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Esophageal Cancer

  • Author: Keith M Baldwin, DO; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
Updated: Sep 18, 2015

Practice Essentials

Esophageal cancer is a disease in epidemiologic transition. Until the 1970s, the most common type of esophageal cancer in the United States was squamous cell carcinoma, which has smoking and alcohol consumption as risk factors; since then, there has been a progressive increase in the incidence of esophageal adenocarcinoma, for which the most common predisposing factor is gastroesophageal reflux disease (GERD). See the image below.

Cascade of events that lead from gastroesophageal Cascade of events that lead from gastroesophageal reflux disease to adenocarcinoma.

Signs and symptoms

Presenting signs and symptoms of esophageal cancer include the following:

  • Dysphagia (most common); initially for solids, eventually progressing to include liquids
  • Weight loss (second most common)
  • Bleeding
  • Epigastric or retrosternal pain
  • Bone pain with metastatic disease
  • Hoarseness
  • Persistent cough

Physical findings include the following:

  • Typically, normal examination results unless the cancer has metastasized
  • Hepatomegaly (from hepatic metastases)
  • Lymphadenopathy in the laterocervical or supraclavicular areas (reflecting metastasis)

See Clinical Presentation for more detail.


Laboratory studies focus principally on patient factors that may affect treatment (eg, nutritional status).

Imaging studies used for diagnosis and staging include the following:

  • Esophagogastroduodenoscopy (allows direct visualization and biopsies of the tumor)
  • Endoscopic ultrasonography (EUS; most sensitive test for T and N staging)
  • Computed tomography of the abdomen and chest (for assessing lung and liver metastasis and invasion of adjacent structures)
  • Positron emission tomography (PET) scanning (for staging)
  • Bronchoscopy (to help exclude invasion of the trachea or bronchi)
  • Laparoscopy and thoracoscopy (for staging regional nodes)
  • Barium swallow (very sensitive for detecting strictures and intraluminal masses, but now rarely used)

Current TNM classification is as follows (staging is detailed in Table 1, below):

  • Tis - Carcinoma in situ/high-grade dysplasia
  • T1 - Lamina propria or submucosa
  • T1a - Lamina propria or muscularis mucosae
  • T1b - Submucosa
  • T2 - Muscularis propria
  • T3 - Adventitia
  • T4 - Adjacent structures
  • T4a - Pleura, pericardium, diaphragm, or adjacent peritoneum
  • T4b - Other adjacent structures (eg, aorta, vertebral body, trachea)
  • N0 - No regional lymph node metastasis
  • N1 - 1-2 regional lymph nodes (N1 is site dependent)
  • N2 - 3-6 regional lymph nodes
  • N3 - More than 6 regional lymph nodes
  • M0 - No distant metastasis
  • M1 - Distant metastasis (M1a and M1b are site dependent)

Table 1. Staging Classification. (Open Table in a new window)

Stage IAT1N0M0
Stage IBT2N0M0
Stage IIAT3N0M0
Stage IIBT1,T2N1M0
Stage IIIAT4aN0M0
Stage IIIBT3N2M0
Stage IIICT4aN1,N2M0
 T4bAny NM0
 Any TN3M0
Stage IVAny TAny NM1

See Workup for more detail.


Treatment of esophageal cancer varies by disease stage, as follows:

  • Stage I – Consideration for endoscopic therapy (eg, mucosal resection or submucosal dissection), particularly for Tis and T1aN0 by EUS; consideration for initial surgery for T1b and any N
  • Stages II-III – Consideration for chemoradiation followed by surgery (trimodality therapy)
  • Stage IV – Chemotherapy or symptomatic and supportive care

Indications for surgical treatment of esophageal cancer include the following:

  • Diagnosis of esophageal cancer in a patient who is a candidate for surgery
  • High-grade dysplasia in a patient with Barrett esophagus that cannot be adequately treated endoscopically[1, 2]

Contraindications for surgical treatment include the following:

