success-
ful thrombectomy, valvular competence in the thrombectomized 
Figure 24-9.
A
B
Figure 24-10.
Autopsy specimen showing a massive pulmonary 
embolism.
Venous Thromboembolism Prophylaxis in Nonorthopedic 
Surgery.
A composite score is created using 
assigned values for each risk factor.
The risks 
for bleeding differ, depending on the dosage.
Lower dosages 
of LMWH appear to be associated with less bleeding risk than 
Figure 24-11.
Source: Adapted with permission from Rogers SO Jr, Kilaru RK, 
Hosokawa P, et al.
J Am Coll Surg.
2007;204:1211.
Copyright © American College of Surgeons.
A validation study of retrospective ve-
nous thromboembolism risk scoring method.
Ann Surg.
2010;251:344.
Copyright Wolters Kluwer Health.
0.2%).
DVT occurred at the insertion site in 3.1% of the 
patients.
IVC patency was 97.1% at 3 years.
Fatal and nonfatal PE can still occur in patients with vena 
cava interruption.
Careful follow-up is required 
to assure all potentially removable filters are in fact removed.
Upper extremity vein 
928
SPECIFIC CONSIDERATIONS
UNIT II
PART II
of all patients with ASVT.
24-13).
A guide-
wire is traversed through the thrombus, and a catheter is placed 
within the thrombus.
Various catheter-based mechanical techniques may also be 
employed to speed thrombus removal.
Heparin is administered 
concurrently with the thrombolytic infusion.
Patients with suppurative SVT may have 
fever and leukocytosis.
Topical medications appear to improve local symptoms.
Primary ASVT occurs in only a small minority 
Figure 24-12.
Figure 24-13.
Upper extremity venogram showing stenosis of the 
right subclavian vein (arrow).
Correctable anatomic abnormalities may then be considered for 
treatment.
MVT is more common in patients with a 
hypercoagulable states, malignancy, and cirrhosis.
Patients with MVT are treated with fluid resuscitation, 
heparin anticoagulation, and bowel rest.
Once the patient’s 
 clinical status improves, oral intake can be carefully started.
Broad-spectrum antibiotics are admin-
istered perioperatively.
Operative findings consist of edema 
and cyanotic discoloration of the mesentery and bowel wall.
In 
more advanced cases, thrombus involves the distal mesenteric 
veins.
The arterial supply to the involved bowel is usually intact.
Nonviable bowel is resected, and primary anastomosis can be 
performed.
A mild amount of edema is often present.
Elastic compres-
sion provides sufficient relief of symptoms in many symptom-
atic patients.
Cosmetic concerns may lead to intervention.
Sclerotherapy acts by 
destroying the venous endothelium.
Sclerosing agents include 
hypertonic saline, sodium tetradecyl sulfate, and polidocanol.
The GSV is removed using a blunt tip catheter or an 
invagination pin stripper.
Larger varicose veins are best treated by surgical excision 
using the “stab avulsion” technique.
24-14).
In most cases the vein 
is simply avulsed with no attempt at ligation.
Importantly, severe CVI is not necessarily associ-
ated with varicose veins.
Venous reflux results from abnormalities of the venous valve.
Secondary valvular reflux is diagnosed when an identifiable 
cause is present.
The most frequent secondary cause is DVT.
The patient is asked to perform 10 tiptoe exercises.
The pressure at this point 
Figure 24-14.
Removal of varicose veins via stab avulsions.
is the AVP, which is measured in millimeters of mercury.
Elevations of AVP 
indicate venous hypertension.
The magnitude of AVP reflects 
the severity of CVI.
Noninvasive plethysmography has been 
used to evaluate CVI.
Pho-
toplethysmography provides a measurement of VRT.
In limbs 
with CVI, VRT is shortened compared with that in a normal 
limb.
AVP and VRT are only measures of the overall venous 
function of a lower extremity venous system.
They cannot local-
ize the site of reflux or evaluate the function of the calf pump.
The patient is 
then asked to assume an upright position with the examined leg 
non-weight bearing.
The venous volume of the examined leg 
is determined when the volume curve flattens.
Next, the patient performs a single 
tiptoe maneuver, and the ejection fraction (EF) is determined.
At this point, the veins of the leg are allowed to 
refill.
The residual volume fraction is 
a reflection of overall venous function.
Venous Duplex Ultrasound.
Pneumatic pressure cuffs 
of appropriate size are placed around the thigh, calf, and fore-
foot.
24-15).
The cuff is then inflated to a standard pressure for  
3 seconds and then rapidly deflated.
Compression therapy is the mainstay 
of CVI management.
24-16), and pneumatic compression devices.
The exact mechanism by which compression 
therapy can improve CVI remains uncertain.
Increases in subcutaneous tissue 
Figure 24-15.
Evaluation of a patient with chronic venous insuf-
ficiency with duplex ultrasonography.
Figure 24-16.
Multilayered dressing for treatment of chronic 
venous insufficiency.
A definitive diagnosis of venous ulceration must be made before 
treatment is initiated.
Arterial insufficiency 
is assessed by physical examination or noninvasive studies.
Compression therapy is most commonly achieved with 
graduated elastic compression stockings.
6 of 11 patients (55%) who were noncompliant  
(P < .0001).
The mean time to ulcer healing was 5 months.
Patients 
were treated with 30- to 40-mmHg elastic compression stock-
ings.
Further improve-
ments were noted at 16 months after treatment.
They may also have difficulty applying elastic stockings.
24-17), and metal fitting aids (Fig.
24-18), are available to 
assist patients in applying elastic stockings.
Another method of compression was developed by the 
German dermatologist Paul Gerson Unna.
Unna’s boot has 
5
932
SPECIFIC CONSIDERATIONS
UNIT II
PART II
Figure 24-17.
Elastic compression device with Velcro to facilitate 
treatment of chronic venous insufficiency.
Figure 24-18.
Metal fitting aid to assist in placement of elastic 
compression stockings.
been used for many years to treat venous ulcers and is available 
in many versions.
The bandage 
becomes stiff after drying, and the rigidity may aid in prevent-
ing edema formation.
However, Unna’s boot has several disadvantages.
It 
is bulky and can be uncomfortable, which may affect patient 
compliance.
Occasionally, 
patients may also develop contact dermatitis to the components 
of Unna’s boot.
The efficacy of Unna’s dressing has been studied.
The median time to healing for 
individual ulcers was 9 weeks.
Unna’s dressing has been com-
pared to other forms of treatment.
It 
must be used within 5 days of release from the manufacturer111  
(Fig.
24-19).
The disk is easily handled and applied and con-
forms to irregularly contoured ulcer beds.
49%, P = .02).
181 days, P = .003).
No evidence of rejection or sensitization has 
been reported in response to Apligraf application.
Surgical/Interventional Treatment of Chronic 
Venous Insufficiency
Perforator Vein Ligation.
The patient is posi-
tioned on the operating table with the affected leg elevated at 
45° to 60°.
An Esmarch bandage and a thigh tourniquet are used 
to exsanguinate the limb.
Carbon dioxide is 
then used to insufflate the subfascial space.
The thigh tourni-
quet is inflated to prevent air embolism.
The perforators are then 
identified and doubly clipped and divided.
After completion of 
Figure 24-19.
Apligraf skin graft material supplied as a disk on an 
agarose gel nutrient medium.
the procedure, the leg is wrapped in a compression bandage for 
5 days postoperatively.
In 
a report from a large North American registry of 146 patients 
undergoing SEPS113 (Fig.
24-20), healing was achieved in 88% 
of ulcers (75 of 85) at 1 year.
Adjunctive procedures, primarily 
superficial vein stripping, were performed in 72% of patients.
Ulcer recurrence was predicted to be 16% at 1 year and 28% at 
2 years by life table analysis.
These results are similar to those 
achieved in some studies with compression therapy alone.
Superficial Venous Surgery.
compression alone 
in the treatment of venous ulcer.
Trocar placement for subfascial endoscopic perfo-
rator vein surgery.
(Used with permission of Dr.
The outcomes for venous 
transposition are similar to those for valve transplantation.
Venous Stenting.
Currently there is great interest in the role 
of venous stents in the treatment of CVI.
The original classification system, described by Allen, 
is based on the cause of the lymphedema.
Lymphedema praecox is the most 
common form of primary lymphedema, accounting for 94% of 
cases.
Lymphedema praecox is far more common in women, 
with the gender ratio favoring women 10:1.
The onset is during 
childhood or the teenage years, and the swelling involves the 
foot and calf.
Lymphedema tarda is uncommon, accounting for 
<10% of cases of primary lymphedema.
The onset of edema is 
after 35 years of age.
Secondary lymphedema is far more common than primary 
lymphedema.
Secondary lymphedema develops as a result of 
lymphatic obstruction or disruption.
Patients 
commonly complain of heaviness and fatigue in the affected 
extremity.
The limb, however, never completely nor-
malizes.
24-21).
Recurrent cellulitis is a common complication of lymph-
edema.
Repeated infection results in further lymphatic damage, 
worsening existing disease.
Many medical conditions can cause edema.
Venous insufficiency is often confused 
with lymphedema.
Bilateral pitting edema is 
Figure 24-21.
Patient with severe longstanding lymphedema.
Radiologic Diagnosis
Duplex Ultrasound.
They are invasive and tedious and rarely 
change the management of a patient with lymphedema.
Lymphoscintigraphy.
It has largely replaced lymphangiography.
24-22).
Within 
3 hours, uptake should be present in the pelvic and abdominal 
lymph nodes.
In patients with lymphedema, various patterns 
may be seen on lymphoscintigraphy.
There may be delayed 
or absent transport to the inguinal nodes.
Increased cutaneous 
Figure 24-22.
Lymphoscintigraphy of the lower extremity.
collaterals may be seen with obstruction of the primary axial 
channels.
Lymphangiography.
An oil-based dye is then injected slowly into the 
lymphatics over several hours.
The lymphatic channels and nodes 
are then visualized with traditional radiographs (Figs.
24-23 and 
24-24).
The primary goals of treatment are to minimize swelling and 
to prevent recurrent infections.
Graded compression stockings 
are widely used in the treatment of lymphedema.
Normal lymphangiogram of the pelvis.
936
SPECIFIC CONSIDERATIONS
UNIT II
PART II
among patients.
The 
stockings should be worn during waking hours.
The garments 
should be replaced approximately every 6 months when they 
lose elasticity.
Bedrest and Leg Elevation.
Elevation is an adjunct to lymphedema ther-
apy but is not the mainstay of treatment.
Intermittent Pneumatic Compression Therapy.
Staphylococcus and β-hemolytic 
Figure 24-24.
Normal lymphangiogram of the thigh and lower leg.
Streptococcus are the most common organisms causing soft tis-
sue infection.
The drug of choice is penicillin or a cephalosporin 
active against Streptococcus for 5 days.
A variety of surgical procedures have been devised 
for the treatment of lymphedema.
This does not 
improve lymphatic drainage but debulks redundant tissue.
Controlling the edema protects the skin and potentially 
prevents cellulitis.
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2010;51:401.
120.
Masuda EM, Kistner RL.
Long-term results of venous valve 
reconstruction: a four- to twenty-one-year follow-up.
J Vasc 
Surg.
1994;19:391.
121.
Rockson SG, Miller LT, Senie R, et al.
American Cancer Soci-
ety Lymphedema Workshop.
Workgroup III: diagnosis and 
management of lymphedema.
Cancer.
1998;83:2882.
122.
Yasuhara H, Shigematsu H, Muto T.
A study of the advan-
tages of elastic stockings for leg lymphedema.
Int Angiol.
1996;15:272.
123.
Feldman JL, Stout NL, Wanchai A, et al.
Intermittent pneu-
matic compression therapy: a systematic review.
Lymphology.
2012;45:13.
124.
Vodder E.
Le Drainage Lymphatique, une Novelle Méthode 
Thérapeutique.
Paris: Santé pour tous; 1936.
125.
Ko DS, Lerner R, Klose G, et al.
Effective treatment of lymph-
edema of the extremities.
Arch Surg.
1998;133:452.
126.
Stevens DL, Bisno AL, Chambers HF, et al.
Practice guide-
lines for the diagnosis and management of skin and soft tissue 
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Clin Infect Dis.
2005;41:1373.
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Miller TA, Wyatt LE, Rudkin GH.
Staged skin and subcutane-
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Plast Reconstr Surg.
1998;102:1486.
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Baumeister RG, Siuda S.
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This page intentionally left blank 
Esophagus and Diaphragmatic 
Hernia
Blair A.
Jobe, John G.
Hunter, and David I.
25-1).
25-2).
Its luminal 
diameter is 1.5 cm, and it is the narrowest point of the esopha-
gus.
The luminal diam-
eter at this point is 1.6 cm.
Laparoscopic hiatal hernia 
repair with fundoplication is the most common approach to 
repair.
5 Achalasia is the most common primary esophageal motor 
disorder.
It 
is best treated with laparoscopic Heller myotomy and par-
tial fundoplication.
a
b
c
d
e
A  
B
sphincter mechanism.
Manometrically, the length of the esophagus between 
Figure 25-1.
A.
B.
Lat-
eral radio-graphic appearance with 
landmarks identified as labeled in  
A.
The location of C6 is also included 
(f).
25-4).
The opening of 
the esophagus is collared by the cricopharyngeal muscle, which 
A
B
Figure 25-2.
Barium esophagogram.
A.
Posterior-anterior view.
White arrow shows deviation to left.
Black arrow shows return to midline.
B.
Lateral view.
Black arrow shows anterior deviation.
Important clinical endoscopic measurements of the 
esophagus in adults.
Philadelphia: Lea & 
Febiger, 1989, p 78.)
 Superior pharyngeal 
constrictor m.
Middle pharyngeal
 constrictor m.
Inferior pharyngeal
 constrictor m.
Cricopharyngeus m.
Esophagus
BA
Figure 25-4.
External muscles of the pharynx.
A.
Posterolateral 
view.
B.
Posterior view.
Dotted line represents usual site of myot-
omy.
Keith 
in 1910 showed that these two parts of the same muscle serve 
totally different functions.
The thoracic portion of the esophagus is approximately 
20 cm long.
It starts at the thoracic inlet.
Just above the tracheal 
bifurcation, the esophagus passes to the right of the aorta.
25-5).
25-6).
25-7).
This portion of the 
esophagus is subjected to the positive-pressure environment of 
the abdomen.
The upper 2 to 6 cm 
of the esophagus contains only striated muscle fibers.
From 
then on, smooth muscle fibers gradually become more abun-
dant.
When a surgical esophageal myotomy is indicated, 
the incision needs to extend only this distance.
25-4).
Figure 25-5.
A.
Cross-section of the thorax at the level of the tracheal bifurcation.
B.
Contraction of 
the longitudinal muscle fibers shortens the esophagus.
The cir-
cular muscle layer of the esophagus is thicker than the outer 
longitudinal layer.
Two esophageal branches arise directly from the aorta.
A.
Cross-section of the thorax at the midleft atrial level.
B.
Attachments and structure of the phrenoesophageal 
membrane.
Transversalis fascia lies just above the parietal perito-
neum.
25-8).
Arterial blood supply of the esophagus.
25-9).
25-10).
Venous drainage of the esophagus.
Innervation of the esophagus.
Philadelphia: Lea & Febiger, 1989, p 85.)
pathways.
25-11).
Lymphatic drainage of the esophagus.
Curr Probl Surg 25:498, 1988.
The three 
valves in the pharyngeal cylinder are the soft palate, epiglottis, 
and cricopharyngeus.
The valve of the esophageal pump is the 
LES.
Once 
initiated, swallowing is entirely a reflex act.
25-12).
25-12).
The backward tilt 
of the epiglottis covers the opening of the larynx to prevent aspi-
ration.
The entire pharyngeal part of swallowing occurs within 
1.5 seconds.
1.
Elevation of tongue
2.
Posterior movement of tongue
3.
Elevation of soft palate
4.
Elevation of hyoid
5.
Elevation of larynx
6.
Tilting of epiglottis
1
2
3
4
5 6
Figure 25-12.
Sequence of events during the oropharyngeal phase 
of swallowing.
I.
Philadelphia: W.B.
Saunders, 1991, p 95.
25-13).
Med Clin 
North Am 65:1237, 1981.
The 
postrelaxation contraction continues down the esophagus as a 
peristaltic wave (Fig.
25-14).
Intraluminal esophageal pressures in response 
to swallowing.
Med Clin North Am 65:1238, 1981.
In 
more severe injury, swallowing can be grossly disrupted, lead-
ing to repetitive aspiration.
The pharyngeal activity in swallowing initiates the 
esophageal phase.
25-13).
The peristaltic wave generates an occlusive pressure vary-
ing from 30 to 120 mmHg (see Fig.
25-14).
This allows a sleeve resection of the esophagus to be done 
without destroying its normal function.
This secondary contraction occurs 
without any movements of the mouth or pharynx.
Current studies suggest that secondary peri-
stalsis is not as common as once thought.
25-15).
25-14).
Wall thickness and orientation of fibers on micro-
dissection of the cardia.
Consequently, there are fewer opportunities for reflux to 
occur in the supine position.
This gradient favors the flow of gastric 
juice up into the thoracic esophagus when upright.
The gradi-
ent diminishes in the supine position.
The LES has intrinsic myogenic tone, which is modu-
lated by neural and hormonal mechanisms.
It is not clear 
to what extent cholinergic nerve activity controls LES pressure.
The vagus nerve carries both excitatory and inhibitory fibers to 
the esophagus and sphincter.
Tests to Detect Structural Abnormalities
Endoscopic Evaluation.
Many different grading systems have 
been proposed.
25-16).
Grade IV esophagitis is the presence of a 
stricture.
Its severity can be assessed by the ease of passing a 
36F endoscope.
When a stricture is observed, the severity of the 
esophagitis above it should be recorded.
25-16).
Histologically, it 
appears as intestinal metaplasia (IM).
Its presence is confirmed by biopsy.
The earliest sign of the latter is high 
grade dysplasia or intramucosal adenocarcinoma (Fig.
25-16).
Changes seen 
in one biopsy are significant.
25-17).
When a submucosal mass is identified, 
biopsy specimens are usually not performed.
This complicates the surgical dissec-
tion by increasing the risk of mucosal perforation.
Endoscopic 
ultrasound provides a better method for evaluating these lesions.
Radiographic Evaluation.
Barium swallow evaluation is 
undertaken selectively to assess anatomy and motility.
25-18), or the hernia is of the paraesopha-
geal variety.
These include small esophageal  
A
CD
B
Figure 25-16.
Complications of reflux disease as seen on endoscopy.
A.
Linear erosions of grade II esophagitis.
B.
Uncomplicated Barrett’s 
mucosa.
C.
High Grade dysplasia in Barrett’s mucosa, D.
Early adenocarcinoma arising in Barrett’s mucosa.
neoplasms, mild esophagitis, and esophageal varices.
952
SPECIFIC CONSIDERATIONS
UNIT II
PART II
B
A
C
Figure 25-17.
A.
Grade I flap valve appearance.
Note the ridge of tissue that is closely approximated to the shaft of the retroflexed endo-
scope.
It extends 3–4 cm along the lesser curve.
B.
Grade II flap valve appearance.
C.
Grade III flap valve appearance.
The ridge is barely present, and there is often failure 
to close around the endoscope.
It is nearly always accompanied by a hiatal hernia.
D.
Grade IV flap valve appearance.
There is no muscular 
ridge at all.
A 
hiatal hernia is always present.
(Reproduced with permission from Hill LD, Kozarek RA, et al.: The gastroesophageal flap valve.
In vitro and 
in vivo observations.
Gastrointest Endosc.
44:541, 1996.
In these situations, esophageal 
function tests are necessary to identify a functional disorder.
Stationary Manometry.
Manometry is indicated whenever a motor 
D
Figure 25-17.
(Continued )
Figure 25-18.
Radiogram of an intrathoracic stomach.
This is the end 
stage of a large hiatal hernia, regardless of its initial classification.
Other specially designed catheters can be used to assess 
the upper sphincter.
25-19).
To 
account for the asymmetry of the sphincter (Fig.
Overall length
Pressure
10 sec.
Esophageal
baseline
pressure Abdominal length
Gastric
baseline
pressure
Figure 25-19.
Manometric pressure profile of the lower esopha-
geal sphincter.
The distances are measured from the nares.
Am J Surg.
155:105, 1988.
Copyright Elsevier.)
LA
LP
L
P
A
RP
R
RA
25
0
50
Figure 25-20.
Radial configuration of the lower esophageal 
sphincter.
Dig Dis Sci 22:348, 1977.
(eds): Surgical 
Treatment of Digestive Disease.
Chicago: Year Book Medical, 1990,  
p 89.
Copyright Elsevier.
Ten 
wet swallows (5 mL water each) are performed.
Ten wet swallows are recorded.
The data are used to identify motor 
disorders of the esophagus.
High-Resolution Manometry.
25-21).
Powerful, computer-
based, and easy-to-use tools give unprecedented data analysis 
capability.
Esophageal Impedance.
Air has a very low electrical con-
ductivity and, therefore, high impedance.
Saliva and food cause 
an impedance decrease because of their increased conductivity.
25-22).
Until recently, this dif-
ferentiation could not be made.
Esophageal Transit Scintigraphy.
Normal high-resolution manometry motility study.
Pressure measurements are recorded with color coding (red = high;  
blue = low).
LES = lower esophageal sphincter; PIP = pressure inversion point; UES = upper esophageal sphincter.
Note the 
absence of lower esophageal sphincter tone.
Pressure measurements are recorded with color coding (red = high; blue = low).
LES = lower esophageal sphincter; PIP = pressure inversion point; UES = upper esophageal sphincter.
High-resolution manometry motility study in patient with deficient esophageal body peristalsis.
Note the very weak peri
-
stalsis in the lower two-thirds of the esophagus.
Pressure measurements are recorded with color coding (red = high; blue = low).
LES = lower esophageal sphincter; PIP = pressure inversion point; UES = upper esophageal sphincter.
High-resolution manometry motility study in patient with achalasia.
Pressure measurements are recorded with color coding (red = high; blue = low).
LES = lower esophageal sphincter; PIP = pressure inversion point; UES = upper esophageal sphincter.
High-resolution manometry motility study in patient with diffuse esophageal spasm.
LES = lower esophageal sphincter; PIP = pressure inversion point; UES = upper esophageal sphincter.
25-23).
Esophageal impedance probe measures electrical 
resistance between evenly spaced electrodes.
LES = lower esopha-
geal sphincter.
abnormal motility of the esophageal body.
Tests to Detect Increased Exposure  
to Gastric Juice
24-Hour Ambulatory pH Monitoring.
It passes spon-
taneously within 1 to 2 weeks.
Esophagograms from a patient with cricopharyngeal achalasia.
A.
B.
3.
Benign Esophageal Disease.
St.
Louis: Mosby, 1987, p 345.
25-24).
The upper limits of normal were established at the 
ninety-fifth percentile.
Most centers use pH 4 as the threshold.
mp = meal period; sp = supine period.
I.
Philadelphia: 
W.B.
Saunders, 1991, p 119.
of episodes 19.00 12.76 46.90
No.
>5 min 0.84 1.18 3.45
Longest episode 6.74 7.85 19.80
SD = standard deviation.
(eds): Surgical 
Treatment of Digestive Disease.
Chicago: Year Book Medical, 1990, 
p 68.
Copyright Elsevier.
The latter is suggested by an 
increased alkaline exposure time above pH 7 or 8.
(eds): Surgical 
Treatment of Digestive Disease.
Chicago: Year Book Medical, 1990,  
p 69.
Copyright Elsevier.
25-27).
Generally, 48 hours of pH data are measured with 
this probe.
The capsule eventually detaches and passes 
through the digestive tract in 5 to 7 days.
Radiographic Detection of Gastroesophageal Reflux.
Gastric Emptying.
Gastric emptying studies are performed 
with radionuclide-labeled meals.
The resulting emptying 
curve can be compared with data obtained in normal volunteers.
In general, normal subjects will empty 59% of a meal within 
90 minutes.
24-Hour Gastric pH Monitoring.
The latter is 
divided into the time spent upright and supine.
25-25).
A.
B.
The gastric tracing (lower) is taken 
from a probe lying 5 cm below the upper esophageal sphincter.
I.
Philadelphia: W.B.
Saunders, 
1991, p 123.
The most simplistic approach is to define the disease by 
its symptoms.
Even when 
excessive, these symptoms are not specific for gastroesophageal 
reflux.
It is commonly, although not universally, relieved by 
antacid or antisecretory medications.
When questioned, most patients can distinguish the two.
Esophageal dysphagia refers to the sensation of food sticking in 
the lower chest or epigastrium.
esophageal origin.
One 
person’s heartburn is another’s chest pain.
Considerable insight has been acquired, however.
The Lower Esophageal Sphincter.
25-26).
The most 
common cause of a defective sphincter is an inadequate abdomi-
nal length.
LES = 
lower esophageal sphincter.
be healed with antisecretory medication, reflux will continue 
to occur.
Reflux may occur in the 
face of a normal LES resting pressure.
Relationship Between Hiatal Hernia and Gastroesopha-
geal Reflux Disease.
25-27).
Yield pressure of the lower esophageal sphincter 
decreases as hiatal hernia size increases.
Summary.
It is believed that GERD has its origins within the 
stomach.
The increased swallow-
ing results in aerophagia, bloating, and belching.
The com-
ponent of duodenal juice thought to be most damaging is bile 
acids.
Conjugation increases the sol-
ubility and ionization of bile acids by lowering their pKa.
Acidification of bile to below pH 2 results in an 
irreversible bile acid precipitation.
(eds): Surgical 
Treatment of Digestive Disease.
Chicago: Year Book Medical, 1990,  
p 81.
Copyright Elsevier.
968
SPECIFIC CONSIDERATIONS
UNIT II
PART II
aspiration studies (Fig.
25-28).
25-29).
25-30).
umol/l
0
Figure 25-28.
A.
Prevalence of reflux types in 53 patients with 
gastroesophageal reflux disease.
B.
Esophageal luminal pH during 
bilirubin exposure.
Ann Surg.
(*P<.03 vs all other 
groups, **P <.03 vs.
Ann Surg.
222:525, 1995.)
969
Esophagus and Diaphragmatic Hernia
CHAPTER 25
eventually intramural fibrosis.
Second, the tubular esophagus 
may become replaced with columnar epithelium.
This specialized IM is currently 
required for the diagnosis of BE.
This continued injury is pH 
dependent and may be modified by medical therapy.
An esophageal stricture can be associated with severe 
esophagitis or BE.
In such patients, dila-
tion usually corrects the problem of dysphagia.
Heartburn, which 
may have occurred only because of the chemical injury, need not 
be treated.
These strictures are often resistant 
to dilation.
He incorrectly 
believed it to be congenital in origin.
The definition of BE has evolved considerably over the 
past decade.
The hallmark of IM is the presence of intestinal goblet 
cells.
Most patients with BE are symptomatic.
Gastric hypersecretion occurs 
in 44% of patients.
Fortunately 
this complication occurs very rarely.
Adenocarcinoma developing in Barrett’s 
mucosa was considered a rare tumor before 1975.
Most, if not all, cases of adenocarcinoma of the esophagus 
arise in Barrett’s epithelium (Fig.
25-31).
About one-third of all 
patients with BE present with malignancy.
Etiology of Reflux-Induced Respiratory Symptoms.
Next, with ambulatory pH testing, acid 
AB
Figure 25-31.
Photomicrographs.
A.
Barrett’s epithelium with severe dysplasia.
(×200.) Note nuclear irregularity, stratification, and loss of 
polarity.
B.
Barrett’s epithelium with intramucosal carcinoma.
I.
Philadelphia: W.B.
Saunders, 1991,  
p 113.
Treatment.
Improvements in pulmonary function can be 
demonstrated in around 30% of patients.
Medical Therapy for Gastroesophageal Reflux Disease.
This approach may successfully and completely resolve 
the symptoms.
In patients with persistent symptoms, the mainstay of 
medical therapy is acid suppression.
This usu-
ally heals mild esophagitis.
In severe esophagitis, healing may 
occur in only one-half of the patients.
This can allow persistent mucosal damage in an 
asymptomatic patient.
However, this hypothesis 
remains controversial.
Suggested Therapeutic Approach.
Traditionally a stepwise 
approach is used for the treatment of GERD.
First-line therapy 
entails antisecretory medication, usually PPIs, in most patients.
Treatment options for these patients entails either long 
term PPI use vs.
antireflux surgery.
These studies will serve to establish the diagnosis 
and assess esophageal body dysfunction.
Surgical Therapy for Gastroesophageal  
Reflux Disease
Selection of Patients for Surgery.
These patients are prone to breakthrough of 
their symptoms while receiving medical therapy.
Patients with BE are at risk of the development of 
an adenocarcinoma.
Preoperative Evaluation.
Before proceeding with an antire-
flux operation, several factors should be evaluated.
The clinical 
symptoms should be consistent with the diagnosis of gastro-
esophageal reflux.
973
Esophagus and Diaphragmatic Hernia
CHAPTER 25
Hiatal anatomy should also be assessed.
When identified these surgeons usually undertake 
add a gastroplasty to the antireflux procedure.
Principles of Surgical Therapy.
This will result in an increase in 
the pressure of the distal esophageal sphincter region.
25-32).
25-33).
However, the aim of any fundoplication 
Distention
Figure 25-32.
Am J 
Surg.
143:43, 1982.
Third, the operation should allow the reconstructed car-
dia to relax on deglutition.
A 360° gastric wrap should be no longer than 2 cm and 
constructed over a large (50 to 60F) bougie.
A bougie is not necessary when construct-
ing a partial wrap.
Procedure Selection.
Primary Antireflux Repairs
Nissen Fundoplication.
The most common antireflux proce-
dure is the Nissen fundoplication.
Hiatal dissection and preservation of both vagi along their 
entire length
2.
Circumferential esophageal mobilization
3.
Hiatal closure, usually posterior to the esophagus
4.
Patient positioning and trocar placement for lap-
aroscopic antireflux surgery.
The patient is placed with the head 
elevated approximately 30° in the modified lithotomy position.
Five ports are usually used (Fig.
A tension-free fundopli-
cation should be constructed.
A.
Laparoscopic Nissen fundoplication is performed with a five-trocar technique.
B.
The liver retractor is affixed to a mechani-
cal arm to hold it in place throughout the operation.
C.
D.
The grasper is withdrawn, pulling the posterior aspect of 
the gastric fundus behind the esophagus.
E.
F.
Final position of the fundoplication.
The fundic lips are manipulated to 
allow the fundus to envelop the esophagus without twisting.
Some surgeons 
use a single U-stitch of 2-0 polypropylene buttressed with felt 
pledgets (Fig.
25-35), and others use 2-4 interrupted sutures.
Posterior Partial Fundoplication.
The commonest approach has been a posterior partial or Toupet 
fundoplication.
25-36).
It is usually stabilized by anchoring the 
wrap posteriorly to the hiatal rim.
Anterior Partial Fundoplication.
(Continued )
Figure 25-36.
Completed laparoscopic posterior partial (Toupet) 
fundoplication.
rim and the esophageal wall.
Various degrees of anterior partial fundoplication have 
been described—90°, 120°, 180°.
The anterior 180° partial fun-
doplication (Fig.
Figure 25-37.
Completed laparoscopic anterior 1800 partial fundo-
plication.
Unlike the Nissen 
procedure, the fundus is not pulled behind the esophagus.
977
Esophagus and Diaphragmatic Hernia
CHAPTER 25
Collis Gastroplasty.
The commonest 
approach to this is the Collis gastroplasty.
Laparoscopic techniques for 
Collis gastroplasty have been described (Fig.
25-38).
A.
The interior end of the staple line is marked 2/5 cm below the angle of His.
B.
C.
D.
Outcome after Fundoplication.
national trends in use and 
outcomes.
Postoperative pH studies indicate that more than 
90% of patients will normalize their pH tracings.
The challenge is to accomplish this without inducing 
dysphagia or other untoward side effects.
Dysphagia, existing 
before surgery, usually improves following laparoscopic fun-
doplication.
Most patients cannot vomit through an intact wrap, 
though this is rarely clinically relevant.
without division of the 
short gastric vessels.
Nissen vs.
Posterior Partial Fundoplication Eleven ran-
domized trials have compared Nissen vs.
posterior partial 
fundoplication.
Lundell et al reported the outcomes of Nissen vs.
Strate et al reported 2 year follow-up in 
a trial that enrolled 200 patients.
8 patients).
Only Booth et al.
demonstrated less dysphagia following posterior fundoplication.
without poor preoperative 
oesophageal motility.
Nissen vs.
Anterior Fundoplication Six trials have evaluated 
Nissen vs.
anterior partial fundoplication variants.
Four have 
assessed Nissen vs.
Two trials compared laparoscopic anterior 90° partial 
fundoplication vs.
Nissen fundoplication (Watson et al–112 
patients, Spence et al–79).
Satisfaction with the overall outcome 
was similar for both fundoplication variants.
Anterior vs.
posterior partial fundoplication Two random-
ized trials have directly compared anterior vs.
posterior par-
tial fundoplication.
Hagedorn et al randomized 95 patients to 
undergo either Toupet vs.
anterior 120° partial fundoplication, 
and Khan et al enrolled 103 patients to anterior 180° vs.
979
Esophagus and Diaphragmatic Hernia
CHAPTER 25
posterior partial fundoplication.
Outcome of Antireflux Surgery in Patients with Barrett’s 
Esophagus.
Parrilla and colleagues reported the only randomized trial 
to evaluate this issue.
They enrolled 101 patients over 18 years 
(1982 to 2000), and median follow-up was 6 years.
About 15 % of patients had abnormal 
acid exposure after surgery.
Within the 
control arm of a randomized trial of ablation vs.
surveillance.
Biopsy specimens should be reviewed by 
a pathologist with expertise in the field.
Reoperation for Failed Antireflux Repairs.
Table 25-7
Symptomatic outcome of surgical therapy for Barrett's esophagus
AUTHOR yEAR NO.
When dysphagia is the cause of failure, the situation can 
be more difficult to manage.
25-39C).
In this situation the 
abnormality is usually referred to as an intrathoracic stomach  
(Fig.
25-39D).
When radiographic 
Figure 25-39.
A.
Radiogram of a type I (sliding) hiatal hernia.
B.
Radiogram of a type II (rolling or paraesophageal) hernia.
C.
Radiogram 
of a type III (combined sliding-rolling or mixed) hernia.
D.
Radiogram of an intrathoracic stomach.
This is the end stage of a large hiatal 
hernia regardless of its initial classification.
The PEH is also known as the giant hiatal hernia.
Over time the 
pressure gradient between the abdomen and chest enlarges 
the hiatal hernia.
In many cases the type 1 sliding hernia will 
evolve into a type III mixed hernia.
Type II hernias are quite rare.
The median age 
of the former is 61 years old; of the latter, 48 years old.
PEHs are 
more likely to occur in women by a ratio of 4:1.
There is usually a 
C
D
Figure 25-39.
Repair of the hernia without addressing the reflux can cre-
ate extremely bothersome heartburn.
The association of anemia and PEH is best proven by fixing 
the hernia.
Anemia is corrected in >90% of patients with this 
condition.
In contrast, many patients with PEH 
are asymptomatic or complain of minor symptoms.
Mano-
metrically, this is reflected by a double-humped high-pressure 
zone at the GEJ.
Consequently, this abnormality is 
often confused with typical GERD.
Surgical reduction of the 
hernia results in relief of the dysphagia in 91% of patients.
This is usually caused by a PEH or an intrathoracic 
stomach.
25-39B and C).
25-40).
Surprisingly, 
esophageal peristalsis in patients with PEH is normal in 88%.
Treatment
The treatment of paraesophageal hiatal hernia is largely surgi-
cal.
Indications and Surgical Approach.
This recommendation is largely 
Figure 25-40.
Note the gastric rugal folds extending 
above the impression caused by the crura of the diaphragm.
Second, emergency repair carries a high mortality.
For the most part, these catastrophes occurred 
without warning.
Others have reported similar findings.
Recent studies suggest that catastrophic complications 
may be somewhat less common.
Watchful waiting of asymptomatic PEHs 
may be an acceptable option.
Each has its advantages and disadvantages.
Laparoscopic repair of PEH would appear to have become 
the standard approach.
There are several reasons for this.
Techniques to reduce hernia recurrence 
continue to evolve.
Role of Fundoplication in Giant Hiatal Hernia 
Repair.
There are several reasons for this.
The presence of a short esophagus increases 
the difficulty of laparoscopic PEH repair.
Hence, the diagnosis of this entity continues to be made 
definitively only in the operating room.
The risk of 
incarceration, strangulation, or obstruction is minimal.
Its significance and pathogenesis are 
unclear (Fig.
25-41).
Below the ring is a hiatal hernia.
the esophagus.
They also have better LES function.
Little is known about the natural progres-
sion of Schatzki’s rings.
In most, the 
disease follows a prolonged course.
Renal involvement occurs 
in a small percentage of patients and signals a poor prognosis.
In the GI tract, 
the predominant feature is smooth muscle atrophy.
25-42).
The LES pressure is progressively 
weakened as the disease advances.
This combined defect can lead 
to severe esophagitis and stricture formation.
25-43).
Only 50% of the patients have a good-to-excellent 
result.
Med Clin North Am.
65:1252, 
1981.
Copyright Elsevier.)
Figure 25-43.
Barium esophagogram of a patient with scleroderma 
and stricture.
Note the markedly dilated esophagus and retained 
food material.
Med Clin North Am.
65:1253, 1981.
Dysphagia may occur with liquids 
or solids, but solid food dysphagia is most common.
Signs
A barium swallow should be the first test obtained in the patient 
with dysphagia.
25-44).
25-45).
Pathology
Endoscopic biopsy specimens should be taken when eosino-
philic esophagus is suspected.
25-46).
If dysphagia is not 
relieved with steroids, it may be necessary to dilate the esopha-
gus.
Great care must be 
exercised, as the inflamed EE is quite friable.
Figure 25-44.
The esophagus on the left shows a 
stacking of rings, demonstrating eosinophilic esopha-
gus.
The esophagus on the right is a normal barium 
swallow.
Figure 25-45.
Diagnostic Assessment of the Cricopharyngeal Segment.
A cluster of eosinophils are visualized in the esophageal epithelium in a patient with EE.
segment, and the dynamics of airway protection during swal-
lowing.
It readily identifies a diverticulum (Fig.
A.
Zenker’s diverticulum, initially discovered 15 years 
ago and left untreated.
B.
Note its marked enlargement and evi-
dence of laryngeal inlet aspiration on recent esophagogram.
Med Clin North 
Am.
65:1257, 1981.
Copyright Elsevier.)
988
SPECIFIC CONSIDERATIONS
UNIT II
PART II
most situations (Fig.
25-48).
A.
Schematic drawing of a pharyngeal pressure 
wave indicating the presence of the bolus pressure.
B.
UES = upper esophageal 
sphincter.
Gastroenterology.
25-49).
This enlarges the pharyngoesophageal segment and reduces 
outflow resistance.
Zenker’s Diverticulum.
Chronic aspiration and repetitive respiratory infec-
tion are common associated complaints.
Once suspected, the 
diagnosis is established by a barium swallow.
Cricopharyngeal Myotomy.
This attitude has resulted in an overall success rate in the relief 
of symptoms of only 64%.
Open Cricopharyngeal Myotomy, Diverticulopexy, and 
Diverticulectomy.
25-50).
It can be difficult to identify the cricopha-
ryngeus muscle in the absence of a diverticulum.
Med Clin North Am.
65:1257, 
1981.
Copyright Elsevier.)
pharyngoesophageal segment.
Oral alimentation is started the 
day after surgery.
The patient is usually discharged on the first 
or second postoperative day.
25-51).
Endoscopic Cricopharyngotomy.
Endoscopic stapled crico-
pharyngotomy and diverticulotomy recently has been described.
More than one stapler application may be needed, depending on 
the size of the diverticulum (Fig.
25-52).
Consequently, after myotomy, there is protection against esoph-
agopharyngeal regurgitation.
body or the relaxation of the LES.
The manometric characteristics of these disorders are 
shown in Table 25-9.
Achalasia.
The technique for transoral cricopharyngotomy and 
Zenker’s diverticulotomy.
I.
Philadelphia: W.B.
Saunders, 1991, p 115.
Copyright Elsevier.
25-53).
25-54).
As the disease progresses, the esophagus becomes massively 
dilated and tortuous.
Pressurization of esophagus: Ambulatory motility 
tracing of a patient with achalasia.
A.
Before esophageal myotomy.
B.
After esophageal myotomy.
The tracings have been compressed 
to exaggerate the motility spikes and baseline elevations.
No such rise occurs 
postmyotomy (panel B).
992
SPECIFIC CONSIDERATIONS
UNIT II
PART II
are a common finding in these patients.
Diffuse and Segmental Esophageal Spasm.
DES is charac-
terized by substernal chest pain and/or dysphagia.
Nonetheless, it is impossible to differentiate achalasia 
from DES on the basis of symptoms alone.
Esophagogram and 
esophageal manometry are required to distinguish these two 
entities.
The causation and neuromuscular pathophysiology of 
DES are unclear.
Figure 25-54.
Med Clin North 
Am.
65:1244, 1981.
However, this figure 
is arbitrary and often debated.
The LES in patients with DES usually shows a normal 
resting pressure and relaxation on swallowing.
A hypertensive 
sphincter with poor relaxation may also be present.
25-55).
25-56).
Nutcracker Esophagus.
The disorder, termed nutcracker or 
supersqueezeresophagus, was recognized in the late 1970s.
It is the most 
common of the primary esophageal motility disorders.
Contraction amplitudes in these patients can easily be above  
400 mmHg.
At the lower end of peak pressure, it is unclear 
whether nutcracker esophagus causes any symptoms.
In fact, 
Figure 25-55.
Barium esophagogram of patient with diffuse 
spasm showing the corkscrew deformity.
Treatment in these patients should be aimed at the treatment 
of GERD.
Hypertensive Lower Esophageal Sphincter.
In the remainder, the disorder exists as an isolated 
abnormality.
Myotomy of the LES may be indicated in patients not respond-
ing to medical therapy or dilation.
Secondary Esophageal Motility Disorders.
Figure 25-56.
Symptoms of these disorders are heartburn and dysphagia.
The latter may be a result of a peptic stricture rather than the 
esophageal dysmotility.
Nonspecific Esophageal Motor Disorders and Ineffec-
tive Esophageal Motility.
These motility 
abnormalities have been termed nonspecific esophageal motility 
disorders.
Their significance in the causation of chest pain or 
dysphagia is still unclear.
Diverticula of the Esophageal Body.
Conse-
quently, earlier texts focused on them as specific entities based 
upon their location.
When a large diverticulum is associated with 
a hiatal hernia, then hiatal hernia repair is added.
All these pro-
cedures may be performed with traditional or minimally inva-
sive techniques.
Midesophageal or traction diverticula were first described 
in the nineteenth century (Fig.
25-57).
It was theorized that adhesions formed 
between the inflamed mediastinal nodes and the esophagus.
25-58).
In such patients, the radiologic abnormality may 
be ignored.
The diverticulum in such patients is most 
likely to have an inflammatory etiology.
Figure 25-57.
Barium esophagogram showing a midesophageal 
diverticulum.
Despite the anatomic distortion, the patient was 
asymptomatic.
Med Clin North Am.
65:1255, 1981.
Copyright Elsevier.)
Inflamed
nodes
Traction diverticulum
Figure 25-58.
The indication for surgical intervention is dictated by 
the degree of symptomatic disability.
Usually, midesophageal 
diverticula can be suspended due to their proximity to the spine.
The symptom of chest 
pain alone is not an indication for a surgical procedure.
25-59).
Most surgeons extend the myotomy 
distally across the LES to reduce outflow resistance.
25-60).
The procedure may be performed either open or via thora-
coscopy.
The open technique is performed through a left thora-
cotomy in the sixth intercostal space (Fig.
25-61).
The 
esophagus is not circumferentially dissected unless necessary.
A tongue of gas-
tric fundus is pulled into the chest.
This exposes the GEJ and 
its associated fat pad.
The latter is excised to give a clear view 
of the junction.
The muscle layer is dissected from the 
mucosa laterally for a distance of 1 cm.
Care is taken to divide 
all minute muscle bands, particularly in the area of the GEJ.
This 
maintains separation of the muscle and acts as a partial fundo-
plication to prevent reflux.
The 
myotomy is then performed on the opposite esophageal wall.
100%
% Symptomatic
10 cm
5 cm
0 cm
80%
60%
40%
20%
0%
Pre Rx
17 N
Eso.
diameter
% Retention
0–24
mo
17
25–48
mo
16
49–72
mo
14
73–120
mo
12
Figure 25-60.
(Based 
on Topart P, et al.: Long-term effect of total fundoplication on the 
myotomized esophagus.
Ann Thorac Surg.
54:1046, 1992.)
996
SPECIFIC CONSIDERATIONS
UNIT II
PART II
Figure 25-61.
Technique of long myotomy: A.
B.
C.
Retraction of tongue of gastric fundus into the chest through the previously made 
incision.
D.
Removal of the gastroesophageal fat pad to expose the gastroesophageal junction.
E.
A myotomy down to the mucosa is started 
on the esophageal body.
F.
Completed myotomy extending over the stomach for 1 cm.
G.
H.
Most patients gain or maintain rather than 
lose weight after the operation.
The thoracoscopic technique may be performed through 
the left or right chest.
Performing abdominal myotomy (and 
diverticulectomy, if present) may be all that is required.
The POEM 
Figure 25-61.
A long submu-
cosal plane is developed with the endoscope, down to and below 
the LES.
The submucosal 
entry site in the esophagus is then closed with endoscopic clips.
25-62).
The neck of the diverticulum is transected with a GIA 
stapler after passage of a 48F dilator.
Closure of the muscle over the 
staple line is preferable.
Solid 
foods are withheld for 2 weeks to decrease the likelihood of 
staple line leak.
Buttressing or sealing the staple line with fibrin 
glue is also an attractive option.
This requires disrupting the LES mus-
cle.
25-63).
Botulinum toxin injection may achieve similar 
Figure 25-62.
A.
B.
Stapler amputates 
neck of diverticulum.
C.
Muscle reapproximated over staple line, and Heller myotomy is performed.
Responsiveness to botulinum toxin injection may predict a good 
response to Heller myotomy.
25-64).
Close follow-
up is required, and if dilation fails, myotomy is indicated.
Dig Dis Sci 41:2138, 1996.
(Data reproduced 
from: Ellis FH Jr.: Oesophagomyotomy for achalasia: A 22-year 
experience.
Br J Surg.
80:882, 1993; Goulbourne IA, Walbaum PR: 
Long-term results of Heller’s operation for achalasia.
J Royal Coll 
Surg.
Ann Tho-
rac Surg.
Dig Dis Sci.
Gastroenterology.
Myotomy of the LES can be accomplished via either an 
abdominal or thoracic approach.
The fourth issue centers on whether or not a cure of this 
disease is achievable.
In fact, primary procedures can almost 
always be successfully completed via laparoscopy.
The esophagus and a tongue of gastric fun-
dus are exposed as described for a long myotomy.
The tongue of gastric fundus is 
allowed to retract into the abdomen.
After dilation, 13% of patients 
regained some peristalsis, compared with 28% after surgery.
Failure to do this will result in continuing dysphagia and a dis-
satisfied patient.
A good therapeutic response improves esophageal emptying 
toward normal.
When an antireflux procedure is 
added to the myotomy, it should be a partial fundoplication.
25-65).
Exposure of the GEJ via removal of the 
gastroesophageal fat pad follows.
The anterior vagus nerve is 
swept right laterally along with the fat pad.
A distal esophageal myotomy is performed.
An antireflux procedure follows completion of 
the myotomy.
Per Oral Endoscopic Myotomy (POEM)
The POEM procedure was developed in Japan.
It is the ultimate 
minimally invasive myotomy as it requires no incisions through 
the skin.
A long 
submucosal plane is developed with the endoscope, down to 
and below the LES.
The submucosal entry site in the esophagus is 
then closed with endoscopic clips.
The use of 
symptoms alone as an endpoint to evaluate therapy for achalasia 
may be misleading.
Esophageal baseline 
pressure is usually negative compared to gastric pressure.
A postdilatation sphincter pressure 
<10 mmHg predicted a good response.
Overall, only 30% of patients dilated remained in symp-
tomatic remission at 5 years.
They concluded that there was a 
Figure 25-65.
A.
Longitudinal muscle is divided.
B.
Mechanical disruption of lower esophageal sphincter muscle fibers.
C.
Myotomy must 
be carried across gastroesophageal junction.
D.
Gastric extension should equal 2 to 3 cm.
E.
Anterior (Dor) fundoplication is sutured to the 
diaphragmatic arch.
F.
Posterior (Toupet) fundoplication is sutured to cut edges of myotomy.
EG jct = esophagogastric junction.
Overall, 89% 
of patients were improved at the 9-year mark.
The outcome of laparoscopic myotomy and hemifun-
doplication has been well documented.
Two reports of over 
1002
SPECIFIC CONSIDERATIONS
UNIT II
PART II
Figure 25-65.
Ann Thorac Surg 58:1343, 1994; Ellis FH Jr.: 
Oesophagomyotomy for achalasia: A 22-year experience.
J R Coll Surg Edinb.
30:101, 1985.
Conversion to an open procedure occurs in 0% to  
5% of patients.
Complications are uncommon, occurring in 
<5% of patients.
The incidence of objective reflux dis-
ease as evidenced by abnormal acid exposure is <10%.
The best treatment for achalasia 
is a laparoscopic Heller myotomy and partial fundoplication.
The role of POEM in the management of classic (nonspastic) 
achalasia is yet to be established.
The presence of these abnormalities signals 
end-stage motor disease.
In these situations esophageal replace-
ment is usually required to establish normal alimentation.
In Western societies, smoking and alcohol 
consumption are strongly linked with squamous carcinoma.
25-66), and 
now accounts for more than 50% of esophageal cancer in most 
Western countries.
Furthermore, the clinical picture of esophageal adenocar-
cinoma is changing.
The potential for cure becomes of paramount importance.
The gross appearance resembles that of squamous cell car-
cinoma.
Either vocal cord may 
6
1004
SPECIFIC CONSIDERATIONS
UNIT II
PART II
U.S.
Incidence and mortality rate trends for esophageal 
cancer.
NCI = National Cancer Institute.
(Reproduced with permis-
sion from the National Cancer Institute.
Systemic organ metastases are 
usually manifested by jaundice or bone pain.
The situation is 
different in high-incidence areas where screening is practiced.
In these communities, the most prominent early symptom is 
pain on swallowing rough or dry food.
Consequently, the dis-
ease is usually advanced if symptoms herald its presence.
With tumors of the cardia, anorexia and 
weight loss usually precede the onset of dysphagia.
When given before surgery, these treat-
ments are referred to as neoadjuvant or induction therapy.
For 
disseminated cancer, treatment is aimed at palliation of symp-
toms.
Staging starts with the history and physical.
Studies also showed that 
patients having five or fewer LN metastases have a better out-
come.
Most surgeons agreed that the 1983 tumor, nodes, and metas-
tasis system left much to be desired.
Clinical Approach to Carcinoma  
of the Esophagus and Cardia
The selection of a curative vs.
Tumor Location.
25-68).
Except in advanced disease, it is unusual 
for intrathoracic LNs to be involved.
Tumors of the lower esophagus and cardia are usually 
adenocarcinomas.
No evidence of primary tumor.
High-grade dysplasia.
Tumor invades lamina propria, muscularis mucosae, or submucosa.
Tumor invades lamina propria or muscularis mucosae.
Tumor invades submucosa.
Tumor invades muscularis propria.
Tumor invades adventitia.
Tumor invades adjacent structures.
Resectable tumor invading pleura, pericardium, or diaphragm.
Unresectable tumor invading other adjacent structures, such as aorta, vertebral body, trachea, etc.
Regional lymph nodes cannot be assessed.
No regional lymph node metastasis.
Metastases in 1–2 regional lymph nodes.
Metastases in 3–6 regional lymph nodes.
Metastases in ≥7 regional lymph nodes.
No distant metastasis.
Distant metastasis.
1007
Esophagus and Diaphragmatic Hernia
CHAPTER 25
Age.
CT = computed tomography; FEV1 = forced expiratory volume in 1 second.
(Reproduced with 
permission from DeMeester TR: Esophageal carcinoma: Current controversies.
Sem Surg Oncol.
Incidence of carcinoma of the esophagus and cardia 
based on tumor location.
established its success in highly selected patients.
Cardiopulmonary Reserve.
Clinical evaluation 
and electrocardiogram are not sufficient indicators of cardiac 
reserve.
Nutritional Status.
Clinical Staging.
Preoperative Staging with Advanced Imaging.
EUS provides the most reliable method of determining 
depth of cancer invasion.
In the absence of enlarged LNs, the 
degree of wall invasion dictates surgical therapy.
It is difficult to provide modern treatment of esophageal 
cancer without access to this modality.
Aortic esophageal fistulas are 
extremely rare and nearly 100% lethal.
In 
a few patients, definitive chemoradiation will be successful in 
all sites but the esophagus.
For individuals with dysphagia grades IV and higher, addi-
tional treatment generally is necessary.
The mainstay of therapy 
is in-dwelling esophageal stents.
The major limitations to stenting exist in cancers at the GEJ.
J Surg Oncol 9:547, 
1977.
In cancers at 
this level, radiation therapy alone may be preferable.
If feeding 
access is desirable, a laparoscopic jejunostomy is usually the 
procedure of choice.
Mucosally Based Cancer.
Nodules should be resected in entirety, as 
they often harbor adenocarcinoma.
In this clinical situation, EMR is typically combined with 
EUS to rule out more invasive disease.
On the other hand, intramucosal cancers have 
little risk of spreading to regional LNs.
This approach dictates the need for future 
therapy such as esophagectomy.
This specimen is then 
removed and sent to pathology.
A positive margin or involvement of the 
submucosa warrants esophagectomy.
Minimally Invasive Transhiatal Esophagectomy.
Several variations of MIS 
transhiatal esophagectomy have been developed.
25-69A).
The conduit 
can be created through a mini-laparotomy or laparoscopically.
A Kocher maneuver releases the duodenum, and a pyloroplasty 
may be performed (optional).
25-69B).
This technique 
is reserved for patients with high-grade dysplasia.
25-69C).
A.
Laparoscopic retrograde inversion.
B.
Laparo-
scopic antegrade inversion.
A silk suture holds the tunnel after the 
esophagus is removed.
C.
Open Transhiatal Esophagectomy.
Minimally Invasive Two- and Three-Field Esophagectomy.
Both proce-
dures will be described.
Double 
lumen intubation is required.
Hilar, and posterior mediastinal nodes are all removed and sent 
with the specimen or individually.
The thoracic duct is divided 
at the level of the diaphragm and removed with the specimen.
A 
feeding tube is placed and the pyloroplasty may be performed 
laparoscopically.
Great care is made 
to avoid stretching the recurrent laryngeal nerve.
Cervical anastomosis is then  
performed.
The MIS transthoracic two-field esophagectomy is slightly 
different.
Other complications of this approach relate to pulmonary and 
cardiac status.
Ivor Lewis (En Bloc) Esophagectomy.
All LNs are removed en bloc with the lesser curvature of 
the stomach.
In the majority of cases, colon interposition is 
unnecessary, and a gastric conduit is used.
Chest tubes are placed, and the patient is 
taken to the intensive care unit.
Three-Field Open Esophagectomy.
Salvage Esophagectomy.
Surprisingly, the cure rate of salvage esophagectomy is not 
inconsequential.
Comparative Studies of Esophagectomy 
Technique
Transthoracic vs.
Transhiatal Esophagectomy.
The mortality and morbidity after transhiatal esopha-
gectomy appeared to be less.
There was no difference in procedure-related 
mortality between the approaches.
Alternative Therapies
Radiation Therapy.
Radiation is effective in patients who have hemorrhage from 
the primary tumor.
Adjuvant Chemotherapy.
This is particularly beneficial in 
the case of squamous cell tumors above the level of the carina.
Preoperative Chemotherapy.
Eight randomized prospec-
tive studies of neoadjuvant chemotherapy vs.
surgery alone 
have demonstrated mixed results.
This 
trial is one of the few to include enough patients (800) to detect 
small differences.
The trial had a 10% absolute survival benefit 
at 2 years for the neoadjuvant chemotherapy group.
Preoperative Combination Chemo- and Radiotherapy.
There have been 10 
randomized prospective studies (Table 25-13).
surgery, or neoadjuvant chemotherapy vs.
bUnpublished thesis.
cYear of activation not reported, but imputed.
dOnly available as an abstract.
SCC = squamous cell carcinoma.
Source: Reproduced with permission from Gebski V, et al.
Lancet Oncol 8:226, 2007.
Table 1, p 228.
Copyright Elsevier.
ARR = absolute risk reduction; NNT = number needed to treat to prevent one death.
Source: Reproduced with permission from Gebski V, et al.
Lancet Oncol 8:226, 2007.
Table 2, p 231.
Copyright Elsevier.
is detected in the specimen after esophagectomy.
After incomplete resection of 
an esophageal cancer, the 5-year survival rates are 0% to 5%.
The importance of 
early recognition and adequate surgical resection cannot be 
overemphasized.
Figure 25-70 is a global algorithm for the 
management of esophageal carcinoma.
25-71).
Table 25-15
Results of neoadjuvant therapy in adenocarcinoma of the esophagus
INSTITUTION yEAR NO.
OF PATIENTS REGIMEN
COMPLETE PATHOLOGIC 
RESPONSE (%) SURVIVAL
M.
D.
Louis 
University Medical Center; VBL = vinblastine.
Ann Thorac Surg 58:1574, 1994.
Copyright Elsevier.
25-72).
Esophagoscopy commonly shows an intraluminal necrotic 
mass.
When this is not done, the biopsy specimen will show only tis-
sue necrosis.
Suggested global algorithm for the management of carcinoma of the esophagus.
CT = computed tomography.
1016
SPECIFIC CONSIDERATIONS
UNIT II
PART II
A
B
Figure 25-71.
A.
B.
There was no evidence of lymph node metastasis at the time of operation.
AB
Figure 25-72.
A.
B.
Operative specimen showing 9-cm polypoid leiomyoblastoma.
1017
Esophagus and Diaphragmatic Hernia
CHAPTER 25
reported 5-year survivals.
Resection also provides an excellent 
means of palliating the patient’s symptoms.
The other 
five patients were reported to have survived more than 5 years.
BENIGN TUMORS AND CYSTS
Benign tumors and cysts of the esophagus are relatively uncom-
mon.
Intramural lesions are either solid tumors or cysts, and the 
vast majority are leiomyomas.
They are made up of varying por-
tions of smooth muscle and fibrous tissue.
Fibromas, myomas, 
fibromyomas, and lipomyomas are closely related and occur 
rarely.
Pedunculated intraluminal tumors 
should be removed.
If the lesion is not too large, endoscopic 
removal with a snare is feasible.
Leiomyoma
Leiomyomas constitute more than 50% of benign esophageal 
tumors.
Leiomyomas 
are twice as common in males.
They are usually solitary, but multiple tumors have been 
found on occasion.
They vary greatly in size and shape.
Actually 
tumors as small as 1 cm in diameter and as large as 10 lb have 
been removed.
Typically, leiomyomas are oval.
The overlying mucosa is 
freely movable and normal in appearance.
A barium swallow is the most useful method to demon-
strate a leiomyoma of the esophagus (Fig.
25-73).
The majority can be removed by 
simple enucleation.
If, during removal, the mucosa is inadver-
tently entered, the defect can be repaired primarily.
The location of the lesion and the 
extent of surgery required will dictate the approach.
Videothoracoscopic and laparoscopic approaches are now fre-
quently used.
Figure 25-73.
Barium esophagogram showing a classical, smooth, 
contoured, punched-out defect of a leiomyoma.
Esophageal Cyst
Cysts may be congenital or acquired.
In some, 
epithelial lining cells may be absent.
Their symptoms are similar to those of a leiomyoma.
The 
diagnosis similarly depends on radiographic, endoscopic, and 
endosonographic findings.
Surgical excision by enucleation is 
the preferred treatment.
ESOPHAGEAL PERFORATION
Perforation of the esophagus constitutes a true emergency.
It 
most commonly occurs following diagnostic or therapeutic pro-
cedures.
If subcutaneous emphysema is present, the diagnosis is almost 
certain.
Spontaneous rupture usually occurs into the left pleu-
ral cavity or just above the GEJ.
This is due to the stretching of the supra-
diaphragmatic portion of the gastric wall.
Mediastinal widening secondary to edema 
may not occur for several hours.
The site of perforation also can 
influence the radiographic findings.
25-74).
A pleural effusion sec-
ondary to inflammation of the mediastinum occurs late.
In 9% 
of patients, the chest radiogram is normal.
The 
use of a water-soluble medium such as Gastrografin is preferred.
Of concern is that there is a 10% false-negative rate.
This may 
be due to obtaining the radiographic study with the patient in 
the upright position.
The studies should be done with the patient 
in the right lateral decubitus position (Fig.
25-75).
Management
The key to optimum management is early diagnosis.
A flap 
of stomach is pulled up and the soiled fat pad at the GEJ is 
removed.
The edges of the injury are trimmed and closed pri-
marily (Fig.
25-77).
Mortality associated with immediate closure varies 
between 8% and 20%.
In some situations, the 
retained esophagus may be so long that it loops down into the 
chest.
The contaminated mediastinum is drained and a feeding 
jejunostomy tube is inserted.
Nonoperative management of esophageal perforation has 
been advocated in select situations.
25-78), (b) symptoms should be mild, 
and (c) there should be minimal evidence of clinical sepsis.
If 
these conditions are met, it is reasonable to treat the patient with 
Figure 25-74.
Figure 25-75.
Figure 25-76.
Oral intake is resumed in  
7 to 14 days, dependent on subsequent radiographic examinations.
Mallory-Weiss tears are characterized by arterial bleeding, 
which may be massive.
In the majority of patients, the bleeding will stop sponta-
neously with nonoperative management.
Endoscopic injec-
tion of epinephrine may be therapeutic if bleeding does not 
stop spontaneously.
Only occasionally will surgery be required 
to stop blood loss.
The procedure consists of laparotomy and 
high gastrotomy with oversewing of the linear tear.
Mortality is 
uncommon, and recurrence is rare.
Pathology
The swallowing of caustic substances causes an acute and a 
chronic injury.
During the chronic phase, the focus is on treatment 
Figure 25-77.
The technique of closure of an esophageal perfora-
tion through a left thoracotomy.
A.
B.
Reinforcement of 
the closure with a parietal pleural patch.
Figure 25-78.
Barium esophagogram showing a stricture and a 
contained perforation following dilation.
Nonoperative management was  
successful.
Acids and alkalis affect tissue in different ways.
Cleansing products can contain up to 
90% sodium hydroxide.
The lesions caused by lye injury occur in three phases.
First is the acute necrotic phase, lasting 1 to 4 days after injury.
Second 
is the ulceration and granulation phase, starting 3 to 5 days 
after injury.
This 
phase lasts 10 to 12 days, and it is during this period that the 
esophagus is the weakest.
Third is the phase of cicatrization and 
scarring, which begins the third week following injury.
Adhesions 
between granulating areas occur, resulting in pockets and bands.
It is during this period that efforts must be made to reduce stric-
ture formation.
The presence of 
fever is strongly correlated with the presence of an esophageal 
lesion.
Bleeding can occur, and frequently, the patient vomits.
These initial complaints disappear during the quiescent period 
of ulceration and granulation.
Of the patients who develop strictures, 60% do so within 1 
month, and 80% within 2 months.
If dysphagia does not develop 
within 8 months, it is unlikely that a stricture will occur.
Conversely, esophageal burns can 
be present without apparent oral injuries.
The degree of injury can be graded according 
to the criteria listed in Table 25-16.
Even if the esophagoscopy 
is normal, strictures may appear later.
The most common locations of caustic injuries are 
shown in Table 25-17.
The immediate treatment consists of limiting the 
burn by administering neutralizing agents.
To be effective, this 
must be done within the first hour.
Lye or other alkali can be 
neutralized with half-strength vinegar, lemon juice, or orange 
juice.
Acid can be neutralized with milk, egg white, or antac-
ids.
If necessary, 
a feeding jejunostomy tube is inserted to provide nutrition.
Oral 
feeding can be started when the dysphagia of the initial phase 
has regressed.
Management of acute injury is summarized in the algo-
rithm in Fig.
25-79.
Some authors have advocated the use of an 
intraluminal esophageal stent (Fig.
Esophagoscopy should be 
done, and, if strictures are present, dilations initiated.
During the treatment 55 patients died.
Algorithm summarizing the management of acute 
caustic injury.
Figure 25-80.
The use of an esophageal stent to prevent stricture.
A Penrose drain is 
placed over the distal end as a flap valve to prevent reflux.
Continuous suction removes saliva and 
mucus trapped in the pharynx and upper esophagus.
Free jejunal grafts based on the supe-
rior thyroid artery have provided excellent results.
25-81).
25-82).
This allows excision of supraglottic strictures and elevation and 
anterior tilting of the larynx.
In both of these situations, the 
patient must relearn to swallow.
The management of a bypassed damaged esophagus after 
injury is problematic.
Traumatic fistulas and 
those associated with esophageal diverticula account for the 
remainder.
To prevent recurrence, a pleural flap should 
be interposed.
Treatment of malignant fistulas is difficult, par-
ticularly in the presence of prior irradiation.
Generally, only pal-
liative treatment is indicated.
This can best be done by using a 
Figure 25-81.
Anastomosis of the bowel to a preserved pyri-
form sinus.
Analysis of 18 cases.
Ann 
Surg.
207:439, 1988.)
Figure 25-82.
Anastomosis of the bowel to the posterior orophar-
ynx.
A triangle-shaped 
piece of the upper half of the cartilage is resected.
Closure of the 
oropharynx is done so that the larynx is pulled up (sagittal sec-
tion).
Analysis of 18 cases.
Ann Surg.
A salivary tube 
is also a good option for proximal esophageal fistulas.
Rarely, combinations of these grafts 
will be the only possible option.
Because 
the anastomosis is within the chest, a thoracotomy is necessary.
A.
B.
Philadelphia: Lea & Febiger, 1989, p 419.]
esophagogastrostomy.
25-83).
Of the two, the colon 
provides the longest graft.
Gastric interposition has the 
advantage that only one anastomosis is required.
When it occurred, the most com-
mon cause was recurrent mediastinal tumor.
This is less likely in patients 
who have had a colonic interposition for esophageal replace-
ment.
The stomach is divided with an Endo-GIA stapler just 
below the GEJ.
The colon is prepared to provide an interposed 
segment as previously described.
The left carotid sheath is 
retracted laterally and the thyroid and trachea medially.
The left recurrent laryngeal nerve is 
identified and protected.
A vein stripper is passed up the 
esophagus into the neck wound.
An end-to-end anastomosis is performed to 
the cervical esophagus using a single layer technique.
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Ellis FH Jr., Gibb SP: Esophageal reconstruction for complex benign 
esophageal disease.
J Thorac Cardiovasc Surg 99:192, 1990.
Finley RJ, Lamy A, et al.: Gastrointestinal function following 
esophagectomy for malignancy.
Am J Surg 169:471, 1995.
Fok M, Cheng SW, Wong J: Pyloroplasty versus no drainage in gas-
tric replacement of the esophagus.
Am J Surg 162:447, 1991.
Surg Endosc 
9:1113, 1995.
Risk factors and management.
J Thorac Cardiovasc Surg 
111:1141, 1996.
Ann Thorac Surg 54:1110, 1992.
Maier G, Jehle EC, Becker HD: Functional outcome following 
oesophagectomy for oesophageal cancer.
A prospective mano-
metric study.
Dis Esophagus 8:64, 1995.
Naunheim KS, Hanosh J, et al.: Esophagectomy in the septuagenar-
ian.
Ann Thorac Surg 56:880, 1993.
Nishihra T, Oe H, et al.: Esophageal reconstruction.
Dis Esophagus 8:30, 1995.
Arch Surg 130:858, 1995.
Am J Surg 172:478, 1996.
A controlled trial.
French Associations for Surgical Research.
Surgery 120:476, 1996.
Watson T, DeMeester TR, Kauer WK, et al.: Esophagectomy for 
end stage benign esophageal disease.
J Thorac Cardiovasc Surg 
115:1241, 1998.
