© 2003 The Society for Surgery of the Alimentary Tract, Inc. 1091-255X/03/$—see front matter Published by Elsevier Science Inc. PII: S1091-255X(02)00158-0 172 Duodenal Reflux Produces Hyperproliferative Epithelial Esophagitis—A Possible Precursor to Esophageal Adenocarcinoma in the Rat Colman K. Byrnes, M.B., B.Ch., Anil Bahadursingh, M.D., Nabeel Akhter, M.D., Narasimham L. Parinandi, Ph.D., Viswanathan Natarajan, Ph.D., Elizabeth Montgomery, M.D., Tarik Tihan, M.D., Mark D. Duncan, M.D., Petra H. Nass, Ph.D., John W. Harmon, M.D. Esophageal reflux of duodenal contents converts a rat nitrosamine esophageal cancer model from squa- mous cell carcinoma to adenocarcinoma. Further, there was a tendency for male rats to have a higher in- cidence of cancer than female rats. However, chemical castration with the gonadotropin-releasing hor- mone analog leuprolide did not protect male or female animals from developing cancer. We have identified an early (6-week) hyperproliferative epithelial cell reaction to duodenal reflux. We carried out experiments to assess the specificity of duodenal reflux in producing the hyperproliferative epithelial pre- cursor lesion. Animals underwent specific surgical procedures to produce esophageal reflux of pure duodenal contents, mixed gastroduodenal, or bland intestinal contents. A hyperproliferative mucosal esophagitis developed in the group with duodenal reflux but not in the other groups. Mucosal thickness in the duodenal reflux group reached seven times that of normal mucosa at 6 weeks. These results suggest that esophageal reflux of duodenal contents plays an important role in the pathogenicity of proliferative esophagitis and the potential development of esophageal adenocarcinoma. (J G ASTROINTEST S URG 2003;7:172–180.) © 2003 The Society for Surgery of the Alimentary Tract, Inc. KEY WORDS: Gastroesophageal reflux disease (GERD), esophageal cancer, rat, N-acetylcysteine, leuprolide In the Western world, esophageal adenocarcinoma is appearing more and more frequently. 1,2 The dis- ease has a male predominance with a male:female ratio of 6:1. Developing an animal model of esoph- ageal adenocarcinogenesis has the potential to as- sist in understanding the mechanisms of carcino- genesis, particularly the metaplasia, which occurs in the esophageal mucosa whereby squamous epi- thelium is replaced by columnar epithelium, and the possible role of androgens in esophageal car- cinogenesis. Previous work has demonstrated that systemic nit- rosamine administration will produce a squamous-type cancer in the rat esophagus. 3 Interestingly, when nitro- samine administration is combined with surgical prep- arations causing reflux of intestinal contents into the esophagus, adenocarcinoma is seen in addition to the squamous-type lesion. 4,5 This model shares features of the presumed mechanism of carcinogenesis in hu- mans where adenocarcinoma develops more fre- quently in patients with gastroesophageal reflux dis- ease. 6 In human carcinogenesis, a precursor lesion to adenocarcinoma develops. This is Barrett’s metapla- sia of the esophageal mucosa in which the squamous epithelium is replaced with columnar epithelium. Our studies were designed to search for a precursor lesion for adenocarcinoma in the rat model. Further, our aim was to determine the relative contributions of Presented at the Forty-Third Annual Meeting of The Society for Surgery of the Alimentary Tract, San Francisco, Caifornia, May 19–22, 2002 (poster presentation). From the Johns Hopkins University School of Medicine (A.B., N.A., N.L.P., V.N., E.M., T.T., M.D.D., P.H.N., J.W.H.), Baltimore, Maryland; and Queen’s University Belfast (C.K.B.), Belfast, Northern Ireland. Reprint requests: John W. Harmon, M.D., Room 5C, “A” Building, Johns Hopkins Bayview Medical Center, 4940 Eastern Ave., Baltimore, MD 21224. e-mail: jharmon@jhmi.edu