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352 Part III Esophagus
tell us which bioprosthesis to use. Another strategy that
appears to be of value is esophageal lengthening. When
used selectively, in 20–40% of patients with giant hernias,
HH recurrence rates seem to have decreased. Additionally, the symptomatic consequence of a small hiatal hernia
recurrence is generally minimal, suggesting that it is a rare
recurrence that will lead to reoperation.
e technique of repair described is little dierent from
our approach, with a few exceptions. A split leg table is superior to low lithotomy stirrups, as the setup is simpler and
the risk of lower extremity nerve compression and deep vein
thrombosis (DVT) is decreased by the elimination of stirrup-related pressure points and knee exion. We also use a
mechanical scope holder, which increases operative eciency
and decreases surgeon fatigue, by maintaining a steady image.
e pneumatic camera holder is attached to the right side of
the bed, near the right hip.
Early in a surgeon’s experience with laparoscopic giant
HH repair, it was customary to recognize three problems:
failure to identify the esophagus (leading to lighted dilator
use), disorientation in the epiphrenic and lesser curvature
fat, and bleeding from the lesser curvature vessels, including
the left gastric artery. All of these problems may be solved by
keeping the dissection focused on the diaphragmatic crura,
detaching the hernia sac from the crura circumferentially
and stripping the peritoneal sac from the lower posterior
mediastinum. With this strategy, the esophagus becomes
readily visible without the need for a lighted bougie, the fat
is reduced by the reduction of the hernia sac, and the lesser
curvature vessels are caudal to the eld of dissection.
While the closure of a large defect may seem daunting,
two strategies seem to allow closure of nearly all large hernias:
(1) start posteriorly, as is described in this chapter, and (2)
reduce the intra-abdominal pneumoperitoneum pressure to
5–8 mm Hg. With these steps it is almost never necessary to
place anterior sutures, which are prone to tearing out because
the diaphragm is often quite attenuated anteriorly, and the
transverse orientation of the anterior crural arch makes closure
technically dicult. Excessive anterior angulation of the distal
esophagus is only a problem if the esophagus is not adequately
mobilized o the aorta in the lower mediastinum.
ESOPHAGEAL MOTILITY DISORDERS
e most common (albeit quite rare) esophageal motility disorder of surgical concern is achalasia. e etiology
of achalasia outside of the tropics is unknown, but the disease is remarkably democratic, aecting young and old,
male and female, and all ethnicities nearly equally.
a pattern strongly suggests the current hypothesis that an
immunologic response to viral exposure is responsible for
the observed myenteric neural degeneration.
pes virus has been implicated as the most likely “culprit” by
some, the evidence is far from convincing.
e treatment of achalasia with laparoscopic Heller myotomy and partial fundoplication has become the predominant
15,16
17,18
While her-
Such
primary therapy over the last 15 years. A recent randomized
trial demonstrating equivalence of balloon dilation and Heller
myotomy is unlikely to change our approach, as the balloon
dilation strategy required intensive surveillance and frequent
retreatment, as compared to laparoscopic Heller myotomy.
19
e only real “debate” in this eld has been whether to fashion
an anterior (Dor) or posterior (Toupet) fundoplication after
dividing the LES. A recent randomized trial, closed due to
lack of accrual, shows a slight, but not signicant, advantage in
diminished post-op reux with the posterior fundoplication.
20
Nonetheless, worldwide, the anterior fundoplication is preferred as it requires less posterior dissection and it does not
angle the GE junction anteriorly as the posterior fundoplication may do. e only “trap” of the Heller myotomy is
carrying the myotomy too far above the diaphragm and inadequately on the stomach. If there is any esophageal outow
obstruction (from reux stricture, angulation, or incomplete
myotomy), the supradiaphragmatic myotomy site, lacking
muscular support, may create an epiphrenic diverticulum, a
result of the pressurized esophagus. Intraoperative endoscopy,
immediately after the creation of the myotomy will identify
easily if the myotomy extends to the dilated esophagus and
onto the proximal stomach. A completely divided LES will
open with air insuations such that the endoscope “perched”
in the distal esophagus can visualize the stomach through the
previously spastic high-pressure zone, which will still appear
as a waist.
Our performance of myotomy varies a bit from the technique described. Without a dilator in the esophagus (which
may be hard to pass in the dilated esophagus), the anterior
esophagus and upper 3 cm of stomach is cleared of all fat and
neurovascular tissue such that the longitudinal muscle is clearly
visible on the anterior wall of the esophagus (12 o’clock). We
divide the epiphrenic fat pad with ultrasonic shears anteriorly,
but we do not remove it as it makes a good handle for the
rst assistant. It is usually necessary to create a passage behind
the anterior vagus nerve to remain on the anterior surface of
the esophagus. When the esophagus and stomach are cleared
o prior to myotomy, bleeding during the performance of
myotomy is dramatically reduced. e submucosal plane is
achieved just superior to the GE junction with Metzenbaumtype laparoscopic scissors. Firm lateral traction and countertraction by the surgeon’s left hand pulling toward the liver and
rst assistant grasping a divided epiphrenic fat pad and pulling
in the opposite direction will frequently disrupt the circular
muscle with minimal sharp dissection. Once the submucosal
plane is achieved, a blunt closed grasper can be run several
centimeters up the esophagus in the submucosal plane, making subsequent division of the circular muscle quite easy with
a pair of scissors. It is not necessary to use any thermal instruments (electrosurgery or ultrasonic dissector) near the mucosa.
