# Esophageal Carcinoma Histology Affects Perioperative Morbidity Following Open Esophagogastrectomy

Authors: Charles E. Woodall; Ryan Duvall; Charles R. Scoggins; Kelly M. McMasters; Robert C. G. Martin
Journal: Journal of Oncology
 (2008)

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## Abstract

Background. Esophagectomy for esophageal cancer is being practiced routinely with favorable results at many centers. We sought to determine if tumor histology is a powerful surrogate marker for perioperative morbidity. Methods. Seventy three consecutive patients managed operatively were reviewed from our prospectively maintained database. Results. Adenocarcinoma (AC) was present in 52 (71%) and squamous cell (SCC) in 21 (29%). The use of neoadjuvant therapy was similar for the AC (34.62%) and SCC (42.86%) groups. The SCC group had a higher incidence of prior pulmonary disease than the AC group (23.8% versus 5.8%, resp.; P=.03). SCC patients were more likely to have a prolonged ICU stay than AC patients (P=.004) despite similar complication rates, EBL, and prognostic nutritional index. The SCC group did, however, experience higher grades of complications (P=.0053). Conclusions. Presence of SCC was the single best predictor of prolonged ICU stay and more severe complications as defined by this study. Only a past history of pulmonary disease was different between the two histologic subgroups.


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## Body

## 1. Introduction

Esophagectomy for
esophageal cancer is being practiced routinely with favorable results at many
centers. Improvements in surgical technique and perioperative care have permitted a procedure once
associated with high mortality rates to now be practiced with a low risk of
postoperative death. However, studies continue to report high morbidity and
there is now a focused effort to identify factors that may predict
perioperative outcome.Pulmonary complications are a major
contributor to mortality in esophageal cancer and efforts to improve pulmonary
hygiene have contributed to reduced perioperative mortality [1]. As an adjunct to further decrease these
complications, the necessity of a thoracic incision when performing
esophagectomy has long been debated.
Proponents have often argued that its use enables a more complete lymphadenectomy,
while opponents feel it contributes significantly to perioperative morbidity
but this has not been shown to affect long-term prognosis [2].Given the importance of
pulmonary status on outcome, the ability to predict those patients at higher
risk for pulmonary complications might then be of some benefit, not only in
predicting their potential for morbidity, but also in choosing the approach that may
mitigate these risks. Many feel
that a minimally invasive approach may be the answer.  Recently, investigators have reported
promising results with minimally invasive approaches [3, 4]. While there is little debate regarding the
role of surgical technique and comorbid conditions on the development of
postoperative complications, little is known about the impact of tumor biology
on morbidity. Based on recent a report suggesting that the esophageal
histology may impact perioperative outcome [5], we sought to further
delineate this relationship. This study is an
attempt to recognize that tumor histology alone can identify patients more
likely to suffer a complication and perhaps guide perioperative decision
making.


## 2. Methods

The records of patients included in a
prospectively maintained upper gastrointestinal malignancy database were
reviewed for this institutional review board approved study. All patients
undergoing esophagogastrectomy for esophageal carcinoma were included in the
study, and all patients underwent a standard combined thoracic and abdominal
esophagogastrectomy (Ivor-Lewis type) procedure. This review was performed
under an IRB approved protocol from the University of Louisville Human Subjects Protection Office. All patients had undergone complete preoperative evaluation with CT chest/abdomen/ pelvis, endoscopic ultrasound, and in some, PET scanning.  Most patients with preoperative T2 or greater, or N1 (by imaging) were given neoadjuvant chemoradiation with either 5-fluorouracil or combined 5 fluorouracil with
cisplatin depending on the histology of the disease and standard radiation
therapy dosing of 5040 cGy. Operative techniques were consistent across this
study with the esophagogastrectomy performed through an abdominal incision
first, with mobilization, celiac and supraceliac lymphadenectomy, pyloroplasty,
and gastric conduit formation followed by a thoracic incision, with
mobilization, thoracic lymphadenectomy, tumor resection, and thoracic
anastomosis.Variables evaluated included demographics
(age, race, and gender), smoking history, alcohol history, histology, cancer
staging, grade and type of complications, nutritional status, length of
intensive care unit stay, and operative factors including estimated blood loss.
Comorbidities, such as prior cardiac and pulmonary disease as well as history
of tobacco and alcohol abuse as reported by the patient were also
recorded.  The prognostic nutritional index (PNI) advocated by
Onodera et al. [6] was calculated to investigate the preoperative nutritional
condition of the patients in both groups. It is calculated from the formula
(giving a percentage) (10 × Albumin) + (0.005 × absolute lymphocyte count). Prior
cardiac history was defined as any patient with a history of angina, previous
coronary artery disease defined by cardiac catheterization, previous myocardial
infarction, cardiac valve dysfunction requiring medication, or a history of
congestive heart failure or tachyarrhythmia. Prior pulmonary disease history
was defined as any patient with abnormal pulmonary function tests, history of
asthma requiring daily meter dosed inhalers, or tobacco use greater than a 25-pack
year history.All postoperative
complications and the length of hospital stay were prospectively entered into
the database. Complications were
identified prospectively and assigned a grade from 1 to 5 based on an
established scale [7]. Examples of the grading of complications
includes (1) uncomplicated urinary tract infection; (3) small, contained
anastomotic leak requiring no further operative therapy or drainage procedures;
(5) death.  In instances where the
grading was unclear, a score was assigned after review of the records and
discussion between two of the senior authors. All in hospital and 90-day
postoperative complications were evaluated with the most severe complication level
recorded. Infectious complications were defined by a positive fluid (sputum,
wound, urine, etc.) culture, with some criteria of a systemic inflammatory
response (i.e., tachycardia, fever, and hypoxia)Statistical analysis was performed with JMP
software (SAS Institute, Cary, NC, USA). Analysis of variance, log-rank analysis, and Pearson correlation coefficient were
used to determine significance, and aP-value <.05 was considered
significant in this study.


