The molecular pathology of Barrett's esophagus

The incidence of adenocarcinoma of the distal esophagus is rapidly increasi ng in the Western world. The histopathological sequence of (Barrett's) meta plasia, which develops as a consequence of chronic reflux, to dysplasia and then to carcinoma is well established for these tumors. In Barrett's esoph agus a variety of molecular changes have been characterized and correlated with tumor initiation and progression. Among the early changes in premalign ant stages of metaplasia are alterations of the transcripts of FHIT, a pres umptive tumor suppressor gene which spans the common fragile site FRA3B. Mu tations of p53 seem to accumulate mainly in the transition from low to high grade dysplasia. Inactivation of other tumor suppressor genes by mutation (APC, p16) or hypermethylation (p16) as well as amplification of oncogenes such as c-erbB2 are relatively late events in the development of adenocarci noma. Among the phenotypic changes in Barrett's esophagus are an expansion of the Ki67 proliferation compartment which correlates with the degree of d ysplasia. Moreover, accumulation of rab11 molecules which are involved in m embrane trafficking has been reported to be specific for the loss of polari ty seen in low grade dysplasia. Reduced expression of the cadherin/catenin complex as well as increased expression of various proteases develop chiefl y in invasive carcinomas. Despite the progress that has been made in the id entification of molecular markers in Barrett's carcinoma, to date the histo pathogical diagnosis of high grade dysplasia in endoscopic biopsies remains the best predictor of invasive cancer. Immunohistochemistry applying a pan el of antibodies including p53, Mib-1 or rab11 can be helpful to diagnose r egenerative metaplastic epithelium or low and high grade dysplasia.