Combined Hepatocellular-Cholangiocarcinoma: A Clinical and Molecular Review

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver malignancy characterized by the coexistence of both hepatocellular and biliary morphological differentiation. It is thought to represent less than 5% of all primary liver cancers and is associated with a dismal clinical course. Due to its rarity and inherent diagnostic challenges, consensus guidelines for the management of patients with cHCC-CCA are lacking, and treatments are usually extrapolated from HCC or CCA guidelines. This review provides an overview of the main clinical and histo-molecular features of cHCC-CCA, along with its diagnostic and therapeutic challenges. Technological advances have allowed researchers to progressively elucidate cHCC-CCA's unique biology and heterogeneity. Several major questions, however, remain, such as the cHCC-CCA cell of origin. Integration of multi-modal data and use of artificial intelligence provide interesting perspectives to further improve patient management; however, they will need to be carefully assessed and validated. A better definition and understanding of this entity will be key to further planning clinical trials.