Intraepithelial Neoplasia of Bile Ducts in Nodular Sclerosing Cholangiocarcinoma: Heterogeneous Categories

The most common gross type of cholangiocarcinoma (CCA) of intrahepatic large bile duct and perihilar and distal bile ducts is the nodular-sclerosing type (NS-CCA). Biliary intraepithelial neoplasia (BilIN) is the term to describe flat or micropapillary or papillotubular dysplastic epithelium in the bile duct and is proposed as a preceding lesion of NS-CCA, particularly those associated hepatolithiasis. Its three-grade classification (BilIN-1, -2, and -3) may reflect multistep carcinogenesis of NS-CCA, and BilIN-3 is regarded as carcinoma in situ. Other intraepithelial growth forms of biliary neoplasia are also not infrequently found in the bile ducts around invasive NS-CCA: intraepithelial invasion of periductal invasive carcinoma through the basement membrane of the bile duct (cancerization). Cancerization in the biliary epithelial layer is a variably differentiated adenocarcinoma and presents flat, micropapillary, and papillotubular patterns. Furthermore, in NS-CCA without preceding chronic biliary diseases, intraepithelial neoplasms are also frequently found in the bile ducts; this lesion may be composed of preinvasive neoplasm (corresponding to BilINs) and cancerization from invasive NS-CCA. In conclusion, the intraepithelial neoplasms of the bile ducts in NS-CCAs could be heterogeneous, and the recognition of these subcategories of intraepithelial neoplasms is important for the evaluation of the development of CCAs, and it is also practically important whether surgical margin of bile duct with intraepithelial neoplasm is BilINs or cancerization.