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Squamous cell carcinoma Factors that cause chronic irritation and esophageal mucosa inflammation may increase the risk for esophageal squamous cell carcinoma. These factors include moderate to heavy alcohol drinking, smoking, achalasia, diverti-culi, and consumption of extremely hot beverages, coarse grains or seeds, lye, and caustic spices.

The importance of alcohol consumption in the carcinogenesis of esophageal squamous cell carcinoma is well recognized. However, the mechanisms by which alcohol increases cancer risk have not been elucidated. Alcohol may cause chronic irritation to the esophagus, and it may increase cell proliferation and enhance the permeability of carcinogens to cells. An alcohol metabolite, acetaldehyde, is known to be a carcinogen. Risk for esophageal squamous cell carcinoma is higher for spirits drinkers, followed by wine and beer drinkers.

Cigarette smoke is a rich source of carcinogens, such as benzo(a)pyrene and volatile nitrosamines. It also contains free radicals, reactive oxygen species, and reactive nitrogen species that are capable of initiating and propagating oxidative damage to lipids, proteins, and DNA, leading to several degenerative diseases including cancer. Alcohol drinking may account for approximately 80% of squamous cell esophageal cancer cases, whereas tobacco use may account for approximately 60%. Simultaneous use of alcohol and tobacco further increases esophageal cancer risk.

Achalasia is a swallowing disorder caused by degeneration of the intrinsic autonomic nerves in the esophagus wall and lower esophageal sphincter, leading to decreased or absent peristalsis in the esophageal smooth muscle or impaired relaxation of the lower esophageal sphincter. Approximately 20-29% of achalasia patients may develop esopha-geal cancer within 15-20 years, predominantly squamous cell carcinoma, possibly because of increased inflammation, bacterial growth, and chemical irritation caused by prolonged contact of food ingredients with esophageal mucosa. In contrast, the likelihood of malignant transformation from diverticuli is less than 1%, although the mechanisms of carcinogenesis are speculated to be the same as those for achalasia.

Low income is associated with squamous cell carcinoma of the esophagus, independent of alcohol and tobacco use, suggesting that other factors associated with poverty may play a role. In Africa and Far East countries, incidences of esophageal cancer are high in regions where starchy food is the predominant food in the diet, and this may have been an indication of poor nutritional status. Several studies have reported that very low intake of fresh fruits and vegetables is associated with higher risk of esophagus cancer. Conversely, high intake of fruits and vegetables, particularly citrus fruits, may confer preventive benefits. Frequent consumption of highly salted meat, pickled vegetables, cured meat, and smoked meat was found to be associated with esophageal cancer risk; these foods contain carcinogenic compounds such as heterocyclic amines and N-nitroso compounds.

Familial aggregation of esophageal squamous cell carcinoma has been reported, but it may reflect genetic predisposition as well as common environmental exposures. Hereditary squamous cell carcinoma of the esophagus develops in approximately 95% of people with a genetic abnormality at chromosome 17q25 that causes a rare autosomal dominant disorder, none-pidermolytic palmoplantar keratoderma.

Adenocarcinoma The risk factor profile of esopha-geal adenocarcinoma is quite different from that of squamous cell carcinoma. Tobacco use is associated with adenocarcinoma of the esophagus, but the association is less strong than that with squamous cell carcinoma. High intakes of fiber, vitamin C, vitamin B6, folate, and ^-carotene were found to be associated with a lower risk. However, unlike squamous cell carcinoma, esophageal adenocarcinoma does not consistently develop more often in people with frequent alcohol consumption or low income.

Gastroesophageal reflux disease (GERD) is strongly associated with adenocarcinoma of the esophagus. In the process of gastroesophageal reflux, acid fluid regurgitates into the gastroeso-phageal junction and causes a sensation of heartburn. GERD can be caused by hiatal hernia, esophageal ulcer, and use of drugs that relax the lower gastroesophageal sphincter and increase reflux. Alcohol, tobacco, obesity, and pregnancy may also contribute to GERD.

Barrett's esophagus represents intestinal metaplasia of the squamous epithelium in the distal esophagus. Barrett's esophagus develops in approximately

5-10% of people with GERD and is associated with a 30- to 125-fold increased risk for esophageal adenocarcinoma.

In the United States, the incidence of adenocar-cinoma of the esophagus has increased more than 350% since the 1970s. Obesity has been hypothesized to be one of the factors responsible for this increase by augmenting abdominal pressure and gastroesophageal reflux frequency. However, evidence has not been consistent to support this hypothesis.

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