The Craniofacial Complex

Thus there is an opportunity for infectious agents or
their byproducts to penetrate the naked epithelial
barrier and initiate an inflammatory response, as hap-
pens in gingival disease.

Special cells in the basal layer of the oral mucosa
generate replacements for surface cells as they
wear out. The painful oral ulcers and oral mucositis
that may develop in patients undergoing radiation
or chemotherapy for head and neck cancer occur
because these cancer-killing agents attack all
cells undergoing rapid turnover, whether healthy or
cancerous.

The Teeth

The most prominent features of the oral cavity are the
teeth. The 20 primary, or deciduous, teeth erupt gen-
erally between 6 months and 2 to 3 years of age and
are succeeded by the permanent teeth beginning at
about age 6. The primary teeth enable infants to eat
solid foods, aid speech development, and serve as
placeholders for the permanent dentition. Keeping
primary teeth healthy is important, not only in spar-
ing an infant pain and disease, but also in preserving
the dimensions of the dental arches and lessening the
risk of dental caries in the permanent teeth. A period
of mixed primary and permanent dentition occurs
from about ages 6 to 13. There are 28 to 32 perma-
nent teeth, depending on whether the 4 wisdom
teeth (third molars), which are last to erupt, are pres-
ent. Teeth are anchored in the jaws by the periodon-
tal ligament. This ligament connects the cervix
(neck) of the tooth, at the junction between the
crown and root, to the gingiva. Below that, the liga-
ment connects the outer layer of the tooth root, the
cementum, to the adjacent alveolar bone (the part of
the jaw bone that supports the tooth roots).
The evolutionary forces that shaped the human
mouth designed an apparatus for optimal food
intake. The front four upper and lower incisor teeth
are chisel-shaped for biting, cutting, and tearing and
exert forces of 30 to 50 pounds. The canines, or
cuspids, are larger and stronger and have deeper
roots than the incisors; their conical cusps are
effective for ripping and tearing. The premolars, or
bicuspids, and the molars are designed for heavy
grinding and chewing, exerting forces as high as 200-
plus pounds. The temporomandibular joint, the most
complex synovial joint in the body, equips the
human jaw with extraordinary mobility, enabling
movements in three dimensions. Its range of motion
is controlled by three sets of muscles of
mastication-the masseter, temporalis, and pterygoid
muscles (Oberg 1994). Chewing reduces food to

small particles and mixes it with saliva to form a
bolus for swallowing.

The Salivary Glands

Saliva is the mixed product of multiple salivary
glands that lie under the mucosa. The three major
glands are the paired parotid, submandibular, and
sublingual glands. The parotids, near the ears, secrete
a watery saliva into the mouth via ducts in the
cheeks. The walnut-sized submandibular glands lie
in the floor of the mouth and secrete a mucous fluid.
The secretions of the almond-shaped sublingual
glands, also in the floor of the mouth but near the
front, usually join with those of the submandibular
glands. Tiny minor salivary glands are scattered with-
in the inner surfaces of the lips, cheeks, and soft and
hard palates; these secrete a mutinous saliva directly
onto the soft tissue surfaces.

Saliva moistens food and provides mutinous pro-
teins to lubricate the bolus for ease of swallowing.
The combined movements of the tongue and cheeks
move the bolus to the back of the mouth. Saliva also
contains the enzyme amylase, which initiates the
digestion of starch. By solubilizing food components
and facilitating their interaction with the taste buds
on the tongue and palate, saliva also contributes to
taste enhancement.

Tissue Protection

The main function of saliva is not-as is commonly
believed-to aid digestion, but to protect the integri-
ty of the oral tissues. The moment a baby passes
through the birth canal and takes its first breath,
microbes begin to take up residence in its mouth.
Later, as the teeth erupt, additional bacteria establish
colonies on tooth surfaces (Mandel 1989). Nearly
500 species of microbes in all, most of which are not
harmful, will colonize the oral cavity (Kroes et al.
1999). The microbes form a biofilm, in which their
numbers greatly exceed the number of human inhab-
itants on Earth.

Millions of years before there were toothbrushes,
dental floss, and water irrigators, evolutionary forces
generated protective mechanisms to combat poten-
tially harmful microbes. The physical flow of saliva
helps to dislodge pathogens (viruses, bacteria, and
yeast) from teeth and mucosal surfaces, just as tear-
ing and blinking, sneezing, and coughing and expec-
torating clear the eye, nose, and throat. Saliva can
also cause microbes to clump together so that they
can be swallowed before they become firmly
attached. Saliva can destroy orally shed infected

26

ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL


\vliite blood cells by virtue of its low salt content: the
,nfected cells-of higher salt content-swell and
lltlrst when exposed to fluids of lower salinity (Baron
C[ al. 1999).

Salivary secretions, like tears and other exocrine
+nd secretions, are rich in antimicrobial compo-
nents. Certain molecules in saliva, such as lysozyme,
lactoferrin, peroxidase, and histatins, can directly kill
Or inhibit a variety of microbes; the histatins are par-
ticularly potent antifungal agents (Xu et al. 1991).
Selreral salivary proteins exhibit antiviral properties,
including secretory leukocyte protease inhibitor
(SLPI), recently discovered to have the ability to
Inhibit HIV from invading cells (Shugars and Wahl
1998).

The ability of saliva to limit the growth of
pathogens, in some instances even preventing them
lrom establishing a niche in the biofilm community
in the first place, is a major determinant of general as
\vell as of oral health. When salivary flow is compro-
mised, the gateway to the body can open wide to
local as well as to systemic pathogens.

Barrier and Buffering Properties

Salivary components protect oral tissues in other
ways as well. Mucins have unique properties that
enable them to concentrate on mucosal surfaces and
provide an effective barrier against drying and physi-
cal and chemical irritants (Tabak 1995). They act as
natural waterproofing, control the permeability of
ihe tissue surfaces, and help limit penetration of
potential irritants and toxins in foods and beverages,
as well as toxic chemicals and potential carcinogens
In tobacco and tobacco smoke and from other
sources. This barrier function complements the bar-
rier formed by the oral mucosa itself. The mucosa has
a specific permeability coefficient that can change
under various conditions of stress, nutritional status,
and other challenges.

Saliva contains several effective buffering sys-
tems that can help maintain a normal pH when acidic
foods and beverages are introduced, thereby protect-
ing oral tissues against acidic attack. When swal-
lowed, these buffers protect the esophagus, helping
neutralize the reflux acids of conditions such as
heartburn and hiatal hernia (Sarosiek et al. 1996).

Wound Healing

Saliva also contains molecules that nurture and pre-
serve the oral tissues, even helping them to repair
and regenerate (Mandel 1989, Tabak 1995, Zelles et
al. 1993). Experimental studies have shown that
ivound healing is significantly enhanced by saliva, in

The Craniofacial Complex

part because of the presence of a potent molecule,
epidermal growth factor (EGF) (Zelles et al. 1995).
When swallowed, EGF can also protect the tissue
surfaces of the esophagus (Sarosiek et al. 1996).
Vascular endothelial growth factor (VEGF) has also
been identified in saliva. VEGF stimulates blood ves-
sels and may contribute to the remarkable healing
capacity of oral tissues (Taichman et al. 1998, Zelles
et al. 1995).

Caries Protection

Saliva also guards against dental caries (tooth decay),
the disease that has been the greatest threat to teeth.
Caries is caused by bacteria that generate acids that
attack tooth mineral (see Chapter 3). The buffering
systems in saliva, augmented by the neutralizing
components urea and ammonium, counter the acid
formation. The physical flow of saliva also helps
flush out sugars and food particles that are the bacte-
rial food source. Mineral salts in saliva-calcium and
phosphate-can remineralize tooth enamel, effec-
tively reversing the decay process. This regenerative
function is greatly enhanced by the presence of fluo-
ride in saliva. Finally, saliva forms a film on teeth
made up of selectively adsorbed proteins that have a
high affinity for tooth mineral. This acquired pellicle
is insoluble and limits the diffusion of acids into the
teeth and the dissolution of tooth mineral (Lamkin
and Oppenheim 1993).

The Immune System

The salivary glands and the oral mucosa, along with
the body's other mucosal linings and the lymphatic
circulation, constitute a major component of the
body's defense system-the mucosal immune system
(Mestecky 1987). When the area of the oral mucosa
is combined with the areas of the mucosal linings and
passageways of the respiratory, gastrointestinal, uri-
nav, and genital tracts, the total represents the largest
surface area of the body-nearly 400 square meters,
or 200 times larger than the total skin area.

The great majority of infectious diseases affect,
or are acquired through. mucosal surfaces. Immune
cells that line the mucous membranes throughout
the body secrete antibodies targeted to specific
disease-causing microbes (Mandel and Ellison 1985).
The mucosal immune system works in concert with
the bloodborne immune system to detect and dispose
of foreign substances and invading microbes.

The two components of the immune system con-
sist of molecules and cells that provide both broad
and specific defense mechanisms. In the broad group

ORAL HE4LTH IN AMERICA: A REPORT OF THE SURGEON GENERAL           27


are some circulating white blood cells (monocytes
and granulocytes) associated with the inflammatory
response. These cells migrate to a site of injury or
infection and move into damaged tissues manifest-
ing the four signs of inflammation: swelling, heat,
redness, and pain. The cells promote an increase in
blood flow to begin the healing process, and they
recruit other cells able to engulf and dispose of the
offending organism.

The specific immune system is associated with
two major classes of immune cells: T cells and B cells.
T cells react to antigens (proteins associated with
microbes or irritants) and can stimulate B cells to
make antigen-specific antibodies. These are the Y-
shaped molecules called immunoglobulins.

T cells are the instruments of cell-mediated
immunity; they are able to detect telltale surface
markers on diseased or foreign cells that distinguish
them from normal body cells. Some T cells can kill
infected cells and cancer cells directly T cells are also
involved in the rejection of organ transplants.

Certain T cells are memory cells, preserving the
information from earlier encounters with specific
pathogens. Thus they are able to initiate more rapid
and effective responses in the event of a repeat
encounter with the pathogen. Helper T cells assist in
activating killer T and B cells. It is the loss of helper
T cells that leads to the many infections that cause ill-
ness and death in HIV disease. Still another group of
T cells, suppressor T cells, moderates the activities of
both B and T lymphocytes.

Activated T cells generate and release
cytokines-potent families of proteins, such as the
interleukins, that can stimulate immune cells to
divide, migrate, attack, and engulf invaders or partic-
ipate in the inflammatory response. Other cytokines
include varieties of tumor necrosis factor and
adhesins (proteins that facilitate the binding of
immune cells to each other or to blood vessel lin-
ings). Feedback mechanisms provide a system of
checks and balances to regulate cytokine production.

The immune system interacts with the nervous
and endocrine systems. For example,  immune
cytokines secreted into the brain can induce the fever
associated with infection: the high temperature may
help destroy the infectious agent. The brain's
response to stress also has repercussions for the
immune system. The hypothalamus-pituitary-adre-
nal axis is a major pathway activated in response to
stress, which results in the secretion of cortisol, the
stress hormone, from the adrenal glands. Cortisol
promotes the body's fight-or-flight mechanisms, but
via feedback loops, cortisol acts to depress immune
reactions.

Much of what we know about the immune sys-
tem has come from studies of serum factors, but
research in the last two decades has generated much
new information about mucosal immunity (McGhee
and Kiyono 1999). The mucosal immune system can
be divided into inductive and effector compartments.
The nasal-associated lymphoreticular tissues (NALT)
in the nasopharyngeal area (which includes the ton-
sils) and the gut-associated lymphoreticular tissues
(GALT) in gut tissue are inductive regions, where
foreign invaders are encountered. If, for example,
infectious bacteria are swallowed, they can stimulate
immune cells in GALT to circulate T and B cells
through the lymph system to various effector sites in
the gastrointestinal and uppe? respiratory tracts and
in the salivary and other exocrine glands. The B cells
in the gland produce antibodies, designated S-IgA, to
which is attached a secretory component (Mestecky
and Russell 1997). These antibodies are the domi-
nant type found in saliva, tears, breast milk, and
colostrum and in the gastrointestinal and genitouri-
nary tracts.