Ann Thorac Surg 
53:798, 1992.
This page intentionally left blank 
Stomach
Yuko Kitagawa and Daniel T.
Treatable diseases of the stomach are 
common, and it is accessible and relatively forgiving.
Thus, 
the stomach is a favorite therapeutic target.
Some important milestones in the history 
of gastric surgery1–6 are listed in Table 26-1.
26-1).7 The part of the stomach attached to the esopha-
gus is called the cardia.
The angle of His is where the fundus meets the left 
side of the GE junction.
Otherwise marginal 
ulceration and/or gastric stasis (Roux syndrome) may become 
problematic.
6 Most patients with primary gastric lymphoma can be 
treated without gastric resection.
7 Gastric carcinoids should usually be removed either endo-
scopically or surgically.
Table 26-1 
Historic milestones in gastric surgery
DATE EVENT DATE EVENT
350 b.c.
– 
201 a.d.
Guy de Chauliac describes closure of 
gastric wound.
Marcellus Donatus of Mantua describes 
gastric ulcer at autopsy.
Reports of surgeons cutting stomach to 
remove foreign bodies.
Muralto describes duodenal ulcer at 
autopsy.
Morgagni describes both gastric and 
duodenal ulcer at autopsy.
William Beaumont reports data recorded 
during his care of Alexis St.
Martin who 
developed a gastric fistula from a left 
upper quadrant musket wound.
Gross.
Sidney Jones in London publishes the first 
successful gastrostomy for feeding.
Paen performed distal gastrectomy and 
gastroduodenostomy.
The patient died  
5 d later.
Rydygier resected a distal gastric cancer, 
and the patient died 12 h later.
Billroth resects distal gastric cancer and 
performs gastroduodenostomy (Billroth I).
Patient Therese Heller recovers and 
survives 4 mo.
Anton Wolfler performs loop 
gastrojejunostomy to palliate an 
obstructing distal gastric cancer.
Rydygier reports an unsuccessful 
gastrojejunostomy for benign gastric outlet 
obstruction.
Mikulicz performs similar operation.
Jaboulay describes bypassing the intact pylorus with 
gastroduodenostomy.
Finney from Baltimore describes pyloroplasty 
technique.
Subtotal gastrectomy grows popular as an operation for 
peptic ulcer.
Von Haberer and Finsterer proponents.
Dragstedt and Owen describe transthoracic truncal 
vagotomy to treat peptic ulcer disease.
Edwards and Herrington (Nashville) describe truncal 
vagotomy and antrectomy for peptic ulcer.
Zollinger and Ellison describe the eponymous 
syndrome.
Evolving role of laparoscopic techniques in the 
treatment of surgical gastric disease.
Dramatic increase in bariatric operations.
Development of natural orifice translumenal endoscopic 
surgery.
26-2).
The left lateral segment of the liver usually covers a large part 
of the anterior stomach.
Inferiorly, the stomach is attached to the 
transverse colon by the gastrocolic omentum.
Posterior to 
the stomach is the lesser omental bursa and the pancreas.
26-3).
The veins draining the stomach generally parallel the 
arteries.
This is 
Figure 26-1.
Anatomic regions of the stomach.
II.
Philadelphia: 
Saunders, 2002, p 3.
Anatomic relationships of the 
stomach.
II.
Philadelphia: Saunders, 
2002, p 3.
The nodes along both the greater and lesser 
curvature commonly drain into the celiac nodal basin.
pancreatic
   duodenal a.
Abdominal
    Aorta
Inferior pancreatic
     duodenal a.
Hepatic a.
Left gastric a.
Branches
to greater
omentum
Splenic a.
& v.
L.
gastroepiploic a.
Sup.
mesenteric
   a.
& v.
Inferior 
mesenteric a.
Ileocolic a.
26-5).
In 50% of patients, 
there are more than two vagal nerves at the esophageal hiatus.
The branch that the posterior vagus sends to the posterior fundus 
Figure 26-3.
Arterial blood supply to the 
stomach.
a.
= artery; v.
= vein.
II.
Philadelphia: Saunders, 
2002, p 3.
Copyright Elsevier.]
1039
Stomach
CHAPTER 26
is termed the criminal nerve of Grassi.
They also play 
a role in appetite control and perhaps even mucosal immunity 
and inflammation.
Stations 3 to 6 are 
commonly removed with D1 gastrectomy.
Stations 1, 2, and 7 to 12 are commonly removed with D2 gastrectomy.
Berlin: 
Springer-Verlag, 1997, p 82–83.
The epithelium, lamina propria, and muscularis 
mucosa constitute the mucosa (Fig.
26-7).14 The epithelium of 
the gastric mucosa is columnar glandular.
26-8, Table 26-2).15,16 There are also 
endocrine cells present in the gastric glands.
Hepatic br.
left vagus
Celiac br.
rt.
vagus
Nerve of Laterjet
Pyloric br.
Left vagus n.
Figure 26-5.
Vagal innervation of the stomach.
br.
= branch; n.
= 
nerve; rt.
= right.
Philadelphia: Saunders, 1976, p 8.
Layers of the gastric wall.
Philadelphia: Saunders, 
1986, p 625.
Copyright Elsevier.]
Figure 26-7.
Gastric mucosa.
(Reproduced with permission from Bloom W, Fawcett DW: A Textbook of Histology,  10th ed.
Philadelphia: 
Saunders, 1975, p 639.)
extend down into the gland pits for variable distances.
In the 
fundus and body, the glands are more tubular and the pits are 
deep.
Parietal and chief cells are common in these glands 
(Fig.
26-9).
26-9).
Mammalian gastric gland from the body of the stom-
ach.
J Cell Biol 16:541, 
1963.
Copyright © 1963 The Rockefeller University Press.
They tend to 
be clustered toward the base of the gastric glands and have a low 
columnar shape.
26-10).
These proenzymes are activated in 
an acidic luminal environment.
The collagen-rich 
submucosa gives strength to GI anastomoses.
Specialized pacemaker cells, the interstitial cells of 
Cajal (ICC), also are present.
The outer layer of the stomach is the serosa, also known as 
the visceral peritoneum.
This layer provides significant tensile 
strength to gastric anastomoses.
In this way, the serosa may be thought of as an 
outer envelope of the stomach.
In 
an acidic environment, pepsin and acid facilitate proteolysis.
The parietal cell is stimulated to secrete acid 
(Fig.
Source: From Antonioli et al,16 with permission.
SC
M
TV
Figure 26-9.
Ultrastructural features of the parietal (oxyntic) 
cell.
SC = secretory canaliculus; M = mitochondria; TV = tubulo-
vesicle.
Baltimore: Williams & Wilkins, 1998, p 13.]
ZG
GA
GER
Figure 26-10.
Ultrastructural features of the chief (zymogenic) 
cell.
GA = Golgi apparatus; GER = granular endoplasmic reticu-
lum; ZG = zymogen granule.
26-12).
Endocrine cells of the stomach—proportion by 
site.
Philadelphia: Saunders, 2002, p 715.
Control of acid secre-
tion in the parietal cell.
II.
Philadelphia: Saunders, 
2002, p 3.
Copyright Elsevier.]
protein kinases and activation of H+/K+-ATPase.
Physiologic Acid Secretion.
Food ingestion is the physi-
ologic stimulus for acid secretion (Fig.
26-13).
Acetylcholine is released, leading to 
stimulation of ECL cells and parietal cells.
When food reaches the stomach, the gastric phase of 
acid secretion begins.
The gastric phase of acid secretion has 
several components.
Antral distention also stimulates 
antral gastrin secretion.
Acetylcholine stimulates gastrin release 
and gastrin stimulates histamine release from ECL cells.
The intestinal phase of gastric secretion is poorly under-
stood.
It accounts for about 10% of meal-
induced acid secretion.
Basal acid secretion is reduced 75% to 90% by vagotomy or H2 
receptor blockade.
26-13.
The mucosal D cell, which releases somatostatin, is also 
an important regulator of acid secretion.
Somatostatin inhibits 
histamine release from ECL cells and gastrin release from antral 
G cells.
Physiologic control of acid secretion.
ECL = 
enterochromaffin-like.
II.
Philadelphia: Saunders, 2002, 
p 3.
Somatostatin inhibits pepsinogen secre-
tion.
Pepsin catalyzes the hydrolysis of proteins 
and is denatured at alkaline pH.
A variety of factors are important in maintain-
ing an intact gastric mucosal layer.
“Back-diffused” hydrogen is 
buffered and rapidly removed by the rich blood supply.
If this protective response is blocked, gross ulcer-
ation can occur.
Sucralfate acts 
locally to enhance mucosal defenses.
Gastric Hormones13,26
Gastrin.
The large majority of gastrin released by the human 
antrum is G17.
26-13).
Gastrin is trophic to gastric parietal cells and 
to other GI mucosal cells.
Somatostatin.
Somatostatin is produced by D cells located 
throughout the gastric mucosa.
The predominant form in 
humans is somatostatin 14, though somatostatin 28 is present 
as well.
Somatostatin inhibits acid secretion from parietal cells 
and gastrin release from G cells.
It also decreases histamine 
release from ECL cells.
Gastrin-Releasing Peptide.
Leptin.
Leptin is a protein primarily synthesized in adipocytes.
Ghrelin levels are decreased after gastrectomy.
J Clin Endocrinol Metab.
10 a.m.
noon
2 p.m.4 p.m.
6 p.m.8 p.m.
10 p.m.
A and B.
Ghrelin 
secretion after bariatric surgery.
B.
Top = 
RYGBP; B bottom = SG.
(Fig.
N Engl J Med 346:1623, 
2002.
Copyright ©2002 Massachusetts 
Medical Society.
All rights reserved.
Fig.
When feeding begins, the stomach 
relaxes to accommodate the meal.
Serotonin has been shown to modulate both contraction 
and relaxation.
Enteric nervous system.
New York: McGraw-Hill, 
2003, p 355.
Segmental Gastric Motility.
Rapid phasic contractions may be superimposed on the slower 
tonic motor activity.
When food is ingested, intragastric pres-
sure falls as the proximal stomach relaxes.
NO and VIP are the principal mediators of proximal gas-
tric relaxation.
The distal stomach breaks up solid food and is the main 
determinant of gastric emptying of solids.
These waves originate from 
the proximal gastric pacemaker, high on the greater curvature.
26-17).
The relationship between intracellular electrical activity and muscle cell contraction.
During mechanical quiescence, there are regular depolarizations that do not reach 
threshold.
Mayo Clin Proc.
Migrating motor complex, the 
fasting pattern of GI activity.
Dig Dis Sci.
27(4):321, 
1982.
26-18).
Phase I 
(about half the length of the entire cycle) is a period of relative 
motor inactivity.
High-amplitude muscular contractions do not 
occur in phase I of the MMC.
Phase IV is a transi-
tion period.
This suggests that phase III is regulated by intrinsic 
nerves and/or hormones.
There are clearly motilin receptors on antral smooth muscle 
and nerves.
Feeding abolishes the MMC and leads to the fed motor 
pattern.
Ileal perfusion with fat has the same effect.
The pylorus is readily apparent grossly as a thick ring of 
muscle and connective tissue.
The motor activity 
of the pylorus is both tonic and phasic.
During phase III of the 
MMC, the pylorus is open as gastric contents are swept into the 
duodenum.
During the fed phase, the pylorus is closed most 
of the time.
Modulation of pyloric motor activity is complex.
There 
is evidence of both inhibitory and excitatory vagal pathways.
Nitric oxide 
is an important mediator of pyloric relaxation.
Gastric Emptying.13 The control of gastric emptying is com-
plex.
In general, liquid emptying is faster than solid emptying.
CCK has been consistently shown 
to inhibit gastric emptying at physiologic doses (Fig.
26-19).
The orexigenic hormone 
ghrelin has the opposite effect.
Liquid Emptying.
26-20).
Up to an osmolarity of 
about 1 M, liquid emptying occurs at a rate of about 200 kcal 
per hour.
Generally, liquid emptying is delayed in the supine position.
Cholecystokinin (CCK) inhibits gastric emptying.
Some observations suggest an active role for the distal 
stomach in liquid emptying.
Solid Emptying.
Normally, the half-time of solid gastric 
emptying is less than 2 hours.
It is during this phase that much of the 
grinding and mixing occurs.
When liquids 
and solids are ingested together, the liquids empty first.
The larger the solid component of 
the meal, the slower the liquid emptying.
Nutrient composition and caloric density affect 
liquid gastric emptying.
Glucose solution (purple circles), the least 
calorically dense, emptied the fastest.
J Physiol.
Three prokinetic agents are commonly used to treat delayed 
gastric emptying.
Typical doses and mechanism of action are 
shown in Table 26-4.
Nausea, vomiting, bloating, and 
anemia also are frequent complaints.
Diagnostic Tests
Esophagogastroduodenoscopy.
The fundus and GE junction are inspected by 
retroflexing the scope.
pylori.
Radiologic Tests.
Computed Tomographic Scanning and Magnetic Resonance 
Imaging.
Usually, significant gastric disease can be diagnosed 
without these sophisticated imaging studies.
26-21).
Endoscopic Ultrasound.
EUS is the best way to 
clinically stage these patients locoregionally.
Suspicious nodes 
can be sampled with EUS-guided endoscopic needle biopsy.
EUS 
also can be used to assess tumor response to chemotherapy.
Submucosal masses are commonly discovered during routine 
EGD.
Submucosal varices also can be assessed by EUS.
Gastric Secretory Analysis.
Normal basal acid output (BAO) is greater than 5 mEq/h.
MAO is the average of the two final stimulated 15-minute peri-
ods and is usually 10 to 15 mEq/h.
Peak acid output is defined 
as the highest of the four stimulated periods.
In patients with gastrinoma, the 
ratio of BAO to MAO exceeds 0.6.
Scintigraphy.
A 
curve for liquid and solid emptying is plotted, and the half-time 
calculated.
Normal standards exist for each facility.
Tests for Helicobacter pylori.
A variety of tests can help the 
clinician to determine whether the patient has active H.
pylori infection in the screened population.
A 
positive test is quite accurate in predicting H.
pylori infection, 
but a negative test is characteristically unreliable.
Thus, in the 
appropriate clinical setting, treatment for H.
Because of the association between 
H.
pylori.
Urease is an omnipresent 
enzyme in H.
pylori strains that colonize the gastric mucosa.
The labeled carbon-13 urea breath test has become the standard 
test to confirm eradication of H.
The labeled urea is acted upon by the urease 
present in the H.
pylori and converted into ammonia and carbon 
dioxide.
26-22).
It also 
can be detected in a blood sample.
The fecal antigen test also 
is quite sensitive and specific for active H.
pylori infection and 
may prove more practical in confirming a cure.
1052
SPECIFIC CONSIDERATIONS
UNIT II
PART II
AB
CD
E
Figure 26-21.
Axial computed 
tomographic scan (B) also shows a protruding polyp (arrow).
EGG consists of the transcutaneous recording of gastric myo-
electric activity.
There are pressure-recording sensors extending from the stom-
ach to the distal duodenum.
Labeled urea breath test to 
detect Helicobacter infection.
N Engl J Med 333:984, 1995.
Copyright ©1995 Massachusetts Medical 
Society.
All rights reserved.)
Acid
Pepsin
NSAIDs
H.
Balance of aggressive and defensive factors in 
the gastric mucosa.
(Reproduced with permission from Mertz HR, 
Walsh JH: Peptic ulcer pathophysiology.
Med Clin North Am 
75:799, 1991.
pylori infection.
Pathophysiology and Etiology
A variety of factors may contribute to the development of PUD.
pylori infection and/or 
NSAID use17,52 (Fig.
Thus, the adage “no acid, no ulcer” remains true.
Acid 
suppression heals both duodenal and gastric ulcers and prevents 
recurrence.
In general H.
NSAID use causes ulcers predominantly by com-
promise of mucosal defenses.
Elimination of H.
pylori infec-
tion, NSAID use, and/or cigarette smoking.
Helicobacter pylori Infection.
With specialized flagella 
and a rich supply of urease, H.
pylori, a 
major cause of chronic gastritis.
Helicobacter also clearly has an 
etiologic role in the development of gastric lymphoma.
The ammonia is damaging to the surface epithelial 
cells.
Mutant strains of H.
pylori that do not produce urease 
are unable to colonize the stomach.
The organism lives in the 
mucus layer atop the gastric SECs, and some attach to these 
cells (Fig.
This is due, in part, to the inhibitory effect that H.
H.
pylori
infection
NSAID
use
None known
Z.E., other
H.
pylori
infection
Duodenal Gastric
Figure 26-24.
“Causes” of peptic ulcer 
disease.
Z.E.
= Zollinger-Ellison syn-
drome.
Philadelphia: 
Saunders, 2002, p 747.
Copyright Elsevier.]
Figure 26-25.
Helicobacter pylori closely adherent to the cell mem-
brane (top), and spiral-shaped H.
pylori attached to epithelial surface 
and surrounding microvilli (bottom).
(From Parsonnet J: Clinician-discoverers—Marshall, Warren, 
and H.
pylori.
N Engl J Med 353:2421, 2005.
These effects are probably mediated 
by H.
pylori–mediated increases in other local mediators 
and cytokines.
The result is hypergastrinemia and acid hyper-
secretion (Fig.
This duodenal metaplasia allows H.
When H.
When H.
pylori infec-
tion is successfully treated, acid secretory physiology tends to 
normalize.
Other mechanisms whereby H.
pylori in 
the pathophysiology of PUD is strong.
Patients with H.
pylori infec-
tion.
pylori infection.
It 
is clear from multiple randomized prospective studies that cur-
ing H.
pylori
infection in stomach
H.
pylori colonization in duodenum Figure 26-26.
Model of Helico-
bacter effects on duodenal ulcer 
pathogenesis.
Am J Med 102:200, 
1997.
pylori infection.
pylori is indubitably 
an important factor in the development and recurrence of PUD.
H.
pylori infection.
In patients with gastric ulcer, acid secretion is variable.
Type IV gastric ulcers occur near the GE junction, and acid 
cag+
H.
Pathogen-host interactions in the pathogenesis of Helicobacter pylori infection.
(Reproduced with permission from Suerbaum 
S, Michetti P: Helicobacter pylori infection.
N Engl J Med 347:1175, 2002.
Copyright ©2002 Massachusetts Medical Society.
All rights 
reserved.)
secretion is normal or below normal.
Type V gastric ulcers are 
medication induced and may occur anywhere in the stomach.
NSAIDs and aspirin have similar effects.
Helicobacter treatment dramatically decreases the 
recurrence rate of duodenal and gastric ulcer.
A randomized controlled study.
Frequency of physiologic abnormalities 
in patients with duodenal ulcer (DU).
HCO3 = bicarbon-
ate; MAO = maximal acid output.
Modified Johnson classification for gastric ulcer.
I.
Lesser curve, incisura.
II.
Body of stomach, incisura + duodenal 
ulcer (active or healed).
III.
Prepyloric.
IV.
High on lesser curve, 
near gastroesophageal junction.
V.
Medication-induced (NSAID/
acetylsalicylic acid), anywhere in stomach.
Philadelphia: 
Mosby Elsevier, 2008, p 81.
Copyright Elsevier.]
1058
SPECIFIC CONSIDERATIONS
UNIT II
PART II
taking NSAIDs.
This risk increases to five times in patients more 
than age 60 years old.
Smoking, Stress, and Other Factors.
Smoking increases gastric acid secretion and 
duodenogastric reflux.
e21% of patients in CLASS study were taking low-dose aspirin.
Gastroenterology 
120:594, 2001.
Copyright Elsevier.
In 1842, Curling described duo-
denal ulcer and/or duodenitis in burn patients.
Even the ancients 
recognized the undeniable links between PUD and stress.
Alco-
hol is commonly mentioned as a risk factor for PUD, but con-
firmatory data are lacking.
The pain is typically nonradiating, burning in quality, and 
located in the epigastrium.
The mechanism of the pain is unclear.
Patients with duodenal ulcer often experience pain 2 to 3 hours 
after a meal and at night.
Two thirds of patients with duodenal 
ulcers will complain of pain that awakens them from sleep.
A double-contrast 
upper GI X-ray study may be useful.
pylori, and for histologic evaluation.
Additional testing for 
H.
pylori may be indicated.
It is not unreasonable to test all pep-
tic ulcer patients for H.
pylori (Table 26-8) 63A baseline serum 
gastrin level is appropriate to rule out gastrinoma.
Chey 
WD, Wong BCY.63 Practice Parameters Committee of the American 
College of Gastroenterology.
Am J Gastroenterol.
2007;102:1808.
Copyright © 2007.
26-31).65 Patients with a bleeding peptic ulcer 
typically present with melena and/or hematemesis.
Nasogas-
tric aspiration is usually confirmatory of the upper GI bleed-
ing.
Abdominal pain is quite uncommon.
Shock may be present, 
necessitating aggressive resuscitation and blood transfusion.
Planned surgery under controlled circumstances often 
yields better outcomes than emergent surgery.
Causes of upper GI bleeding.
BMJ 323:1115, 2001.
The complete Rockall score ranges from 0 to 11, with higher scores indicating higher 
risk.
N Engl J Med.
359:928, 2008.
Copyright 
©2008 Massachusetts Medical Society.
All rights reserved.
The patient can often give the exact time of onset of the 
excruciating abdominal pain.
The patient is in 
obvious distress, and the abdominal examination shows perito-
neal signs.
Usually, marked involuntary guarding and rebound 
tenderness is evoked by a gentle examination.
Upright chest 
X-ray shows free air in about 80% of patients (Fig.
26-32).
Gastric outlet obstruction occurs in no more than 5% of 
patients with PUD.
Pain or discomfort is common.
Weight loss may be promi-
nent, depending on the duration of symptoms.
A succussion 
splash may be audible with stethoscope placed in the epigas-
trium.
The diagnosis is 
confirmed by endoscopy.
Patients hospital-
ized for ulcer complications should receive PPI by continuous 
Figure 26-32.
Pneumoperitoneum on upright chest X-ray in 
patient with perforated ulcer.
Peptic ulcer patients should 
stop smoking and avoid alcohol and NSAIDs (including 
aspirin).
If H.
If initial H.
pylori testing is negative 
and ulcer symptoms persist, an empirical trial of anti-H.
pylori 
therapy is reasonable since false-negative H.
pylori tests are 
common.
Generally, acid suppression can be stopped after 3 
months if the ulcerogenic stimulus (usually H.
pylori, NSAIDs, 
or aspirin) has been removed.
26-33).
Copyright 
Elsevier.
6–8cm    
7cm
Figure 26-33.
Highly selective vagotomy.
I.
Stamford, Connecticut: Appleton & Lange, 
1997, p 987.
HSV may be substituted for truncal 
vagotomy.
The advantage of V + D is that it can be performed 
safely and quickly by the experienced surgeon.
During truncal vagotomy 
(Fig.
26-34), care must be taken not to perforate the esophagus, 
a potentially lethal complication.
Unlike HSV, V + D is widely 
accepted as a successful definitive operation for complicated 
PUD.
When applied to gastric ulcer, the ulcer 
should be excised or biopsied.
26-35).
Marginal ulceration is a potential com-
plication.
26-36).
Other 
occasionally useful techniques include the Finney (Fig.
26-37) 
and the Jaboulay pyloroplasties (Fig.
26-38).
26-39) or a Billroth II 
loop gastrojejunostomy (Fig.
26-40).
26-41).
Resected segment Resected segment
Celiac branch
Hepatic branch
Figure 26-34.
Truncal vagotomy.
[Reproduced with permission 
from Zollinger RM Jr., Zollinger RM Sr.
(eds): Zollinger’s Atlas of 
Surgical Operations, 8th ed.
New York: McGraw-Hill, 2003, p 45.
Copyright © The McGraw-Hill Companies, Inc.]
Figure 26-35.
Retrocolic gastrojejunostomy.
Note 
mesocolon sutured to stomach (b, c, d).
Vol.
II.
Philadelphia: 
Saunders, 2002, p 129.
Table 26-12 shows the surgical options for managing 
various aspects of PUD.
Because ulcer recurrence often is related to H.
A through D.
Heineke-Mikulicz pyloroplasty.
[Reproduced with permission from Zinner MJ (ed): Atlas of Gastric Surgery.
New York: Churchill Livingstone, 1992, p 17.
Gastric ulcer requires biopsy if not resected.
The management of bleeding peptic ulcer is summarized 
in the algorithm provided in Fig.
26-42.
tier)
Duod.
Cushing
seromuscular
suture (2nd ant.
tier)
Posterior
through &
through suture
Figure 26-37.
A through D.
Finney pyloroplasty.
ant.
= anterior; Duod.
= duodenum; Stom.
= stomach.
Philadelphia: Saunders, 
1996, p 150.
The mortality rate for surgery for 
bleeding peptic ulcer is around 20%.
Angiography and emboli-
zation may be useful in some patients.
Operation for Bleeding Peptic Ulcer (Fig.
Patients 
who are in shock or medically unstable should not have gastric 
resection.
Multiple sutures are usually necessary.
Once the surgeon is 
  S t o m a ch
  S t o m .
A
B 
D
C
Pylorus
Inverted
incision
Gall
bladder
Duodenum
Connell
through & through
suture (1st ant.
tier)
Duod.
Cushing
seromuscular
suture (2nd ant.
tier)
Posterior
through &
through suture
Figure 26-38.
A through D.
Jaboulay pyloroplasty.
ant.
= anterior; Duod.
= duodenum; Stom.
= stomach.
Philadelphia: 
Saunders, 1996, p 150.
A though C.
Billroth I gastroduodenostomy.
[Reproduced with permission from Zinner MJ (ed): Atlas of Gastric Surgery.
New York: Churchill Livingstone, 1992, p 35.
Copyright Elsevier.]
Figure 26-40.
A through D.
Billroth II antecolic gastrojejunostomy.
I.
Stamford, Connecticut: 
Appleton & Lange, 1997, p 1112.
Roux-en-Y gastrojejunostomy.
Oversewa
2.
Oversew, V + D
3.
V + A
1.
Oversew and biopsya
2.
Oversew, biopsy, V + D
3.
Distal gastrectomyb
Perforation 1.
Patcha
2.
Patch, HSV
3.
Patch, V + D
1.
Biopsy and patcha
2.
Wedge excision, V + D
3.
Distal gastrectomyb
Obstruction 1.
HSV + GJ
2.
V + A
1.
Biopsy; HSV + GJ
2.
Distal gastrectomyb
Intractability/
nonhealing
1.
HSVb
2.
V + D
3.
V + A
1.
HSV and wedge 
excision
2.
bOperation of choice in low-risk patient.
Right upper quadrant closed suction 
peritoneal drainage is important.
Use of a feeding jejunostomy 
is also considered.
A Billroth II anastomosis reestablishes gas-
trointestinal continuity.
Second best 
is V + D with oversewing and biopsy of the ulcer to rule out 
cancer.
Perforated Peptic Ulcer (Fig.
In stable patients without longstanding perforation, the addition 
of HSV may be considered.
Vagotomy is usually added for type II and III gastric 
ulcers.
However, 
potentially curable gastric or duodenal cancers can be missed 
with this approach.
pylori
Avoid NSAIDs/ASA if possible
Yes Shock?
No
YesT ransfusion?
No
Yes Active bleeding on EGD?N o
YesV isible vessel on EGD?N o
Yes Abnormal PT, PTT, or platelets?
No
Figure 26-42.
Algorithm for the treatment of bleeding peptic ulcer.
ASA = acetylsalicylic acid; EGD = esophagogastroduodenoscopy; 
O.R.
Because 
acid secretion can be totally blocked and H.
Or
High operative risk?
or
difficult duodenum?
Algorithm for operation for bleeding peptic ulcer.
Figure 26-44.
Algorithm for operation for perforated peptic ulcer.
Or
Perforation on RX?
Or
NSAIDs/ASA necessary?
Gastric ulcer*  Duodenal ulcer* 
Hemodynamically unstable?
Or
High operative risk?
Or
Perforation >24 hours
 * In all patients, test and treat for H.
pylori, and if vagotomy not performed (most patients today)
  consider lifelong PPI.
If surgery is necessary, a lesser operation may be preferable.
Otherwise, distal gastrectomy (to include the ulcer) is 
recommended.
26-45).
Most cases (80%) are sporadic, but 
20% are inherited.
Gastrinoma is the most common pancreatic 
tumor in patients with MEN I.
Five-year survival in patients present-
ing with metastatic disease is approximately 40%.
The larger the 
primary gastrinoma, the higher the likelihood of metastatic dis-
ease.
More than 90% of patients with sporadically, completely 
resected gastrinoma will be cured.
The most common symptoms of ZES are epigastric pain, 
GERD, and diarrhea.
More than 90% of patients with gastri-
noma have peptic ulcer.
Operations for gastric ulcer.
Philadelphia: Saunders, 1998, 
p 702.
ZES is an important part of the differential diagnosis of 
hypergastrinemia (Fig.
26-46).
26-46).
pylori
give B12
Significant elevation in serum
gastrin in response to IV secretin?
Algorithm for diagnosis and management of hypergastrinemia.
the secretin stimulation test.
An increase in serum gastrin of 200 pg/mL or greater suggests 
the presence of gastrinoma.
About 80% of primary tumors are found in the gastrinoma 
triangle (Fig.
26-47), and many tumors are small (<1 cm), mak-
ing preoperative localization difficult.
Transabdominal ultra-
sound is quite specific, but not very sensitive.
CT will detect 
most lesions >2 cm in size and MRI is comparable.
26-48).
Currently, angiographic localiza-
tion studies are infrequently performed for gastrinoma.
Secre-
tin is injected into the visceral artery and gastrin is sampled in 
the hepatic vein.
This test should be performed if pancreaticoduodenectomy is 
contemplated.
Probably the most important means of locating 
gastrinomas is intraoperative exploration.
Intraoperative EGD 
with transillumination may be considered.
If the tumor can 
not be located, generous longitudinal duodenotomy with 
Figure 26-47.
Gastrinoma triangle.
Philadelphia: Lippincott, 1995, p 128.]
Figure 26-48.
Positive octreotide scan in patient with gastrinoma.
Lymph nodes from the portal, peripancreatic, and celiac drain-
age basins should be sampled.
Ablation or resection of hepatic 
metastases should be considered.
Acid hypersecretion in patients with gastrinoma can 
always be managed with high-dose PPIs.
Gastrectomy for ZES is no longer 
indicated.
GASTRITIS AND STRESS ULCER
Pathogenesis and Prevention
Gastritis is mucosal inflammation.
Additionally, there is poor correlation between symp-
toms and histologic gastritis.
The most common cause of gastritis 
is H.
pylori.
These agents cause injury by a variety of different mecha-
nisms.
When blood flow is inadequate, these processes fail and muco-
sal breakdown occurs.
Angiographic 
embolization and endoscopic hemostatic treatment should be 
considered as well.
Other rare primary malignancies 
Table 26-14 
Frequency of gastric tumors
TUMOR TyPE NO.
Washington DC: American Registry of Pathology, 
1973, p 82, Table VI.
include carcinoid, angiosarcoma, carcinosarcoma, and squa-
mous cell carcinoma.
Adenocarcinoma
Epidemiology.
26-49).
In Asia and Eastern Europe, gas-
tric cancer remains a leading cause of cancer death.
Gastric cancer has a 
higher incidence in groups of lower socioeconomic status.
Etiology.
This strongly 
suggests an environmental influence on the development of gas-
tric cancer.
The commonly accepted risk factors 
for gastric cancer are listed in Table 26-15.
Dietary nitrates have been impugned as a possible cause of 
gastric cancer.
Regular aspirin use may be protective.
Helicobacter pylori 54,84 The risk of gastric cancer in patients 
with chronic H.
pylori infection is increased about threefold.
As diagrammed in Fig.
Not all 
patients with gastric cancer have H.
pylori, and there are some 
geographic areas with a high prevalence of chronic H.
pylori infec-
tion and a low prevalence of gastric cancer (the “African enigma”).
Death rates for gastric 
cancer in different countries.
Epstein-Barr Virus About 10% of gastric adenocarcinomas 
carry the EBV virus.
Most gastric cancers 
are aneuploid.
The most common genetic abnormalities in spo-
radic gastric cancer affect the p53 and COX-2 genes.
Additionally, approxi-
mately the same proportion have overexpression of COX-2.
Gastric tumors that overexpress COX-2 are more aggressive 
tumors.
By far the most common precancerous lesion is 
atrophic gastritis.
Hyperplastic pol-
yps usually occur in the setting of chronic inflammation.
Gastric adenomas are premalignant, similar to colon adenomas.
Helicobacter and gastritis, and the 
pathogenesis of duodenal ulcer (DU) or gastric 
cancer.
pylori Diet low in vitamin C, E
High-salt diet
Figure 26-51.
Gastric carcinogenesis.
Philadelphia: Saunders, 2002.
Copyright Elsevier.
Precancerous lesions of the stomach.
Atrophic Gastritis Chronic atrophic gastritis (Fig.
26-52).
In many patients, it is likely that H.
pylori is involved 
in the pathogenesis of atrophic gastritis.
26-54).
There is evidence that eradication of H.
Therefore, treatment of 
H.
pylori infection.
Figure 26-53.
Chronic atrophic gastritis.
The risk is controversial, 
but the phenomenon is real.
Periodic surveillance 
EGD is prudent in all the above conditions.
Figure 26-54.
Complete intestinal metaplasia of the stomach.
Note 
intestinal type crypts lined with goblet cells and intestinal absorp-
tive cells.
Approximately 10% of patients with early 
gastric cancer will have lymph node metastases.
There are sev-
eral types and subtypes of early gastric cancer (Table 26-17 and 
Fig.
26-55).
The over-
all cure rate with adequate gastric resection and lymphad-
enectomy is 95%.
In some Japanese centers, 50% of the 
gastric cancers treated are early gastric cancer.
In the United 
States, less than 20% of resected gastric adenocarcinomas are 
early gastric cancer.
In the first two, the bulk of the tumor mass is 
intraluminal.
In the 
latter two gross subtypes, the bulk of the tumor mass is in the 
wall of the stomach.
Palliative chemo-
therapy may prolong median survival94A.
Type 0-IIa Slightly elevated tumors.
(superficial 
elevated)
 Type 0-IIb Tumors without elevation or depression.
(superficial flat)
 Type 0-IIc Slightly depressed tumors.
Several decades ago, the large 
majority of gastric cancers were in the distal stomach.
There are several histologic classifications of gastric can-
cer.
The World Health Organization recognizes several histologic 
types (Table 26-18).
The Japanese classification is similar but 
more detailed.
Pathologic types of early gastric cancer.
Semin Oncol.
23(3):292, 
1996.
Baltimore: Williams & 
Wilkins, 1998.
gastric cancer, HER2 overexpression has been reported in 13% 
to 30% of patients.
Clinical Manifestations.
Abdominal pain (usually not severe and often 
ignored) also is common.
Other symptoms include nausea, 
vomiting, and bloating.
Dysphagia is 
common if the tumor involves the cardia of the stomach.
Physical examination typically is normal.
Other than signs 
of weight loss, specific physical findings usually indicate incur-
ability.
Diagnostic Evaluation.
In some patients with gastric tumors, upper GI series can be 
helpful in planning treatment.
The image of virtual endoscopy is now quite 
similar to that of upper endoscopy.
In the near future, this novel 
technology may play a role in the screening of the stomach.
MRI is probably comparable.
However, there are limitations to tumor staging 
with EUS.
EUS is most accurate in distinguishing 
early gastric cancer (T1) from more advanced tumors.
Unfortunately, 
it is also unclear how much these patients benefit from gastric 
resection.
Treatment.
The goal of curative surgical treatment is resection of all 
tumor (i.e., R0 resection).
Generally, the surgeon strives for a grossly 
negative margin of at least 5 cm.
26-56).
Reconstruction 
Gastroepiploic
vs.
A and B.
Radical subtotal gastrectomy.
vs.
= vessels.
[Reproduced with permission from Daly JM, Cady B, Low DW 
(eds): Atlas of Surgical Oncology.
St.
Louis: Mosby-Year Book, 
1993, p 231.
The oper-
ative mortality is around 2% to 5%.
In the absence of involvement by direct extension, the 
spleen and pancreatic tail are not removed.
Total gastrectomy with Roux-en-Y esophagojejunostomy 
may be required for R0 resection (Fig.
26-57), and may be the 
best operation for patients with proximal gastric adenocarcinoma.
26-4).
According to the type of gas-
trectomy, the definition of extent of lymphadectomy is different.
The standard opera-
tion for gastric cancer in Asia and specialized U.S.
centers is 
60 cm
Figure 26-57.
Reconstruction after total gastrectomy.
Jejunal 
pouch (not shown here) should be considered.
[Reproduced with 
permission from Zinner MJ (ed): Atlas of Gastric Surgery.
New York: 
Churchill Livingstone, 1992, p 167.
This stage shift suggests that many patients in the U.S.
Therefore, in the 
U.S.
The Surgical Cooperative Group.
Lancet.
347:995, 1996.
cancer as well as several types of cancer, such as colon and lung.
In 
Europe, triple therapy is more often epirubicin, cisplatin, and 
5-FU.
EMR is indicated for patients in 
whom the probability of lymph node metastasis is low.
New indications 
for minimally invasive treatment will require evaluation before 
implementation.
The addition of laparoscopic lymph node sampling may be 
considered in selected patients.
Prognosis.
Survival is dependent on pathologic stage (TNM stage) 
and degree of tumor differentiation.
Thus, screening is effective in a high-risk population.
Gastric Lymphoma
Gastric lymphomas generally account for about 4% of gastric 
malignancies.
Over half of patients with non-Hodgkin’s lym-
phoma have involvement of the GI tract.
The stomach is the most 
common site of primary GI lymphoma, and over 95% are non-
Hodgkin’s type.
Interest-
ingly, the normal stomach is relatively devoid of lymphoid tissue.
Again, H.
pylori is thought to be the culprit.
In populations with a high inci-
dence of gastric lymphoma, there is a high incidence of H.
pylori 
infection; patients with gastric lymphoma also usually have H.
pylori.
Remarkably, 
when the H.
pylori is eradicated and the gastritis improves, the 
low-grade MALT lymphoma often disappears.
Thus, low-grade 
MALT lymphoma is not a surgical lesion.
If low-grade lymphoma persists after H.
26-58).
The tumors may 
bleed and/or obstruct.
Lymphadenopathy and/or organomegaly 
suggest systemic disease.
Diagnosis is by endoscopy and biopsy.
Much of the tumor may be submucosal, and an assiduous attempt 
at biopsy is necessary.
Primary lymphoma is usually nodular with 
enlarged gastric folds.
This includes EUS; CT scanning of the chest, abdomen, 
and pelvis; and bone marrow biopsy.
Treatment-related 
perforation or bleeding is unusual but recognized.
Palliative gastrectomy for 
tumor complications also has a role.
Any lesion >1 cm 
can behave in a malignant fashion and may recur.
Thus, all GISTs 
are best resected along with a margin of normal tissue.
Two-thirds of all GISTs occur in the stomach.
The glomus tumor type is seen only in the stomach.
GISTs are submucosal tumors that are slow growing.
An abdom-
inal mass may be palpable.
EUS may be help-
ful, but symptomatic tumors and tumors >1 cm in size should 
be removed.
They are almost 
always solitary.
Wedge resection with clear margins is adequate 
surgical treatment.
True invasion of adjacent structures by the 
primary tumor is evidence of malignancy.
Five-year survival 
6
1085
Stomach
CHAPTER 26
following resection for GIST is about 50%.
Interme-
diate risk was defined as <5 cm and 6 to 10/50 HPF or 5 to 
10cm and >5/50 HPF.
It was known that the risk of recurrence differs by the 
primary site of the tumor.
26-59.
They arise from gastric enterochromaffin-like 
(ECL) cells and some have malignant potential.
pylori eradication therapy
and chemo** +/– XRT*
H.
pylori eradication therapy
Re-evaluate at 3–6 months
H.
pylori eradication therapy
Re-evaluate at 12 months
Figure 26-58.
Algorithm for the treatment of gastric lymphoma.
MALT = mucosa-associated lymphoid tissue.
Gastric carcinoids are classified into one of three differ-
ent types.
Type I is the most common type of gastric carcinoid, 
accounting for about 75% of patients.
Type II gastric carcinoids are associated with MEN1 and 
ZES.
Type III gastric carcinoids are sporadic tumors.
They are 
most often solitary (usually >2 cm) and occur more commonly 
in men.
They are not associated with hypergastrinemia and 
biopsy shows a heterogeneous cell population.
Algorithm for the treatment of gastrointestinal stromal tumor.
Ann Surg 244:176, 2006.)
Gastric carcinoids are usually diagnosed with endoscopy and 
biopsy.
Some tumors are submucosal and may be quite small.
They 
are often confused with heterotopic pancreas or small leiomyomas.
Plasma chromogranin A levels are elevated in patients with gastric 
carcinoid.
CT scan and octreotide scan are useful for staging.
Gastric carcinoids should be resected.
Careful follow-up 
is necessary.
Larger lesions should be removed by D1 or D2 gastrec-
tomy.
Gastri-
noma should be resected if located in patients with type II carcinoid.
Surgical debulking may have a role in selected patients with meta-
static disease.
BENIGN GASTRIC NEOPLASMS
Leiomyoma
The typical leiomyoma is submucosal and firm.
If ulcerated, it has 
an umbilicated appearance and may bleed.
Histologically, these 
7
1087
Stomach
CHAPTER 26
lesions appear to be of smooth muscle origin.
Lesions <2 cm are 
usually asymptomatic and benign.
Excision is unnec-
essary unless the patient is symptomatic.
Eighty percent of these patients are women; some are 
diabetic.
An upper GI 
series may suggest slow gastric emptying and relative atony, 
or it may be normal.
EGD may show bezoars or retained food 
but is frequently normal.
Gastric emptying scintigraphy shows 
delayed solid emptying, and often delayed liquid emptying.
Gastroparesis can be a manifestation of a variety of problems 
(Table 26-22).
Risk stratification 
is essentially accomplished by answering the following questions:
a.
What is the magnitude and acuity of the hemorrhage?
This is a high-risk situation.
b.
If yes, this is a high-risk situation.
c.
Is the patient anticoagulated, or immunosuppressed?
If yes, 
this is a high-risk situation.
d.
Could the 
patient be bleeding from an Arterio enteric fistula?
If yes, 
this is a high-risk situation.
Park-
man HP et al.
Gastroduodenal motility and dysmotility: An update on 
techniques available for evaluation.
Am J Gastroenterol.
1995;90:869.
Copyright © 1995.
Selected patients may 
be discharged from the emergency room and managed on an 
outpatient basis.
Type and cross-match for transfusion of blood products.
2.
Admit to ICU or monitored bed in specialized unit.
3.
Consult surgeon.
4.
Consult gastroenterologist.
5.
Start continuous infusion of PPI.
6.
Perform upper endoscopy within 12 hours, after resuscita-
tion and correction of coagulopathy.
Mucosal lesions can usually be controlled with endo-
scopic hemotherapy and medical management.
26-43).
The operative mor-
tality is 5%.
Liver transplantation should always be considered 
in the cirrhotic patient.
The latter is characteristically associated with protein-
losing gastropathy and hypochlorhydria.
There are large rugal 
folds in the proximal stomach, and the antrum is usually spared.
26-60).
This results in the selective expansion of surface 
mucous cells in the gastric body and fundus.
There may be an increased risk of gastric 
cancer.
Sometimes, the disease regresses spontaneously.
Gastric 
resection may be indicated for bleeding, severe hypoprotein-
emia, or cancer.
Mucosal fibromuscular hyperplasia and hyalinization often are 
present (Fig.
26-61).
Patients with GAVE 
are usually elderly women with chronic GI blood loss requiring 
transfusion.
Figure 26-60.
Mucosal biopsy in Ménétrier’s disease.
If this artery is eroded, impressive pulsatile bleeding may occur.
Treatment options include endoscopic 
hemostatic therapy, angiographic embolization, or operation.
At 
surgery, the lesion may be oversewn or resected.
Bezoars/Diverticula
Bezoars are concretions of indigestible matter that accumulate in 
the stomach.
Trichobezoars, composed of hair, occur most com-
monly in young women who swallow their hair (Fig.
26-62).
They also are associated with persimmon inges-
tion.
Most commonly, bezoars produce obstructive symptoms, but 
they may cause ulceration and bleeding.
Diagnosis is suggested by 
upper GI series and confirmed by endoscopy.
Gastric diverticula are usually solitary and may be congeni-
tal or acquired.
Most gastric diverticula occur in the posterior cardia 
or fundus (Fig.
26-63) and are usually asymptomatic.
However, 
they can become inflamed and may produce pain or bleeding.
Perforation is rare.
Asymptomatic diverticula do not require treat-
ment, but symptomatic lesions should be removed.
This can often 
be done laparoscopically.
Foreign Bodies
Ingested foreign bodies are usually asymptomatic.
Removal 
of sharp or large objects should be considered.
This can usu-
ally be done endoscopically, with an overtube technique.
Figure 26-61.
Gastric antral vascular ectasia (watermelon stom-
ach).
Baltimore: 
Williams & Wilkins, 1998, p 577.]
Figure 26-62.
Trichobezoar forming cast of stomach and duode-
num; removed from 15-year-old girl.
[Reproduced with permission 
from DeBakey M, Ochsner A: Bezoars and concretions.
Surgery 
4:934, 1938.
Copyright Elsevier.]
Figure 26-63.
Gastric diverticulum.
East Norwalk, 
Connecticut: Appleton & Lange, 1989, p 577.
Surgical removal is 
recommended in body packers, and in patients with large jag-
ged objects.
Corrosive objects (e.g., watch batteries) should be 
removed promptly.
It presents 
with upper GI bleeding, often with hematemesis.
Surgical treatment consists of oversewing 
the bleeding lesion through a long gastrostomy.
It also can occur in patients 
with an unusually mobile stomach without hiatal hernia.
26-64C).
If the 
stomach twists around the transverse axis, it is called mesentero-
axial rotation (Fig.
26-64A and Fig.
26-64B).
Often, volvulus 
is a chronic condition that can be surprisingly asymptomatic.
The risk of strangulation 
and infarction has been overestimated in asymptomatic patients.
Symptoms are often relieved with 
vomiting or passage of a nasogastric tube.
Gastric infarction is 
a surgical emergency, and the patient can be moribund.
Gastric 
necrosis may be extensive or focal.
The open techniques include the 
Stamm method (Fig.
26-65), the Witzel method (Fig.
26-66), 
and the Janeway method (Fig.
26-67).
A through C.
Gastric 
volvulus.
[Reproduced with permis-
sion from Buchanan J: Volvulus of 
the stomach.
Br J Surg.
18:99, 1930.
© British Journal of Surgery Soci-
ety, Ltd.
Permission is granted by 
John Wiley & Sons, Ltd on behalf of 
BJSS, Ltd.] A BC
Figure 26-65.
Stamm gastrostomy.
II.
These symp-
toms may be ameliorated by recumbence or saline infusion.
Crampy abdominal pain is not uncommon and diarrhea often 
follows.
Late dumping is associated 
with hypoglycemia and hyperinsulinemia.
Often, symptoms improve if the patient avoids liquids during 
meals.
Hyperosmolar liquids (e.g., milk shakes) may be particu-
larly troublesome.
There is some evidence that adding dietary 
fiber compounds at mealtime may improve the syndrome.
This can be increased 
up to 500 μg twice daily if necessary.
The long-acting depot 
octreotide preparation is useful.
Only a very small percentage of patients with dumping symp-
toms ultimately require surgery.
Most patients improve with time 
(months and even years), dietary management, and medication.
Figure 26-66.
A through F.
Witzel gastrostomy.
II.
Multidisciplinary nonsurgi-
cal management must be optimized first.
The results of remedial operation for dumping are variable 
and unpredictable.
There are a variety of surgical approaches, 
none of which work consistently well.
Long-term follow-up is rare.
The reversed intesti-
nal segment is rarely used today—and rightly so.
This slows gastric emp-
tying, but often leads to obstruction, requiring reoperation.
26-68).
A through D.
Janeway gas-
trostomy.
II.
Philadelphia: 
Saunders, 2002, p 46.]
Figure 26-68.
Duodenal switch operation.
Surg Clin North Am.
72:487, 1992.
Truncal vagotomy is 
associated with clinically significant diarrhea in 5% to 10% of 
patients.
The 
symptoms tend to improve over the months and years after the 
index operation.
The cause of postvagotomy diarrhea is unclear.
Octreotide should also be tried.
This can be confirmed with 
a qualitative test for fecal fat and treated with acid suppression.
Postvagotomy diarrhea usually does not respond to treatment 
with pancreatic enzymes.
Another option is the onlay antiperistaltic distal ileal 
graft.
Endoscopy 
shows gastritis and retained food or bezoar.
The anastomosis 
and efferent limb should be evaluated for stricture or narrow-
ing.
This consists of dietary 
modification and promotility agents.
The latter should be dealt with at reoperation.
Endoscopic dilation 
is occasionally helpful.
If total gastrectomy 
is performed, a jejunal reservoir should be fashioned.
Curiously, symptoms often 
develop months or years after the index operation.
Excessively long limbs may be associated with 
obstruction or malabsorption.
26-68).
The Achilles’ heel of this operation is, not sur-
prisingly, marginal ulceration.
These 
patients present with vomiting, epigastric pain, and weight loss.
This clinical scenario has been labeled the Roux syndrome.
Anastomotic 
inflammation and stricture from marginal ulceration is a con-
founding finding.
An upper GI series confirms these findings 
and may show delayed gastric emptying.
Pre-
sumably, the disordered motility in the Roux limb occurs in all 
patients with this operation.
Why only a subset develops the 
Roux syndrome is unclear.
Perhaps those patients with disor-
dered gastric motility are at most risk.
The disorder seems to 
be more common in patients with a generous gastric remnant.
Truncal vagotomy also has been implicated.
Medical treatment consists of promotility agents.
Surgi-
cal treatment consists of paring down the gastric remnant.
Care 
should be taken to preserve adequate blood supply to the new 
gastric pouch.
If gastric motility 
is severely disordered, 95% gastrectomy or total gastrectomy 
should be done.
Weight Loss
Weight loss is common in patients who have had a vagotomy 
and/or gastric resection.
The degree of weight loss tends to 
parallel the magnitude of the operation.
It may be insignificant 
in the large person, or devastating in the asthenic female.
Consultation with 
an experienced dietitian may prove invaluable.
Vitamin B12 bioavailability also 
is facilitated by an acidic environment.
It also occurs 
in up to one third of patients who have had a vagotomy and/or 
gastric resection.
Marginal nutrient status should be 
corrected with oral and/or parenteral supplementation.
Bone Disease
Gastric surgery sometimes disturbs calcium and vitamin D 
metabolism.
Calcium absorption occurs primarily in the duo-
denum, which is bypassed with gastrojejunostomy.
This can significantly affect the absorp-
tion of vitamin D, a fat-soluble vitamin.
The problems 
usually manifest as pain and/or fractures years after the index 
operation.
Musculoskeletal symptoms should prompt a study 
of bone density.
Dietary supplementation of calcium and vitamin 
D may be useful in preventing these complications.
Combined endoscopic and lapa-
roscopic techniques occasionally are useful.
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The Surgical Management of 
Obesity
Philip R.
Outcomes, as reported for review by the 
oversight committee, are better than ever.
Our patients have thus 
been well served.
Obesity is a disease and is likely multifactorial in its ori-
gin.
The 
components of the disease likely include a combination of envi-
ronmental and genetic factors.
Long-term 
follow-up is essential before the merits of an operation can 
be confirmed.
which to classify obesity.
The World Health Organization classifica-
tion of obesity is given in Table 27-1.
Source: Adapted from the World Health Organization (WHO) 2000205.
Data on obesity statistics have been updated annu-
ally since 1985.
The latest figures for obesity incidence in the 
United States are that 35.7% of U.S.
The weight of adopted children correlates 
strongly with the weight of their birth parents.
Other factors appear to contribute significantly to severe 
obesity.
Intermittent or consistent excessive caloric intake 
occurs.
As yet, the physiologic basis for 
the explanation of such lack of satiety is not understood.
Weight gain results from increase in both 
adipose cell size and number.
This preju-
dice against obesity remains the last unlegislated discrimina-
tion in existence.
Obese individuals are routinely discriminated 
against in terms of employment.
Public facilities often do not 
allow them to participate in activities.
They often endure 
not only discrimination and prejudice, but outright ridicule and 
disrespect.
Poor self-image is almost universal among obese 
individuals.
1
1102
SPECIFIC CONSIDERATIONS
UNIT II
PART II
There are two main reasons for this.
Medi-
cal comorbidities must be identified and treated.
Most patients also 
have attempted commercially sponsored diets and diet plans.
Dietary 
restriction and exercise can each independently create a 
caloric deficit.
Longer follow-up shows recidivism.
Pharmacologic therapy is also an option for patients 
attempting to lose weight.
Pharmacotherapy is normally used only after life-
style changes and dietary therapies have failed.
That number has now increased, but still is not over 2% of 
individuals.
Part of this issue may be patient aversion to surgical therapy.
The 
most common is restriction of intake.
Malabsorption of ingested 
food is the second mechanism.
Restrictive operations may 
include no or only a modest malabsorptive component.
Since the procedure was easily done, some surgeons performed 
it in prolific numbers.
Staple breakdown predictably occurred 
months to years later, with subsequent weight regain.
In 2001, LAGB was approved for use in 
the United States.
Its popularity increased annually until 2009, 
but since then, it has decreased in popularity.
The field then literally exploded in terms of growth 
in the United States.
Operative procedures increased nearly 
eight-fold.
Patients who 
had or were contemplating surgery were able to communicate 
via the Internet.
Many U.S.
Hospitals without programs 
recruited surgeons so they could offer the service.
Bariatric 
surgery presentations at national surgical meetings became 
common instead of rare.
These were defined by the CMS in 2005 as 
those listed in Table 27-2, with the exception of SG.
This factor, however, is normally beyond 
surgeon control.
Number of Roux-en-Y gastric bypass operations per-
formed in the United States by year.
Body mass index ≥40 kg/m2 with or without comorbid 
medical conditions associated with obesity
 2.
Has failed attempt at medically supervised diet
 4.
The NIH criteria do not set limits for age, and surgeon 
opinion on this issue varies widely.
Surgeons have variable 
practice patterns as to performance of surgery in the older 
patient.
Known and documented drug 
or alcohol addiction is a contraindication to surgery.
A poorly controlled eat-
ing disorder, especially bulimia, is also a contraindication to 
surgery.
Table 27-4 summarizes potential contraindications for 
surgery.
Table 27-4
Potential contraindications for bariatric surgery
1.
Mentally incompetent to understand procedure
3.
Inability or unwillingness to change lifestyle 
postoperatively
4.
Drug, alcohol, or other addiction
5.
Active problem of bulimia or other eating disorder
6.
Psychologically unstable
7.
Nonambulatory status
8.
An estimation of the patient’s motivation to change eating 
habits is important.
The operation to be performed requires spe-
cific nutritional counseling and education.
Psychological assessment is required by most insurance 
carriers.
Its treatment is felt to improve 
postoperative outcomes.
Some will decide against the 
procedure after thorough educational and counseling sessions.
Such sessions are imperative for improving outcomes.
Potentially undiag-
nosed medical problems are sought.
A diagnostic sleep study is indicated for these individuals.
Pulmonary consultation is indi-
cated for patients with hypoventilation syndrome.
Preoperative weight loss is not necessary to achieve good out-
comes from surgery.
Some sur-
geons make this an absolute requirement, while others do not.
Serum chemistries, liver function tests, and 
usual screening blood tests are done.
However, the primary 
reason to correct low vitamin D is improved long-term bone 
disease health.
Jugular cannulation is often very difficult due to neck 
adipose tissue.
However, ultrasound guidance can facilitate this 
procedure.
Subclavian access is performed when other central 
access routes are not feasible.
Experience is key in performing smooth intuba-
tion of this patient population.
Calculation of the dosage should be done by lean body 
weight.
Benzodiazepines also exhibit a prolonged elimination 
phase, causing persistence of their effects.
An 
angled telescope is quite helpful.
Postoperative Follow-Up
Short-term follow-up is defined as follow-up of up to 2 years.
Failure to establish an adequate pneumoperitoneum
2.
Hemodynamic adverse reaction to pneumoperitoneum
3.
Intraoperative complications such as hemorrhage that are 
best managed with an open approach
6.
Exceedingly thick body wall precluding adequate trocar 
access or manipulation
7.
Medium-term follow-up is defined as that from 2 to 5 
years.
Few 
publications have met these criteria.
open) have been performed.
Improvement 
in study design and more complete data in future publications 
are indicated.
Regular counseling sessions with the nutritionist are always 
helpful.
Diligence to avoid 
snacking and returning to other poor eating habits is also impor-
tant.
laparoscopic Adjustable gastric Banding
Background.
LAGB involves placement of an inflatable sili-
cone band around the proximal stomach.
Figure 27-2 shows 
the LAGB apparatus in place.
Two major types of bands have been used for this pro-
cedure.
Technique.
Port placement for LAGB has varied among surgeons.
Figure 27-2 shows a common configuration used.
Laparoscopic adjustable band overall scheme.
(From 
Schauer PR, et al, eds.
Minimally Invasive Bariatric Surgery, 1st ed.
New York: Springer; 2007.
Reprinted with permission, Cleveland 
Clinic Center for Medical Art & Photography © 2005-2009.
All 
rights reserved.)
1109
T
HE
 S
UR
g
ICA
l M
ANA
g
EMENT
 
OF
 O
BESITY
CHAPTER 27
Figure 27-3.
Grasper being passed through under stomach to grasp 
tubing during placement.
(From Schauer PR, et al, eds.
Minimally 
Invasive Bariatric Surgery, 1st ed.
New York: Springer; 2007.
Reprinted with permission, Cleveland Clinic Center for Medical 
Art & Photography © 2005-2009.
All rights reserved.)
His in the area of the divided peritoneum (Fig.
27-3).
27-4A,B).
27-5).
A
Figure 27-4.
A.
Lap-Band in place around stomach.
(From Schauer PR, et al, eds.
Minimally Invasive Bariatric Surgery, 1st ed.
New York: 
Springer; 2007.
Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography ©  2005-2009.
All rights reserved.
B.
Realize (Swedish) Band around stomach.
The port is secured to the anterior abdominal 
wall fascia.
The band is initially placed empty of 
fluid in most circumstances.
Patient Selection and Preparation.
Most LAGB procedures 
are done on an outpatient basis.
Technically the operation is 
not as difficult as the other operations described later.
An orogastric 
tube is inserted into the stomach.
These preoperative measures 
are recommended in all the procedures described later as well.
Postoperative Care and Follow-Up.
The majority of LAGB 
procedures are performed on an outpatient basis.
The first postoperative evaluation after LAGB generally 
occurs 2 to 3 weeks after surgery.
Wounds are assessed, as are medical problems, oral intake, and 
adherence to diet.
Recommendations for timing of band 
adjustments vary from practice to practice.
Band fills usually are accomplished in the outpatient clinic 
setting.
Stomach imbricated 
over band.
A careful record should be maintained of the amount of 
fluid in each patient’s band.
Some surgeons will withdraw all 
the fluid at each fill, reinserting the desired amount.
Many will 
just add additional fluid as indicated.
The amount of fluid added 
is based on hunger, weight loss, and ability to eat meat or bread.
However, changing life and clinical circumstances 
can require adjustments at any time thereafter.
Outcomes.
Overall mortal-
ity for LAGB was given as 0.1%.
Can still eat
chicken,
steak, or
bread?
Can still eat
chicken,
steak, or
bread?
Can eat
chicken,
steak, or
bread?
Weight
loss?
Weight
loss?
Weight
loss?
Adjustment
(How much?)
Adjustment
(How much?)
Adjustment
(How much?)
Adjustment
(How much?)
Hungry?
Hungry?
Hungry?
Hungry?
Algorithm for postoperative band adjustment.
RTC = return to clinic.
(Reproduced with permission from Ren CJ.
Laparoscopic 
adjustable gastric banding: postoperative management and nutritional evaluation.
In: Schauer PR, et al, eds.
Minimally Invasive Bariatric 
Surgery.
1st ed.
New York: Springer; 2007:200.
Prolapse is perhaps the most common emergent compli-
cation that requires reoperation after LAGB.
The incidence of 
reoperation is generally around 3%.
Postoperative vomiting pre-
disposes to this problem.
The lower stomach is pushed upward 
and trapped within the lumen of the band.
If the band is in a horizontal position, pro-
lapse must be strongly suspected.
Initial treatment for a prolapse is to remove all the fluid 
from the system.
This often allows reduction of the prolapse and 
resolution of symptoms.
If symptoms resolve, the necessity of 
performing an upper gastrointestinal series is lessened.
Longer-
term follow-up rates may show higher rates of prolapse.
Band erosion is uncommon, reported in 1% to 2% of 
most series.
Endoscopy can be 
diagnostic.
Laparoscopic removal of the band is indicated, 
with repair of any gastric perforation.
The true inci-
dence probably varies widely.
Angrisani et al77 reported a 40.9% 
incidence of band removal after 10-year follow-up.
One of the positive outcomes of LAGB is the safety of 
the procedure.
While complications are not rare, most of them 
involve non–life-threatening events.
Nutritional complications 
are uncommon and easily treated.
The Lap-Band also has its limitations, which may be the 
cause of its reduced popularity.
It is often ineffective in pro-
ducing adequate weight loss.
Patients must have enough willpower to avoid such foods.
laparoscopic Roux-en-Y gastric Bypass
Background.
Currently over 90% of gastric 
bypass operations nationally are performed laparoscopically.
Figure 27-7 depicts the configuration of the LRYGB.
A Roux limb of proximal jejunum is brought up and 
anastomosed to the pouch.
Experience has resolved several controversies about gas-
tric bypass, but others are still debated.
Configuration of laparoscopic gastric bypass.
(From 
Schauer PR, et al, eds.
Minimally Invasive Bariatric Surgery, 1st 
ed.
New York: Springer; 2007.
Reprinted with permission, Cleve-
land Clinic Center for Medical Art & Photography © 2005-2009.
All rights reserved.)
(150 cm) Roux limb for patients with a BMI over 60 or even  
50 kg/m2.
The gastrojejunal anastomosis can be constructed 
in a variety of ways.
The operation generally is performed using five 
ports plus a liver retractor.
The telescope requires a 
port, usually in the supraumbilical region.
27-8).
Port scheme for laparoscopic gastric bypass.
(From 
Schauer PR, et al, eds.
Minimally Invasive Bariatric Surgery, 1st ed.
New York: Springer; 2007.
Reprinted with permission, Cleveland 
Clinic Center for Medical Art & Photography © 2005-2009.
A Penrose drain or suture is sutured to the proximal Roux limb 
(Fig.
27-9) for identification and facilitation of advancement to 
the gastric pouch.
The length of the Roux limb (usually 100–150 cm) to be 
created is now measured.
A side-to-side stapled 
anastomosis is performed (Fig.
27-10).
Passage of the Roux limb toward the stomach is now per-
formed.
27-11).
The left lobe of the liver is now retracted using any one 
of several retractor types.
The patient is moved to a reverse 
Trendelenburg position.
The harmonic scalpel divides the peri-
toneum in the area of the angle of His.
27-12).
Once the pouch is created, the Roux limb is brought up to 
the proximal gastric pouch.
27-13).
Figure 27-9.
Creating Roux limb during 
laparoscopic gastric bypass.
Figure 27-10.
Enteroenterostomy of lapa-
roscopic Roux-en-Y gastric bypass.
This is accomplished 
by pulling the anvil transorally via an endoscopically placed 
Figure 27-11.
Passage of Roux limb.
(From Schauer PR, et al, eds.
Minimally Invasive Bariatric Surgery, 1st ed.
New York: Springer; 
2007.
Reprinted with permission, Cleveland Clinic Center for Med-
ical Art & Photography © 2005-2009.
All rights reserved.)
Figure 27-12.
Creation of gastric pouch for laparoscopic Roux-en-
Y gastric bypass.
(From Schauer PR, et al, eds.
Minimally Invasive 
Bariatric Surgery, 1st ed.
New York: Springer; 2007.
Reprinted with 
permission, Cleveland Clinic Center for Medical Art & Photogra-
phy © 2005-2009.
All rights reserved.)
3
2 1
Figure 27-13.
Gastrojejunostomy in laparoscopic Roux-en-Y 
gastric bypass.
(From Schauer PR, et al, eds.
Minimally Invasive 
Bariatric Surgery, 1st ed.
New York: Springer; 2007.
Reprinted with 
permission, Cleveland Clinic Center for Medical Art & Photogra-
phy © 2005-2009.
All rights reserved.)
guidewire (Fig.
27-15).
Patient Selection and Preparation.
Postoperative Care and Follow-Up.
LRYGB patients are 
usually hospitalized for 2 to 3 days.
Figure 27-14.
(From Schauer 
PR, et al, eds.
Minimally Invasive 
Bariatric Surgery, 1st ed.
New York: 
Springer; 2007.
Reprinted with per-
mission, Cleveland Clinic Center 
for Medical Art & Photography 
©  2005-2009.
All rights reserved.)
Figure 27-15.
(Repro-
duced with permission from Schneider BE, et al.
Circular stapled 
transabdominal technique.
In: Schauer PR, et al, eds.
Minimally 
Invasive Bariatric Surgery.
1st ed.
New York: Springer; 2007:248.
Discharge on 
a blenderized diet is standard for our practice.
Diet advancement occurs after the first clinic visit, usually 
approximately 3 weeks after surgery.
At that time, an exercise 
plan is initiated if not already started.
Outcomes.
Hyperlipidemias are almost always improved and resolve totally in 
about 70% of cases.
Hypertension resolves in 50% to 65% of cases 
(see Table 27-7).
Several complications that are specific to LRYGB must be 
emphasized.
One of the most important is small bowel obstruc-
tion.
Thus, treatment 
for these patients differs from most patients with small bowel 
obstruction.
27-16).
If the bowel is viable, suturing the mesenteric defect is all that 
is needed for treatment.
Marginal ulcers are another complication relatively spe-
cific to RYGB, either LRYGB or open RYGB.
The patient 
presents with pain in the epigastric region that is not altered by 
eating.
Diagnosis is by endoscopy.
Treatment is medical with 
proton pump inhibitors, which are effective in 90% of cases.
Diagnosis is 
by upper endoscopy.
Treatment is balloon dilatation.
Resolution 
normally occurs with one or two treatments.
Open Roux-en-Y gastric Bypass
Background.
It has been the most 
time-tested and proven of all bariatric operations.
Technique.
RYGB is performed essentially the same as 
LRYGB.
Closure of the midline wound is per-
formed using a running monofilament suture.
Subcutaneous 
tissues are thoroughly irrigated, and skin is closed with a skin 
stapler.
Patient Selection and Preparation.
Patient selection is 
essentially the same as for LRYGB, since the operation is the 
same.
Preparation for open RYGB is identical to LRYGB.
Postoperative Care and Follow-Up.
Other visits, follow-up schedule, and 
blood testing are identical to LRYGB.
Outcomes.
Christou and colleagues107 showed a lower incidence 
of mortality (0.68% vs.
This was a reduc-
tion of 89% in the death rate.
Biliopancreatic Diversion and Duodenal Switch
Background.
However, 
the procedure did develop a devoted following among a few 
bariatric surgeons.
This 
new procedure was originally called BPD with DS.
It is illustrated in Fig.
27-18.
Figure 27-17.
Diagram of biliopancreatic diversion.
(From 
Schauer PR, et al, eds.
Minimally Invasive Bariatric Surgery, 1st 
ed.
New York: Springer; 2007.
Reprinted with permission, Cleve-
land Clinic Center for Medical Art & Photography © 2005-2009.
All rights reserved.)
Figure 27-18.
Diagram of duodenal switch.
(From Schauer PR, 
et al, eds.
Minimally Invasive Bariatric Surgery, 1st ed.
New York: 
Springer; 2007.
Reprinted with permission, Cleveland Clinic Center 
for Medical Art & Photography © 2005-2009.
Technique.
The terminal ileum is 
identified and divided 250 cm proximal to the ileocecal valve.
The DS procedure differs from the BPD only in the proxi-
mal gut portion of the operation.
This end of the duodenum is 
then anastomosed to the distal 250 cm of ileum.
This anastomo-
sis is often done in an end-to-end fashion with a circular stapler.
The distal 
bowel configuration and cholecystectomy are similar to BPD.
