Journal of Liver Cancer

Original Articles

Enhancing non-LR-5 liver lesion diagnoses: the incremental value of serum alpha-fetoprotein and PIVKA-II for detecting hepatocellular carcinoma components: Junghoan Park, Jeong Min Lee, Rae Rim Ryu, Seok Jin Hong; Received December 15, 2025 Accepted May 26, 2026 Published online June 26, 2026; DOI: https://doi.org/10.17998/jlc.2026.05.26 [Accepted]

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Abstract PDF: Backgrounds/Aims
To investigate whether incorporating serum alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) into gadoxetic acid-enhanced liver MRI improves the accuracy of differentiating hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular-cholangiocarcinoma (cHCC-CC) from non-LR-5 lesions.
Methods
This retrospective study included 123 patients comprising 70 HCC, 30 ICC, and 23 cHCC-CC cases who underwent preoperative MRI and tumor marker analysis. Two abdominal radiologists independently interpreted the MRI without markers (Decision 1). Then, lesions were reclassified as HCC if either marker was elevated, regardless of the initial interpretation (Decision 2, biomarker-assisted override strategy). Outcomes included the diagnostic performance for identifying HCC versus non-HCC malignancies and distinguishing the presence of HCC components (HCC or cHCC-CC) from ICC. The McNemar’s test and Cohen’s κ compared diagnostic performance and evaluated interobserver agreement, respectively.
Results
Adding AFP and PIVKA-II (Decision 2) improved the sensitivity and accuracy of detecting HCC components from 62.4–76.3% to 81.7–90.3% (P<0.001) and 66.7–76.4% to 81.3–87.0% (P<0.001), respectively. The overall accuracy for differentiating HCC from non-HCC malignancies did not improve. However, the accuracy for detecting HCC in small tumors (<3 cm) significantly improved from 68.8–72.5% to 81.3–82.5% (P= 0.002–0.008). Interobserver agreement also increased, from moderate (κ = 0.48) to substantial (κ = 0.68) after adding tumor marker values.
Conclusions
In non-LR-5 hepatic lesions, adding AFP and PIVKA-II to MRI interpretations significantly improved the accuracy of identifying HCC components, as well as HCC detection in small tumors.

Outcomes of Early-Stage HCC patients treated by resection or ablation: real-life data from the French administrative health care database (SNDS): Marie Decraecker, Boris Guiu, Emmanuel Boleslawski, Pierre Nahon, Manel Dhaoui, Danko Stamenic, Moreau Manoel, Alicia Fravalo, Jean Frédéric Blanc; Received January 16, 2026 Accepted April 24, 2026 Published online May 14, 2026; DOI: https://doi.org/10.17998/jlc.2026.04.24 [Accepted]

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Abstract PDF: Background/Aims
Surgical resection and percutaneous ablation are considered curative treatments for hepatocellular carcinoma (HCC). However, both approaches are associated with a high risk of recurrence. Real-world data on outcomes and post-curative management remain scarce. This study aimed to assess survival and healthcare pathways of patients treated with resection or ablation in routine clinical practice.
Methods
We conducted a retrospective analysis using the French National Health Data System. Patients who underwent resection or percutaneous ablation as first-line treatment for HCC between January 2014 and December 2021 were included. The primary endpoint was overall survival (OS); secondary endpoints focused on subsequent treatment sequences and healthcare pathways
Results
Among 10,810 patients included, 5,488 underwent ablation and 5,322 resection as first-line treatment. One- and two-year OS rates were 90% and 78% after ablation (median OS [mOS] 56 months, 95% CI [54–58]) and 88% and 80% after resection (mOS 75 months, 95% CI [72–79]). Median time to next treatment or death was 20 months (95% CI [18–21]) after ablation and 29 months (95% CI [27–30]) after resection. Following initial treatment, 27% of patients in the ablation group and 39% in the resection group received no further therapy.
Conclusions
This nationwide real-world study provides comprehensive data on survival and treatment sequences after curative-intent therapy for HCC in France. Despite frequent recurrence, survival outcomes remained favourable, reflecting access to repeated and effective subsequent treatments, underscoring the importance of long-term follow-up in routine care.