The uses of the mucosal immune system extend
beyond its normal surveillance and defense func-
tions. The tissues can be used as routes for delivery
of oral (swallowed) or nasal (inhaled) vaccines, as
sites for gene transfer to augment host defenses, and
as a means of invoking oral tolerance-the suppres-
sion of overactive or inappropriate immune respons-
es that occur in chronic inflammatory and autoim-
mune diseases (Baum and O'Connell 1995,
Hajishengallis and Michalek 1999).

CRANIOFACIAL ORIGINS

The extraordinary successes of research in molecular
genetics over the past decade, coupled with the
National Institutes of Healths project to map and
sequence the human genome, have proved to be a
boon in understanding craniofacial development.
The use of automated gene-sequencing equipment,
the Internet availability of genome databases, and the
ability to transfer genes or create "knockout" ani-
mals-in which a gene of interest has been eliminat-
ed-have greatly facilitated progress. The events that
govern the transformation of a fertilized human egg
cell into a healthy newborn with all organs and sys-
tems in place are being unfolded at the molecular
level. Families of master and regulatory genes have
been identified, and their role in controlling how the
body's general shape and specialized tissues and
organs are formed is coming to light.

`8        ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL


Early Development

The Three Germ Cell Layers

gy the time the face and the mouth are ready to form,
the human embryo is in the third week of develop-
ment. The embryo has evolved from a sphere to an
oval two-layered disk with a head-to-tail orientation.
The outer layer is the epiblast and will become the
ectodermal germ layer. A narrow groove, called the
primitive streak, extends from the tail toward the
center of the disk, where it ends in a spot surround-
ing a small depression called the primitive pit.
Epiblast cells migrate toward the streak and pit,
detach from the surface, and slip downward to form
the two additional germ cell layers, the mesoderm
and, below that, the endoderm.

The ectodermal layer gives rise to tissues that
relate the body to the outside world: the nervous SYS-
tern; the sensory epithelium of the ears, nose, and
eyes; skin, hair, nails, salivary glands, tonsils, and
tooth enamel; and the pituitary.mammary, and sweat
glands. At the head end, the mesodermal layer gives
tise to a primitive connective tissue, called mes-
enchyme, which will interact with the ectoderm to
form parts of the head and mouth. The remaining
mesoderm develops into the muscle, cartilage, bone,
and subcutaneous skin tissue of the rest of the body.
The mesoderm is also the origin of the vascular and
urogenital systems (except for the bladder), the
spleen, and the adrenal cortex. The innermost, endo-
dermal layer provides the linings of the gut, the res-
piratory system, bladder, liver, pancreas, thyroid and
parathyroid glands, and parts of the middle ear.

Neural Tube and Neural Crest

Further migrations and descending movements of
cells result in the formation of the notochord, a solid
cord of cells along the midline that will become the
backbone. The ectoderm above the notochord next
thickens to form a neural plate. The sides of the plate
curve up and inward to form a neural tube, beginning
at the head, with fusion completed by the end of the
fourth week. The tail end of the tube will form the
spinal cord; the head end differentiates into the three
parts of the primitive brain: the forebrain, midbrain,
and hindbrain.

What happens next is of central importance to
the craniofacial complex: cells that were at the edges
of the neural plate break away to form neural crest
cells, which migrate to the forebrain area and to the
nearby branchial arches, a series of swellings on
either side of the embryo, adjacent to the hindbrain.
The hindbrain becomes organized into eight rhom-

bomeres, segments of future nerve tissue arranged in
an orderly fashion so that the first two rhombomeres
innervate branchial arch 1, and so on.

During the formation of the midbrain and hind-
brain, cranial neural crest cells migrate into the
developing facial areas and differentiate into neu-
ronal and nonneuronal tissues. The neuronal tissues
include the clusters of nerve cells (ganglia) that lie
adjacent to the spinal cord, parts of the ganglia of
four cranial nerves, and two of the meningeal layers
of the brain. The nonneuronal tissues include major
bones, cartilage, the dentin and cementum of teeth,
and the various types of connective tissues of the
craniofacial complex, as well as the muscles of the
eye. The branchial arches give ris6 to the bones, car-
tilage, nerves, muscles, and blood supply of succes-
sive segments of the head and neck.

The Face and Mouth

The branchial arches play a key role in the formation
of the facial structures. Toward the end of the fourth
week of gestation, a primitive mouth appears. This
"stomadeum" is flanked by a series of swellings, or
prominences, derived from the first pair of branchial
arches. A single frontonasal prominence forms the
upper border of the stomadeum. On either side of
this prominence are two thickened regions of ecto-
derm-the nasal placodes. At the sides of the stom-
adeum and below it are pairs of maxillary and
mandibular prominences.

In the course of the next 3 weeks, differential
growth and movements of the various prominences
and fusions of tissues that come together at the mid-
line will sculpt the bridge, crest, sides, and tip of the
nose, the upper and lower lips, and the upper and
lower jaws (Bhaskar and Orban 1990, Sadler and
Langman 1995).

The external merger at the midline of a pair of
prominences that helps to form the nose occurs
inside the mouth as well, resulting in an intermaxil-
laty segment that will contribute to the formation of
the four upper incisors and parts of a small triangu-
lar-shaped primary palate and the upper jaw. The
bulk of the palate, the secondary palate, forms from
shelflike outgrowths of the maxillary prominences.
These growths appear in the sixth week, and in the
following week fuse along the midline above the
tongue. (The tongue appears at approximately 4
weeks, the front two-thirds forming from the first
branchial arch, and the posterior third from parts of
the second, third, and fourth branchial arches.) The
palatal shelves also fuse with the primary palate
along a triangular border called the incisive foramen.

ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL           73


The Craniofacial Cornples

This border is considered the line of division among
clefting abnormalities. Lateral cleft lip, cleft upper
jaw, and clefts between the primary and secondary
palates are associated with defects anterior to the
incisive foramen. Cleft palate and cleft uvula occur
because of defects affecting closure of the palatal
shelves posterior to the foramen (Bhaskar and Orban
1990, Sadler and Langman 1995).

The Teeth

Tooth development begins in the sixth week with the
appearance of an epithelial band lining the upper and
lower jaws. A part of the band develops into a dental
lamina, which forms a series of projections into the
jaw. These are the tooth buds and correspond to the
sites of deciduous teeth. The epithelial tissue of the
bud develops into an enamel organ that forms a cap
over tissue that is differentiating in the jaw to become
the dental papilla. The two structures-the enamel
organ. derived from the epithelium, and the dental
papilla, derived from neural crest mesenchyme-
constitute the tooth germ.

With further development, the tooth germ
assumes a bell shape and separates from the oral
epithelium. At the same time, the internal epithelial
layer of the enamel organ undergoes a series of
infoldings that will shape the future crown of the
tooth.

Mineralization of the tooth begins at the late bell
stage. The first mineralized tissue to form is dentin,
which provides the foundation for the deposition of
enamel. The differentiation of the odontoblasts (the
dentin-producing cells) depends on organizing
influences from enamel organ cells. Thus the
development of these two different hard tissues is a
mutually dependent process.

  As dentin is laid down, the odontoblasts move
toward the center of the papilla, trailing thin cellular
processes, which become embedded in the mineral-
ized matrix. When dentin formation is completed,
dentin completely surrounds the pulp, protecting it
from injury. The enamel layer of the tooth starts to
form soon after the first dentin appears, synthesized
by special enamel-forming cells, or ameloblasts,
which develop from the enamel organ. The tooth
root, and its outer layer of cementum, form only after
the crown erupts.

Genetic Controls

Only in the last decade have scientists begun to
understand how certain genes and gene families
control embryonic development. Their findings have

come from detailed studies of species ranging from
fruit flies, nematodes, and zebrafish to frog, chick,
mouse, and human embryos. In many cases, the
simpler organism has been the source of discoveries
of genes or developmental processes that are highly
conserved in the course of evolution (Alberts et al.
1994).

Research on the fruit fly, for example, has
revealed that particular families of genes are respon-
sible for the fundamental head to thorax to tail pat-
terning of the fly's body. Another set of genes deter-
mines the back-to-front positioning of organs, and a
third set subdivides this general body plan into a
series of discrete segments. With further develop-
ment, yet another family of genes confers a position-
al memory on the cells within a segment. These
"homeotic selector" genes ensure that cells in one
part of a particular segment "know" that they are des-
tined to be wings and not legs, or to be eyes and not
antennae. In flies the homeotic genes are known as
Horn genes. Their arrangement on the fly chromo-
some is ordered with genes at one end of the chro-
mosome specifying the developmental destiny of
cells in the most anterior segments of the fly's body
and genes at the other end specifying the fate of cells
in the most posterior segments.

In the course of evolution, mammals have devel-
oped four overlapping sets of positional memory
gene clusters homologous to the fly's single Horn
complex. The four mammalian Hex gene families are
ordered in a similar anterior-posterior fashion along
four different chromosomes. The mammalian genes
appear to operate like the Horn genes: they code for
DNA-binding proteins that control gene expression.
The similarity from fly to human is particularly evi-
dent when maps of the expression domains of Horn
genes in anterior segments of the fly embryo are com-
pared to maps of Hex gene expression as seen in the
rhombomeres and branchial arches of mammals.

Molecular genetic studies of flies and other non-
mammalian species show some variation in how and
when the basic body patterns and repeating segments
are formed. Sometimes the head-to-tail pattern is laid
down in the egg cell before fertilization-dictated by
egg polarity genes. Although egg polarity genes do
not operate in humans, mutations have been found
in a human gene homologous to the fly egg polarity
gene and account for serious syndromes in which
there are defects in anterior organs, such as the pitu-
itary gland and heart.

None of these developmental controls work in
isolation. Much remains to be understood about the
genetic clock that determines when and where devel-
opmental genes act, how they interact, and what

30         ORAL HEALTH IN AMERICA: .4 REPORT OF THE SURGEON GENERAL


mechanisms are used to sustain as well as terminate
their function. The systems that govern programmed
cell death are also important: normal development
depends as much on the elimination of cells as it does
on the orderly movement, proliferation, and differen-
tiation of cells.

When it comes to processes that control the
development of particular tissues or organs-bones,
skin, or heart-developmental biologists observe
that there is often an "organizer," that is, a cell or set
of cells that initiates the process. The organizer
induces changes in the behavior of neighboring cells
through cell-cell interactions, so that these cells
develop into the specified type-bone or skin or
heart muscle. The interaction with the neighboring
cell is often in the form of a signaling molecule, such
as a growth factor (e.g., transforming growth factor
b, epidermal growth factor, fibroblast growth factor)
that attaches to a receptor on the surface membrane
of the recipient cell. This interaction is translated to
the interior of the cell, where a chain of molecular
interactions eventually reaches the cell nucleus to
effect gene expression. One of the more startling dis-
coveries of the past decade has been the finding that
a series of mutations, each associated with a change
in only one nucleotide of the gene for the fibroblast
growth factor receptor-a so-called point muta-
tion-accounts for a range of organ defects seen in at
least a  half dozen craniofacial syndromes.
Interestingly, all these syndromes include craniosyn-
ostosis, a premature closure of the bones .that form
the skull.

THE AGING OF CRANIOFACIAL
TISSUES

Normal aging describes the developmental processes
that begin at conception, continue in childhood, and
merge gradually into maturation and senescence. The
milestones of development such as the age when
children teethe, begin to walk, talk, enter puberty,
attain their full height, and so on, are under genetic
and hormonal controls, subject to important envi-
ronmental factors such as nutrition and exercise.
Despite the complexity and interrelationships of the
variables involved, a reasonably accurate picture of
normal age-related changes in the craniofacial com-
plex is emerging (Ship 1999).

Barring major illness or injury, destructive
behaviors, or severe or unusual environmental cir-
cumstances, the cells, tissues, and fluids of the face
and mouth are hardy survivors, eminently durable
and functional over a long life span. For any given
individual the combination of life experience and

The Craniofacial Complex

lifestyle (including medical and dental history) cre-
ates a unique craniofacial portrait, one that inspired
George Orwell to remark, "By the age of fifty, a man
gets the face he deserves."