  • Metastasis to N2 (celiac, cervical, supraclavicular) nodes or solid organs (eg, liver, lungs)
  • Invasion of adjacent structures (eg, recurrent laryngeal nerve, tracheobronchial tree, aorta, pericardium)
  • Severe associated comorbid conditions (eg, cardiovascular disease, respiratory disease)
  • Impaired cardiac or respiratory function

Surgical options include the following:

  • Transhiatal esophagectomy (THE)
  • Transthoracic esophagectomy (TTE)
  • Minimally invasive esophagectomy
  • Endoscopic mucosal resection (EMR)

Neoadjuvant therapy for esophageal cancer is as follows:

  • Combination of radiotherapy and chemotherapy
  • Usually administered over a 45-day period, with esophageal resection after approximately 4 weeks
  • Most chemotherapy agents for esophageal cancer are used off-label

Palliative care options for patients who are not candidates for surgery are as follows:

  • Chemotherapy
  • Radiotherapy
  • Laser therapy
  • Stents

See Treatment and Medication for more detail.



Esophageal cancer is a devastating disease. Although some patients can be cured, the treatment for esophageal cancer is protracted, diminishes quality of life, and is lethal in a significant number of cases.

The principal histologic types of esophageal cancer are squamous cell carcinoma and adenocarcinoma. As squamous cells line the entire esophagus, squamous cell carcinoma can occur in any part of the esophagus; it often arises, however, in the upper half of the esophagus. Adenocarcinoma typically develops in specialized intestinal metaplasia (Barrett metaplasia) that develops as a result of gastroesophageal reflux disease (GERD); thus, adenocarcinoma typically arises in the lower half of the distal esophagus. (See Pathophysiology and Etiology.)


The most common presenting symptom of esophageal cancer is dysphagia (see Presentation). Esophagogastroduodenoscopy allows direct visualization and biopsies of the tumor, while endoscopic ultrasonography is the most sensitive test for determining the depth of penetration of the tumor and the presence of enlarged periesophageal lymph nodes. In patients who appear to have localized esophageal cancer, positron emission tomography (PET) scanning may be useful as part of the baseline staging. Other imaging studies may be valuable in selected patients. (See Workup.)


Surgery has traditionally been the treatment for esophageal carcinoma. The first successful resection was performed in 1913 by Torek.[3] In the 1930s, Ohsawa in Japan and Marshall in the United States were the first to perform successful single-stage transthoracic esophagectomies with continent reconstruction.[4, 5] Nonoperative therapy is usually reserved for patients who are not candidates for surgery because of clinical conditions or advanced disease. (See Treatment.)

The ideal treatment for localized esophageal cancer is sometimes debated across practice cultures and subspecialties. Defendants of surgical treatment argue that resection is the only treatment modality to offer curative intent; defendants of the nonsurgical approach claim that esophagectomy has a prohibitive index of mortality and that esophageal cancer is an incurable disease.


Esophageal lesions other than cancer can cause dysphagia. These include peptic strictures from gastroesophageal reflux and benign esophageal tumors (principally esophageal leiomyoma). Imaging studies help to differentiate these lesions from esophageal cancer. Other differentials include the following

Patient education

For patient education information, see the Heartburn and GERD Center and Esophageal Cancer (Cancer of the Esophagus).


The esophagus is a muscular tube that extends from the level of the 7th cervical vertebra to the 11th thoracic vertebra. The esophagus can be divided into the following anatomic parts:

  • Cervical esophagus
  • Thoracic esophagus
  • Abdominal esophagus

The blood supply of the cervical esophagus is derived from the inferior thyroid artery, while the blood supply for the thoracic esophagus comes from the bronchial arteries and the aorta. The abdominal esophagus is supplied by branches of the left gastric artery and inferior phrenic artery.

Venous drainage of the cervical esophagus is through the inferior thyroid vein, while the thoracic esophagus drains via the azygous vein, the hemiazygous vein, and the bronchial veins. The abdominal esophagus drains through the coronary vein.