Pain, analgesic use and misconceptions in patients with hepatocellular carcinoma: a cross-sectional survey: Jina Park, Jiwon Yang, Sung Won Chung, Won-Mook Choi, Ju Hyun Shim, Danbi Lee, Kang Mo Kim, Young-Suk Lim, Han Chu Lee, Jonggi Choi; Received January 15, 2026 Accepted March 19, 2026 Published online April 29, 2026; DOI: https://doi.org/10.17998/jlc.2026.03.19 [Epub ahead of print]

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Abstract PDF Supplementary Material: Backgrounds/Aims
Cancer-related pain remains undertreated despite established guidelines. In hepatocellular carcinoma (HCC), underlying chronic liver disease may amplify concerns regarding analgesic safety. We aimed to evaluate pain prevalence, analgesic use, pain-related perceptions, and educational needs among patients with HCC.
Methods
We conducted a cross-sectional survey of 200 adult patients with HCC receiving systemic therapy at a tertiary referral center. A 30-item questionnaire assessed pain presence and intensity using a numeric rating scale (NRS), analgesic use patterns, liver-related safety concerns, opioid-related stigma, and educational needs. Clinical characteristics, including tumor burden and liver function, were analyzed in relation to pain and perception domains.
Results
Fifty-five patients (27.5%) reported current pain (mean NRS, 3.6±2.5; mean worst pain 5.2±2.8). Among them, 31 patients (56.3%) were using analgesics; however, 51.6% reported using them only when pain became unbearable. Misconceptions regarding analgesic safety were prevalent: 70.0% believed long-term analgesic use damages the liver, 56.0% believed analgesics are unsafe with impaired liver function, 46.5% associated opioids with addiction, and 30.0% hesitated due to the term “narcotic.” These beliefs were not associated with Child-Pugh class or serum albumin level. Extrahepatic metastasis was associated with higher liver-related concern scores and a trend toward increased pain prevalence. Patients with elementary school education or less had poorer pain scale knowledge and no prior counseling.
Conclusions
Pain undertreatment and safety-related misconceptions are common in HCC and appear independent of objective liver function. Structured, proactive education, particularly for patients with untreated pain and low educational attainment, may improve pain control in this population.

Review Articles

Combined hepatocellular-cholangiocarcinoma: a contemporary pathologic and molecular perspective: Taek Chung; J Liver Cancer. 2026;26(1):1-8. Published online March 9, 2026; DOI: https://doi.org/10.17998/jlc.2026.03.06

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Abstract PDF

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.

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Curative Effect Evaluation of Targeted Therapy and Chemotherapy for Non-Resectable Combined Hepatocellular-Cholangiocarcinoma: A Systematic Review and Meta-Analysis
永豪林
Advances in Clinical Medicine.2026; 16(05): 920. CrossRef

Imaging differentiation of hepatocellular carcinoma, combined hepatocellular-cholangiocarcinoma, and intrahepatic cholangiocarcinoma: pitfalls and advances: Jaeseung Shin, Taek Chung, Sang Yun Ha, Hyungjin Rhee; J Liver Cancer. 2026;26(1):9-18. Published online March 5, 2026; DOI: https://doi.org/10.17998/jlc.2026.03.05

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126 Downloads

Abstract PDF: Accurate non-invasive differentiation of primary liver cancers, such as hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and combined hepatocellular-cholangiocarcinoma (cHCC-CCA), is crucial for optimal management but challenging due to shared risk factors and overlapping imaging phenotypes. While the Liver Imaging Reporting and Data System category M effectively captures the classic targetoid appearance of large duct type iCCA, the small duct type frequently exhibits HCC-mimicking non-rim arterial phase hyperenhancement and non-peripheral washout, potentially compromising diagnostic specificity. Furthermore, cHCC-CCA presents a formidable diagnostic dilemma, existing on a continuous imaging spectrum that reflects its histologic dominance. This continuous imaging spectrum not only blurs radiologic distinctions but also complicates tissue sampling, limiting the diagnostic accuracy of core needle biopsies and highlighting the risk of misclassification. To enhance diagnostic clarity, this review highlights their key imaging hallmarks: while HCC typically shows non-rim arterial phase hyperenhancement (APHE) and non-peripheral washout, large duct iCCA displays a classic targetoid appearance with rim APHE and progressive central enhancement. Conversely, small duct iCCA often mimics HCC, and cHCC-CCA exhibits a variable spectrum depending on its predominant histologic component. Ultimately, overcoming these diagnostic pitfalls requires a rigorous, multidisciplinary approach that synthesizes imaging findings, serologic tumor markers, and clinical contexts.

