Morphological subclassification of intrahepatic cholangiocarcinoma: etiological, clinicopathological, and molecular features

Abstract

On the basis of morphological features, we subclassified 189 intrahepatic cholangiocarcinomas into two subtypes: bile duct and cholangiolar. The cholangiolar type is composed of cuboidal to low columnar tumor cells that contain scanty cytoplasm. The bile duct type is composed of tall columnar tumor cells arranged in a large glandular pattern. In this study, 77 (41%) tumors were classified as the cholangiolar type and 112 (59%) tumors were classified as the bile duct type. The cholangiolar-type intrahepatic cholangiocarcinoma was more frequently associated with viral hepatitis, whereas all but one intrahepatic cholangiocarcinoma associated with intrahepatic lithiasis were classified as the bile duct type. Biliary intraepithelial neoplasm or intraductal papillary neoplasm of the bile duct could be identified in 50 bile duct-type intrahepatic cholangiocarcinomas (45%), but in only 3 cholangiolar-type intrahepatic cholangiocarcinomas (4%). Cholangiolar-type intrahepatic cholangiocarcinomas frequently expressed N-cadherin, whereas bile duct intrahepatic cholangiocarcinomas were more likely to express S100P, Trefoil factor 1, and anterior gradient 2. KRAS is mutated in 23 of 98 (23%) bile duct-type intrahepatic cholangiocarcinomas and in only 1 of 76 (1%) cholangiolar-type intrahepatic cholangiocarcinomas. Cholangiolar-type intrahepatic cholangiocarcinomas had a higher frequency of IDH1 or 2 mutations than did the bile duct-type intrahepatic cholangiocarcinomas. The molecular features of the bile duct-type intrahepatic cholangiocarcinoma were similar to those of hilar cholangiocarcinoma. Patients with the cholangiolar-type intrahepatic cholangiocarcinoma had higher 5-year survival rates than those of patients with the bile duct-type intrahepatic cholangiocarcinoma. Our results indicated that intrahepatic cholangiocarcinoma was a heterogeneous tumor. Subclassification of intrahepatic cholangiocarcinomas based on cholangiocytic differentiation divides them into two groups with different etiologies, clinical manifestations, and molecular pathogeneses.

Intraductal tubulopapillary neoplasms of the bile ducts: clinicopathologic, immunohistochemical, and molecular analysis of 20 cases

“…Additionally, an attempt was made to further classify the tubular type invasion into the recently proposed categories of 'cholangiolar' or 'bile duct' pattern. 27 …”

“…Forty-four percent were graded as well-differentiated (G1), 50% moderately differentiated (G2), and 6% poorly differentiated (G3). In the recently proposed scheme of classification of cholangiocarcinomas by Liau et al, 27 9/16 (56%) cases were felt to qualify as 'cholangiolar,' 5/16 (31%) of cases were indeterminate, and two cases showed tubulocystic invasion (9%). One of the cases classified as indeterminate had clear cell differentiation reminiscent of the bile duct type (Figure 3e), but besides this case, no convincing examples of 'bile duct type' cases could be identified.…”

“…Both our findings of peculiar invasive carcinoma patterns and our molecular findings seem to indicate that the latter possibility is in play. Along these lines, it may be also interesting to note that even the ordinary invasive adenocarcinomas arising from intraductal tubulopapillary neoplasms are more of the 'cholangiolar' rather than 'bile duct' type in the Liau classification, 27 which were reported to be less aggressive. This may also be a factor in the more indolent behavior of intraductal tubulopapillary neoplasms-associated invasive carcinomas.…”

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

“…Conversely, iCCAs are highly heterogeneous tumours and several classifi cations have been proposed 11,13,17,18 . However, despite differences in nomenclature, iCCAs show two main histological subtypes, reflecting their anatomical origin along the intrahepatic biliary tree: bile ductular type (mixed) (FIG.…”

“…3A), arising from small intrahepatic bile ducts, and bile duct type (mucinous) (FIG. 3B), arising from large intrahepatic bile ducts 11,13,17,18 . Interestingly, this histological sub classification corresponds to different clinico pathological features.…”