The esophagus is characterized by a rich network of lymphatic channels in the submucosa that can facilitate the longitudinal spread of neoplastic cells along the esophageal wall. Lymphatic drainage is to cervical nodes, tracheobronchial and mediastinal nodes, and gastric and celiac nodes.



The progression of Barrett metaplasia to adenocarcinoma is associated with several changes in gene structure, gene expression, and protein structure.[6, 7, 8] The oncosuppressor gene TP53 and various oncogenes, particularly erb -b2, have been studied as potential markers.

Casson and colleagues identified mutations in the TP53 gene in patients with Barrett epithelium associated with adenocarcinoma.[9] In addition, alterations in p16 genes and cell cycle abnormalities or aneuploidy appear to be some of the most important and well-characterized molecular changes.



The etiology of esophageal carcinoma is thought to be related to exposure of the esophageal mucosa to noxious or toxic stimuli, resulting in a sequence of dysplasia to carcinoma in situ to carcinoma. In Western cultures, retrospective evidence has implicated cigarette smoking and chronic alcohol exposure as the most common etiologic factors for squamous cell carcinoma. High body mass index, GERD, and resultant Barrett esophagus are often the associated factors for esophageal adenocarcinoma.[10]

Nutritional deficiencies have been recognized as contributing factors. In high-risk regions such as parts of China and Iran, deficiencies in vitamins (eg, riboflavin) or micronutrients may play a role in causation.

A variety of other factors may promote esophageal cancer. These include the following:

  • Caustic injuries
  • Certain foodstuffs (eg, betel nut)
  • Drinking scalding-hot liquids
  • Environmental contributors (eg, nitrosamines in soil)
  • Certain fungi, molds, or yeasts
  • Acquired conditions (eg, achalasia)

A genome-wide association study by Wu et al identified seven susceptibility loci on chromosomes 5q11, 6p21, 10q23, 12q24, and 21q22, suggesting the involvement of multiple genetic loci and gene-environment interaction in the development of esophageal cancer.[11] Individuals with the genetic disorder tylosis palmaris et plantaris are at very high risk for esophageal cancer. Plummer-Vinson syndrome also increases its risk.

Bisphosphonate use can result in esophagitis and has been suggested as a risk factor for esophageal carcinoma. However, a large study found no significant difference in the frequency of esophageal or gastric cancers between the bisphosphonate cohort and the control group.[12]

Smoking and alcohol use

The Netherlands Cohort Study, a prospective study in 120,852 participants, demonstrated the combined effects of smoking and alcohol consumption on risk of squamous cell carcinoma of the esophagus.[13] Among participants who drank 30 g or more of ethanol daily, the multivariable adjusted incidence rate ratio (RR) for esophageal squamous cell carcinoma was 4.61 compared with abstainers. The RR for current smokers who consumed more than 15 g/day of ethanol was 8.05 when compared with nonsmokers who consumed less than 5 g/day of ethanol.

No associations were found between alcohol consumption and esophageal adenocarcinoma.

In contrast, the risk of squamous cell carcinoma and adenocarcinoma of the esophagus was increased among current smokers.[13]

A study by Steevens et al found that among current smokers, increased consumption of specific groups of vegetables and fruits were inversely associated with esophageal squamous cell carcinoma and esophageal adenocarcinoma risk.[14] Total vegetable consumption nonsignificantly reduced the risk for both esophageal cancer types. Consumption of raw vegetables and of citrus fruits was inversely associated with risk for esophageal adenocarcinoma.


Human papillomavirus (HPV) infection has been recognized as a contributing factor to esophageal cancer. However, Sitas et al reported limited serologic evidence of an association between esophageal squamous cell carcinoma and HPV in a study of more than 4000 subjects. The study could not exclude the possibility that certain HPV types may be involved in a small subset of cancers, although HPV does not appear to be an important risk factor.[15]

Helicobacter pylori infection, which can cause stomach cancer, has not been associated with esophageal cancer.