Patient Selection and Preparation.
Frequent and large-quantity bowel 
movement after any large amount of oral intake is common.
Patients who undergo either operation must 
agree to close follow-up preferably by the surgeon.
Disastrous results may then 
occur.
Postoperative Care and Follow-Up.
Postoperatively, BPD 
and DS patients face the same potential complications as seen 
after RYGB.
Distal anastomotic problems can occur with 
either procedure as well.
Fat-soluble vitamins must be supplemented in 
parenteral form.
Careful monitoring of protein intake and serum 
albumin is necessary.
Outcomes.
Weight loss results with BPD or DS are both excel-
lent and comparable.
They also are very durable.
When it is diagnosed, the 
treatment is parenteral nutrition.
SG had its origins in the early 
days of laparoscopic bariatric surgery.
After patients had lost 
weight, the malabsorptive component of the procedure was then 
performed.
Until 2009, SG was considered an “experimental” proce-
dure by insurance carriers.
27-19.
National U.S.
Bariatric Volume Percent-
age by Procedure Type.
Obes Surg.
2013;23:427.
Whether a second stage is indicated 
depends on the effectiveness of the SG.
The one exception is 
GERD.
Technique.
The patient is positioned supine, with foot sup-
port to allow reverse Trendelenburg positioning.
27-21.
The other of 
these ports is a 12-mm port.
A liver retractor is placed in the epigastric 
region.
This can be a Nathanson or T-Boone retractor.
The harmonic scalpel works nicely to perform this tissue divi-
sion.
Asia/Pacific 
Bariatric Volume Percentage by 
Procedure Type.
Obes Surg.
2013;23:427.
With 
kind permission of Springer 
Science+Business Media.)
Figure 27-21.
Port scheme for Laparoscopic sleeve gastrectomy.
Stapled division of the stomach now follows.
This bougie 
then serves as a guide for further gastric division.
It is most important not to narrow the stomach lumen at the 
incisura.
27-22).
At 
this point, changing staple loads to lower staple height is advis-
able.
Figure 27-23 shows the com-
pleted operation.
Controversy still exists as to the optimal size of the bougie 
used during the procedure.
Performing sleeve gastrectomy.
(From Schauer 
PR, et al, eds.
Minimally Invasive Bariatric Surgery, 1st ed.
New 
York: Springer; 2007.
Reprinted with permission, Cleveland Clinic 
Center for Medical Art & Photography © 2005-2009.
All rights 
reserved.)
Figure 27-23.
Completed sleeve gastrectomy.
(From Schauer PR, 
et al, eds.
Minimally Invasive Bariatric Surgery, 1st ed.
New York: 
Springer; 2007.
Reprinted with permission, Cleveland Clinic Center 
for Medical Art & Photography © 2005-2009.
All rights reserved.)
with staple buttressing material.
Some surgeons advocate rou-
tine staple line reinforcement, whereas others advocate none.
Postoperative Care and Follow-Up.
SG usually is performed 
with an overnight stay of 2 nights after surgery.
Longer hos-
pitalizations are indicated for patients with more severe medi-
cal problems.
Follow-
up is similar to that after LRYGB.
Most surgeons advocate routine vitamin B12.
Outcomes and Complications.
Studies with 5-year follow-up for SG are 
not yet common.
60.5%) at 1 year after surgery.
It is certain that appropriate stapling technique in dividing the 
stomach is important.
Whether but-
tress materials do decrease the leak rate with SG is very con-
troversial.
This increased intraluminal pressure places the 
staple line at risk for leakage.
Proximal staple line leaks may also present as 
late leaks.
Late leaks are generally felt to be those that occur 6 
weeks or longer after surgery.
Late leaks are rare in other bar-
iatric procedures, but are seen with SG.
The increased pressure 
of the system may be a reason SG is associated with late leaks.
Confirmation and treatment of stenosis symptoms early after SG 
may prevent such leaks.
Endoscopic treatment can help straighten and 
markedly alleviate the obstruction in such cases.
Such cases are now only recently being published 
and discussed in the literature.
Reports of such leaks persisting for multiple months 
postoperatively exist.
However, longer duration leaks are less likely to close.
Physiology of Weight loss.
SG is a fairly simple technical 
operation, amenable to performance by many surgeons.
This will ensure optimal patient outcomes.
population has risen dramat-
ically during the past two decades.
This increase has included 
children and adolescents as well.
Obese adolescents have a high likelihood of being obese 
adults.
Clearly the younger the patient, the more rel-
evant the latter concern becomes.
How-
ever, it is still limited.
There were two late deaths at 2 and 6 years of 
follow-up unrelated to surgery.
Most comor-
bidities resolved at 1 year after surgery.
Self-image was greatly 
enhanced and social stigmatization greatly decreased.
After an average 5.5-year follow-up, aver-
age BMI for the group was 28 kg/m2.
No deaths occurred, but 
two patients required revisional surgery.
No mortality or mor-
bidity was reported, and all comorbidities resolved.
Abu-Abeid 
and colleagues137 treated 11 adolescents with LAGB.
The most common complication in the 
meta-analysis was nutrient deficiencies.
The elderly patient population certainly suffers from 
severe obesity.
There has been an increasing tendency to offer bariatric 
surgery to patients over the age of 60.
Accumulation of data may also change these limits in 
the future.
Macrosomia 
is increased.
There is a two- to three-fold increase in the rate 
of cesarean sections, with more complications.
However, iron replacement was cited as a criti-
cal need for these pregnant women.
The adjustability of the 
band provides a potential advantage for the pregnant woman.
These prob-
lems were virtually eliminated after weight loss.
Type 2 Diabetes.
There has been a dramatic increase in the 
potential application of surgical therapy to treat T2DM.
Reversal of the 
operation led to return of the disease state.
Metabolic Syndrome.
These operations also are 
effective in treating the other components of metabolic  syndrome.
Cardiovascular Disease.
These 
manifestations occur after all the various bariatric operations 
that produce weight loss.
Heart failure also is increased in the setting of severe 
obesity.
LAGB improves GERD but to a consider-
ably lesser extent than RYGB.
OSA is a disturbance of sleep associated with obesity.
It 
is a measurable problem, quantitated by polysomnography.
It is estimated that 20% of 
U.S.
adults have NAFLD, largely because of the high incidence 
of obesity.
Biopsy reports showing 
any degree of fibrosis should be further followed up by a hepa-
tologist.
Symptoms often resolve and usually improve in patients who 
experience significant weight loss.
Excess skin can 
be a limiting factor in exercise and sexual activity.
Many patients desire to be rid of the extra skin and its 
associated problems.
Most insurance companies consider 
this “cosmetic” surgery and will not authorize coverage.
A standard 
abdominoplasty to remove this excessive tissue is performed.
The central abdominal fascia often 
requires imbrication.
Medial thighplasty also may be needed for patients with 
significant excess medial thigh skin.
This is done transversely.
Excess skin redundancy distal to the mid-thighs requires 
long vertical medial excision of skin.
Frontal, right lateral, and left anterior oblique views 6 weeks after surgery for the woman in Fig.
27-24.
All redundant skin has been removed, leaving well-positioned scars and feminine features.
A mean excess weight loss of 23% was reported at 
16-month follow-up for the second U.S.
Intragastric balloon placement has resurfaced on the bariat-
ric scene in the past few years.
It may have potential use 
only as a preliminary procedure prior to a more definitive one.
Mean weight loss at 3 months was 
19.0% in the study group and 6.9% in the control group.
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The position of endoscopic pro-
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Gaitonde S, Kohli R, Seeley R.
The role of the gut hormone 
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Small Intestine
Ali Tavakkoli, Stanley W.
Ashley, and  
Michael J.
The ileum is demarcated from the cecum by the ileocecal 
valve.
These folds are more prominent in the proximal intestine than in 
the distal small intestine.
28-1).
Gross examina-
tion of the small-intestinal mucosa also reveals aggregates of 
lymphoid follicles.
Those follicles, located in the ileum, are the 
most prominent and are designated Peyer’s patches.
Their venous 
drainage occurs via the superior mesenteric vein.
Lymph drain-
age occurs through lymphatic vessels coursing parallel to corre-
sponding arteries.
28-2).
The mucosa is organized into villi and crypts (crypts of 
Lieberkuhn).
Our understanding of these 
crypt cells is rapidly expanding.
It appears that there are two 
subgroups of intestinal stem cells, with specific cell markers.
2 Small bowel obstruction is one of the most common surgical 
diagnoses.
4 Tumors and malignancies of the small bowel are rare and dif-
ficult to diagnose.
5 Small bowel may be the source of gastrointestinal bleeding, 
which may be difficult to diagnose.
Jejunum
lleum
Figure 28-1.
Gross features of jejunum 
contrasted with those of ileum.
Enterocytes are the predominant absorptive cell of the 
intestinal epithelium.
Goblet cells produce mucin believed to play a role in mucosal 
defense against pathogens.
In addition, the intestinal 
epithelium contains M cells and intraepithelial lymphocytes.
These two components of the immune system are discussed 
later.
The gut tube is divided into forgut, 
midgut, and hindgut.
The yolk 
sac and vitelline duct usually undergo obliteration by the end  
of  gestation.
Also during the fourth week of gestation, the mesoderm 
of the embryo splits.
Subsequently, the duodenum becomes 
a retroperitoneal structure.
28-3).
Errors in this recanaliza-
tion may account for defects such as intestinal webs and steno-
ses.
Organogenesis is complete by approximately the 
twelfth week of gestation.
4.
Mucosa
Circular layer
Longitudinal
layer
2.
Muscularis propria
Subserous layer
1.
Submucosa
4
3
2
1
Opening of crypts (of Lieberkühn)
Figure 28-2.
Layers of wall of the 
small intestine.
The individual layers 
and their prominent features are repre-
sented schematically.
Solutes can traverse the epithelium by active or passive 
transport.
Similarly, understanding of the paracellular pathway is evolving.
Water and Electrolyte Absorption and Secretion.
Eight 
to nine L of fluid enters the small intestine daily.
28-4).
Figure 28-3.
Developmental rotation of the 
intestine.
A.
B and C.
D.
Stomach
Duodenum
Proximal limb of prim.
intestinal loop
Vitelline 
duct
Distal limb of prim.
Small intestinal fluid fluxes.
28-5.
Carbohydrate Digestion and Absorption.
Glycogen derived from meat contributes only a small 
fraction of dietary carbohydrate.
Figure 28-5.
Model of transepithelial sodium (Na+) absorption.
28-6).
28-7).
Extruded monosaccharides diffuse into venules 
and ultimately enter the portal venous system.
Ten to fifteen percent of 
energy consumption in the average Western diet consists of pro-
teins.
Protein 
digestion begins in the stomach with action of pepsins.
Digestion continues in the 
duodenum with the actions of a variety of pancreatic peptidases.
Carbohydrate digestion.
Hexose transporters.
Fructose enters through facilitated diffusion via glu-
cose transporter 5 (GLUT5).
Fructose is extruded basolaterally via GLUT5.
These enzymes are secreted as inactive proenzymes.
This is in 
contrast to pancreatic amylase and lipase, which are secreted 
in their active forms.
28-8).
Absorbed amino acids and peptides then enter the portal venous 
circulation.
Of all amino acids, glutamine appears to be a unique, 
major source of energy for enterocytes.
Fat Digestion and Absorption.
Approximately 40% of the 
average Western diet consists of fat.
Over 94% of the ingested fats are absorbed in 
the proximal jejunum.
28-9).
Protein digestion.
Instead, 
they are directly absorbed and enter the portal venous  circulation 
Figure 28-9.
Fat digestion.
These reactions are catalyzed by gastric 
and pancreatic lipases.
Vitamin and Mineral Absorption.
Vitamin B12 (cobalamin) 
malabsorption can result from a variety of surgical manipula-
tions.
The vitamin is initially bound by saliva-derived R pro-
tein.
Fat-soluble vitamins A, D, and E appear to be absorbed 
through passive diffusion.
Vitamin K appears to be absorbed 
through both passive diffusion and carrier-mediated uptake.
Calcium is absorbed through both transcellular transport 
and paracellular diffusion.
Iron and magnesium are each absorbed through both tran-
scellular and paracellular routes.
28-10).
Overlying Peyer’s 
patches are a specialized epithelium containing microfold (M) 
cells.
Effector lymphocytes are distributed into distinct compart-
ments.
IgA-producing plasma cells are derived from B cells and 
are located in the lamina propria.
CD4+ T cells are also located 
in the lamina propria.
CD8+ T cells migrate preferentially to 
the epithelium, but are also found in the lamina propria.
This configuration renders IgA resistant to proteolysis 
by digestive enzymes.
Gut-associated lymphoid tis-
sue.
Select components of the gut-associated 
lymphoid tissue (GALT) are schematically 
represented.
Contractions 
of the muscularis propria are responsible for small-intestinal 
peristalsis.
28-11).
These two 
EMN
SN
IMN
ProximalD istal
Figure 28-11.
Ascending excitation and descending inhibition.
It contributes to peristalsis.
Rhythmic segmentations or pressure waves traveling only short 
distances also are observed.
The fasting 
pattern or interdigestive motor cycle (IDMC) consists of three 
phases.
This pattern is hypothesized to expel residual 
debris and bacteria from the small intestine.
The median dura-
tion of the IDMC ranges from 90 to 120 minutes.
This intrinsic contractile mechanism is subject to neural 
and hormonal regulation.
The enteric nervous system (ENS) 
provides both inhibitory and excitatory stimuli.
Thus, they may act as true 
blood-borne hormones as well as through local effects.
Some of these peptides, or their 
analogues, are used in routine clinical practice.
Postresection intestinal adapta-
tion has been studied extensively using animal models.
The most commonly encountered etiologies of small 
bowel obstruction are summarized in Table 28-3.
Jejunal resection 
is generally better tolerated, as ileum shows better capacity to 
compensate.
However, the magnitude of this response is limited.
This condition is 
discussed in the Short Bowel Syndrome section at the end of 
this chapter.
Intraluminal (e.g., foreign bodies, gallstones, or meconium)
2.
Intramural (e.g., tumors, Crohn’s disease–associated inflam-
matory strictures)
3.
These peptides 
are also widely expressed in nonintestinal tissues.
The intestinal motility is eventually reduced with fewer  
contractions.
This condition is termed strangulated 
bowel obstruction.
Vomiting is a more 
prominent symptom with proximal obstructions than distal.
Mild leukocytosis is common.
The diagnosis of small bowel obstruction is usually con-
firmed with radiographic examination.
The latter situation is associ-
ated with closed-loop obstruction.
28-12).
28-13 and 28-14).
28-15).
The water-soluble 
contrast has been shown to have prognostic and therapeu-
tic value too.
In such cases,  contrast 
Figure 28-12.
Small bowel obstruction.
Figure 28-13.
Small bowel obstruction.
A computed tomography 
scan of a patient presenting with signs and symptoms of bowel 
obstruction.
At laparotomy, adhe-
sive bands from a previous surgery were identified and divided.
Figure 28-14.
Chronic partial small bowel obstruction.
Patient’s vomitus had characteristic fecu-
lent smell and quality.
At exploratory laparotomy, adhesive band 
were identified and divided.
Abdomi-
nal radiographs are then taken serially as the contrast travels 
distally in the intestine.
Therefore, fluid resuscitation is integral to treatment.
The stomach should be continuously evacuated of air and 
fluid using a nasogastric (NG) tube.
Intestinal pneumatosis.
This computed tomography 
scan shows intestinal pneumatosis (arrow).
The cause of this radio-
logic finding was intestinal ischemia.
Such patients need to be observed closely and 
undergo serial exams.
Therefore, the goal is to operate before the onset of irreversible 
ischemia.
28-16 for a proposed management algorithm).
Partial small bowel obstruction
2.
Obstruction occurring in the early postoperative period
3.
Intestinal obstruction due to Crohn’s disease
4.
In a recent study, using the National Inpatient Sample, this 
principle was further highlighted.
CT scanning or a small bowel series is often 
required to make the diagnosis.
Patients with obvious carcinomatosis 
pose a difficult challenge, given their limited prognosis.
For example, adhesions are lysed, tumors are resected, 
and hernias are reduced and repaired.
Criteria suggesting viability are normal color, 
peristalsis, and marginal arterial pulsations.
Usually, visual 
inspection alone is adequate in judging viability.
However, neither technique 
has been found to be superior to clinical judgment.
At that time, definitive resection of nonviable 
bowel is completed.
Develop signs or symptoms
of intestinal ischemia?
Yes
No
Yes Yes
Yes
Improving after 24 hours of
conservative management?
Figure 28-16.
Management algorithm of small bowel obstruction.
IVF = intravenous fluid; NG = nasogastric; NPO = nothing by mouth.
1151
S
MALL
 I
NTESTINE
CHAPTER 28
 adhesive band are best suited for this approach.
Mortality rates associated with surgery for stran-
gulating obstruction range from 8% to 25%.
These measures alone are often inadequate.
Ileus is a major 
cause of morbidity in hospitalized patients.
Both sporadic and familial forms of 
visceral myopathies and neuropathies exist.
Vomiting and abdominal distension may occur.
Diagnosis
Routine postoperative ileus should be expected and requires 
no diagnostic evaluation.
Fluid and electrolytes should 
be administered intravenously until ileus resolves.
If the dura-
tion of ileus is prolonged, TPN may be required.
Surgery should be 
avoided if at all possible.
Prokinetic agents, such as 
metoclopramide and erythromycin, are associated with poor 
efficacy.
Incidence 
rates have been stable since the 1980s.
The incidence 
of Crohn’s disease varies among ethnic groups within the same 
geographic region.
However, the 
age at diagnosis can range from early childhood through the 
entire lifespan.
Higher socioeconomic status is associated with an 
increased risk of Crohn’s disease.
Crohn’s disease is more prevalent among 
smokers.
Pathophysiology
Crohn’s disease is characterized by sustained inflammation.
Many infec-
tious agents have been suggested to be the causative organism 
of Crohn’s disease.
There is no 
conclusive evidence that any of these organisms is the causative 
agent.
The IBD1 locus has 
been identified as the NOD2 gene.
The earliest lesion character-
istic of Crohn’s disease is the aphthous ulcer.
In the small intestine, aphthous ulcers typically 
arise over lymphoid aggregates.
As disease progresses, aphthae coalesce into larger, 
 stellate-shaped ulcers.
With transverse coalescence of ulcers, 
a cobblestoned appearance of the mucosa may arise.
With advanced disease, inflammation can be transmural.
28-17).
This finding is virtually pathognomonic of Crohn’s 
disease.
Figure 28-17.
Crohn’s disease.
There is substantial 
overlap among these disease patterns in individual patients, 
 however.
The disease affects the small bowel in 80% of cases and 
the colon alone in 20%.
In those with small bowel disease, 
the majority have ileocecal disease.
The small bowel alone is 
affected in 15% to 30% of patients.
Isolated perineal and ano-
rectal disease occurs in 5% to 10% of affected patients.
Uncom-
mon sites of involvement include the esophagus, stomach, and 
duodenum.
One fourth of those affected will have more than one manifesta-
tion.
The most common extraintestinal manifesta-
tions are listed in Table 28-7.
No single symptom, sign, or diagnostic test establishes 
the diagnosis of Crohn’s disease.
Pseudopolyps, as seen in 
ulcerative colitis, are also often present.
Esophagogastro-
duodenoscopy (EGD) is done for disease of the proximal ali-
mentary tract.
Crohn’s disease.
It demonstrates a superficial ulceration in the small 
bowel consistent with Crohn’s disease.
(Used with permission from  
Dr.
Anne C.
Medical therapy is used to induce and maintain 
disease remission.
Surgery is reserved for specific indications 
described later.
Medical Therapy.
Their efficacy in the maintenance 
of remission is less clear.
Patients with severe active disease 
usually require intravenous administration of glucocorticoids.
Therefore, they 
should be tapered once remission is achieved.
Such patients are said to have 
steroid dependence.
A response to these medications is usually observed in 
3 to 6 months.
In cases 
of relapse, azathioprine can be considered.
In patients with fis-
tulas, infliximab and azathioprine are drugs of choice.
Growth retardation constitutes an indica-
tion for surgery in 30% of children with Crohn’s disease.
One of the most common indications for surgical inter-
vention is intestinal obstruction.
Both conditions should be treated medically; 
ileal resection is not generally indicated.
The length of uninvolved 
small intestine should be noted.
28-19).
In this technique, the bowel 
Figure 28-19.
Stricturoplasty.
The wall of the strictured bowel is 
incised longitudinally.
A
B
is opened longitudinally to expose the lumen.
Any intralumi-
nal ulcerations should be biopsied to rule out the presence of 
neoplasia.
Most patients whose disease is resected eventually develop 
recurrence.
Pathophysiology
The manifestations of fistulas depend on which structures are 
involved.
Enterovesicular fistulas often cause recurrent urinary tract infec-
tions.
Fistulas have the potential to close spontaneously.
These fistulas are often asso-
ciated with intra-abdominal abscesses.
Leakage of contrast material from 
the intestinal lumen can be observed.
Occasionally, contrast administered into the intestine 
does not demonstrate the fistula tract.
Stabilization.
Fluid and electrolyte resuscitation is begun.
Nutrition is provided, usually through the parenteral route 
initially.
Sepsis is controlled with antibiotics and drainage of 
abscesses.
The skin is protected from the fistula effluent with 
ostomy appliances or fistula drains.
2.
Investigation.
The anatomy of the fistula is defined using the 
studies described earlier.
3.
Decision.
4.
Definitive management.
5.
Rehabilitation.
The overall objective is to increase the probability of spon-
taneous closure.
Nutrition and time are the key components 
of this approach.
Timing of Surgical Intervention.
Patients with intestinal fistulas typically have extensive 
and dense intra-abdominal adhesions.
As a result, operations 
performed for nonhealing fistulas can present formidable chal-
lenges.
The indications for their use remain to be defined.
Outcomes
Over 50% of intestinal fistulas close spontaneously.
Morbidity was over 80%.
Other benign tumors include fibromas, lipomas, hem-
angiomas, lymphangiomas, and neurofibromas.
This suggests that the majority of small 
bowel tumors are asymptomatic.
28-20).
In a ret-
rospective review of a large U.S.
Figure 28-20.
Duodenal polyp.
This polyp was incidentally 
encountered during esophagogastroduodenoscopy.
It was biopsied 
and found to be an adenoma.
Melanoma, in particular, is associated with a propen-
sity for metastasis to the small intestine.
Most patients with small-intestinal cancers are in their 
fifth or sixth decade of life.
Adenomas are histologi-
cally classified as tubular, villous, and tubulovillous.
Tubular 
adenomas have the least aggressive features.
The risk of duodenal cancer in these patients 
is over 100-fold that in the general population.
28-21).
Pathologic KIT signal transduction is believed to be a cen-
tral event in GIST pathogenesis.
The majority of GISTs have 
Figure 28-21.
Small bowel polyp in Peutz-Jeghers syndrome.
(Used with permission from 
Dr.
Anne C.
Clinical Presentation
Most small-intestinal neoplasms are asymptomatic until they 
become large.
Hemorrhage, usually indolent, is the second most 
common mode of presentation.
Physical examination may be unrevealing.
Findings of intestinal obstruction 
are reported to be present in 25% of patients.
Fecal occult blood 
test may be positive.
Jaundice secondary to biliary obstruction 
or hepatic metastasis may be present.
Cachexia, hepatomegaly, 
and ascites may be present with advanced disease.
Lesions in the periampullary location can cause obstruc-
tive jaundice or pancreatitis.
As a result, symptoms of carcinoid 
syndrome are rare in the absence of liver metastases.
Sixty to seventy percent of GISTs are located in the stom-
ach.
The small intestine is the second most common site, con-
taining 25% to 35% of GISTs.
There appears to be no regional 
variation in the prevalence of GISTs within the small intestine.
28-22).
Metastatic tumors involving the small intestine can induce 
intestinal obstruction and bleeding.
Contrast radiography of the small intestine may demon-
strate benign and malignant lesions.
Tumors located in the duodenum can be visualized and 
biopsied on EGD.
Occasionally, the dis-
tal ileum can be successfully visualized during colonoscopy.
Recently, capsule endoscopy and double-balloon 
endoscopy have been used to evaluate small bowel.
In general, duodenal tumors less 
than 1 cm in diameter are amenable to endoscopic polypectomy.
Surgical options include transduodenal polypectomy and 
segmental duodenal resection.
Jejunal gastrointestinal (GI) stro-
mal tumor (GIST).
This patient presented with 
overt obscure GI bleeding and was found to have a 
7-cm jejunal GIST.
He underwent a successful laparoscopic resection.
with those limited to the mucosa being amenable to endoscopic 
 polypectomy.
Further, localized resections are complicated 
by high recurrence rates.
The goal of surgical therapy for carcinoids is resection of 
all visible disease.
In approximately 
30% of cases, multiple small-intestinal carcinoid tumors are 
present.
Therefore, the entire small intestine should be exam-
ined before planning extent of resection.
The value to adjuvant chemotherapy after 
resection of localized lymphoma is controversial.
Small-intestinal GISTs should be treated with segmental 
intestinal resection.
GISTs are resistant to 
conventional chemotherapy agents.
Studies have 
emphasized the potential for development of tumor resistance to 
this agent.
Systemic therapy 
may be offered if effective chemotherapy exists for the primary 
cancer.
The recurrence rate after resection of GISTs averages 
35%.
The 5-year survival rate after surgical resection has been 
reported to range from 35% to 60%.
Both tumor size and mitotic 
index are independently correlated with prognosis.
With severe cases, mucosal sloughing, 
ulceration, and hemorrhage are observed.
Symptoms are generally transient and subside after the discon-
tinuation of radiation therapy.
The 
terminal ileum is the most frequently affected segment.
28-23).
CT scan 
findings are neither very sensitive nor specific for chronic radi-
ation enteritis.
Therapy
Most cases of acute radiation enteritis are self-limited.
Support-
ive therapy, including the administration of antiemetics, is usu-
ally sufficient.
Rarely are symptoms severe enough to necessitate reduction in 
or cessation of radiation therapy.
In contrast, the treatment of chronic radiation enteritis 
represents a formidable challenge.
Radiation enteritis.
This condition is discussed in detail 
later in the Short Bowel Syndrome section.
28-24).
Meckel’s diverticulum.
This intraoperative photograph 
shows Meckel’s diverticulum in ileum that has been eviscerated.
1164
SPECIFIC CONSIDERATIONS
UNIT II
PART II
gastric mucosa.
Volvulus of the intestine around the fibrous band attaching 
the diverticulum to the umbilicus
2.
Entrapment of intestine by a mesodiverticular band (Fig.
28-25)
3.
Intussusception with the diverticulum acting as a lead point
4.
These hernias, when 
incarcerated, can cause intestinal obstruction.
Bleeding associated with Meckel’s 
diverticula is rare among patients older than 30 years of age.
Intestinal obstruction is the most common presentation in 
adults with Meckel’s diverticula.
28-26).
Figure 28-25.
A.
Meckel’s diverticulum with 
mesodiverticular band.
B.
No controlled data supporting 
or refuting these recommendations exist.
Approximately 75% of juxtapapillary diverticula 
arise on the medial wall of the duodenum.
Acquired diverticula 
in the jejunum or ileum are known as jejunoileal diverticula.
The prevalence of duodenal diverticula, as detected on 
upper GI examinations (Fig.
A 23% prevalence rate 
has been reported in an autopsy series.
The mean age of diagnosis ranges 
from 56 to 76 years.
The prevalence of jejunoileal diverticula (Fig.
Figure 28-26.
Meckel’s diverticulum with ectopic gastric tissue.
The diagnosis was made in this patient using 99mTc-pertechnetate scintig-
raphy.
Figure 28-27.
Duodenal diverticulum.
Figure 28-28.
Jejunoileal diverticula.
The diverticula are typically located on the mesenteric aspect of the jejunum.
Resection was not indicated because the diverticula were 
asymptomatic.
The relationship between these symptoms and the 
presence of diverticula is similarly unclear.
Enteroclysis is the most sensitive test for detecting jejunoileal 
diverticula.
Therapy
Asymptomatic acquired diverticula should be left alone.
Bacte-
rial overgrowth associated with acquired diverticula is treated 
with antibiotics.
Similarly, perforation 
can be managed with wide drainage rather than complex sur-
gery.
Four distinct pathophysiologic mechanisms can lead to 
acute mesenteric ischemia:
1.
Arterial embolus
2.
Arterial thrombosis
3.
Vasospasm (also known as nonocclusive mesenteric isch-
emia [NOMI])
4.
Acute thrombosis is usually 
superimposed on pre-existing atherosclerotic lesions at these 
sites.
The pain 
is typically perceived to be colicky and most severe in the mid-
abdomen.
Associated symptoms can include nausea, vomiting, and 
diarrhea.
Physical findings are characteristically absent early in the 
course of ischemia.
Chronic mesenteric ischemia presents insidiously.
Overt GI bleeding 
refers to the presence of hematemesis, melena, or hematochezia.
Meckel’s diverticulum is the most com-
mon etiology of obscure GI bleeding in children.
Enteroscopy is playing 
an increasingly important role.
This procedure can allow for visualization of approximately  
60 cm of the proximal jejunum.
Diagnostic yield in patients 
with obscure GI bleeding ranges from 3% to 65%.
In addition to 
diagnosis, push enteroscopy allows for cauterization of  bleeding 
sites.
However, this instru-
ment lacks biopsy or therapeutic capability.
This technique has reported 
success rates as high as 90% in identifying a small bowel 
pathology.
In a randomized study 
of patients with obscure GI bleeding, evaluation with capsule 
endoscopy vs.
small bowel contrast study had a much higher 
diagnostic yield (30% vs.
7%, respectively); however, this 
did not translate into an improvement in outcomes.
For persistent mild bleeding from an obscure GI source, 
push and capsule enteroscopy can be used.
Therapy can be tailored based on the source.
Intra-
operative enteroscopy can be done during either laparotomy or 
laparoscopy.
Fig.
28-29 provides a diagnostic and management algo-
rithm for patients with obscure GI bleeding.
This complication occurs in 0.3% to 2.1% of cases.
If perforation is suspected but not clinically obvious, CT scan-
ning should be performed.
Jejunal and ileal perforations require 
surgical repair or segmental resection.
Diagnostic and management algorithm for obscure gastrointestinal (GI) bleeding.
EGD = esophagogastroduodenoscopy;  
RBC = red blood cell.
Patients with chylous ascites develop abdominal distention 
over a period of weeks to months.
Postoperative chylous ascites 
can present acutely during the first postoperative week.
Dyspnea may result if 
abdominal distention is severe enough.
Paracentesis is the most important diagnostic test.
Fluid triglyceride concentrations above  
110 mg/dL are diagnostic.
There are few data on optimal management of patients 
with chylous ascites.
This regimen is designed to minimize chyle production and 
flow.
Patients who do not respond to this approach should be 
fasted and placed on TPN.
Octreotide can further decrease 
lymph flow.
Paracentesis is indicated for respiratory difficul-
ties related to abdominal distention.
Overall, two thirds of 
patients will respond to conservative therapy.
However, one 
third of patients will require surgical therapy for chylous asci-
tes.
Lymphatic leaks are localized and repaired with 
fine nonabsorbable sutures.
Because of the viscosity of chyle, these shunts 
are associated with a high occlusion rate.
CT scan is the investigation of choice, 
where a “target sign” may be seen (Fig.
28-30).
It may affect any region of the GI tract, but is most 
Figure 28-30.
Small bowel intussusception.
Panel B demonstrates the distal bowel clearly within the lumen of the proximal bowel (arrow).
1171
S
MALL
 I
NTESTINE
CHAPTER 28
commonly seen in the jejunum.
The pathogenesis of pneumatosis intestinalis is not 
fully understood.
28-15).
The prevalence of short bowel syndrome is hard to esti-
mate.
The most recent available data on chronic home total TPN 
administration were obtained in 1992.
At that time, approxi-
mately 40,000 patients were receiving TPN chronically at home.
The colon has the capacity to absorb large fluid and 
electrolyte loads.
Second, an intact ileocecal valve is believed to 
be associated with decreased malabsorption.
As this pro-
cess completes, some patients are successfully weaned off TPN.
Therapy
Medical Therapy.
Most patients will 
require TPN, at least initially.
Enteral nutrition should be gradu-
ally introduced, once ileus has resolved.
Because of these problems, alternative therapies for short bowel 
syndrome are under investigation.
Nontransplant Surgical Therapy.
Reported experience with these procedures is limited 
to case reports or series of a few cases.
This proce-
dure has the potential to double the length of small intestine to 
which it is applied.
This procedure has generally been used for 
pediatric patients with dilated residual small bowel.
28-31).
Nearly 80% of survivors have full intestinal graft function 
with no need for TPN.
Alternative Therapies.
This figure depicts the 
serial transverse enteroplasty (STEP) 
procedure.
Information on survival among patients with short bowel 
syndrome is limited.
1.
Tavakkolizadeh A, Whang EE, Ashley SW, Zinner MJ.
Small 
intestine.
In: Brunicardi F, Andersen D, Billiar T, et al, eds.
Principles of Surgery.
9th ed.
New York: McGraw-Hill; 
2004:28-1.
2.
McMinn RMH.
Last’s Anatomy: Regional and Applied.
9th ed.
Singapore: Churchill Livingstone; 1994:337.
3.
Yan KS, Chia LA, Li X, et al.
The intestinal stem cell markers 
Bmi1 and Lgr5 identify two functionally distinct populations.
Proc Natl Acad Sci U S A.
2012;109:466.
4.
Thomson ABR, Keelan M, Thiesen A, et al.
Small bowel 
review: normal physiology part 2.
Dig Dis Sci.
2001;46:2588.
5.
Laforenza U.
Water channel proteins in the gastrointestinal 
tract.
Mol Aspects Med.
2012;33:642.
6.
Dyer J, Wood IS, Palejwala A, Ellis A, Shirazi-Beechy SP.
Expression of monosaccharide transporters in intestine of dia-
betic humans.
Am J Physiol.
2002;282:G241.
7.
Powell DR, DaCosta CM, Gay J, et al.
Improved glycemic 
control in mice lacking Sglt1 and Sglt2.
Am J Physiol Endo-
crinol Metab.
2013;304:E117.
8.
Rolfs A, Hediger MA.
Intestinal metal ion absorption: an 
update.
Curr Opin Gastroenterol.
2001;17:177.
9.
Nagler-Anderson C.
Man the barrier!
Strategic defenses in the 
intestinal mucosa.
Nat Rev Immunol.
2001;1:59.
10.
Mowat AM.
Anatomical basis of tolerance and immunity to 
intestinal antigens.
Nat Rev Immunol.
2003;3:331.
11.
Jarchum I, Pamer EG.
Regulation of innate and adaptive 
immunity by the commensal microbiota.
Curr Opin Immunol.
2011;23:353.
12.
Rehfeld JF.
The new biology of gastrointestinal hormones.
Physiol Rev.
1998;78:1087.
13.
Tavakkolizadeh A, Whang EE.
Understanding and augmenting 
human intestinal adaptation: a call for more clinical research.
JPEN J Parenter Enteral Nutr.
2002;26:251.
14.
Scott FI, Osterman MT, Mahmoud NN, Lewis JD.
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trends in small-bowel obstruction and adhesiolysis in the 
United States: 1988-2007.
Am J Surg.
2012;204:315.
15.
Maglinte DD, Heitkamp DE, Howard TJ.
Current concepts 
in imaging of small bowel obstruction.
Radiol Clin N Am.
2003;41:263.
16.
Abbas S, Bissett IP, Parry BR.
Oral water soluble contrast 
for the management of adhesive small bowel obstruction.
Cochrane Database Syst Rev.
2007;3:CD004651.
17.
Brolin RE, Krasna MJ, Mast BA.
Use of tubes and radiographs 
in the management of small bowel obstruction.
Ann Surg.
1987;206:126.
18.
Chu DI, Gainsbury ML, Howard LA, Stucchi AF, Becker JM.
J Gastrointest Surg.
2013;17:288.
19.
Stewart RM, Page CP, Brender J, et al.
The incidence and risk 
of early postoperative small bowel obstruction: a cohort study.
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1987;154:643.
20.
Krouse RS, McCahill LE, Easson A, et al.
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21.
Mancini GJ, Petroski GF, Lin WC, Sporn E, Miedema BW, 
Thaler K.
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2008;207:520.
22.
Ghosheh B, Salameh JR.
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Surg Endosc.
2007;21:1945.
23.
Foster NM, McGory ML, Zingmond DS, Ko CY.
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bowel obstruction: a population-based appraisal.
J Am Coll 
Surg.
2006;203:170.
24.
Wahl WL, Wong SL, Sonnenday CJ, et al.
Implementation of 
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ciency.
Surgery.
2012;152:626.
25.
Ellis H, Moran BJ, Thompson JN, et al.
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1999;353:1476.
26.
Angenete E, Jacobsson A, Gellerstedt M, Haglind E.
Effect of 
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Arch Surg.
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27.
Fazio VW, Cohen Z, Fleshman JW, et al.
Dis Colon Rectum.
2006;49:1.
28.
Kumar S, Wong PF, Leaper DJ.
Cochrane Database Syst Rev.
2009;CD005080.
29.
Lucky A, Livingsdtone E, Tache Y.
Mechanisms and treat-
ment of postoperative ileus.
Arch Surg.
2003;138:206.
30.
Doorly MG, Senagore AJ.
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nomic consequences of postoperative ileus.
Surg Clin North 
Am.
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31.
Charoenkwan K, Phillipson G, Vutyavanich T.
Cochrane Database 
Syst Rev.
2007;4:CD004508.
32.
Gendall KA, Kennedy RR, Watson AJ, Frizelle FA.
The effect 
of epidural analgesia on postoperative outcome after colorectal 
surgery.
Colorectal Dis.
2007;9:584.
33.
Noblett SE, Snowden CP, Shenton BK, Horgan AF.
Br J Surg.
2006;93:1069.
34.
Tan EK, Cornish J, Darzi AW, Tekkis PP.
Meta-analysis: alvi-
mopan vs.
placebo in the treatment of post-operative ileus.
Ali-
ment Pharmacol Ther.
2007;25:47.
35.
Gaines SL, Giroux K, Thomas S, Gregory JS.
Am J Surg.
2012;203:308.
36.
Lubbers T, Luyer MD, de Haan JJ, Hadfoune M, Buurman 
WA, Greve JW.
Ann Surg.
2009;249:481.
37.
Loftus EV Jr, Schoenfeld P, Sandborn WJ.
Ali-
ment Pharmacol Ther.
2002;16:51.
1174
SPECIFIC CONSIDERATIONS
UNIT II
PART II
38.
Zheng JJ, Zhu XS, Huangfu Z, Gao ZX, Guo ZR, Wang Z.
Crohn’s disease in mainland China: a systematic analysis of 
50 years of research.
Chin J Dig Dis.
2005;6:175.
39.
Nikolaaus S, Schreiber S.
Diagnosis of inflammatory bowel 
disease.
Gastroenterology.
2007;133:1670.
40.
Regueiro M, Schraut W, Baidoo L, et al.
Infliximab prevents 
Crohn’s disease recurrence after ileal resection.
Gastroenterol-
ogy.
2009;136:441.
41.
Gardiner KR, Dasari BV.
Operative management of small 
bowel Crohn’s disease.
Surg Clin North Am.
2007;87:587.
42.
Solberg IC, Vatn MH, Hoie O, et al.
Clin Gastroenterol Hepatol.
2007;5:1430.
43.
Fazio VW, Marchetti F, Church JM, et al.
Effect of resection 
margins on the recurrence of Crohn’s disease of the small 
bowel.
Ann Surg.
1996;224:563.
44.
McLeod RS, Wolff BG, Ross S, Parkes R, McKenzie  
M.
Dis Colon Rectum.
2009;52:919.
45.
Michelassi F, Upadhyay GA.
Side-to-side isoperistaltic stric-
tureplasty in the treatment of extensive Crohn’s disease.
J Surg 
Res.
2004;117:71.
46.
Tan JJ, Tjandra JJ.
Laparoscopic surgery for Crohn’s disease: 
a meta-analysis.
Dis colon Rectum.
2007;50:576.
47.
Delaney CP, Fazio VW.
Crohn’s disease of the small bowel.
Surg Clin N Am.
2001;81:137.
48.
Penner RM, Madsen KL, Fedorak RN.
Postoperative Crohn’s 
disease.
Inflamm Bowel Dis.
2005;11:765.
49.
Evenson AR, Shrikhande G, Fischer JE.
Abdominal abscess 
and enteric fistula.
In: Zinner MJ, Ashley SW, eds.
Main-
got’s Abdominal Operations.
11th ed.
New York: McGraw 
Hill; 2007:184.
50.
Fazio VW, Coutsoftides T, Steiger E.
Factors influencing the 
outcome of treatment of small bowel cutaneous fistula.
World 
J Surg.
1983;7:481.
51.
Owen RM, Love TP, Perez SD, et al.
Definitive surgical treat-
ment of enterocutaneous fistula: outcomes of a 23-year experi-
ence.
Arch Surg.
2012;15:1.
52.
Martinez JL, Luque-de-Leon E, Ballinas-Oseguera G, Mendez 
JD, Juarez-Oropeza MA, Roman-Ramos R.
Factors predictive 
of recurrence and mortality after surgical repair of enterocuta-
neous fistula.
J Gastrointest Surg.
2012;16:156.
53.
Jepsen JM, Persson M, Jakobsen NO, et al.
Scand J Gastroenterol.
1994;29:483.
54.
Jemal A, Murray T, Sammuels A, et al.
Cancer statistics, 2003.
CA Cancer J Clin.
2003;53:5.
55.
Qubaiah O, Devesa SS, Platz CE, Huycke MM, Dores GM.
Can-
cer Epidemiol Biomarkers Prev.
2010;19:1908.
56.
Ceppa EP, Burbridge RA, Rialon KL, et al.
Endoscopic versus 
surgical ampullectomy: an algorithm to treat disease of the 
ampulla of Vater.
Ann Surg.
2013;257:315.
57.
Judson I, Demetri G.
Advances in the treatment of gastrointes-
tinal stromal tumors.
Ann Oncol.
2007;18:S20.
58.
Agrawal S, McCarron EC, Gibbs JF, Nava HR, Wilding 
GE, Rajput A.
Surgical management and outcome in pri-
mary adenocarcinoma of the small bowel.
Ann Surg Oncol.
2007;14:2263.
59.
Girvent M, Carlson GL, Anderson I, et al.
Intestinal failure 
after surgery for complicated radiation enteritis.
Ann R Coll 
Surg Engl.
2000;82:198.
60.
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Radiother Oncol.
2000;57:125.
61.
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Petrelli NJ.
Arch Surg.
2000;135:1212.
62.
Yahchouchy EK, Marano AF, Etienne JC, et al.
Meckel’s 
diverticulum.
J Am Coll Surg.
2001;192:654.
63.
Cullen JJ, Kelly KA, Moir CR, et al.
Surgical management of 
Meckel’s diverticulum.
An epidemiologic, population-based 
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1994;220:564.
64.
Lobo DN, Balfour TW, Iftikhar SY, et al.
Periampullary diver-
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Br J Surg.
1999;86:588.
65.
Chow DC, Babaian M, Taubin HL.
Jejunoileal diverticula.
Gastroenterologist.
1997;5:78.
66.
Kumar S, Sarr MG, Kamath PS.
Mesenteric venous thrombo-
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N Engl J Med.
2001;345:1683.
67.
Gralnek IM.
Obscure-overt gastrointestinal bleeding.
Gastro-
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2005;128:1424.
68.
Szold A, Katz LB, Lewis BS.
Surgical approach to occult gas-
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1992;163:90.
69.
Laine L, Sahota A, Shah A.
Does capsule endoscopy improve 
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Randomized 
trial versus dedicated small bowel radiography.
Gastroenterol-
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2010;138:1673.
70.
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Am J Gastroenterol.
1999;94:1267.
71.
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Contemporary 
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World J Surg.
2013;37:1872.
72.
Varban O, Ardestani A, Azagury D, et al.
Resection or reduc-
tion?
The dilemma of managing retrograde intussuscep-
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Surg Obes Relat Dis.
2013;9:725.
73.
Buchman AL, Solapio J, Fryer J.
AGA technical review on 
short bowel syndrome and intestinal transplantation.
Gastro-
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2003;124:1111.
74.
Thompson JS, Langnas AN.
Surgical approaches to improving 
intestinal function in the short-bowel syndrome.
Arch Surg.
1999;134:706.
75.
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Intestinal loop lengthening: a technique for increas-
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Colon, Rectum, and Anus
Kelli M.
Bullard Dunn and David A.
Both midgut and hindgut contribute to the colon, 
rectum, and anus.
The dentate 
line divides the endodermal hindgut from the ectodermal distal 
anal canal.
Anatomy
The large intestine extends from the ileocecal valve to the anus.
It is divided anatomically and functionally into the colon, rectum, 
and anal canal.
Colon Landmarks.
As a result, the cecum is most 
vulnerable to perforation and least vulnerable to obstruction.
The ascending colon is usually fixed to the retroperitoneum.
The hepatic flexure marks the transition to the transverse colon.
3 Ostomies: Preoperative marking for a planned stoma is critical 
for a patient’s quality of life.
Risk depends on the amount of colon 
involved and the duration of disease.
Surgery is reserved for patients 
with persistent or recurrent disease.
8 Rectal prolapse: Rectal prolapse occurs most commonly in 
elderly women.
They are thought to play a role in maintaining 
continence.
Resection is only indicated for refractory 
symptoms.
The greater omentum is attached to the anterior/superior edge 
of the transverse colon.
The splenic flexure marks the transition 
from the transverse colon to the descending colon.
The descending colon is 
relatively fixed to the retroperitoneum.
The sigmoid colon is the 
narrowest part of the large intestine and is extremely mobile.
Colon Vascular Supply.
The arterial supply to the colon is 
highly variable (Fig.
29-1).
This arcade is complete 
in only 15% to 20% of people.
29-2).
Colon Lymphatic Drainage.
Lymphatic vessels and lymph nodes follow the 
Middle
colic a.
Right
colic a.
Left
colic a.
Ileocolic a.
Superior
mesenteric a.
Superior
rectal a.
Sigmoidal a.
Inferior
mesenteric a.
Figure 29-1.
Arterial blood supply to the colon.
a.
= artery.
Inferior
mesenteric v.
Middle
colic v.
Right
colic v.
Superior
mesenteric v.
Portal v.
Left
colic v.
Sigmoidal v.
Superior
rectal v.
Ileocolic v.
Figure 29-2.
Venous drainage of the colon.
v.
= vein.
(Reproduced 
with permission from Bell RH, Rikkers LF, Mulholland M, eds.
Digestive Tract Surgery: A Text and Atlas.
Philadelphia: Lippincott 
Williams & Wilkins; 1996:1459.)
regional arteries.
The utility of sentinel lymph node dissection and analy-
sis in colon cancer remains controversial.
Colon Nerve Supply.
Sympathetic nerves 
arise from T6-T12 and L1-L3.
Anorectal Landmarks.
The rectum is approximately 12 to 
15 cm in length.
Three distinct submucosal folds, the valves of 
Houston, extend into the rectal lumen.
The lateral liga-
ments support the lower rectum.
The anatomic anal canal extends from the dentate or 
pectinate line to the anal verge.
These crypts are the source of crypto-
glandular abscesses (Fig.
29-3).
It begins at the anorectal junction and terminates at 
the anal verge.
The deep 
external anal sphincter is an extension of the puborectalis muscle.
29-4).
Anorectal Vascular Supply.
The lining of the anal canal.
(From Goldberg SM, Gordon PH, Nivatvongs S, eds.
Essentials of Anorectal Surgery.
Philadelphia: 
J.B.
Lippincott Company; 1980:4.
Reproduced with permission from Stanley M.
Goldberg, MD.)
supplies the upper rectum.
29-5).
The venous drainage of the rectum parallels the arterial 
supply.
The superior rectal vein drains into the portal system via 
the inferior mesenteric vein.
The middle rectal vein drains into 
the internal iliac vein.
Anorectal Lymphatic Drainage.
Lymphatic drainage of the 
rectum parallels the vascular supply.
Conjoined
longitudinal m.
Superficial external
sphincter m.
Subcutaneous external
sphincter m.
Valve of Houston
Internal rectal
plexus
Muscularis 
submucosa ani m.
Transverse septum
of ischiorectal fossa
External rectal
plexus
Internal
sphincter m.
Figure 29-4.
The distal rectum and anal canal.
m.
= muscle.
1179
Colon, Rectum, and Anus
CHAPTER 29
mesenteric lymph nodes.
The anal 
canal has a more complex pattern of lymphatic drainage.
Anorectal Nerve Supply.
Both sympathetic and parasym-
pathetic nerves innervate the anorectum.
Sympathetic nerve 
fibers are derived from L1-L3 and join the preaortic plexus.
Parasympathetic 
nerve fibers are known as the nervi erigentes and originate from 
S2-S4.
These fibers join the sympathetic fibers to form the pel-
vic plexus.
Sympathetic and parasympathetic fibers then supply 
the anorectum and adjacent urogenital organs.
While the rectum 
is relatively insensate, the anal canal below the dentate line is 
sensate.
Failure of canalization of the primitive gut can result in colonic 
duplication.
Arterial supply to the rectum and anal canal.
The colon is a major site for water absorption and 
electrolyte exchange.
Sodium is absorbed actively via sodium-
potassium (Na+/K+) ATPase.
The colon can absorb up to 400 mEq 
of sodium per day.
Water accompanies the transported sodium 
and is absorbed passively along an osmotic gradient.
Potassium 
is actively secreted into the colonic lumen and absorbed by 
passive diffusion.
Chloride is absorbed actively via a chloride-
bicarbonate exchange.
Bacterial degradation of protein and urea produces 
ammonia.
Ammonia is subsequently absorbed and transported 
to the liver.
Absorption of ammonia depends in part on intra-
luminal pH.
Escherichia 
coli are the most numerous aerobes (108–1010 organisms/mL).
Colonic bacteria also are necessary for production of vitamin 
K.
Intestinal gas arises from swallowed air, diffusion from 
the blood, and intraluminal production.
Nitrogen and oxygen are largely derived from 
swallowed air.
Hydrogen and methane are produced by 
colonic bacteria.
The production of methane is highly variable.
1180
SPECIFIC CONSIDERATIONS
UNIT II
PART II
Motility, Defecation, and Continence
Motility.
Instead, the colon displays intermittent 
contractions of either low or high amplitude.
In general, 
cholinergic activation increases colonic motility.
Defecation.
Continence.
The maintenance of fecal continence is at least 
as complex as the mechanism of defecation.
The internal and external sphincters are tonically active 
at rest.
Branches of the pudendal nerve innervate 
both the internal and external sphincter.
Medi-
cation use must be detailed as many drugs cause gastrointestinal 
symptoms.
Before recommending operative intervention, the 
adequacy of medical treatment must be ascertained.
Endoscopy
Anoscopy.
The anoscope is a useful instrument for examina-
tion of the anal canal.
Anoscopes are made in a variety of sizes 
and measure approximately 8 cm in length.
It is rotated 90° and reinserted to 
allow visualization of all four quadrants of the canal.
Proctoscopy.
The standard proctoscope is 25 cm in length 
and available in various diameters.
Most often, a 15- or 19-mm 
diameter proctoscope is used for diagnostic examinations.
Suc-
tion is necessary for an adequate proctoscopic examination.
Flexible Sigmoidoscopy and Colonoscopy.
Sigmoidoscopes 
measure 60 cm in length.
Both sig-
moidoscopy and colonoscopy can be used diagnostically and 
therapeutically.
Capsule Endoscopy.
Capsule endoscopy is an emerging tech-
nology that uses a small ingestible camera.
Capsule endoscopy largely has been used to detect small bowel 
lesions.
Double-contrast barium enema has been used as a 
back-up examination if colonoscopy is incomplete.
Computed Tomography.
Computed Tomography Colonography.
When the radial margin is threatened, neoadjuvant 
chemoradiation is generally indicated.
MRI also can be helpful 
in the detection and delineation of complex fistulas in ano.
The 
use of an endorectal coil may increase sensitivity.
Positron Emission Tomography.
PET/CT 
increasingly is used to diagnose recurrent and/or metastatic 
colorectal cancer.
However, the efficacy and utility of this tech-
nology remains unproven.
Angiography.
Angiography is occasionally used for the detec-
tion of bleeding within the colon or small bowel.
CT and magnetic resonance angiography are also useful 
for assessing patency of visceral vessels.
This technique uses 
three-dimensional reconstruction to detect vascular lesions.
Endorectal and Endoanal Ultrasound.
The normal rectal wall appears 
as a five-layer structure (Fig.
29-6).
Ultrasound can also dif-
ferentiate superficial T1-T2 from deeper T3-T4 tumors.
Ultrasound may also prove useful 
for early detection of local recurrence after surgery.
Endoanal ultrasound is used to evaluate the layers of the 
anal canal.
Internal anal sphincter, external anal sphincter, and 
puborectalis muscle can be differentiated.
Manometry.
Anorectal manometry is performed by placing a 
pressure-sensitive catheter in the lower rectum.
A balloon attached to the tip of the catheter also can be used 
to test anorectal sensation.
The high-pressure 
zone estimates the length of the anal canal (normal, 2.0–4.0 cm).
Neurophysiology.
A.
Schematic of the layers of the rectal wall observed 
on endorectal ultrasonography.
B.
Normal endorectal ultrasonography.
(A.
Used with permission of Charles O.
However, this examination is painful 
and poorly tolerated by most patients.
Rectal Evacuation Studies.
Rectal evacuation studies include 
the balloon expulsion test and video defecography.
Balloon 
expulsion assesses a patient’s ability to expel an intrarectal balloon.
Video defecography provides a more detailed assessment of 
defecation.
Laboratory Studies
Fecal Occult Blood Testing.
Increased specificity is now possible by using immunochemical 
FOBT.
Any positive FOBT mandates further investigation, 
usually by colonoscopy.
Stool Studies.
Stool studies are often helpful in evaluating the 
etiology of diarrhea.
coli or Shigella species.
Stool cultures can detect pathogenic 
bacteria, ova, and/or parasites.
C.
Serum Tests.
Specific laboratory tests that should be per-
formed will be dictated by the clinical scenario.
Preoperative 
studies generally include a complete blood count and electrolyte 
panel.
Tumor Markers.
Carcinoembryonic antigen (CEA) may be 
elevated in 60% to 90% of patients with colorectal cancer.
Despite this, CEA is not an effective screening tool for this 
malignancy.
However, this tumor marker is nonspecific, 
and no survival benefit has yet been proven.
It is also important 
to note that CEA may be mildly elevated in patients who smoke 
tobacco.
However, 
in the absence of an identified mutation, a negative result is 
uninformative.
Evaluation of Common Symptoms
Pain
Abdominal Pain.
Abdominal pain is a nonspecific symptom 
with myriad causes.
Pelvic Pain.
Pelvic pain can originate from the distal colon and 
rectum or from adjacent urogenital structures.
Tenesmus may 
result from proctitis or from a rectal or retrorectal mass.
Pelvic 
inflammatory disease also can produce significant abdominal 
and pelvic pain.
CT 
scan and/or MRI may be useful in differentiating these diseases.
Proctoscopy (if tolerated) also can be helpful.
Occasionally, 
laparoscopy will yield a diagnosis.
Anorectal Pain.
Physical examination can usually differentiate these 
conditions.
Proctalgia fugax results from levator spasm and may 
present without any other anorectal findings.
Physical exam is 
critical in evaluating patients with anorectal pain.
MRI or other imaging studies may be 
helpful in select cases where the etiology of pain is elusive.
Lower Gastrointestinal Bleeding.
The second goal is to identify the source of hemorrhage.
Anoscopy and/or 
limited proctoscopy can identify hemorrhoidal bleeding.
Colectomy may be required 
if bleeding persists despite these interventions.
Intraoperative 
colonoscopy and/or enteroscopy may assist in localizing bleed-
ing.
29-7).
Unexplained iron-deficiency 
anemia is also an indication for colonoscopy.
Hematochezia is commonly caused by hemorrhoids or 
a fissure.
Failure to diagnose a source in the distal anorectum should 
prompt colonoscopy.
Constipation and Obstructed Defecation.
A careful his-
tory of these symptoms often clarifies the nature of the problem.
Constipation has many causes.
A stricture or mass 
lesion should be excluded by colonoscopy, barium enema, or 
CT colonography.
Defecography can identify rectal pro-
lapse, intussusception, rectocele, or enterocele.
Algorithm for treatment of colorectal hemorrhage.
NG = nasogastric; 99mTc = technetium-99; RBC = red blood cell.
(Reproduced with permission of Taylor & Francis, LLC from Gordon PH, Nivatvongs S, eds.
Principles and Practice of Surgery for the 
Colon, Rectum, and Anus.
2nd ed.
New York: Marcel Dekker, Inc.; 1999:1279.
Bloody diarrhea and pain are characteristic of colitis; 
etiology can be an infection (invasive E.
coli, Shigella, Salmo-
nella, Campylobacter, Entamoeba histolytica, or C.
difficile), 
inflammatory bowel disease (ulcerative colitis or Crohn’s coli-
tis), or ischemia.
Stool wet-mount and culture can often diag-
nose infection.
Sigmoidoscopy or colonoscopy can be helpful in 
diagnosing inflammatory bowel disease or ischemia.
Chronic diarrhea may present a more difficult diagnos-
tic dilemma.
Large villous lesions may cause secretory diarrhea.
Collag-
enous colitis can cause diarrhea without any obvious mucosal 
abnormality.
Biopsies should be taken even if the 
colonic mucosa appears grossly normal.
Workup reveals no 
underlying anatomic or physiologic abnormality.
Antispasmodics and bulking agents may be helpful.
Incontinence.
The underlying cause of incontinence is often multifactorial, 
and diarrhea is often contributory.
In general, causes of inconti-
nence can be classified as neurogenic or anatomic.
Other causes include anorectal surgery, impalement, 
and pelvic fracture.
Pudendal nerve terminal motor latency testing may 
detect neuropathy.
Anal manometry can detect low resting and 
squeeze pressures.
Physical examination and defecography can 
detect rectal prolapse.
Endoanal ultrasound is invaluable in 
diagnosing sphincter defects (Fig.
29-8).
Therapy depends on the underlying abnormality.
Diarrhea 
should be treated medically (fiber, antidiarrheal agents).
Even in the absence of frank diarrhea, the addition of dietary 
fiber may improve continence.
Some patients may respond to 
biofeedback.
Many patients with a sphincter defect are candi-
dates for an overlapping sphincteroplasty.
A
B
Figure 29-8.
A.
Endoanal ultrasonography showing the normal 
layers of the anal canal.
B.
Endoanal ultrasonography with anterior 
sphincter defect from birthing injury.
EAS = external anal sphincter; 
IAS = internal anal sphincter.
(Both images used with permission 
of Charles O.
29-9).
Resection of a benign process does not 
require wide mesenteric clearance.
Emergency Resection.
Emergency resection may be required 
because of obstruction, perforation, or hemorrhage.
For left-sided tumors, the traditional 
BA
DC
FE
Figure 29-9.
Extent of resection for carcinoma of the colon.
A.
Cecal cancer.
B.
Hepatic flexure cancer.
C.
Transverse colon cancer.
D.
Splenic flexure cancer.
E.
Descending colon cancer.
F.
Sigmoid colon cancer.
Minimally Invasive Techniques of Resection.
Return of bowel function and length of 
hospital stay are highly variable.
Colectomy.
A variety of terms are used to describe different 
types of colectomy (Fig.
29-10).
Ileocolic Resection.
An ileocolic resection describes a lim-
ited resection of the terminal ileum, cecum, and appendix.
The ileocolic vessels are ligated and divided.
A 
variable length of small intestine may be resected depending on 
the disease process.
A primary anastomosis is created between 
the distal small bowel and the ascending colon.
Right Colectomy.
Approximately 10 cm of terminal ileum are usually included in 
the resection.
A primary ileal-transverse colon anastomosis is 
almost always possible.
Extended Right Colectomy.
The right colon and proximal transverse colon are 
A
BC
D
E
FG
H
I
J
K
L
Figure 29-10.
(Reproduced with 
permission from Fielding LP, Goldberg SM, eds.
Rob & Smith’s 
Operative: Surgery of the Colon, Rectum, and Anus.
Such an anastomosis relies 
on the marginal artery of Drummond.
Transverse Colectomy.
Left Colectomy.
A colocolonic anastomosis can 
usually be performed.
Extended Left Colectomy.
An extended left colectomy is an 
option for removing lesions in the distal transverse colon.
Sigmoid Colectomy.
Full mobilization of the splenic flexure is often required to cre-
ate a tension-free anastomosis.
Total and Subtotal Colectomy.
The superior rectal 
vessels are preserved.
Proctocolectomy
Total Proctocolectomy.
Restorative Proctocolectomy (Ileal Pouch–Anal  
Anastomosis).
Bowel continuity is restored by 
anastomosis of an ileal reservoir to the anal canal.
The original 
technique included a transanal mucosectomy and hand-sewn 
ileoanal anastomosis.
29-12).
Anterior Resection.
(Reproduced with permission from Bell RH, Rikkers 
LF, Mulholland M, eds.
Digestive Tract Surgery: A Text and Atlas.
Philadelphia: Lippincott Williams & Wilkins; 1996:1527.)
other incision.
Three types of anterior resection have been 
described.
High Anterior Resection.
Low Anterior Resection.
A low anterior resection is used to 
remove lesions in the upper and mid rectum.
Extended Low Anterior Resection.
An end-to-end stapled or hand-sewn anastomosis 
has traditionally been the procedure of choice.
Ileal S-pouch anal anastomosis with temporary loop 
ileostomy.
(Reproduced with permission from Bell RH, Rikkers LF, 
Mulholland M, eds.
Digestive Tract Surgery: A Text and Atlas.
Finally, a very low anastomosis may involve and compromise 
the upper sphincter.
In such patients, an end colostomy may be a more satisfac-
tory option.
Hartmann’s Procedure and Mucus Fistula.
Abdominoperineal Resection.
Anastomoses
Anastomoses may be created between two segments of bowel in 
a multitude of ways.
The geometry of the anastomosis may be 
end-to-end, end-to-side, side-to-end, or side-to-side.
The anas-
tomotic technique may be hand-sewn or stapled (Fig.
29-13).
The choice of anastomosis depends on the opera-
tive anatomy and surgeon preference.
Although many surgeons 
advocate one method over another, none has been proven to 
be superior.
Anastomotic Configuration
End-to-End.
End-to-Side.
An end-to-side configuration is useful when one 
limb of bowel is larger than the other.
This most commonly 
occurs in the setting of chronic obstruction.
Side-to-End.
Ileo-
rectal anastomoses commonly make use of this configuration.
Figure 29-13.
A.
Sutured end-to-end colocolic anastomosis.
B.
Sutured end-to-side ileocolic anastomosis.
C.
Stapled side-to-side, functional 
end-to-end ileocolic anastomosis.
(Reproduced with permission from Bell RH, Rikkers LF, Mulholland M, eds.
Digestive Tract Surgery: A 
Text and Atlas.
Side-to-Side.
This technique is commonly used 
in ileocolic and small bowel anastomoses.
Anastomotic Technique
Hand-Sutured Technique.
Suture material may be either permanent  
1191
Colon, Rectum, and Anus
CHAPTER 29
or absorbable.
Stapled Techniques.
The anastomosis may be reinforced with interrupted sutures if 
desired.
Circular cutting/stapling devices can create end-to-end, 
end-to-side, or side-to-end anastomoses.
The sta-
pler is opened, and the distal purse-string is tied.
Technique of end-to-end colorectal anastomosis using a circular stapler.
A.
The patient is in modified lithotomy position.
B.
C.
D.
The stapler is closed and fired.
E.
The stapler is removed, leaving a circular stapled end-to-end anastomosis.
colon is placed over the anvil and the purse-string tightened.
The stapler is closed and fired (Fig.
29-14).
The anastomosis in then completed as described ear-
lier (see Fig.
29-11).
A temporary proximal ileostomy may be indicated as well.
It may be end-on or a loop.
Preoperative planning includes counseling, education, 
and stoma siting.
Postoperatively, the ET nurse assists with local 
skin care and pouching.
Preoperative stoma siting is crucial for a patient’s postoper-
ative function and quality of life.
A poorly placed stoma can result 
in leakage and skin breakdown.
29-15).
In emergencies, placement high on the 
abdominal wall is preferred to a low-lying site.
Marking of an ideal site for ileostomy.
(Repro-
duced with permission from Bell RH, Rikkers LF, Mulholland M, 
eds.
Digestive Tract Surgery: A Text and Atlas.
Philadelphia: 
Lippincott Williams & Wilkins; 1996:1273.)
Figure 29-16.
Brooke ileostomy.
A.
B.
(Reproduced with permission from Bell RH, Rikkers LF, Mulholland 
M, eds.
Digestive Tract Surgery: A Text and Atlas.
Philadelphia: 
Lippincott Williams & Wilkins; 1996:1278.)
vein.
The bowel is then brought through the 
defect and secured with sutures.
In order to make appliance use easier, 
a protruding nipple is fashioned by everting the bowel.
29-16).
Ileostomy
Temporary Ileostomy.
In this setting, the stoma is often constructed as 
a loop ileostomy (see Fig.
29-12).
A segment of distal ileum 
is brought through the defect in the abdominal wall as a loop.
An enterotomy is created and the stoma matured as described 
earlier.
The loop may be secured with or without an underly-
ing rod.
This 
avoids a long laparotomy incision and generally is well tolerated.
A patient’s nutritional status 
should be optimized.
Permanent Ileostomy.
29-16).
The end of the small intestine is brought through 
the abdominal wall defect and matured.
Stitches are often used 
to secure the bowel to the posterior fascia.
Complications of Ileostomy.
Stoma retraction may occur early or 
late and may be exacerbated by obesity.
Local revision may 
be necessary.
Ideally, ileos-
tomy output should be maintained at less than 1500 mL/d to 
avoid this problem.
Bulk agents and opioids (Lomotil, Imodium, 
tincture of opium) are useful.
The somatostatin analogue, 
octreotide, has been used with varying success in this setting.
Skin irritation can also occur, especially if the stoma appliance 
fits poorly.
Skin-protecting agents and custom pouches can help 
to solve this problem.
Obstruction may occur intra-abdominally 
or at the site where the stoma exits the fascia.
In general, symptomatic parastomal hernias should be repaired.
Prolapse is a rare, late 
complication and is often associated with a parastomal hernia.
Colostomy.
Most colostomies are created as end colostomies 
rather than loop colostomies (Fig.
29-17).
Most colos-
tomies are created on the left side of the colon.
An abdominal 
wall defect is created and the end of the colon mobilized through 
it.
Tacking the distal end of the colon to the abdominal wall or 
Figure 29-17.
Intraperitoneal end colostomy.
The stoma is dissected free of the abdominal wall and the distal 
bowel identified.
An end-to-end anastomosis is then created.
Complications of Colostomy.
Obstruction 
is unusual, but may also occur.
Prolapse occurs rarely, but is more com-
mon with a loop colostomy.
Interestingly, it is almost always 
the efferent limb of the loop that prolapses.
Dehydration is rare 
after colostomy, and skin irritation is less common than with 
ileostomy.
Unfortunately, complications, 
especially complications related to valve slippage, are common.
Up to 50% have some degree of nocturnal incontinence.
Pouch failure rate averages 5% to 
10%.
The inci-
dence of pouchitis ranges from 30% to 55%.
Symptoms include 
increased diarrhea, hematochezia, abdominal pain, fever, and 
malaise.
Diagnosis is made endoscopically with biopsies.
Dif-
ferential diagnosis includes infection and undiagnosed Crohn’s 
disease.
The etiology of pouchitis is unknown.
Salicylate and corticosteroid 
enemas have also been used with some success.
Occasionally, pouch excision is necessary to control the 
symptoms of chronic pouchitis.
Anesthesia Considerations
Local Anesthesia.
Many anorectal procedures can be per-
formed with local anesthetic alone.
Intravenous sedation is often 
provided to calm the patient.
The addition of dilute epinephrine 
decreases bleeding and prolongs the anesthetic effect.
Regional Anesthesia.
Postoperative epidural anesthesia provides excellent pain relief 
and improves pulmonary function.
General Anesthesia.
General anesthesia is required for the 
vast majority of intra-abdominal procedures.