“Blanching” of the mucosa should be treated as a perforation in
situ and should be oversewn as described in the text. e best
strategy for dividing the proximal gastric portion of the LES is
teasing distraction of the muscle bers with two Hunter-type
or Maryland-type graspers. It is critical that the mucosa be
cleared of all circular smooth muscle, and blunt undermining
Chapter 16 Perspective on Benign Esophageal Disease 353
of the myotomy allows the cut edges of the muscle to retract
out of sight behind the esophagus (frequently) just above the
angle of His. Endoscopy is then performed as mentioned
previously, and a “leak test” with air insuation is then performed. Finally, a large (56–60F) Maloney dilator is passed
by the surgeon or assistant to ensure that all circular muscle
has been divided and undermining is adequate. en, partial
anterior (our favorite) or posterior fundoplication, as elegantly
described in the previous chapter, is performed.
Failures of Heller myotomy are thankfully few, and the appropriate approach to failure has not been entirely dened. Some
prefer balloon dilation, with a 3- to 3.5-cm balloon, but the
same risk of perforation as with primary balloon dilation drives
most surgeons to consider remyotomy. Esophagogastroduodenoscopy (EGD), to rule out cancer, ulcer, or stricture, should
be complemented by video esophagram and high-resolution
esophageal motility study. e appearance of a diverticulum
at the supradiaphragmatic myotomy site should be addressed
by an attempt at relieving the esophageal outow obstruction.
Rarely is diverticulectomy indicated and it will be ineective
at relieving recurrent dysphagia if the primary problem is not
addressed. After complete LES myotomy, LESresting pressure
should be less than 10 mmHg. If the LES resting pressure is
above 12–15, we usually recommend redo Heller myotomy. If
thesphincter is already completely ablated (LES resting pressure <10), redo myotomy is unlikely to be successful. Under
these circumstances, and especially with a mega or sigmoid
esophagus, esophagectomy may be the best next step. e endstage achalasic esophagus is amenable to minimally invasive
surgery (MIS) esophagectomy techniques, but should not be
treated with transhiatal esophagectomy or esophageal stripping,
as the mediastinal blood vessels supplying a mega esophagus are
much larger than normal and stripping may result in uncontrolled mediastinal bleeding.
e approach to other “named” esophageal motor disorders is a bit more controversial. As a general principle,
nutcracker esophagus should not be treated with a long
myotomy, (it won’t help), and the dysphagia associated with
diuse esophageal spasm is best alleviated when the LES is
divided. It may be unnecessary to take the myotomy as high
as the top of the corkscrew appearance on contrast esophagram to achieve a successful outcome. In other words, the
laparoscopic Heller myotomy and partial fundoplication may
be the best operation for this condition. is is indeed a relief,
as it may be dicult to tell vigorous achalasia from diuse
esophageal spam (DES) in many patients. e treatment of
esophageal diverticula is well described in the prior chapter.
Because of the propensity of distal esophageal diverticulectomy staple lines to leak (up to 30% in some early studies), we
have taken the following three steps that seem to have solved
the problem: (1) perform a Heller myotomy to decrease intraesophageal pressure, even in the absence of demonstrable LES
hypertension, (2) sew the esophageal smooth muscle over the
site of the staple line if possible and perform the myotomy 90
degrees away from the staple line and at least as far proximal
as the proximal border of the diverticulum, and (3) leave the
patient on a liquid diet for 7days postoperatively to allow
staple line healing before introducing solid foods. Occasionally, safe and complete diverticulectomy can only be performed with thoracoscopic access when laparoscopic access
cannot safely expose the proximal extent of the diverticulum.
GASTROESOPHAGEAL
REFLUX DISEASE
e diagnosis, evaluation, and management of gastroesophageal reux disease (GERD) is extremely well covered in the
text. I focus, in this commentary, on only four things: indications for surgery, proper use of the many tests available to
assess the anatomy and pathophysiology of the esophagus and
stomach, choice of an operation, and long-term eectiveness
of laparoscopic antireux surgery, especially as compared to
treatment with proton pump inhibitor (PPI).
As has been pointed out, GERD is a very common condition, and a very small proportion of GERD patients elect to
have antireux surgery. While it is clear that the majority of
patients are eectively managed with daily PPI, it is now recognized that as many as 40% of individuals will have persistent
troublesome symptoms despite PPI treatment. Troublesome
reux is dened as mild GERD symptoms daily, or moderate
to severe symptoms two to three times per week. Of all reux
symptoms, PPI therapy is most likely to control chest pain and
heartburn. Only 17% of GERD patients will have regurgitation
symptoms adequately controlled with PPI.
can dene two populations poorly served with PPI for typical
(esophageal) GERD symptoms, those with troublesome heartburn and chest pain despite adequately dosed PPI, and those
with troublesome regurgitation that is unlikely to benet from
PPI. Both of these groups are ideally suited for laparoscopic
antireux surgery, as long as the diagnosis of GERD is secure,
based on a standard evaluation.
e use of laparoscopic antireux surgery for laryngopharyngeal reux (LPR) may be equally eective, if used in the
right patient. Because supraesophageal and/or laryngopharyngeal symptoms may be caused by so many common problems (eg, allergies, environmental factors, cigarette smoking,
postnasal drip, infections), it is more dicult than it might
appear to determine who truly has symptomatic LPR that
would be improved by the elimination of all gastroesophageal
reux. While many technologies have been developed over
the years to detect LPR, including dual-channel pH recording
and nasopharyngeal pH recording, both these methods have
proven dicult to validate. Two new promising methodologies,
22
sputum pepsin measurement
and esophageal/nasopharyngeal
impedance measurement, appear to be much more accurate for
determining the presence of LPR and will probably become the
test of choice in the near future to establish this diagnosis.
