Combined hepatocellular-cholangiocarcinoma: a contemporary pathologic and molecular perspective

Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a rare primary liver carcinoma characterized by the unequivocal coexistence of hepatocytic and cholangiocytic differentiation within a single tumor. Despite its low incidence, cHCC-CCA has received considerable attention because of its marked histologic heterogeneity, diagnostic challenges, and poorer clinical outcomes than conventional hepatocellular carcinoma. Historically, the biological nature of cHCC-CCA has been controversial, with competing hypotheses, including derivation from hepatic progenitor cells, collision of independent tumors, and transdifferentiation between hepatocytic and biliary lineages. Recent advances in genomic and transcriptomic profiling have substantially improved this understanding. Accumulating evidence indicates that most cHCC-CCAs arise from a common clonal origin and subsequently undergo divergent differentiation rather than representing true collision tumors. Transcriptomic analyses further demonstrate that cHCC-CCAs span a biological continuum between hepatocellular- and cholangiocytic-like states, with intermediate tumors characterized by lineage plasticity, activation of developmental pathways, and heterogeneous tumor microenvironments. This review provides a pathology-centered overview of cHCC-CCAs, summarizing the key histopathological features and the supportive role of immunohistochemistry, followed by an integrated discussion of recent genomic, transcriptomic, and immune profiling studies. Additionally, it highlights emerging applications of artificial intelligence and digital pathology, which may assist in biological stratification. Collectively, the current evidence supports viewing cHCC-CCA not as a single static entity, but as a spectrum of primary liver carcinomas unified by lineage plasticity, underscoring the importance of integrated pathological and multi-omics approaches for future classification and research.