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Peer-reviewedCC BY 4.0Journal of Clinical Medicine

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

  • Lo-Yip Yu1,2,3
  • Hung-Ju Ko1,3
  • Yang-Che Kuo1,2,3
  • Ying-Chun Lin4,5
  • Shou-Chuan Shih1,2,3
  • Chuan-Chuan Liu1,3
  • Kuang-Chun Hu1,2,3,6
6 affiliations
  1. 1Healthy Evaluation Center, Mackay Memorial Hospital, Taipei 10449, Taiwan
  2. 2Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei 10449, Taiwan
  3. 3Department of Medicine, MacKay Medical University, Taipei 104, Taiwan
  4. 4Department of Anesthesiology, Mackay Memorial Hospital, Taipei 10449, Taiwan
  5. 5Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei 104, Taiwan
  6. 6MacKay Junior College of Medicine, Nursing, and Management, Taipei 104, Taiwan
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{yu2026clinical,
  title = {{Clinical Management and Molecular Landscape of Combined Hepatocellular–Cholangiocarcinoma: A Comprehensive Review}},
  author = {Lo-Yip Yu and Hung-Ju Ko and Yang-Che Kuo and Ying-Chun Lin and Shou-Chuan Shih and Chuan-Chuan Liu and Kuang-Chun Hu},
  journal = {Journal of Clinical Medicine},
  year = {2026},
  month = oct,
  doi = {10.3390/jcm15218429},
  url = {https://www.mdpi.com/2077-0383/15/21/8429},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Clinical Management and Molecular Landscape of Combined Hepatocellular–Cholangiocarcinoma: A Comprehensive Review
AU  - Lo-Yip Yu
AU  - Hung-Ju Ko
AU  - Yang-Che Kuo
AU  - Ying-Chun Lin
AU  - Shou-Chuan Shih
AU  - Chuan-Chuan Liu
AU  - Kuang-Chun Hu
PY  - 2026
DA  - 2026/10/29
JO  - Journal of Clinical Medicine
DO  - 10.3390/jcm15218429
UR  - https://www.mdpi.com/2077-0383/15/21/8429
AB  - 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.
SN  - 2077-0383
ER  -