Viral hepatitis is associated with intrahepatic cholangiocarcinoma with cholangiolar differentiation and N-cadherin expression.

Viral hepatitis-associated intrahepatic cholangiocarcinoma is thought to have common disease processes with hepatocellular carcinoma, but until now the histomorphological and genetic features of viral hepatitis-associated intrahepatic cholangiocarcinoma is still unknown. From 2000 to 2010, 170 patients with intrahepatic cholangiocarcinoma who received detailed pathological assessment and regular follow-up at the National Taiwan University Hospital were selected for this study. Of 170 patients, 69 (41%) were positive for hepatitis B and/or C virus. These patients were younger, were more frequently male, and had elevated serum α-fetoprotein levels as compared with seronegative intrahepatic cholangiocarcinoma patients. Grossly these tumors were mostly of the mass-forming type, and histologically, cholangiolar differentiation was more frequently seen. We identified N-cadherin as an immunohistochemical marker strongly associated with hepatitis virus infection. The prevalence of viral hepatitis in patients with N-cadherin-positive intrahepatic cholangiocarcinoma was 75%, and that in N-cadherin-negative patients was only 37%. N-cadherin-positive patients were younger, had elevated α-fetoprotein, and had no hepatolithiasis. All N-cadherin-positive intrahepatic cholangiocarcinomas were of the mass-forming type. N-cadherin positivity was strongly associated with cholangiolar morphology and lack of carcinoembryonic antigen and MUC2 expression, whereas K-RAS mutations were less frequent. Our results indicate that a subgroup of intrahepatic cholangiocarcinoma characterized by cholangiolar differentiation and N-cadherin expression is strongly associated with viral hepatitis.