Mutation and altered expression of beta-catenin during gallbladder carcinogenesis

Gallbladder carcinoma has two main morphologic developmental pathways: a dysplasia-carcinoma sequence and an adenoma-carcinoma sequence. beta-Catenin is a key regulator of the cadherin-mediated cell adhesion system, and altered expression and mutation of beta-catenin have been identified in many human malignancies. To clarify its role in gallbladder carcinogenesis, we investigated mutation and immunohistochemical expression of beta-catenin in adenomas, dysplasias, and carcinomas. We classified adenomas according to the expression of apomucins and cytokeratin and compared the mutational and expression pattern among each type. beta-Catenin mutations were identified in 58% (14 of 24) of the adenomas, and they were absent from all carcinomas (37 cases) and dysplasias (13 cases). Altered expression of beta-catenin, such as nuclear or cytoplasmic expression and loss of membranous expression, was also significantly higher in adenomas than in dysplasias or carcinomas (p <0.001). Of the adenomas, papillary adenomas and tubular adenomas of intestinal type showed infrequent beta-catenin abnormality, which was similar to the carcinomas. The cytoplasmic and nuclear expression of beta-catenin in carcinomas was correlated with less aggressive tumor behavior; in particular, cytoplasmic expression was associated with improved patient outcome (p = 0.028). Gallbladder adenoma may be a heterogeneous entity, and the majority of adenomas are not responsible for carcinoma progression.