Prevention and Management
of Early Esophageal Cancer
W. Michael Korn, MD
University of California, 2340 Sutter Street, San Francisco, CA 94115, USA.
Current Treatment Options in Oncology 2004, 5:405–416
Current Science Inc. ISSN 1527-2729
Copyright © 2004 by Current Science Inc.
During 2004, an estimated 14,250 new cases of esoph-
ageal cancer will be diagnosed in the United States. The
disease represents a significant medical challenge
because of its dismal prognosis, as indicated by the esti-
mated 13,300 disease-specific deaths in 2004 . Partic-
ularly worrisome is a dramatic increase in incidence of
esophageal adenocarcinomas in white males since the
mid-1970s . Moreover, the disease is the sixth leading
cause of death from cancer worldwide , and there are
regions with extremely high incidence, such as Nan’ao
County in southern China, where a mortality rate of 110/
100,000 has been observed . Thus, improvements in
prevention, detection, and treatment of esophageal can-
cer are urgently needed.
Most esophageal cancers are squamous cell car-
cinomas (SSCs) or adenocarcinomas, and other
malignant tumors (spindle cell carcinomas, mucoepi-
dermoid carcinoma, small cell carcinoma, leiomyosar-
coma, malignant melanoma, rhabdomyosarcoma, and
granular cell tumors) are rare. squamous cell carcino-
mas (SSCs) occur mostly in the midesophagus,
whereas adenocarcinomas are preferentially found in
the lower third. Tumors frequently demonstrate intrae-
sophageal spread and may span more than 10 cm.
Metastasis into regional lymph nodes occurs very early
because of an extensive lymphatic drainage system and
involves cervical, mediastinal, and perigastric nodes.
Unfortunately, tumors are rarely (18%) detected at
early stages. Distant metastases are present in 25% to
30% of cases at the time of diagnosis and involve
mainly liver, lungs, and bone. For the purpose of this
article, early-stage esophageal cancer is defined as a
malignant tumor that is limited to the epithelium
(including high-grade intraepithelial neoplasia) or
lamina propria mucosa (stage T1a), or submucosa
(stage T1b) . The insidious character of esophageal
Early esophageal cancer is defined by its limitation to the esophageal mucosa and
submucosa. It has become a curable malignant disease, in sharp contrast to the dis-
mal prognosis of esophageal cancer at advanced stages, which still represents the
majority of patients. Understanding the risk factors, establishing surveillance pro-
grams for patients at risk, and developing preventative interventions such as dietary
and lifestyle changes or pharmacologic interventions hold the potential of reducing
the incidence of the disease and of shifting the stage distribution toward early cancer.
Endoscopic ultrasound examination is pivotal for distinguishing early from advanced
stages of the disease because it allows for accurate assessment of tumor infiltration
and regional lymph node involvement. The therapeutic mainstay for early esophageal
cancer remains surgery. New, less invasive surgical techniques are being tested that
are associated with less morbidity and mortality than standard radical esophagecto-
mies. For patients who are not candidates for surgery, definitive chemoradiation is a
viable alternative. New endoscopic ablation techniques, such as endoscopic mucosa
resection and photodynamic therapy, are potential alternatives to surgery in patients
with cancers limited to the mucosa. For patients with adenocarcinoma of the gastroe-
sophageal junction with submucosal involvement, adjuvant chemoradiation should be
considered because of its potential to increase survival.
cancer is underscored by the observation that the prev-
alence of lymph node metastases in stage T1b cancers
is as high as 20% .
The spectra of environmental and endogenous risk
factors for the development of squamous cancer and ade-
nocarcinomas show significant differences. squamous
cell carcinoma (SSC) is unambiguously associated with
cigarette smoking and alcohol consumption. Synergistic
tumor promoting effects of both agents have been dem-
onstrated and are associated with an increase in cancer
risk of up to 100-fold [7,8]. Consumption of exception-
ally hot beverages and a lack of fruits and vegetables have
also been reported to be important factors . Further-
more, infection with the human papilloma virus has
been implicated in endemic occurrences of SSC .
Other predisposing conditions include tylosis, a rare
autosomal-dominant inherited disease that is also
known as nonepidermolytic palmo-plantar hyperkerato-
sis and is associated with mutations of the TOC locus on
chromosome 17q25 . Patients with achalasia, an
esophageal motility disorder that is characterized by
abnormally high pressures of the lower esophageal
sphincter, have been demonstrated to have an up to 140-
fold increased risk for the development of SSC of the
esophagus . A history of head and neck cancer and
other conditions, including Plummer-Vinson syndrome
(iron-deficiency anemia, glossitis, chelosis, splenome-
galy, and esophageal webs) and previous caustic injury
has also been associated with SSC of the esophagus.
