Once rare, esophageal adenocarcinoma (EAC) is the most rapidly increasing malignancy in many developed countries, such as the United States, United Kingdom, Australia, and Norway, and now is surpassing esophageal squamous cell carcinomas in certain populations (1, 2). EAC has very specific clinical and epidemiologic characteristics: It involves the distal but not proximal esophagus, preferentially affects males and people of higher socioeconomic status, and unlike esophageal squamous cell carcinoma, is not related to drinking alcohol or smoking (3). The rapid increase in EAC is not an artifact of surveillance or classification (4); it is real and frightening. A smaller increase in adenocarcinomas involving the gastric cardia is probably related to the increase in EAC (5); however, this relationship is unclear because the origin of cardia tumors, which frequently are advanced when diagnosed, could be esophageal or gastric.

In recent years, it has become clear that EAC is a consequence of long-term gastroesophageal reflux disease, an inflammatory condition of the distal esophagus (6), often through progression to Barrett's esophagus, a metaplastic malady that may become dysplastic (7, 8). The three progressive and related conditions—gastroesophageal reflux disease, Barrett's esophagus, and EAC—have been increasing over the past several decades in developed countries; their substantial increase is a late 20th century phenomenon; and they were essentially unknown before 1900 (9). Numerous hypotheses have been raised to explain the origins of these maladies, which are not obvious (10). Nevertheless, reports going back more than 10 years have linked the rising tide of gastroesophageal reflux disease and its consequences with Helicobacter (H.) pylori (gram-negative bacteria that colonize the human stomach), especially the cagA+ variety, but inversely (8, 11, 12). This inverse association raised an intriguing question: How could the lack of an organism predispose to a cancer?