Esophageal cancer (American English) or oesophageal cancer (British English) is cancer arising from the esophagus—the food pipe that runs between the throat and the stomach. Symptoms often include difficulty in swallowing and weight loss. Other symptoms may include pain when swallowing, a hoarse voice, enlarged lymph nodes ("glands") around the collarbone, a dry cough, and possibly coughing up or vomiting blood.
The two main sub-types of the disease are esophageal squamous-cell carcinoma (often abbreviated to ESCC),Even by those using the British English spelling "oesophagus" which is more common in the developing world, and esophageal adenocarcinoma (EAC), which is more common in the developed world. A number of less common types also occur. Squamous-cell carcinoma arises from the epithelial cells that line the esophagus. Adenocarcinoma arises from glandular cells present in the lower third of the esophagus, often where they have already transformed to intestinal cell type (a condition known as Barrett's esophagus).
Causes of the squamous-cell type include tobacco, alcohol, very hot drinks, poor diet, and chewing betel nut. The most common causes of the adenocarcinoma type are smoking tobacco, obesity, and acid reflux. In addition, for patients with achalasia, candidiasis (overgrowth of the esophagus with the fungus candida) is the most important risk factor.
The disease is diagnosed by biopsy done by an endoscope (a fiberoptic camera). Prevention includes stopping smoking and eating a healthy diet. Treatment is based on the cancer's stage and location, together with the person's general condition and individual preferences. Small localized squamous-cell cancers may be treated with surgery alone with the hope of a cure. In most other cases, chemotherapy with or without radiation therapy is used along with surgery. Larger tumors may have their growth slowed with chemotherapy and radiation therapy. In the presence of extensive disease or if the affected person is not fit enough to undergo surgery, palliative care is often recommended.
As of 2018, esophageal cancer was the eighth-most common cancer globally with 572,000 new cases during the year. It caused about 509,000 deaths that year, up from 345,000 in 1990. Rates vary widely among countries, with about half of all cases occurring in China. It is around three times more common in men than in women. Outcomes are related to the extent of the disease and other medical conditions, but generally tend to be fairly poor, as diagnosis is often late. Five-year survival rates in the United States are around 22% (2016–2022).
Signs and symptoms Prominent symptoms usually do not appear until the cancer has infiltrated over 60% of the circumference of the esophageal tube, by which time the tumor is already in an advanced stage. Onset of symptoms is usually caused by narrowing of the tube due to the physical presence of the tumor.
The first and the most common symptom is usually difficulty in swallowing, which is often experienced first with solid foods and later with softer foods and liquids. Pain when swallowing is less usual at first. Weight loss is often an initial sign in cases of squamous-cell carcinoma, though not usually in cases of adenocarcinoma. Eventual weight loss due to reduced appetite and undernutrition is common. Pain behind the breastbone or in the region around the stomach often feels like heartburn. The pain can frequently be severe, worsening when food of any sort is swallowed. Another sign may be an unusually husky, raspy, or hoarse-sounding cough, a result of the tumor affecting the recurrent laryngeal nerve.
The presence of the tumor may disrupt the normal contractions of the esophagus when swallowing. This can lead to nausea and vomiting, regurgitation of food and coughing. There is also an increased risk of aspiration pneumonia due to food entering the airways through the abnormal connections (fistulas) that may develop between the esophagus and the trachea (windpipe). Early signs of this serious complication may be coughing on drinking or eating. The tumor surface may be fragile and bleed, causing vomiting of blood. Compression of local structures occurs in advanced disease, leading to such problems as upper airway obstruction and superior vena cava syndrome. Hypercalcemia (excess calcium in the blood) may occur.
If the cancer has spread elsewhere, symptoms related to metastatic disease may appear. Common sites of spread include nearby lymph nodes, the liver, lungs and bone. Liver metastasis can cause jaundice and abdominal swelling (ascites). Lung metastasis can cause, among other symptoms, impaired breathing due to excess fluid around the lungs (pleural effusion), and dyspnea (the feelings often associated with impaired breathing).
Causes The two main types (i.e. squamous-cell carcinoma and adenocarcinoma) have distinct sets of risk factors. Squamous-cell carcinoma is linked to lifestyle factors such as smoking and alcohol. Adenocarcinoma has been linked to effects of long-term acid reflux. Tobacco is a risk factor for both types. Both types are more common in people over 60 years of age.
Squamous-cell carcinoma The two major risk factors for esophageal squamous-cell carcinoma are consumption of alcoholic beverages, and using tobacco (smoking or chewing). The combination of tobacco and alcohol has a strong synergistic effect, which raises risks compared to either substance alone. Some data suggest that about half of all cases are due to tobacco and about one-third to alcohol, while over three-quarters of the cases in men are due to the combination of smoking and heavy drinking. Risks associated with alcohol appear to be linked to its aldehyde metabolite and to mutations in certain related enzymes. Such metabolic variants are relatively common in Asia.
