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.