Simultaneous adeno- and squamous cell carcinoma with different phenotypic profiles in a rat model of chronic gastroesophageal reflux

Abstract

The aim of our study was to investigate the incidence of duodeno-gastroesophageal reflux-induced malignant transformation in a series of duodeno-esophageal anastomosis operations in rats. This surgical method provides a model for reflux-induced esophageal pathologies, without carcinogen administration. The study design included the follow-up of 31 cases. Thirty weeks of duodeno-gastroesophageal reflux disease significantly increased the risk of the development of Barrett's esophagus, and reflux-induced esophageal adenocarcinoma formation was evident in four animals. In one of these particular cases, a superficial squamous cell cancer was noted in close vicinity to the adenocarcinoma formation. For further analysis, a detailed immunohistochemical staining protocol was used. The immunophenotypes revealed cyclin D1 expression (nuclear positivity in 35% of all the squamous cells), p53 protein accumulation (50% nuclear positivity), with a low expression of cox-2, and negative c-erbB2 staining in the squamous carcinoma cells. The specialized intestinal metaplasia and mucinous adenocarcinoma cells exhibited exclusively diffuse cox-2 positivity (90% of all glandular cells) and weak focal c-erbB2 (5%) staining, without cyclin D1 expression or p53 protein accumulation. Real-time polymerase chain reaction was applied to quantify the abundance of p53, cyclin D1 and cox-2 mRNAs in this biopsy. The most dramatic changes were observed in the level of expression of cyclin D1 (a 9.08-fold expression as compared with the non-treated esophagus samples), while the p53 and cox-2 gene expressions were increased by 1.61 and 2.45-fold, respectively, relative to the non-treated samples. The results afford evidence of the simultaneous activation of more than one possible carcinogenetic pathway in experimental gastroesophageal reflux disease. Synchronous neoplasm formation with different growth pattern characteristics is a rarity in humans, and this phenomenon suggests that the presented model is a suitable means of mimicking the whole spectrum of human gastroesophageal reflux disease pathology. © 2007 The AuthorsJournal compilation © 2007 The International Society for Diseases of the Esophagus.