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

Pathologists play a central role in the diagnosis and classification of intrahepatic cholangiocarcinoma (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, cholangiolocellular carcinoma), uncommon variants are recognized. A tubulocystic variant is often misinterpreted as a benign neoplasm. Mucoepidermoid and enteroblastic variants are under-recognized and pose a diagnostic challenge. Cholangioblastic cholangiocarcinoma characterized by inhibin-A expression was recently found to have an NIPBL-NACC1 gene fusion. Despite significant advances in hepatobiliary 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 invasive malignancy at the initial presentation and lacks unique molecular features. Therefore, some pathologists prefer the term "papillary cholangiocarcinoma" over type 2 IPNB.