Clinicopathological characteristics of cholangiocarcinoma : comparison between cholangiolar differentiation and bile ductal differentiation

Abstract

Recently intrahepatic cholangiocarcinoma (ICC) has been subclassified into cholangiolar differentiation and bile ductal differentiation; however their clinicopathological and molecular characteristics have not been fully understood. We studied 142 human ICC cases of Severance hospital from 1997 to 2013, and there were 20 cases (14.1%) of ICC with cholangiolar differentiation, and 122 cases (85.9%) of ICC with bile ductal differentiation. The expression of c-reactive protein (CRP), claudin 18 (CLDN18), N-cadnerin, Neural cell adhesion molecule (NCAM), vimentin, and epithelial-mesenchymal transition (EMT)-related markers (ZEB1, ZEB2, TWIST, SNAIL and loss of E-cadherin) were evaluated by immunohistochemistry or real-time PCR. The expression levels of these markers and clinicopathological features were compared between two groups. ICC patients with cholangiolar differentiation revealed higher incidence of female and viral hepatitis, and less incidence of hepatolithiasis, ductal epithelial dysplasia compared to those with the ICC with bile ductal differentiation (P <0.05, for all). The mass-forming gross type was found in all of ICCs with cholangiolar differentiation in contrast that it was detected in 72 cases (59%) of ICCs with bile ductal differentiation (P = 0.005). The ICCs with cholangiolar differentiation showed less perineural invasion compared to ICCs with bile ductal differentiation (P = 0.013). The protein expression of CRP, N-cadherin and NCAM was more frequently found in ICCs with cholangiolar differentiation compared to those with bile ductal differentiation (P < 0.05, for all). The protein expression of CLDN18 and ZEB1 was more frequently detected in ICCs with bile ductal differentiation compared to those with cholangiolar differentiation (P < 0.05, for all). The protein expression of TWIST and E-cadherin loss showed no significant difference between two groups. The mRNA expression levels of SNAIL and ZEB1 were lower in ICCs with cholangiolar differentiation compared to ICCs with bile ductal differentiation (P <0.05, for both), whereas that of ZEB2 showed no significant difference between two groups. ICCs with cholangiolar differentiation showed better overall survival compared to ICCs with bile ductal differentiation (P = 0.021). ICCs with CRP expression or N-cadherin expression revealed better prognosis compared those without (P <0.05, for all). In conclusion, ICC with cholangiolar differentiation and ICC with bile ductal differentiation are suggested to be distinct based on clinicopathological characteristics. ICC with cholangiolar differentiation is considered to be less aggressive type of ICC with better prognosis compared to ICC with bile ductal differentiation. CRP and N-cadherin are suggested to be good markers for cholangiolar differentiation.