Patients should 
undergo a thorough preoperative cardiovascular evaluation.
In 
patients with significant comorbid disease, an anesthesia con-
sultation may be appropriate.
Positioning.
Most abdominal colectomies can be performed 
in the supine position.
Anorectal procedures may be performed in lithotomy 
or in the prone jackknife position.
Operative Preliminaries
Bowel Preparation.
PEG solutions require patients to drink a large volume 
of fluid and may cause bloating and nausea.
Both are equally 
efficacious in bowel cleansing.
There is no proven benefit to using 
antibiotics postoperatively after an uncomplicated colectomy.
European surgeons in particular have advo-
cated abandoning this practice.
Lighted stents may be helpful in laparoscopic 
and robotic resections.
Patients often have transient hematuria 
postoperatively, but major complications are rare.
Multidisciplinary Teams.
INFLAMMATORY BOWEL DISEASE
General Considerations
Epidemiology.
The incidence of Crohn’s disease is slightly lower, 
1 to 5 people per 100,000.
Crohn’s disease also affects North-
ern European and white populations disproportionately.
Etiology.
Many different etiologies for inflammatory bowel 
disease have been proposed, but none are proven.
Alcohol and oral contraceptive 
use have also been implicated.
Smoking has been implicated in 
the etiology and exacerbation of Crohn’s disease in particular.
Finally, as noted earlier, an autoimmune 
mechanism has been postulated.
Pathology and Differential Diagnosis.
The mucosa may be atrophic, and crypt abscesses 
are common.
Symptoms are related to the degree of mucosal inflammation 
and the extent of colitis.
Patients typically complain of bloody 
diarrhea and crampy abdominal pain.
Proctitis may produce 
tenesmus.
Severe abdominal pain and fever raise the concern 
of fulminant colitis or toxic megacolon.
In the nonemergent setting, the 
diagnosis is typically made by colonoscopy and mucosal biopsy.
Skip lesions and rectal sparing are 
common.
Strictures 
may produce symptoms of obstruction.
Weight loss is common, 
both because of obstruction and from protein loss.
Physical findings are also related to 
the site and severity of disease.
These patients typically present with symptoms similar 
to ulcerative colitis.
Endoscopic and pathologic findings usually 
include features common to both diseases.
diffi-
cile, Neisseria gonorrhoeae, Salmonella, and Shigella species.
Extraintestinal Manifestations.
The liver is a common site 
of extracolonic disease in inflammatory bowel disease.
Forty percent to 60% of patients with primary sclerosing 
cholangitis have ulcerative colitis.
Bile 
duct carcinoma is a rare complication of long-standing inflam-
matory bowel disease.
Arthritis usually 
improves with treatment of the colonic disease.
Medical 
and surgical treatment of the colonic disease does not impact 
symptoms.
Women are affected three to four times more 
frequently than men.
The characteristic lesions are raised, red, 
and predominantly on the lower legs.
The lesions progress and ulcerate, leading to a painful, 
necrotic wound.
Pyoderma gangrenosum may respond to resec-
tion of the affected bowel in some patients.
In others, this disor-
der is unaffected by treatment of the underlying bowel disease.
Up to 10% of patients with inflammatory bowel disease 
will develop ocular lesions.
These include uveitis, iritis, episcle-
ritis, and conjunctivitis.
They usually develop during an acute 
exacerbation of the inflammatory bowel disease.
The etiology 
is unknown.
Principles of Nonoperative Management.
In 
general, mild to moderate flares may be treated in the outpatient 
setting.
More severe signs and symptoms mandate hospitalization.
Pancolitis generally requires more aggressive therapy than lim-
ited disease.
Systemic therapy is rarely required in 
these patients.
Salicylates.
They 
require direct contact with affected mucosa for efficacy.
Antibiotics.
Antibiotics are often used to decrease the intra-
luminal bacterial load in Crohn’s disease.
Fluoroquinolones may also be effec-
tive in some cases.
Corticosteroids.
Failure to wean 
corticosteroids is a relative indication for surgery.
Budesonide is available as an oral preparation.
Immunomodulating Agents.
However, the majority of these patients will ulti-
mately require colectomy.
Improvement is generally apparent within 2 weeks of beginning 
cyclosporine therapy.
Methotrexate is a folate antagonist that also has been used 
to treat inflammatory bowel disease.
Intravenous infusion of these agents decreases 
inflammation systemically.
Recurrence is common, however; and many 
patients require infusions on a bimonthly basis.
Patients with inflammatory bowel disease are often 
malnourished.
Abdominal pain and obstructive symptoms may 
decrease oral intake.
Diarrhea can cause significant protein loss.
Ongoing inflammation produces a catabolic physiologic state.
The severity of symptoms depends on 
the degree and extent of inflammation.
Although anemia is 
common, massive hemorrhage is rare.
Physical findings are 
often nonspecific.
The diagnosis of ulcerative colitis is almost always made 
endoscopically.
Because the rectum is invariably involved, 
proctoscopy may be adequate to establish the diagnosis.
In more advanced disease, char-
acteristic findings include mucosal friability and ulceration.
Pus 
and mucus may also be present.
However, 
this modality is less sensitive than colonoscopy and may not 
detect early disease.
Because the inflammation in ulcerative colitis is purely 
mucosal, strictures are highly uncommon.
Indications for Surgery.
Indications for surgery in ulcer-
ative colitis may be emergent or elective.
Colonoscopy and barium enema are contraindicated, and 
antidiarrheal agents should be avoided.
Deterioration in clinical 
condition or failure to improve within 24 to 48 hours mandates 
surgery.
However, the adequacy 
of this type of screening is controversial.
For this rea-
son, any patient with dysplasia should be advised to undergo 
proctocolectomy.
Neither approach has been shown definitively to 
decrease mortality from colorectal cancer.
1198
SPECIFIC CONSIDERATIONS
UNIT II
PART II
Operative Management
Emergent Operation.
Definitive surgery may 
then be undertaken at a later date once the patient has recovered.
Elective Operation.
Most patients function well physically and psychologically after 
this operation.
Crohn’s disease, however, may 
affect any portion of the intestinal tract, from mouth to anus.
Indications for Surgery.
Crohn’s disease may present as an acute inflammatory 
process or as a chronic fibrotic process.
Parenteral 
nutrition should be considered if the patient is malnourished.
Most intra-abdominal abscesses can be drained percutaneously 
with the use of CT scan guidance.
Simple 
closure of the secondary fistula site usually suffices.
Chronic fibrosis may result in strictures in any part of the 
gastrointestinal tract.
Chronic strictures almost never improve with medical therapy.
Strictures may be treated with resection or stricturoplasty.
Distal ileal strictures are sometimes amenable to colonoscopic 
balloon dilatation.
Laparoscopy is also increasingly used in this setting.
Ileocolic and Small Bowel Crohn’s Disease.
Psoas abscess may result from ileo-
colic Crohn’s disease.
Parenteral nutrition may be necessary in patients with chronic 
obstruction.
The extent of resection depends on the amount of 
involved intestine.
Isolated chronic strictures should 
also be resected.
29-18).
Crohn’s Colitis.
Crohn’s disease of the large intestine may 
present as fulminant colitis or toxic megacolon.
An 
elective proctectomy may be required if the patient has refrac-
tory Crohn’s proctitis.
Unlike ulcerative colitis, Crohn’s 
colitis may be segmental, and rectal sparing is often observed.
A segmental colectomy may be appropriate if the remaining 
colon and/or rectum appear normal.
An isolated colonic stricture 
may also be treated by segmental colectomy.
Although it was 
long thought that Crohn’s disease did not increase the risk of 
Figure 29-18.
Alternative stricturoplasty techniques.
A.
A short stricture is opened along the antimesenteric surface of the bowel wall.
B.
The 
enterotomy is closed transversely.
C.
A long stricture is opened along the antimesenteric surface of the bowel wall.
D.
The bowel is folded 
into an inverted “U.” E.
A side-to-side anastomosis is made.
(Reproduced with permission from Corman ML.
Colon & Rectal Surgery.
2nd ed.
As in ulcerative 
colitis, dysplasia is an indication for total proctocolectomy.
Anal and Perianal Crohn’s Disease.
Isolated anal Crohn’s 
disease is uncommon, affecting only 3% to 4% of patients.
The most common perianal lesions in Crohn’s disease 
are skin tags that are minimally symptomatic.
Fissures are also 
common.
Perianal abscess and fistulas are common and can be particu-
larly challenging.
Fistulas tend to be complex and often have 
multiple tracts (Fig.
29-19).
Recurrent abscess(es) or complex anal fistulae should raise 
the possibility of Crohn’s disease.
Endoanal ultrasound and pelvic 
MRI are useful for mapping complex fistulous tracts.
Liberal 
use of setons can control many fistulas and avoid division of 
the sphincter.
Photograph of a patient with multiple perianal 
fistulas secondary to Crohn’s disease.
(Reproduced with permis-
sion from Hamilton SR, Borson BC.
Crohn’s disease: Pathology.
In: Berk JE, ed.
Bockus Gastroenterology.
4th ed.
Philadelphia: 
Saunders; 1985:2229, Fig.
127-5.
Copyright Elsevier.)
inflammation.
In 10% to 15% of cases, intractable perianal sep-
sis requires proctectomy.
Rectovaginal fistula can be a particularly difficult problem 
in these patients.
Metronidazole has 
been used with some success in this setting.
Proinflammatory 
cytokines such as interleukin-12 and interferon-γ are potential 
targets.
Pathologic examination of the entire colon may then 
allow a more accurate diagnosis.
Diverticulosis refers to the 
presence of diverticula without inflammation.
Diverticulitis 
refers to inflammation and infection associated with diverticula.
They are thought to be pulsion diverticula resulting 
from high intraluminal pressure.
Diverticular bleeding can be 
massive but usually is self-limited.
Diverticulosis is extremely common in the United States 
and Europe.
It is estimated that half of the population older than 
age 50 years has colonic diverticula.
The sigmoid colon is the 
most common site of diverticulosis (Fig.
29-20).
Diverticulosis 
is thought to be an acquired disorder, but the etiology is poorly 
understood.
The high radial pressures 
directed against the bowel wall create pulsion diverticula.
Peridiverticular and pericolic 
Figure 29-20.
Diverticulosis of sigmoid colon on barium enema.
(Reproduced with permission from Nivatvongs S, Becker ER.
Colon, rectum, and anal canal.
In: James EC, Corry RJ, Perry JCF 
Jr, eds.
Basic Surgical Practice.
Philadelphia: Hanley & Belfus; 
1987.
Most patients present with left-
sided abdominal pain, with or without fever, and leukocytosis.
A mass may be present.
Plain radiographs are useful for detect-
ing free intra-abdominal air.
CT scan is extremely useful for 
defining pericolic inflammation, phlegmon, or abscess.
Uncomplicated Diverticulitis.
Uncomplicated diverticulitis is 
characterized by left lower quadrant pain and tenderness.
CT 
findings include pericolic soft tissue stranding, colonic wall 
thickening, and/or phlegmon.
Antibi-
otics should be continued for 7 to 10 days.
Most patients improve within 48 to 72 hours.
Failure to improve may suggest abscess formation.
Colonoscopy is recommended 
4 to 6 weeks after recovery.
Inability to exclude malignancy is 
another indication for resection.
Increasingly, laparoscopy is being used for elec-
tive sigmoid colectomy for diverticular disease.
Complicated Diverticulitis.
Small abscesses (<2 cm 
in diameter) may be treated with parenteral antibiotics.
Larger 
abscesses are best treated with CT-guided percutaneous drain-
age (Fig.
29-21) and antibiotics.
In almost all 
cases, an attempt should be made to resect the affected seg-
ment of bowel.
A.
Computed tomography scan demonstrating pelvic abscess from perforated diverticular disease.
B.
(Both images used with permission of Charles O.
Relief of obstruction allows 
full bowel preparation and elective resection.
A high-volume  
oral bowel preparation is contraindicated in the presence of 
obstructive symptoms.
Obstruction that does not rapidly respond 
to medical management mandates laparotomy.
Sigmoid colec-
tomy with end colostomy is the safest procedure to perform in this 
setting.
Colovesical fistulas are most common, followed by colovagi-
nal and coloenteric fistulas.
Colocutaneous fistulas are a rare 
complication of diverticulitis.
CT 
scan can identify associated abscesses or masses.
The differ-
ential diagnosis includes malignancy, Crohn’s disease, and 
radiation-induced fistulas.
Suspicion 
of carcinoma may mandate a wider, en bloc resection.
Consequently, the exact bleeding source may be dif-
ficult to identify.
Fortunately, in 80% of patients, bleeding stops 
spontaneously.
Angiography may be diagnos-
tic and therapeutic in this setting.
Giant Colonic Diverticulum
Giant colonic diverticula are extremely rare.
Most occur on 
the antimesenteric side of the sigmoid colon.
Plain radiographs may 
suggest the diagnosis.
Barium enema is usually diagnostic.
Complications of a giant diverticulum include perforation, 
obstruction, and volvulus.
Resection of the involved colon and 
diverticulum is recommended.
Most patients with right-sided diverticula are 
asymptomatic.
However, diverticulitis does occur occasionally.
Aging.
More than 90% 
of cases diagnosed are in people older than age 50 years.
Hereditary Risk Factors.
Environmental and Dietary Factors.
In contrast, a diet high in 
vegetable fiber appears to be protective.
In general, the duration and extent of colitis 
correlate with risk.
Other Risk Factors.
Pelvic irradiation may increase 
the risk of developing rectal carcinoma.
29-22).
Defects in the APC gene were first described in patients 
with FAP.
By investigating these families, characteristic muta-
tions in the APC gene were identified.
They are now known to 
be present in 80% of sporadic colorectal cancers as well.
The APC gene is a tumor suppressor gene.
Mutations 
in both alleles are necessary to initiate polyp formation.
The 
majority of mutations are premature stop codons, which result in 
a truncated APC protein.
In FAP, the site of mutation correlates 
with the clinical severity of the disease.
Thus, knowledge of the specific 
mutation in a family may help guide clinical decision making.
APC inactivation alone does not result in a carcinoma.
Additional mutations 
may include activation or inactivation of a variety of genes.
One of the most commonly involved genes in colorectal 
cancer is K-ras.
The K-ras gene product is a G-protein involved in 
intracellular signal transduction.
It is thought that this 
then leads to uncontrolled cell division.
The tumor suppressor gene p53 has been well character-
ized in a number of malignancies.
p53 Other changes
Figure 29-22.
Schematic showing progression from normal colonic epithelium to carcinoma of the colon.
Mutations in p53 are present in 75% of 
colorectal cancers.
The Loss of Heterozygosity Pathway.
The LOH pathway 
is characterized by chromosomal deletions and tumor aneu-
ploidy.
Eighty percent of colorectal carcinomas appear to arise 
from mutations in the LOH pathway.
Another example of LOH occurs in the region of chromo-
some 18q.
This region has been found to be deleted in up to 
70% of colorectal cancers.
DCC 
is a tumor suppressor gene, and loss of both alleles is required 
for malignant degeneration.
Loss of either of these genes 
is thought to promote cancer progression.
The Microsatellite Instability Pathway.
These 
mismatch repair genes include MSH2, MLH1, PMS1, PMS2, 
and MSH6/GTBP.
Accumulation of these errors then 
leads to genomic instability and ultimately to carcinogenesis.
CpG Island Methylation Pathway.
In normal cells, methylation is critical for regulation of 
gene expression.
For example, a mismatch repair gene may be 
inactivated by methylation.
Errors in mismatch repair may then 
allow mutations to inactivate a tumor suppressor gene.
Neoplastic Polyps.
By definition, these lesions are dysplas-
tic.
The risk of malignant degeneration is related to both the 
size and type of polyp.
Tubulovillous adenomas are at 
intermediate risk (22%).
Invasive carcinomas are rare in polyps 
smaller than 1 cm; the incidence increases with size.
The risk of 
carcinoma in a polyp larger than 2 cm is 35% to 50%.
Polyps may be pedunculated or sessile.
Most pedun-
culated polyps are amenable to colonoscopic snare excision.
Removal of sessile polyps is often more challenging.
Complications of polypectomy include perforation and 
bleeding.
Bleeding may occur immediately after  
polypectomy or may be delayed.
Occasionally angiography 
and infusion of vasopressin may be necessary.
Rarely, colec-
tomy is required.
Hyperplastic Polyps.
Hyperplastic polyps are extremely 
common in the colon.
In contrast, large hyperplastic 
polyps (>2 cm) may have a slight risk of malignant degenera-
tion.
Moreover, large polyps may harbor foci of adenomatous 
tissue and dysplasia.
These patients are at slightly increased risk for the development 
of colorectal cancer.
Serrated Polyps.
Serrated polyps are a recently recognized, 
histologically distinct group of neoplastic polyps.
However, it has become clear that 
some of these polyps will develop into invasive cancers.
In addi-
tion, a familial serrated polyposis syndrome has recently been 
described.
These lesions are the 
characteristic polyps of childhood but may occur at any age.
Bleeding is a common symptom, and intussusception and/or 
obstruction may occur.
Annual 
screening should begin between the ages of 10 and 12 years.
Treatment is surgical and depends in part on the degree of rectal 
involvement.
If the 
rectum is carpeted with polyps, total proctocolectomy is the 
more appropriate operation.
These patients are candidates for 
ileal pouch–anal reconstruction to avoid a permanent stoma.
Characteristic melanin spots are often noted 
on the buccal mucosa and lips of these patients.
However, carcinoma may occasionally develop.
Patients should be screened 
for cancers.
Treatment is otherwise based on symptoms.
Inflammatory Polyps (Pseudopolyps).
Polyposis may be extensive, especially in patients with severe 
colitis, and may mimic FAP.
Familial Adenomatous Polyposis.
The genetic abnormality in FAP is 
a mutation in the APC gene, located on chromosome 5q.
Of 
patients with FAP, APC mutation testing is positive in 75% of 
cases.
Clinically, patients develop hundreds to thou-
sands of adenomatous polyps shortly after puberty.
The lifetime 
risk of colorectal cancer in FAP patients approaches 100% by 
age 50 years.
Periampullary carcinoma is a particular concern.
Once the diagnosis of FAP has been made and polyps are 
developing, treatment is surgical.
COX-2 inhibitors and nonsteroidal, 
anti-inflammatory drugs may also be beneficial in this setting.
Attenuated Familial Adenomatous Polyposis.
AFAP is a 
recognized variant of FAP.
Patients are also at risk for duo-
denal polyposis.
When present, these mutations are expressed in an autosomal 
dominant pattern.
When positive, genetic counseling and testing may be 
used to screen at-risk family members.
Hereditary Nonpolyposis Colon Cancer (Lynch’s  
Syndrome).
Approximately 70% 
of affected individuals will develop colorectal cancer.
The risk of synchronous or metachronous colorectal carcinoma 
is 40%.
The diagnosis of HNPCC is made 
based on family history.
The presence of other HNPCC-related carcinomas should 
raise the suspicion of this syndrome.
MSH6 inactivation also appears to be associated 
with a higher risk for endometrial cancer.
Further significance 
of these specific mutations remains to be determined.
Annual proctos-
copy is necessary because the risk of developing rectal cancer 
remains high.
Familial Colorectal Cancer.
The lifetime risk of developing colorectal cancer 
increases with a family history of the disease.
Fecal Occult Blood Testing.
FOBT is known to reduce 
colorectal cancer mortality by 33% and metastatic disease by 
50%.
Its specificity 
is low because 90% of patients with positive tests do not have 
colorectal cancer.
Flexible Sigmoidoscopy.
Colonoscopy.
Colonoscopy is currently the most accurate and 
most complete method for examining the large bowel.
Nevertheless, 
deaths have been reported.
Air-Contrast Barium Enema.
Unfortunately, there are no studies proving its 
efficacy for screening large populations.
Computed Tomography Colonography (Virtual Colonos-
copy).
A 
present, patients require a mechanical bowel preparation.
Guidelines for Screening.
Routes of Spread and Natural History
Carcinoma of the colon and rectum arises in the mucosa.
The 
tumor subsequently invades the bowel wall and eventually 
adjacent tissues and other viscera.
Tumors may become bulky 
and circumferential, leading to colon obstruction.
The T stage (depth of invasion) is the single most 
significant predictor of lymph node spread.
Four or more involved lymph nodes 
predict a poor prognosis.
Lymphatic spread from the rectum follows 
two routes.
In the 
lower rectum, lymphatic drainage may course along the middle 
rectal vessels.
29-23).
The most common site of distant metastasis from colorec-
tal cancer is the liver.
These metastases arise from hematog-
enous spread via the portal venous system.
However, even small tumors may pro-
duce distant metastasis.
The lung is also a site of hematogenous 
spread, but this rarely occurs in isolation.
Staging and Preoperative Evaluation
Clinical Presentation.
The classic first symptoms are a change in bowel 
habits and rectal bleeding.
Rectal 
tumors may cause bleeding, tenesmus, and pain.
Staging.
The preoperative evaluation usually identifies stage IV 
disease.
Disease 
stage correlates with 5-year survival.
Patients with stages I and 
II disease can expect excellent survival rates.
The presence of 
nodal metastases (stage III) decreases survival (Table 29-4).
The 5-year survival rate with stage IV disease is less than 16%.
Sources: Data adapted from Smith et al,6 Pignone et al,68 and Levin et al.67
Inferior
mesenteric a.
Superior
rectal a.
Middle
rectal a.
Inferior
rectal a.
Common 
iliac a.
Figure 29-23.
Lymphatic drainage of the rectum.
a.
= artery.
Source: From Gunderson et al.76 Copyright Elsevier.
prognosis.
This circumferential or radial margin is probably 
best assessed preoperatively by MRI.
Preoperative Evaluation.
Once a colon or rectal carcinoma 
has been diagnosed, a staging evaluation should be undertaken.
The colon must be evaluated for synchronous tumors, usually 
by colonoscopy.
Synchronous disease will be present in up to 
5% of patients.
29-24).
A chest/abdominal/pelvic 
Figure 29-24.
Endorectal ultrasonography showing a T3 rectal 
carcinoma.
The dotted line is being used to measure the diameter 
of the lesion.
(Used with permission of Charles O.
Preoperative 
CEA is often obtained and may be useful for postoperative 
follow-up.
Therapy for Colonic Carcinoma
Principles of Resection.
Stage-Specific Therapy
Stage 0 (Tis, N0, M0).
Polyps containing carcinoma in situ 
(high-grade dysplasia) carry no risk of lymph node metastasis.
Most pedunculated 
polyps and many sessile polyps may be completely removed 
endoscopically.
In cases where the 
polyp cannot be removed entirely, a segmental resection is rec-
ommended.
Stage I: The Malignant Polyp (T1, N0, M0).
Segmental colectomy is then indicated.
29-25).
Stages I and II: Localized Colon Carcinoma (T1-3, N0, 
M0).
The majority of patients with stages I and II colon cancer 
will be cured with surgical resection.
Levels of invasive carcinoma in pedunculated and 
sessile polyps.
ca = carcinoma.
1213
Colon, Rectum, and Anus
CHAPTER 29
survival in these patients.
It remains 
controversial as to whether chemotherapy improves survival 
rates in these patients.
Molecular profiling holds promise for 
improving patient selection in these early cancers.
Stage III: Lymph Node Metastasis (Tany, N1, M0).
MSI status 
in particular predicts good prognosis.
Survival 
is extremely limited in stage IV colon carcinoma.
The most common site of metastasis is the 
liver.
Of patients with systemic disease, approximately 15% will 
have metastases limited to the liver.
Of these, 20% are poten-
tially resectable for cure.
All patients require adjuvant 
chemotherapy.
Hemorrhage in an unresectable tumor 
can sometimes be controlled with angiographic embolization.
External beam radiation also has been used for palliation.
Therapy for Rectal Carcinoma
Principles of Resection.
Therefore, local recurrence is higher than 
with similar stage colon cancers.
Local Therapy.
The distal 10 cm of the rectum are accessible 
transanally.
For this reason, several local approaches have been 
proposed for treating rectal neoplasms.
Ablative techniques, such as electrocautery or endocavi-
tary radiation, also have been used.
Radical Resection.
Radical resection is preferred to local 
therapy for most rectal carcinomas.
TME both decreases local recurrence rates and 
improves long-term survival rates.
The principles of 
TME should be applied to all radical resections for rectal cancer.
Recurrence of rectal cancer generally has a poor prog-
nosis.
A permanent colostomy and an ileal conduit to drain the urinary 
tract may be necessary.
The sacrum may also be resected if nec-
essary (sacrectomy) up to the level of the S2-S3 junction.
1214
SPECIFIC CONSIDERATIONS
UNIT II
PART II
Stage-Specific Therapy (Fig.
29-26).
Ultrasound evaluation can 
guide choice of therapy in most patients.
MRI is useful to assess 
mesorectal involvement.
When the radial margin is threatened 
or involved, neoadjuvant chemoradiation is recommended.
Stage 0 (Tis, N0, M0).
A 1-cm margin should be obtained.
Stage I: Localized Rectal Carcinoma (T1-2, N0, M0).
For this reason, radical resection 
is strongly recommended in all good-risk patients.
Diagnostic algorithm for rectal cancer.
CT = computed tomography; MRI = magnetic resonance imaging; U/S = ultrasound.
tolerate radical surgery has been controversial.
There are two schools of thought, each 
differing in their approach to control local recurrences.
Stage III: Lymph Node Metastasis (Tany, N1, M0).
Appropriate timing of chemoradiation for locally advanced 
rectal cancer has been debated.
In addi-
tion, the absence of small bowel adhesions in the pelvis may 
decrease toxicity.
In addition, postoperative pelvic radiation may 
compromise function of the neorectum.
Postoperative chemoradiation, 
however, doubled the risk of postoperative stricture formation.
In addition, preoperative chemoradiation halved the risk of local 
recurrence (6% vs.
12%).
Occasionally, a proximal diverting 
colostomy will be required to alleviate obstruction.
A mucus 
fistula should be created if possible to vent the distal colon.
If that 
study is normal, colonoscopy should be repeated every 3 to 
5 years thereafter.
The optimal method of following patients for recurrent 
cancer remains controversial.
Thus, only selected patients who 
would tolerate such an approach should be followed intensively.
CEA is often followed every 3 to 6 months for 2 years.
Resection of other involved organs may be necessary.
Nevertheless, radical salvage surgery can 
prolong survival in selected patients.
Sev-
eral trials have laid to rest many of these fears.
Most small rectal carcinoids are benign, and 
overall survival is greater than 80%.
Small carcinoids can be locally resected transanally.
Larger 
tumors or tumors with obvious invasion into the muscularis 
require more radical surgery.
Carcinoid tumors in the proximal 
colon are less common and are more likely to be malignant.
These tumors should usually be treated with 
radical resection.
Tumor debulking can offer effective palliation in 
selected patients.
Carcinoid Carcinomas.
Lipomas.
Lipomas occur most commonly in the submucosa 
of the colon and rectum.
Small asymptomatic lesions 
do not require resection.
Lymphoma.
The cecum is most often involved, probably as a result of 
spread from the terminal ileum.
Bowel resection is the treatment of 
choice for isolated colorectal lymphoma.
Adjuvant therapy may 
be given based on the stage of disease.
Leiomyoma and Leiomyosarcoma.
Most patients are 
asymptomatic, but large lesions can cause bleeding or obstruc-
tion.
Leiomyosarcoma is rare in the gastrointestinal tract.
When 
this malignancy occurs in the large intestine, the rectum is the 
most common site.
Symptoms include bleeding and obstruction.
A radical resection is indicated for these tumors.
Gastrointestinal Stromal Tumor.
They are often mistaken 
for leiomyomas.
Thirty percent to 50% are malignant; thus all 
lesions should be resected.
Tumors that develop in this 
space are often heterogeneous.
Congenital lesions are most common, comprising almost 
two thirds of retrorectal lesions.
The remainder are classified as 
neurogenic, osseous, inflammatory, or miscellaneous lesions.
Dermoid 
and epidermoid cysts are benign lesions that arise from the 
ectoderm.
Enterogenous cysts arise from the primitive gut.
Solid lesions include teratomas, chordomas, neurologic 
tumors, or osseous lesions.
Teratomas are true neoplasms and 
contain tissue from each germ cell layer.
They often contain 
both cystic and solid components.
Chordomas arise from the notochord and are the 
most common malignant tumor in this region.
These are slow-
growing, invasive cancers that show characteristic bony destruc-
tion.
Most lesions are palpable on digital rectal examination.
Myelogram is occasionally necessary if there is central 
nervous system involvement.
Treatment is almost always sur-
gical resection.
The approach depends in part on the nature of 
the lesion and its location.
Intermediate lesions may require 
a combined abdominal and sacral operation.
The role of biopsy in this setting has been controversial.
Lymph from the anal canal distal to the dentate line usually 
drains to the inguinal nodes.
29-27).
In many cases, therapy depends on whether the tumor 
is perianal or intra-anal.
Squamous Intraepithelial Lesions.
Anal canal and peri-
anal dysplasia have long had a potpourri of nomenclature.
Superior
rectal a.
Middle
rectal a.
Inferior
rectal a.
Common 
iliac a.
Figure 29-27.
Lymphatic drainage of the anal canal.
a.
= artery.
1218
SPECIFIC CONSIDERATIONS
UNIT II
PART II
disease, and carcinoma in situ.
Both HSIL and LSIL are associated with infection 
with HPV, especially types 16 and 18.
Treatment of HSIL is 
ablation.
Rarely, extensive disease 
may require resection with flap closure.
Medical therapy for 
HPV has also been proposed.
Epidermoid Carcinoma.
The clinical behav-
ior and natural history of these tumors are similar.
Pain and bleeding may be present.
More than 80% of these tumors can be cured by using this 
regimen.
Recurrence usually requires radical resection (APR).
Metastasis to inguinal lymph nodes is a poor prognostic sign.
Verrucous Carcinoma (Buschke-Lowenstein Tumor, Giant 
Condyloma Acuminata).
Verrucous carcinoma is a locally 
aggressive form of condyloma acuminata.
Basal Cell Carcinoma.
This is a slow-
growing tumor that rarely metastasizes.
Wide local excision 
is the treatment of choice, but recurrence occurs in up to 30% 
of patients.
Radical resection and/or radiation therapy may be 
required for large lesions.
Adenocarcinoma.
Adenocarcinoma may occasionally arise from the 
anal glands or may develop in a chronic fistula.
Radical resection 
with or without adjuvant chemoradiation is usually required.
The lesion is typically plaque-like and may be indistin-
guishable from HSIL.
Characteristic Paget’s cells are seen histo-
logically.
Wide local excision is 
usually adequate treatment for perianal Paget’s disease.
Melanoma.
In adults, this condition is far more common among 
women, with a female-to-male ratio of 6:1.
Prolapse becomes 
more prevalent with age in women and peaks in the seventh 
decade of life.
In men, prevalence is unrelated to age.
Mucus discharge and 
leakage may accompany the protrusion.
Operations can be categorized as either abdomi-
nal or perineal.
29-28).
In some cases, resection is combined with rectal 
fixation (resection rectopexy).
29-29).
Reefing the rectal mucosa is effective 
for patients with limited prolapse.
Anal encirclement procedures 
generally have been abandoned.
Solitary Rectal Ulcer Syndrome.
Patients may complain of pain, 
bleeding, mucus discharge, or outlet obstruction.
In colitis cystica profunda, 
nodules or a mass may be found in a similar location.
Biofeedback has also 
been reported to be effective in some patients.
The symptoms of volvulus are those of acute bowel 
obstruction.
Patients present with abdominal distention, nau-
sea, and vomiting.
Symptoms rapidly progress to generalized 
abdominal pain and tenderness.
Fever and leukocytosis are her-
alds of gangrene and/or perforation.
Sigmoid Volvulus.
29-30).
A rec-
tal tube may be inserted to maintain decompression.
Figure 29-28.
Transabdominal proctopexy for rectal 
prolapse.
The fully mobilized rectum is sutured to the 
presacral fascia.
A.
Anterior view.
B.
Lateral view.
If 
desired, a sigmoid colectomy can be performed con-
comitantly to resect the redundant colon.
Cecal Volvulus.
Cecal volvulus results from nonfixation of the 
right colon.
Unlike sigmoid volvulus, cecal volvulus can almost never 
be detorsed endoscopically.
Simple detor-
sion or detorsion and cecopexy are associated with a high rate 
of recurrence.
Transverse Colon Volvulus.
Transverse colon volvulus is 
extremely rare.
Megacolon
Megacolon describes a chronically dilated, elongated, hypertro-
phied large bowel.
In general, the degree of megacolon is related to 
the duration of obstruction.
The proximal, healthy bowel becomes 
progressively dilated.
Surgical resection of the aganglionic 
segment is curative.
Perineal rectosigmoidec-
tomy shown in lithotomy position.
A.
A 
circular incision is made 2 cm proximal to 
the dentate line.
B.
The anterior peritoneal 
reflection is opened.
C.
The mesentery is 
divided and ligated.
D.
The peritoneum 
may be sutured to the bowel wall.
E.
The 
bowel is resected.
F.
A hand-sewn anasto-
mosis is performed.
Acquired megacolon may result from infection or chronic 
constipation.
Pseudo-
obstruction is thought to result from autonomic dysfunction and 
severe adynamic ileus.
Strict bowel rest and intravenous hydration are crucial.
Most patients will respond to these measures.
In patients who 
fail to improve, colonoscopic decompression often is effective.
Up to 40% of 
patients recur.
Ischemic Colitis
Intestinal ischemia occurs most commonly in the colon.
Instead, most colonic isch-
emia appears to result from low flow and/or small vessel occlu-
sion.
Occasionally, thrombosis or embolism may 
cause ischemia.
The rectum is relatively spared because of its rich col-
lateral circulation.
AB
Figure 29-30.
Sigmoid volvulus: (A) Illustration and (B) Gastrografin enema showing “bird-beak” sign (arrow).
(B: Reproduced with per-
mission from Nivatvongs S, Becker ER.
Colon, rectum, and anal canal.
In: James EC, Corry RJ, Perry JCF Jr, eds.
Basic Surgical Practice.
Philadelphia: Hanley & Belfus; 1987.
In mild cases, patients may have diarrhea 
(usually bloody) without abdominal pain.
Peritonitis and/or systemic toxicity are signs of full-
thickness necrosis and perforation.
The diagnosis of ischemic colitis is often based on the 
clinical history and physical examination.
CT often shows nonspecific colonic 
wall thickening and pericolic fat stranding.
Angiography is 
usually not helpful because major arterial occlusion is rare.
Treatment of ischemic colitis depends on clinical sever-
ity.
Long-term sequelae 
include stricture (10%–15%) and chronic segmental ischemia 
(15%–20%).
In this setting, all necrotic bowel should 
be resected.
Primary anastomosis should be avoided.
Occasion-
ally, repeated exploration (a second-look operation) may be 
necessary.
Infectious Colitis
Pseudomembranous Colitis (Clostridium difficile Colitis).
Pseudomembranous colitis is caused by C.
difficile, a gram-
positive anaerobic bacillus.
C.
C.
difficile is carried in the 
large intestine of many healthy adults.
Although 
clindamycin was the first antimicrobial agent associated with 
C.
difficile colitis, almost any antibiotic may cause this disease.
Moreover, although the risk of C.
The pathogenic changes associated with C.
Diagnosis of this disease was tradition-
ally made by culturing the organism from the stool.
Management should include immediate cessation of 
the offending antimicrobial agent.
Proctosigmoiditis may 
respond to vancomycin enemas.
A total abdomi-
nal colectomy with end ileostomy may be lifesaving.
Over the 
past decade, C.
Common bacterial infections include enterotoxic  
E.
coli, Campylobacter jejuni, Yersinia enterocolitica, Salmo-
nella typhi, Shigella, and N.
gonorrhoeae.
Serum immunoassays may also be useful (amebia-
sis, HIV, CMV).
Occasionally, endoscopy with biopsy may be 
required.
Treatment is tailored to the infection.
29-4).
Bleeding, thrombosis, and symptomatic hemorrhoidal prolapse 
may result.
External hemorrhoids are located distal to the dentate line 
and are covered with anoderm.
Skin tags are often confused with symptomatic hem-
orrhoids.
Treatment of exter-
nal hemorrhoids and skin tags is only indicated for symptomatic 
relief.
Internal hemor-
rhoids are graded according to the extent of prolapse.
Second-degree hemor-
rhoids prolapse through the anus but reduce spontaneously.
Third-degree hemorrhoids prolapse through the anal canal and 
require manual reduction.
Fourth-degree hemorrhoids prolapse 
but cannot be reduced and are at risk for strangulation.
Hemorrhoidectomy is often required for 
large, symptomatic, combined hemorrhoids.
Rectal varices, however, may 
occur and may cause hemorrhage in these patients.
In general, 
rectal varices are best treated by lowering portal venous pressure.
Rarely, suture ligation may be necessary if massive bleeding 
persists.
Treatment
Medical Therapy.
Associated pruritus often may improve with improved 
hygiene.
Rubber Band Ligation.
29-31).
In general, only one or two quadrants are banded 
per visit.
Other complications of rubber band ligation include urinary 
retention, infection, and bleeding.
Necrotizing infection is an uncommon, but life-threatening 
complication.
Infrared Photocoagulation.
The instrument is applied to the apex of each hem-
orrhoid to coagulate the underlying plexus.
All three quadrants 
may be treated during the same visit.
Sclerotherapy.
Excision of Thrombosed External Hemorrhoids.
Because the clot is usually loculated, simple incision and 
drainage is rarely effective.
After 72 hours, the clot begins to 
resorb, and the pain resolves spontaneously.
Excision is unnec-
essary, but sitz baths and analgesics are often helpful.
Operative Hemorrhoidectomy.
Closed Submucosal Hemorrhoidectomy.
The anal canal is 
examined and an anal speculum inserted.
The apex of the hemorrhoidal plexus is then ligated 
and the hemorrhoid excised.
The wound is then closed with a 
running absorbable suture.
29-32).
Open Hemorrhoidectomy.
Whitehead’s Hemorrhoidectomy.
After excision, the 
rectal mucosa is then advanced and sutured to the dentate line.
Procedure for Prolapse and Hemorrhoids/Stapled Hemor-
rhoidectomy.
These vessels are then ligated.
Pain can also lead to fecal impaction.
Bleeding may occur 
Elastic
bands
Elastic
bands
Elastic
bands
Figure 29-31.
Rubber band ligation of internal 
hemorrhoids.
The mucosa just proximal to the inter-
nal hemorrhoids is banded.
Severe pain, 
fever, and urinary retention may be early signs of infection.
Anal stenosis may result from 
scarring after extensive resection of perianal skin.
Ectropion 
may occur after Whitehead’s hemorrhoidectomy.
Anal Fissure
A fissure in ano is a tear in the anoderm distal to the dentate 
line.
The vast major-
ity of anal fissures occur in the posterior midline.
Ten percent 
to 15% occur in the anterior midline.
Less than 1% of fissures 
occur off midline.
Symptoms and Findings.
Anal fissure is extremely common.
Patients 
are often too tender to tolerate digital rectal examination, anos-
copy, or proctoscopy.
There often is an associated external skin tag 
and/or a hypertrophied anal papilla internally.
These fissures 
are more challenging to treat and may require surgery.
Technique of closed sub-
mucosal hemorrhoidectomy.
A.
The patient 
is in prone jackknife position.
B.
A Fansler 
anoscope is used for exposure.
C.
A narrow 
ellipse of anoderm is excised.
D.
E.
F.
Additional quad-
rants are excised to complete the procedure.
1226
SPECIFIC CONSIDERATIONS
UNIT II
PART II
or leukemia.
Treatment.
Internal
sphincter m.
Fissure Fissure-in-ano
A
B
C
D
Figure 29-33.
A through D.
Open lateral internal sphincterotomy 
for fissure in ano.
m = muscle.
Anal 
fissure
Sentinel
 pile
AB
DC
dividing a portion of the muscle.
29-33) or closed (Fig.
29-34) technique.
Healing 
is achieved in more than 95% of patients using this technique, 
Figure 29-34.
A through D.
Closed lateral internal 
sphincterotomy for fissure in ano.
1227
Colon, Rectum, and Anus
CHAPTER 29
and most patients experience immediate pain relief.
Anorectal Sepsis and Cryptoglandular Abscess
Relevant Anatomy.
The intersphincteric space separates 
the internal and external anal sphincters.
It is continuous with 
the perianal space distally and extends cephalad into the rectal 
wall.
The ischio-
rectal space contains the inferior rectal vessels and lymphatics.
The anatomy of these spaces influences the location 
and spread of cryptoglandular infection (Fig.
29-35).
As an abscess enlarges, it spreads in one of several direc-
tions.
These abscesses may become 
extremely large and may not be visible in the perianal region.
Digital rectal exam will reveal a painful swelling laterally in the 
ischiorectal fossa.
29-36).
Levator ani m.
Internal sphincter m.
Puborectalis and
deep external sphincter m.
Superficial external
sphincter m.
Subcutaneous
external sphincter m.
Deep postanal space
Superficial
postanal space
A
B
Figure 29-35.
Anatomy of perianorectal spaces.
(A) Anterior view and (B) lateral view.
m = muscle.
1228
SPECIFIC CONSIDERATIONS
UNIT II
PART II
Diagnosis.
Severe anal pain is the most common presenting 
complaint.
Occasionally, 
patients will present with fever, urinary retention, or life-
threatening sepsis.
Treatment.
Anorectal abscesses should be treated by drainage as 
soon as the diagnosis is established.
Antibiot-
ics alone are ineffective at treating perianal or perirectal infection.
Larger, more complicated 
abscesses may require drainage in the operating room.
A skin 
incision is created, and a disk of skin excised to prevent prema-
ture closure.
No packing is necessary, and sitz baths are started 
the next day (Fig.
29-37).
Simple ischiorectal abscesses are drained through an 
incision in the overlying skin.
29-38).
Perianal space
abscess
Levator
ani m.
External
sphincter m.
Longitudinal m.
Pelvirectal space
abscess
Intersphincteric space
abscess
Ischiorectal fossa
abscess
Figure 29-36.
A and B.
Pathways of anorectal infection in perianal spaces.
m = muscle.
A
B
C
Figure 29-37.
A through C.
Technique of drainage of perianal abscess.
infection.
The pain is so intense that it usually precludes a digital 
rectal examination.
Digital 
rectal examination may reveal an indurated, bulging mass above 
the anorectal ring.
It is essential to identify the origin of a supra-
levator abscess prior to treatment.
Drainage of this type of abscess through the rectum 
may result in an extrasphincteric fistula.
An increase in pain or 
fever and/or clinical deterioration mandates an exam under 
anesthesia.
Most of these infections are polymicrobial and 
synergistic.
Occasionally, these infections may be encountered 
postoperatively (e.g., after hemorrhoidectomy).
Immunocom-
promised patients and diabetic patients are at increased risk.
Physical examination may reveal necrotic skin, bullae, 
or crepitus.
Patients often have signs of systemic toxicity and 
may be hemodynamically unstable.
Multiple operations 
may be necessary to ensure that all necrotic tissue has been 
resected.
Fistula In Ano
Drainage of an anorectal abscess results in cure for about 50% 
of patients.
The remaining 50% develop a persistent fistula in 
ano.
The course of the fistula can often be predicted 
by the anatomy of the previous abscess.
A complex, recurrent, or nonhealing fis-
tula should raise the suspicion of one of these diagnoses.
Diagnosis.
Patients present with persistent drainage from the 
internal and/or external openings.
An indurated tract is often pal-
pable.
Goodsall’s rule can be used as a guide in determining the loca-
tion of the internal opening (Fig.
29-39).
However, exceptions to this rule often occur if an anterior 
Figure 29-38.
Drainage of horseshoe abscess.
The deep postanal 
space is entered, incising the anococcygeal ligament.
Counter drain-
age incisions are made for each limb of the ischiorectal space.
Goodsall’s rule to identify the internal opening of 
fistulas in ano.
Such fistulas usually track to the posterior midline.
29-40A).
29-40B).
29-40C).
29-40D).
Treatment.
The goal of treatment of fistula in ano is eradica-
tion of sepsis without sacrificing continence.
The internal 
opening may be more difficult to identify.
Injection of hydrogen 
peroxide or dilute methylene blue may be helpful.
29-40A).
Treatment of a transsphinc-
teric fistula depends on its location in the sphincter complex.
Figure 29-40.
A.
Intersphincteric fistula with simple low tract.
B.
Uncomplicated transsphincteric fistula.
C.
Uncomplicated suprasphinc-
teric fistula.
D.
Extrasphincteric fistula secondary to anal fistula.
(Data from Gordon PH, Nivatvongs S, eds.
Principles and Practice of Surgery 
for the Colon, Rectum, and Anus.
2nd ed.
29-40B).
Simi-
larly, suprasphincteric fistulas are usually treated with seton 
placement (see Fig.
29-40C).
In general, the portion of the fistula outside the 
sphincter should be opened and drained.
A primary tract at the 
level of the dentate line may also be opened if present.
Liberal use of drains and 
setons is helpful.
Failure to heal may ultimately require fecal 
diversion (see Fig.
29-40D).
Biopsies of the fistula tract should 
be taken to rule out malignancy.
A seton is a drain placed through a fistula to maintain drain-
age and/or induce fibrosis.
Alternatively, the seton may be left in 
place for chronic drainage.
Higher fistulas may be treated by an 
endorectal advancement flap (see below).
High rectovaginal fistulas result from operative or 
radiation injury.
Complicated diverticulitis may cause a colo-
vaginal fistula.
Diagnosis.
Most patients experience some degree of 
fecal incontinence.
Contamination may result in vaginitis.
Occasionally, a barium enema or vaginogram may identify 
these fistulas.
Endorectal ultrasound may also be useful.
Treatment.
Low and mid-rectovaginal fistulas are usually best treated 
with an endorectal advancement flap.
29-41).
Fecal diversion is rarely 
required.
Fistulas caused by 
malignancy should be treated with resection of the tumor.
Perianal Dermatitis
Pruritus Ani.
Pruritus ani (severe perianal itching) is a com-
mon problem with a multitude of etiologies.
Perianal infection 
may also present with pruritus ani.
pallidum [syphilis]), 
or viruses (HPV [condyloma acuminata]).
Antibiotic use may 
also cause itching, usually by precipitating fungal infection.
Noninfectious dermatologic causes include seborrhea, psoriasis, 
and contact dermatitis.
Occa-
sionally, systemic diseases such as jaundice and diabetes may 
present with pruritus ani.
Biopsy and/or culture may be required to rule out 
an infectious or dermatologic cause.
Skin barriers such as Calmoseptine can also provide 
relief.
Systemic antihistamines or tricyclic antidepressants have 
also been used with some success.
Nonpruritic Lesions.
Several perianal skin conditions may 
present with perianal skin changes.
Biopsy can usually distinguish 
these diagnoses.
Endorectal advancement flap for rectovaginal fistula.
(Reproduced with permission of Taylor & Francis, LLC from Gordon 
PH, Nivatvongs S, eds.
Principles and Practice of Surgery for the Colon, Rectum, and Anus.
2nd ed.
New York: Marcel Dekker, Inc.; 1999:412.
Proctitis is a common symptom of ano-
rectal bacterial infection.
N.
Chlamydia trachomatis infec-
tion may be asymptomatic or may produce similar symptoms.
T.
Condyloma lata 
are characteristic of secondary syphilis.
Inguinal lymphadenopathy and fluctuant, 
draining lymph nodes are characteristic.
Parasitic Infections.
Entamoeba histolytica is an increas-
ingly common sexually transmitted disease.
Amebas produce 
ulcerations in the gastrointestinal mucosa and can infect any 
part of the gut.
Symptoms include diarrhea, abdominal pain, 
and tenesmus.
Giardia lamblia is also common and produces 
diarrhea, abdominal pain, and malaise.
Viral Infections
Herpes Simplex Virus.
Herpes proctitis is extremely common.
Patients com-
plain of severe, intractable perianal pain and tenesmus.
Diagnosis is confirmed by viral culture of tissue or vesicular 
fluid.
Human Papillomavirus.
Condylomas occur in the 
perianal area or in the squamous epithelium of the anal canal.
Occasionally, the mucosa of the lower rectum may be affected.
There are approximately 30 serotypes of HPV.
Treatment of anal condyloma depends on the location and 
extent of disease.
Larger and/
or more numerous warts require excision and/or fulguration in 
the operating room.
Excised warts should be sent for pathologic 
examination to rule out dysplasia or malignancy.
Human Immunodeficiency Virus.
Once an 
acute episode has resolved, recurrence is common.
An acute abscess should be incised and drained as soon 
as the diagnosis is made.
A number of procedures have been proposed to treat a 
chronic pilonidal sinus.
Alternatively, a small lateral incision can be created and 
the pit excised.
This method is effective for most primary pilo-
nidal sinuses.
In general, extensive resection should be avoided.
Infected glands rupture and form subcutane-
ous sinus tracts.
Radical excision 
and skin grafting are almost never necessary.
Intractable rectal bleeding may require angio-
graphic embolization.
Iatrogenic Injury
Intraoperative Injury.
The key to managing these injuries is early 
recognition.
Injury from Barium Enema.
Colonoscopic Perforation.
Fortunately, this complication is rare and occurs 
in less than 1% of procedures.
Biopsy or fulguration can also cause 
perforation.
A large perforation recognized during the procedure requires 
surgical exploration.
It is also important to 
know the indication for and findings at the time of colonoscopy.
If the patient has an underlying neoplasm and is stable, defini-
tive resection is best.
Evidence of peritonitis or any deterioration in clinical condition 
mandates exploration.
Principles and Practice of Surgery for the Colon, Rectum, and 
Anus.
2nd ed.
New York: Marcel Dekker, Inc; 1999:1249.
Surgical exploration is indicated if any clinical deteriora-
tion occurs.
More severe incontinence may require surgical repair.
Isolated sphincter injuries that do not involve 
the rectum may be repaired primarily.
Sig-
nificant perineal tissue loss may require extensive débridement 
and a diverting colostomy.
Surgical Repairs.
The most common method of repair of the 
anal sphincter is a wrap-around sphincteroplasty (Fig.
The internal and 
external sphincters may be overlapped together or separately.
The approach is via the intersphincteric plane 
posteriorly.
It may be performed concomitantly with a perineal 
repair of rectal prolapse.
These elective pro-
cedures usually do not require a diverting colostomy.
Another alternative in patients who have 
failed other repairs is the artificial anal sphincter.
Gen-
eralized abdominal pain suggests intraperitoneal perforation.
Plain films of the abdomen are mandatory to detect 
free intra-abdominal air.
Objects impacted higher in the rectum may require 
regional or general anesthesia for removal.
Only rarely will a 
laparotomy be required to remove the object.
Proctoscopy and/or flexible sigmoidos-
copy should be performed.
A hematoma without evidence of 
perforation requires no surgical treatment.
Diarrhea, in particular, is extremely 
common.
Overlapping sphincteroplasty for incontinence from 
sphincter disruption.
A.
The external sphincter muscle with scar at 
site of injury is mobilized.
B.
The muscle edges are aligned in an 
overlapping fashion.
C.
Mattress sutures are used to approximate 
the muscle.
D.
The completed operation.
C.
Patients may be asymptomatic or may develop 
bleeding or obstruction.
Gastrointestinal lymphoma (usually 
non-Hodgkin’s lymphoma) is also common.
Perianal disease is extremely common in patients with 
HIV infection.
In these patients, infection and medication 
are the most common causes of diarrhea.
Immunosuppressant 
medications, in particular, may cause diarrhea.
CMV infection 
is common and may be severe.
C difficile colitis also occurs 
commonly.
CT scan of the abdomen often shows a dilated cecum 
with pericolic stranding.
However, a normal-appearing CT scan 
does not exclude the diagnosis.
An increase in 
pain or fever and/or clinical deterioration mandates an exam 
under anesthesia.
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The Appendix
Mike K.
Liang, Roland E.
Andersson,  
Bernard M.
Jaffe, and David H.
She developed abdom-
inal pain and died.
He operated on an 11-year-old 
boy with a scrotal hernia and a fecal fistula.
Within the hernia 
sac, Amyand found a perforated appendix surrounded by omen-
tum.
The appendix and omentum were amputated.
Only sporadic cases of right lower quadrant pain were 
treated with appendectomy.
In 1886, Reginald H.
In this situation, the appendix will remain 
in the left upper quadrant of the abdomen.
Lymphoid aggregates occur in the 
submucosal layer and may extend into the muscularis mucosa.
Lymphatic channels are prominent in regions underlying these 
lymphoid aggregates.
The mucosa is like that of the large intes-
tine, except for the density of the lymphoid follicles.
4 Computed tomography scan has improved diagnostic accu-
racy in individual studies.
However, in population-wide 
studies, the rate of misdiagnosis of appendicitis remains con-
stant.
5 The role of nonoperative treatment for uncomplicated appen-
dicitis remains controversial.
Currently, appendectomy 
remains the standard of care.
Laparoscopic appendectomy 
has a slight benefit over open appendectomy.
The role of interval appendectomy in these 
cases remains controversial.
Natural orifice transluminal endoscopic surgery remains 
an investigational procedure.
Postoperative anti-
biotics are unnecessary following uncomplicated appen-
dicitis.
For complicated appendicitis, a treatment 
duration of 4 to 7 days is recommended.
12  The prevalence of appendiceal malignancy remains at or 
below 1% of appendectomies.
Carcinoid and mucinous 
adenocarcinoma remain the most frequent histologic 
diagnosis.
The appendix may function as a reservoir to recolonize 
the colon with healthy bacteria.
The frequency of obstruction rises with the 
severity of the inflammatory process.
This causes reflex nausea 
and vomiting, and the visceral pain increases.
As pressure in 
the organ increases, venous pressure is exceeded.
This produces the characteristic shift in 
pain to the right lower quadrant.
Microbiology
Appendicitis may occur in clusters, suggesting an infectious 
genesis.
But, when combined, they yield high discriminatory power.
68%; specificity, 36%).
Diarrhea may occur in 
association with perforation, especially in children.
Signs.
Early in presentation, vital signs may be minimally 
altered.
The body temperature and pulse rate may be normal 
or slightly elevated.
On abdominal palpation, there 
is tenderness with a maximum at or near McBurney’s point  
(Fig.
Rebound 
tenderness can be very sharp and uncomfortable for the patient.
Laboratory Findings.
Laboratory examinations are therefore an impor-
tant part of the diagnosis.
Counts above this level raise the possibility 
of a perforated appendix with or without an abscess.
Therefore, all inflammatory variables 
should be viewed together.
McBurney’s point (1 = anterior superior iliac spine; 
2 = umbilicus; x = McBurney’s point).
all normal.
The inflammatory response in acute appendicitis 
is a dynamic process.
Early in the process, the inflammatory 
response can be weak.
CRP elevation, in particular, can have up 
to a 12-hour delay.
A decreasing inflammatory response may 
indicate spontaneous resolution.
Bacteri-
uria is generally not seen.
Clinical Scoring Systems.
The Alvarado score is the most widespread scoring system.
Imaging Studies.
A chest radiograph is helpful to rule out referred pain 
from a right lower lobe pneumonic process.
Outpatient follow-up.
5–8: Indeterminate group.
Active observation or diagnostic laparoscopy.
9–12: High probability.
Surgical exploration.
Ultrasonography has its limitations, particularly the operator-
dependent nature of results.
In the adult population, ultrasonog-
raphy remains limited in its use.
Fecaliths can be often visualized; 
however, their presence is not pathognomonic of appendicitis.
The additional use of rectal contrast does not improve the results 
of CT scanning.
Despite the potential usefulness of CT, there are signifi-
cant disadvantages.
The role of CT scanning in patients who present with right 
lower quadrant pain is unclear.
One rationale is universal CT 
scanning.
9.3%).50,51 The negative appendectomy rate is highest in women 
of reproductive age.
The accuracy of preoperative diagnosis should be higher 
than 85%.
Acute mesenteric adenitis is the disease 
most often confused with acute appendicitis in children.
Almost 
invariably, an upper respiratory tract infection is present or has 
recently subsided.
The pain usually is diffuse, and tenderness 
is not as sharply localized as in appendicitis.
Voluntary guard-
ing is sometimes present, but true rigidity is rare.
Generalized 
lymphadenopathy may be noted.
Elderly Patient.
These entities should be considered, particularly in older 
patients.
Female Patient.
As a 
result, the rate of misdiagnosis remains higher among female 
patients.
of studies 22 21 57 25 6
No.
1248
SPECIFIC CONSIDERATIONS
UNIT II
PART II
inflammatory disease.
Pain and tenderness are usually lower, 
and motion of the cervix is exquisitely painful.
Intracellular dip-
lococci may be demonstrable on smear of the purulent vaginal 
discharge.
Pain and tenderness may be rather diffuse, and leukocytosis and 
fever minimal or absent.
Serous cysts of the ovary are common and generally remain 
asymptomatic.
Patients develop right lower quadrant pain, tenderness, rebound, 
fever, and leukocytosis.
Both transvaginal ultrasonography and 
CT scanning can be diagnostic.
Torsion requires emergent operative treatment.
Blastocysts may implant in the fallopian tube (usually the 
ampullary portion) and in the ovary.
Rupture of right tubal or 
ovarian pregnancies can mimic appendicitis.
Unfortunately, patients 
do not always realize they are pregnant.
The development of 
right lower quadrant or pelvic pain may be the first symptom.
The diagnosis of ruptured ectopic pregnancy should be rela-
tively easy.
The presence of blood and particularly decidual tissue is 
pathognomonic.
The treatment of ruptured ectopic pregnancy is 
emergency surgery.
Immunosuppressed Patient.
Follow-up was not longer than 1 year in any study.
Certain 
subgroups with uncomplicated appendicitis may do well with 
nonoperative therapy.
bStandard deviation.
cStandard error of the mean.
eStudy did not report the meaning of these values.
gThese patients declined to be included in the study and opted for surgical management.
Once diagnosed, a patient was emergently 
taken to the operating room for surgical treatment.
Complicated Appendicitis.
The proportion of perforation increases 
with increasing duration of symptoms.
There is, however, 
no association of in-hospital delay with perforation.
This suggests 
that most perforations occur early, before the patient arrives to 
hospital.
In many cases, 
rupture is contained and patients display localized peritonitis.
In 2% to 6% of cases, a palpable mass is detected on physical 
examination.
CT scan may 
be beneficial in establishing a diagnosis and guiding therapy.
Two meta-analyses have been performed.
This sub-
group had an overall complication rate of 13.5%.
The recurrence 
rate was 7.4%, which does not necessitate interval appendectomy.
St.
Peter 
and colleagues72 demonstrated that 20% of patients failed con-
servative treatment.
Early surgical intervention had equivalent 
results to interval appendectomy.
30%, P = .003), intra-abdominal abscesses (37% vs.
19%, 
P = .02), small bowel obstruction (10.4% vs.
0%, P = .01), and 
readmissions (31% vs.
8%, P = .06).
The incidence of complicated appen-
dicitis following recurrence was low (2.4%).
Malignancy was 
noted in 1.3% of cases where pathology was reported.
Most patients 
underwent interval appendectomy 2 to 4 months after their acute 
presentation.
The entire abdomen should 
be prepped and draped in case a larger incision is needed.
If the appendix is not easily identified, the 
cecum should be located.
The appendix will often have attachments to the lateral 
wall or pelvis that can be dissected free.
The appendiceal stump can be man-
aged by simple ligation or by ligation and inversion.
Inversion of the stump 
with plication of the cecum has also been described.
If appendicitis is not found, a methodical search must be 
made for an alternative diagnosis.
The cecum and mesentery 
should be inspected.
The small bowel should be evaluated in a 
retrograde fashion beginning at the ileocecal valve.
Concerns 
for Crohn’s disease or Meckel’s diverticulum should be of 
priority.
In female patients, the reproductive organs should be 
closely inspected.
If purulent or bilious fluid is encountered, it 
is imperative that the source be identified.
This may be due to 
the small incision already commonly used with open appen-
dectomy.
Laparoscopic appendectomy is performed under general 
anesthesia.
An oro- or nasogastric tube and urinary catheter are 
placed.
Both 
surgeon and assistant should be standing on the patient’s left 
facing the appendix.
The laparoscopic screens should be posi-
tioned on the patient’s right or at the foot of the bed.
Standard 
laparoscopic appendectomy typically uses three ports.
The patient should be placed in Trendelenburg and 
tilted to the left (Fig.
30-2).
Typically the base of the appendix is stapled, 
followed by stapling of the mesentery.
The appendix is 
removed through the infraumbilical trocar in a retrieval bag.
There is less pain, shorter length of stay, and 
Figure 30-2.
Operating room setup.
Patients 
tend to have improved satisfaction scores with laparoscopic 
appendectomy.
Instead of two or three incisions, a single inci-
sion is made, typically periumbilical.
Under general anesthesia, the patient is secured in a supine posi-
tion with the left arm tucked.
The surgeon and assistant stand on 
the left side facing the appendix and the screen.
The appendix may be placed in a 
retrieval bag or removed through the single incision.
In this meta-analysis, there was no difference in operative 
time (57 ± 10 vs.
55 ± 13 minutes), complications (11% vs.
8.3%), incisional surgical site infections (5.6% vs.
4.9%), intra-
abdominal abscesses (1.8% vs.
1.4%), or length of stay (3 ± 2 
vs.
4 ± 1 days).
There was no difference in overall 
cost.
Late outcomes and patient quality-
of-life outcomes remain to be investigated.
A and B.
Appendiceal critical view.
of studies 25 16 44 12 34 8 11 28 16
No.
1256
SPECIFIC CONSIDERATIONS
UNIT II
PART II
and 11 transgastric).
The main concern with NOTES has been complications 
with closure of the enterotomy.
Antibiotic coverage is lim-
ited to 24 to 48 hours in cases of nonperforated appendicitis.
A  history 
of periumbilical pain migrating to the right lower quadrant  
is reported infrequently.
The use of laparoscopy in the elderly has significantly 
increased in recent years.
The incidence is approxi-
mately 1 in 766 births.
The physiologic leukocytosis of pregnancy has been defined as 
high as 16,000 cells/mm3.
Another option is magnetic resonance 
imaging, which has no known deleterious effects on the fetus.
It is important to note that a negative appendectomy 
is not a benign procedure.
Maternal mortality after appendectomy is extremely rare 
(0.03%).
These patients are at increased risk for surgical site 
infections.
Patients with cellulitis can be started on antibiotics.
Most 
commonly, percutaneous drainage with CT or ultrasound guid-
ance is effective.
A review of literature 
has revealed only 60 reports of this phenomenon.
Likely, incom-
plete appendectomy is underreported, and the true prevalence is 
much higher.
There was no difference 
in initial surgery between laparoscopic and open procedures.
However, there were more complicated appendectomies on 
initial surgery.
The key to avoiding stump appendicitis is prevention.
Prior appendectomy should not be an absolute crite-
rion in ruling out acute appendicitis.
On an annual basis, $20,000,000 had to be spent to 
save the $6,000,000 cost of appendicitis.
Appendiceal carcinoid and appendiceal adenomas are the 
most common lesions identified.
There is no clear age 
relationship associated with the identification of these 
masses.
The mean age in this case 
series was 69 years (range, 42 to 89 years).
Treatment for tumors ≤1 cm is appendectomy.
Recently, a more 
aggressive approach to ruptured appendiceal neoplasms has 
been advocated.
NR = not reported.
1259
T
HE
 A
PPENDI
x
CHAPTER 30
implants on peritoneal surfaces and omentum.
Pseudomyxoma 
is two to three times more common in females than in males.
Pseudomyxoma is invariably caused 
by neoplastic mucus-secreting cells within the peritoneum.
Patients with pseudomyxoma usually 
present with abdominal pain, distention, or a mass.
Primary 
pseudomyxoma usually does not cause abdominal organ dys-
function.
The use of imaging before surgery is advantageous to plan 
surgery.
CT scanning is the preferred imaging modality.
Peritoneal surfaces of the bowel are usu-
ally free of tumor.
Thorough surgical debulking is the main-
stay of treatment.
All gross disease and the omentum should be 
removed.
If not done previously, appendectomy is routinely per-
formed.
Hysterectomy with bilateral salpingo-oophorectomy is 
performed in women.
In addition, morbidity (38%) and mor-
tality (6%) are high.
Recur-
rences are usually treated by additional surgery.
The management of appendiceal lymphoma confined 
to the appendix is appendectomy.
A postoperative staging workup is indicated before 
 initiating adjuvant therapy.
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SPECIFIC CONSIDERATIONS
UNIT II
PART II
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Are we missing diagnostic oppor-
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Pickhardt PJ, Levy AD, Rohrmann CA Jr, Abbondanzo SL, 
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Muller G, Dargent JL, Duwel V, et al.
Leukaemia and lym-
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Liver
Elaine Y.
Cheng, Ali Zarrinpar, David A.
Geller, 
John A.
Goss, and Ronald W.
2000 B.C.) con-
sidered the liver to be the seat of the soul.
2 The liver is the largest gland in the body and performs a 
diverse spectrum of functions.
The only defini-
tive treatment is orthotopic liver transplantation.
9 Surgical resection is the treatment of choice for hilar 
cholangiocarcinoma.
LIVER ANATOMY
The liver is the largest organ in the body, weighing approxi-
mately 1500 g.
It is 
reddish brown and is surrounded by a fibrous sheath known as 
 Glisson’s capsule.
The liver is held in place by several ligaments 
(Fig.
31-1).
The left and right triangular ligaments 
secure the two sides of the liver to the diaphragm.
Extending 
from the triangular ligaments anteriorly on the liver are the 
coronary ligaments.
31-2).
31-2).
31-3).
Segment IV can be subdivided into segment 
IVA and segment IVB.
Hepatic ligaments suspending the 
liver to the diaphragm and anterior abdominal 
wall.
In situ liver hilar anatomy with hepatoduodenal and 
gastrohepatic ligaments.
Foramen of Winslow is depicted.
Liver in situ
Foramen of
winslow
Gastrohepatic
ligament
Open hepato-
duodenal ligament
Figure 31-3.
Couinaud’s liver segments (I through VIII) num-
bered in a clockwise manner.
IVC = inferior vena cava.
Segment IVB is caudad and adjacent 
to the gallbladder fossa.
Many anatomy textbooks also refer to seg-
ment IV as the quadrate lobe.
Quadrate lobe is an outdated term, 
and the preferred term is segment IV or left medial segment.
Most 
surgeons still refer to segment I as the caudate lobe, rather than 
segment I.
The main scissura 
contains the middle hepatic vein and separates the right and left 
livers.
a.
= artery; LHA =  
left hepatic artery; RHA = right hepatic artery.
25% of the blood supply, and the portal vein approximately 
75%.
31-4).
The hepatic artery proper divides 
into the right and left hepatic arteries.
The most common hepatic arterial variants are shown 
(Fig.
31-5).
Common hepatic 
artery anatomic variants.
SMA = 
superior mesenteric artery.
31-5).
31-6).
31-7).
The left portal vein then 
Figure 31-6.
Portal vein anatomy.
The portal vein is formed by 
the confluence of the splenic and superior mesenteric veins.
The 
inferior mesenteric vein drains into the splenic vein.
The coronary 
(left gastric) vein drains into the portal vein in the vicinity of the 
confluence.
v.
= vein.
Coronary v.
Portal v.
Superior mesenteric v.
Inferior
mesenteric v.
Splenic v.
Figure 31-7.
Anatomy of the left portal vein (LPV).
Cadaver cast 
shows the transverse and umbilical portions of the LPV.
The por-
tal vein pressure in an individual with normal physiology is low 
at 3 to 5 mmHg.
31-8).
The caudate lobe is unique 
because its venous drainage feeds directly into the IVC.
This can be a source 
of torrential bleeding if control of it is lost during right hepatec-
tomy.
In general, the hepatic 
ducts follow the arterial branching pattern inside the liver.
Anterior 
segment
structures
Gall bladder
Portal v.
Hepatic a.
Confluence of the three hepatic veins (HVs) and the inferior vena cava (IVC).
Note that the middle and left HVs drain into 
a common trunk before entering the IVC.
a.
= artery; v.
= vein.
(Adapted with permission from Cameron JL, ed.
Atlas of Surgery.
Vol.
I, 
Gallbladder and Biliary Tract, the Liver, Portasystemic Shunts, the Pancreas.
31-9).
The cystic duct itself also has 
a variable pattern of drainage into the common bile duct.
The gallbladder sits adherent to hepatic 
segments IVB (left lobe) and V (right lobe).