The Teeth

One of the more dramatic discoveries in biomedical
science in the twentieth century has been the realiza-
tion that tooth loss is not an inevitable consequence
of aging, but the result of disease or injury. Aging
does produce a number of other dental changes,
however. Teeth change in form and color with age.
Wear and attrition alter the biting and chewing sur-
faces, as do food choices and oral habits. The altered
surface structure produces a different pattern of light
reflection in older teeth, resulting in some yellowing
and a general loss of translucency (Mjor 1986). Fully
formed enamel is acellular, hence there is no meta-
bolic activity or turnover as occurs in skin, for exam-
ple. Dentin and cementum have limited cellular
activity. In contrast, tooth pulp and periodontal liga-
ment undergo relatively high levels of tissue
turnover.

Tooth surfaces can be eroded by chemical
dissolution from fruit acids and from acids from
sugars in foods such as soft drinks and candies. This
destructive process can occur at any age, resulting in
loss of translucency as well as some tissue loss from
demineralization (Zero 1996). Countering the
erosive forces are the natural components in saliva
that help remineralize the enamel surface, a process
that is enhanced when fluoride is present (see
"Caries Protection" above).

The cementum increases in thickness with age.
Gingival recession caused by normal aging exposes
the cementum to the oral environment (and is the
origin of the expression "long in the tooth"). The
exposed cementum can often be worn away mechan-
ically, exposing the underlying dentin, which can
then become hypersensitive. Dentin responds
through a series of protective changes that work to
close off the connections between dentin and nerves
in the pulp, reducing transmission of painful stimuli.

The Jaws

The bones of the maxilla and mandible that support
the teeth, called the alveolar processes, are, like bone
elsewhere in the body, subject to cellular turnover
in a coordinated process of bone resorption and

ORAL HEALTH IN AMERICAz A REPORT OF THE SURGEON GENERAL           31


formation. Alveolar bone is well adapted to
mechanical stresses, and changes continuously
during facial growth, tooth eruption, tooth wear, and
tooth loss.  This lifelong adaptation makes
orthodontic treatments to reposition teeth in adults
possible.

Because the primary function of alveolar bone is
to support the teeth, the loss of teeth will lead to
bone atrophy, making prosthetic replacements diffi-
cult. The rate of bone loss is affected by both local
disease such as periodontal disease and systemic con-
ditions such as osteoporosis (Bhaskar 1991).

The Oral Mucosa

The oral mucosa appears to age in much the same
way as skin does. The oral epithelium thins and
becomes less hydrated, increasing vulnerability to
injury The rate of cell division is slower, but the basic
cell architecture and patterning of cell types through-
out the oral cavity are maintained. It is not certain to
what extent these changes are a natural consequence
of aging; they may be due to altered protein synthe-
sis or lowered responsiveness to regulatory mole-
cules. They may also be an effect of diminished vas-
cularity, which could limit cellular access to oxygen
and nutrients (Mjor 1986).

Overall immune system function deteriorates
with age, and it is likely that mucosal immunity does
as well. Such a decline could result in an increased
risk of transmission of infectious agents across the
mucosa and probably contributes to delayed wound
healing in oral tissues with aging.

Sensory and Motor Functioning
The high density of sensory nerve endings in the
craniofacial tissues and their functional abilities are
well-preserved in aging. There may be minor increas-
es in threshold detection levels or in judgments of
intensity, but, for the most part, sensory cells can
turn over or have a built-in reserve capacity that
allows for near-optimal functioning in aging. The
exception is olfaction, which declines in both men
and women with age. This decrement in smell may
lead to some dissatisfaction with how foods taste and
increased use of flavor enhancers to compensate. But
for most people, the ability to enjoy food is not
appreciably diminished as time goes by. Any dramat-
ic change in sensory function-complaints of a con-
tinued unpleasant taste or smell or the sudden com-
plete loss of a sensory modality-should be taken
seriously as a sign of possible oral or systemic disease

-

or a side effect of medication and not dismissed as a
natural by-product of aging.

  The distribution of motor fibers in the craniofa-
cial tissues is also abundant and sufficiently fine-
tuned to allow for a full range of movement of the
tongue, jaws, and oral-facial muscles. There is some
loss of muscle tone in aging, along with changes in
tongue shape and function in articulating specific
speech sounds. Subtle changes may also occur in
preparing food for swallowing. As with sensory
changes, these developments do not seriously inter-
fere with motor function in healthy older adults.

The Salivary Glands

Studies of normative aging indicate that individuals
vary in the quantity of "whole" saliva they produce.
Whole saliva consists of the secretions of the various
salivary glands plus other oral contents, such as cells
shed from the mucosa. These individual patterns are
consistent across the life span. In healthy adults,
there is no diminution in the production of saliva
from the major salivary glands in the course of aging.

This constancy may seem surmising given the
morphological changes documented in aging salivary
glands. Both the parotid and the submandibular
glands lose between 20 and 30 percent of their essen-
tial tissue volume in the course of aging. The loss pri-
marily affects the acinar components, the cells that
secrete saliva. Increases in the number of ductal cells
and in fat, vascular, and connective tissues compen-
sate for this loss, however-vidence of the remark-
able functional reserve capacity of the glands, which
enables them to maintain a stable salivary output
across the life span (Baum 1986).

In contrast, studies of age-related changes in the
chemistry of salivary secretions suggest that there are
significant reductions in the concentration of mucins
from the submandibular gland (Navazesh et al.
1992>, which could result in reduced lubrication and
contribute to a sensation of mouth dryness. There are
also subtle changes in the protective ability of sali-
vary secretory IgA antibody (Smith et al. 1987).

FINDINGS

Natural selection has served Homo sapiens well in
evolving a craniofacial complex with remarkable
functions and abilities to adapt, enabling the organ-
ism to meet the challenges of an ever-changing envi-
ronment. An examination of the various tissues
reveals elaborate designs that have evolved to serve
the basic needs and functions of a complex mammal
as well as those that are uniqely human, such as

32

ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL


speech. The rich distribution of nerves, muscles, and
blood vessels in the region as well as extensive
endocrine and immune system connections is an
indication of the vital role of the craniofacial complex
in adaptation and survival over a long life span. In
particular,
   o  Genes controlling the basic patterning and
segmental organization of human development, and
specifically the craniofacial complex, are highly con-
served in nature. Mutated genes affecting human
development have counterparts in many simpler
organisms.

. There is considerable reserve capacity or
redundancy in the cells and tissues of the craniofacial
complex, so that if they are properly cared for, the
structures should function well over a lifetime.

   0  The salivary glands and saliva subserve tast-
ing and digestive functions and also participate in the
mucosal immune system, a main line of defense
against pathogens, irritants, and toxins.
o Salivary components protect and maintain
oral tissues through antimicrobial components,
buffering agents, and a process by which dental
enamel can be remineralized.

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Baum BJ. Age changes in salivary glands and salivary
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Baiim BJ and O'Connell BC. The impact of gene thera-
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Hajishengallis G, and Michalek SM. Current status of a
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Lamkin MS, Oppenheim FG. Structural features of sali-
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Mestecky J, Russell MW Mucosal immunoglobulins
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Mjor IA. Age changes in the teeth. In: Holm-Pedersen P,
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Navazesh M, Mulligan RA, Kipnis V, Denny PA, Denny
PC. Comparison of whole saliva flow rates and
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Sadler Tw, Langman J. Langman's medical embryology
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Sarosiek J, Scheurich CJ, Marcinkiewicz M, McCaIlum
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Ship JA. The oral cavity In: Hazzard WR et al., editors.
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Shugars DC, Wahl SM. The role of the oral environment
in HIV-l transmission. J Am Dent Assoc 1998
Ju1;129(7):851-8.

Smith DJ, Taubman MA, Ebersole JL. Ontogeny and
senescence of salivary immunity J Dent Res 1987
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Tabak L. In defense of the oral cavity: structure, biosyn-
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The Craniofacial Complex

Taichman NS. Cruchley AT, Fletcher LM. Hagi-Pavli EP
Paleolog EM. Abrams WR, Booth V, Edwards RM,
Malamud D. Vascular endothelial growth factor in
normal salivary glands and saliva: a possible role in
the maintenance of mucosal homeostasis. Lab Invest
1998 Ju1;78(7):869-75.

Wilentz J. The senses of man. New York: Thomas Y.
Crowell; 1968.

Xu T, Levitz SM, Diamond RD, Oppenheim FG.
Anticandidal activity of major human salivav his-
tatins. Infect Immun 1991 Aug;59(8):2549-54.
Young PT. Role of hedonic processes in development of
sweet taste. In: Weiffenbach, JM, editor. Taste and
development-the genesis of sweet preference.

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Education and Welfare Report no. NIH 77-1068;
1977. p. 399-417.

Zelles T, Purushotham KR, Macauley SP Oxford GE,
Humphreys-Beher MG. Saliva and growth factors:
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Zero DT. Etiology of dental erosion-extrinsic factors.
Eur J Oral Sci 1996 Apr;104(2 Pt 2):162-77.

34

ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL


What Is the Status of Oral Health
in America?

To begin to answer this question, Chapter 3 guides the reader through a discussion of oral diseases
and disorders in such categories as infections, inherited disorders, and neoplasms. Whether or not
an individual succumbs to the disease or disorder in question depends on subtle interactions of
genetic, environmental, and behavioral variables. Risk factors common to systemic diseases and
disorders, such as tobacco use, excessive alcohol use, and inappropriate dietary practices, also
contribute to many oral diseases and disorders. As more details on the causes of diseases unfold,
specific strategies for disease prevention can be developed.

Chapter 4 describes the magnitude of the problem facing the nation due to oral diseases and
disorders. These conditions are prevalent and complex, and they affect individuals across the life
span. Although major improvements have been seen nationally for most Americans, disparities
exist in some population groups as classified by age, sex, income, and race/ethnicity. National and
state-based epidemiologic data presented against the backdrop of demographic and socioeconomic
variables provide some information on racial and ethnic minorities, but serious shortcomings exist.
The paucity of data at national, state, and local levels extends to other populations, including indi-
viduals with disabilities, those with alternate sexual orientation, migrant populations, and the
homeless, and limits the capacity to fully document the magnitude of the problem and develop
needed programs. The chapter provides a basis for understanding disparities in oral health by pre-
senting available data on dental visits. More work is needed to understand the dimensions of oral
health problems in the United States and the reasons for differences among populations.

OR4L Hl%4LTH IN AMERICA: A REPORT OF THE SURGEON GENERAL

35


Diseases and Disorders

As the gateway to the body, the mouth is challenged
by a constant barrage of invaders-bacteria, viruses,
parasites, fungi. Thus infectious diseases, notably
dental caries and periodontal diseases, predominate
among the ills that can compromise oral health.
Injuries take their toll as well, with the face and head
particularly vulnerable to sports injuries, motor vehi-
cle crashes, violence, and abuse. Less common but
very serious are oral and pharyngeal cancers, with a
5-year survival rate of hardly better than 50 percent
(Kosary et al. 1995). Birth defects and developmental
disorders frequently affect the craniofacial complex.
These appear most commonly as isolated cases of
cleft lip or palate, but clefting or other craniofacial
defects can also be part of complex hereditary dis-
eases or syndromes. Additionally, acute and chronic
pain can affect the oral-facial region, particulaily in
and around the temporomandibular (jaw) joint, and
accounts for a disproportionate amount of all types of
pain that drive individuals to seek health care.
Many systemic diseases such as diabetes, arthri-
tis, osteoporosis, and AIDS, as well as therapies for
systemic diseases, can directly or indirectly compro-
mise oral tissues. The World Health Organization's
International Classification of Diseases and
Stomatology currently lists more than 120 specific
diseases, distributed in 10 or more classes, that have
manifestations in the oral cavity (WHO 1992).
This chapter concentrates on six major oral dis-
ease categories: dental and periodontal infections;
mucosal disorders; oral and pharyngeal cancers;
developmental disorders; injuries; and a sampling of
chronic and disabling conditions, including Sjiigren's
syndrome and oral-facial pain.

