Journal of Liver Cancer

Review Articles

Systemic therapy for combined hepatocellular-cholangiocarcinoma: a comprehensive review of chemotherapy, immunotherapy, and targeted therapy: Jung Yong Hong, Dong Hyun Sinn, Sang Yun Ha; J Liver Cancer. 2026;26(1):36-44. Published online March 5, 2026; DOI: https://doi.org/10.17998/jlc.2026.03.02

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Abstract PDF: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver malignancy exhibiting both hepatocytic and cholangiocytic differentiation. Since the 2019 World Health Organization (WHO) reclassification, growing molecular and clinical evidence has reshaped our understanding of this entity. However, patients with cHCC-CCA have been systematically excluded from landmark clinical trials in both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), leaving clinicians without prospective evidence to guide treatment selection. This review comprehensively evaluates the current evidence on systemic therapy for advanced cHCC-CCA, encompassing cytotoxic chemotherapy, immune checkpoint inhibitors (ICIs), tyrosine kinase inhibitors, and molecularly targeted agents. Retrospective data indicate that gemcitabine plus platinum-based chemotherapy achieves the most consistent efficacy among conventional regimens, with median overall survival of 10-16 months. ICIs demonstrate objective response rates of 20-33% with durable responses in a subset of patients, supported by the finding that approximately 57% of cHCC-CCA tumors harbor an immune-high phenotype. Nearly 25% of tumors carry potentially actionable genomic alterations, including fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, and human epidermal growth factor receptor 2 (HER2) amplification. The molecular heterogeneity of cHCC-CCA, with tumors classifiable as HCC-like or CCA-like in approximately 75% of cases, provides a rational framework for personalized treatment selection. We propose an emerging molecular classification-based treatment algorithm and identify critical gaps requiring dedicated prospective investigation. For clinical settings where comprehensive genomic profiling is not feasible, we discuss a pragmatic surrogate-based approach using imaging characteristics and serum tumor markers to guide initial treatment selection. We also address post-progression treatment considerations, including phenotype-based regimen switching and the role of re-biopsy

Epidemiology and genomic features of biliary tract cancer and its unique features in Korea: Seonjeong Woo, Youngun Kim, Sohyun Hwang, Hong Jae Chon; J Liver Cancer. 2025;25(1):41-51. Published online March 4, 2025; DOI: https://doi.org/10.17998/jlc.2025.02.27

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5 Citations

Biliary tract cancer (BTC) is a rare but highly aggressive malignancy that includes intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma, and gallbladder cancer (GBC). While BTC has a low global incidence, its regional variations are notable. Among nations, Korea has the second-highest incidence of BTC globally, with the highest mortality rate worldwide, underscoring the need for a deeper understanding of this cancer. Liver fluke infection and hepatitis B virus infection are key risk factors unique to Korea, contributing to regional differences in BTC incidence. Additionally, genomic alterations in Korean patients with BTC differ from those in other populations, including lower frequencies of IDH1 mutations and FGFR2 fusions in ICC and a higher prevalence of ERBB2 amplification in GBC. Recognizing the clinical significance of these alterations, ivosidenib and pemigatinib have been approved in Korea for BTC patients with IDH1 mutations and FGFR2 fusions, respectively. This review explores the epidemiology, risk factors, and molecular features of BTC, along with corresponding targeted therapies. Furthermore, we compare the unique characteristics of BTC in Korea with global data to inform future research and clinical practice.

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Conditional survival after curative resection for extrahepatic cholangiocarcinoma: a comprehensive analysis of overall, recurrence-free, and relative survival
Hea Lim Choi, Danbee Kang, In Woon Han, Hong Kwan Kim, Hyeong Seok Kim, Sang Hyun Shin, Jin Seok Heo, Dong Wook Shin, Hongbeom Kim
HPB.2026;[Epub] CrossRef
Epidemiologic transition of biliary tract cancers in an endemic region of Korea: insights from a regional cancer center cohort
Aelee Jang, Jonghyun Lee
BMC Gastroenterology.2026;[Epub] CrossRef
Global, regional, and national burden of gallbladder and biliary tract cancer among adults aged 55 years and older, 2010–2021
Mingjuan Li, Jiaguang Li, Shuangjiang Li, Minmin Zhang, Shuang Li, Jiahui Zhao, Tao Gan, Min Wu, Shunwen Luo, Yunying Liang, Qiuyun Li, Guangdong Pan, Jianqing Yang, Guoqing Ouyang
Frontiers in Nutrition.2025;[Epub] CrossRef
Changing patterns of cholangiocarcinoma and gallbladder cancer: A regional perspective from Northeastern Italy
Duygu Kirkik, Ayse Naz Ozabaci, Sevgi Kalkanli Tas
World Journal of Gastrointestinal Oncology.2025;[Epub] CrossRef
Gallbladder large cell neuroendocrine carcinoma in a patient with multiple myeloma: a case report and literature review
Yuhan Yin, Xinjie Dai, Dan Li, Xinyu Yang, Nan Ming, Kang Xiang, Dengding Wu, Kong Ai, Rucheng Yao, Jun Hu
Frontiers in Oncology.2025;[Epub] CrossRef