The role of radiotherapy in the management of combined hepatocellular-cholangiocarcinoma: current evidence and future perspectives: Seo Hee Choi, Woong Sub Koom, Ik Jae Lee; J Liver Cancer. 2026;26(1):55-64. Published online March 5, 2026; DOI: https://doi.org/10.17998/jlc.2026.03.04

3,213 Views
73 Downloads
1 Web of Science

Abstract PDF: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare and highly aggressive hybrid malignancy characterized by a poor prognosis and high recurrence rates due to its dual histological nature. In the absence of established standard-of-care protocols, clinical management strategies are frequently extrapolated from the guidelines for its components, hepatocellular carcinoma and intrahepatic cholangiocarcinoma (iCCA). This review evaluates the evolving role of radiotherapy (RT) as an integral part of the multidisciplinary care for cHCC-CCA. Adjuvant RT may be considered for patients exhibiting high-risk pathological features, such as positive or close resection margins, lymphovascular invasion, and perineural invasion. For unresectable disease unfeasible for surgery or transarterial therapies, definitive RT using intensified doses, analogous to iCCA protocols, is employed to improve local control. High-precision modalities, particularly particle therapies such as proton or carbon ion RT, are emphasized as preferred options for delivering ablative doses while minimizing toxicity and preserving functional liver reserve. Furthermore, preliminary clinical evidence suggests a potential synergy between RT and immune checkpoint inhibitors, with reported cases demonstrating complete responses or successful conversion to curative-intent resection. While current evidence remains limited to retrospective cohorts and case series, the strategic integration of precision RT offers a rational pathway for optimizing outcomes in cHCC-CCA, necessitating further prospective validation.

Contemporary overview of liver transplantation for intrahepatic cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma: Hae Won Lee; J Liver Cancer. 2026;26(1):29-35. Published online March 5, 2026; DOI: https://doi.org/10.17998/jlc.2026.03.03

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63 Downloads

Abstract PDF: Historically, intrahepatic cholangiocarcinoma (iCCA) and combined hepatocellular-cholangiocarcinoma (cHCC-CCA) were regarded as absolute contraindications for liver transplantation (LT) due to dismal outcomes characterized by high recurrence rates and poor long-term survival in early experiences. Consequently, these malignancies have been systematically excluded from standard transplant criteria for decades. However, the landscape of transplant oncology is undergoing a significant paradigm shift, driven by a deeper understanding of tumor biology and refined patient selection strategies. Recent multicenter retrospective studies have identified a distinct subgroup of patients-specifically those with “very early” iCCA in the setting of cirrhosis-who achieve excellent post-transplant outcomes comparable to those of hepatocellular carcinoma. This evidence has prompted major international societies to update their guidelines, cautiously opening the door for LT in this selected population. Conversely, cHCC-CCA remains a diagnostic and therapeutic challenge. This narrative review critically analyzes the pivotal data driving the current paradigm shift and synthesizes the latest clinical practice guidelines to provide a contemporary roadmap for the management of iCCA and cHCC-CCA in the transplant setting.

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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111 Downloads
1 Citation

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

Citations

Citations to this article as recorded by

Curative Effect Evaluation of Targeted Therapy and Chemotherapy for Non-Resectable Combined Hepatocellular-Cholangiocarcinoma: A Systematic Review and Meta-Analysis
永豪林
Advances in Clinical Medicine.2026; 16(05): 920. CrossRef

Systemic treatment strategies for combined hepatocellular-cholangiocarcinoma: current evidence and future direction: Jeesun Yoon; J Liver Cancer. 2026;26(1):45-54. Published online February 26, 2026; DOI: https://doi.org/10.17998/jlc.2026.02.24