The denervated liver after 
hepatic transplantation seems to function with normal capacity.
These include processes such as 
storage, metabolism, production, and secretion.
Main variations of hepatic duct confluence.
CHD = common hepatic duct; lh = left hepatic; R = right; ra = right anterior; rp = right posterior.
(Reproduced with permission from Blumgart LH, Fong Y, eds.
Surgery of the Liver and Biliary Tract.
3rd ed, Vol.
I.
London: Elsevier  Science; 
2000.
Bilirubin is bound to albumin in the circulation and sent to the 
liver.
This glucuro-
nide is then excreted into the bile canaliculi.
A small amount 
dissolves in the blood and is then excreted in the urine.
Bile is produced by hepatocytes and secreted through the 
biliary system.
Upon entry of food into the duodenum, bile is released 
from the gallbladder to aid in digestion.
The human liver can 
produce about 1 L of bile daily.
Bile salts are sodium and potassium salts of bile 
acids conjugated to amino acids.
The bile acids are deriva-
tives of cholesterol synthesized in hepatocytes.
Bacteria in 
the intestine can remove glycine and taurine from bile salts.
Bile salts secreted into the intestine are efficiently reab-
sorbed and reused.
Those lost in the stool 
are replaced by synthesis in the liver.
In most cases, a drug is rela-
tively lipophilic to ensure good absorption.
There are 
two main reactions important for drug metabolism.
Phase I reac-
tions include oxidation, reduction, and hydrolysis of molecules.
These result in metabolites that are more hydrophilic than the  
original chemicals.
These subgroups 
include glucuronate, acetate, glutathione, glycine, sulfate, and 
methyl groups.
These drug reactions occur mainly in the smooth 
endoplasmic reticulum of hepatocytes.
Many factors can affect drug metabolism in the liver.
An example is acetaminophen when 
taken in larger doses.
ALT is predominately found in the liver and thus is more 
specific for liver disease.
Hepatocellular injury is the trigger for 
release of these enzymes into the circulation.
In alcoholic liver disease, an AST:ALT ratio of >2:1 is 
common.
Moderate increases in the levels of 
these enzymes are common in acute viral hepatitis.
The 
liver produces approximately 10 g of albumin per day.
PT measures the rate of conversion of prothrombin to throm-
bin.
To standardize the reporting of PT and avoid interlabora-
tory variability, the INR was developed.
The INR is the ratio 
of the patient’s PT to the mean control PT.
Bilirubin is a 
breakdown product of hemoglobin metabolism.
Unconjugated 
bilirubin is insoluble and thus is transported to the liver bound 
to albumin.
In the liver, it is conjugated to allow excretion  
in bile.
Normally, 
>90% of serum bilirubin is unconjugated.
AP is an enzyme with a wide tissue distribution but is 
found primarily in the liver and bones.
In the liver, it is expressed 
by the bile duct epithelium.
GGT is another enzyme found in hepatocytes and released 
from the bile duct epithelium.
Elevation of GGT is an early 
marker and also a sensitive test for hepatobiliary disease.
For example, a raised GGT level with 
increased AP level supports a liver source.
Jaundice can be caused by a wide range 
of benign and malignant disorders.
Dysfunction in any of these phases can lead to jaundice.10
Prehepatic.
Insufficient conju-
gation is often seen in processes that result in excessive heme 
metabolism.
Causes of hemolysis include inherited and acquired hemolytic 
anemias.
In contrast, direct Coombs’ 
test results are negative in nonimmune hemolytic anemias.
Intrahepatic.
It is a benign condition that affects 
approximately 4% to 7% of the population.
These episodes are self-limited and usually do not require fur-
ther treatment.
Another inherited disorder of bilirubin conjuga-
tion is Crigler-Najjar syndrome.
Posthepatic.
There is a 
wide spectrum of pathologies that may present with obstructive 
jaundice.
Extrinsic compression of the 
biliary tree is commonly due to pancreatic disorders.
Ultrasound tech-
nology is based on the pulse-echo principle.
This real-
time gray scale (B-mode) imaging is augmented by Doppler 
flow imaging.
It is excellent for diagnosing biliary pathology and focal liver 
lesions.
Moreover, obesity and overlying bowel gas also can interfere 
with image quality.
In addition, biopsy of lesions and 
ablation of tumors can be guided by intraoperative ultrasound.
A CT scan with a   
Figure 31-10.
Upper panel 
shows the portal vein bifurcation with echogenic Glissonian sheath.
An accessory LHV is present in 
this patient.
Lower panel is a color Doppler image showing flow.
The 
liver is unique in that it has a dual blood supply.
However, many 
liver tumors receive the majority of their blood supply from the 
hepatic artery.
31-11).
Computed tomographic (CT) images of hepatic 
veins and Couinaud’s liver segments.
LHV = left hepatic vein; 
MHV = middle hepatic vein; RHV = right hepatic vein.
CT cholangiography has emerged as a new imaging modal-
ity for biliary disease.
In this technique, a vibration device is used 
to induce a shear wave in the liver.
One of the most common clinical 
indications for MRCP is biliary obstruction.
Fluorodeoxyglucose (FDG) is 
the most common metabolic molecule used in PET imaging.
For this reason, dual-tracer PET has been introduced to improve 
sensitivity in detecting all HCC.
It 
was initially described as a specific disease entity in the 1950s.
It also has been referred to as fulminant hepatic failure.
ALF is a 
rare disorder affecting approximately 2000 patients annually in 
the United States.
Even with current medical care, ALF 
can progress rapidly to hepatic coma and death.
The U.S.
Hepatic coma grade at presentation 
was approximately equally distributed across grades I to IV.
In addition, 
44% of the patients acquired a culture-proven infection.
The possibility of previous liver disease 
needs to be explored.
4
safest to obtain the tissue via a transjugular approach.
Patients 
with ALF should be admitted to the hospital and monitored fre-
quently.
Most instances of drug-induced hepatotoxicity occur in 
the first 6 months after drug initiation.
Serum phosphorus levels need to 
be monitored.
Sedation should be avoided, and the head of the 
bed should be elevated at least 30°.
Neurologic examinations 
1277
L
IVER
CHAPTER 31
should be  performed frequently.
Several systems have 
been tested without definitive evidence of efficacy.
Conversely, a single disease process can demonstrate several 
morphologic patterns.
Liver biopsy will reveal the typical findings of alcoholic 
Figure 31-13.
Histology of cirrhotic liver with regenerating mac-
ronodules.
Upper panel: Grossly cirrhotic liver.
Antimitochon-
drial antibodies will test positive in the vast majority of cases.
Hereditary hemochromatosis is the most common meta-
bolic disorder causing cirrhosis.
On physical examination, a number of findings have 
been described in patients with cirrhosis.
Ascites and pleural effu-
sion can be seen with fluid accumulation.
Jaun-
dice usually does not appear until the bilirubin rises above  
2 to 3 mg/dL.
Asterixis can be detected in patients with hepatic 
encephalopathy.
Although fat stores and muscle mass are reduced, rest-
ing energy expenditure is increased.
Spontaneous bacterial peritonitis also is seen 
in cases of cirrhosis with ascites.
The cirrhotic patient usually has a mild 
normocytic normochromic anemia.
The white blood cell and 
platelet counts are reduced, and the bone marrow is macro-
normoblastic.
Urobilinogen is present and urinary sodium excretion is dimin-
ished in the presence of ascites.
The serum levels of bilirubin, 
transaminases, and alkaline phosphatase may all be elevated.
However, normal liver function test results do not eliminate the 
possibility of cirrhosis.
Liver 
biopsy can be performed via a percutaneous, transjugular, or 
laparoscopic approach.
However, no currently available 
marker is sufficiently accurate for clinical use.
A number of laboratory tests have been used to assess 
hepatic reserve in patients with cirrhosis.
In the 
average adult, 1000 to 1500 mL/min of portal venous blood is 
supplied to the liver.
However, this amount can be significantly 
increased in the cirrhotic patient.
31-14).
The simplest initial investigation is abdominal ultrasonography.
A large portal vein suggests portal hypertension but is not diag-
nostic.
Doppler 
ultrasound also is useful in evaluating blood flow through sur-
gical shunts and TIPS.
The most accurate method of determining portal hyperten-
sion is hepatic venography.
Clinically significant portal hypertension is 
evident when HVPG exceeds 10 mmHg.
Intra-abdominal venous flow pathways leading to 
engorged veins (varices) from portal hypertension.
a 1
a
F
G
E
1
A
B
b
D
2
4
c
d e 
3 C
5
causing leukopenia, thrombocytopenia, and anemia.
One third of all patients with varices will 
experience variceal bleeding.
Each episode of bleeding is asso-
ciated with a 20% to 30% risk of mortality.
The needle track is dilated until a portal pressure 
gradient of ≤12 mmHg is achieved.
Patient survival 
is determined by hepatic reserve.
The Eck fistula also makes subsequent hepatic trans-
plantation much more technically difficult.
The surgical shunt currently used most often is the distal spl-
enorenal or Warren shunt (Fig.
31-15).
This shunt is technically 
6
1283
L
IVER
CHAPTER 31
the most difficult to perform.
Surgical shunts for portal hypertension.
Types of portacaval anastomoses.
A.
Normal anatomy.
B.
Side-to-side portacaval shunt.
C.
End-to-side portacaval 
shunt.
D.
Mesocaval shunt.
E.
Distal splenorenal (Warren) 
shunt.
(Reproduced with permission from Doherty GM, 
Way LW, eds.
Current Surgical Diagnosis and Treatment.
12th ed.
New York: McGraw-Hill; 2006).
Copyright © The 
McGraw-Hill Companies, Inc.
of the hemodynamic and humoral changes associated with 
 cirrhosis.
BCS is defined as primary when the obstructive 
process involves an endoluminal venous thrombosis.
All 
known inherited thrombophilias also have been implicated in the 
development of BCS.
The obstruction 
results in hepatomegaly, liver congestion, and right upper quad-
rant pain.
This caudate lobe hypertrophy, in 
turn, can result in further obstruction of the IVC.
Thrombolytic therapy alone 
may be attempted for acute thrombosis.
Due to the high level of retic-
uloendothelial cells in the liver, nonviral infections are unusual.
Anaerobic organisms such as Bacteroides fragilis also are seen 
frequently.
There appears 
Figure 31-16.
Computed tomographic scan of pyogenic liver 
abscesses.
Multiple hepatic abscesses are seen in a patient after an 
episode of diverticulitis.
Note the loculated large central abscess as 
well as the left lateral segment abscess.
Patients commonly present with right upper quadrant pain 
and fever.
Jaundice occurs in up to one third of affected patients.
Significant abnor-
malities in the results of the remaining liver function tests are 
unusual.
Blood cultures will only reveal the causative organism 
in approximately 50% of cases.
31-16).
Ana-
tomic surgical resection can be performed in patients with 
recalcitrant abscesses.
Amebi-
asis is most common in subtropical climates, especially in areas 
with poor sanitation.
E.
They con-
tain a proteolytic enzyme that also destroys liver parenchyma.
The abscesses formed are variable in size and can be single or 
multiple.
This material has been 
likened to anchovy paste or chocolate sauce.
Amebic abscesses 
are the most common type of liver abscesses worldwide.
The most common biochemical abnormality is a 
mildly elevated AP level.
Most patients have a positive fluorescent antibody test 
for E.
histolytica, and test results can remain positive for some 
time after a clinical cure.
The central cavity may have septations as well as fluid 
levels.
CT scanning is also useful in the detection of extrahe-
patic involvement.
Each worm sheds approximately 
500 ova into the bowel.
The ova have chitinous envelopes that are dissolved by gastric 
juice.
Hydatid disease is most common in sheep-raising areas, 
where dogs have access to infected offal.
These include South 
Australia, New Zealand, Africa, Greece, Spain, and the Middle 
East.
The 
uncomplicated cyst may be silent and found only incidentally 
or at autopsy.
Eosinophilia is 
seen in approximately 30% of infected patients.
The appearance of the cysts on 
images depends on the stage of cyst development.
Typically, 
hydatid cysts are well-defined hypodense lesions with a dis-
tinct wall.
Ring-like calcifications of the pericysts are present 
in 20% to 30% of cases.
Medical treatment with albendazole relies on 
drug diffusion through the cyst membrane.
If complete cystectomy is not possible, then formal 
anatomic liver resection can be undertaken.
Infection 
of the lung also is common (alveolar echinococcosis).
Ascariasis
Ascaris infection is particularly common in the Far East, India, 
and South Africa.
The Ascaris may serve as 
a nidus for the development of intrahepatic gallstones.
Occasionally, worms can be seen moving into and 
out of the biliary tree from the duodenum.
Surgical intervention may become necessary if the Ascaris can-
not be removed via ERCP.
Schistosomiasis
Schistosomiasis affects >200 million people in 74 countries.
They then re-enter human skin during contact with infected 
water.
Those entering the intrahepatic portal system grow rapidly, 
resulting in a granulomatous reaction.
The degree of consequent 
portal fibrosis is related to the adult worm load.
Active infection is detected by stool examination.
A negative serologic test 
result excludes the presence of schistosomal infection.
Serum 
levels of transaminases are usually normal, but the AP level may 
be mildly elevated.
A decreased serum albumin level is usually 
the result of frequent GI bleeds and malnutrition.
GI bleeding usually is controlled by endoscopic variceal ligation.
Viral Hepatitis
The role of the surgeon in the management of viral hepatitis is 
somewhat limited.
The most com-
mon physical findings are jaundice and hepatomegaly.
Because 
the disease is self-limited, the treatment is usually supportive.
Hepatitis B and C, on the other hand, can both lead to 
chronic liver disease, cirrhosis, and HCC.
The prevalence of 
chronic hepatitis B infection in the U.S.
On the other hand, 
the nucleoside analogs are generally well-tolerated by patients.
Untreated, most of these patients will eventually 
develop chronic infection.
31-17).
Angiogram
Occult primary eval.
Algorithm for diagnostic workup of 
an incidental liver lesion.
In these patients, laparoscopic liver biopsy can 
be considered.
Hepatic cysts 
are usually identified incidentally and can occur at any time 
throughout life.
The most common benign lesion found in the 
liver is the congenital or simple cyst.
The exact prevalence of 
simple hepatic cysts in the U.S.
The cyst 
epithelium is cuboidal and secretes a clear nonbilious serous 
fluid.
With the exception of large cysts, simple cysts are usually 
asymptomatic.
Large simple cysts may cause abdominal pain, 
epigastric fullness, and early satiety.
Occasionally the affected 
patient presents with an abdominal mass.
Asymptomatic simple cysts are best managed conser-
vatively.
This approach is approximately 90% effective 
in controlling symptoms and ablating the cyst cavity.
The 
laparoscopic approach is being used more frequently and is 90% 
effective.
Although these lesions are usually benign, they can 
undergo malignant transformation.
Patients with biliary cystad-
enomas commonly present with abdominal pain.
An abdominal 
mass occasionally can be identified on physical examination.
Surgical 
resection is the preferred mode of treatment.
Patients with a small number of cysts or with small cysts (<2 cm) 
usually remain asymptomatic.
Disease 
progression often results in renal failure and the need for hemo-
dialysis.
The principal aim of treatment for PCLD is to ameliorate 
symptoms by decreasing liver volume.
Medical therapy options 
for PCLD remain experimental at this time.
Common agents used for sclerosis 
include ethanol, minocycline, and tetracycline.
OLT represents the only definitive therapy for patients 
with symptomatic PCLD.
Most patients present by the age of 30 years, 
and males and females are affected equally.
Rarely, patients 
can present later in life with complications secondary to portal 
hypertension.
The 
diagnosis of Caroli’s disease is made based on imaging stud-
ies.
If the 
disease is limited to a single lobe of the liver, hepatic resec-
tion can be beneficial.
Many of these lesions have typical features in 
imaging studies that help confirm the diagnosis.
They are predomi-
nantly seen in women and occur in 2% to 20% of the popula-
tion.
They can range from small (≤1 cm) to giant cavernous 
hemangiomas (10 to 25 cm).
Most hemangiomas are discov-
ered incidentally with little clinical consequence.
The majority of hemangiomas can be diagnosed by liver 
imaging studies.
31-18).
Adenoma
Hepatic adenomas are benign solid neoplasms of the liver.
On gross examination, they appear 
soft and encapsulated and are tan to light brown.
31-18).
Computed tomographic scans showing classic appearance of benign liver lesions.
Adenoma is hypovascular (lower left 
panel).
Hemangioma shows asymmetrical peripheral enhancement (lower right panel).
Hepatic adenomas carry a significant risk of spontaneous 
rupture with intraperitoneal bleeding.
Hepatic adenomas also have a risk of malignant transformation to 
a well-differentiated HCC.
31-18).
After gadolinium administration, lesions 
are hyperintense but become isointense on delayed images.
The fibrous septa extending from the central scar are also more 
readily seen with MRI.
Oral contraceptive or estrogen use 
should be stopped when either FNH or adenoma is diagnosed.
They 
are firm, smooth, and whitish yellow in appearance.
Hence, the most common tumor seen 
in the liver is metastatic colorectal cancer.
This compares with 
approximately 18,000 new cases of HCC diagnosed annually in 
the United States.
HCCs are typically hypervascular with 
blood supplied predominantly from the hepatic artery.
Thus, 
the lesion often appears hypervascular during the arterial phase 
of CT studies (Fig.
MRI imaging also is effective in character-
izing HCC.
HCC is variable on T1-weighted images and usu-
ally hyperintense on T2-weighted images.
The treatment of HCC is complex and is best managed 
by a multidisciplinary liver transplant team.
A complete algo-
rithm for the evaluation and management of HCC is shown  
(Fig.
31-20).
For patients without cirrhosis who develop 
HCC, resection is the treatment of choice.
Extrahepatic bile duct cancer can be located dis-
tally or proximally.
When proximal, it is referred to as a hilar 
cholangiocarcinoma (Klatskin’s tumor).
Therefore, a search for a primary site should 
Figure 31-19.
CT 
scans reveal a large (upper panel) and small (middle panel) hyper-
vascular HCC.
A hypovascular left lobe peripheral cholangiocarci-
noma (CholangioCA) is also shown (lower panel).
This led transplant centers to consider 
OLT for patients with hilar cholangiocarcinoma.
Gallbladder Cancer
Gallbladder cancer is a rare aggressive tumor with a very poor 
prognosis.
Over 90% of patients have associated cholelithia-
sis.
In another study, a German registry of incidental 
gallbladder cancer identified 439 patients.
Algorithm for the management of hepatocellular carcinoma (HCC).
= vascular.
invasion
No metastasis
Not Tx candidate
Co-morbid factors
≥4 lesions
Gross vasc.
invasion
LN (+) or metastasis
LDLT ?
> 3 mos)
Perc/lap.
Major hepatectomy was performed in 91 patients (54%), 
and recurrence rate was 84% at 5 years.
The treatment plan is 
individualized and modified according to the response of the 
patient.
A partial solution has been the use of living 
donor grafts.
The resistance of the tissue to the rapidly alternating cur-
rent produced heat.
This discovery contributed to the development 
of the surgical application of electrocautery.
In 1908, Beer used 
RF coagulation to destroy urinary bladder tumors.
Cushing and 
Bovie later applied RF ablation to intracranial tumors.
He found that RF caused local 
tissue destruction with uniform necrosis.
In 
a multicenter phase II U.S.
The average tumor size was 3.6 cm (range, 
0.5 to 9.0 cm).
At a mean follow-up of 19 months, 47% of the 
patients were alive with no evidence of disease.
There were no procedure-
related deaths.
It is most commonly used for treatment of 
unresectable HCC.
31-21).
IVC RHV
MHV
VII
VIII IVa
II
VI
V
IVb
III
Falciform lig.
Portal vein
IVC
LHV
I
Figure 31-21.
Hepatic anatomy.
Hepatic segments removed in 
the formal major hepatic resections are indicated.
2.
Open and explore the abdomen, and place a fixed table 
retractor (e.g., Thompson or Bookwalter).
3.
Examine the liver with bimanual palpation.
Perform liver 
ultrasound, and confirm the operation to be performed.
4.
Take down the round and falciform ligaments, and expose 
the anterior surface of the hepatic veins.
5.
6.
7.
Right Hepatic Lobectomy (Right Hepatectomy or 
 Hemihepatectomy)
 8.
9.
10.
Doubly ligate and divide a replaced or accessory RHA if 
present.
11.
Expose the portal vein, identifying its right and left 
branches.
Divide the RPV either with a vascular 
stapler or between vascular clamps.
12.
Pass a 
silastic tube of a Jackson-Pratt drain through this gap.
13.
14.
Hang the liver over the drain by pulling up as you divide 
through the liver parenchyma.
15.
16.
17.
Continue parenchymal division until the RHV is encoun-
tered.
18.
Divide the RHV between vascular clamps and suture ligate 
the RHV.
19.
20.
Ensure hemostasis of the transected liver edge with an 
argon beam coagulator and suture ligation.
21.
Inspect the transection surface for bile leaks.
These should 
be clipped or suture ligated.
Applying a dilute solution of 
hydrogen peroxide can facilitate the visualization of bile 
leaks.
22.
Inspect the IVC and right retroperitoneal space for 
 hemostasis.
23.
24.
Fix the proximal falciform ligament back to the diaphragm 
side with figure-of-eight sutures.
25.
31-22).
As for the transection plane, the key is to perform 
Figure 31-22.
The right hepatic vein is ligated and 
divided.
Middle hepatic vein branches inside the liver are divided.
Weaving in and out or bisecting the 
MHV can leading to torrential back bleeding.
9.
Doubly ligate and divide a replaced or accessory left hepatic 
artery (LHA) if present.
10.
11.
Divide any existing parenchymal bridge between segments 
III and IVB.
12.
13.
14.
15.
Expose the portal vein, identifying the right and left 
branches.
Divide the LPV either with a vascular stapler or 
between vascular clamps.
16.
Ligate and divide the ligamentum venosum caudally.
17.
Identify the long extrahepatic course of the left hepatic duct 
(LHD) behind the portal vein.
Ligate and divide the LHD 
at the umbilical fissure.
18.
19.
Do not force it or 
perforate the IVC or MHV.
20.
Pass the silastic tube of a Jackson-Pratt drain through this 
window.
21.
22.
Hang the liver over the drain by pulling up as you divide 
through the liver parenchyma.
23.
Do 
not bisect the MHV as it passes tangentially from the left 
to the right lobe.
24.
25.
Continue parenchymal division until the left/middle hepatic 
veins are encountered.
26.
Divide the LHV and MHV between vascular clamps and 
suture the ligate the LHV/MHV.
27.
28.
Inspect the transection surface for bile leaks.
These should 
be clipped or suture ligated.
Apply dilute solution of hydro-
gen peroxide to facilitate the visualization of bile leaks.
29.
Perform completion ultrasound to confirm RPV inflow and 
RHV outflow.
30.
Apply tissue sealant to the transected surface of the liver.
Place a Jackson-Pratt drain in the left subphrenic space and 
close the abdomen (Fig.
31-23).
Completed left hepatic lobectomy (left hepatectomy) 
resecting segments II, III, and IV.
1300
SPECIFIC CONSIDERATIONS
UNIT II
PART II
of devascularized liver remaining.
Left Lateral Segmentectomy (Left Lateral Sectionectomy)
 8.
9.
Doubly ligate and divide a replaced or accessory LHA if 
present.
10.
Clamp the round ligament and pull it anteriorly as a handle 
to expose the left hilum.
11.
Divide any existing parenchymal bridge between segments 
III and IVB.
12.
13.
This will 
facilitate encircling the segment III and II pedicles, which 
can be divided separately.
14.
15.
Divide the LHV as the parenchymal transection is  complete.
16.
Therefore, all 
efforts should be made to minimize blood loss during hepatic 
resection.
A 
larger remnant may also be needed when patients have received 
preoperative chemotherapy.
The specimen 
is then removed from the hand-port incision.
Results with laparoscopic liver resections have been 
excellent.
There were no differences in operative time or postoperative 
mortality.
There were no reported 
cases of port site recurrences or peritoneal dissemination.
Complication rates are com-
parable to those reported for open living-donor hepatectomies.
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UNIT II
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This page intentionally left blank 
Gallbladder and the Extrahepatic 
Biliary System
Thai H.
Pham and John G.
The fundus is the rounded, blind 
end that normally extends 1 to 2 cm beyond the liver’s margin.
32-1).
The epithelial lining of the gallbladder is supported by 
a lamina propria.
The muscle layer has circular longitudinal 
and oblique fibers, but without well-developed layers.
It is covered by the serosa except 
where the gallbladder is embedded in the liver.
Gallbladder lymphatics drain into nodes 
at the neck of the gallbladder.
chapter 
The preganglionic sympathetic level is T8 and T9.
2 In Western countries, the most common type of gallstones are 
cholesterol stones.
4 Common bile duct injuries, although uncommon, can be 
devastating to patients.
5 The main risk factor for gallbladder disease in Western 
countries is cholelithiasis.
a
b
c
d
e
f
g
h
i
j
k
l
m
n
Figure 32-1.
Anterior aspect of the biliary anatomy.
The two ducts join to form a common hepatic duct, 
close to their emergence from the liver.
The common hepatic 
duct is 1 to 4 cm in length and has a diameter of approximately 
4 mm.
It lies in front of the portal vein and to the right of the 
hepatic artery.
The length of the cystic duct is quite variable.
32-2).
They do not have any valvular function but may make cannula-
tion of the cystic duct difficult.
The common bile duct is about 7 to 11 cm in length and 
5 to 10 mm in diameter.
There, the pancreatic duct fre-
quently joins it.
In about 10%, they exit via separate openings into 
the duodenum.
32-3).
It controls the flow of bile, and in some 
cases pancreatic juice, into the duodenum.
A fibroareolar tissue containing scant smooth muscle cells sur-
rounds the mucosa.
A distinct muscle layer is not present in 
the human common bile duct.
These arteries anastomose freely within the duct 
walls.
Variations of the cystic duct anatomy.
A.
Low junction between the cystic duct and common hepatic duct.
B.
Cystic duct adher-
ent to the common hepatic duct.
C.
High junction between the cystic and the common hepatic duct.
D.
Cystic duct drains into right hepatic 
duct.
E.
Long cystic duct that joins common hepatic duct behind the duodenum.
F.
Absence of cystic duct.
G.
Cystic duct crosses posterior 
to common hepatic duct and joins it anteriorly.
H.
Cystic duct courses anterior to common hepatic duct and joins it posteriorly.
Pancreatic duct
Common
bile duct 
Sphincter
of Oddi
Duodenum
Duodenal wall
Figure 32-3.
The sphincter of Oddi.
Iso-
lated congenital absence of the gallbladder is very rare, with a 
reported incidence of 0.03%.
Small ducts (of Luschka) may drain directly from the liver 
into the body of the gallbladder.
An accessory right 
hepatic duct occurs in about 5% of cases.
In about 20% of patients, the right hepatic artery 
comes off the superior mesenteric artery.
The right hepatic 
artery may course anterior to the common duct.
32-4).
The secre-
tion of bile is responsive to neurogenic, humoral, and chemical 
stimuli.
With an intact sphincter of Oddi, bile flow 
is directed into the gallbladder.
Bile is mainly composed of water, electrolytes, bile salts, 
proteins, lipids, and bile pigments.
Variations in the arterial supply to the gallbladder.
A.
Cystic artery from right hepatic artery, about 80% to 90%.
B.
C.
Two cystic arter-
ies, one from the right hepatic, the other from the common hepatic 
artery, rare.
D.
Two cystic arteries, one from the right hepatic, the 
other from the left hepatic artery, rare.
E.
F.
Two cystic arteries arising from the right 
hepatic artery, rare.
or extracellular fluid.
The synthesis of phospholipids 
and cholesterol by the liver is, in part, regulated by bile acids.
Absorption and Secretion.
During fasting, 
the gallbladder does not simply fill passively.
This process is mediated at 
least in part by the hormone motilin.
One of the 
main stimuli to gallbladder emptying is the hormone cholecys-
tokinin (CCK).
Over the following 60 to 90 minutes, the gallbladder 
gradually refills.
This is correlated with a reduced CCK level.
Parasympatho-
mimetic drugs contract the gallbladder, whereas atropine leads 
to relaxation.
It also relaxes the terminal bile duct, 
the sphincter of Oddi, and the duodenum.
Vasoactive intestinal polypeptide inhibits contraction and 
causes gallbladder relaxation.
Somatostatin and its analogues 
are potent inhibitors of gallbladder contraction.
32-5).
For decades, it was the mainstay of investigation for gallstones.
An elevated 
white blood cell (WBC) count may indicate or raise suspicion of 
cholecystitis.
Serum aminotransferases may 
be normal or mildly elevated.
In patients with biliary colic or 
chronic cholecystitis, blood tests will typically be normal.
Adjacent organs can frequently 
be examined at the same time.
Obese patients, patients with 
Figure 32-5.
The effect of cholecystokinin on the gallbladder and 
the sphincter of Oddi.
A.
During fasting, with the sphincter of Oddi 
contracted and the gallbladder filling.
B.
In response to a meal, the 
sphincter of Oddi relaxed and the gallbladder emptying.
Ultrasound will show stones in the gallbladder with sensi-
tivity and specificity of >90%.
Stones are acoustically dense and 
reflect the ultrasound waves back to the ultrasonic transducer.
32-6).
Stones move with changes in position.
Polyps may be calcified 
and reflect shadows, but do not move with change in posture.
Some stones form a layer in the gallbladder; others a sediment 
or sludge.
A thickened gallbladder wall and local tenderness 
indicate cholecystitis.
A contracted, thick-walled gallbladder is indicative of chronic 
cholecystitis.
Frequently, the site 
and, sometimes, the cause of obstruction can be determined by 
ultrasound.
Stones are noted on a film as filling defects 
in a visualized, opacified gallbladder.
Figure 32-6.
An ultrasonography of the gallbladder.
Arrows indi-
cate the acoustic shadows from stones in the gallbladder.
The sensitivity and specificity for the diag-
nosis are about 95% each.
Use of CT scan is an integral part of the differential diagnosis 
of obstructive jaundice (Fig.
32-7).
Spiral CT scanning provides 
Figure 32-7.
The can-
cer obstructs the common bile duct as well as the pancreatic duct.
32-8).
As with any invasive procedure, there are potential risks.
32-9).
32-10).
The procedure requires intravenous (IV) sedation 
for the patient.
It is of particular value in the evaluation of 
tumors and their resectability.
A.
Dilated intrahepatic bile duct is 
entered percutaneously with a fine needle.
B.
Small guidewire is passed through the 
needle into the duct.
C.
A plastic catheter 
has been passed over the wire, and the wire 
is subsequently removed.
A cholangiogram is 
performed through the catheter.
D.
An external 
drainage catheter in place.
E.
Long wire placed 
via the catheter and advanced past the tumor 
and into the duodenum.
F.
Internal stent has 
been placed through the tumor.
ultrasonic guidance.
Certain conditions predispose to the 
development of gallstones.
Magnetic resonance cholangiopancreatography.
Figure 32-10.
Endoscopic retrograde cholangiography.
A.
B.
An endoscopic cholangiography showing stones in the common bile duct.
The catheter has been placed 
in the ampulla of Vater (arrow).
Note the duodenal shadow indicated with arrowheads.
Rarely, complication 
of gallstones is the presenting picture.
Once symptomatic, patients 
tend to have recurring bouts of biliary colic.
Complicated gall-
stone disease develops in 3% to 5% of symptomatic patients per 
year.
Gallstone Formation
Gallstones form as a result of solids settling out of solution.
The 
major organic solutes in bile are bilirubin, bile salts, phospho-
lipids, and cholesterol.
Pigment stones can be further classified as either black or brown.
Both 
types of pigment stones are more common in Asia.
Cholesterol Stones.
Pure cholesterol stones are uncommon 
and account for <10% of all stones.
They usually occur as single 
large stones with smooth surfaces.
32-11).
Colors range from 
whitish yellow and green to black.
Most cholesterol stones are 
radiolucent; <10% are radiopaque.
Cholesterol is highly nonpolar and 
insoluble in water and bile.
Vesicular maturation occurs 
when vesicular lipids are incorporated into micelles.
Vesicular 
phospholipids are incorporated into micelles more readily than 
vesicular cholesterol.
Therefore, vesicles may become enriched 
Figure 32-12.
The three major components of bile plotted on trian-
gular coordinates.
A given point represents the relative molar ratios 
of bile salts, lecithin, and cholesterol.
(Reproduced with permission from Holzbach RT.
Pathogenesis and medical treatment of gallstones.
In: Slesinger 
MH, Fordtran JS, eds.
Gastrointestinal Diseases.
Philadelphia: WB 
Saunders; 1989:1672.)
Figure 32-11.
Gallbladder with cholesterol stones.
Note the dif-
ferent shapes and sizes.
in cholesterol, become unstable, and then nucleate cholesterol 
crystals.
In unsaturated bile, cholesterol enrichment of vesicles 
is inconsequential.
32-12).
Pigment Stones.
Black pigment stones are usually small, brittle, black, 
and sometimes spiculated.
Like 
cholesterol stones, they almost always form in the gallbladder.
Unconjugated bilirubin is much less soluble than conjugated 
bilirubin in bile.
Deconjugation of bilirubin occurs normally in 
bile at a slow rate.
Cirrhosis may lead to increased secre-
tion of unconjugated bilirubin.
Brown stones are usually <1 cm in diameter, brownish-
yellow, soft, and often mushy.
Precipitated calcium bilirubinate 
and bacterial cell bodies compose the major part of the stone.
Clinical Presentation The chief symptom associated with 
symptomatic gallstones is pain.
32-13).
The pain is severe and 
comes on abruptly, typically during the night or after a fatty 
meal.
It often is associated with nausea and sometimes vomit-
ing.
The pain is episodic.
The patient suffers discrete attacks of 
pain, between which they feel well.
Physical examination may 
reveal mild right upper quadrant tenderness during an episode of 
pain.
If the patient is pain free, the physical examination is usu-
ally unremarkable.
Atypical presentation of gallstone disease is common.
Asso-
ciation with meals is present in only about 50% of patients.
Some 
patients report milder attacks of pain, but relate it to meals.
The pain may be located primarily in the back or the left upper 
or lower right quadrant.
Bloating and belching may be present 
and associated with the attacks of pain.
Many 
patients with other conditions have gallstones.
An impacted stone without chole-
cystitis will result in what is called hydrops of the gallbladder.
A.
B.
Sites of pain radiation 
(%) during an episode of biliary pain in the same group of patients.
(Reprinted from Gunn A, Keddie N.
Some clinical observations on 
patients with gallstones.
Lancet.
1972;300(7771):239-241, Copy-
right 1972, with permission from Elsevier.)
is not tender.
In <1% of 
acute cholecystitis, the cause is a tumor obstructing the cystic 
duct.
Why inflammation develops 
only occasionally with cystic duct obstruction is unknown.
It 
is probably related to the duration of obstruction of the cystic 
duct.
Increase in prostaglandin synthesis amplifies the inflammatory 
response.
Pericholecystic fluid often is present.
The mucosa 
may show hyperemia and patchy necrosis.
Rarely, perforation of ischemic areas occurs.
The perforation is usually contained in the subhepatic space 
by the omentum and adjacent organs.
It is usu-
ally more severe than the pain associated with uncomplicated 
biliary colic.
A mild to moderate leukocytosis (12,000–15,000 cells/mm3)  
is usually present.
However, some patients may have a normal 
WBC.
Diagnosis Ultrasonography is the most useful radiologic test 
for diagnosing acute cholecystitis.
It has a sensitivity and speci-
ficity of 95%.
32-14).
Biliary radionuclide 
scanning (HIDA scan) may be of help in the atypical case.
CT scan is frequently 
performed on patients with acute abdominal pain.
The antibiotics should 
cover gram-negative aerobes as well as anaerobes.
The procedure is more 
tedious and takes longer than in the elective setting.
For those unfit for surgery, a percutaneous  
Figure 32-14.
Ultrasonography from a patient with acute chole-
cystitis.
The arrowheads indicate the thickened gallbladder wall.
There are several stones in the gallbladder (arrows) throwing 
acoustic shadows.
cholecystostomy or an open cholecystostomy under local 
analgesia can be performed.
For these patients, surgery is unavoidable.
The incidence 
increases with age.
Clinical Manifestations Choledochal stones may be silent and 
often are discovered incidentally.
Nausea and vomiting are common.
A 
small stone may pass through the ampulla spontaneously with 
resolution of symptoms.
Finally, the stones may become com-
pletely impacted, causing severe progressive jaundice.
It has the distinct advan-
tage of providing a therapeutic option at the time of diagnosis.
32-15).
If a choledochotomy is performed, a T tube is left 
in place.
In these cases the common 
bile duct is usually quite dilated (about 2 cm in diameter).
32-16).
If the stones were 
Figure 32-15.
An endoscopic 
sphincterotomy.
A.
The sphinctero-
tome in place.
B.
Completed sphinc-
terotomy.
C.
Endoscopic picture of 
completed sphincterotomy.
The T tube 
is then removed and a catheter passed through the tract into 
the common bile duct.
Under fluoroscopic guidance, the stones 
are retrieved with baskets or balloons.
Recurrent stones may be 
multiple and large.
Mechanical hindrance 
to bile flow facilitates bacterial contamination.
The patient with gall-
stone-induced cholangitis is typically older and female.
The most 
common presentation is fever, epigastric or right upper quad-
rant pain, and jaundice.
A
B
Figure 32-16.
Retained common bile duct stones.
The patient pre-
sented 3 weeks after laparoscopic cholecystectomy.
A.
An ultra-
sound shows a normal or mildly dilated common bile duct with a 
stone.
B.
However, the presentation may be atypical, with little if any 
fever, jaundice, or pain.
Patients with indwelling stents rarely 
become jaundiced.
The definitive diagnostic test is ERC.
In cases 
in which ERC is not available, PTC is indicated.
These patients may 
require intensive care unit monitoring and vasopressor sup-
port.
Most patients will respond to these measures.
However, 
the obstructed bile duct must be drained as soon as the patient 
has been stabilized.
The selection of procedure should 
be based on the level and the nature of the biliary obstruction.
Acute cholangitis is associated with an overall mortality 
rate of approximately 5%.
Biliary Pancreatitis.
Gallstones in the common bile duct are 
associated with acute pancreatitis.
An ultrasonogram of the biliary 
tree in patients with pancreatitis is essential.
Once the pancreatitis has subsided, the gallbladder should be 
removed during the same admission.
It affects both sexes equally and occurs 
most frequently in the third and fourth decades of life.
Cholan-
giohepatitis is caused by bacterial contamination (commonly 
E.
Bacterial enzymes cause deconjuga-
tion of bilirubin, which precipitates as bile sludge.
The sludge 
and dead bacterial cell bodies form brown pigment stones.
The 
nucleus of the stone may contain an adult Clonorchis worm, 
an ovum, or an ascarid.
Recurrence 
of symptoms is one of the most characteristic features of the 
disease.
MRCP and PTC are the mainstays of biliary 
imaging for cholangiohepatitis.
Hepatic abscesses may 
be drained percutaneously.
The long-term goal of therapy is to 
extract stones and debris and relieve strictures.
Occasionally, resection of 
involved areas of the liver may offer the best form of treatment.
32-17).
The 
gallbladder can be removed later, if indicated, usually by lapa-
roscopy.
Carl Langenbuch performed the 
Figure 32-17.
Percutaneous cholecystostomy.
Open cholecystectomy was a safe and effective treatment for both 
acute and chronic cholecystitis.
Today, 
laparoscopic cholecystectomy is the treatment of choice for symp-
tomatic gallstones.
Serious complications are rare.
The mortality rate for lapa-
roscopic cholecystectomy is about 0.1%.
The patient should be instructed to empty their bladder before 
coming to the operating room.
Urinary catheters are rarely 
needed.
Laparoscopic Cholecystectomy.
Initially, a small incision is made in the upper edge of the umbi-
licus.
Three additional ports are 
placed under direct vision (Fig.
32-18).
Through the lateral-most port, a grasper is used to grasp 
the gallbladder fundus.
The dissection starts at the junction of the gallbladder 
and the cystic duct.
A helpful anatomic landmark is the cys-
tic artery lymph node.
A hemoclip is placed on the proximal cystic duct.
The cystic artery is then clipped and divided.
The gallbladder is removed through the umbili-
cal incision.
The fascial defect and skin incision may need to 
be enlarged if the stones are large.
Open Cholecystectomy.
The same surgical principles apply 
for laparoscopic and open cholecystectomies.
Intraoperative Cholangiogram or Ultrasound.
32-19A).
32-19B).
32-20).
If 
needed, a flexible choledochoscope is the next step.
The cystic 
duct may have to be dilated to allow its passage.
Occasionally, a choledochotomy, 
an incision into the common bile duct itself, is necessary.
The choledochotomy is sutured 
Figure 32-18.
Laparoscopic cholecystectomy.
A.
The trocar placement.
B.
C.
A clip is being placed on the cystic duct–gallbladder 
junction.
D.
A small opening has been made into the cystic duct, and a cholangiogram catheter is to be inserted.
E.
The cystic duct has been 
divided, and the cystic artery is being divided.
F.
The cystic artery can be seen crossing the dissected area upward and to the left.
32-21).
The duodenum is incised trans-
versely.
The sphincter then is incised at the 11 o’clock position 
to avoid injury to the pancreatic duct.
The impacted stones are 
removed, as are large stones from the duct.
There is no need to 
Figure 32-19.
A.
An intraoperative cholangiogram.
The bile ducts are of normal size, with no intraluminal filling defects.
B.
An intraoperative cholangiogram 
showing common bile duct stone (arrow).
A small amount of contrast has passed into the duodenum.
AB
fully clear the duct of stones, as they can pass spontaneously 
through the cut sphincter.
Acalculous cholecystitis typically develops in critically 
ill patients in the intensive care unit.
Laparoscopic bile duct exploration.
I.
Transcystic basket retrieval using fluoroscopy.
A.
The basket has been advanced past 
the stone and opened.
B.
The stone has been entrapped in the basket, and together, they are removed from the cystic duct.
II.
Transcystic 
choledochoscopy and stone removal.
C.
D.
Entrapped stone.
E.
A view from the choledochoscope.
III.
Choledochotomy and stone removal.
F.
A small incision 
is made in the common bile duct.
G.
The common bile duct is cleared of stones.
H.
AB C
D
FG H
E
1329
Gallbladder and the Extrahepatic Biliary System
CHAPTER 32
Figure 32-21.
Biliary enteric anastomoses.
There are three types.
I.
Choledochoduodenostomy.
A.
The distal common bile duct is opened 
longitudinally, as is the duodenum.
B.
Interrupted sutures are placed between the common bile duct and the duodenum.
C.
Completed cho-
ledochoduodenostomy.
II.
Choledochojejunostomy.
D.
The common bile duct and small bowel are divided.
E.
A Roux-en-Y limb of jejunum 
is anastomosed to the choledochus.
III.
Hepaticojejunostomy.
F.
G.
Percutaneous transhepatic stents are placed across hepaticojejunostomy.
32-17).
If the diagnosis 
is uncertain, percutaneous cholecystostomy is both diagnostic 
and therapeutic.
About 90% of patients will improve with the 
percutaneous cholecystostomy.
Choledochal cysts affect females 
three to eight times more often than males.
The cause is 
unknown.
Classification of choledochal cysts.
Type II, saccular diverticulum of an extrahepatic bile duct.
Rare, <5% of choledochal cysts.
Types IVa and IVb, mul-
tiple cysts, make up 5% to 10% of choledochal cysts.
Type V, intrahepatic biliary cysts, is very rare and makes up 1% of choledochal cysts.
cyst formation.
Choledochal cysts are classified into five types (Fig.
32-22).
Adults commonly present with jaundice or cholangitis.
It is a progressive disease that eventually 
results in secondary biliary cirrhosis.
It is associated with ulcerative colitis in about 
two thirds of patients.
Patients with sclerosing cholangitis are at risk for 
developing cholangiocarcinoma.
Eventually, 10% to 20% of the 
patients will develop cancer.
The mean age of presentation is 30 to 45 years, and men 
are affected twice as commonly as women.
Symptoms of acute cholangitis are rare, 
without preceding biliary tract intervention or surgery.
More 
than one half of patients are symptomatic when diagnosed.
Colectomy for the colitis makes no 
difference to the course of primary sclerosing cholangitis.
The hepatic 
duct bifurcation is often the most severely affected segment.
Sclerosing cholangitis is followed by ERC and liver biopsies to 
provide appropriate management.
Biliary strictures can be 
dilated and stented either endoscopically or percutaneously.
It offers excellent results, with overall 5-year survival 
as high as 85%.
Episodic pain of the biliary 
type with abnormal liver function tests is a common presenta-
tion.
However, recurrent jaundice or pancreatitis also may play 
a role.
Ampullary manometry and special provocation tests 
are available in specialized units.
Less commonly, they may pres-
ent with jaundice without evidence of infection.
Liver function 
tests usually show evidence of cholestasis.
MRC will also provide good anatomic informa-
tion about the location and the degree of dilatation.
32-23).
An endoscopic cholangiogram will outline the distal bile duct.
Treatment depends on the location and the cause of the stricture.
INJURY TO THE BILIARY TRACT
Gallbladder
Injuries to the gallbladder are uncommon.
Nonpenetrat-
ing trauma is extremely rare.
These include 
acute or chronic inflammation, obesity, anatomic variations, and 
bleeding.
An endoscopic retrograde cholangiography show-
ing stricture of the common hepatic duct (arrow).
most common cause of significant biliary injury.
The bile ducts 
may be narrow and can be mistaken for the cystic duct.
A number of intra-
operative technical factors have been implicated in biliary 
injuries.
An angled scope also will aid in the proper 
placement of clips.
Careless use of electrocautery may lead to 
thermal injury.
Critical 
to the successful use of cholangiography is accurate interpretation 
of the imaging.
Diagnosis.
More than half of patients 
with biliary injury will present within the first postoperative 
month.
32-24).
Bilious drainage through 
operatively placed drains or through the wounds is abnormal.
The site of the bile leak can be confirmed noninvasively with 
a HIDA scan.
32-23).
Management.
This 
injury usually requires a biliary enteric anastomosis with a jeju-
nal loop.
A.
Computed tomographic scan of a patient with bile leak after cholecystectomy.
The short arrows indicate the intraperitoneal 
collections.
Both air and bile are seen in the gallbladder bed (long arrow) as well as a surgical clip.
B.
Note the filling of the pancreatic duct.
32-24).
When the acute inflammation has resolved 6 to 8 
weeks later, operative repair is performed.
An anastomosis is performed 
between the duct proximal to the injury and a Roux loop 
of jejunum.
Outcome.
Approximately two thirds of recurrent 
strictures become symptomatic within 2 years after repair.
The 
more proximal strictures are associated with a lower success 
rate than are distal ones.
Patients with 
deteriorating liver function are candidates for liver transplants.
The overall 
reported 5-year survival rate is about 5%.79
Incidence.
Gallbladder cancer is the fifth most common GI 
malignancy in Western countries.
The 
pathogenesis has not been defined but is probably related to 
chronic inflammation.
These gallbladders should be 
removed, even if the patients are asymptomatic.
Pathology.
Between 80% and 90% of the gallbladder tumors 
are adenocarcinomas.
Squamous cell, adenosquamous, oat 
cell, and other anaplastic lesions occur rarely.
The histologic 
subtypes of gallbladder adenocarcinomas include papillary, 
nodular, and tubular.
The gallbladder 
veins drain directly into the adjacent liver, usually segments 
Figure 32-25.
Computed tomography scan of a patient with gall-
bladder cancer.
The image shown is at the level of the liver hilum.
The portal vein is bifurcating into the left and right portal branch.
IV and V, where tumor invasion is common (Fig.
32-25).
Lymphatics are 
present in the subserosal layer only.
These include abdominal discomfort, right upper quadrant pain, 
nausea, and vomiting.
Jaundice, weight loss, anorexia, ascites, 
and abdominal mass are less common presenting symptoms.
More than one half of gallbladder cancers are not diagnosed 
before surgery.
The sensitivity of 
ultrasonography in detecting gallbladder cancer ranges from 
70% to 100%.
Treatment.
One half of patients with T2 
tumors are found to have nodal disease on pathologic examina-
tion.
Prognosis.
Most patients with gallbladder cancer have unre-
sectable disease at the time of diagnosis.
25% 
to 40%, respectively.
The prognosis for recurrent disease is very poor.
Death 
occurs most commonly secondary to biliary sepsis or liver fail-
ure.
The main goal of follow-up is to provide palliative care.
About 
two thirds are located at the hepatic duct bifurcation.
Most patients with unresectable disease die 
within 1 year of diagnosis.89
Incidence.
The autopsy incidence of bile duct carcinoma is 
about 0.3%.
Etiology.
Features common to most risk factors include biliary 
stasis, bile duct stones, and infection.
Over 95% of bile duct cancers are adenocarcino-
mas.
Anatomically, they are divided into distal, proximal, or peri-
hilar tumors.
About two thirds of cholangiocarcinomas are 
located in the perihilar location.
32-26).
Type I tumors are confined to the common 
Figure 32-26.
Bismuth-Corlette classification of bile duct tumors.
Type IV tumors involve both the right and 
left secondary intrahepatic ducts.
Clinical Manifestations and Diagnosis.
Painless jaundice 
is the most common presentation.
Pruritus, mild right upper 
quadrant pain, anorexia, fatigue, and weight loss also may be 
present.
Except for jaundice, physical examination is 
usually normal in patients with cholangiocarcinoma.
32-27).
It is usually difficult to visualize the tumor itself 
on ultrasound or on a standard CT scan.
Either ultrasound or 
spiral CT can be used to determine portal vein patency.
The 
biliary anatomy is defined by cholangiography.
PTC defines 
BA
Figure 32-27.
A.
The gallbladder is not visualized because 
of tumor obstructing its neck.
B.
the proximal extent of the tumor, which is the most important 
factor in determining resectability.
ERC is used, particularly in 
the evaluation of distal bile duct tumors.
For the evaluation of 
vascular involvement, celiac angiography may be necessary.
Surgical excision is the only potentially cura-
tive treatment for cholangiocarcinoma.
They 
are treated with pylorus-preserving pancreatoduodenectomy 
(Whipple procedure).
However, for distal bile duct tumors, endoscopic place-
ment is often the preferred approach (Fig.
32-28).
Patients with unresectable disease 
Figure 32-28.
A through F.
Percutaneous transhepatic cholangiography and placement of a biliary drainage catheter.
External-beam radiation has not been shown to be an 
effective treatment for unresected disease.
Most patients with perihilar cholangiocarcinoma 
present with advanced, unresectable disease.
Patients with unre-
sectable disease have a median survival between 5 and 8 months.
The most common causes of death are hepatic failure and chol-
angitis.
Therapy for recurrent disease is palliation of symptoms.
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Unusual cases of 
acute cholecystitis and cholangitis: Tokyo Guidelines.
J Hepa-
tobiliary Pancreat Surg.
2007;14:98.
64.
Lipsett PA, Pitt HA.
Surgical treatment of choledochal cysts.
J Hepatobiliary Pancreat Surg.
2003;10:352.
65.
Ahrendt SA, Pitt HA, Nakeeb A, et al.
Diagnosis and manage-
ment of cholangiocarcinoma in primary sclerosing cholangitis.
J Gastrointest Surg.
1999;3:357.
66.
Ahrendt SA, Pitt HA, Kalloo AN, et al.
Primary scleros-
ing cholangitis: resect, dilate, or transplant?
Ann Surg.
1998;227:412.
67.
Goss JA, Shackleton CR, Farmer DG, et al.
Orthotopic liver 
transplantation for primary sclerosing cholangitis.
A 12-year 
single center experience.
Ann Surg.
1997;225:472.
68.
Ahrendt SA, Pitt HA.
Surgical treatment for primary scleros-
ing cholangitis.
J Hepatobiliary Pancreat Surg.
1999;6:366.
69.
Linder JD, Klapow JC, Linder SD, et al.
Am J 
Gastroenterol.
2003;98:1738.
70.
Lillemoe KD, Melton GB, Cameron JL, et al.
Postoperative 
bile duct strictures: Management and outcome in the 1990s.
Ann Surg.
2000;232:430.
71.
Melton GB, Lillemoe KD.
The current management of postop-
erative bile duct strictures.
Adv Surg.
2002;36:193.
72.
Archer SB, Brown DW, Smith CD, et al.
Bile duct injury dur-
ing laparoscopic cholecystectomy: results of a national survey.
Ann Surg.
2001;234:549.
73.
Ahrendt SA, Pitt HA.
Surgical therapy of iatrogenic lesions of 
biliary tract.
World J Surg.
2001;25:1360.
74.
Strasberg SM.
Avoidance of biliary injury during laparoscopic 
cholecystectomy.
J Hepatobiliary Pancreat Surg.
2002;9:543.
75.
Way LW, Stewart L, Gantert W, et al.
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2003;237:460.
76.
Flum DR, Flowers C, Veenstra DL.
J Am 
Coll Surg.
2003;196:385.
77.
Lee CM, Stewart L, Way LW.
Postcholecystectomy abdomi-
nal bile collections.
Arch Surg.
2000;135:538.
78.
Melton GB, Lillemoe KD, Cameron JL, et al.
Ann Surg.
2002;235:888.
79.
Grobmyer SR, Lieberman MD, Daly JM.
Gallbladder cancer 
in the twentieth century: single institution’s experience.
World 
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2004;28:47.
80.
Pandey M, Shukla VK.
Diet and gallbladder cancer: a case-
control study.
Eur J Cancer Prev.
2002;11:365.
81.
Serra I, Calvo A, Baez S, et al.
Risk factors for gallbladder 
cancer.
An international collaborative case control study.
Cancer.
1996;78:1515.
82.
Lowenfels AB, Walker AM, Althaus DP, et al.
Gallstone 
growth, size, and risk of gallbladder cancer: an interracial 
study.
Int J Epidemiol.
1998;18:50.
83.
Csendes A, Burgos AM, Csendes P, et al.
Late follow-up of 
polypoid lesions of the gallbladder smaller than 10 mm.
Ann 
Surg.
2001;234:657.
84.
Wagholikar G, Behari A, Krishnani N, et al.
Early gallbladder 
cancer.
J Am Coll Surg.
2002;194:137.
85.
Kim JH, Kim TK, Eun HW.
J Magn Reson Imaging.
2002;16:676.
86.
Bartlett DL, Fong Y, Fortner JG, et al.
Long-term results after 
resection for gallbladder cancer.
Implications for staging and 
management.
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1996;224:639.
87.
Wakai T, Shirai Y, Hatakeyama K.
World J Surg.
2002;26:867.
88.
Noshiro H, Chijiiwa K, Yamaguchi K, et al.
Factors affecting 
surgical outcome for gallbladder carcinoma.
Hepatogastroen-
terology.
2003;50:939.
1340
SPECIFIC CONSIDERATIONS
UNIT II
PART II
89.
Strasberg SM.
Resection of hilar cholangiocarcinoma.
HPB 
Surg.
1998;10:415.
90.
Tocchi A, Mazzoni G, Liotta G, et al.
Ann Surg.
2001;234:210.
91.
Ahrendt SA, Rashid A, Chow JT, et al.
J Hepatobiliary Pancreat Surg.
2000;7:426.
92.
Nehls O, Gregor M, Klump B.
Serum and bile markers for 
cholangiocarcinoma.
Semin Liver Dis.
2004;24:139.
93.
Siqueira E, Schoen RE, Silverman W, et al.
Detecting cholan-
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Gastrointest Endosc.
2005;56:40.
94.
Ahrendt SA, Nakeeb A, Pitt HA.
Cholangiocarcinoma.
Clin 
Liver Dis.
2001;5:191.
95.
Lillemoe KD, Cameron JL.
Surgery for hilar cholangiocarci-
noma: the Johns Hopkins approach.
J Hepatobiliary Pancreat 
Surg.
2000;7:115.
96.
Mulholland MW, Yahanda A, Yeo CJ.
Multidisciplinary 
management of perihilar bile duct cancer.
J Am Coll Surg.
2001;193:440.
97.
Vollmer CM, Drebin JA, Middleton WD, et al.
Utility of stag-
ing laparoscopy in subsets of peripancreatic and biliary malig-
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Ann Surg.
2002;235:1.
98.
Strasberg SM.
ERCP and surgical intervention in pancreatic 
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Gastrointest Endosc.
2002;56:S213.
99.
Ortner ME, Caca K, Berr F, et al.
Gastroenterology.
2003;125:1355.
Pancreas
William E.
Fisher, Dana K.
Andersen,  
John A.
Windsor, Ashok K.
Saluja,  
and F.
33-1).
In an adult, the pancreas weighs 
75 to 100 g and is about 15 to 20 cm long.
The neck of the pancreas lies directly 
anterior to the portal vein.
The inferior mesenteric vein often joins the splenic vein near its 
junction with the portal vein.
33-2).
The body and tail of the pancreas lie 
just anterior to the splenic artery and vein.
These 
branches must be divided to perform a spleen-sparing distal 
pancreatectomy.
The splenic artery often is tortuous.
The anterior surface of the body of the pancreas is covered by 
peritoneum.
“Thin cut” multidetector com.
Aggressive fluid resuscitation and early enteral feeding 
both reduce the risk of complications.
6 The nidus of inflammation in chronic pancreatitis due to 
any cause is the head of the gland.
Pancreatic anatomy as seen on computed tomography.
IMV = inferior mesenteric vein; SMA = superior mesenteric 
artery; SMV = superior mesenteric vein.
aorta at the origin of the superior mesenteric artery.
The neck divides the pancreas into approximately 
two equal halves.
Figure 33-2.
Variations in portal venous anatomy.
The pancreas 
is formed by the fusion of a ventral and dorsal bud (Fig.
33-3).
The length of the common channel is variable.
33-3).
33-4).
The right gastric artery branches off the gastroduodenal 
artery just superior to the duodenum.
A posterior ulcer in the duodenal 
bulb can erode into the gastroduodenal artery in this location.
Therefore, it is impossible to resect the head of the 
Figure 33-3.
Embryology of pancreas and duct variations.
The duct of Santorini can persist as a blind accessory duct or drain 
through the lesser papilla.
Variations in the arterial anatomy occur in one out of 
five patients.
The 
body and tail of the pancreas are supplied by multiple branches 
of the splenic artery.
They are, 
from medial to lateral, the dorsal, great, and caudal pancreatic 
arteries.
33-5).
The veins are usually 
Figure 33-4.
Arterial supply to the pan-
creas.
Multiple arcades in the head and 
body of the pancreas provide a rich blood 
supply.
Venous drainage from the pancreas.
There is an anterior and posterior venous arcade within the head 
of the pancreas.
The superior veins drain directly into the portal 
vein just above the neck of the pancreas.
These venous tribu-
taries must be divided during a Whipple procedure.
Venous return from the 
body and tail of the pancreas drains into the splenic vein.
The lymphatic drainage from the pancreas is diffuse and 
widespread (Fig.
33-6).
Neuroanatomy
The pancreas is innervated by the sympathetic and parasympa-
thetic nervous systems.
These somatic fibers travel superiorly to the celiac ganglia  
(Fig.
33-7).
Interruption of these somatic fibers can stop trans-
mission of pain sensation.
Lymphatic supply to the 
pancreas.
Pan-
creatic juice is a combination of acinar cell and duct cell secre-
tions.
The acinar cells are pyramid-
shaped, with their apices facing the lumen of the acinus.
33-8).
The proteolytic enzymes are secreted as proenzymes that 
require activation.
Trypsin, in turn, activates the 
other proteolytic enzymes.
Innervation of the pancreas.
Acinar cell.
(Reproduced with permission from Bloom W, 
Fawcett DW: A Textbook of Histology, 10th ed.
This accounts for about two-thirds of cases of hereditary pan-
creatitis.
Chymotrypsinogen is activated to form chymotrypsin.
Pancreatic lipase hydrolyzes triglycerides to 2-monoglyceride 
and fatty acid.
Pancreatic lipase is secreted in an active form.
Phospholipase A2 is secreted by the pancreas as a proenzyme 
that becomes activated by trypsin.
About 
40 acinar cells are arranged into a spherical unit called an aci-
nus.
These 
cells contain the enzyme carbonic anhydrase, which is needed 
for bicarbonate secretion.
33-9).
CCK also stimulates bicarbon-
ate secretion, but to a much lesser extent than secretin.
CCK 
potentiates secretin-stimulated bicarbonate secretion.
The pancreatic juice then travels into small 
intercalated ducts.
Several small intercalated ducts join to form an 
interlobular duct.
Endocrine Pancreas
There are nearly 1 million islets of Langerhans in the normal 
adult pancreas.
They vary greatly in size from 40 to 900 μm.
1349
P
ANCREAS
CHAPTER 33
Insulin is the best-studied pancreatic hormone.
Figure 33-9.
Composition of pancreatic exocrine secretions.
In contrast, sodium and potassium concentrations are 
independent of the secretory rate.
Acta Phys Scandinav.
There are two phases of insulin 
secretion.
In the first phase, stored insulin is released.
This phase 
lasts about 5 minutes after a glucose challenge.
The diagnosis of diabetes is made 
by using oral and intravenous (IV) glucose tolerance tests.
As a result, oral glucose is a more vigorous stimulus to 
insulin secretion than IV glucose.
Forty g/m2or 75 g of glucose is given orally 
over 10 minutes.
Blood samples are taken every 30 minutes for 
2 hours.
There is a considerable 
amount of functional reserve in insulin secretory capacity.
Glucagon release is stimulated by hypoglycemia, and by 
the amino acids arginine and alanine.
The major stimulant is probably intraluminal fat.
Acetylcholine from the 
cholinergic neurons inhibits somatostatin release.
[Reproduced with permission from Cui YF & Andersen DK.
Vagal stimulation of the pancreas is 
the most important regulator of PP secretion.
In fact, vagotomy 
eliminates the rise in PP levels usually seen after a meal.
The other 
cell types are located predominantly in the periphery.
However, individual islet cells can secrete multiple 
hormones.
There is diversity 
among the islets depending on their location within the pancreas.
Its hall-
mark is acute pancreatic inflammation associated with little or 
no fibrosis.
Philadelphia: Saunders, 2000, p 1117.
Copyright Elsevier.
consumed (typically 100 to 150 grams per day) and the pattern of  
drinking.
There are several mechanisms by which 
ethanol causes acute pancreatitis.
Poisoning with antiacetylcholin-
esterase insecticides has a similar effect.
33-10).
Precipitating Initial Events
Acinar Cell Events.
Pathophysiology of acute pancreatitis.
This initiates the apoptotic cascade and 
results in the apoptotic death of the acinar cells (Fig.
Fluid may collect in 
and around the pancreas.
33-12).
Schematic representation of the 
acinar cell events in acute pancreatitis.
Increased cytosolic calcium is 
required for colocalization.
The NFκB- dependent inflammatory pathway is one such key 
pathway.
Pancreas surrounded 
by fluid, inflammation, and possible peripancreatic fat necrosis.
Commentary.
Gut.
2013;62:4.
With permission from 
the BMJ Publishing Group.
early, or later secondary to the development of infected local 
complications.
The 
three organ systems most frequently involved are cardiovascu-
lar, respiratory, and renal.
Management of the Patient
General Considerations.
The management of acute pancre-
atitis covers a wide spectrum of severity.
Patients with sus-
pected acute pancreatitis should be admitted to hospital.
The risk of mortality reflects this spectrum of severity.
Am J Gastroenterol 77:633, 1982, 
and From Ranson JH, Rifkind KM, Roses DF, et al.
Prognostic signs 
and the role of operative management in acute pancreatitis.
Surg Gyne-
col Obstet 139:69, 1974.
Epi = epineptvine.
Norepi = norepinephrine.
∗Adrenergic agents administered for at least 1 h (doses given in μg/kg per min).
A score of 2 or more in any two systems indicates the presence of multiple organ failure.
it is important to measure either the pancreatic isoenzyme of 
amylase or lipase.
For these reasons, it is recommended that amylase 
concentrations also be measured in the urine.
Hemoconcentration then 
results in an elevated hematocrit.
However, there also may be 
bleeding into the retroperitoneum or the peritoneal cavity.
There is a lack of high quality evidence 
to guide the choice of analgesic.
Morphine is to be 
avoided, due to its potential to cause sphincter of Oddi spasm.
Both use clinical and biochemical 
parameters scored over the first 48 hours of admission.
It can also be used in retrospect for 
audit purposes.
Gallstones should be inves-
tigated by ultrasonography.
Figure 33-13.
Corresponding CT (A) and MR (B) images of a patient with a symptomatic pseudocyst.
(Reproduced with permission from Bollen TL et al.
Imaging of acute pancreatitis: Update 
of the revised Atlanta Classification.
Radiol Clin North Am.
2012;50:429.
MR is 
superior to CT scanning in detecting any solid content within 
collections (Fig.
33-13).
The decisions regarding how and when 
Figure 33-14.
Operative view of infected acute pancreatitis.
to intervene are often difficult.
33-14).
33-15).
Two minimally invasive interventions for local complications of acute pancreatitis: A.
video-assisted retroperitoneal debride-
ment and B.
endoscopic transgastric necrosectomy 76.
(Reproduced with permission from Bakker OJ et al.
JAMA.
2012;307(10):1053.
Copyright © 2012 American Medical 
Association.
33-15).
When symptoms of pain or inability to eat persist 
or infection occurs, intervention is required.
The severity of organ failure can be scored (Table 33-6).
1.
Local
 A.
Pancreatic phlegmon
 B.
Pancreatic abscess
 C.
Pancreatic pseudocyst
 D.
Pancreatic ascites
 E.
Systemic
 A.
Pulmonary
   1.
Pneumonia, atelectasis
   2.
Acute respiratory distress syndrome
   3.
Pleural effusion
 B.
Cardiovascular
  1.
Hypotension
  2.
Hypovolemia
   3.
Sudden death
   4.
Nonspecific ST-T wave changes
   5.
Pericardial effusion
 C.
Hematologic
  1.
Hemoconcentration
   2.
Disseminated intravascular coagulopathy
 D.
GI hemorrhage
   1.
Peptic ulcer
   2.
Erosive gastritis
   3.
Portal vein or splenic vein thrombosis with varices
 E.
Renal
  1.
Oliguria
  2.
Azotemia
   3.
Renal artery/vein thrombosis
 F.
Metabolic
  1.
Hyperglycemia
  2.
Hypocalcemia
  3.
Hypertriglyceridemia
  4.
Encephalopathy
   5.
Sudden blindness (Purtscher’s retinopathy)
 G.
Central nervous system
  1.
Psychosis
   2.
Fat emboli
   3.
Alcohol withdrawal syndrome
 H.
Fat necrosis
   1.
Intra-abdominal saponification
   2.
New York: McGraw-
Hill, 1994, p 1524.
Copyright © The McGraw-Hill Companies, Inc.
hepatis.
The incidence is equal in both sexes.
Subse-
quently, the region was sequenced and revealed eight trypsino-
gen genes.
Men, with only one X chromo-
some, have no protection if they inherit a CLDN2 mutation.
33-16).
33-17).
33-18).
Schematic model of genetic causes of chronic pan-
creatitis.
Cationic and 
anionic trypsinogen are normally active in the duodenum by entero-
kinase (EK).
(Adapted with permission from Macmillan Publishers, Ltd.
Nat Genet.
2012;44:1349.
Etiologies of chronic pancreatitis.
(Reproduced 
with permission from Whitcomb DC.
Acad Med.
“Multiple hit” theory of the etiology of chronic 
pancreatitis.
33-19).
ETOH =  
ethyl alcohol.
Multiple classification  
systems have been proposed.
From Singer et al.116
1366
SPECIFIC CONSIDERATIONS
UNIT II
PART II
Wirsung’s duct (Fig.
33-20).
Increased levels of 
serum β-globulin or immunoglobulin G4 are also present.
Pancreas divisum.
(Reproduced with permission of Wiley-Blackwell.
A variable percentage of 
SPINK1 and CFTR mutations have been described in various 
studies.
Pathology
Histology.
33-21).
33-22).
Histology of early chronic pancreatitis.
(Courtesy of Rhonda 
Yantiss, Weill Cornell Medical College.)
Figure 33-22.
Gross appearance of chronic pancreatitis.
(Courtesy of Rhonda Yantiss, Weill Cornell Medical College.)
areas of necrosis.
33-23).
33-19.
Stone Formation.