Adenocarcinoma and GERD

GERD is the most common predisposing factor for adenocarcinoma of the esophagus. Adenocarcinoma may represent the last event of a sequence that starts with irritation caused by the reflux of acid and bile and progresses to specialized intestinal (Barrett) metaplasia, low-grade dysplasia, high-grade dysplasia, and finally adenocarcinoma. Approximately 10-15% of patients who undergo endoscopy for evaluation of GERD symptoms are found to have Barrett epithelium. (See the chart below.)

Cascade of events that lead from gastroesophageal Cascade of events that lead from gastroesophageal reflux disease to adenocarcinoma.

In 1952, Morson and Belcher published the first description of a patient with adenocarcinoma of the esophagus arising in a columnar epithelium with goblet cells.[16] In 1975, Naef et al emphasized the malignant potential of Barrett esophagus.[17] The risk of adenocarcinoma among patients with Barrett metaplasia has been estimated to be 30-60 times that of the general population.

A nationwide population-based case-control study performed in Sweden found an odds ratio of 7.7 for adenocarcinoma among persons with recurrent symptoms of reflux, as compared with persons without such symptoms, and an odds ratio of 43.5 among patients with long-standing and severe symptoms of reflux.[10]

Although the annual risk of developing esophageal adenocarcinoma in people with GERD has been reported at 0.5%, some studies have found lower risk. Data from the Northern Ireland Barrett Esophagus Register, which is one of the largest population-based registries in the world, found that the malignant progression among patients with Barrett esophagus was 0.22% per year. This suggests that current surveillance approaches may not be cost effective.[18]

A study by Hvid-Jensen et al examined a large Danish registry (11,028 patients over a median of 5.2 y) and found the incidence of esophageal adenocarcinoma to be 1.2 cases per 1000 person-years (or 0.12% annual risk). Low-grade dysplasia detected on index endoscopy was associated with an incidence rate of 5.1 cases per 1000 person-years, compared with 1 per 1000 person-years among those without dysplasia.[19]



United States statistics

Esophageal cancer is the seventh most common cause of cancer death in males.[20] The 5-year survival rate from 2001 to 2007 was 19%.[21]

The American Cancer Society estimates that 17,990 new cases of esophageal cancer (14,440 in men and 3,550 in women) will occur in the United States in 2013; 15,210 persons (12,220 men and 2,990 women) are expected to die of the disease.

The incidence rate of adenocarcinoma of the esophagus in the United States showed an average annual increase of 1.7% in men and 1.9% in women from 1999 to 2008.[21] The incidence of esophageal carcinoma is approximately 3-6 cases per 100,000 persons, although certain endemic areas appear to have higher per-capita rates. The age-adjusted incidence is 5.8 cases per 100,000 persons.

The epidemiology of esophageal carcinoma has changed markedly over the past several decades in the United States.[22] Until the 1970s, squamous cell carcinoma was the most common type of esophageal cancer (90-95%). It was located in the thoracic esophagus and most frequently affected African-American men with a long history of smoking and alcohol consumption.

Over the last 4 decades, the incidence of adenocarcinoma of the distal esophagus and gastroesophageal junction has increased progressively. Currently, it accounts for more than 70% of all the new cases of esophageal cancer.

International statistics

Esophageal cancer is the seventh leading cause of cancer death worldwide. In some regions, such as areas of northern Iran, some areas of southern Russia, and northern China, the incidence of esophageal carcinoma may be as high as 800 cases per 100,000 population. Unlike in the United States, squamous cell carcinoma is responsible for 95% of all esophageal cancers worldwide.

Sex- and age-related demographics

Esophageal cancer is generally more common in men than in women. The male-to-female ratio is 3-4:1.

Esophageal cancer occurs most commonly during the sixth and seventh decades of life. The disease becomes more common with advancing age; it is about 20 times more common in persons older than 65 years than it is in individuals below that age.



Survival in patients with esophageal cancer depends on the stage of the disease. Squamous cell carcinoma and adenocarcinoma, stage-by-stage, appear to have equivalent survival rates.

