Differing rates of loss of Dpc4 expression and of p53 overexpression amongcarcinomas of the proximal and distal bile ducts - Evidence for biologic distinction

BACKGROUND. Biliary tract carcinomas are clinically heterogeneous. It is no t known if molecular heterogeneity underlies the clinical differences. METHODS. The authors evaluated 128 bile duct carcinomas, 88 of the distal c ommon bile duct and 40 of more proximal origin (28 perihilar carcinomas, 12 intrahepatic carcinomas), immunohistochemically for abnormalities in the e xpression of the products of the DPC4 and p53 tumor-suppressor genes. Progn ostic factors were evaluated in the series of distal bile duct carcinomas f or which follow-up information was available. RESULTS. The authors found that a significantly higher percentage of distal bile duct carcinomas (55%) demonstrated loss of DPC4 expression than did t he proximal bile duct carcinomas (15%; P < 0.001). They also found that a s ignificantly higher percentage of the distal tumors abnormally expressed th e p53 gene product (51% vs. 26%; P < 0.001). Among the distal common bile d uct carcinomas, the presence of poorly differentiated histology correlated with decreased survival in multivariate analysis, while labeling for p53 or Dpc4, margin status, lymph node status, and tumor dimension did not correl ate significantly with survival. CONCLUSIONS. These results demonstrate that abnormalities in DPC4 and p53 g ene expression are frequent in distal common bile duct carcinomas, just as they are in pancreatic ductal adenocarcinoma, suggesting that these two tum or types might share a similar molecular pathogenesis. They also show that proximal and distal bile duct carcinomas have different patterns of inactiv ation of tumor-suppressor genes, indicating that they often arise through d ifferent molecular mechanisms likely reflecting their differing etiologies. (C) 2001 American Cancer Society.