Other relevant risk factors include regular consumption of very hot drinks (over 65 °C or 149 °F) and ingestion of caustic substances. High levels of dietary exposure to nitrosamines (chemical compounds found both in tobacco smoke and certain foodstuffs) also appear to be a relevant risk factor. Unfavorable dietary patterns seem to involve exposure to nitrosamines through processed and barbecued meats, pickled vegetables, etc., and a low intake of fresh foods. Other associated factors include nutritional deficiencies, low socioeconomic status, and poor oral hygiene. Chewing betel nut (areca) is an important risk factor in Asia.
Physical trauma may increase the risk. This may include the drinking of very hot drinks.
A large UK study of 977,282 adults found that drinking beverages very hot was associated with a substantially higher risk of oesophageal squamous cell carcinoma. Drinking six or more hot drinks daily was also associated with increased squamous cell carcinoma risk.
Adenocarcinoma
Male predominance is particularly strong in esophageal adenocarcinoma, occurring about 7 to 10 times more frequently in men. This imbalance may be related to the characteristics and interactions of other known risk factors, including acid reflux and obesity.
Gastroesophageal reflux disease The long-term erosive effects of acid reflux (an extremely common condition, also known as gastroesophageal reflux disease or GERD) have been strongly linked to this type of cancer. Longstanding GERD can induce a change of cell type in the lower portion of the esophagus in response to erosion of its squamous lining. This phenomenon, known as Barrett's esophagus, seems to appear about 20 years later in women than in men, possibly due to hormonal factors.
At a mechanistic level, in the esophagus there is a small HOXA13 expressing compartment that is more resistant to bile and acids as the normal squamous epithelium and that is prone to both intestinal differentiation as well as oncogenic transformation. Following GERD this HOXA13-expressing compartment outcompetes the normal squamous compartment, leading to the intestinal aspect of the esophagus and increased propensity to the development of esophageal cancer.
Having symptomatic GERD or bile reflux makes Barrett's esophagus more likely, which in turn raises the risk of further changes that can ultimately lead to adenocarcinoma. Bile reflux containing unconjugated bile acids, including deoxycholic acid and chenodeoxycholic acid, appears to contribute to esophageal adenocarcinoma carcinogenesis by inducing oxidative stress and DNA damage. The risk of developing adenocarcinoma in the presence of Barrett's esophagus is unclear, and may in the past have been overestimated.
Obesity Being obese or overweight is strongly associated with risk of developing esophageal adenocarcinoma, and may in fact be the strongest of any type of obesity-related cancer, though the reasons for this remain unclear. Abdominal obesity seems to be of particular relevance, given the closeness of its association with this type of cancer, as well as with both GERD and Barrett's esophagus. This type of obesity is characteristic of men. Physiologically, it stimulates GERD and also has other chronic inflammatory effects.
Helicobacter pylori Helicobacter pylori infection (a common occurrence thought to have affected over half of the world's population) is not a risk factor for esophageal adenocarcinoma and actually appears to be protective. Despite being a cause of GERD and a risk factor for gastric cancer, the infection seems to be associated with a reduced risk of esophageal adenocarcinoma of as much as 50%. The biological explanation for a protective effect is unclear. One explanation is that some strains of H. pylori reduce stomach acid, thereby reducing damage by GERD. Decreasing rates of H. pylori infection in Western populations over recent decades, which have been linked to less overcrowding in households, could be a factor in the concurrent increase in esophageal adenocarcinoma.
Other risk factors for esophageal adenocarcinoma Female hormones may also have a protective effect, as EAC is not only much less common in women but develops later in life, by an average of 20 years. Although studies of many reproductive factors have not produced a clear picture, risk seems to decline for the mother in line with prolonged periods of breastfeeding.
Tobacco smoking increases risk, but the effect in esophageal adenocarcinoma is slight compared to that in squamous cell carcinoma, and alcohol has not been demonstrated to be a cause.
Related conditions Head and neck cancer is associated with second primary tumors in the region, including esophageal squamous-cell carcinomas, due to field cancerization (i.e. a regional reaction to long-term carcinogenic exposure). History of radiation therapy for other conditions in the chest is a risk factor for esophageal adenocarcinoma. Corrosive injury to the esophagus by accidentally or intentionally swallowing caustic substances is a risk factor for squamous cell carcinoma. Tylosis with esophageal cancer is a rare familial disease with autosomal dominant inheritance that has been linked to a mutation in the RHBDF2 gene, present on chromosome 17: it involves thickening of the skin of the palms and soles and a high lifetime risk of squamous cell carcinoma. Achalasia (i.e. lack of the involuntary reflex in the esophagus after swallowing) appears to be a risk factor for both main types of esophageal cancer, at least in men, due to stagnation of trapped food and drink. Plummer–Vinson syndrome (a rare disease that involves esophageal webs) is also a risk factor. There is some evidence suggesting a possible causal association between human papillomavirus (HPV) and esophageal squamous-cell carcinoma. The relationship is unclear. Possible relevance of HPV could be greater in places that have a particularly high incidence of this form of the disease, as in some Asian countries, including China.