The fibrillar center of most stones contains no 
calcium but rather a mixture of other metals.
Histology of severe chronic pancreatitis.
OPD Controls
Figure 33-24.
(Reproduced with 
permission of Wiley-Blackwell.
33-24).
Duct Distortion.
But some patients with complete duct obstruction have 
prolonged periods of painlessness.
Radiology.
33-25).
EUS has heavily impacted the evaluation and manage-
ment of patients with chronic pancreatitis.
33-26).
33-27).
Source: Reproduced with permission from Wiley-Blackwell.
33-28).
Sonography in chronic pancreatitis.
(Reproduced with permission from Bolondi  
et al.
Radiol Clin North Am.
27: 815, 1989.)
Figure 33-26.
Endoscopic ultrasound of chronic pancreatitis.
Computed tomographic imaging of chronic pancre-
atitis.
(Reproduced with permission 
from Forsmark CE:201 Management of pancreatitis.
Gastroenterol.
2013;144:1282.
© 2013 AGA Institute.
Published by Elsevier, Inc.
33-29).
Severe pancre-
atitis and deaths have occurred after ERCP.
Figure 33-28.
Pancreatic duct stenting.
Pancreatic duct stents are left in place for only a limited time to 
avoid further inflammation.
Figure 33-30.
Pain location in chronic pancreatitis.
(Reproduced 
with permission from Murayama KM, Jochl RJ.
Pain is the most common 
symptom of chronic pancreatitis.
33-30).
The pain is typically steady 
and boring, but not colicky.
Unlike ureteral stone pain or biliary 
colic, the pain causes the patient to be still.
Nausea or vomit-
ing may accompany the pain, but anorexia is the most common 
associated symptom.
Pain from chronic pancreatitis has been ascribed to three 
possible etiologies.
33-31).
80
75
70
65
60 MIF
Pe
r
cent S
ympt
om R
elief (%)
INF SEF
Figure 33-31.
P<0.05 for MIF vs.
SEF by chi-
square analysis.
J Gastrointest Surg.
2013;17:682.
Relationship of lipase output to fat malabsorption.
(Data from DiMagno  
et al.151)
Malabsorption and Weight Loss.
33-32).
In severe steatorrhea, an orange, 
oily stool is often reported.
As exocrine deficiency increases, 
symptoms of steatorrhea are often accompanied by weight loss.
As a result, 
many patients with severe chronic pancreatitis are below ideal 
body weight.
With progressive destruction of the gland, 
endocrine insufficiency commonly occurs.
33-33).
This form of 
diabetes is referred to as brittle diabetes and requires special 
attention.
Laboratory Studies.
Copyright Elsevier.)
Table 33-14
Tests for chronic pancreatitis
I.
Measurement of pancreatic products in blood
 A.
Enzymes
 B.
Pancreatic polypeptide
II.
Measurement of pancreatic exocrine secretion
 A.
Direct measurements
  1.
Enzymes
  2.
Bicarbonate
 B.
Indirect measurement
   1.
Bentiromide test
   2.
Schilling test
   3.
Fecal fat, chymotrypsin, or elastase concentration
  4.
[14C]-olein absorption
III.
Imaging techniques
 A.
Plain film radiography of abdomen
 B.
Ultrasonography
 C.
Computed tomography
 D.
Endoscopic retrograde cholangiopancreatography
 E.
Magnetic resonance cholangiopancreatography
 F.
33-34).
Pancreatic polypeptide (PP) response to a test meal.
A test meal was adminis-
tered at 0 minutes.
Means ± standard error of the mean are shown.
Pancrea-
tography in chronic pancreatitis: International definitions.
Gut 25:1107, 
1984.
With permission from the BMJ Publishing Group.
cystic disease is present, but is not accurate in the absence of 
these findings.
Continued 
alcohol abuse has a similar effect on the response to surgical 
treatment (Fig.
33-36).
Effect of alcohol use on survival 
after surgical procedures.
Cumulative risk of pancreatic cancer in patients 
with chronic pancreatitis.
The number of patients evaluated at  
different time intervals is shown in parentheses.
(Reproduced with 
permission from Lowenfels AB et al.
Copyright © 1993 Massachusetts 
Medical Society.
All rights reserved.177)
and elsewhere.
Complications
Pseudocyst.
This 
is referred to as an acute pseudocyst.
Pseudocysts are multiple in 17% of patients,182 or may 
be multilobulated.
33-37).
Pseudocysts may become secondarily infected, in which 
case they become abscesses.
33-38).
They also can perforate and 
cause peritonitis or intraperitoneal bleeding.185
Figure 33-37.
Extensive pseudocyst disease.
Figure 33-38.
Pseudoaneurysm of the gastroduodenal artery.
(Reproduced with permission from Balthazar EJ: CT 
diagnosis and staging of acute pancreatitis.
Radiol Clin North Am.
1989;27:19.
Pseudocysts usually cause symptoms of pain, fullness, 
or early satiety.
The timing and method of treatment requires careful con-
sideration.
Surgical options include a cystogastrostomy (Fig.
33-39), a 
Roux-en-Y cystojejunostomy, or a cystoduodenostomy.
Cystogastrostomy can be 
performed endoscopically187 (Fig.
Cystogastrostomy drainage of a retrogastric pancre-
atic pseudocyst.
Suture 
reinforcement of the communication is performed to avoid the com-
plication of bleeding.
Technique of endoluminal cystogastrostomy.
A.
Endoscopic ultrasound (EUS)-guided transgastric puncture of 
pancreatic pseudocyst.
B.
Transgastric stents placed across fused 
posterior wall of stomach and anterior wall of pseudocyst.
(Repro-
duced with permission from Chauhan SS, Forsmark CE.
Evidence-
based treatment of pancreatic pseudocysts.
Gastroenterol 2013; 
145: 512 Copyright Elsevier.)
cystoenterostomy.
Pancreatic Ascites.
Transpapillary drainage of a pancreatic pseudocyst.
A.
B.
Placement of a stent over the wire into the pseudocyst with 
transpapillary drainage.
Pain 
and nausea are rarely present.
33-42).
Serum amylase may also 
be elevated, presumably from reabsorption across the parietal 
membrane.
Serum albumin may be low, and patients may have 
coexisting liver disease.
Paracentesis is therefore critical to dif-
ferentiate pancreatic from hepatic ascites.
33-43).
Pancreatic-Enteric Fistula.
The most common site of communication is the 
transverse colon or splenic flexure.
The fistula usually presents 
with evidence of GI or colonic bleeding and sepsis.
When the fis-
tula involves the colon, operative correction is usually required.196
Figure 33-42.
Pancreatic ascites.
(Reproduced with permission from Cameron JL, 
Cameron AM (eds): Current Surgical Therapy, 11th ed.
Philadelphia: 
Elsevier, 2014, p 458.
Copyright Elsevier.)
1379
P
ANCREAS
CHAPTER 33
Head-of-Pancreas Mass.
Splenic and Portal Vein Thrombosis.
Vascular complica-
tions of chronic pancreatitis are fortunately infrequent, because 
Figure 33-43.
Internal drainage for leaking pancreatic duct.
From 
Beger et al.197
they are difficult to treat successfully.
Although bleeding complications 
are infrequent, the mortality risk of bleeding is >20%.
Treatment
Medical Therapy.
Analgesia.
It is essential for patients to abstain from alcohol.
Enzyme Therapy.
If pain relief is 
achieved, therapy is continued.
33-44).
Antisecretory Therapy.
Neurolytic Therapy.
Endoscopic Management.
An average meal requires roughly 90,000 
USP units of lipase for fat digestion.
(Reproduced with permission from Forsmark CE.
Management of chronic pancreatitis.
Gastroenterol 2013; 144: 1282.
© 2013 
AGA Institute.
Published by Elsevier, Inc.
Management algorithm for chronic pancreatitis.
(Reproduced with permission from Forsmark CE: Management of pancreatitis.
Gastroenterol.
2013;144:1282.
© 2013 AGA Institute.
Published 
by Elsevier, Inc.
33-45).
Extracorporeal shock wave lithotripsy treatment of 
pancreatic duct stones.
The choice of resection vs.
33-47).
33-48).
Head-of-pancreas mass after Puestow procedure.
33-49).
33-50).
33-51).
Schematic diagram of the 
ampullary, biliary, and pancreatic duct sphinc-
ters.
Operative sphincteroplasty of the biliary and pancre-
atic duct.
(Data from Moody et al.223)
Figure 33-49.
Duval’s caudal pancreaticojejunostomy.
Norwalk: Appleton-Century-Crofts, 1983, p 289.
Copyright © The McGraw-Hill Companies, Inc.)
Figure 33-50.
Puestow and Gillesby’s longitudinal pancreaticoje-
junostomy.
Norwalk: Appleton-Century-
Crofts, 1983, p 290.
33-52).
Advocates of the 
Figure 33-51.
Longitudinal dochotomy in obstructing calcific 
pancreatitis.
(Data from Partington et al.228)
A
B
Splenic artery
Figure 33-52.
Distal (spleen-sparing) pancreatectomy.
In the presence of minimal inflammation, a spleen-sparing 
version can be performed, as shown here.
33-56).
33-57).
33-59).
Figure 33-53.
The pylorus-sparing version of the procedure is used most commonly.
33-60).
33-61).
The duodenum-preserving pancreatic head resec-
tion described by Beger and colleagues.
A.
B.
Intraoperative view of the Beger procedure.
The 
gastroduodenal artery is encircled by a vessel loop.
A rim of well-vascularized pancreatic 
tissue remains in the duodenal C-loop.
Frey procedure.
Reconstruction is performed with a side-to-side Roux-en-Y pancreaticojeju-
nostomy.
(Reproduced with permission from Bell.188)
Figure 33-57.
Operative view of excavated head of the pancreas 
during the Frey procedure.
J Gastrointest Surg.
9:400, 2005.With kind permission 
from Springer Science + Business Media.)
Figure 33-58.
Complete excavation of the pancreatic head and 
distal pancreatic dochotomy.
Reconstruction is performed with a single side-to-side 
Roux-en-Y pancreaticojejunostomy.
Arch Surg.
139:375, 2004.
Copyright © 2004 American 
Medical Association.
All rights reserved.)
1389
P
ANCREAS
CHAPTER 33
Figure 33-59.
New York: Saunders, 2007, p 1310.
Excavation of pancreatic head without longitudinal 
pancreaticojejunostomy.
(Data from Ho HS, Frey CF.259)
Figure 33-61.
Dig Surg.
18:21, 2001.
Copyright © 2001, Karger Publishers.)
chronic pancreatitis.
Pain control was similar between the two procedures.
The degree of pain relief was equal 
over a 1- to 3-year follow-up.
hybrid or 
resectional procedures for patients with persistent symptoms.
The MEN1 syndrome involves pituitary tumors, 
parathyroid hyperplasia, and pancreatic neoplasms.
Unresectable disease in the liver is 
often addressed with chemoembolization.
Neuroendocrine tumors of the 
1391
P
ANCREAS
CHAPTER 33
pancreas often enhance with contrast.
33-62).
Routine laboratory studies will uncover a low blood sugar, 
the cause of all of these symptoms.
Serum insulin levels are 
elevated.
insulin  production leads to excess C-peptide.
However, this can be dangerous and 
must be done with close supervision.
Insulinomas are usually localized with CT scanning and 
EUS.
They are typically cured by simple enucleation.
Approximately 90% of insulinomas are sporadic, and 10% 
are associated with the MEN1 syndrome.
However, in the era of effective antacid therapy, the 
 presentation can be less dramatic.
At the time of diagnosis, 21% of patients with gas-
trinoma have diarrhea .
The diagnosis of ZES is made by measuring the serum 
gastrin level.
It is important that patients stop taking proton 
pump inhibitors for this test.
In most patients with gastrinomas, 
the level is >1000 pg/mL.
Gastrin levels can be elevated under-
conditions other than ZES.
33-63).
However, because gastrinomas 
can be found almost anywhere, whole-body imaging is required.
The test of choice is SSTR (octreotide) scintigraphy in combi-
nation with CT.
EUS is another modality that assists in the 
preoperative localization of gastrinomas.
A combination of 
octreotide scan and EUS detects >90% of gastrinomas.
Only one fourth of gastrinomas occur in association with the 
MEN1 syndrome.
Multiple tumors are more common in patients with  
Figure 33-63.
Passaro’s triangle.
Passaro.
Am J Surg.
1984;147:25.
Copyright Elsevier.)
MEN1 syndrome.
Aggressive surgical treatment is justified 
in patients with sporadic gastrinomas.
All lymph nodes in 
Passaro’s triangle are excised for pathologic analysis.
Pancreatic resection is justified 
for solitary gastrinomas with no metastases.
This may reduce the 
amount of expensive proton pump inhibitors required.
In gas-
trinomas, liver metastases decrease survival rates, but lymph 
node metastases do not.
Large amounts of potassium are lost in the stool.
The diabetes usually is mild.
Patients 
also complain of an enlarged, sensitive tongue.
The diagnosis is 
confirmed by measuring serum glucagon levels, which are usu-
ally >500 pg/mL.
Glucagon is a catabolic hormone, and most 
patients present with malnutrition.
The rash associated with glu-
cagonoma is thought to be caused by low levels of amino acids.
Again, debulking operations are 
recommended in good operative candidates to relieve symptoms.
The tumor frequently 
enhances with arterial contrast.(Fig.
33-64) Sometimes a cystic 
component is seen due to central necrosis.
Octreoscan (soma-
tostatin receptor scintigraphy) can be helpful to stage the dis-
ease.
Surgical resection is always recommended in fit patients 
in the absence of metastatic disease.
Neoplasms of the Exocrine Pancreas
Epidemiology and Risk Factors.
However, epidemiologic studies link-
ing various environmental and host factors provide some clues.
Pancreatic cancer is more common in the elderly with most 
patients being >60 years old.
Pancreatic cancer is more common 
in African Americans and slightly more common in men than 
women.
Another risk 
factor that is consistently linked to pancreatic cancer is cigarette 
smoking.
1394
SPECIFIC CONSIDERATIONS
UNIT II
PART II
Figure 33-64.
Pancreatic neuroendocrine tumor (PNET) demonstrating enhancement during arterial phase of CT scan.
Diabetes has been known to be associated with pancreatic 
cancer for many years.
The mechanisms involved in carcino-
genesis in patients with pre-existing pancreatitis are unknown.
Genetics of Pancreatic Cancer.
Pathology.
33-65).
Three stages of pancreatic intraepithelial neoplasia 
have been defined.
Adeno-
squamous carcinoma is a variant that has both glandular and 
squamous differentiation.
Diagnosis and Staging.
The 
tumor-node-metastasis (TNM) staging of pancreatic cancer is 
shown in Table 33-21 .
T1 lesions are ≤2 cm in diameter and are limited to the pan-
creas.
T2 lesions also are limited to the pancreas, but are >2 cm.
T4 lesions involve the 
celiac axis or superior mesenteric artery and are not resectable.
T1 
and T2 tumors with no lymph node involvement are considered 
stage I disease (stage IA and IB).
More extensive invasion, such 
as that associated with T3 tumors, indicates stage IIA disease.
Any lymph node involvement indicates stage IIB disease.
Pancreatic intraepithelial neoplasia (PanIN).
Am J Surg Pathol.
Ultimately, the majority of patients pres-
ent with pain and jaundice.
from  choledocholithiasis), this aphorism is not accurate.
Serum levels are elevated in about 75% of patients 
with pancreatic cancer.
If bile duct 
dilation is not seen, hepatocellular disease is likely.
33-66).
Computed tomography scan demonstrating resectable pancreatic cancer.
SMA = superior mesenteric artery.
ascites, and distant metastases (e.g., liver).
33-67).
A 
general exploration of the peritoneal surfaces is carried out.
The 
ligament of Treitz and the base of the transverse mesocolon are 
examined for tumor.
The gastrocolic ligament is incised, and the 
lesser sac is examined.
As the quality of CT scanning has improved, the value 
Figure 33-67.
Liver metastases identified at diagnostic laparoscopy.
1399
P
ANCREAS
CHAPTER 33
of routine diagnostic laparoscopy has decreased.
Biliary obstruction can be relieved with an endoscopic 
approach in almost all cases.
An 
algorithm for the diagnosis, staging, and treatment of pancreatic 
cancer is shown in Fig.
33-68.
Palliative Surgery and Endoscopy.
The mainstay of pain control is oral 
narcotics.
Sustained-release preparations of morphine sulfate 
are frequently used.
If an operative bypass is performed, choledochoje-
junostomy is the preferred approach.
Diagnostic and treatment algorithm for pancreatic cancer.
1400
SPECIFIC CONSIDERATIONS
UNIT II
PART II
Figure 33-69.
Biliary-enteric bypass to palliate unresectable pan-
creatic cancer.
Philadelphia: 
Lippincott-Raven, 1996, p 1074.)
Figure 33-70.
Expandable metallic 
biliary stent.
33-69).
33-70).
Endoscopic stents are definitely not as durable as 
a surgical bypass.
In such a patient, it is better to place an endoscopic stent.
Palliative Chemotherapy and Radiation.
Gemcitabine (Gemzar®) was approved by the U.S.
Food and 
Drug Administration (FDA) for use in pancreatic cancer in 
1996.
Ablation for Locally Advanced Unresectable Disease.
Persistent arterial vascular encasement after neoadjuvant ther-
apy contraindicates resection.
Randomized prospective trials are needed.
Surgical Resection: Pancreaticoduodenectomy.
Tumor seeding along the subcutaneous tract of the needle is 
uncommon.
Likewise, FNA under EUS guidance is safe and 
well tolerated.
The initial portion of the procedure is an assess-
ment of resectability.
The liver and visceral and parietal peritoneal 
surfaces are thoroughly assessed.
A Kocher maneuver is performed by dissecting 
behind the head of the pancreas.
The gastroepiploic vein and 
artery are ligated to prevent any traction injury.
Mesenteric vascular involvement is best determined by a 
high quality preoperative CT scan.
The porta hepatis is examined.
The hepatic artery is dis-
sected and traced toward the porta hepatis.
The gastroduodenal branch of the hepatic 
artery is identified.
Dissection is performed only on the 
anterior surface of the vein.
If there is no tumor involvement, the 
neck of the pancreas will separate from the vein easily.
A large, 
blunt-tipped clamp is a safe instrument to use for this dissection.
The common hepatic duct is circumferentially dissected.
The pancreatic neck is divided anterior to 
the portal vein (Fig.
33-71).
33-72).
Division of the pancreatic neck.
The pancreatic 
neck is separated from the anterior surface of the portal vein and 
then divided.
If there is no tumor involvement, the neck of the pan-
creas will separate from the vein easily.
A large, blunt-tipped clamp 
is a safe instrument to use for this dissection.
Philadelphia: Lippincott-Raven, 1996, p 1054.)
Figure 33-72.
Dissection of the pancreatic head and uncinate pro-
cess.
There are various techniques for the pancreatic anastomoses, and 
all have equivalent outcomes.
This is usually performed in an end-to-side fashion with one 
layer of interrupted sutures.
Pancreaticoduodenectomy with Vascular Resection.
Reconstruction can often be accomplished with a primary 
anastomosis of the vein.
This approach 
is associated with decreased blood loss and quicker recovery.
1403
P
ANCREAS
CHAPTER 33
Variations and Controversies.
Techniques for pancreaticojejunostomy.
A to D.
Duct-to-mucosa, end-to-side E.
Intraoperative photographs of end-to-side 
pancreaticojejunostomy.
F to J.
End-to-end invagination.
K to O.
End-to-side invagination.
33-73).
Pancreaticogastrostomy has also been 
investigated.
Therefore, the choice of techniques 
depends more on the surgeon’s personal experience.
(
Continued
)
1405
P
ANCREAS
CHAPTER 33
Figure 33-73.
(Continued) 
the  pancreaticojejunostomy cannot be avoided in one out of  
10 patients.
Impending catastrophe is often preceded by 
a small herald bleed from the drain site.
Open packing may be necessary to control diffuse necro-
sis and infection.
Jejunostomy tubes are certainly not benign and can result 
in leaks and intestinal obstruction.
Total pancreatec-
tomy has also been considered in the past.
Pancreatic cancer can recur locally after pancreaticoduo-
denectomy.
IORT may improve local con-
trol and palliate symptoms after pancreaticoduodenectomy.
In the 
acute phase, IV erythromycin may help but the problem usually 
improves with time.
Many technical modifications to the classic pancreatico-
duodenectomy have been described.
the invagination 
techniques.
Intraoperative hemorrhage typically occurs during the 
dissection of the portal vein.
Sometimes, 
the vein can be sutured closed with minimal narrowing.
Other 
times, a segmental resection and interposition graft (internal 
jugular vein) may be needed.
Uncom-
monly, a stress ulcer, or later, a marginal ulcer, can result in GI 
hemorrhage.
Outcome and Value of Pancreaticoduodenectomy for 
Cancer.
The tumor tends to recur locally 
with retroperitoneal and regional lymphatic disease.
In addition, 
most patients also develop hematogenous metastases, usually 
in the liver.
Malignant ascites, peritoneal implants, and malig-
nant pleural effusions are all common.
Median survival after 
pancreaticoduodenectomy is about 22 months.
Adjuvant Chemotherapy and Radiation.
Neoadjuvant Treatment.
For example, it avoids the risk that adjuvant 
treatment is delayed by complications of surgery.
It 
may even decrease the incidence of pancreatic fistula.
349
Postoperative Surveillance.
Recurrence after successful 
resection usually manifests as hepatic metastases.
Future Therapy.
Clinical trials 
for pancreatic cancer are ongoing and offer hope for more mean-
ingful treatment.
Ampullary and Periampullary Cancer.
Ampullary can-
cers need to be distinguished from periampullary cancers.
The 
ampulla is the junction of the biliary and pancreatic ducts within 
the duodenum.
The term ampullary cancer is more specific and is 
reserved for tumors that arise at the ampulla.
Management of Periampullary Adenomas.
Benign tumors 
such as ampullary adenomas can also originate at the ampulla.
However, benign villous adenomas of the ampullary region can 
be excised locally.
EUS may help to accurately determine if 
there is invasion into the duodenal wall.
In some centers, small periampullary adenomas 
can also be removed endoscopically.
Cystic Neoplasms of the Pancreas.
33-74).
Mucinous cystic neoplasm in tail of pancreas.
1409
P
ANCREAS
CHAPTER 33
CT scanning has increased.
The dilemma for 
the surgeon is an accurate assessment of the risk-benefit ratio 
of resection vs.
observation of these lesions in individual 
patients.
33-75).
Pseudocysts.
Although not usually necessary, analysis of 
pseudocyst fluid would reveal a high amylase content.
Cystadenoma.
Serous cystadenomas are essentially con-
sidered benign tumors without malignant potential.
Serous 
cystadenocarcinoma has been reported very rarely (<1%).
The average rate of growth is about  
0.45 cm/year.
About 50% of cystadenomas are asymptom-
atic and detected as an incidental finding.
Algorithm for management of pancreatic cystic neoplasms.
1410
SPECIFIC CONSIDERATIONS
UNIT II
PART II
moderate weight loss.
33-76).
For symptomatic patients with serous 
cystadenoma, surgical resection is indicated.
For lesions in the 
tail, splenectomy is not necessary, given the benign nature of 
the tumor.
If a conservative management is adopted, it is important to be 
sure of the diagnosis.
Mucinous Cystadenoma and Cystadenocarcinoma.
33-74).
There may be nodules or calcifications 
within the wall of the cyst.
The cysts are lined by tall columnar 
epithelium that fills the cyst with viscous mucin.
Elevated 
CEA levels in the fluid (>200 ng/mL) may suggest malig-
nant transformation.
Resection is the 
treatment of choice for most mucin-producing cystic tumors.
Malignancy cannot be ruled out without removal and extensive 
sampling of the tumor.
Malignancy has been reported in 6% 
to 36% of MCNs.
Current thinking is that all of these tumors 
will eventually evolve into cancer if left untreated.
Malignant 
transformation is more common with larger tumors, and older 
Figure 33-76.
Table 33-23.
World Health Organization classification of primary tu-
mors of the exocrine pancreas
A.
Benign
   1.
Serous cystadenoma (16%)
   2.
Mucinous cystadenoma (45%)
 3.
Intraductal papillary-mucinous adenoma (32%)
 4.
Mature cystic teratoma
B.
Borderline
 1.
Mucinous cystic tumor with moderate dysplasia
 2.
Intraductal papillary mucinous tumor with moderate 
dysplasia
 3.
Solid pseudopapillary tumor
C.
Malignant
 1.
Ductal adenocarcinoma
 2.
Serous/mucinous cystadenocarcinoma (29%)
 3.
There-
fore, a laparoscopic approach may not be appropriate for larger 
lesions.
Completely resected MCNs without atypia are usually 
cured especially if small (<3 cm).
Intraductal Papillary Mucinous Neoplasm.
(Fig.
33-77).
33-78).
33-79).
Intraductal papillary mucinous neoplasm histology.
(From Asiyanbola B, Andersen 
DK: IPMN.
Editorial Update.
Access Surgery, McGraw-Hill, 2008, 
with permission.
Copyright © The McGraw-Hill Companies, Inc.)
be resected in fit surgical candidates.
Branch-
duct IPMNs >3cm should be resected353.
Mucus can dilate the duct proximal and distal to the lesion.
33-78).
Survival of patients with IPMN, even when malignant and 
invasive, can be quite good.
As with MCN, patients with bor-
derline tumors or carcinoma in situ are usually cured.
Solid-Pseudopapillary Tumor.
Solid-pseudopapillary tumors 
are rare and typically occur in young women.
They are typi-
cally well circumscribed on CT (Fig.
33-80).
Most are cured by resection but liver 
and peritoneal metastasis has been reported.
Other Cystic Neoplasms.
It is more common, 5% to 10%, for neuroendocrine tumors of 
the pancreas to contain cysts.
These cysts are filled with sero-
sanguineous fluid rather than necrotic debris.
Lymphoepithe-
lial cysts of the pancreas usually occur in men in their fifth to 
sixth decade.
These benign lesions may be unilocular or mul-
tilocular and vary widely in size.
Intraductal papillary mucinous neoplasm (IPMN).
A.
Examples of “fish-eye deformity” of IPMN.
Mucin is seen extruding 
from the ampulla.
B.
Intraoperative 
pancreatic ductoscopy to assess the pancreatic tail (right).C.
Views of pancreatic duct during ductoscopy; normal (left) and IPMN (right).
1413
P
ANCREAS
CHAPTER 33
material if there is increased keratin formation.
There may 
be multiple lesions scattered throughout the pancreas.
Pancreatic Lymphoma.
Lymphoma can affect the pancreas.
Primary involvement of the pancreas with no disease outside the 
pancreas also occurs.
Percuta-
neous or EUS-guided biopsy will confirm the diagnosis in most 
cases.
Figure 33-80.
At surgery, the tumor was adherent to the splenic artery.
Pathologic diagnosis was solid-pseudopapillary 
carcinoma.
Figure 33-79.
(From Asiyanbola B, 
Andersen DK: IPMN.
Editorial Update.
Access Surgery, McGraw-
Hill, 2008, with permission.
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1422
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UNIT II
PART II
344.
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Spleen
Adrian E.
Park, Eduardo M.
Hippocrates1-3 in the fourth century bc was one of the first to 
write on the spleen.
He taught broadly on the need for balance 
and equilibrium between the patient and his environment.
The 
influence of Galen’s teaching endured for more than 1200 years.
The 
patient apparently survived.
Most patients who underwent sple-
nectomy in the three centuries that followed fared badly.
The 
vast majority of splenectomies performed were partial.
There soon followed an enthusiastic effort by surgeons to cure 
leukemia by splenectomy.
Dr.
Thomas Bryant performed the 
first splenectomy in 1866 in a patient with leukemia.
Unfortunately, it took several decades for his words to be 
heeded.
It may be most suitable in 
cases of enlarged spleen.
Conclusive evidence is lacking.
The laparoscopic approach has emerged 
as the standard for elective, nontraumatic splenectomy.
8 Overwhelming postsplenectomy infection (OPSI) is an 
uncommon but potentially grave disease.
Children and 
those undergoing splenectomy for hematologic malig-
nancy are at elevated risk.
9 Antibiotic prophylactic strategies against OPSI vary 
widely.
Data regarding their use are lacking.
Preop-
erative vaccination before elective splenectomy is most 
prudent.
Over 80% of accessory spleens are 
found in the region of the splenic hilum and vascular pedicle.
The average adult spleen is 7 to 11 cm in length and weighs 150 g 
(range, 70 to 250 g).
34-2).
The 
relationship of the pancreas to the spleen also has important 
clinical implications.
The splenic artery can be characterized by 
the pattern of its terminal branches.
Sites where accessory spleens are found in order of 
importance.
A.
Hilar region, 54%; B.
pedicle, 25%; C.
tail of pan-
creas, 6%; D.
splenocolic ligament, 2%; E.
greater omentum, 12%; 
F.
mesentery, 0.5%; G.
left ovary, 0.5%.
A
B
C
D
E
F
G Figure 34-2.
Suspensory ligaments of the spleen.
(Data from 
 Poulin EC, Thibault C.
The anatomical basis for laparoscopic 
 splenectomy.
Can J Surg.
This gross 
observation reflects the spleen’s microstructure.
34-3).
At the interface between the red and 
white pulp is the narrow marginal zone.
Unlike the 
cords of the red pulp, the sinuses of the red pulp are lined 
by endothelial cells.
The former 
play an important role in the targeting and clearance of 
certain bacterial pathogens.
In 
humans, the capsule is rich in collagen and contains some elas-
tin fibers.
The human splenic capsule and trabecu-
lae, by contrast, contain few or no smooth muscle cells.
Total splenic inflow of blood is approximately 250 to 300 
mL/min.
Splenic architecture.
From that entry, the flow rate through 
the spleen may vary greatly.
Most of the spleen’s filtration func-
tion occurs via the slower circulation.
The white pulp, 
by contrast, is involved only in adaptive immunity.
A minimum of 2 days of the 
erythrocyte’s 120-day life cycle is spent sequestered in the 
spleen.
Daily, approximately 20 mL of aged red blood cells are 
removed.
The spleen can also serve as an extra medullary site for 
hematopoiesis, if required.
Another role played by the spleen is 
in recycling iron.
Erythrocytes in large numbers are destroyed 
intravascularly throughout the body.
This gives rise to the elaboration of immunoglobulins 
(predominantly IgM).
Antigen clearance is then facili-
tated by the splenic and hepatic reticuloendothelial systems.
Splenomegaly 
refers simply to abnormal enlargement of the spleen.
Hypersplenism often is found in association with splenomegaly 
but is not synonymous with it.
The life cycles of cellular elements vary widely in human 
blood.
A neutrophil in circulation has a normal half-life of 
approximately 6 hours.
The spleen’s role in the normal clearance 
of neutrophils is not well established.
Platelets, on 
the other hand, generally survive in the circulation for 10 days.
A
B
C
Figure 34-4.
Splenomegaly.
A.
Computed tomography (CT) scan.
B.
Three-dimensional reconstruction of CT scan.
C.
Postoperative 
specimen.
Splenomegaly may result in 
sequestration of up to 80% of the platelet pool.
In addition, in response to some anemias, 
elements of the red pulp may revert to hematopoiesis.
Ultrasound
Ultrasound is the least invasive mode of splenic imaging.
It is 
rapid, easy to perform, and does not expose the patient to ioniz-
ing radiation.
Splenic artery and vein 
patency may be assessed using Doppler imaging.
The frequency of these artifacts increases with advanc-
ing patient age.
Plain films may also demonstrate 
1429
Spleen
CHAPTER 34
splenic calcifications.
The spleen will gener-
ally have a homogeneous MR signal on noncontrast images.
This becomes important in deciding whether or 
not a patient will benefit from a splenectomy.
Subsequent scintigraphy 
demonstrates the site(s) of platelet sequestration and clearance.
Man-
agement of splenic injury in the trauma patient is beyond the 
scope of this chapter.
The most common indication for elective 
splenectomy is ITP.
Benign Disorders
Red Blood Cell Disorders
Congenital
Hereditary Spherocytosis.
Splenomegaly usually is present on physical examination.
The mean corpuscular volume is typically low to nor-
mal or slightly decreased.
Spherocytes are readily apparent on 
peripheral blood film.
Near total splenectomy is advocated in children.
Red Blood Cell Enzyme Deficiencies.
Transfusions are given in cases of symp-
tomatic anemia.
All underwent splenectomy.
However, 
warm-antibody AIHA has clinical consequences with which the 
surgeon should be familiar.
Warm-antibody AIHA, although occurring primarily 
in midlife, can affect individuals at all ages.
Clinical presentation may be acute 
or gradual.
Findings include mild jaundice and symptoms and 
signs of anemia.
One-third to one-half of patients present with 
splenomegaly.
Sometimes in such cases the spleen is palpable 
on physical examination.
Treatment of AIHA depends on the severity of the disease 
and whether it is primary or secondary.
Severe symptomatic 
anemia demands prompt attention, often requiring red blood cell 
transfusion.
Mutant β 
chains included in the hemoglobin tetramer create HbS.
Deoxy-
genated HbS is insoluble and becomes polymerized and sickled.
The disorder is characterized by painful intermittent episodes.
Sequestration occurs in the spleen, with splenomegaly 
resulting early in the disease course.
It is only 
indicated in cases of massive splenomegaly or frequent seques-
tration crisis.
The patients often have a functional asplenia.
The clinical spectrum of the thalassemias is wide.
Het-
erozygous carriers of the disease are usually asymptomatic.
Careful assessment of the 
risk-benefit ratio is essential.
The duration of the bleeding helps to distinguish acute 
from chronic forms of ITP.
In contrast, adults experience a more chronic form of 
disease with an insidious onset.
Up to 
10% of children, however, have a palpable spleen tip.
Response rates range from 50% to 75%, 
but relapses are common.
An immediate response is common, but a sustained remis-
sion is not.
Therapeutic recommendations are summarized in Table 34-2.
Mortality was very low (1%), 
and morbidity was 10%.
Thrombotic Thrombocytopenic Purpura.
Hemolysis may also be due in part to sequestration 
and destruction of erythrocytes in the spleen.
Petechial hemorrhages in the lower 
extremities are the most common presenting sign.
Along with 
fever, patients may experience flu-like symptoms, malaise, or 
fatigue.
Plasma exchange is the first-line therapy for TTP.
The role of splenectomy 
in patients with white blood cell disorders varies.
Many HCL 
patients have few symptoms and require no specific therapy.
More than 90% of patients with HD present with lymph-
adenopathy above the diaphragm.
The spleen is often an occult 
site of spread, but massive splenomegaly is not common.
The most fre-
quent finding is lymphadenopathy.
When the spleen is enlarged, 
it may be massive or barely palpable below the costal margin.
Palliative splenectomy also is indi-
cated for symptomatic splenomegaly.
Bone Marrow Disorders (Myeloproliferative Disorders).
Hypersplenism, when 
it occurs in these conditions, usually is associated with spleno-
megaly.
Enlargement of the spleen is found in roughly one-
half of patients with CML.
Current therapy includes imatinib or 
allogeneic stem cell transplantation.
Unlike CML, AML has a presentation that is more rapid 
and dramatic.
Death usually results within weeks to months if AML 
goes untreated.
Splenomegaly occurs in one-
third to one-half of patients with ET.
AMM also can be referred to as myeloscle-
rosis, idiopathic myeloid metaplasia, and osteosclerosis.
In this 
chapter, the term myelofibrosis is synonymous with AMM.
Marrow failure is common.
Teardrop 
poikilocytosis is another frequent finding.
A thorough preoperative workup must precede sple-
nectomy in patients with AMM.
Primary infections of the spleen 
are infrequently reported.
The true incidence may be underreported, however.
Percuta-
neous drainage is successful for patients with unilocular disease.
Cysts.
Splenic cysts (Fig.
Such cysts are more commonly found in areas where the 
pathogen is endemic.
Symptomatic parasitic cysts are best treated with 
splenectomy.
Cysts resulting from trauma are termed pseudocysts due 
to their lack of cellular lining.
Both of 
these operations may be performed laparoscopically.66
Tumors and Metastasis.
The most common primary tumor 
of the spleen is sarcoma.
In 
some circumstances, colorectal, ovary, and melanoma metasta-
ses can be isolated to the spleen.
The underlying 
abnormality is a deficiency in the activity of a lysosomal hydro-
lase.
A.
Computed tomography (CT) scan of giant splenic cyst.
B.
Three-dimensional CT reconstruction of splenic cyst.
C and D.
Macroscopic aspect of a multicystic spleen lesion.
1438
SPECIFIC CONSIDERATIONS
UNIT II
PART II
in the spleen.
Four 
types of the disease (A, B, C, and D) exist, with unique clinical 
presentations.
Amyloidosis Amyloidosis is a disorder of abnormal extracellu-
lar protein deposition.
Symptoms of splenomegaly are relieved by splenectomy.
Any 
organ system may be involved.
The most commonly involved 
organ is the lung, followed by the spleen.
Splenomegaly occurs 
in approximately 25% of patients.
Women 
are four times more likely to be affected than men.
An excellent prognosis follows elective treatment.
Portal hypertension secondary to splenic vein thrombosis 
is potentially curable with splenectomy.
In Felty’s syndrome the spleen 
is four times heavier than normal.
The wandering 
spleen is not normally attached to adjacent viscera in the splenic 
fossa.
This may lead to splenic torsion and infarction.
The mechanism by which 
vaccination protects asplenic patients is not entirely understood.
Serum antibody titers do not necessarily correspond to clinical 
immunity.
Moreover, antibody levels after pneumococcus vac-
cination decline steadily within 5 to 10 years.
Anemic patients should be transfused before sur-
gery to a hemoglobin level of 10 g/dL.
Thrombocytopenia may be transiently corrected with platelet 
transfusions.
Bowel preparation is not routinely 
performed for patients undergoing elective splenectomy.
All 
splenectomy patients do receive DVT prophylaxis, as discussed 
previously.
After endotracheal intubation, a nasogastric (NG) 
tube is inserted for stomach decompression.
Traumatic rupture of the spleen continues as the most 
common indication for OS.
A midline incision is optimal for exposure when the spleen is 
ruptured or massively enlarged.
34-6).
Splenic hilar dissection then takes place.
Splenocolic ligament is divided at the beginning of 
open splenectomy.
1440
SPECIFIC CONSIDERATIONS
UNIT II
PART II
them.
The splenic bed is not routinely drained.
At the completion 
of surgery, the nasogastric tube is removed.
34-7).
The double-access 
technique requires the placement of five or six trocars.
34-7.
Use of an angled (30° or 45°) 
laparoscope (2, 5, or 10 mm) greatly facilitates the procedure.
Figure 34-7.
Patient positioning and trocar placement for laparoscopic splenectomy.
nificantly reduce the available operating space.
The splenic 
artery and vein are divided separately when possible.
Good 
long-term outcomes, however, are increasingly being achieved 
with mass hilar stapling (Fig.
34-8).
6
1441
Spleen
CHAPTER 34
Once excised, the spleen is placed in a durable ripstop 
nylon sack (Fig.
34-9), the neck of which is drawn through one 
of the 10-mm trocar sites.
Morcellation of the spleen takes place 
A
B
Figure 34-9.
Spleen extraction.
A.
Spleen is placed into a ripstop 
nylon bag before morcellation.
B.
Splenic morcellation.
34-10).
295 minutes).
34-11).
A 7- to 8-cm incision should be made 2 to 4 cm caudal 
to the inferior pole of the enlarged spleen.
Figure 34-10.
(Illustration 
is reproduced with permission from Park A et al.
Laparoscopic vs 
open splenectomy.
Arch Surg.
1999;134:1263.
Copyright © 1999 
American Medical Association.
All rights reserved.)
1442
SPECIFIC CONSIDERATIONS
UNIT II
PART II
A
B
C
Figure 34-11.
A.
Patient table placement for hand-assisted laparoscopic splenectomy (HALS) in case of splenomegaly.
B and C.
Intraop-
erative images of HALS.
This approach for 
solid organs poses several technical challenges.
Both the 
laparoscopic and open approaches for partial splenectomy have 
been well described.
The devascularized segment of spleen 
is transected along an obvious line of demarcation.
The true incidence is unknown.
The 
gravity of such injury is not to be underestimated.
There are also reports of splenic injuries 
after endoscopic procedures, such as colonoscopy.
Incisions and approaches must be tailored to both 
patient circumstances and surgeon experience.
As with all hemorrhage, prompt temporary control 
of bleeding is required.
The spleen is mobilized from its peritoneal attachments 
and the nature of the injury assessed.
After splenectomy, leukocytosis and increased platelet counts 
are common as well.
Hem-
orrhage can occur intraoperatively or postoperatively, present-
ing as subphrenic hematoma.
Sub-
phrenic abscess and wound infection are among the periopera-
tive infectious complications.
Hematologic responses may be 
divided into initial and long-term responses.
These results are consistent with the long-term 
success rate associated with OS.
A meta-analysis of perioperative outcomes of laparoscopic splenectomy for hematological diseases.
World J 
Surg.
2012;36:2349-2358.
With kind permission from Springer Science+Business Media.
due to spherocytosis, the success rate is usually higher, ranging 
from 90% to 100%.
Results of few prospective, randomized trials comparing 
LS and OS have been published.
Sepsis in splenectomized patients is a 
medical emergency.
Reason for splenectomy is 
the single most influential determinant of OPSI risk.
Finally, 
time interval from spleen removal must be considered.
A 
large number of OPSI cases occur many years to decades later.
Microbiology and Pathogenesis.
pneumoniae, H.
influenzae, 
and N.
meningitidis are classic examples).
Other 
potential infectious bacterial sources include group A streptococci, 
C.
Source: Data from Park A, McKinlay R.
Spleen.
In: Brunicardi FC, Andersen DK, Billiar TR, et al, eds.
Schwartz’s Principles of Surgery.
8th ed.
New 
York: McGraw-Hill; 2005:1312.
Antibiotics and the Asplenic Patient.
Optimal 
duration of chemoprophylaxis in children is unclear.
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1448
SPECIFIC CONSIDERATIONS
UNIT II
PART II
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Abdominal Wall, Omentum, 
Mesentery, and Retroperitoneum
Neal E.
Seymour and Robert L.
35-1).
35-1).
35-2).
These relationships are of critical signifi-
cance in the management of inguinal hernias.
35-3).
35-4).
Anterior abdominal wall innervation is segmental.
Anterior abdominal wall.
(Reproduced with 
permission from Moore KL, Dalley AF, 
eds.
Clinically Oriented Anatomy.
4th ed.
There is no aponeurotic posterior covering 
on the lower portion of the rectus muscles.
A lower recurrence rate benefit 
remains controversial.
levels.
35-5).
External oblique m.
All of the 
truncal muscles are involved in raising intra-abdominal pres-
sure.
This begs practical questions 
of where and how to make incisions.
Incisions for open surgery 
Figure 35-2.
(Reproduced with permission from Moore KL, Dalley AF, eds.
Clinically Oriented Anatomy.
4th ed.
Philadelphia: 
Lippincott Williams & Wilkins; 1999:181.)
Figure 35-3.
Cross-sectional anatomy of the abdominal wall above and below the arcuate line of Douglas.
(Reproduced with permission from Moore KL, Dalley AF, eds.
Clinically Oriented Anatomy.
4th ed.
35-6).
Dermatomal sensory innervation of the abdominal 
wall.
(Reproduced with permission from Moore KL, Dalley AF, 
eds.
Clinically Oriented Anatomy.
4th ed.
Philadelphia: Lippincott  
Williams & Wilkins; 1999:86.)
Figure 35-6.
Various anterior abdominal wall incisions for expo-
sure of peritoneal structures.
A.
Midline incision; B.
paramedian 
incision; C.
right subcostal incision and “saber slash” extension to 
costal margin (dashed line); D.
Rocky-Davis incision and Weir extension (dashed 
line); F.
McBurney incision; G.
transverse incision and extension 
across midline (dashed line); and H.
Pfannenstiel incision.
Figure 35-4.
Lymphatic drainage is via axillary 
or inguinal nodal basins.
(Reproduced with permission from Moore 
KL, Dalley AF, eds.
Clinically Oriented Anatomy.
4th ed.
Philadel-
phia: Lippincott Williams & Wilkins; 1999:188.)
procedures on the gastrointestinal tract.
The posterior, deeper layer consists of internal 
oblique and transversus abdominis muscle.
Abdominal incisions can lead to short- and long-term 
complications and patient disability.
The question of how large 
an incision ought to be has no simple answer.
35-7).
Examples include the Bookwalter™, 
Omni-Tract, and Thompson retractors.
The vitelline duct connects the 
embryonic and fetal midgut to the yolk sac.
At the end of 
the twelfth week, it returns to the abdominal cavity.
Defects in 
abdominal wall closure may lead to omphalocele or gastroschi-
sis.
During the third trimester, the vitelline duct regresses.
Per-
sistence of a vitelline duct remnant on the ileal border results in 
a Meckel’s diverticulum.
Bookwalter™ retractor in use for exposure of peri-
toneal structures during abdominal surgery.
pelvic position.
These are treated by urachal excision 
and closure of any bladder defect that may be present.
Acquired Abnormalities
Rectus Abdominis Diastasis.
Diastasis is usually easily identified 
on physical examination (Fig.
35-8).
Rectus Sheath Hematoma.
Figure 35-8.
Diastasis recti visible in the midepigastrium with 
Valsalva maneuver.
This should not be mistaken for a ventral hernia.
A 
hemoglobin/hematocrit level and coagulation studies should be 
obtained.
Both ultrasonography and CT (Fig.
35-9) can provide 
confirmatory imaging information and exclude other disorders.
Specific treatment depends on the severity of the hemor-
rhage.
Small, unilateral, and stable hematomas may be observed 
without hospitalization.
Trans-
fusion or coagulation factor replacement may be indicated in 
some situations.
Desmoid Tumors.
As many as 10% to 15% of FAP patients develop 
Figure 35-9.
Computed tomography scan showing a medium-
sized right rectus sheath hematoma.
This occurred in an elderly, 
anticoagulated patient without a clear history of trauma.
Involvement of margins is associated 
with recurrence rates as high as 80%.
Other Abdominal Wall Tumors.
Abdominal Wall Hernias.
Ventral hernias may be 
congenital or acquired.
The most common finding is a 
mass or bulge, which may increase in size with Valsalva.
Primary ventral hernias (nonincisional) are generally 
named according to their anatomic location.
Epigastric hernias 
are located in the midline between the xiphoid process and the 
umbilicus.
Most congenital umbilical hernias close 
spontaneously by 5 years.
If closure does not occur, elective sur-
gical repair is usually advised.
Adults with small, asymptomatic 
umbilical hernias should be followed clinically.
Umbilical hernia repair should be deferred until after the ascites 
is controlled.
Repair may be accomplished 
with either open or laparoscopic procedures.
Incisional Hernias.
The etiology of any given case of incisional 
hernia can be difficult to determine.
Primary repairs of incisional hernia include both simple 
suture closure and components separation.
Mesh repair has become the standard in the elective man-
agement of most incisional hernias.
Laparo-
scopic repairs use an underlay technique.
Each mesh material 
type has specific density, porosity, and strength characteristics.
Some of the commercially available meshes for incisional her-
nia repair are listed in Table 35-1.
Permanent mesh implants 
are made of prosthetic materials that do not degrade over time.
Their principal advantages are ease of use, relatively low cost, 
and durability.
These characteristics 
may be useful in the setting of contaminated or infected fields.
This method isolates mesh from the peritoneal contents.
Laparoscopic incisional hernia repair was first described 
by LeBlanc and Booth in 1993.
Since that time, numerous 
studies have examined early and late results compared to open 
repair.
35-10).
within the peritoneal cavity.
Abdominal examination may reveal a tender, palpable mass.
However, some cases may be indistinguishable 
from more worrisome surgical conditions.
Omental cysts are far 
less common than mesenteric cysts.
Physical 
examination may reveal a freely mobile intra-abdominal mass.
Treatment 
involves resection of all symptomatic omental cysts.
Resection 
of these benign lesions is readily accomplished using laparo-
scopic techniques.
Omental Neoplasms
Primary tumors of the omentum are rare.
Benign tumors of the 
omentum include lipomas, myxomas, and desmoid tumors.
35-11).
The 
related anatomic anomalies of the mesentery include paraduo-
denal or mesocolic hernias (Fig.
35-12), which can present as 
chronic or acute intestinal obstruction in children or adults.
(Reproduced with 
permission from Healy JE, Hodge J (eds).
Surgical Anat-
omy, 2nd ed.
Toronto: BC Decker, 1990:151.) 
Figure 35-12.
(Reproduced with permission from Healy JE, 
Hodge J, eds.
Surgical Anatomy.
2nd ed.
Toronto: BC Decker; 
1990:153.)
rise to the various terms used to describe this condition.
mesenteric artery
Aorta
Mesosigmoid, not fixed
Transv.
mesen-
teric art.
Mesentery
fixed
A' A'
A'
A'"
A"
B"
B'
B' B'
B'"
A
B
Inferior mesenteric v.
Left colic a.
35-13).
Operative findings range from a discrete mesenteric mass 
(Fig.
35-14) to broad areas of mesenteric nodularity and thick-
ening.
Rarely, an ostomy of some type for fecal diversion in the face of 
obstruction can be considered.
Clinical symptoms 
Figure 35-13.
Computed tomography scan of sclerosing mes-
enteritis (mesenteric lipodystrophy).
Figure 35-14.
Mesenteric cysts may be asymptomatic or cause acute 
or chronic symptoms of a mass lesion.
CT (Fig.
35-15), ultrasound, and MRI all have been used 
to evaluate patients with mesenteric cysts.
Cysts generally 
appear unilocular without solid component on imaging.
These can be difficult to 
treat and almost invariably recur after excision.
In this case, segmental bowel resec-
tion inclusive of the adjacent mesentery is performed.
Mesenteric Tumors
Primary tumors of the mesentery are rare.
Benign tumors of the 
mesentery include lipoma, cystic lymphangioma, and desmoid 
tumors.
Primary malignant tumors of the mesentery are similar 
to those described for omentum.
Treatment of mesenteric malignancies involves wide 
resection of the mass.
35-16).
Accordingly, 
Figure 35-15.
Computed tomography (CT) scan of a mesenteric cyst (left panel).
The site of pain may be 
variable and can include the back, pelvis, or thighs.
Erythema 
may be observed around the umbilicus or flank.
35-17).
The disease primarily affects individu-
als in the fourth to the sixth decades of life.
Anatomy of the retroperitoneum.
(Reproduced with permission from Healy JE, Hodge J, eds.
Surgical Anatomy.
2nd ed.
Toronto: BC Decker; 1990:201.)
Figure 35-17.
in defining an autoimmune cause of retroperitoneal fibrosis.
The relationship of 
these finding to the occurrence of fibrosis remains uncertain.
The fibrotic process begins in the ret-
roperitoneum just below the level of the renal arteries.
Bilateral involvement 
is noted in 67% of cases.
Psoas major m.
Common
iliac a.
The retroperitoneal fibrosis regresses upon 
discontinuation of these medications.
Presenting symptoms depend on the structure or structures 
affected by the fibrotic process.
Initially, patients complain of 
the insidious onset of dull, poorly localized abdominal pain.
Sudden-onset or severe abdominal pain may signify acute mes-
enteric ischemia.
Laboratory evaluation may reveal elevated 
blood urea nitrogen and/or creatinine levels.
It may be useful 
if iliocaval compressive or renal symptoms predominate.
Corticosteroids, with or without surgery, are the 
mainstay of medical therapy.
Laparoscopic ure-
terolysis has been shown to be as efficacious as open the open 
procedure.
Therapeutic efficacy is assessed 
based on patient symptoms and interval imaging studies.
Because 
long-term recurrences have been described, lifelong follow-up 
is warranted.
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Soft Tissue Sarcomas
Janice N.
Cormier, Alessandro Gronchi, and  
Raphael E.
The primary focus of 
this chapter is soft tissue sarcomas.
More often, a minor 
injury calls attention to a pre-existing tumor.
4 Overall 5-year survival rate for patients with all stages of soft 
tissue sarcoma is 50% to 60%.
6 The treatment algorithm for soft tissue sarcomas depends 
on tumor stage, site, and histology.
The two genes 
most relevant to soft tissue sarcoma are retinoblastoma (Rb) and 
figure 36-1.
The 
dominant pattern of metastasis is hematogenous, primarily to 
the lungs.
Tumors often grow centrifugally and can compress surrounding 
normal structures.
Ultrasonography.
Finally, ultrasonography can be 
used for postoperative surveillance and to guide biopsies.
Computed Tomography.
CT is also the preferred imaging technique for 
evaluating retroperitoneal sarcomas (Fig.
For extremity sarcomas, CT may be useful if MRI is 
not available or cannot be used.
Sagittal and coronal views 
allow evaluation of anatomic compartments in three dimensions  
(Fig.
36-3).
Soft tissue sarcomas of the extremities usually pres-
ent on MRI as a heterogeneous mass.
Their signal intensity tends 
figure 36-2.
A 69-year-old woman with a leiomyosarcoma involv-
ing the inferior vena cava.
Hemorrhagic, cystic, or necrotic changes 
may also be observed in the tumor.
MRI is also valuable for assessing tumor recurrence after 
surgery.
A baseline image is usually obtained 3 months after 
surgery.
Positron Emission Tomography.
PET imaging allows evaluation of the entire body.
Core Needle Biopsy.
The reported complication rate for core needle biopsy is less 
than 1%.45,46
Incisional Biopsy.
A 62-year-old man presented with right thigh pain.
Magnetic resonance imaging demonstrated a 20-cm high-grade sar-
coma within the medial compartment.
Excisional Biopsy.
However, excisional biopsy rarely provides 
benefits over other biopsy techniques.
Wide en bloc excision is seldom performed as a diagnostic 
procedure.
Histologic Grade of Aggressiveness.
Histologic grade is the 
most important prognostic factor for patients with soft tissue 
sarcoma.
The number of grades varies according to the classifica-
tion system used.
Tumor Size and Location.
Tumor size is an important prog-
nostic variable in soft tissue sarcomas.
Nodal Metastasis.
Distant Metastasis.
Distant metastases occur most often in 
the lungs (Fig.
36-4).
Other potential sites of metastasis include bone 
(Fig.
36-5), brain (Fig.
36-6), and liver (Fig.
36-7).
Visceral and 
figure 36-4.
figure 36-5.
figure 36-6.
figure 36-7.
Prognostic factors.
2.
3.
4.
5.
6.
1473
S
O
f
T
 T
ISSUE
 S
ARCOMAS
CHAPTER 36
radical or complete anatomic compartment resection.
Amputation.
However, survival rates did not differ between the groups.
The vessels are dissected, and all collateral vessels are ligated.
Chemothera-
peutic agents are then added to the perfusion circuit and circu-
lated for 90 minutes.
This report led to larger 
studies geared specifically to patients with sarcoma.
Conventional fractionation is usually 1.8 to 2 Gy per day.
Doses of 60 to 70 Gy are usually 
necessary for postoperative treatment.
No consensus exists on the optimal sequence of radia-
tion therapy and surgery.
The available data come largely from 
single-institution, nonrandomized studies.
For most patients with sarcoma, 
results of conventional chemotherapy regimens have been poor.
Targeted Therapies.
Several targeted agents are being investi-
gated for the treatment of soft tissue sarcomas.
The use of adjuvant and 
neoadjuvant chemotherapy for soft tissue sarcomas remains 
controversial.
Recurrence is common after surgery for abdominal soft tis-
sue sarcomas.
The most common initial site of distant metastasis of soft tis-
sue sarcomas is the lung.
36-9).
figure 36-9.
Adjuvant Therapy.
Unfortunately, 
the study was closed prematurely in 2006 because of low patient 
accrual.
Treatment of Recurrence.
Retroperitoneal sarcomas recur 
more often than extremity and trunk wall ones.
Retroperitoneal sarcomas can also recur diffusely 
throughout the peritoneal cavity (sarcomatosis).
Establishing the diagnosis of a gastrointestinal sarcoma 
preoperatively is often difficult.
Patients 
with localized disease frequently present with a large intra-
abdominal mass.
local) failure, is to resect the tumor with a 2- to 4-cm 
margin of normal tissue.
For sarcomas of the small or large intestine, segmental 
bowel resection is the standard treatment.
For small, low 
rectal lesions, clear margins may be achievable with a transanal 
excision.
Mammography is often nonspecific, and diagnosis 
requires punch or incisional biopsy.
Local and distant recurrences 
are more common in patients with high-grade lesions.
Complete 
excision with negative margins is the primary therapy.
Uterine Sarcoma
Sarcomas account for less than 5% of uterine malignancies.
Bilateral salpingo-oophorectomy is mandatory only 
in endometrial stromal sarcoma.
Pelvic post-
operative irradiation has been studied instead in a randomized 
fashion.
Adjuvant pelvic radia-
tion therapy can be considered for selected high-risk patients.
Adjuvant chemotherapy is controversial.
Endometrial stromal sarcomas account for approximately 
7% to 10% of uterine sarcomas.
Tamoxifen is not recommended because 
it may be proestrogenic in this setting.
It is associated with a poor prognosis even in patients 
presenting with localized disease.
Systemic agents for 
other soft tissue sarcomas are used for recurrent and/or meta-
static disease.
In a phase II 
trial, patients with KIT exon 11 mutations had better response 
rates (83.5% vs.
GIST most frequently metastasizes to the liver 
and/or abdominal cavity.
Extended anatomic 
resection and lymphadenectomy are not required.
The primary endpoint of the trial was sur-
vival.
In February 2002, the U.S.
When feasible, imatinib should be 
continued in the absence of disease progression.
Many patients with GIST develop resistance to imatinib.
Sunitinib has both antiangio-
genic and antiproliferative activity.
36-10A [before imatinib], 
Fig.
36-10B [after imatinib]).
The mechanisms of imatinib 
resistance are currently being investigated.
A.
Before imatinib.
B.
After imatinib.
determined.
Adjuvant treatment with imatinib for GIST 
patients was then examined in two key trials.
Food and Drug Administration in 2008 
and by the European Medical Agency (EMA) in 2009.
Beside the risk of recurrence, the other important factor 
to consider is the tumor genotype.
Patients with sporadic wild-type GIST could be treated on an 
individual basis.
Fortunately.
If not, then mutation status should be 
investigated before continuing the treatment.
Preoperative treatment may shrink the tumor and allow 
a more conservative local excision.
This is why there is growing 
evidence that the primary approach could be more conserva-
tive.
When used, a dose of 50 
to 54 Gy is usually recommended.
Systemic treatment is another 
option, when surgery is not indicated.
3.9 per million per year).
Satellite lesions may be found in patients with larger tumors.
Two primary histologic sub-
types account for 90% of cases: embryonal (70%) and alveolar 
(20%).
Extent of disease is the strongest predictor of long-term 
outcome.
Several staging systems for rhabdomyosarcoma are 
available.
The Intergroup Rhabdomyosarcoma Study Group 
system is based on surgical-pathologic groupings.
Recent findings suggest that 
chemotherapy alone can adequately control many such tumors.
Therefore, multiagent chemo-
therapy is recommended for all patients with rhabdomyosarcoma.
The 5-year disease-free survival rate for all patients 
has been reported to be 65%.
No single his-
tology accounts for more than 15% of all cases.
A CT scan of the chest 
is important for evaluation of metastatic disease.
A core needle 
biopsy is generally required to establish a diagnosis.
The natural history of soft tis-
sue sarcomas is well established.
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This page intentionally left blank 
Inguinal Hernias
Justin P.
Wagner, F.
Charles Brunicardi, Parviz K.
Amid, and David C.
Approximately 75% of abdominal wall hernias occur in 
the groin.
Abramson demonstrated the age 
dependence of inguinal hernias in 1978.
For those that survived 
the operation, recurrence of the hernia was common.
Outcomes improved, but recurrence 
rates remained high with prolonged follow-up.
Modifications of the Bassini repair were 
manifest in the McVay and Shouldice repairs.
37-1).
It is enveloped in three lay-
ers of spermatic fascia.
Key Points
1 Conservative management of asymptomatic inguinal hernias 
is acceptable.
3 Elective repair of inguinal hernias can be undertaken using an 
laparoscopic or open approach.
5 Recurrence, pain, and quality of life are important outcome 
factors.
2
ligament, and the conjoined tendon (Fig.
37-2).
It 
forms on the deep inferior margin of the transversus abdomi-
nis and transversalis fascia.
Direct 
hernias protrude medial to the inferior epigastric vessels, within 
Hesselbach’s triangle.
Femoral 
hernias protrude through the small and inflexible femoral ring.
The 
Nyhus classification categorizes hernia defects by location, size, 
and type (Table 37-2).
37-3).
37-4).
Two potential spaces exist within the pre-
peritoneum.
This area contains preperitoneal fat and areolar tissue.
37-5).
The inferior epigastric artery supplies 
the rectus abdominis.
37-6 and 37-7).
The ilioinguinal and iliohypogas-
tric nerves arise together from the first lumbar nerve (L1).
The 
Internal ring
External ring
Aponeurotic arch of
transverse abdominus m.
Spermatic cord
Femoral vessels
Inguinal ligament
Inguinal canal
Figure 37-1.
Location and orientation of the inguinal canal within the pelvic basin.
m.
= muscle.
Adductor brevis m.
Adductor magnus m.
Gracilis
Figure 37-2.
m.
= muscle.
It supplies 
somatic sensation to the skin of the upper and medial thigh.
In 
males, it also innervates the base of the penis and upper scrotum.
In females, it innervates the mons pubis and labium majus.
The 
iliohypogastric nerve arises from T12–L1.
It then divides into lateral 
and anterior cutaneous branches.
It then divides into genital and 
femoral branches.
Anatomy of the groin region from the posterior perspective.
Posterior view of intraperitoneal folds and associ-
ated fossa: A.
Umbilicus.
B.
Median umbilical ligament.
C.
Medial 
umbilical ligament (obliterated umbilical vein).
D.
Lateral umbili-
cal ligament (inferior epigastric vessels).
E.
Lateral fossa (indirect 
hernia).
F.
Medial fossa (direct hernia).
G.
Supravesical fossa.
(Modified with permission from Rowe JS Jr, Skandalakis JE, Gray 
SW.
Multiple bilateral inguinal hernias.
Am Surg.
In females, it supplies the ipsilateral mons 
pubis and labium majus.
37-8).
and v.
Vas deferens Obturator n.
Obturator vessels
Lacunar ligament
Cooper's ligament
Figure 37-5.
Posterior view of the myopectineal orifice of Fruchaud.
a.
= artery; n.
= nerve; v.
= vein.
Ilioinguinal n.
Iliohypogastric n.
Iliac m.
Lateral femoral
cutaneous n.
Femoral n.
Inguinal ligament
Genitofemoral n.
Retroperitoneal view of major inguinal nerves and their courses.
m.
= muscle; n.
= nerve.
37-10).
Anterior view of the five major nerves of the inguinal region.
Femoral branch of
genitofemoral n.
Ilioinguinal n.
Lateral femoral
cutaneous n.
Medial and intermediate
femoral cutaneous nn.
Saphenous n.
Iliohypogastric n.
Genital branch of
genitofemoral n.
Figure 37-8.
Sensory dermatomes of the major nerves in the groin 
area.
n.
= nerve.
Overall, there are 
limited data regarding the etiology of inguinal hernia devel-
opment.
& v.
Lateral border:
reflected 
peritoneum
Lat.
femoral cutaneous n.
Ant.
femoral cutaneous n.
or 
other variable branches
Femoral br.
of genitofemoral n.
Femoral n.
Borders and contents of the (A) triangle of doom and (B) triangle of pain.
a.
= artery; Ant.
= anterior; br.
= branch; Lat.
= 
lateral; n.
= nerve; v.
= vein.
(Modified with permission from Colborn GL, Skandalakis JE.
Laparoscopic cadaveric anatomy of the inguinal 
area.
Probl Gen Surg.
DIAgNOsIs
History
Inguinal hernias present along a spectrum of scenarios.
Varying degrees of closure of the processus vagi-
nalis (PV).
A.
Closed PV.
B.
Minimally patent PV.
C.
Moderately 
patent PV.
D.
Scrotal hernia.
Extrainguinal symptoms such as 
a change in bowel habits or urinary symptoms are less com-
mon.
Neurogenic pain may be referred to the scrotum, 
testicle, or inner thigh.
Questions should be directed to elicit and 
characterize extrainguinal symptoms.
Important considerations of the patient’s history include 
the duration and timing of symptoms.
Hernias will often increase 
in size and content over a protracted time.
Questions should also be 
directed to characterize whether the hernia is reducible.
Physical examination
Physical examination is essential to the diagnosis of inguinal 
hernia.
37-11).
This allows the inguinal canal to be explored.
The patient is then asked to perform Valsalva’s maneuver to 
protrude the hernia contents.
This is especially useful 
in the case of a small hernia.
Digital examination of the inguinal canal.
A further challenge to the physical examination is 
the identification of a femoral hernia.
Femoral hernias should 
be palpable below the inguinal ligament, lateral to the pubic 
tubercle.
Imaging in obvious cases is unnecessary and costly.
US is the least invasive technique and does not impart any 
radiation to the patient.
Positive intra-abdominal pressure is used to elicit the 
herniation of abdominal contents.
37-12).
Figure 37-12.
Computed tomography scan depicting a large 
right inguinal hernia (arrow).
A smaller left inguinal hernia is also 
visualized.
The indication for emergent inguinal hernia repair is 
impending compromise of intestinal contents.
As such, stran-
gulation of hernia contents is a surgical emergency.
The option to administer locoregional anesthesia is an 
advantage of the open approach.
In advance of the initial inci-
sion, a field block or ilioinguinal nerve block may be employed.
Exposure of the anterior inguinal region is common to 
the open approaches.
An oblique or horizontal incision is per-
formed over the groin (Fig.
37-13).
The incision begins two 
fingerbreadths inferior and medial to the anterior superior iliac 
spine.
It is then extended medially for approximately 6 to 8 cm.
The  subcutaneous tissue is dissected using electrocautery.
Scarpa’s fascia is divided to expose the external oblique aponeu-
rosis.
The flaps of the external oblique aponeurosis are elevated 
with Hemostat clamps.
The interior oblique fibers are dissected 
bluntly from the overlying external oblique flaps.
Dissection of 
the inferior flap reveals the shelving edge of the inguinal liga-
ment.
The iliohypogastric and ilioinguinal nerves are identified 
and preserved.
37-14).
The floor of the ingui-
nal canal is fully assessed for direct hernias.
The sac 
can then be grasped with a tissue forceps and bluntly dissected 
from the cord.
The dissection is carried proximally toward the 
deep inguinal ring.
The defect should be enlarged to 
augment blood flow to the sac contents.
At this point, the inguinal canal is reconstructed, either 
with native tissue or with prostheses.
Tissue Repairs.
Bassini Repair The Bassini repair was an historic advancement 
in operative technique.
Its current use is limited, as modern tech-
niques reduce recurrence.
37-15).
A triple-layer repair is then 
performed.
The 
lateral aspect of the repair reinforces the medial border of the 
internal inguinal ring.
A.
Layers of the abdominal wall in the anterior open approach to hernia repair.
B.
Ex.
= external; SQ = subcutaneous.
Figure 37-14.
Anterior open exposure of the inguinal canal.
m.
= 
muscle; n.
= nerve; v.
= vein.
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tissue layers results in lower recurrence rates (Fig.
37-16).
At the pubic tubercle, this 
suture is tied to the tail of the original stitch.
McVay Repair The McVay repair addresses both inguinal and 
femoral ring defects.
37-17).
Bassini repair.
A.
The transversalis fascia is opened 
B.
EO = external oblique aponeurosis.
A
B
Figure 37-16.
Shouldice repair.
A.
B.
Two 
more suture lines affix the internal oblique and transversus muscles 
medially.
Cooper’s ligament
Figure 37-17.
McVay Cooper’s ligament repair.
The upper flap is mobilized by 
gentle blunt dissection of underlying tissue.
Cooper’s ligament 
is bluntly dissected to expose its surface.
The 
transversalis is then sutured to the inguinal ligament laterally to 
the internal ring.
Prosthetic Repairs.
The techniques of the most commonly performed 
prosthetic repairs are presented in this section.
37-18).
Initial exposure and mobiliza-
tion of cord structures is identical to other open approaches.
37-19).
In the case of an indirect 
Figure 37-18.