## 3. Results

Seventy three
consecutive patients undergoing combined abdominal and thoracic
esophagogastrectomy for cancer were identified and included in the study, with
a median age was 61 (range 26 to 80). 55 (75.3%) were male and 18 female
(24.7%).  Fifty four patients (74%) were
Caucasian, 12 (16%) were African-American, and the race of 7 (9%) was not
recorded. There were 3 (4.1%) perioperative deaths, all occurring in the AC
group. Adenocarcinoma (AC) was present in 52 (71%) and squamous cell (SCC) in
21 (29%).  In Caucasians, AC occurred
more often than SCC (84% versus 47%, resp.;P=.004). Adenocarcinoma was
also much more common in males (86%) than SCC (47%; P=.0007). The AC
patients were slightly younger (59 versus 63) than those in the SCC group (P=.21)
(Table 1).Table 1
Adenocarcinoma and squamous cell carcinoma groups patient demographics.
Adenocarcinoma,n (%)Squamous cell carcinoma,n (%)P-valuen52 (71%)21 (29%)Median age5963.21Caucasian
race44 (8462%)10 (47.62%).0004Male
gender45 (86.54%)10 (47.62%).0007Alcohol
abuse6 (11.54%)8 (38.1%).012Tobacco
use36 (69.23%)13 (61.9%).5492Prior
cardiac disease13 (25%)4 (19.05%).573Prior
pulmonary disease3 (5.77%)5 (23.81%).034FEV1<75%3 (5.77%)4 (19%).06Patients in the SCC
group were significantly more likely to have a history of alcohol abuse (8/21,
38.1%) versus those in the AC group (6/52, 11.5%;P=.012). They were
also more likely to have a history of pulmonary disease (asthma, COPD,
pneumonia) than the AC group (23.8% versus 5.77%; P=.034).
Interestingly, there was no difference in the rate of COPD between the two
groups (2.8% versus 3.9%; P=.133) and no difference in rates of tobacco
use (61.9% versus 69.2%; P=.5492), mean pack years (56.6% versus 51.0%; P=.573),
or prior cardiac disease history (CAD, atrial fibrillation, prior MI, or
percutaneous coronary intervention (PCI); 19.1% versus 25.1%; P=.5806).
At the time of operation, median estimated blood loss was similar for both
groups (551 mL for AC and 600 mL for SCC, P=.7626).In the AC group, there were two (3.9%)
patients with in situ disease, five (9.8%) with T0 disease, five (9.8%) T1s, 10
(19.6%) T2s, 27 (52.9%) with T3 disease, and 2 (3.9%) with T4 disease on final
pathology (Table2). The SCC group had a similar distribution: 2 (9.5%) T0s, 4 (19.0%) T1s, 2 (9.5%) T2s, 9 (42.8%) T3s, and 4 (19.1%) T4s; the differences
were not significant (P=.2). Nodal staging for the AC group consisted of
24 patients (47%) with N0 disease, 25 (49%) with N1 disease, and 2 (3.9%)
patients with N2 disease. In the SCC group, there were 14 (66.7%) with N0
disease and 7 (33.3%) with N1 disease. There were no patients with N2 disease
in the SCC group. The differences were not statistically significant (P=.25).
Metastatic disease was found in one patient in each group (P=.5).Table 2
Adenocarcinoma and squamous
cell carcinoma tumor features and perioperative data.
Adenocarcinoma,n (%)Squamous
cell carcinoma,n (%)P-valueT stage.2032T05
(9.80%)2
(9.52%)Tis2
(3.92%)0T15
(9.80%)4
(19.05%)T210
(19.61%)2
(9.52%)T327
(52.94%)9
(42.86%)T42
(3.92%)4
(19.05%)N stage.1933N024
(47.06%)14
(66.67%)N125
(49.02%)7
(33.33%)N22
(3.92%)0Neoadjuvant therapy18
(34.62%)9
(42.86%).5114Weight loss29
(55.77%)13
(61.90%).6301Mean BMI26.7222.89.0299Mean PNI33.6133.00.6921Epidural anesthesia44
(85%)18
(87%).78Anastomosis.8892Stapled17
(33.33%)6
(31.58%)Sewn34
(66.67%)13
(68.42%)Mean EBL551.065600.000.7626Margin Pos1
(2%)1
(4%).08Time from OP to extubation0.5
(0–48)1
(0–72).86Complications34
(65.38%)18
(85.71%).0693Grade of complications.00531 or 215
(44.12%)6
(35.29%)3, 4, or 519
(55.88%)11
(64.71%)ICU stay>3 days23
(47.92%)16
(76.19%).0259The use of neoadjuvant chemoradiation between
the AC and SCC groups was similar. Overall, 36% of patients received
preoperative therapy: 18 (34%) of the AC group and 9 (42%) of the SCC group (P=.5).
A similar proportion of patients in each group had experienced weight loss
prior to undergoing operative therapy: 55.7% (29) of AC and 61.9% (13) of SCC.
There was a trend in patients with AC to have a BMI greater than 20, while
patients with SCC tended to have a BMI less than 20 (P=.056). The