1,580 Views
54 Downloads
1 Citation

Abstract PDF

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare primary liver malignancy characterized by biphenotypic differentiation and marked biologic heterogeneity. Owing to its low incidence, diagnostic complexity, and lineage plasticity, standardized systemic treatment strategies remain undefined. Molecular and pathologic studies suggest a progenitor cell origin, with tumors exhibiting genomic, transcriptomic, and immunologic features overlapping with both hepatocellular carcinoma and intrahepatic cholangiocarcinoma. This heterogeneity contributes to variable therapeutic responsiveness and underscores the need for biologically informed treatment approaches. Current systemic treatment evidence is derived predominantly from retrospective analyses. Platinum-based cytotoxic chemotherapy has demonstrated modest but consistent clinical activity and remains the most commonly adopted palliative backbone. More recently, immunotherapy has shown encouraging anti-tumor activity, including combination strategies incorporating anti-angiogenic agents. Biomarker signals provide mechanistic rationale for immune-angiogenic therapeutic integration. Emerging platforms, including programmed cell death-1 (PD-1)/vascular endothelial growth factor (VEGF) bispecific antibodies, further expand the systemic treatment landscape. In parallel, multimodal strategies integrating locoregional interventions with systemic therapy are gaining traction, particularly for patients with liver-dominant disease. Despite these advances, prospective disease-specific trials remain lacking, and optimal therapeutic sequencing and patient selection strategies are yet to be defined. Future progress will depend on biomarker-driven trial design, incorporation of molecular lineage stratification, and rational combination approaches. A deeper understanding of the pathological and molecular architecture of cHCC-CC will be essential to establish optimized, disease-specific systemic treatment paradigms for this rare but clinically challenging malignancy.

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A Comprehensive Understanding of DCTPP1 as an Emerging Therapeutic Target in Liver Cancer
Hye In Ka, Se Ha Jang, Hyung Seok Kim, Hyun Sun Jung, Jung Woo Eun
Current Issues in Molecular Biology.2026; 48(8): 770. CrossRef

Original Article

Liver resection versus radiofrequency ablation or transarterial chemoembolization for early multinodular BCLC-A hepatocellular carcinoma: a systematic review and meta-analysis: Maria F. F. Viana, Arthur A. Braga, Lucas B. Carvalho, Danilo C. M. S. Vasconcellos, Bianca C. M. R. Alexandrino, Felipe J. F. Coimbra; J Liver Cancer. 2026;26(1):157-168. Published online February 26, 2026; DOI: https://doi.org/10.17998/jlc.2026.02.21

2,241 Views
91 Downloads

Abstract PDF Supplementary Material: Backgrounds/Aims
Hepatocellularcarcinoma (HCC) is the most common form of liver cancer, with high mortality rates worldwide. The optimal treatment strategy for patients with multinodular early-stage HCC (BCLC-A) is still controversial, particularly regarding liver resection (LR), radiofrequency ablation (RFA), and transarterial chemoembolization (TACE). This meta-analysis aims to evaluate the overall survival (OS) and disease-free survival (DFS) in patients with multinodular BCLC-A HCC treated with LR compared to RFA and TACE.
Methods
A systematic literature review and meta-analysis were performed by searching PubMed, Embase, and the Cochrane Library for studies comparing LR with RFA and TACE. Pooled analyses of OS and DFS were performed using hazard ratios (HR) with 95% confidence intervals (CI).
Results
Fifteen studies, including two randomized controlled trials and 13 cohort studies, with a total of 2,869 patients, were included. LR was significantly associated with improved OS (HR, 1.38; 95% CI, 1.03-1.84; P=0.01) and DFS (HR, 2.16; 95% CI, 1.26-3.70; P=0.001) compared with RFA. Similarly, LR demonstrated superior OS (HR, 2.11; 95% CI, 1.37-3.25; P<0.0001) and DFS (HR, 2.77; 95% CI, 1.04-7.36; P=0.04) when compared with TACE. The more pronounced benefit observed for DFS likely reflects improved local tumor control achieved with surgical resection.
Conclusions
In selected patients with multinodular BCLC-A HCC and preserved liver function (predominantly Child-Pugh A or B), LR is associated with significant improvements in OS and DFS compared with RFA and TACE when liver transplantation is not feasible. These findings support reconsideration of current treatment algorithms to prioritize LR in appropriately selected candidates.

