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.