The dominant risk factor for the development of
adenocarcinoma of the esophagus is Barrett’s esopha-
gus, which is characterized by a specialized columnar
epithelium replacing the normal squamous epithelium
in the distal esophagus. Barrett’s esophagus is a result of
chronic mucosal injury by gastroesophageal reflux and
is associated with progression into adenocarcinoma of
the esophagus at an estimated rate of 0.5% per year
. Patients with long-standing and severe symptoms
of gastroesophageal reflux disease (GERD) are at a 40-
fold increased risk for the development of esophageal
adenocarcinoma [13•]. In patients with GERD, the
increase in risk of developing esophageal cancer was
found to be independent of the presence of Barrett’s
esophagus [13•]. Not surprisingly, obesity, a condition
known to promote gastroesophageal reflux, was found
to be an independent risk factor for adenocarcinoma
. As for squamous cancer, smoking was found to
contribute to the development of esophageal adenocar-
cinoma, although this association appears to be weaker
than for SSC . Furthermore, a diet deficient of fruit,
vegetables, and fiber and high in fat content, increases
the risk of esophageal cancer [14,16,17]. Therefore,
strategies for identifying patients at increased risk may
allow for preventive interventions that are being clini-
Early esophageal cancer is diagnosed on endoscopy
when biopsies are obtained from small mucosal irregu-
larities, nodules, or ulcerations. In patients with Bar-
rett’s esophagus, malignant lesions can be detected by
surveillance endoscopies that include systematic sam-
pling from all four quadrants of the esophageal circum-
ference every 2 cm throughout the entire area of
Barrett’s mucosa. The histologic diagnosis of high-grade
dysplasia or mucosal cancer is sometimes difficult and
should be confirmed by an expert pathologist [18•]. In
the Western world, the value of surveillance programs in
patients with Barrett’s esophagus has been questioned
because most esophageal adenocarcinomas are not
associated with Barrett’s esophagus . However, it
appears that the tumors that are detected during surveil-
lance are of lower stage and associated with improved
survival . Surveillance programs in Western coun-
tries have been credited with improving the rate of early
cancers to 40% of all resected esophageal adenocarcino-
mas in some centers . SSCs are the target of inten-
sive screening efforts in Japan, which has led to frequent
detection of squamous cancers at early stage in that
Although computerized tomographic and positron
emission tomographic scans are crucial for ruling out
tumor spread to distant sites, a significant improvement
of the accuracy of staging of early esophageal cancer
resulted from the introduction of endoscopic ultra-
sound (EUS) techniques. EUS has been demonstrated
to be superior over computerized tomography, mag-
netic resonance imaging, or positron emission tomogra-
phy scanning in assessing local-regional disease, with
false-positive and false-negative detection rates of 5%
and 7%, respectively [22,23]. Because of the strikingly
higher rate of lymph node metastases in T1b tumors, it
is essential to distinguish these from tumors restricted
to the mucosa. Therefore, it is important to note that
conventional echoendoscopes using frequencies of 7.5
or 12 MHz are limited in their ability to make this dis-
tinction. High-resolution (20 MHz) ultrasound probes
provide an improved resolution, which results in an
overall accurate T staging in 80% of early esophageal
cancers [24,25]. However, submucosal infiltration is
still being missed in up to 40% of the cases, particularly
in tumors located at the gastroesophageal junction .
Prevention and Management of Early Esophageal Cancer
39.Zhang F, Altorki NK, Wu YC, et al.: Duodenal reflux
induces cyclooxygenase-2 in the esophageal mucosa
of rats: evidence for involvement of bile acids. Gastro-
enterology 2001, 121:1391–1399.
Sampliner RE: Practice guidelines on the diagnosis,
surveillance, and therapy of Barrett's esophagus. Am J
Gastroenterol 1998, 93:1028–1032.
Canto MI, Setrakian S, Willis J, et al.: Methylene blue-
directed biopsies improve detection of intestinal
metaplasia and dysplasia in Barrett's esophagus. Gas-
trointest Endosc 2000, 51:560–568.
Corley DA, Kerlikowske K, Verma R, et al.: Protective
association of aspirin/NSAIDs and esophageal cancer:
a systematic review and meta-analysis. Gastroenterology
Morris CD, Armstrong GR, Bigley G, et al.: Cyclooxygen-
ase-2 expression in the Barrett's metaplasia-dysplasia-
adenocarcinoma sequence. Am J Gastroenterol 2001,
Hur C, Nishioka NS, Gazelle GS: Cost-effectiveness of
aspirin chemoprevention for Barrett's esophagus. J
Natl Cancer Inst 2004, 96:316–325.
Lerut T, Coosemans W, Van Raemdonck D, et al.: Surgical
treatment of Barrett's carcinoma; correlations between
morphologic findings and prognosis. J Thorac Cardiovasc
Surg 1994, 107:1059–1065; discussion 1065–1066.