e preoperative evaluation of the patient with GERD is
well described in the chapter outlined previously. Several years
ago, we observed that all patients with heartburn responsive
to PPI and erosive esophagitis, stricture, or Barrett’s esophagus had an abnormal 24-hour pH study. us, we dropped
routine pH testing in these patients as the diagnosis of GERD
21
erefore, we
354 Part III Esophagus
was secure without pH testing in this population. Currently,
we reserve pH testing for patients with no esophagitis, Barrett’s esophagus or stricture, and for those with atypical
symptoms. As mentioned previously, a pH study is not really
needed prior to repair of the giant hiatal hernia, unless the
patient’s only symptom is heartburn and the EGD shows a
pristine esophagus. is is rare indeed.
Operation choice for GERD is still a matter of some debate
focused on the comparative long-term eectiveness of partial
posterior (Toupet) fundoplication and total (Nissen) fundoplication. For many years the partial fundoplication was used in
North America only for patients with ineective or absent
esophageal motility, as reux control was less when a partial
fundoplication was performed. When ineective peristalsis is
detected, it now appears that total and partial fundoplication
create equivalent low levels of postoperative dysphagia. When
peristalsis is completely absent (eg, achalasia or scleroderma),
one should consider a partial fundoplication. Having said this,
23
randomized data from Europe
suggest that the partial fun-
doplication provides equivalent reux control in most GERD
related symptoms. Bottom line: either type of laparoscopic
fundoplication may be performed. East of the Atlantic Ocean,
perform a posterior partial fundoplication. On the west “bank”
of the Atlantic Ocean, perform a total fundoplication.
Finally, there is great debate over the long-term eectiveness
of laparoscopic Nissen fundoplication as compared to chronic
PPI use. If one solely relies on the resumption of PPI as the
indicator of fundoplication failure, the surgical failure rate may
approach 30–40%, but physiologic assessment of these patients
demonstrates that only 30% of this group will truly be reuxing, bringing the true failure rate (at 10 years) to about 10%.
24
Most patients who have had a good result from a rst fundoplication will desire a redo fundoplication when the valve truly
fails. e most common failure pattern is the recurrent HH,
often a result of intra-abdominal stressors such as retching,
straining, coughing, obesity, trauma, and excessive heavy lifting.
e rate of reoperation following laparoscopic fundoplication
performed by an expert is approximately 1%/year.
e comparative eectiveness of fundoplication to medical
therapy has been tested in several randomized trials. When
study entrance is restricted to those rendered asymptomatic
on standard doses of PPI, surgery and medical therapy per-
25
form equivalently.
When the entrance criteria are broadened
to include those with a partial response to PPI, fundoplication
usually emerges as the most reliable and durable method for
elimination of GERD symptoms.
REFERENCES
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meta-analysis. Eur J Gastroenterol Hepatol. 2011;23:133–138.
2. Luketich JD, Nason KS, Christie NA, et al. Outcomes after a decade of
laparoscopic giant paraesophageal hernia repair. J orac Cardiovasc Surg.
2010 Feb;139:395–404.
3. Polomsky M, Siddall KA, Salvador R, et al. Association of kyphosis and
spinal skeletal abnormalities with intrathoracic stomach: a link toward
understanding its pathogenesis. J Am Coll Surg. 2009;208:562–569.
4. Schuchert MJ, Adusumilli PS, Cook CC, et al. e impact of scoliosis
among patients with giant paraesophageal hernia. J Gastrointest Surg.
2011;15:23–28.
5. Asling B, Jirholt J, Hammond P, et al. Collagen type III alpha I is a
gastro-oesophageal reux disease susceptibility gene and a male risk factor
for hiatus hernia. Gut. 2009;58:1063–1069.
6. Curci JA, Melman LM, ompson RW, Soper NJ, Matthews BD. Elastic
ber depletion in the supporting ligaments of the gastroesophageal
junction: a structural basis for the development of hiatal hernia. J Am
Coll Surg. 2008;207:191–196.
7. Melman L, Chisholm PR, Curci JA, et al. Dierential regulation of
MMP-2 in the gastrohepatic ligament of the gastroesophageal junction.
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8. El Sherif A, Yano F, Mittal S, Filipi CJ. Collagen metabolism and recurrent
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9. Gordon C, Kang JY, Neild PJ, Maxwell JD. e role of the hiatus
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10. Schieman C, Grondin SC. Paraesophageal hernia: clinical presentation, evaluation, and management controversies. orac Surg Clin. 2009;
19:473–484.
11. Wo JM, Branum GD, Hunter JG, Trus TN, Mauren SJ, Waring JP.
Clinical features of type III (mixed) paraesophageal hernia. Am J
Gastroenterol. 1996;91:914–916.
12. Davis SS, Jr. Current controversies in paraesophageal hernia repair. Surg
Clin North Am. 2008;88:959–978.
13. Terry ML, Vernon A, Hunter JG. Stapled-wedge collis gastroplasty for the
shortened esophagus. Am J Surg. 2004;188:195–199.
