Duodenal-content reflux esophagitis induces the development of glandular metaplasia and adenosquamous carcinoma in rats

Recent studies have demonstrated that refluxed duodenal contents cause esophageal carcinoma in rats without exposure to carcinogens, The histopathological spectrum of these carcinomas includes squamous-cell carcinoma, adenocarcinoma and adenosquamous carcinoma. Pure adenocarcinomas are thought to arise in areas of columnar metaplasia adjacent to the anastomosis, similar to Barrett's esophagus in humans. In contrast, the histogenesis of adenosquamous carcinomas is unclear. The purpose here was to investigate the pathogenesis of esophageal adenosquamous carcinomas in a time-course experiment of chronic duodenal-content reflux without carcinogen. Forty-two 8-week-old male Sprague-Dawley rats were divided into seven groups and exposed to duodenal-content esophageal reflux during 10, 15, 20, 25, 30, 35 and 40 weeks, respectively. All animals underwent an esophagojejunostomy with gastric preservation in order to produce chronic esophagitis, The rats received a standard diet without addition of carcinogens, An increasing incidence of glandular metaplasia and carcinoma was observed over the time course, starting at 20 weeks. After 40 weeks of reflux, multiple foci of glandular metaplasia and adenosquamous carcinoma were found in 83 and 50% of the animals, respectively. Most of the carcinomas occurred in the middle and proximal esophagus and had a dual pattern of differentiation, glandular and squamous, These findings confirm that duodenal content reflux alone has a carcinogenic effect. We propose that chronic duodenal reflux induces the development of metaplastic cells with glandular differentiation from the stem cells of squamous epithelium, and that glandular metaplastic foci are the morphological element from which tumors with a dual pattern of differentiation arise.