Review Articles

Immune-related adverse events in hepatocellular carcinoma: organ-specific patterns and management approaches: Sul Ki Choi, Seonjeong Woo, Hong Jae Chon; J Liver Cancer. 2026;26(1):65-82. Published online December 29, 2025; DOI: https://doi.org/10.17998/jlc.2025.12.21

2,984 Views
200 Downloads
2 Web of Science
2 Citations

Abstract PDF

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. The recent introduction of immune checkpoint inhibitors (ICIs) has transformed the therapeutic landscape for advanced HCC. Combination regimens such as atezolizumab plus bevacizumab, durvalumab plus tremelimumab, and nivolumab plus ipilimumab have demonstrated significant survival improvements over conventional tyrosine kinase inhibitors and have become the new standard of care. However, ICIs can trigger immune-related adverse events (irAEs) through overactivation of the immune system, affecting multiple organs including the skin, gastrointestinal tract, liver, endocrine system, lungs, and heart. Patients with HCC frequently have underlying liver diseases such as chronic hepatitis or cirrhosis, placing them at higher risk of hepatic irAEs compared to that with other cancer types, which can markedly influence prognosis. The pathophysiology of irAEs is driven by a series of interconnected immune mechanisms, including excessive T-cell activation, disruption of immune tolerance, cytokine dysregulation, complement-mediated injury, and innate immune activation. Clinical decisions regarding the continuation, interruption, or discontinuation of ICIs, as well as the administration of corticosteroids or immunosuppressants, should be guided by the severity of toxicity. Organ-specific management strategies and multidisciplinary collaboration are essential, particularly for severe presentations. This review summarizes the incidence, mechanisms, and management strategies for ICI-related irAEs in advanced HCC, and provides practical insights for clinical decision-making.

Citations

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Response: Reassessing the Use of Nivolumab Plus Ipilimumab After Atezolizumab Plus Bevacizumab in Advanced HCC
Jung Sun Kim, Thomas Yau, Hong Jae Chon
Liver International.2026;[Epub] CrossRef
Comparative efficacy and safety of first-line treatments for advanced hepatocellular carcinoma: a Bayesian network meta-analysis
Yun Su, Tongze Cai, Jingxuan Wei, Qiuju Huang, Chun Yao, Lei Fu, Jinghui Zheng, Hongwei Guo, Xiongbin Gui
Frontiers in Immunology.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; J Liver Cancer. 2026;26(1):83-92. Published online December 27, 2025; DOI: https://doi.org/10.17998/jlc.2025.12.12

1,922 Views
115 Downloads

Abstract PDF: The emergence of systemic therapies has ushered in an era of chemo-diversity for hepatocellular carcinoma, in which drug sequencing is pivotal for maximizing outcomes. Among available agents, lenvatinib is notable for its potent anti-angiogenic and immunomodulatory properties. This review proposes a structured building-block strategy for optimizing sequential drug therapy, conceptualizing each treatment line as a block that contributes cumulatively to survival, and grounding the discussion in clinical insights from lenvatinib administration. We comprehensively evaluated clinical trials, preclinical investigations, and real-world data to identify actionable approaches that enhance tolerability and prolong progression-free survival, with a particular focus on mitigating adverse events, optimizing dosing schedules, and integrating with transarterial therapies. Five refinements emerge as central to maximizing therapeutic benefit: early detection and classification of adverse events, use of supportive agents such as L-carnitine and branched-chain amino acids, structured telephone follow-up, optimization of dosing schedules, including weekend-off regimens, and strategic combination with transarterial therapy. In addition, rationale-based sequencing and clinically relevant switching criteria that extend beyond RECIST are summarized. Collectively, these measures increase the height of each therapeutic block, thereby contributing to cumulative survival within the building-block strategy. In the current era of chemo-diversity, lenvatinib remains a cornerstone agent when accompanied by these clinical refinements. The review provides a practical and conceptual framework for enhancing efficacy through structured sequencing, proactive adverse-event mitigation, and synergistic locoregional strategies, with broad applicability to real-world clinical practice.

Case Report

A rare case of IgG4-related sclerosing cholangitis followed by rapid subsequent diagnosis of cholangiocarcinoma: Gordon Hong, Amber Hussain, Eduardo Thadeu de Oliveira Correia, Akram Shalaby, Leonardo K. Bittencourt, