Adenocarcinoma of the Esophagus: Risk Factors and Prevention

Esophageal cancer poses an interesting challenge for oncologists. Esophageal squamous cell cancer has the most varied geographical incidence of any cancer, suggesting the existence of critically important environmental and molecular epidemiologic factors. These factors remain largely unrecognized. Equally puzzling is the dramatic increase in the incidence of adenocarcinomas of the esophagus and gastro-esophageal junction or cardia that has occurred in western societies during the past 3 decades.[1,2] This increase in incidence is particularly disturbing in view of the highly lethal nature of esophageal cancer. For the year 2000, the estimated number of new cases of esophageal cancer in the United States is 12,300 and the estimated number of deaths due to this cancer is 12,100.[3] In response to these challenges, there has been a great increase in the amount of research and the number of publications on malignant and premalignant esophageal diseases. In the 2-week period following January 26, 2000, for example, 136 new English language entries using any of the key words “esophageal neoplasms, Barrett’s esophagus, gastric cardia, and gastro-esophageal reflux” were added on Medline. Many readers of Oncology are thus likely to welcome the efforts by Forastiere et al to review this increasing mass of information. Barrett’s Esophagus and Esophageal Adenocarcinoma The main risk factor for esophageal adenocarcinoma is the presence of Barrett’s esophagus. This is currently defined by most investigators as the replacement of the normal squamous epithelium of the distal esophagus by a visible segment of columnar mucosa containing intestinal metaplasia on microscopic examination. Similar to adenocarcinoma, the incidence of Barrett’s esophagus has been rising rapidly,[4,5] suggesting that the increase in esophageal adenocarcinoma incidence is explained, at least in part, by this increase in Barrett’s. However, another possible explanation is that the proportion of patients with Barrett’s who progress to malignancy has increased. The latter explanation is not supported by recent prospective analyses of the risk of cancer developing in patients with Barrett’s,[6,7] but large population-based studies are needed to properly evaluate this possibility. It may be that the incidence of nonvisible intestinal metaplasia, termed either “ultra-short segment Barrett’s esophagus” or “cardiac mucosa with intestinal metaplasia,” is increasing. Indeed, recent studies have found intestinal metaplasia at the gastroesophageal junction in 9% to 36% of individuals undergoing endoscopy.[8-10] The normal-appearing gastroesophageal junction was rarely studied prior to the mid-1990s. Consequently, a rise in intestinal metaplasia at this site cannot be confirmed. It has been hypothesized that the increasing incidence of adenocarcinoma at the gastroesophageal junction or cardia is a consequence of this putative increase in the incidence of nonvisible areas of intestinal metaplasia. As Forastiere et al note, there is considerable variability in the reported risk of developing adenocarcinoma within a segment of Barrett’s esophagus. In part, this reflects the fact that none of the reported prospective studies has included sufficient numbers of patients to make definitive estimates, and that the size of a study required to provide these estimates is prohibitively large. Furthermore, because only a small proportion of Barrett’s mucosa is usually biopsied at endoscopy, there is considerable risk that patients with Barrett’s are staged incorrectly for the presence and grade of dysplasia, thus confounding estimates of the cancer risk in supposedly nondysplastic Barrett’s epithelium. Even when Barrett’s segments are carefully evaluated histologically, with a large number of biopsies taken throughout the Barrett’s segment, conventional examination of the