Immunohistochemical demonstration of MET overexpression in human intrahepatic cholangiocarcinoma and in hepatolithiasis.

Expression of MET, the c-met-encoded receptor for hepatocyte growth factor, has not been investigated in proliferative biliary diseases of human liver, including hepatolithiasis and cholangiocarcinoma. Comparatively, we analyzed by immunohistochemistry the expression of MET in normal adult human livers (n = 20), normal postnatal preadult livers (n = 21), fetal livers (n = 36), hepatolithiatic livers (n = 32), and intrahepatic cholangiocarcinomas (n = 26). In normal adult livers, obvious MET immunoreactivity was not found in any cell types. In fetal liver, MET was weakly expressed in primitive biliary cells (ductal plate and immature bile ducts) and immature hepatocytes during 8 to 30 gestational weeks but was essentially negative thereafter. In hepatolithiasis, a condition of risk for cholangiocarcinoma development, MET was overexpressed in proliferated biliary cells in 26 of 32 cases (81%). In this nonneoplastic proliferative biliary condition, MET immunoreactivity was observed to be most prominent in the hyperplastic septal and large bile ducts of liver, and in the proliferated peribiliary glands associated with intrahepatic large bile ducts. In intrahepatic cholangiocarcinoma, MET overexpression in neoplastic biliary epithelium was observed in 15 of 26 cases (58%) and correlated with the degree of tumor differentiation, being highest in well-differentiated tumors and relatively low in poorly differentiated tumors. These data show for the first time that overexpression of MET is a common feature of hyperplastic and neoplastic biliary epithelial cells in human liver and suggest that MET/hepatocyte growth factor may be playing an important role in human biliary hyperplasia and in cholangiocarcinogenesis in vivo.