Dichotomy in intrahepatic cholangiocarcinomas based on histologic similarities to hilar cholangiocarcinomas

Abstract

Intrahepatic cholangiocarcinomas were classified into two types based on their microscopic appearance. Tumors with histologic similarities to hilar cholangiocarcinomas (predominantly ductal adenocarcinomas with minor tubular components, if present, restricted to the invasive front) were defined as the perihilar type, whereas the others were classified as peripheral cholangiocarcinomas. Among the 47 cases examined in the present study, 26 (55%) were classified as the perihilar type, whereas 21 (45%) were the peripheral type. The perihilar type had higher pT stages and more frequently showed a periductal-infiltrating gross appearance and microscopic perineural infiltration than peripheral cholangiocarcinomas. The presence of low-grade biliary intraepithelial neoplasia in the adjacent bile ducts was only found in perihilar cholangiocarcinomas (6/21, 29%). The immunophenotype also differed between the two types with MUC5AC and MUC6 being more commonly expressed in the perihilar type. One-third of perihilar cholangiocarcinomas lacked the expression of SMAD4, suggesting SMAD4 mutations, whereas the loss of BAP1 expression and IDH1 mutations were almost restricted to the peripheral type (35 and 15%, respectively). Patients with perihilar cholangiocarcinoma had worse overall survival than those with peripheral cancer (P=0.027). A multivariate analysis identified the histologic classification as an independent prognostic factor (P=0.005, HR=3.638). Comparisons between intrahepatic and hilar cholangiocarcinomas also revealed that the molecular features and prognosis of perihilar cholangiocarcinomas were very similar to those of hilar cholangiocarcinomas. In conclusion, this histology-based classification scheme of intrahepatic cholangiocarcinomas will be useful and clinically relevant because it represents different underlying molecular features and has an independent prognostic value.

Proteomic Landscape of Cholangiocarcinomas Reveals Three Different Subgroups According to Their Localization and the Aspect of Non‐Tumor Liver

“…Cluster 1 contained most of the iCC C (7/8), while cluster 2 included two subgroups, one composed of most of the iCC N (7/9) and one regrouping CC H and CC P . Altogether, these data clearly demonstrate that, among CC, 1) iCC C defines a specific entity, and 2) CC H and CC P are very close, belonging to a common entity, confirming genomic molecular signatures …”

Interleukin‐33 overexpression reflects less aggressive tumour features in large‐duct type cholangiocarcinomas

“…This histology-based classification also closely correlates with underlying genetic features, with IDH1 and BAP1 mutations and FGFR2 fusions being highly specific for small-duct cases, and the loss of SMAD4 expression and MDM2 amplification being mostly restricted to large-duct cases. 5,6 Furthermore, the clinicopathological and molecular features of large-duct iCCAs are very similar to those of pCCAs, with similar postoperative survival, indicating that these two may be grouped together distinctly from small-duct iCCAs.…”

“…The study cohort consisted of 55 consecutive patients with iCCA and 32 patients with pCCA who underwent surgical resection at Kobe University Hospital between 2008 and 2016. Cases were classified into small‐duct ( n = 33) and large‐duct ( n = 22) types on the basis of the recently proposed morphological standard . Briefly, small‐duct iCCAs were defined as cancers with tubular components, at least focally, in the central parts of tumours, whereas large‐duct iCCAs were adenocarcinomas with a predominantly ductal morphology and minor tubular components, if present, restricted to the tumour–liver interface (Figure ).…”

“…Sequencing results were analysed with sequencing analysis 5.2 (Applied Biosystems). Some mutational data were used in our previous study …”

“…Recent studies reported that iCCAs may be classified into small-duct and large-duct types with distinct pathological features. 5,6 According to our proposed histopathological criteria for this separation scheme,~60% of surgically resected iCCAs were classified as the small-duct type, and the remainder were classified as the large-duct type. A history of chronic liver diseases was more commonly observed in patients with small-duct iCCA than in those with large-duct iCCA (62% versus 15%).…”