Combined Hepatocellular and Cholangiocarcinoma Pathogenesis and Management

Combined hepatocellular and cholangiocarcinoma (cHCC-CCA) is an uncommon yet highly aggressive primary liver malignancy characterised by mixed hepatocytic and biliary differentiation within the same tumour. Its pathogenesis involves complex genetic and epigenetic alterations that give rise to biphenotypic cellular lineages. Recent molecular studies support a monoclonal origin in which a single progenitor cell acquires mutations driving divergent differentiation pathways. Intratumour heterogeneity, stemness traits and interactions with the surrounding microenvironment further complicate diagnostic accuracy and therapeutic targeting. Clinically, the dual nature of cHCC-CCA presents challenges for imaging, biopsy and tumour marker interpretation, often resulting in delayed or suboptimal management. Curative‐intent resection with lymph node assessment remains the cornerstone for eligible patients, yet high rates of recurrence demand novel adjuvant strategies. Liver transplantation is considered in selected cases but lacks uniform criteria. Systemic treatments are extrapolated from hepatocellular carcinoma and cholangiocarcinoma regimens, with emerging interest in immunotherapy and targeted agents. Multidisciplinary collaboration, refined molecular classification and standardised treatment protocols are essential to improve outcomes for this rare cancer that carries a global burden of morbidity and mortality.

Research from Nature Portfolio

Recent studies have shown that deep learning–based phenotyping can distinguish cHCC-CCA from hepatocellular and cholangiocarcinoma subtypes with high accuracy, reclassifying ambiguous cases in line with genetic alterations and clinical prognosis. This approach integrates in situ spatial gene expression profiling to map regional differentiation patterns and may guide personalised treatment decisions. Foundational whole-exome sequencing analyses have revealed that despite substantial private mutations in each component, ubiquitous driver mutations point to a single‐cell origin. These data highlight both monoclonal development and significant intratumour heterogeneity, reinforcing the need for comprehensive genomic profiling to inform targeted therapies.

Combined Hepatocellular and Cholangiocarcinoma Pathogenesis and Management publication trend

The graph below shows the total number of articles in combined hepatocellular and cholangiocarcinoma pathogenesis and management across all publications each year (not limited to Nature Index journals).

Technical terms

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA): A primary liver cancer exhibiting both hepatocytic and biliary differentiation within the same lesion.

Tumour microenvironment (TME): The non-malignant cells, extracellular matrix and signalling molecules surrounding and influencing cancer cells.

Deep learning–based phenotyping: Use of artificial neural networks to classify tumour subtypes and predict behaviour from complex datasets.

Monoclonal origin: Derivation of all tumour components from a single ancestral cell that acquired key driver mutations.

Microvascular invasion (MVI): The presence of cancer cells within small blood vessels adjacent to the primary tumour, associated with recurrence risk.

References

1. Deep learning-based phenotyping reclassifies combined hepatocellular-cholangiocarcinoma. Nature Communications (2023).
2. CD34+CLDN5+ tumor associated senescent endothelial cells through IGF2-IGF2R signaling increased cholangiocellular phenotype in hepatocellular carcinoma. Journal of Advanced Research (2024).
3. An international multicentre evaluation of treatment strategies for combined hepatocellular-cholangiocarcinoma✰. JHEP Reports (2023).
4. Case report: Remarkable response to sintilimab, lenvatinib, and nab-paclitaxel in postoperative metastatic chemotherapy-resistant combined hepatocellular-cholangiocarcinoma. Frontiers in Pharmacology (2023).
5. Whole-exome sequencing reveals the origin and evolution of hepato-cholangiocarcinoma. Nature Communications (2018).