DENTAL AND PERIODONTAL
INFECTIONS
The most common oral diseases are dental caries and
the periodontal diseases. Individuals are vulnerable
to dental caries throughout life, with 85 percent of
adults aged 18 and older affected. Periodontal dis-
eases are most often seen in maturity, with the major-
ity of adults experiencing some signs and symptoms
by the mid-30s. Certain rare forms of periodontal dis-
ease affect young people. The major oral health suc-
cess story of the past half century is that both caries
and periodontal diseases can be prevented by a com-
bination of individual, professional, and community
measures.

Dental Caries

The word.caries derives from the Latin for rotten, and
many cultures early on posited a tooth worm as the
cause of this rottenness. By the twentieth century,
caries came to describe the condition of having holes
in the teeth-cavities. This description, although not
incorrect, is misleading. In actuality, a cavity is a late
manifestation of a bacterial infection.
The bacteria colonizing the mouth are known as
the oral flora. They form a complex community that
adheres to tooth surfaces in a gelatinous mat, or
biofilm, commonly called dental plaque. A cariogenic
biofilm at a single tooth site may contain one-half-
billion bacteria, of which species of mutans
streptococci are critical components. These bacteria
are able to ferment sugars and other carbohydrates to
form lactic and other acids. Repeated cycles of acid
generation can result in the microscopic dissolution
of minerals in tooth enamel and the formation of an
opaque white or brown spot under the enamel
surface (Mandel 1979). Frequency of carbohydrate
consumption (Gustafsson et al. 1954), physical

ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL

37


Diseases and Disorders

characteristics of food (e.g., stickiness), and timing of
food intake (Burt and Ismail 1986) also play a role.

  The essential role of bacteria in caries initiation
was established in landmark experiments in the
1950s. Investigators observed that germ-free ani-
mals fed high-sugar diets remained caries-free until
the introduction of mutans streptococci (a particular
group of bacterial strains having a number of com-
mon characteristics, and which adhere tightly to the
tooth). Later experiments demonstrated the trans-
missibility of the bacteria from mother to litter and
from caries-infected to uninfected cage-mates
(Fitzgerald and Keyes 1960). Species of Lactobacillus,
Actinomyces. and other acid-producing streptococci
within the plaque may also contribute to the process
(Bowden 1990).

If the caries infection in enamel goes unchecked,
the acid dissolution can advance to form a cavity that
can extend through the dentin (the component of the
tooth located under the enamel) to the pulp tissue,
which is rich in nerves and blood vessels. The result-
ing toothache can be severe and often is accompanied
by sensitivity to temperature and sweets. Treatment
requires endodontic (root canal) therapy. If untreat-
ed, the pulp infection can lead to abscess, destruction
of bone, and spread of the infection via the blood-
stream.

Dental caries can occur at any age after teeth
erupt. Particularly damaging forms can begin early,
when developing primary teeth are especially vulner-
able. This type of dental caries is called early child-
hood caries (ECC). Some 6 out of 10 children in the
United States have one or more decayed or filled pri-
mary teeth by age 5 (U.S. Department of Health and
Human Services, National Center for Health
Statistics 1997). EGG may occur in children who are
given pacifying bottles of juice, milk, or formula to
drink during the day or overnight. The sugar con-
tents pool around the upper front teeth, mix with
cariogenic bacteria, and give rise to rapidly progress-
ing destruction (Ripa 1988). Other risk factors for
ECC include arrested development of tooth enamel,
chronic illness, altered salivary composition and vol-
ume (resulting from the use of certain medications or
malnourishment), mouth breathing, and blockage of
saliva flow in a bottle-fed infant (Bowen 1998, Seow
1998).

Although there have been continuing reductions
in dental caries in permanent teeth among children
and adolescents over the past few decades, caries
prevalence in the primary dentition may have stabi-
lized or increased slightly in some population groups
(Petersson and Bratthall 1996, Rozier 1995).
Reductions in caries in permanent teeth also have

been proportionately greater on the smooth surfaces
rather than on the pit-and-fissure surfaces character-
istic of chewing surfaces. The gingival tissues tend to
recede over time, exposing the tooth root to cario-
genie bacteria that can cause root caries. An impor-
tant risk factor for root caries in older people is the
use of medications that inhibit salivary flow, leading
to dry mouth (xerostomia).

Saliva contains components that can directly
attack cariogenic bacteria, and it is also rich in calci-
um and phosphates that help to remineralize tooth
enamel. Demineralization of enamel occurs when pH
levels fall as a result of acid production by bacteria. It
can be reversed at early stagesif the local environ-
ment can counteract acid production, restoring pH to
neutral levels. Remineralization can occur through
the replacement of lost mineral (calcium and phos-
phates) from the stores in saliva. Fluoride in saliva
and dental plaque and the buffering capacity of sali-
va also contribute to this process. Indeed. it is now
believed that fluoride exerts its chief caries-preven-
tive effect by facilitating remineralization. Several
studies have demonstrated that remineralization
results in an increase in tooth hardness and mineral
content. rendering the tooth surface more resistant to
subsequent acid attack (Larsen 1987, Linton 1996,
Retief 1983, Shannon 1978, Vissink et al. 1985,
White 1988).

Overt caries lesions develop when there is insuf-
ficient time for remineralization between periods of
acidogenesis, or when the saliva production is com-
promised. Over 400 medications list dry mouth as a
side effect, notably some antidepressants, antipsy-
chotics, antihistamines, decongestants, antihyperten-
sives, diuretics, and antiparkinsonian drugs (Sreebny
et al. 1992). The effects of xerostomia may be partic-
ularly severe in cancer patients receiving radiation to
the head or neck because the rays can destroy sali-
vary gland tissue rather than simply inhibiting sali-
vary secretion.

The professional application of dental sealants
(plastic films coated onto the chewing surfaces of
teeth) is an important caries-preventive measure that
complements the use of fluorides, The films prevent
decay from developing in the pits and fissures of
teeth, channels that are often inaccessible to brushing
and where fluoride may be less effective.

The rate of caries progression through enamel is
relatively slow (Berkey 1988, Ekanayake 1987,
Shwartz et al. 1984) and may be slower in patients
who have received regular fluoride treatment or who
consume fluoridated water (Pitts 1983, Shwartz et al.
1984). Because a large percentage of enamel lesions
remain unchanged over periods of 3 to 4 years, and

38          ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL
         


Diseases and Disorders

because progression rates through dentin are
comparably slow (Craig et al. 1981, Emslie 1959,
Kolehmainen and Rytomaa 1977), the application of
infection control and monitoring procedures to
assess caries risk status, lesion activity status,
evidence of lesion arrest, and evidence of lesion
remrneralization over extended periods of time is
recommended.

Experts believe that the earlier mutans strepto-
cocci are acquired in infancy, the higher the caries
risk. Most studies indicate that infants are infected
before their first birthday, around the time the first
incisors emerge. However, one study found the medi-
an age of acquisition to be 26 months, coinciding
with the emergence of the primary molars (Bowen
1998, Caufield et al. 1993, Seow 1998). DNA finger-
printing has demonstrated that the source of trans-
mission is usually the mother (Caufield et al. 1993).
It is not clear why some individuals are more sus-
ceptible and others more resistant to caries. Genetic
differences in the structure and biochemistry of
enamel proteins and crystals (Slavkin 1988), as well
as variations in the quality and quantity of saliva and
in immune defense mechanisms are among the fac-
tors under study. Analysis of mutans streptococci
genomes may also shed light, indicating which
species are particularly virulent and which genes
contribute to that virulence.

Even the most protective genetic endowment
and developmental milieu are unlikely to confer
resistance to decay in the absence of positive person-
al behaviors. These include sound dietary habits and
good oral hygiene, including the use of fluorides, and
seeking professional care. There are indications,
however, that some destructive oral habits are on the
rise, such as the use of smokeless (spit) tobacco
products by teenage boys. Although the chief con-
cern here lies in the long-term risk for oral cancers,
spit tobacco that contains high levels of sugar is also
associated with increased levels of decay of both
crown and root surfaces (Tomar and Winn 1998).

Periodontal Diseases

Like dental caries, the periodontal diseases are infec-
tions caused by bacteria in the biofilm (dental
plaque) that forms on oral surfaces. The basic divi-
sion in the periodontal diseases is between gingivitis,
which affects the gums, and periodontitis, which may
involve all of the soft tissue and bone supporting the
teeth. Gingivitis and milder forms of periodontitis are
common in adults. The percentage of individuals
with moderate to severe periodontitis, in which the

destruction of supporting tissue can cause the tooth
to loosen and fall out, increases with age.

Gingivitis

Gingivitis is an inflammation of the gums character-
ized by a change in color from normal pink to red,
with swelling, bleeding, and often sensitivity and ten-
derness. These changes result from an accumulation
of biofilm along the gingival margins and the
immune system's inflammatory response to the
release of destructive bacterial products. The early
changes of gingivitis are reversible with thorough
toothbrushing and flossing to reduce plaque.
Without adequate oral hygiene, however, these early
changes can become more severe, with'infiltration of
inflammatory cells and establishment of a chronic
infection. Biofilm on tooth surfaces opposite the
openings of the salivary glands often mineralizes to
form calculus or tartar, which is covered by unmin-
eralized biofilm-a combination that can exacerbate
local inflammatory responses (Mandel 1995). A gin-
gival infection may persist for months or years, yet
never progress to periodontitis.

Gingival inflammation does not appear until the
biofilm changes from one composed largely of gram-
positive streptococci (which can live with or without
oxygen) to one containing gram-negative anaerobes
(which cannot live in the presence of oxygen).
Numerous attempts have been made to pinpoint
which microorganisms in the supragingival (above
the gum line) plaque are the culprits in gingivitis.
Frequently   mentioned  organisms   include
Fusobacterium nucleatum, Veillonella parvula, and
species of Campylobacter and Treponema. But as
Ranney (1989) notes, "The complexity of the results
defies any attempt to define a discrete group clearly
and consistently associated with gingivitis."

Gingival inflammation may be influenced by
steroid hormones, occurring as puberty gingivitis,
pregnancy gingivitis, and gingivitis associated with
birth control medication or steroid therapy. The pres-
ence of steroid hormones in tissues adjacent to
biofilm apparently encourages the growth of certain
bacteria and triggers an exaggerated response to
biofilm accumulation (Caton 1989). Again, thorough
oral hygiene can control this response.

Certain prescription drugs can also lead to gingi-
val overgrowth and inflammation. These include the
antiepileptic drug phenytoin (Dilantin); cyclosporin,
used for immunosuppressive therapy in transplant
patients; and various calcium channel blockers used
in heart disease. Treatment often requires surgical
removal of the excess tissue followed by appropriate
personal and professional oral health care.

ORAL HEtZLTH IN AMERICA: A REPORT OF THE SURGEON GENERAL

39


Diseases and Disorders

A form of gingivitis common 50 years ago but
relatively rare today is acute necrotizing ulcerative
gingivitis, also known as Vincent's infection or trench
mouth. This aggressive infection is characterized by
destruction of the gingiva between the teeth, sponta-
neous bleeding, pain, and oral odor. People under
extreme stress have an increased susceptibility.
Spirochetes and other bacteria have been found in
the connective tissue of those affected. An associa-
tion between smoking and this type of gingivitis is
well recognized and was demonstrated as early as
1946 (Pindborg 1947, 1949). This condition has
been seen in some HIV-positive patients (Murray
1994). Treatment requires a combination of profes-
sional periodontal treatment and antibacterial thera-
py along with professional smoking cessation assis-
tance as appropriate.