14. Oelschlager BK, Pellegrini CA, Hunter JJ, et al. Biologic prosthesis to prevent
recurrence after laparoscopic paraesophageal hernia repair: long-term follow-up from a multi-center, prospective, randomized trial. J Am Coll Surg.
Presented at the 2010 American College of Surgeons 96th Annual Clinical
Congress, Washington DC, October, 2010.
15. Marlais M, Fishman JR, Fell JM, Haddad MJ, Rawat DJ. UK incidence
of achalasia: an 11-year national epidemiological study. Arch Dis Child.
2011;96:192–194.
16. Sadowski DC, Ackah F, Jiang B, Svenson LW. Achalasia: incidence,
prevalence and survival. A population-based study. Neurogastroenterol
Motil. 2010;22:e256–e261.
17. Castagliuolo I, Brun P, Costantini M, et al. Esophageal achalasia: is
the herpes simplex virus really innocent? J Gastrointest Surg. 2004;
8:24–30.
18. Lau KW, McCaughey C, Coyle PV, Murray LJ, Johnston BT. Enhanced
reactivity of peripheral blood immune cells to HSV-1 in primary achalasia.
Scand J Gastroenterol. 2010;45:806–813.
19. Boeckxstaens GE, Annese V, des Varannes SB, et al. Pneumatic dilation
versus laparoscopic Heller’s myotomy for idiopathic achalasia. N Engl J
Med. 2011;364:1807–1816.
20. Rawlings A, Soper NJ, Oelschlager B, et al. Laparoscopic Dor versus
Toupet fundoplication following Heller myotomy for achalasia: results
of a multicenter, prospective randomized-controlled trial. Surg Endosc.
2012;26(1):18–26.
21. Kahrilas PJ, Howden CW, Hughes N. Response of regurgitation to proton
pump inhibitor therapy in clinical trials of gastroesophageal reux disease.
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22. Wang L, Liu X, Liu YL, et al. Correlation of pepsin-measured laryngopharyngeal reux disease with symptoms and signs. Otolaryngol Head Neck
Surg. 2010;143:765–771.
23. Mardani J, Lundell L, Engstrom C. Total or posterior partial fundoplication
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24. Morgenthal CB, Shane MD, Stival A, et al. e durability of laparoscopic
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693–700.
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CANCER OF THE ESOPHAGUS
Simon Law
17
HISTORICAL PERSPECTIVES
One of the earliest descriptions of esophageal cancer was
in the second century , when Galen described a eshy
obstructing growth in the esophagus, which was responsible for the inability to swallow and led to emaciation
and death. In early Chinese literature, a patient who had
esophageal cancer was described as “one su ers in autumn,
and does not live to see the coming summer.” Improvement in treatment strategies has resulted in better outcome. However, most patients are still diagnosed at an
advanced disease stage, with consequent poor prognosis.
In 1877, Czerny was the rst to successfully resect a cervical esophageal cancer and the patient lived for 15 months.
Torek in 1913 performed the rst successful transthoracic
resection.
cancer of the midesophagus. rough a left thoracotomy,
the esophagus was resected. e proximal cervical esophagus was brought out through an incision anterior to the
sternocleidomastoid muscle and tunneled subcutaneously
along the anterior chest wall, where a cutaneous esophagostomy was fashioned. e patient was fed via a rubber
tube connecting the esophagostomy with a gastrostomy.
e patient lived for 17 years.
cer with reconstruction using the stomach was performed
by Ohsawa, a Japanese surgeon in Kyoto, who reported the
technique in 18 patients in 1933.
esophageal resection using a two-phase approach via a right
thoracotomy and laparotomy.
described the procedure in 1947.
treatment for esophageal cancer, recent years have seen a
proliferation of treatment options especially with regards to
di erent combinations of chemotherapeutic agents, radiotherapy and surgery. ere has also been a divergence in the
epidemiological pattern between Western and Eastern countries, which has made a major impact on the management
of this disease.
1
A 67-year-old woman had a squamous cell
e rst successful resection of a thoracic esophageal can-
2
In 1946, Lewis described
3
Tanner independently also
4
Although surgical resection has remained the mainstay
EPIDEMIOLOGY
Esophageal cancer is the eighth most common cancer
worldwide and the sixth most common cause of death from
5
ere is marked geographic variation in the inci-
cancer.
dence of cancer of the esophagus and, to some extent, among
di erent ethnic groups within a common area. e disease
is especially common in countries of the so-called “Asian
esophageal cancer belt,” which stretches from eastern Turkey
and east of the Caspian Sea through northern Iran, northern Afghanistan, and southern areas of the former Soviet
Union, such as Turkmenistan, Uzbekistan, and Tajikistan, to
northern China and India. High incidences are also found,
in the Transkei province of South Africa and Kenya. In highincidence areas, the occurrence of esophageal cancer is 50- to
100-fold higher than that in the rest of the world. It is the
fourth most common cancer in China.
incidence rate of esophageal cancer in China is 27.4 per
100,000, compared to 10 in Japan, 7.9 in northern Europe
and 7.6 in western Europe, 5.8 in North America, and 5.5
in Australia/New Zealand.