Lymph node or solid organ metastases are associated with low survival rates. In 2001-2007, the overall 5-year survival rate for esophageal cancer was 19%.[21] Patients without lymph node involvement have a significantly better prognosis and 5-year survival rate than patients with involved lymph nodes. Stage IV lesions are associated with a 5-year survival rate of less than 5%. (See the table below.)

Five-year survival for esophageal cancer based on Five-year survival for esophageal cancer based on TNM stage.

A report of 1085 patients who underwent transhiatal esophagectomy for cancer showed that the operation was associated with a 4% operative mortality rate and a 23% 5-year survival rate. A better 5-year survival rate (48%) was identified in a subgroup of patients who had a complete response (ie, disappearance of the tumor) following preoperative radiation and chemotherapy (ie, neoadjuvant therapy).[23]

Transhiatal and transthoracic esophagectomies have equivalent long-term survival rates.[24, 25]

Imaging and prognosis

Suzuki et al found that a higher initial standardized uptake value on positron emission tomography (PET) scanning is associated with poorer overall survival among patients with esophageal or gastroesophageal carcinoma receiving chemoradiation. The authors suggested that PET scanning may become useful for individualizing therapy.[26]

A study by Gillies et al also found that PET-computed tomography (CT) scanning can be used to predict survival; in this study, the presence of fluorodeoxyglucose (FDG)-avid lymph nodes was an independent adverse prognostic factor.[27]

HER-2 and prognosis

A study by Prins et al of human epidermal growth factor 2 (HER-2) protein overexpression and HER-2 gene amplification in esophageal carcinomas found that HER-2 positivity and gene amplification are independently associated with poor survival. In their study, which involved 154 patients with esophageal adenocarcinoma, HER-2 positivity was seen in 12% of these patients and overexpression was seen in 14% of them.[28]

Contributor Information and Disclosures

Keith M Baldwin, DO IMPH, Assistant Professor of Surgery, Boston University School of Medicine; Endocrine and Surgical Oncologist, Department of General Surgery, Roger Williams Cancer Center

Keith M Baldwin, DO is a member of the following medical societies: American College of Surgeons, Society of Surgical Oncology, American Association of Endocrine Surgeons, Americas Hepato-Pancreato-Biliary Association, Society of International Humanitarian Surgeons/Surgeons OverSeas (SOS)

Disclosure: Nothing to disclose.


Marco G Patti, MD Professor of Surgery, Director, Center for Esophageal Diseases, University of Chicago Pritzker School of Medicine

Marco G Patti, MD is a member of the following medical societies: American Association for the Advancement of Science, American Surgical Association, American College of Surgeons, American Gastroenterological Association, American Medical Association, Association for Academic Surgery, Pan-Pacific Surgical Association, Society for Surgery of the Alimentary Tract, Society of American Gastrointestinal and Endoscopic Surgeons, Southwestern Surgical Congress, Western Surgical Association

Disclosure: Nothing to disclose.

N Joseph Espat, MD, MS, FACS Harold J Wanebo Professor of Surgery, Assistant Dean of Clinical Affairs, Boston University School of Medicine; Chairman, Department of Surgery, Director, Adele R Decof Cancer Center, Roger Williams Medical Center

N Joseph Espat, MD, MS, FACS is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Surgeons, American Medical Association, American Society for Parenteral and Enteral Nutrition, American Society of Clinical Oncology, Americas Hepato-Pancreato-Biliary Association, Association for Academic Surgery, Central Surgical Association, Chicago Medical Society, International Hepato-Pancreato-Biliary Association, Pancreas Club, Sigma Xi, Society for Leukocyte Biology, Society for Surgery of the Alimentary Tract, Society of American Gastrointestinal and Endoscopic Surgeons, Society of Surgical Oncology, Society of University Surgeons, Southeastern Surgical Congress, Southern Medical Association, Surgical Infection Society

Disclosure: Nothing to disclose.