Molecular and immune landscape of hepatocellular carcinoma for therapeutic development: Hiroyuki Suzuki, Sumit Mishra, Subhojit Paul, Yujin Hoshida; J Liver Cancer. 2025;25(1):9-18. Published online December 6, 2024; DOI: https://doi.org/10.17998/jlc.2024.12.02

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9 Citations

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Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with an estimated 750,000 deaths in 2022. Recent emergence of molecular targeted agents and immune checkpoint inhibitors and their combination therapies have been transforming HCC care, but their prognostic impact in advanced-stage disease remains unsatisfactory. In addition, their application to early-stage disease is still an unmet need. Omics profiling studies have elucidated recurrent and heterogeneously present molecular aberrations involved in pro-cancer tumor (immune) microenvironment that may guide therapeutic strategies. Recurrent aberrations such somatic mutations in TERT promoter and TP53 have been regarded undruggable, but recent studies have suggested that these may serve as new classes of therapeutic targets. HCC markers such as alpha-fetoprotein, glypican-3, and epithelial cell adhesion molecule have also been explored as therapeutic targets. These molecular features may be utilized as biomarkers to guide the application of new approaches as companion biomarkers to maximize therapeutic benefits in patients who are likely to benefit from the therapies, while minimizing unnecessary harm in patients who will not respond. The explosive number of new agents in the pipelines have posed challenges in their clinical testing. Novel clinical trial designs guided by predictive biomarkers have been proposed to enable their efficient and cost-effective evaluation. These new developments collectively facilitate clinical translation of personalized molecular-targeted therapies in HCC and substantially improve prognosis of HCC patients.

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A novel link between tumor cell metabolism and patient prognosis: Editorial on “Molecular classification of hepatocellular carcinoma based on zoned metabolic feature and oncogenic signaling pathway”
Eun Ji Jang, Pil Soo Sung
Clinical and Molecular Hepatology.2026; 32(1): 420. CrossRef
Citrullinated matrisome: An emerging stromal determinant in hepatocellular carcinoma prognostication
Zhi-Feng Xu, Yu-Ru Yao, Shen-Yi Ye, Cheng-Fei Zhao
World Journal of Gastrointestinal Oncology.2026;[Epub] CrossRef
Strategic drug sequencing in hepatocellular carcinoma in the era of chemo-diversity: maximizing the therapeutic benefit of lenvatinib
Hideki Iwamoto, Shigeo Shimose, Hironori Koga, Takumi Kawaguchi
Journal of Liver Cancer.2026; 26(1): 83. CrossRef
Global Clinical Trial Landscape of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Where Are We Headed?
K. Luo, S. Liu, Y. Liu
Clinical Oncology.2026; 54: 104157. CrossRef
Paracancerous binuclear hepatocytes assessed by computer program is a novel biomarker for short term recurrence of hepatocellular carcinoma after surgery
Yifan Zhang, Yiquan Lu, Nan Wang, Fengjie Hao, Yongjun Chen, Xiaochun Fei, Junqing Wang
Scientific Reports.2025;[Epub] CrossRef
Differential Infiltration of T-Cell Populations in Tumor and Liver Tissues Predicts Recurrence-Free Survival in Surgically Resected Hepatocellular Carcinoma
Eun Ji Jang, Ho Joong Choi, Young Kyoung You, Deok Hwa Seo, Mi Hyun Kwon, Keungmo Yang, Jaejun Lee, Jeong Won Jang, Seung Kew Yoon, Ji Won Han, Pil Soo Sung
Cancers.2025; 17(9): 1548. CrossRef
Decision-Making Biomarkers Guiding Therapeutic Strategies in Hepatocellular Carcinoma: From Prediction to Personalized Care
Dongming Liu, Norihiro Imai
Cancers.2025; 17(19): 3105. CrossRef
YKL-40 in Virus-Associated Liver Disease: A Translational Biomarker Linking Fibrosis, Hepatocarcinogenesis, and Liver Transplantation
Jadranka Pavicic Saric, Dinka Lulic, Dunja Rogic, Stipislav Jadrijevic, Danko Mikulic, Tajana Filipec Kanizaj, Nikola Prpic, Laura Karla Bozic, Ivona Adamovic, Iva Bacak Kocman, Zrinka Sarec, Gorjana Erceg, Mirta Adanic, Petra Ozegovic Zuljan, Filip Jadri
International Journal of Molecular Sciences.2025; 26(19): 9584. CrossRef
Clinical significance of citrullinated glial fibrillary acidic protein in predicting outcomes in hepatocellular carcinoma
Yoon Ah Cho, Dong Woo Shin, Mo-Jong Kim, Ji-Won Park, Ji-Young Choe, Jung-Woo Lee, Sung-Hoon Moon, Akihito Ishigami, Eun Kyoung Choi, Sung-Eun Kim
World Journal of Gastrointestinal Oncology.2025;[Epub] CrossRef