Shanxi in central/northern China, and areas within, such as
Linxian and Cixian, have particularly high incidences.
crude age-adjusted mortality is up to 140 per 100,000 and is
the most common cause of cancer death.
most commonly presents in the sixth and seventh decades
of life. In most countries it is a male-predominant disease,
although in high-incidence areas, the male-to-female ratio
approaches unity.
e most striking change in epidemiological pattern for
esophageal cancer in the past three decades has been the
shift from squamous cell cancers to adenocarcinomas of the
lower esophagus and cardia in the Caucasian populations
in Western countries. In the United States, squamous cell
cancers predominate in African Americans, but the incidence of this cancer has seen a decline since the mid-1980s,
while adenocarcinoma has been rising in incidence rapidly
in the white population. e incidence of adenocarcinoma
has surpassed squamous cell cancers since 1990.
5
e provinces of Henan, Hebei,
6
e age- standardized
7,
8 e
8
Esophageal cancer
9
Similar
355
356 Part III Esophagus
changes have been observed in Europe and Australia. In
Asia, however, esophageal cancers remain predominantly
squamous cell in type and are mostly located in the mid-
10
esophagus.
Apart from squamous cell cancers and adenocarcinomas,
other tumor types less commonly encountered include muco-
11
epidermoid cancer,
12
basaloid squamous tumor, 13 sarcomatoid carcinoma,
cer,
lymphoma, melanoma,
15
tumors.
adenosquamous cancer, small cell can-
14
and various subtypes of stromal
ETIOLOGIC FACTORS
Various factors associated with the development of esophageal cancer are shown in ( Table 17-1 ). Smoking and drinking
as independent contributing factors are shown by prospective studies of patients who drink but do not smoke and,
conversely, of patients who smoke but do not drink.
Genetic predisposition may be important in the pathogenesis of esophageal squamous cell cancer. Case-controlled
studies have identi ed familial aggregation; suggesting that
17
the cancer may be heritable.
Mitochondrial studies have
proved historical population migrations from central/northern to south-eastern China, where another high-incidence
TABLE 17-1: ETIOLOGIC FACTORS
ASSOCIATED WITH PATHOGENESIS OF
ESOPHAGEAL CANCER
Factor
Smoking
Alcohol consumption
Hot beverages
N -nitroso compounds, eg,
pickled vegetables
Chewing betel nut
Maté drinking
De ciencies of green
vegetables, fruits, and
vitamins
Low socioeconomic class
Fungal toxin or virus
History of radiation to
mediastinum
Lye corrosive stricture
History of aerodigestive
malignancy
Plummer-Vinson syndrome
Achalasia
Obesity −
Gastroesophageal re ux −
Barrett’s esophagus −
Squamous
Cell Cancer Adenocarcinoma
+++ +
+++ −
+ −
+ −
+ −
+ −
+ −
+ −
+ −
+ +
+ −
+++ −
+ −
+ −
16
++
+++
++++
area is found, again suggesting that hereditary factors may
play a part.
viduals with chronic alcohol consumption.
18,
19 Genetic polymorphism is important in indi-
20
Approximately
36% of East Asians show a physiologic response to drinking that includes facial ushing, nausea, and tachycardia.
is facial ushing response is predominantly related to an
inherited de ciency in the enzyme aldehyde dehydrogenase 2
(ALDH2). Alcohol is metabolized to acetaldehyde by alcohol
dehydrogenase and the acetaldehyde is in turn metabolized
by ALDH2 to acetate. Two main variants for ALDH2 exist,
resulting from the replacement of glutamate with lysine at
position 487. Only individuals homozygous with the glutamate allele have normal catalytic activity. Homozygotes with
the lysine alleles have no detectable activity, while heterozygotes with Glu/Lys alleles have much reduced ALDH2 activity. e inability to fully metabolize acetaldehyde results in its
accumulation in the body leading to the facial ushing and
unpleasant side e ects. Lys/Lys homozygotes could not tolerate much alcohol because of the intensity of the side e ects,
and so paradoxically they do not have increased risk because
they simply would not consume signi cant amount of alcohol. Individuals who are glu/lys heterozygotes may become
habitual drinkers because they could become tolerant to the
side e ects of alcohol and yet they had suboptimal catalytic
activity and thus the acetaldehyde accumulates. ese are
the individuals most susceptible to the carcinogenic e ects
of alcohol consumption, which is related to acetaldehyde
causing DNA damage and other cancer-promoting e ects.
21
A simple questionnaire that elicits the history of a ushing
response was shown to be useful in identifying at-risk individuals. ey could be advised against drinking or to undergo
screening endoscopy. e risk of developing cancer may be
22,
reduced or earlier diagnosis possible.
23
For squamous cell cancer, in addition to drinking and
smoking, dietary and environmental factors are important,
especially in Asian countries. Nitrosamines and their precursors (nitrate, nitrite, and secondary amines), such as pickled
24
vegetables, are incriminated.
Nutritional depletion of certain
micronutrients, particularly vitamins A, C, E, niacin, ribo avin, molybdenum, manganese, zinc, magnesium, selenium,
as well as fresh fruits and vegetables, together with an inadequate protein intake, predisposes the esophageal epithelium
25
to neoplastic transformation.
Change in speci c dietary habits, such as replacing traditional methods of food preservation
and storage with refrigeration, together with consumption of
vitamin-rich food, may have produced a drop in incidence
rates in certain areas of China, especially in urban cities such
26
as Shanghai.
Other dietary risk factors include consumption
of hot beverages, opium smoking, chewing betel nuts, and
maté drinking in South American countries.
27
e human papillomaviruses
and certain fungi belonging
to the genera Fusarium , Alternaria, Geotrichum , Aspergillus ,
Cladosporium , and Penicillium are infective agents variably
found to be associated with esophageal cancer.