difference in mean BMI among groups was significant, however. In the AC group,
the mean was 26.7 while in the SCC group it was 22.889 (P=.0299). Also,
female patients tended to have a decreased BMI (81.2%) versus male patients
(36.7%); this was significant (P=.002) as well. The African-American
patients also had lower BMI (80% less than 20) than Caucasians (42.8% less than
20; P=.06).There were 65
independently identified complications among 52 of the 73 patients comprising
the cohort (Table3). Complications were graded on the basis of an established
scale. Seventy percent of patients experienced some sort of complication: 9
(12%) were grade 1, 12 (16%) were grade 2, 23 (31.5%) were grade 3, 1 (1%) was grade 4, and 6 (8%)
were grade 5. The grade 5 complications included the three aforementioned
deaths. The rate of complications between the AC and SCC groups (65.4% versus
85.7%) approached statistical significance (P=.0693). However, when the
patients with no complications were excluded, the distribution of the most
severe complication in each patient (grade 1 or 2 versus grade 3, 4, or 5)
revealed a statistically significant disproportion with more severe
complications occurring the SCC group versus the AC group (64.7% versus 55.9%, P=.0053).
No difference existed among races or genders in complications. Pulmonary
complications (including pneumonia) were the most predominant, comprising 29.3%
of all complications. These were most strongly associated with prior cardiac
disease (P=.056), and not with prior COPD history (P=.225),
pulmonary history (P=.336), histologic subtype (P=.503), or
increasing pack-year history of tobacco (P=.609). Esophageal leak (a
grade 3 complication) was the second most common complication, with 10 (13.7%)
occurrences. There was no significant difference in leak rate among histologic
groups (P=.805) or anastomosis type (P=.965).Table 3
All inhospital and 90-day postoperative complications and grade by histology.
ComplicationAdenoSCCn34/52 (65%)17/21 (81%)Grade 1:63Pneumonia—1Fever11Partial cord paralysis—1Anastomotic leak1—Hypertension1—Decubitus ulcer1—Hypovolemia1—Urinary tract infection1—Grade 2:93Fever11Mediastinitis—1Prolonged enteral feeding—1Excessive pain1—Pneumonia2—Pleural effusion1—Readmission1—Anastomotic leak1—Atrial fibrillation2—Grade 3:158Pleural effusion, pneumonia—1Anastomotic leak, EtOH withdrawal—1Anastomotic leak, pleural effusion—1Anastomotic leak32Delayed gastric emptying—1Pleural effusion11Respiratory compromise11Confusion, esophageal leak1—Confusion, pneumonia, respiratory failure1—Pleural effusion, atelectasis1—Anastomotic leak, pneumonia1—Anastomotic leak, pneumonia, SVT1—Anastomotic leak, evisceration1—Anastomotic leak, paraesophageal hernia1—SVT1—Pneumonia1—Hemorrhage1—Grade 4:10Anastomotic leak1—Grade 5:33Anastomotic leak—1Pneumonia—1Pulmonary embolus1—Death21Among the patients in the SCC group, the
median PNI was 40.95 (range 27.56 to 61.36); in the AC group the median was
39.78 (range 27.75 to 57.16;P=.6983). PNI did not appear to affect
morbidity. In the group of patients with a PNI less than 40, there was a
complication rate of 70.83%; in those with a PNI greater than 40, the rate was
79.17% (P=.5042). The distribution by grade of complications was
equivalent between those patients with a PNI of greater than 40 versus those
with a PNI less than 40 (P=.9986).
Patients with a PNI less than 40 were also not any more likely to have a
major (grade 3, 4, or 5) complication versus those with a PNI greater than 40 (P=.9396).
The differences in distributions of pulmonary (P=.7452) and anastomotic
leak (P=.1501) were also not statistically significant between the PNI
groups.Despite the similarities among the groups in
total complications, SCC patients were more likely to have a 3-day or longer
ICU stay than AC patients (P=.004). The higher incidence of pulmonary
disease in these patients was the largest contributor to this finding (P=.0016).
However, prior tobacco use (P=.8254), total pack years (P=.1286)
or cardiac disease (P=.5803) were not associated with a prolonged ICU
course. SCC was more likely in patients and 60 years of age (P=.004) but
age was not an independent factor for prolonged ICU stay.


