Different roles of inducible nitric oxide synthase and cyclooxygenase-2 in carcinogenesis and metastasis of intrahepatic cholangiocarcinoma.

Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) have been implicated in chronic inflammatory conditions and carcinogenesis. However, little is known about the biological significance of iNOS and COX-2 in cholangiocarcinoma or its precursors or metastatic lesions. We examined iNOS and COX-2 immunohisotochemical expression in 40 biliary intraepithelial neoplasias, 134 primary intrahepatic cholangiocarcinoma cases, and 27 metastatic lymph nodes and analyzed the correlations with grade of atypia of biliary intraepithelial neoplasia, clinicopathological factors and outcomes of intrahepatic cholangiocarcinoma. iNOS and COX-2 expression was highly expressed in reactive epithelium and biliary intraepithelial neoplasia. In intrahepatic cholangiocarcinoma, lymphatic invasion and lymph node metastasis were significantly correlated with negative iNOS expression (P = .0002, P = .0324, respectively) and positive COX-2 expression (P = .0012, P = .0063, respectively). Vascular endothelial growth factor-C expression was associated with COX-2 expression (P = .0053), but not with iNOS expression. COX-2 expression in primary intrahepatic cholangiocarcinoma was higher than that in metastatic lymph nodes (P < .0001). COX-2-positive expression indicated a poor intrahepatic cholangiocarcinoma outcome (P = .0273). This study indicates that iNOS and COX-2 may play roles in carcinogenesis via biliary intraepithelial neoplasia, but play different roles in metastasis of intrahepatic cholangiocarcinoma. COX-2 may participate in a higher lymphatic invasion and metastasis via the vascular endothelial growth factor-C pathway.