Risk Factors

In the U.S. and other developed countries, the major cause for SCC of the esophagus is smoking and alcohol consumption. The risk of developing cancer was influenced most by the amount of alcohol consumed per day, the lifetime duration of cigarette smoking, the type of tobacco smoked (black tobacco had two-fold higher risk than blond or mixed tobacco), and time since quitting either habit. Recent data suggests that only after abstinence from drinking for 10 years does cancer risk decrease to levels of those who did not drink. After abstinence from smoking for five years, the risk of cancer is cut by 50%.2

Dietary factors likely play a major role in the pathogenesis of SCC of the esophagus. Inverse association of SCC with vitamins C and E, niacin, and p-carotene have been demonstrated.2 Several studies of upper GI tract neoplasms in the U.S. and Europe suggest that fiber intake from fruits, vegetables, and grains may have a protective effect on the development of SCC of the esophagus. A recent Swedish study by Terry et al., however, found no association between the intake of cereal fiber and SCC risk.4 Several studies have observed that the consumption of hot beverages and soups are positively associated with the risk of SCC.2

Endemic SCC of the esophagus in Southern Africa has been shown to have a positive association with the consumption of maize meal. This is believed to be due to the conversion of nonesterified linoleic acid in maize meal to prostaglandin E2, which affects pH and fluid content of the esophagus and could thus predispose to SCC of the esophagus. High levels of nonesterified linoleic acid were found in maize meal from Southern Africa as well as the foods prepared from it (beer, porridge, maize/pumpkin mash).5

In the Linxian province of China, where SCC is also endemic, riboflavin deficiency (manifest by cheilosis and glossitis) is common. In this region, the soil is low in molybdenum, a key factor in nitrate reductase (an enzyme necessary for converting nitrates from the soil to amino acids). When soil molybdenum content is low, plant conversion of nitrates to nitrosamines increases, resulting in increased nitrosamine exposure for those who eat the plants. Increased intake of nitrosamines, which are known carcinogens, may be one of a number of dietary and environmental factors that contributes to the development of gastroesophageal cancer in this population. It is not clear whether dietary molybdenum supplementation is beneficial in decreasing the risk of gastroesophageal cancer. In a large intervention trial, dietary supplementation of molybdenum (30^g/day) and vitamin C (120mg/day) did not decrease the incidence of gastroesophageal cancer or other cancers in residents of Linxian over a 5-year period.6

The cause for the increase in the incidence of EAC is unclear. Several risk factors for the development of adenocarcinoma of the esophagus have been proposed, including tobacco use, ethanol use, dietary factors, medications, Helicobacter pylori infection, Barrett's esophagus, and gastro-esophageal reflux disease (GERD). Further research into the causes of this malignancy as well as their preceding pathologic conditions will be needed in order to understand the changing epidemiologic conditions.

Tobacco and alcohol consumption have been found to be more prevalent in patients with EAC as compared with patients with uncomplicated Barrett's esophagus. Recent case-controlled studies suggest that the risk of esophageal and esophago-gastric junction adenocarcinoma is doubled among smokers.2 Although the data suggest that tobacco is an etiologic factor for adenocarcinoma, it does not explain why the rate of EAC is increasing while squamous cell carcinoma of the esophagus (for which smoking is a major risk factor) is not increasing.

Obesity is a major risk factor for a number of chronic diseases and different types of cancers. A multicenter population-based case-control study revealed that excess weight was a strong risk factor for EAC. Risk rose with increasing BMI (body mass index). Interestingly, the greatest risk was seen in the youngest age group (<50 years old).2 This suggests that obesity may be particularly important for early-onset tumors. It is unclear how obesity contributes to increased risk. One hypothesis suggests that obesity increases the risk of hiatal hernia and GERD, which in turn increases the risk of Barrett's esophagus (a precursor lesion to EAC). Several studies, however, have shown that obesity per se is a strong risk factor for EAC independent of reflux symptoms.2

Most dietary data pertain to squamous cell cancer of the esophagus. One multicenter case-controlled study identified a high intake of fat with increased risk for EAC. An inverse association between fruit and vegetable consumption and EAC has also been demonstrated.2 Terry et al. found a strong inverse association between fiber intake and adenocarcinoma at the esophago-gastric junction. The association was with the consumption of cereal fiber (intake of fruits and vegetables were unrelated to the risk). A protective trend was seen with EAC, but the data were not statistically significant. It is believed that wheat fiber may act as a scavenger of nitrites (carcinogenic material) that are produced by swallowed air and saliva in the proximal portion of the stomach.4

Medications that relax the lower esophageal sphincter may contribute to increasing the subsequent risk for EAC by promoting GERD. Daily long-term users (>5 years) of any of these medications had an increased risk as compared with patients who had never used medications that relax the lower esophageal sphincter.2 The association was particularly strong for anticholinergic medications.

H. pylori is an important risk factor for gastric cancer but not EAC.2 It is of interest to note that there is an inverse relationship between cagA+ strain of H. pylori infection and risk of EAC. This is consistent with reports that the cagA- strain is more commonly seen in patients with EAC, GERD, and Barrett's esophagus.2

Strong evidence supports the association of GERD and EAC. In a Swedish population-based case-control study, subjects with EAC were almost eight times as likely to report at least weekly symptoms of reflux or regurgitation than control subjects. A dose-response relationship was also noted to exist. If patient's symptoms were long-standing (>20 years) and severe, the odds ratio for EAC increased. No association was found between reflux symptoms and squamous cell carcinoma risk.7 This suggests that recall bias did not explain the observed association. Similar studies in the U.S. have demonstrated a dose-response relationship between frequency of reflux symptoms and risk of EAC. Although there is a strong association of GERD with EAC, it should be mentioned that the annual incidence of cancer in patients with long-term GERD is 1 in 1000. More importantly, about 40% of patients who develop EAC do not even present with GERD symptoms.8 For these reasons, the use of GERD symptoms to assess risk of the development of EAC is unlikely to be of much benefit.

A recent study by Freedman et al.9 noted a moderately increased risk of EAC in patients who underwent cholecystectomy (CCK). There was no association of CCK with SCC of the esophagus. Patients with gallstone disease, who did not undergo CCK, did not have an increased incidence of EAC or SCC of the esophagus. It is postulated that after CCK, patients have increased reflux of bile and pancreatic juice from the duodenum to the stomach. This then reaches the esophageal mucosa, on which it has a toxic effect. Such toxic effects can predispose to the formation of EAC. Further studies are needed to identify a link between bile reflux and EAC.

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