## 4. Discussion

Advances in technique and patient care have
lead to overall decreases in esophagectomy mortality in the last 5 years [8]. However, morbidity remains high (60% in
some series) and appears to be associated with tumor histology. Thus the aim of
the present study was to delineate the role of tumor histology in regards to
perioperative morbidity and possibly preoperative decision making. Our study
suggests that tumor histology may be a significant predictor of morbidity,
primarily as a surrogate for increased pulmonary complications. These findings
are supported by a similar study from the United Kingdom [9], and might function as an adjunct to other
prognostic scoring systems [10].Despite advances in surgical technique and
perioperative care, the types of complications in esophageal cancer are fairly
consistent [11] (Table 4). Pulmonary morbidity and anastomotic leaks
remain the most common [12]; both of which can significantly effect a
patient's long-term quality of life [13] when they occur. Pulmonary complications
contribute to most cases of mortality in esophageal cancer and active efforts
to minimize their effects have been attributed as one of the most significant
causes of decreased perioperative mortality [14]. The historically dreaded anastomotic leak
has been delegated to a lesser standing; this is in large part due to new
minimally invasive endoscopic techniques that have been described for the
management of leaks [15], making what was once a devastating problem
somewhat more easily managed and no longer a source of increased mortality or
decreased long-term survival [16]. However, the pulmonary problems are more
difficult in a population in which, at least in the case of SCC, patients are
more likely to be smokers and thus more likely to carry a diagnosis of
underlying COPD. This was likely the root cause of the prolonged intensive care
unit stays seen in the SCC cohort in this study.Table 4
Recent studies of morbidity in SCC patients undergoing esophagectomy.
AuthorYearnSCC %SCC approachSCC pulmonarySCC anastomotic leakSCC median EBL (mL)SCC ICU stay (days)SCC mortalityWhooley2001710100%TTE (100%)32%3.5%832—11%Ferguson200229034.5%—39%————Fang2003441>90%3 Field (100%)7.3%32.65%587.5–642.1—2.5%Law2004421100%TTE (83%)15.9%3.1%700—1.4%Alexiou200662131.72%TTE (55%)18.3%8.6%——8.1%Woodall20077329%TTE (100%)28.57%26.32%60060%The perioperative risks for patients with
COPD are well known [17]. However, age, operative duration, and
proximal tumor location have also been identified as factors contributing to
pulmonary morbidity [18], of which all are more likely to be
associated with SCC histology than AC. Despite an efficient resection, patients
who suffer complications are at increased risk of surgical oncotaxis [19], the acceleration of their disease caused by
operative factors. The patients reported in this study by Hirai et al. had
earlier metastasis and poorer long-term outcomes. Therefore, at least from one
study, minimizing morbidity is important not only from a short-term
perioperative perspective but also from a long-term cancer prognosis
standpoint. Although it should be noted that another study, by Ferri et al.,
showed an increased short-term mortality in SCC patients suffering a complication, there are no long-term effects
in those that survived [20].Nutrition remains the
focus in many studies of esophagectomy, but its role in morbidity is somewhat
unclear. Few other malignancies affect the nutritional status of the patient
prior to diagnosis more than esophageal cancer, and are thus a potential
powerful marker of surgical outcome. Most surgeons would associate esophageal
cancer with malnutrition, noting the diminution in the ability of the patient
to take in adequate calories in addition to the wasting normally seen with
other malignancies, and thus try to supplement feedings. Advocates of this
approach stress the benefits of preoperative enteral supplementation. The
perioperative advantages of this were identified in a paper by Nozoe demonstrating
decreased complications and better long-term survival in patients with higher
prognostic nutritional index (PNI), a mathematical computation of the patients
albumin and absolute lymphocyte count [21]. As discussed by Onodera in the initial
description of PNI, a minimum value of 40 is recommended prior to undertaking
an esophageal resection. In the present study, a PNI of less than 40 did not