Systemic Therapy for Advanced Hepatocellular Carcinoma: Targeted Therapy and Immunotherapy: Kim, Bo Hyun , Park, Joong Won; J Liver Cancer. 2018;18(1):17-22. Published online March 31, 2018; DOI: https://doi.org/10.17998/jlc.18.1.17

4,127 Views
81 Downloads
2 Citations

Abstract PDF

Systemic therapy for hepatocellular carcinoma (HCC) has markedly changed since 2007, with the approval of sorafenib. Sorafenib improved the overall survival of patients with advanced HCC; however, the modest efficacy and toxicity of this therapy present unmet needs. Subsequently, a variety of molecular targeted agents have been tested as first-line or secondline therapies but have failed, and sorafenib has remained the only approved systemic agent for almost 10 years. Recently, regorafenib significantly improved overall survival and was approved for patients with HCC who have been previously treated with sorafenib. Nivolumab, a programmed death protein-1 inhibitor, was also approved as second-line therapy, based on remarkable response rates.

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Sequential Use of Sorafenib and Regorafenib in Hepatocellular Cancer Recurrence After Liver Transplantation: Treatment Strategies and Outcomes
Mehmet Fatih Ozbay, Hakan Harputluoglu, Mustafa Karaca, Omer Tekin, Mehmet Ali Nahit Şendur, Muhammed Ali Kaplan, Berksoy Sahin, Caglayan Geredeli, Fatih Teker, Deniz Tural, Sezer Saglam, Timuçin Çil, Ahmet Bilici, Cihan Erol, Ziya Kalkan, Ertugrul Bayram
Cancers.2024; 16(22): 3880. CrossRef
Analysis of Existing Guidelines and Randomized, Controlled, Clinical Trials for Development of [Guideline of Clinical Trial on Herbal Medicinal Product for Liver Cancer]
Ga-jin Han, Dong-hun Kim, Eun-joo Park, Sin Seong, Sung-su Kim, Jung-tae Leem
The Journal of Internal Korean Medicine.2019; 40(1): 89. CrossRef

Case Report

A Case of Management for Hepatocellular Carcinoma with Lung Metastasis: Han Jo Jeon, Tae Hyung Kim, Soon Ho Um, Yeon Seok Seo, Hyun Seo Kim, Ki Joon Lim, Seung Woon Park, Han Ah Lee, Dong-Sik Kim; J Liver Cancer. 2016;16(2):129-133. Published online September 30, 2016; DOI: https://doi.org/10.17998/jlc.16.2.129

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Abstract PDF: Liver cancer is the 2nd most common cause of cancer related death in Korea. Especially, patients who present extrahepatic spread of hepatocellular carcinoma (HCC) have a shorter life expectancy (50% survival at 1 year and less than 4 months of median overall survival). Molecular target agent like sorafenib was usually mentioned as a treatment for them, but that was still not firmly established. We present a 75 year-old who had expanding nodular type of HCC. The mass was removed by resection and radiofrequency ablation. However, lung metastasis were revealed shortly after surgery. That lesions were treated with lenvatinib and systemic chemotherapy.

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