Patients with other aerodigestive malignancies have a particularly high risk of developing squamous cell carcinoma
(SCC) of the esophagus, presumably because of exposure
Chapter 17 Cancer of the Esophagus 357
to similar environmental carcinogens and “eld cancerization.” Using esophageal cancer as the index tumor, multiple
primary cancers were found in 9.5% of patients, of whom
28
70% were in the aerodigestive tract.
e overall incidence of
synchronous or metachronous esophageal cancer in patients
with primary head and neck cancer is estimated to be 3%.
29
Diseases that are known to predispose to esophageal cancer
are few. e risk from achalasia is estimated to be 7- to 33-fold,
but symptoms of achalasia are present for an average of 15–20
30
years before the emergence of cancer.
Other diseases include
lye corrosive strictures, Plummer-Vinson syndrome, tylosis,
and celiac disease.
e reasons accounting for the dramatic rise in incidence
of adenocarcinoma in Caucasian population is widely attributed to obesity, gastroesophageal reux disease, and Barrett’s
31–33
esophagus,
which are uncommon in Asian populations.34
Gastroesophageal reux disease aects up to 44% of the
general population in the United States, and approximately
35
5–8% will develop Barrett’s esophagus,
annual rate of neoplastic transformation of 0.5%.
with an estimated
36
Epide-
miological data suggest a protective role of Helicobacter pylori
against reux. e high prevalence of H. pylori infection in
Eastern populations may guard against reux and Barrett’s
esophagus, and may account for the dierences in cancer cell
37
However, this association remains controversial.
type.
A
DIAGNOSIS
Screening, Surveillance, and
Prevention for Early Cancer
SQUAMOUS CELL DYSPLASIA AND CANCER
Diagnosing esophageal cancer at its asymptomatic or early
stage is crucial in improving prognosis, although at present
this is only possible in the minority of patients. In high-incidence areas such as in China, abrasive cytology has been used
for population screening. Two principal types of samplers have
been used: an inatable balloon developed in China
an encapsulated sponge sampler developed in Japan.
early-stage cancers are diagnosed by this method, excellent
long-term results with 5-year survival rate approaching 90%
and 25-year survival rate of 50% can be achieved, comparable
to those of the normal population.
40
Primary endoscopic screening with chromoendoscopy
using Lugol’s iodine as a useful adjunct is carried out in highincidence areas in China (Fig. 17-1). It has been shown that
dysplastic lesions seen in the esophagus have a quantiable risk
41
of malignant transformation.
Long-term endoscopic screening studies are ongoing, integrating with early treatment and
chemoprevention programs.
42
Nutritional intervention trials were undertaken in Linxian
in China for the general population in the 1980s as a form of
chemoprevention. e trial was tested in 29,584 participants.
At the end of 5-year intervention, the group receiving selenium,
β-carotene and vitamin E was found to have a statistically
38
and
39
When
B
FIGURE 17-1 A. Endoscopy using Lugol’s iodine stain. e unstained
area is abnormal, showing an early squamous cell cancer of the esophagus.
B. Narrow band imaging of the same lesion.
358 Part III Esophagus
signi cant reduction in all causes of mortality and cancer death.
However, mortality reduction in combined esophageal/gastric
43
cardia cancer was 10%, not reaching statistical signi cance.
To
date, no conclusive evidence is available for chemopreventive
strategies for squamous cell esophageal cancer.
BARRETT’S ESOPHAGUS AND
ADENOCARCINOMA
For cancer due to Barrett’s esophagus, screening and surveillance for early cancers have been controversial. Gastroesophageal re ux is prevalent; approximately 20% of adults have
heartburn at least once per week, 5% of whom have Barrett’s
esophagus; thus a very substantial number of patients will
require screening. However, the absolute risk of adenocarcinoma is low even in subgroups of patients with severe re ux
symptoms. Moreover, 40% or more of patients with esophageal
adenocarcinoma have no prior re ux symptoms and therefore
would not be detected through screening programs targeted
32
to those with such re ux symptoms.
rett’s esophagus also die from unrelated causes,
Most patients with Bar-
44
and the pres-
ence of Barrett’s esophagus does not change life expectancy or
45,
overall survival.
46 ese arguments, together with the high
cost of endoscopy, mitigate against general population screening. Although retrospective studies have demonstrated survival bene ts in patients with Barrett’s esophagus undergoing
47,
surveillance,
selection, lead time, and length bias.
48 these studies may have been biased because of
49
ere is currently no
con rmed evidence proving that screening or surveillance will
lead to improved survival in patients with Barrett’s esophagus.
50
Screening for Barrett’s esophagus in the general population is
not recommended. e use in selective populations at higher
48
risk remains to be established.
Despite the lack of clear evidence, individuals who are
identi ed to have Barrett’s esophagus should enter surveillance
programs. Systemic four-quadrant, 2-cm biopsy protocol
48
using large biopsy forceps is recommended.
Dysplasia is so
far the only reliable indicator of risk development of invasive
cancer. e recommendation given by the American College of Gastroenterology with regards to endoscopy interval
and treatment is shown in Table 17-2 . Endoscopy is performed every 3 years for those with no dysplasia and yearly
for low-grade dysplasia. Diagnosis of high-grade dysplasia
implies the need for intervention (by surgery or endoscopic
means), or intensive surveillance at 3-month intervals. If the
latter is preferred, a four-quadrant, 1-cm protocol is required
for diagnosis of early invasive cancer.
