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Other risk factors for development of esophageal cancer include tobacco smoking and alcohol intake (especially their dreaded combination), long-standing achalasia, nitrites in the diet, and the presence of esophageal webs (Paterson-Kelly syndrome). Esophageal cancers are divided topographically by their location in the esophagus as upper third (15%), middle third (45%) and lower third (40%). Histologically, esophageal cancers are divided into squamous cell carcinomas and adenocarcinomas. The most established risk factor in the development of adenocarcinomas, essentially limited to the lower third of the esophagus, is chronic gastric reflux, resulting in intestinal metaplasia (Barrett's esophagus). Patients with Barrett's esophagus, especially those with high-grade dysplasia, have a 50 times greater risk of developing esophageal adenocarcinomas. Although the exact risk of progression is not known, less than 1% of the population with Barrett's esophagus actually goes on to develop cancer. The frequency of squamous cell carcinoma has remained relatively constant in this country, while the incidence of adenocarcinomas has risen steadily. The prognosis of esophageal cancer is poor, and less than a fifth of patients with gross tumor resection survive more than five years.
Esophageal squamous cell carcinomas, like their histologic counterparts in other organs, are preceded by a stage of progressive dysplasia of the squamous epithelium from which they arise. Many of the tumor suppressor genes implicated in squamous cell carcinogenesis at other anatomic sites have also been found to be critical in the esophagus. For example, loss of p53 function is seen in 50% of squamous cancers. Inactivation of cell cycle inhibitors p16INK4a and p27KIP1 are frequent, as is overexpression of cyclin D1. Human papilloma DNA has been detected in about a quarter of esophageal squamous cancers by in situ hybridization techniques. Many of these genetic aberrations have a direct bearing on prognosis; for example, abnormal expression of p53, high MIB-1 labeling index, and overexpression of the epidermal growth factor (EGF) or the EGF receptor are all associated with poor patient survival.
Esophageal adenocarcinomas as explained earlier are preceded by chronic acid reflux and intestinal metaplasia of the lower esophagus. The molecular abnormalities in Barrett's leading to cancer follow a sequence and usually starts with increased cell proliferation, followed by acquisition of p53 and p16INK4a abnormalities, and aneuploidy. All of these critical changes can be detected in premalignant epithelium before the histologic appearance of malignancy. Therefore, their detection in dysplastic Barrett's epithelium (especially changes such as aneuploidy which are considered "late" changes) is ominous. At the adenocarcinoma stage, greater than 90% of cases demonstrate p53 abrogation and nearly 70% have p16INK4a loss. Other molecular abnormalities associated with esophageal adenocarcinomas are inactivation of APC and DCC function, manifested at the DNA level as loss of chromosome 5q and 18q deletions, respectively.
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