Clinical Management and Molecular Landscape of Combined Hepatocellular–Cholangiocarcinoma: A Comprehensive Review

Combined hepatocellular–cholangiocarcinoma (cHCC-CCA) is a rare and highly aggressive primary liver cancer. It is distinguished by the unequivocal coexistence of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) components within a single tumor. cHCC-CCA accounts for between 0.4% and 14.2% of primary liver cancers, presenting a complex clinical and pathological challenge because of its dual histological morphology and phenotypic diversity. In the past, its classification faced significant diagnostic challenges. However, these issues have been largely addressed by the 2019 World Health Organization 5th Edition reclassification, which requires clear differentiation of hepatocytic and cholangiocytic features using hematoxylin and eosin (H&E) staining. Recent genomic profiling has shown that cHCC-CCA exists on a molecular spectrum, with about 75% of individual tumors being HCC-like or CCA-like. Biliary-dominant subtypes, similar to CCA, often contain actionable alterations like FGFR2 fusions, IDH1 mutations, and HER2 amplification, providing significant opportunities for precision oncology. In contrast, subtypes resembling HCC are commonly driven by mutations in TP53 and the TERT promoter. Major hepatectomy combined with regional lymphadenectomy continues to be a fundamental curative treatment. However, liver transplantation is increasingly being recognized as a viable option for carefully selected patients with early-stage cirrhosis. In the advanced or recurrent stage, the traditional preferred treatment continues to be cytotoxic gemcitabine combined with platinum-based therapies. Meanwhile, combinations involving immune checkpoint inhibitors, like atezolizumab and bevacizumab, or more complex regimens that integrate locoregional therapy, TKIs, and PD-(L)1 inhibitors, offer hopeful prospects for improving survival rates. This review provided an overview of the current knowledge of the clinical classification, risk stratification, histogenesis, molecular biology and clinical management of cHCC-CCA to inform current management approaches and outline future paths in precision oncology.