Endoscopy and systemic biopsies remains the gold standard for diagnosis of Barrett’s esophagus, dysplasia, and early
cancer. Other modalities such as cytology with or without
uorescence in situ hybridization (FISH), auto uorescence
imaging, narrow band imaging, optical coherence tomography, and confocal laser endomicroscopy are investigational
techniques aimed at enhancing diagnostic capabilities.
Chemoprevention can potentially prevent Barrett’s esophagus from developing into invasive cancer. Proton pump
inhibitors (PPIs) and nonsteroidal anti-in ammatory drugs
(NSAIDs) have drawn the most attention in recent years. Currently there are no data that directly support the use of PPIs
to prevent cancer, although retrospective studies have shown
decrease in development of dysplasia in long-term users.
NSAIDs, a meta-analysis of pooled studies found a protective
53
of both histologic types.
However, a randomized controlled
trial showed that celecoxib, a COX-2 inhibitor, was not more
e ective than placebo in patients with Barrett’s esophagus and
dysplasia in changing the proportion of biopsies with dyspla-
54
An ongoing phase III randomized trial in the United
sia.
Kingdom (AspECT [Aspirin Esomeprazole Chemoprevention
Trial] trail) aims at assessing whether intervention with aspirin
results in decreased mortality or conversion rate from Barrett’s
metaplasia to adenocarcinoma or high-grade dysplasia.
Advanced Cancer
For symptomatic patients, the spectrum of symptoms varies
depending on the extent of disease. Elderly patients who
complain of dysphagia must be assumed to have esophageal
cancer until proven otherwise, especially in high-risk areas.
Patients with chronic re ux symptoms who develop dysphagia
must have the diagnosis of tumor entertained in addition to a
re ux stricture. In advanced cases the most common presenting symptom is dysphagia (80–95%), which is progressive in
51
52
For
55
TABLE 17-2: DYSPLASIA GRADE AND SURVEILLANCE INTERVAL
Dysplasia Documentation Follow-up
None Two EGDs with biopsy within 1 y Endoscopy every 3 y
Low grade •
•
High grade •
•
•
EGD, esophagogastroduodenoscopy.
Am J Gastroenterol . 2008;103:788–797.
1-y interval until no dysplasia × 2
Endoscopic resection
Continue 3-mo surveillance or intervention based
on results and patient
Chapter 17 Cancer of the Esophagus 359
TABLE 17-3: COMPARISONS OF PATIENTS WITH SCC AND ADENOCARCINOMAS OF THE
ESOPHAGUS ASIDE FROM ETIOLOGY: ASIA VERSUS WEST
Asia West
Cell type Squamous cell cancer Adenocarcinoma
Location Mid and lower esophagus Lower esophagus/cardia
Comorbid diseases •
•
Identi able premalignant lesions
Screening/surveillance
Surgical approaches Predominantly transthoracic, two- and three- eld
Prognosis Worse? Better?
SCC, squamous cell cancer.
Dysplasia
•
•
lymphadenectomy
oracoscopic ± laparoscopic surgery
Ischemic heart disease
Barrett’s esophagus and dysplasia
Endoscopic surveillance for Barrett’s esophagus and
dysplasia
Transthoracic/transhiatal, two- eld or minimal
lymphadenectomy
oracoscopic ± laparoscopic or laparoscopic only
severity. However, many patients delay seeking medical attention until severe dysphagia and weight loss have occurred.
symptom may be worse at night when the patient lies supine.
Fluid regurgitation can lead to bouts of coughing, aspiration,
and even chest infection. Odynophagia (retrosternal pain
associated with swallowing) is not uncommon. Hoarseness is
the result of recurrent laryngeal nerve compression, either by
the primary tumor or by metastatic lymph nodes.
e demographics of patients who su er from squamous
56
cell cancers and adenocarcinomas are di erent.
Patients
with adenocarcinomas tend to be of higher socioeconomic
class and have obesity-related chronic disease such as ischemic
heart disease ( Table 17-3 ). Examination of these patients
therefore rarely reveals a wasted individual. Patients with
squamous cell cancers are blue-collar workers, and general
examination may show evidence of weight loss and muscle
wasting. Chronic smoking and alcohol consumption leads to
a higher prevalence of chronic lung disease and liver cirrhosis.
e more proximal tumor location more easily predisposes
to pneumonia from aspiration or the development of a tracheoesophageal stula. Lymph nodes in the supraclavicular
regions should be sought in all patients.
TUMOR STAGING
Staging System
Accurate staging serves to provide information for stage-directed
therapies and is important for quality control for clinical trials.
e clinical staging system follows the American Joint
Committee on Cancer (AJCC) staging or the International
Union Against Cancer (UICC) TNM (tumor-node-metastasis) system, which are recently modi ed.
of TNM, tumor grade, level of tumors and nodal stations
areshown in Tables 17-4 to 17-7 and Figs. 17-2 and 17-3 .
