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.
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)
Epigastric or retrosternal pain
Bone pain with metastatic disease
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 IV||Any T||Any N||M1|
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
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:
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.  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
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:
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.  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. 
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:
Certain foodstuffs (eg, betel nut)
Drinking scalding-hot liquids
Environmental contributors (eg, nitrosamines in soil)
Certain fungi, molds, or yeasts
Acquired conditions (eg, achalasia)
High body mass index (>25 kg/m 2) 
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.  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. 
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.  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. 
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.  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. 
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.)
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.  In 1975, Naef et al emphasized the malignant potential of Barrett esophagus.  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. 
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. 
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. 
United States statistics
The American Cancer Society estimates that 16,910 new cases of esophageal cancer (13,460 in men and 3,450 in women) will occur in the United States in 2016; 15,690 persons (12,720 men and 2,970 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.  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.  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.
Subsequently, rates of esophageal adenocarcinoma rose markedly, particularliy in whites. In white males, the incidence rate of esophageal adenocarcinoma exceeded that of squamous cell carcinoma around 1990, while in white women aged 45–59 years, adenocarcinoma overtook squamous cell carcinoma in 2006–2010. 
Rates of increase in adenocarcinoma appear to be slowing, however. From 1973 to 1996, the incidence of esophageal adenocarcinoma increased by 8.2% annually. From 1996 to 2006, the rate of increase fell to 1.3% annually, principally because of a plateau in the incidence of early-stage disease. Prior to 1996, early-stage cases increased by 10% annually; subsequently, they declined by 1.6% annually. 
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%.  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.)
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). 
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. 
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. 
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. 
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