Intrahepatic cholangiocarcinoma: contemporary classification, molecular pathology, and emerging concepts

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive primary liver malignancy with poor outcome. It is characterized by heterogeneous clinicopathological features as well as molecular landscapes. The updated World Health Organization (WHO) classification system underscores the critical distinction between small-duct and large-duct types, which exhibit distinct morphologic patterns, immunohistochemical profiles, molecular alterations, and clinical outcomes. Besides, rare and unique morphologic subtypes of iCCA continue to challenge diagnostic and treatment paradigms. This review provides an overview of the 2026 WHO classification and evolving concepts in iCCA, with a particular emphasis on the practical application of immunohistochemical and emerging molecular biomarkers essential for an accurate diagnosis and guiding targeted therapies. Furthermore, this manuscript addresses contemporary controversies and unresolved emerging practical issues with iCCA that are reshaping personalized therapeutic strategies and prognostication.