Adult Periodontitis

The most common form of adult periodontitis is
described as general and moderately progressing; a
second form is described as rapidly progressing and
severe, and is often resistant to treatment. The mod-
erately progressive adult form is characterized by a
gradual loss of attachment of the periodontal liga-
ment to the gingiva and bone along with loss of the
supporting bone. It is most often accompanied by
gingivitis (Genco 1990). It is not necessarily preced-
ed by gingivitis, but the gingivitis-related biofilm
often seeds the subgingival plaque. The destruction
of periodontal ligament and bone results in the for-
mation of a pocket between the tooth and adjacent
tissues, which harbors subgingival plaque. The cal-
culus formed in the pocket by inflammatory fluids
and minerals in adjacent tissues is especially damag-
ing (Mandel and Gaffar 1986).

The severity of periodontal disease is determined
through a series of measurements, including the
extent of gingival inflammation and bleeding, the
probing depth of the pocket to the point of resist-
ance, the clinical attachment loss of the periodontal
ligament measured from a fixed point on the tooth
(usually the cemento-enamel junction), and the loss
of adjacent alveolar bone as measured by x-ray
(Genco 1996). Severity is determined by the rate of
disease progression over time and the response of the
tissues to treatment.
Adult periodontitis often begins in adolescence
but is usually not clinically significant until the mid-
30s. Prevalence and severity increase but do not
accelerate with age (Beck 1996). One view proposes
that destruction occurs at a specific site during a
defined period, after which the disease goes into
remission (Socransky et al. 1984). The current view

is that the disease process may not be continuous but
rather progresses in random bursts in which short
periods of breakdown of periodontal ligament and
bone alternate with periods of quiescence. These
episodes occur randomly over time and at random
sites in the mouth. Part of the difficulty in determin-
ing the pattern of progression reflects variation in the
sensitivity of the instruments used to measure the
loss of soft tissue and bone. The latest generation of
probes finds evidence of both continuous and multi-
ple-burst patterns of loss in different patients and at
different times (Jeffcoat and Ready 1991).
Most researchers agree that periodontitis results
from a mixed infection but that a particular group of
gram-negative bacteria are key to the process and
markedly increase in the subgingival plaque. The
bacteria most frequently cited are Porphyromonas gin-
givalis, Prevotella intermedia, Bacteroides forsythus,
Treponema denticola, and Actinobacillus actino-
mycetemcomitans (Genco 1996). Their role in disease
initiation and progression is determined in part by
their "virulence factors." These include the ability to
colonize subgingival plaque, generate products that
can directly injure tissues, and elicit an inflammatory
or immune response. The potentially noxious bacte-
rial products include hydrogen sulfide, polyamines,
the fatty acids butyrate and propionate, lipopolysac-
charide (also known as endotoxin), and a number of
destructive enzymes. The interaction of this arsenal
with the host response is at the core of periodontal
pathology (Genco 1992, Socransky and Haffajee
1991, 1992). Sequencing of the genomes of several
key periodontal pathogens is under way and should
provide further insight into these pathogens as well
as catalyze new treatment approaches.

Delicate Balances. Neutrophils (a type of white blood
cell) and antibodies are the major immune defenses
against bacterial attack. Neutrophils move to the site
of infection, where they engulf bacteria and elaborate
antibacterial agents and enzymes to destroy bacteria.
Although stimulation of the immune system to attack
the offending bacteria is generally protective,
immune hyperresponsiveness and hypersensitivity
can be counterproductive, leading to the destruction
of healthy tissue. Nevertheless, the neutrophiuanti-
body axis is critical for full protection against peri-
odontal diseases (Genco 1992).

Also important is the release of certain potent
molecules called cytokines and prostaglandins,
especially prostaglandin E2 (PGE,) which can
contribute to tissue destruction. Cytokines are
proteins secreted by immune cells that help regulate
immune responses and also affect bone, epithelial,

-lo       ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL


and connective  tissues.  Most prominent in
periodontal diseases are interleukin 1 (IL-l), tumor
necrosis factor OL (TNF-a), and interferon y (IFN-?I).
These cytokines mediate the processes of bone
resorption and connective tissue destruction.

Susceptibility and Resistance. PGE, may play a central
role in the tissue destruction that occurs in peri-
odontal diseases. Levels of PGE, in periodontal tissue
are low or undetectable in health, increase in gingivi-
tis, and rise significantly in periodontitis. Now there
is increasing evidence that the level of PGE, pro-
duced in response to bacterial challenge (especially
by endotoxin) can be used as a measure of suscepti-
bility (Offenbacher et al. 1993).
Presumably, the level of PGE, production is sub-
ject to genetic influence. Studies of identical and fra-
ternal twins, either reared together or apart, provide
evidence that genetic factors may indeed influence
susceptibility or resistance to the common adult form
of periodontitis (Michalowicz 1994). Recently, a
commercial test for a genetic marker of susceptibility
has been introduced. The marker is associated with
increased production of a particular form of inter-
leukin lfi (IL-lp) when stimulated by periodonto-
pathic bacteria (Kornman et al. 1997). Newman
(1996) found that nonsmoking adults who are posi-
tive for the marker are 6 to 19 times more likely to
develop severe periodontitis.

Susceptibility to adult periodontitis has also been
explored in relation to a variety of behavioral and
demographic variables as well as to the presence of
other diseases. One of the strongest behavioral asso-
ciations is with tobacco use. The risk of alveolar bone
loss for heavy smokers is 7 times greater than for
those who have not smoked (Grossi et al. 1995).
Cigarette smoking also may impair the normal host
response in neutralizing infection (Seymour 199 l),
resulting in the destruction of healthy periodontal
tissues adjacent to the site of infection (Lamster
1992). Smokers also have decreased levels of salivary
and serum immunoglobulins to Prevotella intermedia
and Fusobacterium nucleatum (Bennet and Reade
1982, Haber 1994) and depressed numbers of helper
T cells as well (Costabel et al. 1986). Finally smok-
ing alters the cells that engulf and dispose of bacte-
rla-neutrophils and other phagocytes-affecting
their ability to clear pathogens (Barbour et al. 1997).
Epidemiologic studies have found that such
additional factors as increasing age, infrequent dental
visits, low education level, low income, co-morbidi-
ties, and inclusion in certain racial or ethnic popula-
tions are associated with increased prevalence of

Diseases and Disorders

periodontitis (Page 1995). It is important that epi-
demiologic studies also take into consideration the
fact that tobacco use, oral hygiene, professional pro-
phylaxis, and routine dental care are correlated to
socioeconomic status, as are race and ethnicity. Sex is
another factor. Males tend to have higher levels of
periodontal diseases, presumably because of a histo-
ry of greater tobacco use and differences in personal
care and frequency of dental visits. However, female
hormones may play a protective role (as they do in
protecting against osteoporosis) (Genco 1996).
Certain systemic diseases heighten susceptibility
Epidemiological studies have confirmed that patients
with diabetes mellitus, both type 1 and type 2, are
more susceptible to periodontal diseases (Genco
1996). Measures such as the gingival index, pocket
depth, and loss of attachment are more severe if the
diabetic patients are smokers (Bridges et al. 1996).
The likelihood of periodontal disease increases
markedly when diabetes is poorly controlled. In con-
trast, periodontal diseases respond well to therapy
and can be managed successfully in patients with
well-controlled diabetes. Such therapy can result in
improvements in the diabetic condition itself
(Mealey 1996) (see Chapter 5).

There is some evidence that osteoporosis may be
a risk factor for periodontal disease. More clinical
attachment loss and edentulousness have been
reported in osteoporotic than in nonosteoporotic
women (Jeffcoat and Chestnut 1993). Two studies in
1996 showed that estrogen replacement therapy in
postmenopausal women not only gives protection
against osteoporosis, but also results in fewer teeth
lost to periodontal disease (Grodstein et al. 1996,
Jacobs et al. 1996).

The less common rapidly progressive form of
adult periodontitis typically affects people in their
early 20s and 30s. It is characterized by severe gingi-
val inflammation and rapid loss of connective tissue
and bone. Many patients have an inherent defect in
neutrophil response to infection. Several systemic
diseases have been associated with this form of peri-
odontal disease, including type 1 diabetes, Down
syndrome, Papillon-Lefevre syndrome, Chediak-
Higashi syndrome, and HIV infection (Caton 1989).
Specific bacteria associated with rapidly progressive
disease include Porphyrornonas gingivalis, PrevoteIla
inter-media, Eikenella corrodens, and Wolinella recta
(Scheutz et al. 1997). Most recently, mutations in the
cathepsin C gene have been associated with the
Papillon-Lefevre syndrome (Hart et al. 1999) and
how the defect can result in periodontal disease
(Toomers et al. 1999).

ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL

41


Diseases and Disorders

Refractory Periodontitis. Refractory periodontitis is
not a specific form of disease, but refers to cases in
which patients continue to exhibit progressive dis-
ease at multiple sites despite aggressive mechanical
therapy to remove biofilm and calculus, along with
the use of antibiotics. Refractory sites exhibit elevat-
ed levels of a number of different bacteria, with the
dominant species different in different subjects. It is
not known whether variations in pathogenicity of the
bacteria, defects in the subject's defense systems, or
combinations of these factors are responsible for the
refractory nature of the disease (Haffajee et al. 1988).
The adoption of new diagnostic technology to detect
predominant bacterial species, followed by selective
antibiotic treatment, may help resolve infection and
disease in these patients.

Early-onset Periodontitis

The forms of periodontitis occurring in adolescents
and young adults generally involve defects in neu-
trophil function (Van Dyke et al. 1980). Localized
juvenile periodontitis (LJP) mainly affects the first
molar and incisor teeth of teenagers and young
adults, with rapid destruction of bone but almost no
telltale signs of inflammation and very little
supragingival plaque or calculus. Actinobacillus actin-
ornycetemcomitans has been isolated at 90 to 100 per-
cent of diseased sites in these patients, but is absent
or appears in very low frequency in healthy or mini-
mally diseased sites (Socransky and Haffajee 1992).
It is possible that the bacteria are transmitted among
family members through oral contacts such as kiss-
ing or sharing utensils, because the same bacterial
strain appears in affected family members. However,
evidence of a neutrophil defect argues for a genetic
component. Another organism frequently associated
with LJP is Capnocytophaga ochracea. Neither of
these bacteria dominate in the generalized adult form
of the disease, where Porphyromonas gingivalis is con-
sidered of greatest significance (Schenkein and Van
Dyke 1994).

Prepubertal periodontitis is rare and can be
either general or localized. The generalized form
begins with the eruption of the primary teeth and
proceeds to involve the permanent teeth. There is
severe inflammation, rapid bone loss, tooth mobility,
and tooth loss. The localized form of the disease is
less aggressive, affecting only some primary teeth.
The infection involves many of the organisms associ-
ated with periodontitis, but the mix may differ some-
what, with Actinobacillus actinomycetemcomitans,
Prevotella interned@ Eikenella corrodens, and several
species of Capnocytophaga implicated (Caton 1989).

Defects in neutrophil function noted in both forms of
the disease (Schenkein and Van Dyke 1994) may
explain why patients are highly susceptible to other
infections as well (Suzuki 1988).

SELECTED MUCOSAL INFECTIONS
AND CONDITIONS

Like the skin, the mucosal lining of the mouth serves
to protect the body from injury This lining is itself
subject to a variety of infections and conditions,
ranging from benign canker sores to often fatal
cancers.

Oral Candidiasis

Chronic hyperplastic candidiasis is a red or white
lesion that may be flat or slightly elevated and may
adhere to soft or hard tissue surfaces, including den-
tal appliances. It is caused by species of Candida,
especially Candida albicans, the most common fungal
pathogen isolated from the oral cavity. Normally, the
fungi are present in relatively low numbers in up to
65 percent of healthy children and adults and cause
no harm (McCullough et al. 1996). Problems arise
when there is a change in oral homeostatis-the nor-
mal balance of protective mechanisms and resident
oral flora that maintain the health of the oral cavity-
so that defense mechanisms are compromised (Scully
et al. 1994). Under these circumstances the fungal
organisms can overgrow to cause disease. A primary
disruption in homeostasis occurs with the use of
antibiotics and corticosteroids, which can markedly
change the composition of the oral flora. Deficiencies
in the immune and endocrine systems are also
important. Indeed, the diagnosis of candidiasis in an
otherwise seemingly healthy young adult may be the
first sign of HIV infection. Other causes of candidia-
sis include cancer chemotherapy or radiotherapy to
the head and neck, xerostomia resulting from radia-
tion to the head and neck, medications, chronic
mucosal irritation, certain blood diseases, and other
systemic conditions. Also, tobacco use has been iden-
tified as a cofactor.