adversely affect outcomes and led to no increase in morbidity.At the opposing end of the spectrum,
increasing BMI has been attributed to the increasing incidence of AC. Even
significantly, overweight patients may be relatively catabolic and
consideration for supplementation should be given in this population as well.
Fortunately, increasing patient BMIs has not been associated with poorer
operative or disease related outcomes. Also, in at least one large study of 400
patients, nutritional status as determined by BMI, PNI, weight loss, and other factors
had no value in predicting perioperative complications [22].Over time, multimodality treatment of
esophageal cancer has improved, offering increased long-term survival [23]. Better results have been noted for factors
most would identify as predictive of long-term success in any cancer, including
low AJCC stage, R0 resection, and M0 status. Neoadjuvant therapy is gaining
acceptance, as it can be given safely, is generally better tolerated than
adjuvant therapy, and does not affect operative morbidity or mortality. SCC can be treated safe
and effectively with multimodality therapy, providing durable results even for
patients with positive nodal disease as well as those from Asian studies
discovered to have early tumors. Regardless of the physician's opinion in regards
to the timing of additional therapy, most agree that esophageal squamous and
adenocarcinoma are not purely surgically treated diseases and that some form of
multimodality treatment is needed to extend quality of life time. Therefore,
from a surgical perspective, optimizing patient selection and operative
technique are important so that patients may recover quickly and go on to their
additional therapy.Technical advances have
allowed for refinement in the techniques in esophageal surgery to reduce
perioperative morbidity and mortality [24]. What technology to apply on a case-to-case
basis is a somewhat more difficult question to answer. Recent studies have also
served to benchmark expected courses for patients with AC, and the outcomes for
all esophageal resections has improved significantly [25]. Because of this, any changes in techniques
or approach need to be critically reviewed. Choice of operative approach has
been extensively studied, but until recently has focused on the transhiatal
versus transthoracic approach [2] or technical factors such as the location of
the conduit in the mediastinum. With the public's growing interest in minimally
invasive approaches, coupled with new techniques and instrumentation, minimally
invasive esophagectomy has been proven safe and feasible both in the United
States and abroad [3]. It also does not adversely affect long-term
survival, a question that has been repeatedly raised when laparoscopic
approaches are used to address surgical oncology diagnoses. The difficulty is
that there are a variety of techniques and combinations of approaches reported
as “minimally invasive,” with no standardized definition and any real benefit
over traditional techniques has yet to be proven. Most advocates of this
approach perceive decreased pulmonary morbidities and improved pulmonary
therapy as the main advantages, but some studies have questioned this benefit.
Preoperative pulmonary evaluations have tended to focus on pulmonary factors
alone, including smoking and COPD. However, given these factors in a high-risk
subgroup (SCC), there might be more of an advantage for minimally invasive
techniques and perhaps we should evaluate these patients for this approach.The limitations of this
study are the small sample size of the SCC patients. This limits the impact of
the data presented, but does not limit the fact that these two types of histologies are both
biologically different and physiologically different and treating physicians
should be aware of these differences and the impact that these play on
perioperative outcomes.


## 5. Conclusion

The presence of SCC was the single best
predictor of prolonged intensive care unit stay and more severe complications
as defined by this study. Only a past history of pulmonary disease was
different between the two histologic subgroups. No other factor, including sex,
gender, age, or nutritional status was predictive of this outcome.  Esophageal histology should therefore be
considered in the perioperative care of patients and may in the future be used
to guide operative strategies.



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