Intrahepatic cholangiocarcinoma: typical features, uncommon variants, and controversial related entities

Pathologists play a central role in the diagnosis and classification of intrahepatic cholangio-carcinoma (iCCA). iCCA is currently classified into small-and large-duct types. Small-duct iCCA is characterized by a mass-forming gross appearance, mucus-poor ductule-like histology, and frequent association with chronic parenchymal liver diseases (eg, cirrhosis). Large-duct iCCA is an infiltrative duct-forming adenocarcinoma with a fibrotic stroma, similar to perihilar cholangiocarcinoma. Chronic cholangiopathies (eg, primary sclerosing cholangitis, liver flukes) are associated with an increased risk of large-duct iCCA. Alterations in IDH1/2, BAP1, or FGFR2 are characteristic molecular features of small-duct iCCA, whereas mutations in KRAS and SMAD4 and the amplification of MDM2 are mainly observed in large-duct iCCA. C-reactive protein and N-cadherin are commonly expressed in small-duct iCCA, and S100P is a good marker for large-duct iCCA. In addition to well-known subtypes (eg, cho-langiolocellular carcinoma), uncommon variants are recognized. A tubulocystic variant is often misin-terpreted as a benign neoplasm. Mucoepidermoid and enteroblastic variants are under-recognized and pose a diagnostic challenge. Cholangioblastic cholangiocarcinoma characterized by inhibin-A expres-sion was recently found to have an NIPBL-NACC1 gene fusion. Despite significant advances in hepa-tobiliary pathology, there are still controversial premalignant entities that require large comprehensive studies. There are morphological overlaps between biliary adenofibroma and the tubulocystic variant of iCCA. Type 2 intraductal papillary neoplasm of the bile duct (IPNB) is typically associated with inva-sive malignancy at the initial presentation and lacks unique molecular features. Therefore, some pa-thologists prefer the term papillary cholangiocarcinoma over type 2 IPNB.(c) 2023 Elsevier Inc. All rights reserved.

Automated summary

Pathologists play a pivotal role in the diagnosis and classification of intrahepatic cholangio-carcinoma (iCCA). iCCA can be divided into small-duct and large-duct types, each with distinct characteristics and molecular features. Chronic liver diseases are associated with small-duct iCCA, while chronic cholangiopathies increase the risk of large-duct iCCA.