Fernando AM Herbella, MD, PhD TCBC, Affiliate Professor, Attending Surgeon in Gastrointestinal Surgery, Esophagus and Stomach Division, Department of Surgery, Federal University of Sao Paulo, Brazil; Private Practice; Medical Examiner, Sao Paulo's Medical Examiner's Office Headquarters, Brazil

Fernando AM Herbella, MD, PhD is a member of the following medical societies: Society for Surgery of the Alimentary Tract

Disclosure: Nothing to disclose.

Chief Editor

N Joseph Espat, MD, MS, FACS Harold J Wanebo Professor of Surgery, Assistant Dean of Clinical Affairs, Boston University School of Medicine; Chairman, Department of Surgery, Director, Adele R Decof Cancer Center, Roger Williams Medical Center

N Joseph Espat, MD, MS, FACS is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Surgeons, American Medical Association, American Society for Parenteral and Enteral Nutrition, American Society of Clinical Oncology, Americas Hepato-Pancreato-Biliary Association, Association for Academic Surgery, Central Surgical Association, Chicago Medical Society, International Hepato-Pancreato-Biliary Association, Pancreas Club, Sigma Xi, Society for Leukocyte Biology, Society for Surgery of the Alimentary Tract, Society of American Gastrointestinal and Endoscopic Surgeons, Society of Surgical Oncology, Society of University Surgeons, Southeastern Surgical Congress, Southern Medical Association, Surgical Infection Society

Disclosure: Nothing to disclose.


Philip Schulman, MD Chief, Medical Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center

Philip Schulman, MD, is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology, and Medical Society of the State of New York

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Endoscopy demonstrating intraluminal esophageal cancer.
Cascade of events that lead from gastroesophageal reflux disease to adenocarcinoma.
Barium swallow demonstrating stricture due to cancer.
Barium swallow demonstrating an endoluminal mass in the mid esophagus.
Chest CT scan showing invasion of the trachea by esophageal cancer.
Transhiatal esophagectomy in which (a) is the abdominal incision, (b) is the cervical incision, and (c) is the stomach stretching from abdomen to the neck.
Five-year survival for esophageal cancer based on TNM stage.
H and E, high power, showing junction of benign glands in the lower right, Barrett's columnar cell metaplasia with a large goblet cell containing blue mucin in the lower center and adenocarcinoma on the left.
Macroscopic image of a resection of the gastroesophageal junction. On the right is non-neoplastic esophagus, consisting of tan, smooth mucosa. On the left is the non-neoplastic rugal folds of the stomach. In the center of the picture is an ulcer with a yellow-green fibrinous exudate surrounded by irregular, heaped-up margins with almost a cobblestone appearance. The latter represents mucosal adenocarcinoma with probably some Barrett's metaplasia in the background.
H and E, high power, demonstrating invasive esophageal squamous cell carcinoma. This carcinoma does not form glands and instead shows features of squamous differentiation, including keratinization and intercellular bridges.
Macroscopic image of an esophageal resection. A polypoid squamous cell carcinoma is visible protruding from the esophageal mucosal surface (left center of specimen).
On this positron emission computed tomography (PET) scan, esophageal cancer is evident as a golden lesion in the chest.
Table 1. Staging Classification.
Stage IAT1N0M0
Stage IBT2N0M0
Stage IIAT3N0M0
Stage IIBT1,T2N1M0
Stage IIIAT4aN0M0
Stage IIIBT3N2M0
Stage IIICT4aN1,N2M0
 T4bAny NM0
 Any TN3M0
Stage IVAny TAny NM1
Table 1. Staging Classification.
Stage IAT1N0M0
Stage IBT2N0M0
Stage IIAT3N0M0
Stage IIBT1,T2N1M0
Stage IIIAT4aN0M0
Stage IIIBT3N2M0
Stage IIICT4aN1,N2M0
 T4bAny NM0
 Any TN3M0
Stage IVAny TAny NM1
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