57
e de nitions
TABLE 17-4: DEFINITIONS OF TNM FOR
ESOPHAGEAL CANCER
T: Primary tumor
Tx Tumor cannot be assessed
T0 No evidence of primary tumor
Tis High-grade dysplasia
T1 Tumor invades lamina propria, muscularis
mucosae, or submucosa
T1a Tumor invades lamina propria or
muscularis mucosae
T1b Tumor invades submucosa
T2 Tumor invades into muscularis propria
T3 Tumor invades adventitia
T4 Tumor invades the adjacent structures
pericardium, or diaphragm
T4b Unresectable tumor invading other
adjacent structures, such as aorta,
vertebral body, trachea, etc
N: Regional lymph nodes
NX
N0 No regional lymph node involvement
N1
N2
N3
M: Distant metastases
MX Distant metastases cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
TNM, tumor-node-metastasis.
a
a
1–2 nodes
3–6 nodes
≥7 nodes
360 Part III Esophagus
TABLE 17-5: DEFINITIONS OF GRADE FOR
ESOPHAGEAL CANCER
Histologic grade (G) a
GX Grade cannot be assessed—stage grouping as G1
G1 Well di erentiated
G2 Moderately di erentiated
G3 Poorly di erentiated
G4 Undi erentiated—stage grouping as G3 squamous
a Highest histologic grade on biopsy or resection specimen is used. If a tumor
is mixed histologic type, it shall be recorded as squamous cell cancer. If grade is
not available, it should be recorded as GX and stage grouped as a G1 cancer. G4,
undi erentiated cancers, should be recorded as such and staged grouped similar
to G3 squamous cell carcinoma.
is recently modi ed TNM system di ers from the previous versions mainly on (1) the regional nodes encompass
areas from the neck, through the mediastinum to the upper
abdomen, including the celiac nodes; previously used M1a
and M1b categories are deleted; (2) the separation of N1 to
N3 depends on the number of nodes involved; (3) squamous
cell cancers are stage-grouped di erently to adenocarcinoma;
and (4) location of tumor and grade of di erentiation are
also taken into consideration. Previously, it has been uncertain whether adenocarcinoma of the cardia should be staged
as gastric or esophageal cancer. In this new edition, tumors
whose epicenter is in the lower thoracic esophagus, gastroesophageal junction (GEJ), or within the proximal 5 cm of
TABLE 17-7: STAGE GROUPINGS FOR
ADENOCARCINOMA
Stage T N M G
0 Tis (HGD) 0 0 1
IA 1 0 0 1–2
IB 1
2
IIA 2 0 0 3
IIB 3
1–2
IIIA 1–2
3
4a
IIIB 3 2 0 Any
IIIC 4a
4b
Any
IV Any Any 1 Any
HGD, high-grade dysplasia.
0
0
0
1
2
1
0
1–2
Any
N3
0
0
0
0
0
0
0
0
0
0
3
1–2
Any
Any
Any
Any
Any
Any
Any
Any
the stomach (cardia) that extend into the GEJ or esophagus
are stage-grouped similar to adenocarcinoma of the esophagus and not that of the stomach. Cancers with their epicenter in the stomach greater than 5 cm distal to the GEJ, or
those within 5 cm of the GEJ but not extending into the
TABLE 17-6: STAGE GROUPINGS FOR
SQUAMOUS CELL CARCINOMA
Stage T N M G Location
0 In situ (HGD) 0 0 1 Any
IA 1 0 0 1 Any
IB 1
2–3
IIA 2–3
2–3
IIB 2–3
1–2
IIIA 1–2
3
4a
IIIB 3 2 0 Any Any
IIIC 4a
4b
Any
IV Any Any 1 Any Any
HGD, high-grade dysplasia.
0
0
0
0
0
1
2
1
0
1–2
Any
N3
0
2–3
0
1
0
1
0
2–3
0
2–3
0
Any
0
Any
0
Any
Any
0
Any
0
Any
0
Any
Any
Lower
Upper, middle
Lower
Upper, middle
Any
Any
Any
Any
Any
Any
Any
O
Ce
S
Ut
B
D
H
EGJ
FIGURE 17-2 Description of the di erent levels of esophageal
tumor. Ae, abdominal esophagus; B, tracheal bifurcation; Ce, cervical
esophagus; D, diaphragm; EGJ, esophagogastric junction; H, hiatus;
Lt, lower third; Mt=middle third; O, esophagus; S, sternal notch; Te,
thoracic esophagus; Ut, upper third.
D
Mt
Lt
Te
Ae
Chapter 17 Cancer of the Esophagus 361
A
FIGURE 17-3 A. Lymph node stations according to the American Joint Committee on Cancer (AJCC) classication. B. Lymph node stations
according to the Japan Esophageal Society.
GEJ or esophagus, are stage-grouped using the gastric cancer
B
METHODS OF STAGING
staging system.
Siewert’s classication aims at classifying tumors that
are located 5 cm proximal and distal to the GEJ into types
I to III (esophageal, cardiac, and subcardiac), depending
on the relative extent of involvement of either the esophagus or stomach (Fig. 17-4). e three types of cancers are
dierent in patient demographics, possible etiology, histo-
58
pathologic features, and prognosis.
is classication is
Apart from physical examination and simple chest radiograph,
specic methods in clinical staging include barium contrast studies, bronchoscopy, computed tomography (CT) scan, percutaneous ultrasound of cervical lymph nodes ± ne-needle aspiration
18
(FNA) cytology, endoscopic ultrasound (EUS) ± FNA, 2-[
F]
uoro-2-deoxy--glocose (FDG) positron emission tomography
(PET) scan, and laparoscopy and/or thoracoscopy.
useful clinically but is not considered in the new staging
system.
e Japan Esophageal Society further classies T1a/T1b
Barium Contrast Studies
tumors into ner categories; as there are important therapeutic implications (Table 17-8). is is discussed in later
sections.
Typical features on a contrast barium study include mucosal irregularity and shouldering, narrowing of the lumen and