Barrett's esophagus: the metaplasia-dysplasia-carcinoma sequence: morphological aspects

In the gastrointestinal tract, epithelial dysplasia is defined as an "unequivocal neoplastic transformation, confined within the boundaries of the basement membrane" or "the presence of unequivocally neoplastic cells that replace a variable proportion of the normal epithelium". It can be recognized by microscopy because of cytological and architectural changes. Reactive changes or equivocal changes should thus not be called "dysplasia". As dysplasia is confined within the basement membrane, it is a noninvasive neoplastic transformation. In the lower esophagus lined by columnar epithelium (Barrett's esophagus) dysplasia is classified as negative, indefinite or positive. Positive lesions are subdivided into low-grade and high-grade dysplasia according to the severity of the lesions. Carcinoma in situ (intraepithelial carcinoma) is included in the category of high-grade dysplasia. The presence of dysplasia can be recognized on biopsies and on cytological preparations. Several techniques have been introduced with the purpose to improve the diagnostic yield. These include special stains for the assessment of mucin, enzymehistochemistry and immunohistochemistry for tumor markers such as CEA and CA 19-9 and molecular techniques. Mucin histochemistry, enzymehistochemistry and immunohistochemistry for traditional markers have limited practical value. The nuclear presence of abnormal products such as mutant p53 can be identified using immunohistochemistry and appropriate antibodies. Flow cytometry can identify aneuploid cell populations and Fluorescent In Situ Hybridization (FISH) can identify chromosomal gains and losses. These techniques provide additional information but they identify other phenomena which do not necessarily appear at the same moment as dysplasia during the process of carcinogenesis. Application of these techniques can however certainly help to support a diagnosis of dysplasia while negative results do not necessarily disproof such a diagnosis. The temporal course of the progression of dysplasia and the development of carcinoma is not well known and seems to be variable. Low-grade dysplasia may persist for long periods. A direct progression towards carcinoma has been noted although more often an increase in the severity of the dysplasia, before the development of carcinoma, was seen during the observation period. High-grade dysplasia can also persist for many months, sometimes even years without obvious evolution but it can also progress rapidly to carcinoma.