Holscher AH, Bollschweiler E, Schneider PM, et al.: Early
adenocarcinoma in Barrett's oesophagus. Br J Surg
Ando N, Ozawa S, Kitagawa Y, et al.: Improvement in
the results of surgical treatment of advanced squa-
mous esophageal carcinoma during 15 consecutive
years. Ann Surg 2000, 232:225–232.
Fujita H, Sueyoshi S, Yamana H, et al.: Optimum treat-
ment strategy for superficial esophageal cancer: endo-
scopic mucosal resection versus radical
esophagectomy. World J Surg 2001, 25:424–431.
Bonavina L, Via A, Incarbone R, et al.: Results of surgi-
cal therapy in patients with Barrett's adenocarcinoma.
World J Surg 2003, 27:1062–1066.
Stein HJ, Feith M, Rahden BA, et al.: Approach to early
Barrett's cancer. World J Surg 2003, 27:1040–1046.
Lerut T, Coosemans W, Decker G, et al.: Cancer of the
esophagus and gastro-esophageal junction: poten-
tially curative therapies. Surg Oncol 2001, 10:113–122.
Law S, Kwong DL, Kwok KF, et al.: Improvement in
treatment results and long-term survival of patients
with esophageal cancer: impact of chemoradiation
and change in treatment strategy. Ann Surg 2003,
238:339–347; discussion 347-338.
53.••Hulscher JB, van Sandick JW, de Boer AG, et al.:
Extended transthoracic resection compared with lim-
ited transhiatal resection for adenocarcinoma of the
esophagus. N Engl J Med 2002, 347:1662–1669.
This is an extensive study highlighting differences in out-
comes and treatment-associated mortality as well as mortality
for the two dominating surgical approaches to adenocarci-
noma of the esophagus.
54.Patti MG, Corvera CU, Glasgow RE, et al.: A hospital's
annual rate of esophagectomy influences the opera-
tive mortality rate. J Gastrointest Surg 1998, 2:186–192.
Swisher SG, Deford L, Merriman KW, et al.: Effect of
operative volume on morbidity, mortality, and hospi-
tal use after esophagectomy for cancer. J Thorac Cardio-
vasc Surg 2000, 119:1126–1132.
Nishihira T, Hirayama K, Mori S: A prospective ran-
domized trial of extended cervical and superior medi-
astinal lymphadenectomy for carcinoma of the
thoracic esophagus. Am J Surg 1998, 175:47–51.
Altorki N, Kent M, Ferrara C, et al.: Three-field lymph
node dissection for squamous cell and adenocarci-
noma of the esophagus. Ann Surg 2002, 236:177–183.
Orringer MB, Marshall B, Stirling MC: Transhiatal
esophagectomy for benign and malignant disease. J
Thorac Cardiovasc Surg 1993, 105:265–276; discussion
Swanstrom LL, Hansen P: Laparoscopic total esoph-
agectomy. Arch Surg 1997, 132:943–947; discussion
Luketich JD, Schauer PR, Christie NA, et al.: Minimally
invasive esophagectomy. Ann Thorac Surg 2000,
Nemoto K, Matsumoto Y, Yamakawa M, et al.: Treat-
ment of superficial esophageal cancer by external
radiation therapy alone: results of a multi-institu-
tional experience. Int J Radiat Oncol Biol Phys 2000,
Sykes AJ, Burt PA, Slevin NJ, et al.: Radical radiotherapy
for carcinoma of the oesophagus: an effective alterna-
tive to surgery. Radiother Oncol 1998, 48:15–21.
63.••Herskovic A, Martz K, al-Sarraf M, et al.: Combined che-
motherapy and radiotherapy compared with radio-
therapy alone in patients with cancer of the
esophagus. N Engl J Med 1992, 326:1593–1598.
This is a landmark study that demonstrated the superiority of
combined modality treatment over radiotherapy alone in
patients with esophageal cancer.
64.Murakami M, Kuroda Y, Nakajima T, et al.: Comparison
between chemoradiation protocol intended for organ
preservation and conventional surgery for clinical T1-
T2 esophageal carcinoma. Int J Radiat Oncol Biol Phys
65. Smith TJ, Ryan LM, Douglass HO Jr, et al.: Combined
chemoradiotherapy vs. radiotherapy alone for early
stage squamous cell carcinoma of the esophagus: a
study of the Eastern Cooperative Oncology Group. Int
J Radiat Oncol Biol Phys 1998, 42:269–276.
66.Muro K, Hamaguchi T, Yamada Y, et al.: Definitive
chemoradiotherapy may be standard treatment options
in clinical stage I esophageal cancer. In ASCO Gas-
trointestinal Cancers Symposium; San Francisco: 2004:27.