Lichtenstein tension-free hernioplasty.
m.
= muscle; 
n.
= nerve; v.
= vein.
Slit
A
B
Figure 37-19.
Plug and patch repair.
A.
B.
Final view of the repair fol-
lowing placement of the plug and patch.
Exposure of the inguinal canal 
is identical to that of other open approaches.
The mesh has an underlay flap and an onlay 
flap, joined by a short cylindrical connector (Fig.
37-20).
The overlay flap reinforces the inguinal floor similar to a 
tension-free repair.
The spermatic cord is placed through a slit 
in the onlay portion of the mesh.
Wound Closure.
Scarpa’s fascia and skin are 
appropriately closed.
giant Prosthetic Reinforcement of the Visceral sac.
The transversalis is incised, and the preperitoneal 
space is dissected widely (Fig.
37-21).
Indirect her-
nias require directed dissection from the internal ring.
The middle por-
tion and lower corners of the mesh are clamped.
The mesh is 
placed flat along the inferior margin of the preperitoneal space 
(Fig.
37-22).
Splitting the mesh to accommodate 
the cord may predispose to hernia recurrence.
The transversalis is reapproximated and the wound 
is closed.
The indications for laparoscopic inguinal hernia repair are 
similar to those for open repair.
The Prolene Hernia System prosthesis.
Peritoneum
Preperitonial
space
Abdominal 
wall
Mesh
Figure 37-21.
Extensive dissection of the preperitoneal space on 
both sides will accommodate a large prosthesis.
The operating room configuration is identical for TAPP, 
TEP, and IPOM procedures.
The surgeon stands contralateral to the hernia, and 
the assistant stands opposite the surgeon.
The patient’s arms are 
tucked to the sides.
Fig.
37-23 demonstrates a typical operating 
room setup for laparoscopic inguinal hernia repair.
Transabdominal Preperitoneal Procedure.
The abdominal cavity is accessed using a dissecting trocar or 
open Hasson technique.
Pneumoperitoneum is instilled to a level 
of 15 mmHg.
37-24).
The patient is then placed in the 
Trendelenburg position, and the pelvis is inspected.
An indirect hernia sac will usually protrude anterior to 
the spermatic cord.
The sac is dissected from 
its adhesions, and the cord is skeletonized.
The mesh usually measures 10 × 15 cm to completely 
cover the myopectineal orifice (Fig.
37-25).
It is rolled length-
wise and placed through the 12-mm trocar.
The mesh is then pulled 
taut and fixed lateral to the anterior superior iliac spine.
The peritoneum should be closed completely to avoid contact 
between the mesh and the intestine.
The abdomen is desufflated 
and the trocars are removed.
The fascial defect of the 12-mm 
port and the skin incisions are appropriately closed.
C
AB
D
A
A
B
B
C
C
D
D
H
H
E
E
F
F
G
G
Figure 37-22.
Giant prosthetic reinforcement of the visceral sac.
A.
Exposure of the preperitoneal space.
B.
Dissection of the hernia sac from 
the spermatic cord.
C.
Reduction of the sac and elevation of the cord.
D.
Orientation and placement of the giant mesh.
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Totally extraperitoneal Procedure.
A small horizontal incision is made inferior to the umbi-
licus.
37-26).
37-24).
No modifications are necessary 
to repair bilateral inguinal hernias with the TEP approach.
Figure 37-23.
Operating room setup for laparoscopic inguinal hernia repair.
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B A 
Figure 37-24.
Figure 37-25.
View of mesh placement in posterior repairs.
A 
large mesh overlaps the myopectineal orifice.
Figure 37-26.
Balloon dissection of the preperitoneal space in a 
totally extraperitoneal inguinal hernia repair.
Trocars are removed, and the anterior rectus sheath is closed 
with an interrupted suture.
Intraperitoneal Onlay Mesh Procedure.
Port placement and inguinal hernia identification are identical to 
TAPP.
Instead, mesh is 
placed directly over the defect and fixed in place with sutures 
or spiral tacks.
synthetic Mesh Material.
A disadvantage of currently available commercial pros-
theses is their high cost.
Biologic Mesh.
While new prosthetic materials continue to be devel-
oped, no single biologic warrants routine use.
Fixation Technique.
Independent of prosthesis material, the 
method of its fixation remains disputed.
In TEP repairs, fixation of mesh may not be compulsory.
A focused physical examination should be performed.
As with primary hernias, US, CT, or MRI can elucidate ambigu-
ous physical findings.
Con-
versely, failed preperitoneal repairs should be approached using 
an open anterior repair.
Nociceptive pain is 
the most common of the three.
Neuropathic pain occurs as a result of direct nerve 
damage or entrapment.
Visceral pain refers to pain 
conveyed through afferent autonomic pain fibers.
CT scan or 
MRI excludes hernia recurrence, and bone scan is confirmatory 
for the diagnosis.
Emergent orchiectomy is only 
necessary in the case of necrosis.
Injury to the vas deferens within the cord may lead to 
infertility.
In laparoscopic approach, 
grasping the vas may result in a crush injury.
Injury to the 
artery of the round ligament does not result in clinically signifi-
cant morbidity.
Urinary Retention.
Failure to void normally 
requires reinsertion of the catheter for up to a week.
Ileus and Bowel Obstruction.
Abdominal imaging may be helpful to confirm the 
diagnosis and to exclude bowel obstruction.
True 
obstruction warrants reoperation.
Visceral Injury.
Small bowel, colon, and bladder are at risk 
for injury in laparoscopic hernia repair.
Direct bowel injuries may also result from tro-
car placement.
Missed bowel injuries are associated 
with increased mortality.
Vascular Injury.
In these cases, exsanguination may be swift.
Accordingly, the surgeon 
should be aware of this intraoperative consideration.
Injury to spermatic cord vessels 
may result in a scrotal hematoma.
Intermittent warm and cold compression aids in 
resolution.
The latter three 
sites are more frequently associated with laparoscopic repair.
Large 
hernia sac remnants may fill with physiologic fluid and mimic 
seromas.
Patients often mistake seromas for early recurrence.
Treatment consists of reassurance and warm compression to 
accelerate resolution.
In 
TAPP repair, the risk of intra-abdominal injury is higher than 
in TEP repair.
Surgeons should tailor this experience to 
optimize outcomes for each patient.
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89.
Willaert W, De Bacquer D, Rogiers X, et al.
Open preperito-
neal techniques versus Lichtenstein repair for elective inguinal 
hernias.
Cochrane Database Syst Rev.
2012;7:CD008034.
90.
McCormack K, Scott NW, Go PM, et al.
Laparoscopic tech-
niques versus open techniques for inguinal hernia repair.
Cochrane Database Syst Rev.
2003;1:CD001785.
91.
Andersson B, Hallen M, Leveau P, et al.
Surgery.
2003;133:464.
92.
Hallen M, Bergenfelz A, Westerdahl J.
Surgery.
2008;143:313.
93.
Lau H, Patil NG, Yuen WK.
Surg Endosc.
2006;20:76.
94.
Neumayer L, Giobbie-Hurder A, Jonasson O, et al.
Open 
mesh versus laparoscopic mesh repair of inguinal hernia.
N Engl J Med.
2004;350:1819.
95.
Lal P, Kajla RK, Chander J, et al.
Laparoscopic total extraperi-
toneal (TEP) inguinal hernia repair: overcoming the learning 
curve.
Surg Endosc.
2004;18:642.
96.
Katkhouda N, Campos GMR, Mavor E, et al.
Laparoscopic 
extraperitoneal inguinal hernia repair.
A safe approach based 
on the understanding of rectus sheath anatomy.
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This page intentionally left blank 
Thyroid, Parathyroid, and Adrenal
Geeta Lal and Orlo H.
even 
though the thyroid gland was not documented as such until the 
Renaissance period.
Burnt seaweed was considered to 
be the most effective treatment for goiters.
The open wound was treated with caustic powder and 
left to heal.
The most notable thyroid surgeons were Emil Theodor Kocher 
(1841–1917) and C.A.
However, as more patients survived thyroid operations, 
new problems and issues became apparent.
It originates at the 
base of the tongue at the foramen cecum.
38-1) that descends in the neck anterior 
to structures that form the hyoid bone and larynx.
The 
epithelial cells making up the anlage give rise to the thyroid fol-
licular cells.
Developmental Abnormalities
Thyroglossal Duct Cyst and Sinus.
Thyroglossal duct cysts 
are the most commonly encountered congenital cervical anoma-
lies.
Rarely, the thyroglossal duct may persist in 
whole or in part.
Medullary thyroid cancers (MTCs) are, however, not 
found in thyroglossal duct cysts.
Lingual Thyroid.
Many of these patients develop 
hypothyroidism.
Ectopic Thyroid.
Thyroid embryology—early development of the 
median thyroid anlage as a pharyngeal pouch.
(Reproduced with 
permission from Embryology and developmental abnormalities.
In: Cady B, Rossi R, eds.
Surgery of the Thyroid and Parathyroid 
Glands.
2 Familial nonmedullary thyroid cancer is increasingly being 
recognized as a separate entity.
Pyramidal Lobe.
Normally the thyroglossal duct atrophies, 
although it may remain as a fibrous band.
38-2.
A pyrami-
dal lobe is present in about 50% of patients.
Blood Supply.
The inferior 
Sup.
thyroid a.
and v.
Pyramidal
lobe
Common carotid a.
Common carotid a.
Thyroid 
cartilage
Int.
jugular v.
Int.
jugular v.
Recurrent laryngeal n.
Recurrent
laryngeal n.
Vagus n.
Vagus n.
Vagus n.
Arch of aorta
Thyrocervical 
trunk
Inf.
thyroid v.
Middle thyroid v.
Ext.
carotid a.
Thyroidea ima a.
(variable)
Trachea
Sternocleido-
mastoid m.
Inf.
thyroid a.
Vertebral
v.
and a.
Thyroid gland
Strap muscles
A
B
Figure 38-2.
a.
= artery;  
m.
= muscle; n.
= nerve; v.
= vein.
The superior thyroid veins run with the superior 
thyroid arteries bilaterally.
The middle vein or veins are the least 
consistent.
The superior and middle veins drain directly into the 
internal jugular veins.
The inferior veins often form a plexus, 
which drains into the brachiocephalic veins.
nerves.
The right RLN arises from the vagus at its crossing with 
the right subclavian artery.
38-3).
The RLNs terminate by entering the 
larynx posterior to the cricothyroid muscle.
The superior laryngeal nerves also arise from the vagus 
nerves.
The internal branch of 
the superior laryngeal nerve is sensory to the supraglottic larynx.
Injury to this nerve is rare in thyroid surgery, but its occurrence 
may result in aspiration.
38-4).
The fibers enter the gland with the blood vessels and 
are vasomotor in action.
Parathyroid Glands.
38-5).
Lymphatic System.
The thyroid gland is endowed with an 
extensive network of lymphatics.
These lymph nodes can 
be classified into seven levels as depicted in Fig.
38-6.
38-7).
There are about 3 × 106 follicles 
in the adult male thyroid gland.
The follicles are spherical and 
average 30 μm in diameter.
Thyroid Physiology
Iodine Metabolism.
The remaining plasma iodine is cleared 
via renal excretion.
Thyroid Hormone Synthesis, Secretion, and Transport.
The synthesis of thyroid hormone consists of several steps 
(Fig.
38-8).
(Reproduced with permission from Bliss RD 
et al.
Surgeon’s approach to the thyroid gland: Surgical anatomy 
and the importance of technique.
World J Surg.
2000;24:893.
Both processes are catalyzed by 
thyroid peroxidase (TPO).
The latter are deiodinated in the fifth step to 
yield iodide, which is reused in the thyrocyte.
T3 is 
less tightly bound to protein in the plasma than T4, and so it 
enters tissues more readily.
The secretion of thyroid hormone is controlled by the 
hypothalamic-pituitary-thyroid axis (Fig.
38-9).
TRH reaches the pituitary via the portovenous 
circulation.
T3 also 
inhibits the release of TRH.
Epinephrine 
and human chorionic gonadotropin hormones stimulate thyroid 
hormone production.
In contrast, glucocorticoids inhibit thyroid 
Lower parathyroid
Upper parathyroid
Int.
jugular v.
Recurrent laryngeal n.
Thyroid
Inferior thyroid a.
Common carotid a.
Figure 38-5.
Relationship of the parathyroids to the recurrent laryngeal nerve.
a.
= artery; v.
= vein.
1527
T
HYROID
, P
ARATHYROID
, 
A
n
D
 A
DRE
n
AL
CHAPTER 38
hormone production.
Thyroid Hormone Function.
In humans, two types of T3 receptor genes (α and β) are 
located on chromosomes 3 and 17.
Sternocleidomastoid m.
Spinal accessory n.
A and B.
Lymph nodes in the neck can be divided into six regions.
Upper mediastinal nodes constitute level VII.
m.
= muscle; 
n.
= nerve.
Thyroid hormones affect almost every system in the body.
They are important for fetal brain development and skeletal mat-
uration.
Myocardial α recep-
tors are decreased, and actions of catecholamines are amplified.
Evaluation of Patients with Thyroid Disease
Tests of Thyroid Function.
A multitude of different tests are 
available to evaluate thyroid function.
Figure 38-7.
Normal thyroid histology—follicular cells surround 
colloid.
The protein kinase C (PKC) pathway is stimulated at higher 
doses of TSH.
Mono- and diiodotyrosyl (MIT, DIT) residues are also coupled to form T4 and T3 by TPO.
Thyroglobulin carrying T4 and T3 is then 
internalized by pinocytosis and digested in lysosomes.
Thyroid hormone is released into the circulation, while MIT and DIT are deiodinated 
and recycled.
(Reproduced with permission from Kopp P.
Pendred’s syndrome and genetic defects in thyroid 
hormone synthesis.
Rev Endocr Metab Disord.
2000;1:114.
Serum TSH levels reflect the ability of the anterior 
pituitary to detect free T4 levels.
Individuals with these latter disorders may be euthyroid if their 
free T4 levels are normal.
Free T4 estimates are not performed as a routine screening 
tool in thyroid disease.
Free T4 levels may also 
be measured indirectly using the T3-resin uptake test.
Therefore, more T3 binds with an ion-exchange resin, and 
the T3-resin uptake is increased.
In a normal individual, TSH levels 
should increase at least 6 μIU/mL from the baseline.
Serum Thyroglobulin Tg is only made by normal or abnormal 
thyroid tissue.
It is also a sensitive marker of MTC.
In contrast, 131I has a half-life 
of 8 to 10 days and leads to higher-dose radiation exposure.
Hypothalamic-pituitary-thyroid hormone axis.
T4 = thyroxine.
(Reproduced with permission from Greenspan FS.
The thyroid gland.
In: Greenspan FS, Gardner D, eds.
Basic and 
Clinical Endocrinology.
6th ed.
New York: McGraw-Hill; 2001:217.
Areas that trap less radioactivity than the 
surrounding gland are termed cold (Fig.
38-10), whereas areas 
that demonstrate increased activity are termed hot.
This isotope is taken up by 
the mitochondria, but is not organified.
It also has the advantage 
of having a shorter half-life and minimizes radiation exposure.
It is particularly sensitive for nodal metastases.
There 
are several recent reports of rates of malignancy in these lesions 
ranging from 14% to 63%.
Ultrasound is also especially help-
ful for assessing cervical lymphadenopathy (Fig.
38-11) and to 
guide FNAB.
An experienced ultrasonographer is necessary for 
the best results.
If contrast is 
necessary, therapy needs to be delayed by several months.
Com-
bined PET-CT scans are increasingly being used for Tg-positive, 
RAI-negative tumors.
Benign Thyroid Disorders
Hyperthyroidism.
Hyperthyroidism may arise from a number of conditions that 
are listed in Table 38-1.
Figure 38-11.
Thyroid ultrasound showing a lymph node (arrow) along the carotid artery.
Figure 38-10.
Etiology, Pathogenesis, and Pathology.
The exact etiology of 
the initiation of the autoimmune process in Graves’ disease is 
not known.
The nuclei exhibit mitosis, and papillary projections of 
hyperplastic epithelium are common.
There may be aggregates 
of lymphoid tissue, and vascularity is markedly increased.
Clinical Features.
The most common GI symptoms include increased frequency 
of bowel movements and diarrhea.
On physical examination, weight loss and facial flush-
ing may be evident.
The skin is warm and moist, and African 
American patients often note darkening of their skin.
38-12).
Gynecomastia is com-
mon in young men.
Onycholysis, or separation of fingernails from their 
beds, is a commonly observed finding.
Diagnostic Tests.
If eye signs are present, other tests are generally not 
needed.
However, in the absence of eye findings, an 123I uptake 
and scan should be performed.
Anti-Tg and anti-TPO antibodies are elevated in 
up to 75% of patients but are not specific.
MRI scans 
of the orbits are useful in evaluating Graves’ ophthalmopathy.
Treatment.
The choice of treatment depends 
on several factors, as discussed in the following sections.
Antithyroid Drugs.
Antithyroid medications generally are admin-
istered in preparation for RAI ablation or surgery.
Methimazole has a longer half-life and can be 
dosed once daily.
Surgery should be 
postponed until the granulocyte count reaches 1000 cells/mm3.
The dose of antithyroid medication is titrated as needed 
in accordance with TSH and T4 levels.
Most patients have 
improved symptoms in 2 weeks and become euthyroid in about 
6 weeks.
The length of therapy is 
debated.
These drugs have the added 
effect of decreasing the peripheral conversion of T4 to T3.
Higher doses are some-
times required due to increased clearance of the medication.
Caution should be exercised in patients with asthma.
Radioactive Iodine Therapy (131I).
RAI forms the mainstay of 
Graves’ disease treatment in North America.
Antithyroid drugs are given until the patient 
A
B
Figure 38-12.
A.
Graves’ ophthalmopathy and (B) pretibial myx-
edema.
After standard treat-
ment with RAI, most patients become euthyroid within 2 months.
Lack of access to a high-volume thyroid surgeon 
is also a consideration.
Surgical Treatment.
Surgery is best performed in 
the second trimester.
The major action of iodine in this situation is to 
inhibit release of thyroid hormone.
Steroids can be a useful adjunct in this situation.
euthyroidism) and surgeon experience.
A subtotal thyroidectomy, leaving a 4- 
to 7-g remnant, was recommended for all remaining patients.
Over several years, enough 
thyroid nodules become autonomous to cause hyperthyroidism.
Diagnostic Studies.
Treatment.
Hyperthyroidism must be adequately controlled.
Both RAI and surgical resection may be used for treatment.
RAI scanning shows a “hot” 
nodule with suppression of the rest of the thyroid gland.
These 
nodules are rarely malignant.
Smaller nodules may be man-
aged with antithyroid medications and RAI.
Larger nodules can 
require higher doses, which can lead to hypothyroidism.
Oxygen supplementation and hemodynamic support 
should be instituted.
Hypothyroidism.
Conditions that cause hypothyroidism are listed in Table 38-2.
Failure to thrive and severe mental retardation often are 
present.
Hair becomes dry and brittle, and severe hair loss 
may occur.
There is also a characteristic loss of the outer two 
thirds of the eyebrows.
Patients may also have nonspecific abdomi-
nal pain accompanied by distention and constipation.
Libido 
and fertility are impaired in both sexes.
Laboratory Findings Hypothyroidism is characterized by low 
circulating levels of T4 and T3.
An electrocardiogram demonstrates 
decreased voltage with flattening or inversion of T waves.
The dose can be slowly increased over weeks to months to 
attain a euthyroid state.
Thyroiditis.
CT 
scans may help to delineate the extent of infection and identify 
abscesses.
Thyroidec-
tomy may be needed for persistent abscesses or failure of open 
drainage.
Subacute Thyroiditis Subacute thyroiditis can occur in the 
painful or painless forms.
History of a preceding upper respiratory tract infection 
often can be elicited.
The gland is enlarged, exquisitely ten-
der, and firm.
The disorder classically progresses through four 
stages.
A few patients develop recurrent disease.
The erythro-
cyte sedimentation rate is typically >100 mm/h.
Painful thyroiditis is self-limited, and therefore, 
treatment is primarily symptomatic.
Short-term thyroid 
replacement may be needed and may shorten the duration of 
symptoms.
The clinical course also paral-
lels painful thyroiditis.
Patients with symptoms may require 
β-blockers and thyroid hormone replacement.
Chronic Thyroiditis
Lymphocytic (Hashimoto’s) Thyroiditis.
Etiology, Pathogenesis, and Pathology.
Once activated, T cells can recruit cytotoxic 
CD8+ T cells to the thyroid.
Clinical Presentation.
An enlarged pyramidal lobe often is palpable.
Diagnostic Studies.
The disease occurs predomi-
nantly in women between the ages of 30 and 60 years old.
Physical examination reveals a hard, “woody” thyroid 
gland with fixation to surrounding tissues.
Surgery is the mainstay of the treatment.
Hypothyroid patients are treated with thyroid hormone 
replacement.
Any enlargement of the thyroid gland is referred to as 
a goiter.
The causes of nontoxic goiters are listed in Table 38-3.
Goiters may be diffuse, uninodular, or multinodular.
The TSH-dependent nodules progress 
to become autonomous.
In the past, dietary 
iodine deficiency was the most common cause of endemic goi-
ter.
In many sporadic goiters, no obvi-
ous cause can be identified.
As the goiters become very large, compres-
sive symptoms such as dyspnea and dysphagia ensue.
Patients 
also describe having to clear their throats frequently (catarrh).
Dysphonia from RLN injury is rare, except when malignancy is 
present.
38-13A).
Sudden enlargement of nodules 
or cysts due to hemorrhage may cause acute pain.
Deviation or compression of the trachea 
may be apparent.
If some nod-
ules develop autonomy, patients have suppressed TSH levels or 
become hyperthyroid.
RAI uptake often shows patchy uptake 
with areas of hot and cold nodules.
CT scans are helpful to evaluate the extent 
of retrosternal extension and airway compression (Fig.
38-13B).
Treatment Most euthyroid patients with small, diffuse goi-
ters do not require treatment.
Endemic goiters are treated by iodine 
administration.
History.
Patients with MTC may complain of a dull, aching 
sensation.
A history of hoarseness is worrisome, as it may be 
secondary to malignant involvement of the RLNs.
The risk is maximum 20 to 30 years 
after exposure, but these patients require lifelong monitoring.
The thyroid gland is best palpated 
from behind the patient and with the neck in mild extension.
The cricoid cartilage is an important landmark, as the isthmus 
is situated just below it.
2
1538
SPECIFIC CONSIDERATIONS
UNIT II
part II
Diagnostic Investigations.
An algorithm for the workup of 
a solitary thyroid nodule is shown in Fig.
38-14.
A.
This may become more prominent when patients raise their arms above the head—Pemberton’s sign.
B.
A sample of the aspirate is 
also placed in a 90% alcohol solution for cytospin or cell pellet.
The slides are stained by Papanicolaou’s or Wright’s stains and 
examined under the microscope.
A “benign” result is obtained in 60% to 70% of thyroid FNAs.
Other diagnoses include lymphocytic (Hashimoto’s) 
thyroiditis and granulomatous thyroiditis.
Management of a solitary thyroid nodule based on Bethesda criteria.
Hürthle cell neo-
plasms are also included in this category.
Laboratory Studies Most patients with thyroid nodules are 
euthyroid.
Determining the blood TSH level is helpful.
There is insufficient evidence to recom-
mend routine calcitonin testing for all nodules.
Ultrasound elastography is used 
to evaluate tissue stiffness noninvasively.
PET scanning does not play a major role in the primary 
evaluation of thyroid nodules.
Management.
When 
FNAB is used in complex nodules, the solid portion should be 
sampled.
If the nodule enlarges, repeat FNAB often is indicated.
In iodine-sufficient populations, the 
data are less impressive.
Thyroid cancer is respon-
sible for six deaths per million persons annually.
Molecular Genetics of Thyroid Tumorigenesis.
The RET 
proto-oncogene (Fig.
38-15) plays a significant role in the 
pathogenesis of thyroid cancers.
The RET protein is expressed in tissues derived 
from the embryonic nervous and excretory systems.
Structure of the RET tyrosine kinase receptor.
FMTC is associated with mutations at codons 768 and 804.
ATP = adenosine 
triphosphate.
(Reproduced with permission from Wells S, Franz C.
Medullary carcinoma of the thyroid.
World J Surg.
2000;24:954.
The tyrosine 
kinase domain of RET can fuse with other genes by rearrange-
ment.
These rearrangements 
confer constitutive activation of the receptor tyrosine kinases.
Aberrant activation of the MAPK pathway leads to 
tumorigenesis.
Aside from RET/PTC alterations, mutations in 
the Ras genes can also activate the MAPK pathway.
There are three 
Raf kinases, A-Raf, B-Raf (BRAF), and C-Raf.
Most patients are euthyroid and 
present with a slow-growing painless mass in the neck.
Dys-
phagia, dyspnea, and dysphonia usually are associated with 
locally advanced invasive disease.
Diagnosis is established by FNAB of the thyroid mass 
or lymph node.
The most common sites are lungs, fol-
lowed by bone, liver, and brain.
Pathology.
Macroscopic calcification, necrosis, or cystic change may be 
apparent.
Histologically, papillary carcinomas may exhibit pap-
illary projections (Fig.
The diagnosis is established by characteristic nuclear 
cellular features.
38-16B]), which allow diagnosis 
by FNAB.
These tumors 
are also being identified more frequently due to the widespread 
use of ultrasound.
About 25% of patients 
with these tumors have associated occult lymph node metastases.
Prognostic Indicators.
In general, patients with PTC have an 
excellent prognosis with a >95% 10-year survival rate.
The MACIS scale 
is a postoperative system modified from the AGES scale.
Surgical Treatment.
38-17).
When final histology confirms carcinoma, 
4
Figure 38-16.
A.
Histomicrograph of a papillary thyroid cancer (hematoxylin-eosin stain).
B.
1544
SPECIFIC CONSIDERATIONS
UNIT II
part II
completion thyroidectomy usually is performed.
Pain is uncommon, unless hemorrhage into the nodule has 
occurred.
FNAB is unable to distinguish 
benign follicular lesions from follicular carcinomas.
Large follicular tumors (>4 cm) in 
older men are more likely to be malignant.
Many of these genetic changes can be identified using tis-
sue obtained during FNAB.
Additional studies are needed to assess its utility in the broader 
clinical setting.41
Pathology.
Follicular carcinomas usually are solitary lesions, 
and the majority are surrounded by a capsule.
Histologically, 
follicles are present, but the lumen may be devoid of colloid.
Architectural patterns depend on the degree of differentiation 
demonstrated by the tumor.
Malignancy is defined by the pres-
ence of capsular and vascular invasion (Fig.
38-18).
They may, in fact, be unencapsulated.
Surgical Treatment and Prognosis.
(Reproduced with permission from Mazzaferri E, Jhiang S.
Am J Med.
1994;97:424.
Copyright Elsevier.)
Figure 38-18.
Hematoxylin-eosin–stained section from follicular 
thyroid carcinoma showing capsular invasion.
1546
SPECIFIC CONSIDERATIONS
UNIT II
part II
of thyroid cancer, or a history of radiation exposure.
Total thyroidectomy should be performed when thyroid cancer 
is diagnosed.
Prophylactic central neck dissection may be con-
sidered in patients with large tumors.
Hence, they are considered to 
be a separate class of tumors by some groups.
Early detection therefore 
appears to be very important to improve prognosis.
Several features place patients at increased risk for local 
recurrences or metastases.
Patients should receive 
T3 during this time period to decrease the period of hypothyroid-
ism.
T3 has a shorter half-life than T4 (1 day vs.
1 week) and needs 
to be discontinued for 2 weeks to allow TSH levels to rise before 
treatment.
Levels >30 mU/L are considered optimal, based on non-
controlled studies.
A low-iodine diet also is recommended during 
this 2-week period.
After a total thyroidectomy, this value should be <1%.
A 30-mCi dose is also effective 
at ablating the remnant with recombinant TSH.
Tumor recurrence at a median of 16.7 years after thyroid surgery.
The P values are derived from log-rank statistical analysis of 40-year life-
table data.
(Reproduced with permission from Mazzaferri E, Kloos R.
Current approaches to primary therapy for 
papillary and follicular thyroid cancer.
J Clin Endocrinol Metab.
2001;86:1453.
Up to 500 mCi can be 
given with proper pretreatment dosimetry.
Other kinases target-
ing the VEGF and RET receptors have also shown promising 
results.
TSH suppression reduces tumor recurrence rates.
Most MTCs occur sporadically.
All these 
variants are known to result secondary to germline mutations in 
the RET proto-oncogene.
The salient 
clinical and genetic features of these syndromes are outlined 
in Table 38-8.
Some clinical features of MEN2B patients are 
shown in Fig.
38-20.
The female-to-male ratio is 1.5:1.
BA
Figure 38-20.
Features of MEN2B: thickened lips (A) and mucosal neuromas (A and B).
1550
SPECIFIC CONSIDERATIONS
UNIT II
part II
Pathology.
Marked heterogeneity is present; cells may be polygo-
nal or spindle shaped.
These tumors also 
stain positively for CEA and calcitonin gene–related peptide.
Diagnosis.
Calcitonin and CEA 
are used to identify patients with persistent or recurrent MTC.
Calcitonin is a more sensitive tumor marker, but CEA is a better 
predictor of prognosis.
Treatment.
Pheochromocytomas 
need to be excluded.
If patients are found to have a pheochro-
mocytoma, this must be operated on first.
These tumors are gen-
erally (>50%) bilateral.
The role of prophylactic lateral neck 
dissection is controversial.
However, chemoembolization may 
be helpful in this setting.
There is no effective chemotherapy 
regimen.
Patients with recurrent/metastatic disease 
should be enrolled in well-designed clinical trials.
Postoperative Follow-Up and Prognosis.
Prognosis is related to dis-
ease stage.
Sur-
vival also is significantly influenced by disease type.
Prognosis is the 
worst (survival of 35% at 10 years) in patients with MEN2B.
The 
typical patient has a long-standing neck mass, which rapidly  
enlarges and may be painful.
Associated symptoms such as  
dysphonia, dysphagia, and dyspnea are common.
38-21).
Lymph nodes usually  
are palpable at presentation.
Evidence of metastatic spread also 
may be present.
Diagnosis is confirmed by FNAB revealing  
characteristic giant and multinucleated cells.
Immunohistochemical markers can aid with excluding other 
diagnoses.
Pathology.
On gross inspection, anaplastic tumors are firm and 
whitish in appearance.
Microscopically, sheets of cells with 
marked heterogeneity are seen.
The three main histologic growth 
patterns are spindle cell, squamoid, and pleomorphic giant cell.
Tumors may show a predominance of one pattern or a mixture 
of various patterns.
Treatment and Prognosis.
All forms of treatment have been disappoint-
ing.
All patients should have preoperative laryngoscopy to assess 
the status of the vocal cords.
Tracheostomy should be avoided as long as 
possible unless there is impending airway loss.
Patients may present with acute 
respiratory distress.
Therefore, needle core or open biopsy may be necessary for 
definitive diagnosis.
Combined treatment with 
radiotherapy and chemotherapy often is recommended.
The patient is positioned supine, with a sandbag 
between the scapulae.
The head is placed on a donut cushion, 
and the neck is extended to provide maximal exposure.
38-22A), although longer incisions may be needed.
Magnetic resonance imaging scan of a patient 
with anaplastic thyroid cancer.
Note heterogeneity consistent with 
necrosis.
38-22B).
The strap muscles rarely need to be divided to 
gain exposure to the thyroid gland.
C
Cricothyroid m.
External branch of
superior laryngeal n.
Superior 
thyroid vessels
D
Figure 38-22.
Conduct of thyroidectomy.
A.
Correct placement of thyroidectomy incision.
B.
Raising subplatysmal flaps.
C.
Dissection of 
middle thyroid vein.
D.
Dissection of the superior pole vessels, which should be individually ligated.
E.
Dissection at the ligament of Berry.
F.
Endoscopic thyroidectomy via axillary 
incisions.
m.
= muscle; n.
= nerve; v.
= vein.
The middle thyroid veins are ligated and 
divided (Fig.
38-22C).
The 
fascia just cephalad and caudad to the isthmus is divided.
38-22D).
The RLNs should then be identified.
The course of the right 
RLN is more oblique than the left RLN.
The nerves can be most 
consistently identified at the level of the cricoid cartilage.
Thyroid
E
F
Figure 38-22.
The RLN is most vulnerable to 
injury in the vicinity of the ligament of Berry.
38-22E).
Use of the electrocautery should 
be avoided in proximity to the RLN.
The procedure 
is repeated on the opposite side for a total thyroidectomy.
The 
sites should be marked with silk sutures and a clip.
The thyroid remnant 
is suture ligated, taking care to avoid injury to the RLN.
Routine 
drain placement rarely is necessary.
After adequate hemostasis 
is obtained, the strap muscles are reapproximated in the midline.
The platysma is approximated in a similar fashion.
The skin can 
be closed with subcuticular sutures or clips.
Video assis-
tance can be used to improve the visualization via the small inci-
sion.
The 
endoscopic approaches can also be performed with the assistance 
of robotic techniques.
38-22F).
An additional 5-mm 
trocar is inserted adjacent to the incision.
The thyroid gland is exposed by split-
ting the sternothyroid muscle.
The lower pole is retracted upward 
and dissected from the adipose tissue to identify the RLN.
The upper pole of the thyroid gland 
then is dissected free.
Mediastinal goiters can be primary or second-
ary.
Virtually all intratho-
racic goiters can be removed via a cervical incision.
The goiter is approached via a neck incision.
The supe-
rior pole vessels and the middle thyroid veins are identified and 
ligated first.
Placement of large 1-0 or 2-0 sutures deep into the goiter, when 
necessary, helps deliver it.
38-23).
1
2
3
Figure 38-23.
Conduct of thyroidectomy.
Incisions for a partial 
sternotomy.
38-24A) to the anterior margin 
of the trapezius muscle.
In contrast to 
1
2
3
McFee incision
A
B
Spinal 
accessory n.
Phrenic n.
Vagus n.
Scalenus
anticus m.
Lymph
nodes
Carotid a.
Internal
jugular v.
Figure 38-24.
Conduct of neck dissection.
A.
Incisions for modified radical neck dissection.
B.
Anatomic relations of structures identified dur-
ing a modified radical neck dissection.
a.
= artery; 
m.
= muscle; n.
= nerve.
38-24B).
Seromas may need 
aspiration to relieve patient discomfort.
Despite this, the technology has become widely adopted.
Not all experts agree with this recommendation.
In 1926, the first parathyroid operation was 
performed at Massachusetts General Hospital.
Olch at the Barnes Hospital in St.
Louis, Missouri.
Postoperatively, the patient 
developed tetany, requiring lifelong supplemental calcium.
The third branchial pouches give rise to the inferior para-
thyroid glands and the thymus (Fig.
38-25).
Approximately 15% of inferior glands are found in the 
thymus.
The frequency of intrathyroidal glands 
is about 2%.
Anatomy and Histology
Most patients have four parathyroid glands.
Parathyroid color depends on cellularity, fat content, and vas-
cularity.
Moreover, they often are embedded in and sometimes 
difficult to discern from surrounding fat.
Normal parathyroid 
glands are located in loose tissue or fat and are ovoid.
They 
measure up to 7 mm in size and weigh approximately 40 to 50 
mg each.
The parathyroid glands drain ipsilaterally by the superior, mid-
dle, and inferior thyroid veins.
Super-
numerary glands were present in 13% of patients, most com-
monly in the thymus.
Only 3% of patients had less than four 
glands.
38-26).
Parathyroid embryology.
(Reproduced 
with permission from Henry J.
Applied embryology of the thyroid 
and parathyroid glands.
In: Randolph G, ed.
Surgery of the Thyroid 
and Parathyroid Glands.
Philadelphia: WB Saunders Company; 
2003.
Copyright Elsevier.)
Figure 38-26.
Normal parathyroid histology showing chief cells 
interspersed with adipose cells.
Calcium is absorbed from the small intestine in its 
inorganic form.
Calcium fluxes in the steady state are depicted 
in Fig.
38-27.
Approximately 50% of the serum cal-
cium is in the ionized form, which is the active component.
The 
remainder is bound to albumin (40%) and organic anions such 
as phosphate and citrate (10%).
Both concentrations are tightly regulated.
Total and, particularly, ionized calcium levels are influenced by 
various hormone systems.
Parathyroid Hormone.
38-28).
The PTH gene is located on 
chromosome 11.
Secreted PTH 
has a half-life of 2 to 4 minutes.
The C-terminal component is excreted by 
the kidneys and accumulates in chronic renal failure.
Calcitonin.
When administered intravenously to 
experimental animals, it produces hypocalcemia.
At the kidney, 
calcitonin increases phosphate excretion by inhibiting its reab-
sorption.
Calcitonin plays a minimal, if any, role in the regula-
tion of calcium levels in humans.
However, it is very useful as 
a marker of MTC and in treating acute hypercalcemic crisis.
Vitamin D.
Vitamin D2 is available commercially in pharma-
PTH
PTH
VIT.
D PTH
Figure 38-27.
Calcium balance and fluxes 
in a normal human.
Solid arrows depict a 
direct effect, whereas dashed arrows depict 
an indirect effect.
The thickness of the arrows 
is representative of the magnitude of the flux.
ECF = extracellular fluid; PTH = parathyroid 
hormone; VIT.
= vitamin.
(Reproduced with 
permission from Bruder J, et al.
Mineral 
metabolism.
In: Felig P, Frohman L, eds.
Endocrinology and Metabolism.
New York: 
McGraw-Hill Publishers, Inc; 2001:1081.
Vitamin D is metabolized in the  
liver to its primary circulating form, 25-hydroxyvitamin D.
Primary Hyperparathyroidism.
PHPT is a common dis-
order, affecting 100,000 individuals annually in the United 
States.
Etiology.
Various diets and inter-
mittent exposure to sunshine may also be related.
Regulation of calcium homeostasis.
PKC = 
protein kinase C; PLC = phospholipase C.
(Reproduced with permission from Carling T.
Molecular pathology of parathyroid tumors.
Trends 
Endocrinol Metab.
2001;12:54.
Genetics Most cases of PHPT are sporadic.
All of these syndromes are 
inherited in an autosomal dominant fashion.
About 50% of patients develop gastri-
nomas, which often are multiple and metastatic at diagnosis.
This makes 
presymptomatic screening for mutation carriers difficult.
HPT develops in about 20% 
of patients with MEN2A and generally is less severe.
MEN2A 
is caused by germline mutations of the RET proto-oncogene 
located on chromosome 10.
This syndrome maps to a tumor suppressor locus 
HRPT2 (CDC73 or parafibromin) on chromosome 1.
Patients 
belonging to isolated HPT kindreds also appear to demonstrate 
linkage to HRPT2.
RET mutations are rare in 
sporadic parathyroid tumors.
These alterations are rare in benign para-
thyroid tumors and may have implications for diagnosis.
The 
p53 tumor suppressor gene is also inactivated in a subset (30%) 
of parathyroid carcinomas.
They are more likely to be mini-
mally symptomatic or asymptomatic.
Complications of 
PHPT are described below.
Renal Disease.
Approximately 80% of patients with PHPT have 
some degree of renal dysfunction or symptoms.
The calculi are typically composed of 
calcium phosphate or oxalate.
Bone Disease.
Advanced PHPT 
with osteitis fibrosa cystica now occurs in <5% of patients.
38-29).
Brown or osteoclastic tumors and bone cysts also 
may be present.
Bone disease correlates 
with serum PTH and vitamin D levels.
Gastrointestinal Complications.
PHPT has been associated with 
peptic ulcer disease.
neuropsychiatric Complications.
The etiology of these symptoms 
is not known.
Other Features.
PHPT and malig-
nancy account for >90% of all cases of hypercalcemia.
Figure 38-29.
Thiazide diuretics cause hypercalcemia by decreasing 
renal clearance of calcium.
Patients 
with FHH have lifelong hypercalcemia, which is not cor-
rected by parathyroidectomy.
Diagnostic Investigations
Biochemical Studies.
Furthermore, they do not cross-
react with PTHrP (Fig.
38-30).
Although extremely rare, 
a patient with hypercalcemia may have a tumor that secretes 
PTH.
In patients with FHH, 24-hour 
urinary calcium excretion is characteristically low (<100 mg/d).
Other biochemical features of 
PHPT are listed in Table 38-10.
(Reproduced with permission from Endres D, et al.
Measure-
ment of parathyroid hormone.
Endocrinol Metab Clin North Am.
1989;18:622.
These patients are prone to developing postoperative hypo-
calcemia due to bone hunger.
Serum and urine protein electro-
phoresis may be necessary to exclude multiple myeloma.
This can be accomplished by administering thiazide 
diuretics.
Radiologic Tests.
Abdominal ultrasound examination is used 
selectively to document renal stones.
Treatment
Indications for Parathyroidectomy and Role of Medical Management.
Average bone mass also remained relatively stable.
Unfortunately, bone density failed to improve in medi-
cally treated patients.
In addition, patients <50 years of age are advised 
to undergo parathyroidectomy.
Similarly, uncertainty is also pres-
ent concerning the cardiovascular consequences of mild HPT.
Localization studies may be 
classified into noninvasive or invasive modalities.
Some studies also show that 
use of localization studies may be more cost-effective.
99mTc-labeled sestamibi (Fig.
Sestamibi scans generally are complemented by neck ultra-
sound (Fig.
More recently, four-dimensional CT (4D-CT) has shown 
utility in parathyroid localization.
IOPTH mea-
surements, like localization studies, are less reliable in multiglan-
dular disease.
A.
B.
Endoscopic approaches include both video-assisted and 
total endoscopic techniques.
The 
procedure usually is performed under general anesthesia.
The 
patient is positioned supine on the operating table with the neck 
extended.
The 
initial dissection and exposure is similar to that used for thy-
roidectomy.
Identification of Parathyroids.
A bloodless field is important to 
allow identification of parathyroid glands.
(Repro-
duced with permission from Irvin G, et al.
Clinical usefulness of 
an intraoperative “quick parathyroid hormone” assay.
Surgery.
1993;114:1020.
This maneuver often causes the parathyroid gland to “pop” out.
Normal parathyroids are light beige and only slightly darker or 
brown compared to adjacent fat.
Hypercellular glands generally are darker, more firm, and more 
vascular than normocellular glands.
Location of Parathyroid Glands.
The majority of lower parathy-
roid glands are found in proximity to the lower thyroid pole 
(Fig.
38-33A).
If not found at this location, the thyrothymic 
ligament and thymus should be mobilized.
One can then “walk down” the thymus with suc-
cessive right-angle clamps (Fig.
38-33B).
Applying light tension 
along with a “twisting” motion helps to free the upper thymus.
38-33C).
The locations of ectopic upper and lower parathyroid glands are 
shown in Fig.
38-34.
Every attempt must be made to identify 
Upper parathyroid gland
Recurrent
laryngeal n.
Inf.
thyroid a.
Thymus
Lower
parathyroid
gland
Thyroid
A
B
C
Figure 38-33.
Conduct of parathyroidectomy.
A.
B.
C.
a.
= artery; Inf.
= inferior;  
n.
= nerve.
1569
T
HYROID
, P
ARATHYROID
, 
A
n
D
 A
DRE
n
AL
CHAPTER 38
all four glands.
Treatment depends on the number of abnormal 
glands.
1.
The vascular pedicle is 
clamped, divided, and ligated.
2.
If two abnormal and two normal glands are identified, the 
patient has double adenomas.
Triple adenomas are present 
if three glands are abnormal and one is normal.
3.
It often is difficult to distinguish multiple adenomas 
from hyperplasia with variable gland size.
Hyperplasia may 
be of the chief cell (more common), mixed, or clear cell 
type.
However, autotransplanted tissue may fail to function in 
about 5% of cases.
All four parathyroid glands are identified and carefully 
mobilized.
The resected parathyroid tis-
sue is confirmed by frozen section or PTH assay.
If the rem-
nant appears to be viable, the remaining glands are resected.
Parathyroid tissue usually is transplanted into the 
nondominant forearm.
A total of 12 to 14 pieces are 
transplanted.
Autotransplanted tissue also has been reported to 
function when transplanted into fat.
Intraoperative 
PTH assay during the operation from large veins may be helpful.
A sternotomy is needed to deliver these tumors in approxi-
mately 5% of cases.
Location of ectopic upper and 
lower parathyroid glands.
(Reproduced with 
permission from Akerström G, et al.
Surgical 
anatomy of human parathyroid glands.
Surgery.
1984;95:15.
The midline 
sternotomy can be extended to the left or right side as required.
Upper glands tend to migrate to the posterior mediastinum in 
the tracheoesophageal groove.
Special Situations
normocalcemic Hyperparathyroidism.
Data regarding the natural history of this 
disorder are limited.
Limited studies show that parathyroidectomy is more 
likely to be unsuccessful in these patients.
Parathyroid Carcinoma.
Parathyroid cancer accounts for approx-
imately 1% of PHPT cases.
Enlarged lymph nodes 
also may be present.
Frozen sections are generally unreliable.
Accurate diagnosis necessitates histologic examination.
The recurrent nerve is not sacrificed unless it is directly 
involved with tumor.
Adherent soft tissue structures (strap 
muscles or other soft tissues) should also be resected.
Prophylactic neck dissection is 
not advised.
If any question exists, 
histologic review by another experienced pathologist can  
be helpful.
Patients with equivocal pathologic findings and normo-
calcemia may be monitored closely.
Reoperation is indicated for 
locally recurrent or metastatic disease to control hypercalcemia.
Chemotherapy is 
not very effective.
Familial Hyperparathyroidism.
PHPT may occur as a component 
of various inherited syndromes such as MEN1 and MEN2A.
Inherited PHPT also can occur as isolated familial HPT (non-
MEN) or familial HPT with jaw tumors.
Moreover, HPT is less aggressive in 
these patients.
Hence, only abnormal parathyroid glands need 
to be resected at neck exploration.
The other normal parathyroid 
glands should be marked with a clip.
neonatal Hyperparathyroidism.
This disorder is associated with homozygous mutations in 
the CASR gene.
Subtotal resection is associated with high recurrence rates.
Parathyromatosis.
The true etiology 
of parathyromatosis is not known.
Aggressive local 
resection of these deposits can result in normocalcemia but is 
rarely curative.
Recurrences are rare (<1%), except in patients with famil-
ial HPT.
Recurrence rates of 15% at 2 years and 67% at 8 years 
have been reported for MEN1 patients.
Persistent and Recurrent Hyperparathyroidism.
38-35).
In particular, a 24-hour urine collec-
tion should be performed to rule out FHH.
There are no published guidelines directly applicable 
to this group of patients.
Preoperative localization studies 
are routinely performed.
Anatomic location of ectopic parathyroid 
glands.
Numbers represent number of glands found in each 
location, with a total of 54.
(Reproduced with permission 
from Shen W, et al.
Re-operation for persistent or recurrent 
primary hyperparathyroidism.
Arch Surg.
1996;131:864.
Copyright © 1996 American Medical Association.
An algo-
rithm for the treatment of patients with recurrent and persistent 
HPT is shown in Fig.
38-36.
Generally, these patients are approached with a focused 
exploration.
The lateral approach is frequently used and can be 
achieved via the previous incision.
Parathyroid tissue is cryopreserved 
routinely.
Blind mediastinal 
exploration is not recommended.
Hypercalcemic Crisis.
Calcium levels are markedly elevated and may be as high as 16 
to 20 mg/dL.
Parathyroid tumors tend to be large or multiple and 
may be palpable.
Treatment consists of therapies to lower serum calcium 
levels followed by surgery to correct HPT.
Occasionally, in life-threatening cases, hemodialysis may be  
of benefit.
Secondary Hyperparathyroidism.
Patients generally are hypocalce-
mic or normocalcemic.
Studies also show 
that calcimimetics may be less cost-effective in the long-term.
Follow-up
if mild
hypercalcemia  
Parathyroidectomy Medical therapy
No Yes
Figure 38-36.
Management of recurrent and persistent hyperpara-
thyroidism (HPT).
FHH = familial hypocalciuric hypercalcemia; 
PTH = parathyroid hormone.
Localization stud-
ies are not necessary but can identify ectopic parathyroid glands.
A bilateral neck exploration is indicated.
All parathyroid glands should be 
identified.
Further studies are needed to define the best operative approach 
for these patients.
Complications of Parathyroid Surgery.
Specific complications include transient and permanent vocal 
cord palsy and hypoparathyroidism.
Acute hypocalcemia results in decreased ionized cal-
cium and increased neuromuscular excitability.
Patients  
initially develop circumoral and fingertip numbness and 
tingling.
Mental symptoms include anxiety, confusion, and 
depression.
38-37).
Therefore, ectopic adrenocortical tissue may be 
found in the ovaries, spermatic cord, and testes.
In contrast, the adrenal medulla is ectodermal in 
origin and arises from the neural crest.
Most extra-adrenal 
neural tissue regresses but may persist at several sites.
Adrenal medullary tissue also may be found in 
neck, urinary bladder, and para-aortic regions.
The normal adrenal gland measures 5 × 3 × 1 cm and 
weighs 4 to 5 g.
The left adrenal is closely associated 
with the aorta, spleen, and tail of the pancreas.
Other vessels originating 
from the intercostal and gonadal vessels may also supply the  
adrenals.
The anatomic rela-
tionships of the adrenals and surrounding structures are depicted 
in Fig.
38-38.
These latter zones are the 
site of production of glucocorticoids and adrenal androgens.
It produces the catechol-
amine hormones epinephrine and norepinephrine.
The cells of 
the adrenal medulla are arranged in cords and are polyhedral in 
shape.
38-39).
Mineralocorticoids.
Cortisol has minimal effects on the kidney due to hor-
mone degradation.
Aldosterone secretion is regulated primarily 
by the renin-angiotensin system.
Renin, in turn, leads to the production of angiotensin I from 
its precursor angiotensinogen.
A small quantity of free aldosterone 
also is excreted in the urine.
Mineralocorticoids cross the cell 
membrane and bind to cytosolic receptors.
9
1
2
3
6
7
8
C
A
4
5
B
Figure 38-37.
(Reproduced with permission from Avisse C, et al.
Surgical 
anatomy and embryology of the adrenal glands.
Surg Clin North 
Am.
2000;80:414.
Glucocorticoids.
and v.
Right phrenic a.
Celiac trunk
Superior
mesenteric a.
Left adrenal gland Right adrenal gland 
Left superior adrenal aa.
Right superior adrenal aa.
Inferior adrenal a.
Renal 
a.
and v.
Left adrenal v.
Inferior adrenal a.
Right
adrenal
v.
Middle
adrenal
a.
Figure 38-38.
Anatomy of the adrenals and surrounding structures.
a.
= artery; v.
= vein.
Synthesis of adrenal steroids.
DHEAS = dehydroepiandrosterone sulfate.
ACTH secretion may be 
stimulated by pain, stress, hypoxia, hypothermia, trauma, and 
hypoglycemia.
38-40).
Corti-
sol controls the secretion of both CRH and ACTH via a negative 
feedback loop.
A similar mechanism leads to the inhibition of 
CRH secretion by ACTH.
Approxi-
mately 10% of circulating cortisol is free and is the biologically 
active component.
A small amount of unmetabolized cortisol is excreted 
unchanged in the urine.
Glucocorticoid hormones enter the cell and bind cytosolic 
steroid receptors.
Cortisol also binds the mineralocorticoid receptor with 
an affinity similar to aldosterone.
Sex Steroids.
Adrenal androgens are weakly bound to plasma albumin.
Androgen metabolites are conju-
gated as glucuronides or sulfates and excreted in the urine.
Dur-
ing fetal development, adrenal androgens promote the formation 
of male genitalia.
Catecholamines.
The substrate, tyrosine, is converted to catechol-
amines via a series of steps shown in Fig.
38-41A.
Diurnal variation in cortisol levels as determined by half-hourly sampling in a 16-year-old girl.
(Reproduced with permission 
from Krieger DT, et al.
Characterization of the normal temporal pattern of corticosteroid levels.
J Clin Endocrinol Metab.
1971;32:269.
In the circulation, these pro-
teins are bound to albumin and other proteins.
38-41B).
Adrenergic receptors are transmembrane-spanning mol-
ecules that are coupled to G proteins.
Disorders of the Adrenal Cortex
Hyperaldosteronism.
Other symp-
toms include muscle weakness, polydipsia, polyuria, nocturia, 
headaches, and fatigue.
Weakness and fatigue are related to the 
presence of hypokalemia.
Diagnostic Studies
Laboratory Studies.
Once the diagnosis 
is suspected, further tests are necessary to confirm the diagno-
sis.
Before testing, patients must receive adequate sodium and 
potassium.
A.
Synthesis of catecholamines.
B.
Metabolism of catecholamine hormones.
Radiologic Studies.
If adrenal hyperplasia is suspected, the algorithm depicted 
in Fig.
38-42 is useful.
This test, however, is not 
widely available.
Rarely, acute 
Addison’s disease may occur 2 to 3 days after adrenalectomy.
Cushing’s Syndrome.
38-43).
Cushing’s 
syndrome (endogenous) is a rare disease, affecting 10 in 1 million  
individuals.
It is more common in adults but may occur in children.
Women are more commonly affected (male:female ratio 1:8).
Management of an adrenal aldosteronoma.
CT = 
computed tomography; MRI = magnetic resonance imaging.
Cushing’s syndrome may be classified as ACTH-dependent 
or ACTH-independent (Table 38-17).
The most common cause 
of hypercortisolism is exogenous administration of steroids.
Primary adrenal hyperplasia may be micronodular, mac-
ronodular, or massively macronodular.
Adrenal hyperplasia 
resulting from ACTH stimulation usually is macronodular 
(3-cm nodules).
Symptoms and Signs The classical features of Cushing’s syn-
drome are listed in Table 38-18.
Progressive truncal obesity is the 
most common symptom, occurring in up to 95% of patients.
Figure 38-43.
Some characteristic features of Cushing’s  
syndrome—moon facies, hirsutism, and acne.
ACTH = adrenocorticotropic hormone; CRH = corticotrophin-releasing 
hormone.
Purple striae are often visible on the protuberant abdomen.
Rounding of the face leads to moon facies, and thinning of 
subcutaneous tissues leads to plethora.
In children, 
Cushing’s syndrome is characterized by obesity and stunted 
growth.
38-44).
Laboratory Studies.
In this test, 1 mg of 
a synthetic glucocorticoid (dexamethasone) is given at 11 p.m.
and plasma cortisol levels are measured at 8 a.m.
the following 
morning.
Diagnosis of Cushing’s syndrome.
This is best accom-
plished by measurement of plasma ACTH levels (normal 10– 
100 pg/mL).
ectopic).
The CRH test also is helpful in determining the etiology 
of Cushing’s syndrome.
CRH stimulation also can enhance the usefulness of petrosal vein 
sampling.
Radiologic Studies.
CT and MRI scans of the abdomen can iden-
tify adrenal tumors with 95% sensitivity.
MRI 
scans have the added advantage of allowing assessment of vas-
cular anatomy.
Adrenal adenomas appear darker than the liver 
on T2-weighted imaging.
In this study, 
catheters are placed in both internal jugular veins and a periph-
eral vein.
Bilateral adrenalectomy is curative for 
primary adrenal hyperplasia.
Duration of steroid therapy 
is determined by the ACTH stimulation test.
This latter group of patients also may require mineralocorticoid 
replacement therapy.
Adrenocortical Cancer.
Adrenal carcinomas are rare neo-
plasms with a worldwide incidence of two per 1 million.
Loci on 11p (Beckwith-Wiedemann syndrome), 2p (Car-
ney complex), and 9q also have been implicated.
Rarely, weight loss, anorexia, and nau-
sea may be present.
CT and MRI scans are useful to image these tumors 
(Fig.
38-45).
Up to 70% of patients present with stage III or IV disease.
Pathology Most adrenocortical cancers are large, weighing 
between 100 and 1000 g.
On gross examination, areas of hem-
orrhage and necrosis often are evident.
Capsular or vascular invasion is the most reliable sign of cancer.
Nodes (N): N0, no involvement of regional nodes; N1, positive regional 
lymph nodes.
Metastasis (M): M0, no known distal metastases, M1, distant metastases 
present.
Source: Used with permission of the American Joint Committee on 
Cancer (AJCC), Chicago, Illinois.
Adrenocortical tumors commonly metasta-
size to the liver, lung, and bone.
However, this modality is used in the 
palliation of bony metastases.
Sex Steroid Excess.
Adrenal adenomas or carcinomas 
that secrete adrenal androgens lead to virilizing syndromes.
Feminizing adrenal tumors are less 
common and occur in men in the third to fifth decades of life.
These tumors lead to gynecomastia, impotence, and testicular 
atrophy.
Women with these tumors develop irregular menses 
or dysfunctional uterine bleeding.
Vaginal bleeding may occur 
in postmenopausal women.
Girls with these tumors experience 
precocious puberty with breast enlargement and early menarche.
Treatment Virilizing and feminizing tumors are treated by adre-
nalectomy.
Congenital Adrenal Hyperplasia.
Partial enzyme deficiency may present at 
birth or later with virilizing features.
These patients are less prone 
to the salt wasting that characterizes complete enzyme deficiency.
Other enzyme deficiencies 
include 3β-hydroxydehydrogenase and 17-hydroxylase defi-
ciency.
Urinary 17-hydroxyprogesterone, andro-
gens, and 17-ketosteroids also are elevated.
CT, MRI, and 
iodocholesterol scans generally are used to localize the tumors.
Disorders of the Adrenal Medulla
Pheochromocytomas.
Pheochromocytomas occur in families with MEN2A and 
MEN2B in approximately 50% of patients.
The incidence of pheochromocytomas 
in the syndrome is approximately 14%.
The gene causing VHL 
has been mapped to chromosome 3p and is a tumor suppres-
sor gene.
The most common clinical sign is hyperten-
sion.
Sudden death may occur in 
patients with undiagnosed tumors who undergo other surgeries 
or biopsy.
Diagnostic Tests
Biochemical Studies.
Many physiologic and pathologic states can alter the levels of 
plasma catecholamines.
Hence, they often are thought to be 
less accurate than urinary tests.
Radiologic Studies.
CT scans are 85% to 95% 
sensitive and 70% to 100% specific for pheochromocytomas 
(Fig.
38-46A).
CT scans do not provide functional information 
and cannot definitively diagnose pheochromocytomas.
MRI 
is also the study of choice in pregnant women as there is no 
risk of radiation exposure.
Normal 
adrenal medullary tissue does not take up appreciable MIBG.
131I-radiolabeled MIBG is, therefore, useful for localizing pheo-
chromocytomas (Fig.
38-46B), especially those in ectopic posi-
tions.
This test has a reported sensitivity of 77% to 89% and 
specificity ranging from 88% to 100%.
Patients should be warned about orthostatic hypotension.
Adrenalectomy is the treatment of choice for patients with 
pheochromocytoma.
Intraoperative arrhythmias are best managed 
by short-acting β-blockers such as esmolol.
However, most pheochromocytomas <5 cm in diameter 
can be safely resected laparoscopically.
Hereditary Pheochromocytomas.
Inherited pheochromo-
cytomas tend to be multiple and bilateral.
Malignant Pheochromocytomas.
There are no definitive 
histologic criteria defining malignant pheochromocytomas.
In 
fact, pleomorphism, nuclear atypia, and abundant mitotic fig-
ures are seen in benign tumors.
Capsular and vascular invasion 
may be seen in benign lesions as well.
When pheochromocytomas develop in the MEN 
syndromes, they rarely are malignant.
In general, soft tissue 
lesions are treated with resection if feasible.
If the tumor is positive on somatostatin receptor 
imaging, long-acting octreotide may be used.
The incidence of these lesions iden-
tified by CT scans ranges from 0.4% to 4.4%.
Differential Diagnosis.
The differential diagnosis of adrenal 
incidentalomas is shown in Table 38-20.
Total cortisol produced and 24-hour urinary cortisol levels may 
be normal.
Other less commonly encountered lesions include 
adrenal cysts, ganglioneuromas, and hemorrhage.
Diagnostic Investigations.
Confirmatory tests can be per-
formed based on the results of the initial screening studies.
Determination of the malignant potential of an inciden-
taloma is more difficult.
The risk of malignancy in an adrenal 
lesion is related to its size.
Carcinomas account for 2% of 
lesions <4 cm and 6% of lesions 4.1 to 6 cm in size.
They also tend to be hypoattenuating lesions (<10 
Hounsfield units) on CT scanning.
Pheochromocytomas are 
extremely bright, with mass-to-liver ratios >3.
Management.
An algorithm for the management of patients 
with incidentalomas is shown in Fig.
38-47.
However, several important points must be considered in 
the management of these patients.
Older patients are more likely to 
have nonfunctioning adenomas.
2
Is the tumor
metastatic?
3
Is it at high
risk of being
malignant?
Figure 38-47.
Management algorithm for an adrenal incidentaloma.
CT = computed tomography; DST = dexamethasone suppression test; 
VMA = vanillylmandelic acid.
Lesions that grow during follow-up also are treated by 
adrenalectomy.
These tumors, even when large, can be 
removed laparoscopically.
Suspected 
adrenal metastases also may be resected for diagnosis.
There is no consensus regarding the follow up of patients 
with adrenal incidentaloma.
Symptoms and Signs.
Symptoms 
include fatigue, salt craving, weight loss, nausea, vomiting, and 
abdominal pain.
Diagnostic Studies.
The peripheral blood 
smear may demonstrate eosinophilia in approximately 20% 
of patients.
Adrenal insufficiency is diagnosed by the ACTH 
stimulation test.
ACTH (250 μg) is infused intravenously, and 
cortisol levels are measured at 0, 30, and 60 minutes.
Peak cor-
tisol levels <20 μg/dL suggest adrenal insufficiency.
ACTH 
levels also allow primary insufficiency to be distinguished from 
secondary causes.
High ACTH levels with low plasma cortisol 
levels are diagnostic of primary adrenal insufficiency.
Treatment.
Dexamethasone 
(4 mg) should be administered intravenously.
The ACTH stimulation test 
should be performed to confirm the diagnosis.
Adrenal Surgery
Choice of Procedure.
Adrenalectomy may be performed via a 
laparoscopic or open approach.
The choice of approach depends on the size and 
nature of the lesion and expertise of the surgeon.
There have been no ran-
domized trials directly comparing open vs.
laparoscopic adre-
nalectomy.
Laparoscopic Adrenalectomy.
The procedure is performed 
under general anesthesia.
A nasogastric tube and Foley catheter are rec-
ommended.
Routine preoperative antibiotics are not needed, 
except in patients with Cushing’s syndrome.
Patients, however, need to be repositioned for a bilateral 
procedure.
The lateral transabdominal approach is widely used and 
described in detail below.
38-48).
The surgeon and assistant both stand on the 
same side, facing the front of the patient.
Pneumoperitoneum is 
created using a Veress needle or insufflation via a Hasson port.
38-48), 
although additional ports may be placed, if needed.
A 30° lapa-
roscope is inserted through the second or midclavicular port.
Most of the dissection is carried out via the two most lateral 
ports.
However, the instruments and ports may be changed to 
provide optimum exposure, as needed.
The right triangular ligament is divided 
and the liver is rotated medially (Fig.
38-49A).
Rarely, the 
hepatic flexure of the colon may need mobilization during a 
right adrenalectomy.
The right kidney is identified visually and 
by palpation with an atraumatic grasper.
The adrenal gland is 
identified on the superomedial aspect of the kidney.
Gerota’s 
fascia is incised with the hook cautery.
Alternatively, a vascular stapler may be 
used to divide the vein endoscopically.
There may be a second 
adrenal vein on the right.
Generally, two clips are left on the 
vena cava side.
For a left adrenalectomy, the fan retractor is used to retract 
the spleen.
Positioning of the patient and placement of trocars for a laparoscopic adrenalectomy.
Four trocars are placed from the mid-
clavicular to the anterior axillary line.
1592
SPECIFIC CONSIDERATIONS
UNIT II
part II
divided using the electrocautery (Fig.
38-49B).
Gravity allows 
the spleen and the pancreatic tail to fall medially.
The remain-
der of the dissection proceeds similarly to that described for the 
right adrenal.
As with the right adrenal 
vein, the left-sided veins also can be divided with a vascular 
stapler.
Once the dissection is complete, the area of the adrenal 
bed can be irrigated and suctioned.
A drain is rarely necessary.
Furthermore, bilateral adrenalectomy can be 
performed without repositioning the patient.
This makes vascular control difficult and also renders it unsuit-
able for large (>5 cm) lesions.
This technique is being increas-
ingly used for small adenomas causing hyperaldosteronism.
Palpation 
is used to identify the position of the twelfth rib.
The 0° laparoscope is replaced by a 45° laparoscope.
Two addi-
tional 5- or 10-mm trocars are placed, one each on either side 
of the first port.
Laparoscopic ultrasound then is used to help 
locate the adrenal gland and vessels.
Open Adrenalectomy.
Recovery time is 
also quicker and hospitalization shorter.
However, it is associated 
with significant morbidity and should be used selectively.
38-50).
38-51A).
The 
lateral and superior surfaces usually are mobilized first.
38-51B).
An alter-
native approach is to enter the lesser sac by division of the 
gastrocolic ligament.
Technique of laparoscopic adrenalectomy.
The gland is then mobilized as on 
the right side.
The pleura also is mobilized cephalad, 
and the adrenal and kidney are identified.
This prevents superior retraction of the adrenal 
gland.
The remainder of the gland is then dissected and the adre-
nal gland and tumor removed.
The resulting space generally is 
filled with perinephric fat and closed in layers.
A chest x-ray is 
obtained postoperatively to rule out a pneumothorax.
The dissection then is performed 
as indicated previously in Anterior Approach.
Complications of Adrenal Surgery.
Incisions for open adrenalectomy.
Anterior approach 
(A), posterior approach (B), and thoracoabdominal approach (C).
A
B
Right
adrenal
Pancreas
Colon
Left 
kidney
Left
adrenal v.
Spleen
Pancreas
Figure 38-51.
Technique of open adrenalectomy.
The left adrenal 
can be exposed by medial visceral rotation of the spleen and pan-
creas (B).
v.
= vein.
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Pediatric Surgery
David J.
Hackam, Tracy Grikscheit, Kasper Wang, 
Jeffrey S.
Upperman, and Henri R.
Robert E.
1.
Children are not little adults, but they are little people.
2.
Sick children whisper before they shout.
Children with sur-
gical diseases can deteriorate very quickly.
But before they 
deteriorate, they often manifest subtle physical findings.
3.
Always listen to the mother and the father.
Barotrauma and hypoxia should be avoided.
Timing and extent of surgery are dictated by the 
stability of the patient.
Early sequelae of NEC include perforation, sepsis, and 
death.
Later sequelae include short bowel syndrome 
and stricture.
unfavorable).
Gross tumor rupture during surgery 
automatically changes the stage to 3 (at a minimum).
10  Injury is the leading cause of death in children older than 
1 year of age.
Blunt mechanisms account for the majority 
of pediatric injuries.
1599
P
EDIATRIC
 S
URGER
y
CHAPTER 39
have closely observed their child and know him or her best.
4.
Children suffer pain after surgery.
Timely and adequate pain 
management must accompany surgical interventions.
5.
Pediatric tissue must be handled delicately and with pro-
found respect.
This is particu-
larly true in infants, who have little reserve when ill.
The infant’s 
physiologic day is approximately 8 hours in duration.
At 12 weeks’ gestation, the total body water of a fetus 
is approximately 94 cc/kg.
Parallel to the drop in total 
body water is the reduction in extracellular fluid.
The capacity to concentrate urine 
is very limited in preterm and term infants.
Potassium requirements are on 
the order of 1 to 2 mEq/kg/d.
Respiratory acidosis implies hypoventilation, the cause 
of which should be apparent.
The 
last factor in the equation should be 0.4 for smaller children and 
0.3 for older children.
One half of the corrective dose is given, and the 
serum pH is measured again.
Respiratory alkalosis is usually caused by hyperventila-
tion, which is readily correctable.
To decrease the need for transfu-
sion, other strategies have been considered.
Plasma is given 
in a dose of 10 to 20 mL/kg, and platelets are given in a dose 
of 1 unit/5 kg.
Each unit of platelets consists of 40 to 60 mL of 
fluid (plasma plus platelets).
The protein 
and caloric requirements for the surgical neonate are shown in 
Table 39-1.
Nutrition can be provided via either the enteral or paren-
teral route.
