Up-to-Date Pathologic Classification and Molecular Characteristics of Intrahepatic Cholangiocarcinoma

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive primary liver malignancy with an increasing incidence worldwide. Recently, histopathologic classification of small duct type and large duct type iCCA has been introduced. Both these types of tumors exhibit differences in clinicopathological features, mutational profiles, and prognosis. Small duct type iCCA is composed of non-mucin-producing cuboidal cells, whereas large duct type iCCA is composed of mucin-producing columnar cells, reflecting different cells of origin. Large duct type iCCA shows more invasive growth and poorer prognosis than small duct type iCCA. The background liver of small duct type iCCA often shows chronic liver disease related to hepatitis B or C viral infection, or alcoholic or non-alcoholic fatty liver disease/steatohepatitis, in contrast to large duct type iCCA that is often related to hepatolithiasis and liver fluke infection. Cholangiolocarcinoma is a variant of small duct type iCCA composed of naïve-looking cuboidal cells forming cords or ductule-like structures, and shows better prognosis than the conventional small duct type. Fibrous tumor stroma, one of the characteristic features of iCCA, contains activated fibroblasts intermixed with innate and adaptive immune cells. The types of stroma (mature versus immature) are related to tumor behavior and prognosis. Low tumor-infiltrating lymphocyte density, KRAS alteration, and chromosomal instability are related to immune-suppressive tumor microenvironments with resistance to programmed death 1/ programmed death ligand 1 blockade. Data from recent large-scale exome analyses have revealed the heterogeneity in the molecular profiles of iCCA, showing that small duct type iCCA exhibit frequent BAP1, IDH1/2 hotspot mutations and FGFR2 fusion, in contrast to frequent mutations in KRAS, TP53, and SMAD4 observed in large duct type iCCA. Multi-omics analyses have proposed several molecular classifications of iCCA, including inflammation class and proliferation class. The inflammation class is enriched in inflammatory signaling pathways and expression of cytokines, while the proliferation class has activated oncogenic growth signaling pathways. Diverse pathologic features of iCCA and its associated multi-omics characteristics are currently under active investigation, thereby providing insights into precision therapeutics for patients with iCCA. This review provides the latest knowledge on the histopathologic classification of iCCA and its associated molecular features, ranging from tumor microenvironment to genomic and transcriptomic research.

Molecular Profile and Prognostic Value of BAP1 Mutations in Intrahepatic Cholangiocarcinoma: A Genomic Database Analysis

“…Similar to unequivocal results with BAP1 mutations, the BAP1 expression had a complicated association with prognosis in CCA, and available studies reported both prolonged and decreased RFS and OS with BAP1 expression loss, as well as no effect of BAP1 expression on survival [ 37 , 38 , 39 ]. These data further support the complex role of BAP1 in CCA prognosis and point out a need for further research [ 40 , 41 , 42 , 43 ]. At the same time, it is worth noting that available data remain still too scarce to investigate the association between BAP1 mutations and OS and RFS in patients receiving radical surgery, and this link has never been confirmed.…”

Pemigatinib in Intrahepatic Cholangiocarcinoma: A Work in Progress

“…Another key point to consider is the development of resistance to FGFR inhibitors, as all the clinical trials that have explored these agents have shown a median PFS approximately ranging from 6 to 9 months. Several mechanisms have been associated with treatment resistance in patients who have received pemigatinib and other anti-FGFR agents, including feedback survival loop activation, gatekeeper mutations modifying drug access, or mutations impairing the binding site [ 52 , 53 , 54 , 55 ]. Of note, some reports have highlighted that covalent inhibitors may inhibit FGFR due to gatekeeper FGFR2 mutations, which impair the efficacy of pemigatinib and other FGFR inhibitors.…”

Development of extrahepatic bile ducts and mechanisms of tumorigenesis: Lessons from mouse models

“…There are two main types of CCAs: intrahepatic CCA (iCCA) and extrahepatic CCA (eCCA), including both perihilar and distal CCA. These types have differences regarding their etiology, molecular alterations, pathogenesis, behavior, potential diagnostic or prognostic biomarkers, and treatment 12–15 . By introducing this knowledge of CCA into animal models, it may be possible to assess how various genetic mutations and changes are related to the pathophysiology of human disease.…”