Candidiasis often causes symptoms of burning
and soreness as well as sensitivity to acidic and spicy
foods. Patients may complain of a foul taste in the
mouth. However, it can also be asymptomatic.
Genomic analysis of the Candida albicans genome is
helping investigators identify numerous genes that
code for virulence factors, including enzymes that
can facilitate adhesion to and penetration of mucous
membranes. At the same time, researchers are explor-
ing novel gene technologies to increase production of

42         ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL


`I family of native salivary proteins, the histatins, that
halve known anticandidal and other antimicrobial
effects.

  The most common form of oral candidiasis is
denture stomatitis. It occurs when tissues are trau-
matized by continued wearing of ill-fitting or inade-
quately cleaned dental appliances and is described as
chronic erythematous candidiasis. Another form,
candidal angular cheilosis, occurs in the folds at the
angles of the mouth and is closely associated with
denture sore mouth (Tyldesley and Field 1995).
Other common forms of Candida infection are
pseudomembranous candidiasis (thrush), which may
affect any of the mucosal surfaces, and acute erythe-
matous candidiasis, a red and markedly painful vari-
ant commonly seen in AIDS patients.

In most cases, Candida infection can be con-
trolled with antifungal medications used locally or
systemically Control is difficult, however, in patients
with immune dysfunction, as in AIDS, or other
chronic debilitating diseases, Often the organisms
become resistant to standard therapy, and aggressive
approaches are necessary (Tyldesley and Field 1995).
The spread of oral candidiasis to the esophagus or
lungs can be life-threatening and is one of the crite-
ria used to define frank AIDS (Samaranayake and
Holmstrup 1989).

Herpes Simplex Virus Infections

In any given year, about one-half-million Americans
will experience their first encounter with the herpes
simplex virus type 1 (HSV-l), the cause of cold sores.
That first encounter usually occurs in the oral region
and may be so mild as to go unnoticed. But in some
people, particularly young children and young
adults, infection may take the form of primary her-
petit stomatitis, with symptoms of malaise, muscle
aches, sore throat, and enlarged and tender lymph
nodes, prior to the appearance of the familiar cold
sore blisters. These blisters usually show up on the
lips, but any of the mucosal surfaces can be affected.
Bright-red ulcerated areas and marked gingivitis may
also be seen (Tyldesley and Field 1995).

Herpes viruses also cause genital infections,
which are transmitted sexually Both HSV- 1 and HSV-
2 have been found in oral and genital infections, with
HSV-1 predominating in oral areas and HSV-2 in gen-
ital areas (Wheeler 1988). Herpes viruses have also
been implicated as cofactors in the development of
oral cancers. Crowded living conditions can result in
greater contact with infected individuals, which aids
in transmission of HSV (Whitley 1992).

Diseases and Disorders

Normally the immune system mounts a success-
ful attack on the viruses, with symptoms abating by
the time neutralizing antibodies appear in the blood-
stream, in about 10 days. However, herpes viruses are
notorious for their ability to avoid immune detection
by taking refuge in the nervous system, where they
can remain latent for years. In oral herpes the virus
commonly migrates to the nearby trigeminal gan-
glion, the cluster of nerve cells whose fibers branch
out to the face and mouth. In about 20 to 40 percent
of people who are virus-positive, the virus may reac-
tivate, with infectious virus particles moving to the
oral cavity to cause recurrent disease (Scott et al.
1997).

  The usual site of a recurrent lesion is on or near
the lips. Recurrences are rarely severe, and lesions
heal in 7 to 10 days without scarring (Higgins et al.
1993). The recurrences may be provoked by a wide
range of stimuli, including sunlight, mechanical trau-
ma, and mild fevers such as occur with a cold.
Emotional factors may play a role as well.

Oral Human Papillomavirus Infections
There are more than 100 recognized strains of oral
human papillomavirus (HPV), a member of the
papovavirus family, implicated in a variety of oral
lesions (Regezi and Sciubba 1993). Most common
are papillomas (warts) found on or around the lips
and in the mouth. HPV is found in 80 percent of
these oral squamous papillomas (de Villiers 1989).
The virus has also been identified in 30 to 40 percent
of oral squamous cell carcinomas (Chang et al. 1990)
and has been implicated in cervical cancer as well.
Whether a cancer or nonmalignant wart develops
may depend on which virus is present or on which
viral genes are activated.

  Oral warts are most often found in children,
probably as a result of chewing warts on the hands.
In adults, sexual transmission from the anogenital
region can occur (Franchesi et al. 1996).

In general, viral warts spontaneously regress
after 1 or 2 years. The immune system normally
keeps HPV infections under control, as evidenced by
the increased prevalence of HPV-associated lesions in
HIV-infected patients and others with immuno-
deficiency

Recurrent Aphthous Ulcers
Recurrent aphthous ulcers (RAU), also referred to as
recurrent aphthous stomatitis, is the technical term
for canker sores, the most common and generally

ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL

43


mild oral mucosal disease. Between 5 and 25 percent
of the general population is affected, with higher
numbers in selected groups, such as health profes-
sional students (Axe11 et al. 1976, Embil et al. 1975,
Ferguson et al. 1984, Kleinman et al. 1991, Ship
1972, Ship et al. 1967).

  The disease takes three clinical forms: RAU
minor, RAU major, and herpetiform UU. The minor
form accounts for 70 to 87 percent of cases. The sores
are small, discrete, shallow ulcers surrounded by a
red halo appearing at the front of the mouth or the
tongue. The ulcers, which usually last up to 2 weeks,
are painful and may make eating or speaking diffi-
cult. About half of RAU patients experience recur-
rences every 1 to 3 months; as many as 30 percent
report continuous recurrences (Bagan et al. 1991).
RAU major accounts for 7 to 20 percent of cases
and usually appears as 1 to 10 larger coalescent
ulcers at a time, which can persist for weeks or
months (Bagan et al. 1991). Herpetiform R4U has
been reported as occurring in 7 to 10 percent of RAU
cases. The ulcers appear in crops of 10 to 100 at a
time, concentrating in the back of the mouth and
lasting for 7 to 14 days (Bagan et al. 1991, Rennie et
al. 1985).

R4U can begin in childhood, but the peak peri-
od for onset is the second decade (Lehner 1968).
About 50 percent of close relatives of patients with
R4U also have the condition (Ship 1965), and a high
correlation of R4U has been noted in identical but
not fraternal twins. Associations have been found
between R4U and specific genetic markers (Scully
and Porter 1989).

R4U has also been associated with hypersensi-
tivities to some foods, food dyes, and food preserva-
tives (Woo and Sonis 1996). Nutritional deficien-
cies-especially in iron, folic acid, various B vita-
mins, or combinations thereof-have also been
reported, and improvements noted with suitable
dietary supplements (Nolan et al. 1991).
  The two factors that have been found to have the
strongest association with R4U are immunologic
abnormality, possibly involving autoimmunity, and
trauma (Lehner 1968, Ship 1996. Woo and Sonis
1996).

Volunteers with and without a history of RAU
were studied for their reaction to the trauma of a nee-
dle prick to the inner cheek tissue. No ulcers devel-
oped in non-R4U subjects, but nearly half of those
prone to canker sores had a recurrence (Wray et al.
1981).

R4U also can occur in a number of systemic dis-
eases, including HIV infection, ulcerative colitis,
Crohn's disease, and Behcet's disease (Ship 1996). In

general, people who are immunocompromised are
more susceptible to RAU, as are people with a variety
of blood diseases.

EWU itself does not give rise to other illnesses
but is uncomfortable. Symptomatic treatment
includes topical analgesics, antibacterial rinses, topi-
cal corticosteroids, and a new prescription medica-
tion that reduces pain and healing time (Khandwala
et al. 1997, Ship 1996).

ORAL AND PHARYNGEAL CANCERS
AND PRECANCEROUS LESIONS
In 2000, oral or pharyngeal cancer will be diagnosed
in an estimated 30,200 Americans and will cause
more than 7,800 deaths (Greenlee et al. 2000). Over
90 percent of these cancers are squamous cell carci-
nomas-cancers of the epithelial cells. The most
common oral sites are on the tongue, the lips, and the
floor of the mouth. Oral cancer is the sixth most
common cancer in U.S. males and takes a dispropor-
tionate toll on minorities; it now ranks as the fourth
most common cancer among African American men
(Kosary et al. 1995). The prominent role of tobacco
use, especially in combination with alcohol, in caus-
ing these cancers is a major incentive to develop
effective health promotion and disease prevention
efforts.

Heightening the Risk

Oral cancer develops as a clone from a single geneti-
tally altered cell (Solt 1981). It generally has a long
latency period and invariably develops from a pre-
cancerous lesion on the oral mucosa, such as a white
leukoplakia, or more commonly, a reddish erythro-
plakia (Mashberg 1978, Shklar 1986). Both kinds of
lesions are usually induced by tobacco use alone or in
combination with heavy use of alcohol. The develop-
ment of squamous cell carcinoma from initial ery-
throplakia lesions has been well demonstrated exper-
imentally. Silverman (1998) reported rates of malig-
nant transformation for leukoplakias of between 0.13
and 17.5 percent. However, there is considerable
debate as to the actual malignant potential of the
leukoplakia lesion associated with the use of smoke-
less (spit) tobacco. Meaningful data for determining
a specific malignant transformation rate or relative
risk of oral cancer due to smokeless tobacco use are
difficult to obtain because of the confounding effects
of other habits such as concurrent smoking and alco-
hol consumption and because of the variations in
smokeless (spit) products and how they are used.

44        ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL


.\nother oral precancerous lesion that has
r,cclved attention is submucous fibrosis. It is com-
,nonly seen in India and Southeast Asia and is relat-
(`1 to betel nut use (Canniff et al. 1986).
Early epidemiologic studies identified behaviors
Guch as smoking and environmental factors such as
,sposure to solar radiation and x-rays as causes of
,rttraoral and lip cancers (Pindborg 1977).
Researchers then sought experimentally to explain
the mechanisms of initiation. In the 1980s and
I99Os. investigators exploited the techniques of
riiolecular biology and genetics to probe what was
going on deep inside the cell. These studies revealed
`m abundance of systemic and local factors, including
\,iral and fungal infections, that affect cell behavior.
Some factors stimulate cell division and others
ttthibit it-even to the point of initiating a program
of cell "suicide," called apoptosis. How a given cell
behaves at any given time in its life cycle is the net
result of the signals it receives from neighboring cells
and molecules, from circulating factors in the blood
or immune system, and from its own internal
controls. The following sections provide a brief
description of these factors and how they may
participate in enhancing the risk for the development
of oral cancers.

Tobacco and Alcohol

Tobacco and alcohol are the major risk factors for
oral cancers, and their effects have been studied for
many years (Rothman and Keller 1972, Decker and
Goldstein 1982). Tobacco contains substances that
are frankly carcinogenic or act as initiators or pro-
moters of carcinogenesis. Among these are N-
nitrosonornicotine. 4-nitroquinoline-N-oxide, and
benzpyrene. The most damaging carcinogens are
found in the tars of tobacco smoke, but many forms
of smokeless (spit) tobacco, including snuff, have
been implicated in the development of mouth cancer
(Advisory Committee to the Surgeon General 1986,
International Agency for Research on Cancer 1985,
Winn 1984). Other habits that have been related to
oral cancer include chewing betel nut in the presence
of tobacco, as is done primarily in Southeast Asia
(Hirayama 1966, Mehta et al. 1981), and, more
recently, using marijuana (Donald 1986).

