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 management of patients with cHCC-CCA are lacking; and treatment 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 unique biology and heterogeneity. Several majors questions however remain, such as cHCC-CCA cell of origin. Integration of multi-modal data and use of artificial intelligence provide interesting perspectives to further improve patients management, however they will need to be carefully assessed and validated. A better definition and understanding of this entity will be key to further plan clinical trials.

Publication History

Received: 09 August 2025

Accepted after revision: 21 October 2025

Accepted Manuscript online:
24 October 2025