67.Wong R, Malthaner R: Combined chemotherapy and
radiotherapy (without surgery) compared with radio-
therapy alone in localized carcinoma of the esophagus
(Cochrane Review) [abstract]. The Cochrane Library, 2001.
68.• Minsky B, Pajak T, Ginsberg R, et al.: INT 0123 (Radia-
tion Therapy Oncology Group 94-05) phase III trial of
combined-modality therapy for esophageal cancer:
high-dose versus standard-dose radiation therapy. J
Clin Oncol 2002, 20:1151–1153.
This paper revealed the limitations of dose escalation as a
means of improving multimodality approaches to esophageal
cancer by demonstrating an increased mortality of patients
treated with high-dose radiation therapy.
69.Waxman I, Saitoh Y, Raju GS, et al.: High-frequency
probe EUS-assisted endoscopic mucosal resection: a
therapeutic strategy for submucosal tumors of the GI
tract. Gastrointest Endosc 2002, 55:44–49.
70. Takeshita K, Tani M, Inoue H, et al.: Endoscopic treat-
ment of early oesophageal or gastric cancer. Gut 1997,
71. Schlemper RJ, Kato Y, Stolte M: Diagnostic criteria for
gastrointestinal carcinomas in Japan and western
countries: proposal for a new classification system of
gastrointestinal epithelial neoplasia. J Gastroenterol
Hepatol 2000, 15(Suppl):G49–G57.
72.• May A, Gossner L, Pech O, et al.: Local endoscopic ther-
apy for intraepithelial high-grade neoplasia and early
adenocarcinoma in Barrett's oesophagus: acute-phase
and intermediate results of a new treatment approach.
Eur J Gastroenterol Hepatol 2002, 14:1085–1091.
This paper describes the experiences with endoscopic ablative
treatments at a high-volume European center, including data
on long-term follow-up.
73.Nijhawan PK, Wang KK: Endoscopic mucosal resection
for lesions with endoscopic features suggestive of
malignancy and high-grade dysplasia within Barrett's
esophagus. Gastrointest Endosc 2000, 52:328–332.
74.Overholt BF, Panjehpour M, Halberg DL: Photodynamic
therapy for Barrett's esophagus with dysplasia and/or
early stage carcinoma: long-term results. Gastrointest
Endosc 2003, 58:183–188.
75. Wolfsen HC, Woodward TA, Raimondo M: Photody-
namic therapy for dysplastic Barrett esophagus and
early esophageal adenocarcinoma. Mayo Clin Proc
76.Pacifico RJ, Wang KK, Wongkeesong LM, et al.: Com-
bined endoscopic mucosal resection and photody-
namic therapy versus esophagectomy for management
of early adenocarcinoma in Barrett's esophagus. Clin
Gastroenterol Hepatol 2003, 1:252–257.
Weston AP, Sharma P: Neodymium:yttrium-aluminum
garnet contact laser ablation of Barrett's high grade
dysplasia and early adenocarcinoma. Am J Gastroenterol
Sampliner RE: Prevention of adenocarcinoma by
reversing Barrett's esophagus with mucosal ablation.
World J Surg 2003, 27:1026–1029.
Kelsen DP, Ginsberg R, Pajak TF, et al.: Chemotherapy
followed by surgery compared with surgery alone for
localized esophageal cancer. N Engl J Med 1998,
Urschel JD, Vasan H, Blewett CJ: A meta-analysis of ran-
domized controlled trials that compared neoadjuvant
chemotherapy and surgery to surgery alone for resect-
able esophageal cancer. Am J Surg 2002, 183:274–279.
Arnott SJ, Duncan W, Gignoux M, et al.: Preoperative
radiotherapy for esophageal carcinoma (Cochrane
Review) [abstract]. The Cochrane Library,
Zieren HU, Muller JM, Jacobi CA, et al.: Adjuvant post-
operative radiation therapy after curative resection of
squamous cell carcinoma of the thoracic esophagus: a
prospective randomized study. World J Surg 1995,
Fok M, Sham JS, Choy D, et al.: Postoperative radio-
therapy for carcinoma of the esophagus: a prospec-
tive, randomized controlled study. Surgery 1993,
Macdonald JS, Smalley SR, Benedetti J, et al.: Chemora-
diotherapy after surgery compared with surgery alone
for adenocarcinoma of the stomach or gastroesoph-
ageal junction. N Engl J Med 2001, 345:725–730.
Macdonald JS, Smalley S, Benedetti J, et al.: Postopera-
tive combined radiation and chemotherapy improves
disease-free survival (DFS) and overall survival (OS)
in resected adenocarcinoma of the stomach and gas-
troesophageal junction: update of the results of Inter-
group Study INT-0116 (SWOG 9008). Gastrointest
Cancers Symp 2004, 6.