There are various enteral feeding preparations available; 
these are outlined in Table 39-2.
The choice of formula is based 
on the individual clinical state of the child.
Pediatric surgeons 
are often faced with situations where oral feeding is not possi-
ble.
Prolonged parenteral 
nutrition is delivered via a central venous catheter.
If the internal jugular 
vein is used, care is taken to prevent venous occlusion.
The catheters are tunneled to an exit site separate from 
the venotomy site.
Premature infants are particularly susceptible to changes in envi-
ronmental temperature.
Transport systems 
incorporating heating units are necessary for premature infants.
During abdominal surgery, extreme 
care is taken to avoid wet and cold drapes.
All fluids used to irri-
gate the chest or abdomen must be warmed to body temperature.
Pain Control
All children, including neonates, experience pain.
For situa-
tions where more pain is expected, IV narcotic agents should be 
used.
Neck lesions are found either in the midline or lateral com-
partments.
Midline masses include thyroglossal duct remnants, 
thyroid masses, thymic cysts, or dermoid cysts.
However, when 
the involved nodes become fluctuant, incision and drainage are 
indicated.
The lymphadenopathy associated 
with infectious mononucleosis can be diagnosed based on serol-
ogy.
Accordingly, 
such biopsies should be done under local anesthesia.
Thyroglossal Duct Remnants
Pathology and Clinical Manifestations.
The 
“descent” of the thyroid is intimately connected with the devel-
opment of the hyoid bone.
Occasion-
ally it presents as an intrathyroidal mass.
Most thyroglossal duct 
cysts are asymptomatic.
Submental lymphadenopathy and midline dermoid 
cysts can be confused with a thyroglossal duct cyst.
Treatment.
If the cyst presents with an abscess, treatment 
should first consist of drainage and antibiotics.
The first cleft and the first, second, third, and 
fourth pouches give rise to adult organs.
In contrast, a third branchial cleft fistula passes posterior 
to the carotid bifurcation.
Treatment.
Complete excision of the cyst and sinus tract is 
necessary for cure.
Injection of a small amount of methylene blue dye into the tract 
also may be useful.
Branchial cleft cysts can present as abscesses.
Lymphatic Malformation
Etiology and Pathology.
The cysts are lined by endothelium and filled with lymph.
Adjacent 
connective tissue may show extensive lymphocytic infiltra-
tion.
39-1A).
Occasionally lymphatic malformations contain nests of 
vascular tissue.
Infection within the cysts, usually caused by Streptococcus or 
Staphylococcus, may occur.
In the neck, this can cause rapid 
enlargement, which may result in airway compromise.
Occasionally, very 
large lesions can cause obstruction of the fetal airway.
Treatment.
39-1B).
Radical ablative surgery is not indicated for this 
lesion.
Postoperative wound drainage is important 
and is best accomplished by closed-suction technique.
This lesion 
results from fibrosis of the sternocleidomastoid muscle.
The 
mass may be palpated in the affected muscle in approximately 
two thirds of cases.
Rarely, surgical transection of the sternocleidomastoid may be 
indicated.
RESPIRATORy SySTEM
Congenital Diaphragmatic Hernia (Bochdalek)
Pathology.
Diaphragmatic defects allow 
abdominal viscera to fill the chest cavity.
The abdominal cavity 
is small and underdeveloped and remains scaphoid after birth.
Both lungs are hypoplastic, with decreased bronchial and pul-
monary artery branching.
A.
Left cervical lymphatic malformation in a 2-day-old baby.
B.
Intraoperative photograph showing a vessel loop around the 
spinal accessory nerve.
1604
SPECIFIC CONSIDERATIONS
UNIT II
part II
on the ipsilateral side.
This anomaly is encountered more com-
monly on the left (80%–90%).
Amniocentesis with karyotype may identify chro-
mosomal defects, especially trisomy 18 and 21.
39-2).
Accurate prenatal 
prediction of outcome for fetuses who have CDH is very diffi-
cult.
Following delivery, the diagnosis of CDH is made by 
chest x-ray (Fig.
39-3).
Second, pulmonary hypertension develops.
Varying degrees of pulmonary hypo-
plasia on the opposite side may compound these effects.
The 
second and third factors are thought to be the most important.
Treatment.
Many infants are symptomatic at birth due to hypoxia, hyper-
carbia, and metabolic acidosis.
Prompt cardiorespiratory stabi-
lization is mandatory.
Levels of PaCO2 in the range 
1
Figure 39-3.
Chest x-ray showing a left congenital diaphragmatic 
hernia.
Figure 39-2.
Prenatal ultrasound of a fetus with a congenital dia-
phragmatic hernia.
Arrows point to the location of the diaphragm.
Arrow head points to the stomach, which is in the thoracic cavity.
The use of ECMO is associated with 
significant risk.
They 
may occur intracranially or at the site of cannula insertion 
and can be life threatening.
Systemic sepsis is a significant 
problem and may necessitate decannulation.
Upon decannulation, some centers repair the carotid artery.
Still others repair the diaphragm only after the infant is 
off bypass.
The anterior 
margin is often apparent, while the posterior muscular rim is 
attenuated.
If the infant is heparinized on bypass, minimal dis-
section of the muscular margins is performed.
Electrocautery is 
used liberally to minimize postoperative bleeding.
Anatomic closure of 
the abdominal wall may be impossible after reduction of the 
viscera.
Very slow weaning from the ventilator is necessary to 
avoid recurrent pulmonary hypertension.
These symptoms may be stationary, or they may 
progress rapidly or result in recurrent pneumonia.
A hyperexpanded hemithorax on the ipsilateral side is 
pathognomonic for CLE.
39-4).
This should be done only in the 
stable patient.
The prognosis is excellent.
Congenital Pulmonary Airway Malformations.
There 
may be a single cyst with a wall of connective tissue contain-
ing smooth muscle.
CPAMs frequently occur 
in the left lower lobe.
Clinical symptoms range from none 
to severe respiratory failure at birth.
39-5).
Prenatal US may suggest the diagno-
sis.
As a result, resection of the affected lobe is usually performed 
(Fig.
39-6).
Figure 39-5.
Figure 39-6.
39-5.
Figure 39-4.
Congenital lobar emphysema of the left upper lobe 
in a 2-week-old boy.
Mediastinal shift is present.
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Pulmonary Sequestration.
There are two kinds of sequestra-
tion.
It 
is commonly found in cases of CDH.
39-7).
Venous drainage of both types can be systemic or 
pulmonary.
Sequestrations 
may, in some cases, exhibit mixed pathology with components 
consistent with CPAMs.
Extralobar sequestration is asymptom-
atic and is usually discovered incidentally on chest x-ray.
If the 
diagnosis can be confirmed (e.g., by CT scan), resection is not 
necessary.
Diagnosis of intralobar sequestration may be made 
prenatally and confirmed on postnatal CT scan.
Prognosis is gener-
ally excellent.
Bronchogenic Cyst.
In the lung parenchyma, they may become infected and 
present with fever and cough.
Rarely, rupture of the 
cyst can occur.
Chest CT delineates bron-
chiectasis with excellent resolution.
Figure 39-7.
1608
SPECIFIC CONSIDERATIONS
UNIT II
part II
Airway Ingestion.
Aspiration of foreign bodies most com-
monly occurs in the toddler age group.
Oil from the peanut 
is very irritating and may cause pneumonia.
Delay in diagnosis 
can lead to atelectasis and infection.
The child usually will cough or choke 
while eating but may then become asymptomatic.
A unilateral 
wheeze is often heard on auscultation.
Bronchoscopy confirms 
the diagnosis and allows removal of the foreign body.
Foreign Bodies and Esophageal Injury.
The most common 
foreign body in the esophagus is a coin, followed by small toy 
parts.
Toddlers are most commonly affected.
There is often a relatively asymptomatic 
period after ingestion.
The initial symptoms are gastrointestinal 
and include dysphagia, drooling, and dehydration.
These findings may be interpreted as signs of upper respiratory 
infections.
The chest x-ray is diagnostic in 
the case of a coin.
Rarely, esophagotomy is required for removal, particularly of 
sharp objects.
In the not-so-distant past, nearly all infants born with EA and 
TEF died.
Subsequently, Dr.
Anatomic Varieties.
The five major varieties of EA and TEF 
are shown in Fig.
39-8.
The most commonly seen variety is EA 
Figure 39-8.
The five varieties of esophageal atresia and tracheoesophageal fistula.
A.
Isolated esophageal atresia.
B.
C.
Esophageal atresia with tracheoesophageal fistula 
between distal esophagus and trachea.
D.
Esophageal atresia with fistula between both proximal and distal ends of esophagus and trachea.
E.
Tracheoesophageal fistula without esophageal atresia (H-type fistula).
39-9).
Etiology and Pathologic Presentation.
The esophagus and 
trachea share a common embryologic origin.
39-8.
Other congenital anomalies commonly occur in asso-
ciation with EA-TEF.
In nearly 
20% of the infants born with EA, some variant of congenital 
heart disease occurs.
Clinical Presentation of Infants with Esophageal Atresia 
and Tracheoesophageal Fistula.
The anatomic variant of infants with EA-TEF predicts the clini-
cal presentation.
As the abdomen distends, it 
becomes increasingly more difficult for the infant to breathe.
This leads to further atelectasis and respiratory compromise.
39-10).
The dilated 
upper pouch may be occasionally seen on a plain chest radio-
graph.
This problem can occur in infants after 
traumatic insertion of a nasogastric or orogastric tube.
Occasionally, a diagnosis of EA-TEF can be suspected 
prenatally on US evaluation.
Typical features include failure 
to visualize the stomach and the presence of polyhydramnios.
These findings reflect the absence of efficient swallowing  
by the fetus.
In a child with EA, it is important to identify whether coex-
isting anomalies are present.
A patent anus should be confirmed clinically.
The kidneys in 
Figure 39-10.
Type C esophageal atresia with tracheoesophageal 
fistula.
Figure 39-9.
Barium esophagram showing H-type tracheoesopha-
geal fistula (arrow).
1610
SPECIFIC CONSIDERATIONS
UNIT II
part II
a newborn may be assessed clinically by palpation.
Rib anomalies may also be pres-
ent.
These may include the presence of a thirteenth rib.
Initial Management.
A sump catheter is placed in the upper pouch on continuous suc-
tion.
IV antibiotic therapy is initiated, and warmed electrolyte solu-
tion is administered.
The timing of repair is influenced by the stability of the 
patient.
Definitive repair of the EA-TEF is rarely a surgical 
emergency.
Management of Esophageal Atresia and Tracheoesopha-
geal Fistula in the Preterm Infant.
This can be accom-
plished using HFOV.
If the gastric distention becomes severe, 
a gastrostomy tube should be placed.
This procedure can be 
performed at the bedside under local anesthetic, if necessary.
If these maneuvers are to 
no avail, ligation of the fistula may be required.
Primary Surgical Correction.
There are two approaches to this operation: 
open thoracotomy or thoracoscopy.
The operative technique for primary repair is as follows 
(Fig.
39-11).
The anastomosis is performed 
in a single layer.
2
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Postoperative Course.
When a transanastomotic tube is placed, feeds are begun slowly 
in the postoperative period.
Some surgeons institute parenteral 
nutrition for several days, using a central line.
If there is no leak, feedings 
are started.
Complications of Surgery.
Revision of the 
anastomosis may be possible.
Strictures are not infrequent (10%–20%), particularly 
if a leak has occurred.
A contrast swallow or esophagoscopy 
is confirmatory, and simple dilatation is usually corrective.
Occasionally, repeated dilatations are required.
A
B
CED
Azygos Vein
Esophagus
Esophagus Azygos Vein
Figure 39-11.
Primary repair of type C tracheosophageal fistula.
A.
Right thoracotomy incision.
B.
Azygos vein transected, proximal and 
distal esophagus demonstrated, and fistula identified.
C.
Tracheoesophageal fistula transected and defect in trachea closed.
D.
End-to-end 
anastomosis between proximal and distal esophagus (posterior row).
E.
Completed anastomosis.
Otherwise, reoperation may be required.
Special Circumstances.
Patients with type E TEFs (also 
called H-type) most commonly present beyond the newborn 
period.
Presenting symptoms include recurrent chest infections, 
bronchospasm, and failure to thrive.
Outcome is usually excellent.
Definitive 
repair can then be performed at a later point in time.
This occasionally allows for primary anastomosis to be 
performed.
Outcome.
Spitz and 
colleagues analyzed risk factors in infants who died with EA-
TEF.
There is no effective immediate antidote.
It is impor-
tant to endoscope only to the first level of the burn in order 
to avoid perforation.
Early barium swallow may delineate the 
extent of the mucosal injury.
Therefore, they are no longer part of the management 
of caustic injuries.
Antibiotics are administered during the 
acute period.
These patients should undergo 
placement of a gastrostomy tube once clinically stable.
When estab-
lished strictures are present (usually 3–4 weeks), dilatation is 
performed.
Pedicled or free grafts of the jejunum 
are less commonly used.
In a recent review of 
patients treated by gastric pull-up, long-term outcome was very 
good.
GERD is particularly problematic in neurologically 
impaired children.
Clinical Manifestations.
A barium swallow should be performed as 
an initial test.
The frequency and severity of reflux should be assessed using a 
24-hour pH probe study.
Treatment.
Most patients with GERD are treated initially by 
conservative means.
In the infant, propping and thickening the 
formula with rice cereal are generally recommended.
Some 
authors prefer a prone, head-up position.
However, as a 
long-term remedy, this therapy is associated with several prob-
lems.
These complications are more common in children 
with neurologic impairment.
GASTROINTESTINAL TRACT
An Approach to the Vomiting Infant
The majority of infants vomit.
This may or may not be of concern, as 
described earlier.
By contrast, vomit that has any 
green color in it is always worrisome.
Hypertrophic Pyloric Stenosis
Clinical Presentation.
Male-to-female ratio 
is nearly 5:1.
Wet diapers become less 
frequent, and there may even be a perception of less passage 
of flatus.
The cause of HPS has not been determined.
Infants with HPS develop a hypochloremic, hypokale-
mic metabolic alkalosis.
When the olive cannot be palpated, US can diagnose 
the condition accurately in 95% of patients.
Criteria for US 
diagnosis include a channel length of over 16 mm and pyloric 
thickness over 4 mm.
Treatment.
After resuscitation, a Fredet-Ramstedt pyloromy-
otomy is performed (Fig.
39-12).
It may be performed using 
an open or laparoscopic approach.
In recent years, the laparo-
scopic approach has gained great popularity.
Most infants can 
be discharged home within 24–48 hours following surgery.
A nasogastric tube is left in place for 24 hours.
The 
outcome is generally very good.
Prompt recognition and treatment of 
neonatal intestinal obstruction can truly be life saving.
The incidence of neonatal intestinal obstruction is 1 in 
2000 live births.
When a neonate develops bilious vomiting, one must 
Pyloric “tumor”
Mucosa
A
B
C
Figure 39-12.
Fredet-Ramstedt pyloromyotomy.
A.
Pylorus deliv-
ered into wound and seromuscular layer incised.
B.
C.
3
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consider a surgical etiology.
Indeed, the majority of newborns 
with bilious emesis have a surgical condition.
As such, contrast imaging may be necessary for diagno-
sis in some instances.
Distal obstructions typically presents with bilious emesis 
and abdominal distention.
Passage of black-green meconium 
should have occurred within the first 24 to 38 hours.
This topic 
is covered in further detail later in this chapter.
Associ-
ated polyhydramnios is common and presents in the third tri-
mester.
Abdominal distention is typically not 
present because of the proximal level of obstruction.
In infants 
with obstruction proximal to the bile duct entry, the vomiting is 
nonbilious.
39-13).
Treatment.
Typically, the abdomen is soft, and the infant is very 
stable.
These patients should be evaluated for 
associated cardiac anomalies.
Associated anomalies should be searched for at the 
time of the operation.
These include malrotation, anterior portal 
vein, a second distal web, and biliary atresia.
Gastrostomy tube placement is not routinely 
performed.
Recently reported survival rates exceed 90%.
The incidence of intestinal atresia has been 
4
Figure 39-13.
Abdominal x-ray showing "double bubble" sign 
in a newborn infant with duodenal atresia.
The two "bubbles" are 
numbered.
39-14).
Surgical correction of the small intestinal atresia should 
be performed urgently.
At laparotomy, one of several types of 
atresia will be encountered.
In type 1, there is a mucosal atresia 
with intact muscularis.
In type 2, the atretic ends are connected 
by a fibrous band.
In type 3A, the two ends of the atresia are 
separated by a V-shaped defect in the mesentery.
39-15).
The 
proximal distended loop can be tapered as described earlier.
Malrotation and Midgut Volvulus
Embryology.
Genetic mutations likely disrupt the 
signaling critical for normal intestinal rotation.
A volvulus 
may therefore occur around the mesentery.
This twist not only 
obstructs the proximal jejunum, but also cuts off the blood 
Figure 39-14.
This child has 
jejunal atresia.
Figure 39-15.
Operative photograph of newborn with “Christmas 
tree” type of ileal atresia.
1617
P
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supply to the midgut.
Presentation and Management.
39-16).
In cases where the child is stable, laparoscopy 
may be considered.
Under these con-
ditions, the patient may have malrotation without volvulus.
Volvulus occurs clockwise and is therefore untwisted coun-
terclockwise.
This procedure is performed as follows 
(Fig.
39-17).
The appendix is removed to avoid diagnostic 
errors in later life.
No attempt is made to suture the cecum 
or duodenum in place.
Frankly necrotic bowel can then 
be resected conservatively.
With early diagnosis and correc-
tion the prognosis is excellent.
A subset of patients with malrotation will demonstrate 
chronic obstructive symptoms.
Meconium Ileus
Pathogenesis and Clinical Presentation.
This phenotype 
is explained by the presence of mutations in the CFTR gene.
Abdominal radiographs show dilated 
loops of intestine.
Figure 39-16.
Abdominal x-ray of a 10-day-old infant with bilious 
emesis.
Note the dilated proximal bowel and the paucity of distal 
bowel gas, characteristic of a volvulus.
Management.
Patients with uncomplicated meconium ileus can be 
treated nonoperatively.
At this point, an end ileostomy may be created.
Figure 39-17.
Ladd procedure for malrotation.
A.
Lysis of cecal and duodenal bands.
B.
Broadening the mesentery.
C.
Appendectomy.
39-18).
Necrotizing Enterocolitis
Clinical Features.
Over 25,000 cases 
of NEC are reported annually.
The overall mortality ranges 
between 10% and 50%.
Multiple risk factors have been associated with the devel-
opment of NEC.
Techniques of intestinal anastomosis for infants with small bowel obstruction.
A.
End to back: distal limb has been incised, 
creating “fish mouth” to enlarge the lumen.
B.
C.
D.
The common wall can be crushed with a special clamp to create a large stoma.
The stoma can be closed in an 
extraperitoneal manner.
Clinical Manifestations.
Infants with NEC present with a 
spectrum of disease.
In the earliest 
stage (Bell stage I), infants present with feeding intolerance.
Infants with Bell stage II have established NEC that is not 
immediately life threatening.
These findings indicate the development of 
intestinal ileus and mucosal ischemia, respectively.
The diagnosis of NEC may be confirmed by abdomi-
nal radiography.
39-19).
Other findings include the presence of ileus or portal venous 
gas.
Infants with Bell stage III have the most advanced form of 
NEC.
Pathogenesis of Necrotizing Enterocolitis.
Several theo-
ries have been proposed to explain the development of NEC.
The infant is 
resuscitated, and inotropes are administered to maintain perfu-
sion as needed.
Intubation and mechanical ventilation may be 
required to maintain oxygenation.
TPN is started.
Subsequent 
treatment may be influenced by the particular stage of NEC that 
is present.
If the infant 
fully recovers, feedings may be reinitiated.
Patients with Bell stage II disease merit close observation.
Serial physical examinations are performed looking for the 
Figure 39-19.
Abdominal radiograph of infant with necrotizing 
enterocolitis.
Arrows point to area of pneumatosis intestinalis.
Two schools of thought direct further 
management.
One group favors exploratory laparotomy.
Necrotizing Enterocolitis in Older Infants.
Spontaneous Intestinal Perforation Versus Necrotizing 
Enterocolitis.
The histopathology of 
SIP is different from NEC.
In contrast to NEC, pneuma-
tosis intestinalis is absent in SIP.
However, both NEC and 
SIP occur with similar frequency in low birth weight infants.
The outcome of patients in the two groups is slightly differ-
ent.
In short, the diagnosis of SIP versus NEC has impor-
tant prognostic significance.
The treatment strategies, however, 
are essentially the same.
Outcome.
At the time of stoma closure, the entire 
intestine should be examined to search for strictures.
As rates of prematurity are increasing, so are 
the numbers of children with SBS.
Rarely, an intussusception may prolapse 
through the rectum.
Clinical Manifestations.
Typically, the infant develops paroxysms 
of crampy abdominal pain and intermittent vomiting.
Bloody mucus (“currant jelly” 
stool) may be passed per rectum.
Treatment.
In the absence of peritonitis, 
the child should undergo radiographic reduction.
Under most instances, this should not exceed 120 mmHg.
This strategy has 
improved the success rate of nonoperative reduction in many 
centers.
Failure to reduce 
the intussusception mandates surgery.
Two approaches are used.
39-20).
Care should be taken not to 
pull the bowel out, as this can cause damage to the bowel wall.
The blood supply to the appendix is often compromised, and 
appendectomy is performed.
If the bowel is frankly gangrenous, 
resection and primary anastomosis are performed.
In experi-
enced hands, laparoscopic reduction may be performed, even in 
very young infants.
Atraumatic bowel 
graspers allow the bowel to be handled without injuring it.
IV fluids are continued until the postoperative ileus 
subsides.
Patients are started on clear liquids, and their diet 
is advanced as tolerated.
Patients pres-
ent with recurrent symptoms in the immediate postoperative 
period.
Treatment involves repeat air enema, which is success-
ful in most cases.
Appendicitis
Presentation.
When children present in this 
manner, there should be little diagnostic delay.
Figure 39-20.
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However, children often do not present in this manner.
Diagnosis of Appendicitis in Children.
In girls, 
ovarian or uterine pathology must also be considered.
When 
there is diagnostic uncertainty, the child may be observed, rehy-
drated, and reassessed.
Surgical Treatment of Appendicitis.
The definitive treat-
ment for acute appendicitis is appendectomy.
Patients should also 
be started on antibiotics (such as a second-generation cepha-
losporin).
In general, the same steps are taken 
when appendectomy is performed through an open approach.
The most common complication after appendectomy is a 
surgical site infection.
Recovery from surgery is dependent on the individual patient.
During the recovery period, over-the-counter 
pain medication may be required.
Older patients tend to require 
a longer time for full recovery.
Management of the Child with Perforated Appendicitis.
Alternatively, the child may present 
with symptoms of intestinal obstruction.
An abdominal mass 
may be present in the lower abdomen.
39-21).
An individualized approach is necessary for the child who 
presents with perforated appendicitis.
The operation can be performed through an open or 
laparoscopic approach.
Drains are seldom used, and the 
skin incisions can be closed primarily.
Thus, these 
patients are more likely to require early surgical intervention.
Patients who have had symptoms of appendicitis for no more 
Figure 39-21.
Other Causes of Abdominal Pain That Mimic Appendicitis 
in Children.
Patients with urinary tract infection 
can present very similar to those with appendicitis.
Constipation may be commonly confused with appendicitis in its 
earliest stages.
Finally, children and young adults are always 
at risk for the development of gastroenteritis.
Duplications may be long and tubular, but usually, they 
are cystic masses.
In all cases, they share a common wall with 
the intestine.
On exami-
nation, a palpable mass is often identified.
Children may also 
develop intestinal obstruction.
Torsion may produce gangrene 
and perforation.
CT, US, 
and technetium pertechnetate scanning can be very helpful.
Occasionally, a duplication can be seen on small bowel follow-
through or barium enema.
39-22).
Pancreatic mucosa may also be present.
Diagnosis may be made 
by technetium pertechnetate scans when the patient presents 
with bleeding.
Treatment is surgical.
A linear stapler is especially useful 
in this circumstance.
However, they do not contain any mucosa 
or muscular wall.
Chylous cysts may result from congenital 
lymphatic obstruction.
Mesenteric cysts can cause intestinal 
obstruction or may present as an abdominal mass.
The diagno-
sis may be made by abdominal US or CT.
Treatment involves 
surgical excision.
Hirschsprung’s Disease
Pathogenesis.
In his classic textbook entitled Pediatric 
Surgery, Dr.
Operative photograph showing the presence of a 
Meckel’s diverticulum (arrow).
This may explain why most cases of aganglionosis involve the 
rectum and rectosigmoid.
In rare instances, total 
colonic aganglionosis may occur.
Recent studies have shed light on the molecular basis for 
Hirschsprung’s disease.
Clinical Presentation.
The incidence of sporadic Hirschsprung’s 
disease is 1 in 5000 live births.
Occasionally such families have mutations in 
the genes described earlier, including the Ret gene.
In children who do not respond to 
nonoperative management, a decompressive stoma is required.
These children have severe constipation, which has usually been 
treated with laxatives and enemas.
Abdominal distention and 
failure to thrive may also be present at diagnosis.
Diagnosis.
The definitive diagnosis of Hirschsprung’s disease 
is made by rectal biopsy.
Samples of mucosa and submucosa 
are obtained at 1, 2, and 3 cm from the dentate line.
In older children, 
the procedure should be performed using IV sedation.
The barium enema in total colonic aganglionosis may show 
a markedly shortened colon.
Treatment.
The diagnosis of Hirschsprung’s disease requires 
surgery in all cases.
The classic surgical approach consisted of 
a multiple-stage procedure.
There are three viable 
options for the definitive pull-through procedure that 
are currently used.
39-23).
Many surgeons perform the intra-abdominal dissection 
using the laparoscope.
In this operation, the aganglionic rectum is dissected in 
the pelvis and removed down to the anus.
The ganglionic colon 
is then anastomosed to the anus via a perineal approach.
This operation may be performed completely from 
below.
In all cases, it is critical that the level at which ganglion-
ated bowel exists be determined.
Up to one third of patients who undergo 
a transition zone pull-through will require a reoperation.
Anorectal Malformations
Anatomic Description.
The embryologic basis includes failure of 
descent of the urorectal septum.
Instead, the 
rectal pouch ends “blindly” in the pelvis, above or below the 
levator ani muscle.
39-24).
The three operations for surgical correction of 
Hirschsprung’s disease.
A.
B.
C.
Figure 39-24.
Low imperforate anus in a male.
Note the well-
developed buttocks.
The perineal fistula was found at the midline 
raphe.
1627
P
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ends as a fistula into the membranous urethra.
In females, high 
imperforate anus often occurs in the context of a persistent clo-
aca.
In both males and females, low lesions are associated with 
a fistula to the perineum.
In males, the fistula connects with the 
median raphe of the scrotum or penis.
39-25).
The third most common defect in 
females is the persistent cloaca.
Typi-
cally, the external genitalia are hypoplastic.
Associated Malformations.
Approximately 60% of patients 
have an associated malformation.
The most common is a urinary 
tract defect, which occurs in approximately 50% of patients.
Skeletal defects are also seen, and the sacrum is most com-
monly involved.
Gastrointestinal anomalies occur, most commonly EA.
Management of Patients with Imperforate Anus.
Patients 
with imperforate anus are usually stable, and the diagnosis is 
readily apparent.
The principles of management center around diagnosing 
the type of defect that is present (high vs.
low) and evaluating 
the presence of associated anomalies.
Other tests 
should include an echocardiogram and spinal radiographs.
A 
US of the spine should be performed to look for the presence of 
a tethered cord.
To further classify the location of the fistula as 
either “high” vs.
“low,” a lateral abdominal radiograph can be 
obtained with a radiopaque marker on the perineum.
This study is imprecise, however, and may add little 
to the overall management of these patients.
The surgical management of infants with imperforate anus 
is determined by the anatomic defect.
The muscles are 
then reconstructed and sutured to the rectum.
The outcome 
of 1192 patients who had undergone this procedure has been 
reviewed by Peña and Hong.
Dilators are then placed over 
Figure 39-25.
Imperforate anus in a female.
A catheter has been 
placed into the fistula, which is in the vestibule of the vagina.
During fetal life, the placenta is the principal 
route of elimination of unconjugated bilirubin.
In the newborn 
infant, bilirubin is conjugated through the activity of glucoronyl 
transferase.
By 
definition, jaundice that persists beyond 2 weeks is considered 
pathologic.
Biliary Atresia
Pathogenesis.
Biliary atresia is a rare disease associated with 
significant morbidity and mortality.
The incidence of this disease is approximately 1 in 8000 
to 1 in 18,000.
The etiology of biliary atresia is likely multi-
factorial.
Recent ani-
mal studies strongly implicate perinatal exposure to reovirus or 
rotavirus.
Clinical Presentation.
Infants with biliary atresia present 
with jaundice at birth or shortly thereafter.
As such, it is not unusual for there 
to be a delay in diagnosis.
Diagnosis.
Workup commonly includes 
the analysis of TORCH infection titers as well as viral hepati-
tis.
The absence of a gallbladder is highly suggestive of the diag-
nosis of biliary atresia.
This may be performed using a laparoscope.
The cholangiogram may demonstrate hypoplasia of the extra-
hepatic biliary system.
Inspissated Bile Syndrome.
In some 
instances, no etiologic factors can be defined.
Neonatal hepatitis 
may present in a similar fashion to biliary atresia.
There may 
be a viral etiology, and the disease is usually self-limited.
In this 
case, cholangiography is both diagnostic and therapeutic.
Treatment.
The purpose 
of this procedure is to promote bile flow into the intestine.
39-26).
39-27).
A com-
mon postoperative complication is cholangitis.
Two of these four biliary atresia studies are therapeutic trials.
Figure 39-26.
Operative photograph showing Kasai portoenteros-
tomy.
Arrows denote site of the anastomosis.
Note the engorged liver.
Figure 39-27.
Schematic illustration of the Kasai portoenteros-
tomy for biliary atresia.
The effect of hospital volume was not the focus 
of this publication.
Recently, Bondoc and colleagues reported on their experience 
with revision of portoenterostomies.
Choledochal Cyst
Classification.
Type I cyst is char-
acterized by fusiform dilatation of the bile duct.
This is the most 
common type and is found in 80% to 90% of cases.
The cyst may be joined 
to the common bile duct by a narrow stalk.
Type IVA cysts 
consist of multiple dilatations of the intrahepatic and extra-
hepatic bile ducts.
Type IVB choledochal cysts are multiple 
dilatations involving only the extrahepatic bile ducts.
The etiology of choledochal 
cyst is controversial.
Clinical Presentation.
Choledochal cyst is more common in 
females than in males (4:1).
Typically these present in children 
beyond the toddler age group.
The classic symptom triad con-
sists of abdominal pain, mass, and jaundice.
However, this com-
plex is actually encountered in fewer than half of the patients.
If left undiagnosed, patients may develop cholangitis or 
pancreatitis.
Cholangitis may lead to the development of cir-
rhosis and portal hypertension.
Often neonates will have an abdominal 
mass at presentation.
Diagnosis.
Choledochal cyst is frequently diagnosed in the 
fetus at a screening prenatal US.
CT will confirm the diagnosis.
Treatment.
The cyst wall is composed of fibrous tissue and 
is devoid of mucosal lining.
Rarely, choledochal cyst 
can lead to the development of a biliary tract malignancy.
This 
provides a further rationale for complete cyst excision.
Resection of the cyst requires circumferential dissection.
More recently, laparoscopic-
assisted resections of choledochal cysts have been described.
The prognosis for children who have undergone complete 
excision of choledochal cyst is excellent.
Complications include 
anastomotic stricture, cholangitis, and intrahepatic stone forma-
tion.
These complications may develop a long time after surgery 
has been completed.
As development is 
completed, the intestine gradually returns to the abdominal cav-
ity.
Contraction of the umbilical ring completes the process of 
abdominal wall formation.
Interruption of 
central migration of the lateral folds results in omphalocele.
In such circumstances, early repair may be 
advisable (Fig.
39-28).
Umbilical hernias are generally asymptomatic protrusions 
of the abdominal wall.
They are generally noted by parents 
or physicians shortly after birth.
The skin is closed using subcuticular sutures.
Persistence of this tract results in a communi-
cation between the bladder and the umbilicus.
The first sign of 
a patent urachus is moisture or urine flow from the umbilicus.
Recurrent urinary tract infections can result.
A urachal cyst usually presents as an inflam-
matory mass inferior to the umbilicus.
Figure 39-28.
Umbilical hernia in a 1-year-old female.
The diagnosis of 
patent urachus is confirmed by umbilical exploration.
The ura-
chal tract is excised and the bladder is closed with an absorbable 
suture.
A patent vitelline duct may also present with umbilical 
drainage.
Treatment includes umbilical exploration with resection of the 
duct remnant (Fig.
39-29).
Omphalocele
Presentation.
39-30).
The umbilical cord inserts into the sac.
Chromosomal anomalies are more 
common in children with smaller defects.
Treatment.
A blood glucose should be evaluated 
because of the association with Beckwith-Wiedemann.
Prophylactic broad-spectrum antibiotics should be 
administered in case of rupture.
The subsequent treatment and 
outcome are determined by the size of the omphalocele.
This involves resec-
tion of the omphalocele membrane and closure of the fascia.
A layer of prosthetic material may be required to achieve clo-
sure.
39-30).
If repair is contraindicated, a nonoperative approach 
can be used.
The omphalocele sac can be treated with topi-
cal treatments.
It typi-
cally takes 2 to 3 months before re-epithelialization occurs.
In cases of giant omphalocele, prolonged 
hospitalization is typical.
Figure 39-29.
Patent vitelline duct.
8
Figure 39-30.
Giant omphalocele in a newborn male.
1633
P
EDIATRIC
 S
URGER
y
CHAPTER 39
Gastroschisis
Presentation.
Unlike omphalo-
cele, there is no overlying sac and the size of the defect is usu-
ally <4 cm.
39-31).
The umbilicus becomes 
partly detached, allowing free communication with the abdomi-
nal cavity.
This defect can readily be diag-
nosed on prenatal US (Fig.
39-32).
There is no advantage 
to performing a cesarean section instead of a vaginal deliv-
ery.
Treatment.
All infants born with gastroschisis require urgent 
surgical treatment.
39-33).
In this case, 
the fascial opening must be enlarged.
Surgical closure can usu-
ally be accomplished within approximately 1 to 2 weeks.
A 
prosthetic piece of material may be required to bring the edges 
of the fascia together.
If an atresia is noted at the time of closure, 
Figure 39-31.
Gastroschisis in a newborn.
Note the location of the 
umbilical cord and the edematous, thickened bowel.
Figure 39-32.
Prenatal ultrasound of a 30-week gestation fetus 
with a gastroschisis.
Arrows point to the bowel outside within the 
amniotic fluid.
8
Figure 39-33.
Intestinal function does not typically return for 
several weeks in patients with gastroschisis.
This is especially 
true if the bowel is thickened and edematous.
Prune-Belly Syndrome
Clinical Presentation.
39-34).
The incidence is significantly higher in males.
Patients 
manifest a variety of comorbidities.
The most significant is pul-
monary hypoplasia, which is not survivable in the most severe 
cases.
Skeletal abnormalities include dislocation or dysplasia of 
the hip and pectus excavatum.
The major genitourinary manifestation in prune-belly syn-
drome is ureteral dilation.
The ureters are typically long and 
tortuous and become more dilated distally.
Treatment.
Inguinal hernia repair represents one of the most common 
operations performed in children.
The presence of an inguinal 
hernia in a child is an indication for surgical repair.
Embryology.
Closure of the processus vaginalis 
normally occurs a few months prior to birth.
This explains the 
high incidence of inguinal hernias in premature infants.
Partial closure can result in entrapped fluid, 
which is known as a hydrocele.
Clinical Manifestation.
39-35).
Older children may notice the bulge themselves.
On examina-
tion, the cord on the affected side will be thicker, and pressure 
Figure 39-34.
Eagle-Barrett (prune-belly) syndrome.
Notice the 
lax, flaccid abdomen.
Figure 39-35.
Right inguinal hernia in a 4-month-old male.
The 
arrows point to the bulge in the right groin.
The child will eventually develop intestinal 
obstruction, peritonitis, and systemic toxicity.
Usually an incarcerated hernia can be reduced.
Occasion-
ally this may require light sedation.
Gentle pressure is applied 
on the sac from below in the direction of the internal inguinal 
ring.
Alternatively, the child may be scheduled for surgery at 
the next available time slot.
This may require a laparotomy and bowel resection.
Transillumination as a method to distinguish between hydrocele 
and hernia is nonspecific.
Surgical Repair.
A small incision is made in a skin crease 
in the groin directly over the internal inguinal ring.
Scarpa’s 
fascia is seen and divided.
The undersurface of the external oblique is 
then cleared from surrounding tissue.
Care is taken not to grasp the vas 
deferens.
The hernia sac is then dissected up to the internal ring 
and doubly suture ligated.
The distal part of the hernia sac is 
opened widely to drain any hydrocele fluid.
The opposite side may readily be explored laparoscopically.
To do so, a blunt 3-mm trocar is placed into the hernia sac of 
the affected side.
The status of the processes vaginalis 
on the opposite side can be visualized.
The long-term results of this technique remain 
to be established.
GENITALIA
Undescended Testis
Embryology.
At birth, approximately 95% of infants have the 
testicle normally positioned in the scrotum.
A distinction should be made between an undescended 
testicle and an ectopic testicle.
1636
SPECIFIC CONSIDERATIONS
UNIT II
part II
Clinical Presentation.
In addition, 
fertility is decreased when the testicle is not in the scrotum.
For 
these reasons, surgical placement of the testicle in the scrotum 
(orchidopexy) is indicated.
Treatment.
Males with bilateral undescended testicles are often 
infertile.
A child with unilateral cryptorchidism should 
have surgical correction of the problem.
The operation is typi-
cally performed through a combined groin and scrotal incision.
An inguinal hernia often 
accompanies a cryptorchid testis.
This should be repaired at the 
time of orchidopexy.
Patients with a nonpalpable testicle present a challenge 
in management.
The current approach involves laparoscopy to 
identify the location of the testicle.
In the first stage, the testicular vessels can be 
clipped via laparotomy or laparoscopically.
This promotes neo-
vasculogenesis along the vas deferens.
This may be done laparo-
scopically as well.
Other surgeons feel 
that the staged approach to orchidopexy is superior.
To date, 
no large-scale trial has been performed to answer this question.
Vaginal Anomalies
Surgical diseases of the vagina in children are either congeni-
tal or acquired.
These defects are pro-
duced by abnormal development of müllerian ducts and/or 
urogenital sinus.
The diagnosis is made most often by physical 
examination.
The anatomy may be defined using US.
Pelvic MRI 
provides the most thorough and accurate assessment of the 
pelvic structures.
Treatment is dependent on the extent of the 
defect.
For an imperforate hymen, division of the hymen is 
curative.
The most common acquired disorder of the vagina is the 
straddle injury.
Typical 
manifestations include vaginal bleeding and inability to void.
Prior to hospital discharge, it 
is important that girls are able to void spontaneously.
Ovarian Cysts and Tumors
Pathologic Classification.
Ovarian cysts and tumors may 
be classified as nonneoplastic or neoplastic.
The most 
common variety is germ cell tumors.
Although these are malignant tumors, they are 
extremely sensitive to radiation and chemotherapy.
The most 
common lesions are the teratomas, which may be mature, imma-
ture, or malignant.
The 
sex cord stromal tumors arise from the mesenchymal compo-
nents of the urogenital ridge.
These include the granulosa-theca 
cell tumors and the Sertoli-Leydig cell tumors.
Although rare, epithelial tumors do occur 
in children.
These include serous and mucinous cystadenomas.
Clinical Presentation.
Children with ovarian lesions usu-
ally present with abdominal pain.
Resection may 
be performed laparoscopically; ovarian tissue should be spared 
in all cases.
Surgical Management.
When a malignancy is suspected, the patient should 
undergo a formal cancer operation.
This procedure is performed 
through either a midline incision or a Pfannenstiel approach.
Ascites and peritoneal washings should be collected for cyto-
logic study.
The liver and diaphragm are inspected carefully 
for metastatic disease.
An omentectomy is performed if there 
is any evidence of tumor present.
Pelvic and para-aortic lymph 
nodes are biopsied, and the primary tumor is resected com-
pletely.
Dysgerminomas 
and epithelial tumors may be bilateral in up to 15% of cases.
It 
is occasionally possible to preserve the ipsilateral fallopian tube.
More radical procedures are not indicated.
Ovarian Cysts in the Newborn.
An increasing number of 
ovarian cysts are being detected by prenatal US.
Typically, resolution occurs 
by approximately 6 months of age.
A laparoscopic approach is 
preferable in these cases.
By contrast, complex cysts of any size 
require surgical intervention at presentation.
Ambiguous Genitalia
Embryology.
Normal sexual differentiation occurs in the 
sixth fetal week.
Normal sexual differentiation is directed by the 
sex-determining region of the Y chromosome (SRY).
This is 
located on the distal end of the short arm of the Y chromo-
some.
Therefore, the result of MIS secretion is a phenotypic male.
Thus, 
the female phenotype prevails.
Ovotesticular DSD or 46,XX Testicular DSD.
This represents 
the rarest form of ambiguous genitalia.
Occasionally, an ovotestis is present on 
one or both sides.
The majority of these patients have a 46,XX 
karyotype.
Both the testis and the testicular portion of the 
ovotestis should be removed.
46,XY DSD.
Bilateral testes are present, but the duct structures differenti-
ate partly as phenotypic females.
The latter dis-
order is termed testicular feminization syndrome.
46,XX DSD.
The most common cause of this disorder is con-
genital adrenal hyperplasia.
These children have a 46,XX 
karyotype but have been exposed to excessive androgens in 
utero.
These patients are unable to synthesize 
cortisol.
39-36).
These infants are prone to 
salt loss and require cortisol replacement.
Those with mineralo-
corticoid deficiency also require fludrocortisone replacement.
Mixed Gonadal Dysgenesis.
This syndrome is associated with 
dysgenetic gonads and retained müllerian structures.
The typical 
karyotype is mosaic, usually 45,XO/46,XY.
Therefore, they should be removed.
Management.
Surgical assignment 
of gender should never be determined at the first operation.
Discussion with the family also plays an important role.
Wilms’ Tumor
Clinical Presentation.
Wilms’ tumor is the most common 
primary malignant tumor of the kidney in children.
Frequently, the mass is discovered by a par-
ent while bathing or dressing the child.
Other symptoms include 
hypertension, hematuria, obstipation, and weight loss.
Occasion-
ally the mass is discovered following blunt abdominal trauma.
Genetics of Wilms’ Tumor.
Most of these tumors are associ-
ated with germline mutations.
It arises from mutations at 
the 11p15.5 locus.
Impor-
tantly, most patients with Wilms’ tumor do not have mutations 
at these genetic loci.
Surgical Treatment.
39-37).
There are 
instances were preoperative chemotherapy is supported by both 
Figure 39-36.
However, the overall survival rates are not different 
between the NWTSG and SIOP approaches.
The goal of surgery is complete removal of the tumor.
It 
is crucial to avoid tumor rupture or injury to contiguous organs.
A sampling of regional lymph nodes should be included, and 
all suspicious nodes should be sampled.
Typically a transverse 
abdominal incision is made, and a transperitoneal approach is 
used.
The opposite side is carefully inspected to ensure that there 
is no disease present.
If there is 
spread above the hepatic veins, an intrathoracic approach may 
be required.
Chemotherapy.
Even in stage IV, cure rates of 80% are achieved.
Neuroblastoma
Clinical Presentation.
Over 80% of cases present before the age 
of 4 years, and the peak incidence is 2 years of age.
Neuro-
blastomas arise from the neural crest cells and show different 
levels of differentiation.
The clinical presen-
tation depends on the site of the primary and the presence of 
metastases.
Two thirds of these tumors are first noted as an asymp-
tomatic abdominal mass.
Occasionally, children may experience pain from the 
tumor mass or from bony metastases.
Proptosis and perior-
bital ecchymosis may occur due to the presence of retrobulbar 
metastasis.
Diagnostic Evaluation.
Wilms’ tumor of the right kidney (arrow) in a 
3-year-old girl.
Table 39-3
Staging of Wilms’ tumor
Stage I: Tumor limited to the kidney and completely 
excised.
Stage II: Tumor that extends beyond the kidney but is 
completely excised.
No residual tumor is apparent at or 
beyond the margins of excision.
The tumor was biopsied, or 
there was local spillage of tumor confined to the flank.
Stage III: Residual tumor confined to the abdomen.
Lymph 
nodes in the renal hilus, the periaortic chains, or beyond 
contain tumor.
Implants are found on the 
peritoneal surfaces.
Tumor extends beyond the surgical 
margins either microscopically or grossly.
Tumor is not 
completely resectable because of local infiltration into vital 
structures.
Treatment of 
Wilms’ tumor.
Results of the Third National Wilms’ Tumor Study.
Cancer.
1989;64:349-360.
39-38).
Prior to the institution 
of therapy, a complete staging workup should be performed.
Any abnormality on 
chest x-ray should be followed up with CT of the chest.
Prognostic Indicators.
A number of biologic variables have 
been studied in children with neuroblastoma.
An open biopsy is 
required in order to provide tissue for this analysis.
Surgery.
The goal of surgery is complete resection.
After neoadjuvant treatment has been administered, surgical 
resection is performed.
Abdominal tumors are approached through a transverse inci-
sion.
These 
may have an intraspinal component.
This typically resolves, 
although it may take many months to do so.
Neuroblastoma in Infants.
These patients may be observed 
safely without surgical intervention or tissue diagnosis.
The clinical presentation of the tumor 
depends on the site of origin.
It is 
shown in Table 39-4.
If this is not possible, the lesion is biopsied, and intensive 
chemotherapy is administered.
It is important to plan the biopsy 
so that it does not interfere with subsequent resection.
After the 
tumor has decreased in size, resection of gross residual disease 
should be performed.
Abdominal neuroblastoma arising from the right 
retroperitoneum (arrow).
Stage 3: Localized disease of any other primary site.
Stage 4: Metastatic disease at diagnosis.
Sources: Lawrence W Jr, Gehan EA, Hays DM, et al.
J Clin Oncol.
1987;5:46-54.
Lawrence W Jr, Anderson JR, Gehan EA, et al.
Children’s Cancer Study Group.
Pediatric 
Oncology Group.
Cancer.
1997;80:1165-1170.
1641
P
EDIATRIC
 S
URGER
y
CHAPTER 39
following initial treatment.
Prognosis.
Tumor histology influences 
prognosis.
The embryonal variant is favorable, whereas the 
alveolar subtype has an unfavorable prognosis.
Teratoma
Teratomas are tumors composed of tissue from all three embry-
onic germ layers.
Thoracic teratomas usually present as an anterior medi-
astinal mass.
Retroperi-
toneal teratomas may present as a flank or abdominal mass.
Tumors of higher grade are 
more likely to have foci of yolk sac tumor.
Sacrococcygeal Teratoma.
Diagnosis may be established by prenatal US.
39-39).
The tumor has been classified based on the 
location and degree of intrapelvic extension.
Lesions that grow 
predominantly into the presacral space often present later in 
childhood.
The differential diagnosis consists of neural tumors, 
lipoma, and myelomeningoceles.
Most tumors are identified at birth and are benign.
Malig-
nant yolk sac tumor histology occurs in a minority of these 
tumors.
Complete resection of the tumor as early as possible 
is essential.
This is of particular concern in small, preterm infants 
with large tumors.
The cure rate is excellent if the tumor is 
excised completely.
Liver Tumors
More than two thirds of all liver tumors in children are malig-
nant.
There are two major histologic subgroups: hepatoblastoma 
and hepatocellular carcinoma.
The age of onset of liver cancer 
in children is related to the histology of the tumor.
The finding of a liver mass does 
not necessarily imply that a malignancy is present.
Nearly 50% 
of all masses are benign, and hemangiomas are the most com-
mon lesion.
The 
patients are rarely jaundiced but may complain of anorexia and 
weight loss.
Most liver function tests are normal.
39-40).
For malignant-appearing lesions, a 
Figure 39-39.
Sacrococcygeal teratoma in a 2-day-old boy.
Figure 39-40.
Computed tomography of the abdomen showing a 
hepatocellular carcinoma in a 12-year-old boy.
The fibrolamellar variant of 
hepatocellular carcinoma may have a better prognosis.
Surgery.
Complete surgical 
resection of the tumor is the primary goal and is essential for 
cure.
Chemotherapy 
is more successful for hepatoblastoma than for hepatocellular 
carcinoma.
For unre-
sectable tumors, liver transplantation may be offered in select 
patients.
TRAUMA IN CHILDREN
Injury is the leading cause of death among children older than 
1 year.
Specific considerations apply to trauma in children that 
influence management and outcome.
Mechanisms of Injury
Most pediatric trauma is blunt.
Age and 
gender significantly influence the patterns of injury.
In the infant and toddler age group, falls 
are a common cause of severe injury.
Injuries in the home are 
extremely common.
These include falls, near-drownings, caus-
tic ingestion, and nonaccidental injuries.
Airway control is the first priority.
In a 
child, respiratory arrest can proceed quickly to cardiac arrest.
The size of the endotracheal tube can 
be estimated by the formula (age + 16)/4.
After evaluation of the airway, 
breathing is assessed.
Pneumothorax 
or hemothorax should be treated promptly.
IV access should be rapidly obtained once the patient arrives in 
the trauma bay.
The first approach should be to use the antecubi-
tal fossa.
Percutaneous neck lines should 
generally be avoided.
If the patient does not respond to two boluses, blood should 
be transfused (10 mL/kg).
The source of bleeding should be 
established.
Common sites include the chest, abdomen, pelvis, 
extremity fractures, or large scalp wounds.
These should be 
carefully sought.
Care is taken to avoid hypothermia by infus-
ing warmed fluids and using external warming devices.
Proc Am Soc Clin Oncol.
1994;13:A-1439.
All extremities that are suspicious 
for fracture should also be evaluated by x-ray.
Significant elevation in these tests 
requires further evaluation by CT scanning.
There is a 
limited role for diagnostic peritoneal lavage (DPL) in children as 
a screening test.
In the toddler age group, nonaccidental trauma 
is the most common cause of serious head injury.
The initial head CT 
can often underestimate the extent of injury in children.
Any change in the neurologic status warrants neurosurgical 
evaluation and repeat CT scanning.
In patients with severe head 
injury (GCS ≤8), urgent neurosurgical consultation is required.
Children who have sustained massive blunt thoracic injury may 
develop traumatic asphyxia.
Man-
agement includes ventilation and treatment of coexisting CNS 
or abdominal injuries.
Duodenal hematomas usually resolve without surgery.
These injuries are usually caused 
by rapid deceleration in the setting of a lap belt.
39-41A).
This should alert the 
caregiver to the possibility of an underlying small bowel injury 
(Fig.
39-41B), as well as to a potential lumbar spine injury 
(Chance fracture).
BA
Figure 39-41.
Abdominal computed tomography of patient who sustained a lap belt injury.
A.
Bruising is noted across the abdomen from 
the lap belt.
B.
At laparotomy, a perforation of the small bowel is identified.
This approach avoids 
surgery in most cases.
This optimizes the chance for healing and minimizes 
the likelihood of reinjury.
At surgery, the spleen can often be salvaged.
The liver is also commonly injured 
after blunt abdominal trauma.
39-42).
Renal contusions may occur after significant blunt abdomi-
nal trauma.
It is 
important to confirm the presence of a normal contralateral 
kidney at the time of surgery.
For the vast 
majority of congenital anomalies, postnatal surgery is the pre-
ferred modality.
The long-term effects on 
subsequent pregnancies remain to be established.
For the fetus, 
in utero surgery carries the risk of premature labor and amni-
otic fluid leak.
Figure 39-42.
Abdominal computed tomography in a child 
demonstrating a grade III liver laceration (arrows).
Organ injury scaling.
Surg Clin North Am.
1995;75:293-303.
Copyright Elsevier.
In 1990, Harrison and colleagues reported the first open 
fetal repair for CDH.
The efficacy of in utero 
treatment vs.
The EXIT Procedure
The EXIT procedure is an abbreviation for ex utero intrapartum 
treatment.
39-43), 
or congenital tracheal stenosis.
Uterine perfusion with warmed saline also 
promotes relaxation and blood flow to the placenta.
On aver-
age, between 20 and 30 minutes of placental perfusion can be 
achieved.
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1646
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1648
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UNIT II
part II
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Anteriorly, they are confined by the posterior layer of 
the peritoneum.
The renal veins, which course anteriorly to the renal 
arteries, drain directly into the vena cava.
The left renal vein 
passes anterior to the aorta and is much longer than the right 
renal vein.
This explains why most surgeons prefer to take the 
left kidney for living donor transplantation.
The right renal vein has no such collateral venous 
drainage.
The renal pelvis can have either a mainly intrarenal or extrarenal 
position.
The renal pelvis tapers into the ureteropelvic junction 
(UPJ) where it joins with the ureter.
The adrenal glands lie superomedially to the kidneys 
within Gerota’s fascia.
There is a layer of Gerota’s fascia 
between the adrenal and the kidney.
On the right, the adrenal is drained 
by a very short (<1 cm) vein to the vena cava.
It can be 
avulsed by moderate traction and can be the source of trou-
blesome bleeding.
The blood supply has implica-
tions for managing ureteral injuries.
They enter the bladder at the lateral aspect of the 
base.
The anatomic relations of the 
bladder are dependent on the degree of filling.
A very distended 
bladder can project above the umbilicus.
At physiologic volumes 
(200–400 mL), the bladder projects modestly into the abdomen.
In males, the prostate is in continuity with the bladder 
neck, and the urethra courses through it.
Proximally, they lie along the medial 
aspects of the inferior pubic rami in the perineum.
Distally, 
they fuse along their medial aspects and form the pendulous 
penis.
Injury or excess traction of these nerves may cause erectile 
dysfunction.
On the underside of the penis lies the corpus 
spongiosum, which surrounds the urethra.
The tip of the penis, called the glans, is in continuity with the 
corpus spongiosum.
Scrotum and Testes
The scrotum is a capacious structure that contains the testes 
and epididymes.
These layers are not always distinct.
The visceral layer 
of the tunica vaginalis is adherent to the testis.
The noncompli-
ant outer testis layer is the tunica albuginea.
Inside the tunica 
are the seminiferous tubules.
The blood supply enters the testis 
at the superior pole by way of the spermatic cord.
Some children are born with an undescended abdominal testicle.
Often, it is difficult to derive enough length to place the testicles 
in the scrotum.
Most of these testicles remain viable as a result of 
collaterals.
Bladder cancer can be categorized into invasive and non-
invasive types.
Management of urothelial carcinoma varies 
greatly, depending on the depth of invasion.
Detubularization decreases 
intrapouch filling pressure, which improves urinary storage 
capacity.
Each segment of bowel that 
is used offers its own advantages and inherent complications.
Tumor grade is extremely important in 
assessing the risk of disease progression.
Surgical Approaches and Complications.
This allows 
adequate exposure of the pelvic contents, iliac vessels, and 
lower abdominal cavity.
In men, the prostate is removed with the bladder.
40-1).
A major risk for the develop-
ment of testicular cancer is cryptorchidism.
The non–germ cell 
tumors are rare and generally follow a more benign course.
Germ 
Figure 40-1.
Testicular cancer.
Patients often present with 
advanced disease despite scrotal enlargement for several months.
Chest and abdominal imaging must 
be performed to evaluate for evidence of metastasis.
Lymphoma 
(especially among the elderly) may involve one or both testes.
Postchemotherapy RPLND for residual 
masses can be challenging.
Surgical Approach and Complications.
Complex renal cyst.
A right kidney with a Bosniak 
type 3 renal cyst.
Note the enhancing septum (arrow).
This cyst 
was removed and found to be a high-grade papillary renal cell 
carcinoma.
40-2).
Renal tumors are usually solid, but they 
also can be cystic.
Simple cysts are very common and are not 
malignant, but more complex cysts may be malignant.
These syndromes frequently involve 
Table 40-1.
Also includes homogeneously hyperdense cysts <3 cm.
May contain nodular calcification.
Also includes hyperdense cysts >3 cm.
∼50%/surgical
IV Same as III, but with enhancing solid components.
∼100%/surgical
Source: Adapted with permission from Israel GM, Bosniak MA.
An update of the Bosniak renal cyst classification system.
Urology.
2005;66:484.
Copyright Elsevier.
1656
SPECIFIC CONSIDERATIONS
UNIT II
PART
 
II
a germline mutation in a tumor suppressor gene.
von Hippel-
Lindau disease is associated with multiple tumors including 
clear cell RCC (Fig.
40-3).
Patients with heredi-
tary papillary RCC and hereditary leiomyomatosis develop pap-
illary RCC.
Patients with localized disease may be cured with either 
partial or radical nephrectomy (Fig.
40-4).
However, patients 
Figure 40-4.
Partial nephrectomy.
A kidney after partial resection 
for a small renal mass.
Note the visible collecting system in the base 
of the defect (arrow).
Figure 40-3.
von Hippel-Lindau disease.
Note the numerous 
cysts in the head of the pancreas (arrow).
Minimally invasive techniques for renal surgery have 
greatly changed the field of kidney cancer.
Surgeons are now capable 
of performing intracorporeal suturing with much greater 
ease.
The degree of venous extension directly impacts the 
surgical approach.
40-5A).
Usually, the thrombus is not adher-
ent to the vessel wall.
40-5B).
Nephrectomy, 
either partial or radical, can be performed through a number 
of surgical approaches.
However, entry into the pleura is not 
uncommon.
If small, the pleurotomy usually can be closed 
without need for a chest tube.
The anterior subcostal approach 
also is used for nephrectomy.
A chest tube 
is used postoperatively.
The adrenal gland is no longer rou-
tinely removed unless the tumor is adherent to it.
The benefit 
of lymph node dissection when the nodes are not clinically 
involved is uncertain.
Partial nephrectomy has the added risks of delayed 
bleeding and urine leak.
Ileus is not common when the perito-
neal cavity is not entered.
The U.S.
Preventive Services Task Force has 
advised against the routine use of prostate cancer screen-
ing.
The American Urological Association has advised for 
screening for men 55 to 69 years of age.
Grades range from 1 for the most differentiated to 5 for the 
least.
The grades are added to give the Gleason score.
In cur-
rent practice, scores below 6 are almost never assigned.
Gleason 
score, preoperative PSA level, and digital rectal exam are used 
Figure 40-5.
Inferior vena cava thrombus.
A.
B.
This patient is alive 6 years after surgery.
After 
definitive treatment, an increasing PSA is indicative of recur-
rent cancer.
The most common site of spread of prostate cancer is the 
pelvic lymph nodes and bone.
For low-risk disease, the efficacy of each 
treatment modality is thought to be similar.
Radical prostatectomy is associated with 
early incontinence and ED (depending on nerve sparing).
Likewise, ED improves with time.
Once prostate cancer has spread, it is no longer cur-
able.
Surgical Approach and Complications.
The peritoneum is not entered.
The cavernosal nerves lay 
immediately posterolateral to the prostatic capsule.
Benefits over open 
Table 40-2.
Organ injury scaling.
Surg Clin North Am.
1995;75:293.
Copyright Elsevier.
radical retropubic prostatectomy include lower blood loss and 
faster convalescence.
Complications of prostatectomy depend on approach.
All approaches carry a small risk of urinary 
incontinence and a more substantial risk of ED.
Renal injuries are classified by extent of damage 
(Table 40-2).
Addi-
tionally, most grade IV injuries can be managed nonoperatively 
(Fig.
40-6).21 Patients typically are placed on restricted activity 
until hematuria resolves.
Table 40-3 lists indications for assess-
ing surgical intervention in renal trauma patients.
Indications for surgical intervention for renal trauma
Absolute indications
 1.
Persistent, life-threatening hemorrhage from probable 
renal injury
 2.
Renal pedicle avulsion (grade 5 injury)
 3.
Expanding, pulsatile, or uncontained retroperitoneal 
hematoma
Relative indications
 1.
Large laceration of the renal pelvis or avulsion of the 
ureteropelvic junction
 2.
Coexisting bowel or pancreatic injuries
 3.
Abnormal intraoperative one-shot intravenous urogram
 5.
Devitalized parenchymal segment with associated urine 
leak
 6.
Renal vascular injuries after failed angiographic 
management
 8.
Renovascular hypertension
Source: Reproduced with permission of Wiley-Blackwell.
From San-
tucci RA, Wessells H, Bartsch G, et al.
Evaluation and management of 
renal injuries: consensus statement of the renal trauma subcommittee.
BJU Int.
2004;93:937.
Figure 40-6.
Blunt renal trauma after a bicycle accident.
A.
Delayed images showed urinary extravasation.
This patient 
was managed nonoperatively.
B.
extent of injury.
If the IVP is abnormal or the hematoma is pul-
satile, renal exploration should be performed.
Renal exploration should begin once the renal hilum is 
controlled.
Complete expo-
sure is necessary to evaluate the extent of injury.
If 
the collecting system is injured, it should be repaired at this 
time.
A stent and percutaneous drain should be considered to 
prevent urinoma formation.
A 
briefly misplaced suture may be removed usually without conse-
quence.
Ureteral stents should be placed in 
this situation to facilitate healing without stricture.
Bladder
Bladder injury can occur from penetrating and blunt trauma.
The diagnosis should be entertained for any lower abdominal 
or pelvic trauma.
Patients clinically present with fevers or a 
prolonged ileus.
Radiographic evaluation begins with either a fluoroscopic 
or CT cystogram.
It is vital to avoid underfilling, as it may lead 
to a false-negative study.
The contrast 
material should be allowed to fill to the natural capacity of the 
bladder.
Extraperitoneal bladder injuries can typically be managed 
with catheter drainage for 7 to 10 days.
Intraperitoneal bladder 
injuries should be explored immediately and repaired.
Catheter placement can be attempted 
in patients with partial urethral injuries.
Those with complete 
disruptions should have placement of a suprapubic tube.
Anterior injuries often are related to blunt straddle inju-
ries and penetrating trauma.
If the patient is stable 
with minimal hematoma formation, repair should be consid-
ered.
For most cases, catheter drainage is 
recommended.
However, a single gentle passage performed by a 
urologist is safe.
The patient’s other injuries dictate urologic 
management.
They should be staged with either a retrograde 
urethrography or voiding cystourethrogram (VCUG).
Patients 
with short defects may be amenable to dilatation or cystoscopic 
urethrotomy.
Depending on location, length, and severity, open 
repairs may be required.
Long defects may require grafting to 
avoid significant penile shortening.
For 
penetrating trauma, immediate exploration is recommended for 
accurate staging and repair.
Although salvage may be possible, an orchiec-
tomy usually is required.
40-7).
Men may notice an immediate audible “pop” and experience 
rapid penile detumescence.
Immediate swelling develops.
Leakage should be visualized if there is 
a urethral disruption.
If present, the urethra should be repaired, 
taking care not to significantly narrow the lumen.
A Foley cath-
eter is left in place for several days after surgery.
Constipation, 
a common side effect of those medications, can itself 
worsen urinary retention.
Treatment should include placement of a 
urethral catheter as quickly as possible.
However, BPH or ure-
thral strictures often make the placement of a catheter difficult.
40-8A).
40-8B).
A common mistake is 
to use a smaller catheter to bypass the enlarged prostate.
Smaller catheters are useful for bypassing a urethral 
stricture.
Using a 12F or 14F catheter often will allow the pas-
sage of the catheter into the bladder.
If catheter placement is 
not successful, a urologic consultation should be requested.
The 
urologist can either choose to (a) use a cystoscope, guidewire, 
7
Figure 40-7.
Penile fracture.
A.
A patient with a penile fracture that was suspected based on history and examination.
Note the lack of skin 
discoloration that is often present.
B.
The 
urethra, which is between the surgeon’s fingers, surprisingly escaped injury.
This is done through a large three-way 
catheter that has an additional port for fluid inflow.
A urinalysis should be checked because a poorly empty-
ing bladder is prone to infection.
Renal function also should be 
assessed for those in AUR by checking the creatinine level.
Once the bladder is adequately drained, the cause of AUR 
should be addressed.
For men with suspected BPH, an α-blocker 
such as tamsulosin should be started.
Narcotics should be tapered as tol-
erated, and constipation should be treated.
However, 
most patients are resistant to this approach.
Testicular Torsion
The differential diagnosis of acute scrotal pain includes testicu-
lar torsion.
This usually occurs in neonates or adolescent males 
but may be observed in other age groups.
Clinical history is vital for diagnosis.
Patients describe a 
sudden onset of pain at a distinct point in time, with subsequent 
swelling.
Children 
normally have a brisk cremasteric reflex that usually is lost in 
the setting of torsion.
Immediate surgical exploration can salvage an isch-
emic testis.
Coude catheter.
A.
B.
The tip of a coude catheter.
Note the curved tip, which should 
always point to 12 o’clock when inserted.
Midline 
(along the median raphe) or bilateral transverse scrotal incisions 
are made.
40-9A).
Clinical signs include fevers, perineal and scrotal pain, 
and associated indurated tissue.
Cellulitis, eschars, necrosis, 
flaking skin, and crepitus may all be observed.
Classically, the 
patient describes pain out of proportion to the physical findings.
40-9B).
Patients frequently require return trips to the oper-
ating room for further débridement.
Tight glucose control and 
adequate nutrition are necessary to facilitate wound healing.
The 
large tissue defect should be initially treated with frequent 
dressing changes.
Priapism is divided into two types, 
based on the underlying pathophysiology.
The most common 
type—low-flow/ischemic priapism—is a medical emergency.
For those with sickle cell disease, hydration and 
9
Figure 40-9.
Fournier’s gangrene.
A.
Necrotic scrotal skin from 
Fournier’s gangrene.
B.
Débridement of gangrenous tissue.
Note 
the extensive débridement, which is commonly required.
If this fails, an operative distal shunt can 
be performed (Al-Ghorab).
This form is not painful because it 
is not related to ischemia and can be managed conservatively.
Paraphi-
mosis is a common problem that represents a true medical 
emergency.
When foreskin is retracted for prolonged periods, 
constriction of the glans penis may ensue.
Edema often forms in the genitals 
of supine patients due to the dependent position of that area.
It is useful to apply firm pressure to the edematous 
distal penis for several minutes.
Although painful, this reduc-
tion in penile edema can be the key to success.
If the foreskin cannot be 
manually reduced, surgical intervention is required.
Emphysematous pyelo-
nephritis can be subdivided based on extent of infection.
An uncomplicated episode of cystitis requires a 3-day 
course of antibiotics.
Those with complicated cystitis require 
7 days of antibiotics and possible imaging studies.
Patients 
typically present with flank pain and fevers.
Other-
wise, they should be hospitalized for IV antibiotics.
Treatment consists of broad-spectrum IV antibi-
otics and percutaneous drainage.
Patients present with 
fevers, dysuria, and perineal or back discomfort.
A digital rectal 
examination may indicate an indurated and tender gland.
Patients require a 4- to 6-week course of antibiotic 
therapy, typically a quinolone.
If present, large abscesses 
can be managed with transurethral unroofing or percutaneous 
drainage.
Chronic prostatitis presents with continued lower urinary 
tract symptoms and pelvic pain.
Chronic 
nonbacterial prostatitis does not respond to antibiotics or most 
other medications.
However, most men will not 
show evidence of urinary tract infection.
The scrotum may be erythematous on the side of 
involvement.
The white blood cell (WBC) count often is ele-
vated.
The onset is fairly rapid, but not as sudden as torsion.
An 
ultrasound may provide supporting evidence such as increased 
blood flow to the epididymis.
A reactive hydrocele may be 
present.
Intratesticular abscesses 
may form and usually result in orchiectomy.
The symptoms of BPH are urinary 
frequency, urgency, hesitancy, slow stream, and/or nocturia.
Medical treatment of BPH is usually the first step.
α-Blockers act on α receptors in the smooth muscle of the 
prostate and decrease its tone.
Both are used either singly 
or in combination as medical therapy for BPH.
Trans-
urethral resection of the prostate is the mainstay of endoscopic 
surgical BPH treatment.
It is extremely effective at improving 
flow and decreasing residual urine.
It is due to hyponatremia and 
fluid overload, and although rare, can result in death.
There also is less bleeding.
U