The role of alcohol in oral carcinogenesis has
been demonstrated experimentally (Wight and
Ogden 1998) and appears to be related to its damag-
ing effect on the liver, Major metabolites of alcohol,
such as acetaldehyde-a known carcinogen in ani-
mals-may also be important. Alcohol is also
thought to act as a solvent that facilitates the pene-

Discscs and Disorders

tration of tobacco carcinogens into oral tissues. That
observation may partly explain why the combined
use of tobacco and alcohol produces a greater risk for
oral cancer than use of either substance alone.
Indeed, tobacco and alcohol, working in tandem, are
thought to account for 75 to 90 percent of all oral and
pharyngeal cancers in the United States (Blot et al.
1988).

Viruses

The role of viruses in causing cancer in animals was
established early in the century when Rous showed
that a virus, later named the Rous sarcoma virus
(RSV), caused tumors in chickens. The issue of
whether viruses could cause cancer in humans
remained unexplored until the mid-1970s when
Varmus and Bishop showed that RSV had a special
gene, which they called src (for sarcoma), that could
transform the cell it infected into a malignant cell
(Bishop et al. 1978). It was an oncogene, or cancer-
causing gene. The researchers subsequently, and sur-
prisingly, discovered that src was not native to the
virus, but had been picked up by some ancestor virus
from a chicken cell's own genome, where src had pre-
sumably played a role in the chicken cell's normal
growth and development. Somehow RSV was able to
subvert src when it infected a chicken cell to cause
the cell to divide uncontrollably. Varmus and Bishop
called the normal cellular src gene a proto-oncogene,
meaning that it had the potential to be converted to
an oncogene. Subsequent research led to the discov-
ery of other viruses that could cause tumors in ani-
mals and revealed the presence of proto-oncogenes in
birds and mammals. These genes could also be con-
verted to oncogenes, behaving exactly like those car-
ried by cancer viruses. In 1982 an oncogene isolated
from a human bladder cancer turned out to be virtu-
ally identical to rus, the oncogene found in a rat sar-
coma virus (Parada et al. 1982).
Viruses that have been implicated in oral cancer
include herpes simplex type 1 and human papillo-
mavirus. Epstein-Barr virus, also a herpes virus, is
now accepted as an oncogenic virus responsible for
Burkitt's lymphoma, occurring primarily in Africa,
and nasopharyngeal carcinoma, occurring primarily
in China. HPV is a major etiologic agent in cervical
cancer (Howley 1991), and has been found in associ-
ation with oral cancer as well (Sugerman and
Shillitoe 1997). HPV DNA sequences have been
found in oral precancerous lesions as well as in squa-
mous cell carcinomas (Adler-Storthz et al. 1986,
Syrjanen et al. 1988), and experimental evidence has
shown that HPV-16 can be an important cofactor in

ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL           45


46

-

Diseases and Disardcrs

oral carcinogenesis (Park et al. 1991, 1995). Herpes
simplex type 1 antibodies were demonstrated in
patients with oral cancer, and herpes was found to
induce dysplasia (abnormal cellular changes) in the
lips of hamsters when combined with the application
of tobacco tar condensate (Park et al. 1986).

More recently, human herpes virus 8, a newly
identified member of the herpes virus family, has
been found in Kaposi's sarcoma, an otherwise rare
cancer occurring in patients with AIDS. These
tumors often appear initially within the oral cavity
(Epstein and Scully 1992). Other uncommon oral
malignant tumors, such as Hodgkin's lymphoma and
non-Hodgkin's lymphoma, can also occur in the
mouths of AIDS patients.

tions in the ~53 gene detected in many types of can-
cer (Greenblatt et al. 1994, Hollstein et al. 1991),
including oral and pharyngeal cancer (Langdon and
Partridge 1992, Somers et al. 1992). The ~53 gene
has been called the "guardian of the genome" (Lane
1992) because of its ability to recognize damage to a
cells DNA and stop the process of growth and divi-
sion until the damage is repaired. If repair is not pos-
sible, ~53 can trigger apoptosis. Mutations in the ~53
gene in oral cancer have been linked to smoking and
alcohol use (Brennan et al. 1995).

Loss of Immunosurveillance and Control

  In addition to viruses, infection with strains of
the fungus Candida albicans has been linked to the
development of oral cancers via the fungal produc-
tion of nitrosamines, which are known carcinogens.

The immune system can, at first noted by Paul
Ehrlich in 1909, seek and destroy initial clones of
transformed cancer cells (Ehrlich 1957). Ehrlich
called this process immunosuweillance, and it has
been confirmed in experimental animals (Burnet
1970, Shklar et al. 1990) and in humans with
induced immunosuppression (Penn 1975).

Genetic Derangements

Of the more than 50 known oncogenes, many have
been reported to be present in oral cancer, and mul-
tiple oncogenes have been reported in oral and pha-
ryngeal cancer (Spandidos et al. 1985). Some of these
are &l-l, c-erb-B2, c-myc, ins-2, and members of the
rus family (Berenson et al. 1989, Bos 1989, Riviere et
al. 1990, Somers et al. 1990, 1992).

The genetic derangements that can give rise to
oral cancer, including many mutations associated
with the transformation of proto-oncogenes, have
received notable attention (Sidransky 1995, Wong et
al. 1996). In some instances a change in a single
nucleotide base-a point mutation-in a gene
encoding a proto-oncogene is enough to transform it
into an oncogene. Cancerous changes may also
involve alterations, deletions, and break points in
chromosomes that affect the position of genes.

  One mechanism of immunosurveillance involves
stimulating cytotoxic macrophages and lymphocytes
to migrate to the tumor site and release tumor necro-
sis factors (Y and l3 (Shklar and Schwartz 1988).
Another mechanism operative in oral cancer appears
to be stimulation of Langerhans cells, a special group
of immune cells, in the oral mucosa (Schwartz et al.
1985). Other immune cells implicated in tumor
rejection are natural killer cells and lymphokine-acti-
vated killer cells (Reif 1997).

  There is an increased incidence of cancer in
patients with AIDS or other immunodeficient condi-
tions or with induced immunosuppression prior to
organ transplantation.

In addition, there is evidence that smoking
depresses the immune system (Chretien 1978), and
this may be one of the ways in which smoking acts as
a major risk factor in oral cancer.

Mutations that disarm the cells DNA repair
mechanisms, as well as mutations in tumor suppres-
sor genes, which inhibit abnormal cell growth, play a
major role in cancer development. If an individual
inherits or acquires a mutation in one or more tumor-
suppressor genes, for example, the loss of this pro-
tective mechanism reduces the number of other dele-
terious changes needed for cancer to develop.

Growth Factors

Tumor suppressor genes suspected to be mutated
in oral and pharyngeal cancers include those for Rb,
~16 (MTSI, CDKNZ, or IN4a), and ~53. Todd et al.
(1995) recently reported a novel oral tumor suppres-
sor gene, named "deleted in oral cancer-l (doe-11." Of
the group of tumor suppressor genes, that coding for
~53 is considered of major importance, with muta-

Immune cells are potent generators of growth factors
and other molecules that can stimulate other cells to
migrate and proliferate. This capacity is important in
normal cell growth and turnover, in wound healing,
and in coping with infection. Unfortunately, the
release of growth factors can contribute to oral can-
cer by stimulating keratinocyte (oral epithelial cell)
proliferation (Aaronson 1991, Issing et al. 1993,
Wong 1993). Increased levels of transforming growth
factor (Y (TGF-a) and epidermal growth factor have
been found in oral and pharyngeal cancers and there-
fore could serve as markers for malignancy (Grandis
and Tweardy 1993). Nicotine at high doses stimulates

ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL


rhe release of growth hormones, among other
endocrine effects (Pomerleau and Pomerleau 1984,
se),ler et al. 1984, 1986).

prevention and Management

Studies of experimental carcinogenesis are elucidat-
ing the role of micronutrients in tumor development
& progression. Alpha tocopherol (vitamin E) also
has been studied as an antioxidant in nutritional
npproaches to the prevention or control of oral can-
cer. Antioxidants can trap free radicals, the highly
reactive molecules that build up in cells and can
damage DNA. The control of oral cancer and precan-
cerous lesions has been demonstrated experimental-
ly using a variety of antioxidant micronutrients, such
as retinoids, carotenoids, and glutathione, as well as
alpha tocopherol. For example, it was found that
alpha tocopherol inhibited tumor development and
tumor angiogenesis (blood vessel formation) in ham-
sters, as well as the expression of TGF-c~, a potent
angiogenesis stimulator (Shklar and Schwartz 1996).
*Animal research and tissue culture studies using ani-
mal- and human-derived cancer cell lines have
shown combinations of micronutrients to be more
effective than single micronutrients and to work syn-
ergistically. The nutrients not only were able to inhib-
it experimental carcinogenesis, but also could com-
pletely prevent tumor development and cause estab-
lished squamous cell carcinomas to regress (Shklar
and Schwartz 1993). The mechanisms of cancer con-
trol by micronutrients are gradually becoming clari-
fied and involve common pathways of activity at the
molecular level (Shklar and Schwartz 1994). Clinical
studies in humans have shown an inhibitory effect on
oral leukoplakia (Benner et al. 1993, Blot et al. 1993,
Garewal 1993, Garewal et al. 1990, Hong et al. 1986),
suggesting a potential role for nutrients in the overall
prevention and management of early oral cancer and
precancerous leukoplakia. However, a recommenda-
tion to employ such approaches clinically at this time
is premature.

DEVELOPMENTAL DISORDERS
The importance of the face as the bearer of identity,
character, intelligence, and beauty is universal.
Craniofacial birth defects, which can include such
manifestations as cleft lip or palate, eyes too closely
or widely spaced, deformed ears, eyes mismatched in
color, and facial asymmetries, can be devastating to
the parents and child affected. Surgery, dental care,
psychological counseling, and rehabilitation may

ORAL HErlLTH IN AMERICA: A REPORT OF THE SURGEON GENERAL           47

Diseases and Disorders

help to ameliorate the problems but often at great
cost and over many years.

Although each developmental craniofacial dis-
ease or syndrome is relatively rare, the number of
children affected worldwide is in the millions. In
addition, craniofacial defects form a substantial com-
ponent of many other developmental birth defects,
largely because they occur very early in gestation,
when many of the same genes that orchestrate the
development of the brain, head, face, and mouth are
also directing the development of the limbs and
many vital internal organs, such as the heart, lungs,
and liver.

By about the third week after fertllization, the
three germ layers of the embryo-the ectoderm,
endoderm, and mesoderm-have formed, as well as
the first of four sets of paired swellings-the
branchial arches-that appear at the sides of the head
end of the embryo. (See Chapter 2 for more details on
this process.) Some craniofacial defects result from
failure of the arches to complete their morphogenet-
ic development. Other craniofacial defects are the
result of the abnormal differentiation of cells derived
from the ectoderm and endoderm or from ectomes-
enchyme cells, which originate in a part of the ecto-
derm (the neural crest), in interaction with future
connective tissue (the mesenchyme).

Craniofacial Anomalies Caused by Altered
Branchial Arch Morphogenesis

Cleft Lip/Palate and Cleft Palate

The most common of all craniofacial anomalies-and
among the most common of all birth defects-are
clefts of the lip with or without cleft palate and cleft
palate alone; these occur at a rate of 1 to 2 out of
1,000 births, resulting in over 8,000 affected new-
borns every year. Cleft lip/palate and cleft palate are
distinct conditions with different patterns of inheri-
tance and embryological origins (Lidral et al. 1997,
Murray et al. 1997). The male to female ratio of cleft
lip/palate is 2:l; the ratio for cleft palate alone is just
the reverse, 1:2.

These anomalies result from the failure of the
first branchial arches to complete fusion processes
(Murray 1995, Robert et al. 1996). Clefting can occur
independently or as part of a larger syndrome that
may include mental retardation and defects of the
heart and other organs. Not all cases of clefting are
inherited; a number of teratogens (environmental
agents that can cause birth defects) have been impli-
cated, as well as defects in essential nutrients such as


Diseases ;tnd Disorders

folic acid. Smoking by the mother during pregnancy
also increases the risk. It is becoming increasingly
evident that most diseases and disorders, not just
craniofacial anomalies, result from interactions
involving multiple genes and environmental factors.

Infants with clefts have difficulty with vital oral
functions such as feeding, breathing, speaking, and
swallowing. They are also susceptible to repeated res-
piratory infections. As these children grow. they must
cope with the social consequences of a facial defor-
mity, delayed and altered speech, frequent illness,
and repeated surgeries that may persist through late
adolescence.

Current molecular epidemiology investigations
have examined both syndromic and nonsyndromic
(isolated) cleft lip/palate and cleft palate. Linkage
studies have identified a number of candidate genes
(Lewanda and labs 1994), including MSXl , RAR, an
X-linked locus, and the genes for TGF-B3 and TGF-
a. The pattern of inheritance in cleft lip/palate and
cleft palate suggests that between 2 and 20 genes may
be involved, with one gene representing a major
component in the development of the cleft. One of
the common syndromic forms of cleft lip/palate, the
Van der Woude syndrome, is caused by an autosomal
dominant form of inheritance at a locus on chromo-
some 1 (Sander et al. 1995). Future molecular genet-
ic studies will be needed to provide the information
necessary for prenatal diagnosis, calculation of risk,
and potential gene therapy.

The Treacher Collins Syndrome-
Mandibulofacial Dysostosis

Children with the Treacher Collins syndrome have
downward-sloping eyelids; depressed cheekbones; a
large fishlike mouth; deformed ears with conductive
deafness; a small, receding chin and lower jaw; a
highly arched or cleft palate; and severe dental mal-
occlusion (Dixon 1996). These defects result from
defective cranial neural crest cell differentiation,
migration, and proliferation (see Chapter 2).
Consequently, the first branchial arch structures are
deficient, and all derivative craniofacial components
are affected.

The underdeveloped facial structures can con-
tribute to airway blockage and repeated upper respi-
ratory infections, either of which can be fatal. The
faulty development of the ears leads to a conductive
deafness. The severe facial deformities exacerbate the
psychological difficulties these youngsters face.
Investigators have identified the gene involved in
an autosomal dominant form of the syndrome (Wise

et al. 1997). The function of the gene is not yet
known, but its identity will provide opportunities for
prenatal diagnosis, gene therapy, and further under-
standing of craniofacial development.

The Pierre Robin Syndrome

Deficient development of the first-branchial-arch-
derived mandibular portion results in the lower jaw's
being set far back in relation to the forehead. As a
result, the tongue is set back and may obstruct the
posterior airway, compromising respiration (Elliott et
al. 1995, Tomaski et al. 1995) and, in severe cases,
leading to inadequate aeration and failure to thrive.
The infant is also at risk for the development of car
pulmonale, an enlargement of the right ventricle of
the heart that occurs secondarily to a chronic lung
condition. Cleft palate may be another consequence.

The DiGeorgeNelocardiofacial Syndrome

The primary defect in the DiGeorge syndrome results
from altered development of the fourth branchial
arch and the third and fourth pharyngeal pouches
(Goldmuntz and Emanuel 1997). Deficiencies affect-
ing the thymus, parathyroid glands, and the great
vessels that derive from these structures result. The
facial features are subtle and include a squared-off
nasal tip, small mouth, and widely spaced eyes.
Similar facial features, along with heart defects, are
seen in the velocardiofacial syndrome. Both syn-
dromes are associated with deletions on the long arm
of chromosome 22 (22qll) (Gong et al. 1997,
Gottlieb et al. 1997). Further characterization of this
chromosomal deletion region will provide informa-
tion on the specific gene(s) affected and its function
in craniofacial development.

The thymus defects severely compromise cellular
immunity, depriving the body of thymus-derived T
cells and paving the way for severe infectious disease.
Inadequate or missing parathyroid glands cause
severe hypocalcemia (low blood calcium levels) and
seizures. The great vessel abnormalities alter cardiac
output and lead to compromised circulation to heart
tissues.

Cranial Bone and Dental Anomalies

Defects in the timing of developmental events can
cause premature fusion of cranial bones.
Impairments of tooth development can result from
interruptions of the developmental sequence at sev-
eral different stages.

48          ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL


CraniosyIIoStOSeS

Some craniofacial anomalies are associated with so-
called master genes that orchestrate a program by
Ivhich the embryo assumes its basic shape.
Craniosynostosis, which occurs in approximately 1
out of 3,000 births, is one such anomaly. It results in
the premature fusion of the cranial sutures, a danger-
ous condition that puts pressure on the developing
brain. A number of diseases and syndromes, includ-
ing Crouzon's, Apert's, Boston-type craniosynostosis,
pfeiffer's, and Saethre-Chotzen, share this anomaly,
but differ in other features, which can include struc-
tural defects such as webbing of the hands and feet as
well as mental retardation. Boston-type craniosynos-
tosis has been linked to MSX2, one of the master
genes. Several of the other syndromes involve point
mutations at one or another locus in genes that code
for fibroblast growth factor receptors (FGFR 1,2, and
3) (Howard et al. 1997, Meyers et al. 1996).
Collectively, these genes are associated with cell reg-
ulation, either through mediating growth factor
effects or by serving as transcription factors (Cohen
1997).

Hereditary Hypodontia or Anodontia
Conditions of underdeveloped teeth (hypodontia) or
their complete absence (anodontia) have been corre-
lated with specific genes, such as MSXl and LEFl.
The complete absence of teeth alters the bony devel-
opment of the mandible and maxilla.

Amelogenesis Imperfecta and Dentinogenesis
Imperfecta

Amelogenesis imperfecta and dentinogenesis imper-
fecta are linked to defects in structural genes that
code for proteins essential to the development of
tooth enamel (amelogenesis imperfecta) or dentin
(dentinogenesis imperfecta). The teeth are weak and
extremely sensitive to temperature and pressure. The
ordinary forces of chewing are painful and can lead to
further wear and pain.

The enamel matrix genes include tuftelin,
ameloblastin, and amelogenin; researchers have
begun to link mutations in these genes with amelo-
genesis imperfecta. Similarly, genes labeled DSP and
DPP have been characterized for dentin matrix and
are associated with the inheritance of dentinogenesis
imperfecta.

Diseases and Disorders

Craniofacial Defects Secondary to Other
Developmental Disorders
A number of genetic diseases occur in which cranio-
facial defects are secondav to a more generalized
structural or biochemical defect.

Osteogenesis Imperfecta

Inherited mutations of collagen genes lead to a num-
ber of "brittle bone" diseases characterized by defects
in mineralized tissues that form from a collagen-rich
matrix. Osteogenesis imperfecta presents a spectrum
of deficiencies that includes fragile bones, clear or
blue sclera, deafness, loose ligaments, and painful
dentinogenesis imperfecta-like chaages in the teeth.

Epidermolysis Bullosa-Recessive Dystrophic
TYPe

The gene defect in epidermolysis bullosa-recessive
dystrophic type-manifests as blisters or bullae that
appear shortly after birth on skin areas following
minor trauma. Mutations in keratin genes that con-
tribute to the epithelial cell cytoskeleton have been
correlated with this condition.

The oral manifestations include both mucosal
bullae and altered teeth. Altered teeth with hypoplas-
tic enamel develop and exhibit an increased suscepti-
bility to caries. Oral bullae develop from even the
slightest mucosal trauma. The condition is painful
and dangerous because of the constant risk that the
bullae will become infected.

Craniofacial Manifestations of Single-Gene
Defects

In many craniofacial defects, mutations within a sin-
gle gene manifest as complex syndromes with varied
organ and limb defects as well as facial anomalies.

Ectodermal Dysplasias

The ectodermal dysplasias (EDs) are a family of
hereditary diseases first observed by Charles Darwin
over a century ago. They involve defects in two or
more tissues derived from the ectoderm-skin, hair,
teeth, nails, and sweat glands. The ectodermal struc-
tures fail to differentiate properly owing to altered
epithelial-mesenchymal signaling. A gene, EDA, at an
X-linked locus has been linked to the syndrome, and
ongoing research is aimed at determining the func-
tion of the gene and the molecular mechanism of the
syndromes (Kere et al. 1996, Zonana et al. 1994).

ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL           49


Diseases and Disorders

More recently, investigators have discovered genes
linked to autosomal (i.e., non-sex-linked) forms of
ED, displaying both dominant and recessive inheri-
tance (Monreal et al. 1999).

Oral manifestations of the ectodermal dysplasias
are associated with the teeth. Alterations in tooth
delrelopment can include hypodontia, anodontia,
and conically shaped teeth.

The Waardenburg Syndrome

The Waardenburg syndrome has been subdivided
into several types. All involve a variety of abnormali-
ties in the position and appearance of the nose and
eyes, with pigment changes that may cause one eye
to differ in color from the other. Other signs include
deafness, a mildly protruding jaw. cleft lip and palate,
and skeletal deformities (Reynolds et al. 1995). The
syndrome is inherited in an autosomal dominant
manner with complete penetrance and variable
expression. Specific genes associated with this syn-
drome are members of the homeobox family that reg-
ulate the transcription of other genes: Waardenburg
type 1 with PAX3; Waardenburg type 2 with IMITF,
3q14.1; and Waardenburg type 3 with PAX3, 2q35
(Asher et al. 1996).

Cleidocranial Dysplasia

The inheritance of a regulatory gene defect in clei-
docranial dysplasia leads to features that include
delayed tooth eruption, supernumerary teeth, altered
or missing collarbones, short stature. and possible
failure of cranial suture closure. The exact mecha-
nism of the associated gene, CBFAI, located on chro-
mosome 6, has not been determined but appears to
be essential for bone development.

INJURY

The common perception is that injuries are random
occurrences that are unpredictable and hence unpre-
ventable. In actuality, experts in the field make the
point that there are no basic scientific distinctions
between injury and disease (Haddon and Baker
1981). Injuries have been categorized as "intention-
al" and "unintentional." People identified as being at
risk for certain injuries. as well as the causes of those
injuries, can be targeted for appropriate prevention
strategies. Such an approach is broadly applicable to
sports, falls, and motor vehicle injuries (unintention-
al) as well as to injuries caused by abusive and vio-
lent behaviors (intentional).

Injuries are a major public health problem. out-
ranking cancer and heart disease as a leading cause of

death in some age groups of the population (Kraus
and Robertson 1992). Cranial injuries in particular
are a leading cause of mortality Oral-facial injuries
can bring disfigurement and dysfunction, greatly
diminishing the quality of life and contributing to
social and economic burdens (Reisine et al. 1989).
The leading causes of oral and craniofacial
injuries are sports. violence, falls, and motor vehicle
collisions (Kraus and Robertson 1992). Oral cavity
injuries may also be caused by foreign objects in food
(Hyman et al. 1993).

sports

Craniofacial sports injuries occur not only in contact
sports, but also in individual activities such as bicy-
cling, skating, and gymnastics, especially on trampo-
lines. Each sport predisposes its participants to a spe-
cific array of extrinsic risk factors (Pinkham and
Kohn 1991). These include physical contact, projec-
tiles such as balls and pucks, and the quality of the
playing field and equipment. In contact sports the
absence of protective equipment such as headguards
and mouthguards is a major risk factor. In a recent
survey of school-aged children in organized sports,
football was the only sport in which the majority of
participants used mouthguards and headgear
(Nowjack-Raymer and Gift 1996).
There are intrinsic risk factors as well, relating to
characteristics of the individual participant. These
include age, sex, injury history, body size, aerobic fit-
ness and muscle strength, central motor control, and
general mental ability (Taimela et al. 1990).

Falls

Falls are a major cause of trauma to teeth, primarily
to incisors. Unlike bone fractures, fractures of the
crowns of the teeth do not heal or repair, and affect-
ed teeth often have an uncertain prognosis. Problems
may develop later due to damage to the pulp.

Motor Vehicle Collisions

The effects of motor vehicle collisions may range
from minor and reversible effects to long-term med-
ical. surgical, and rehabilitative consequences. Post-
traumatic headaches and chronic oral-facial pain can
occur. Neuromuscular and glandular damage may
cause short- or long-term problems with chewing,
swallowing, and tearing or result in facial tics or
paralysis.

50

ORAL HEALTH IN :lILlERICS: ;I REPORT OF THE SURGEON GENERAL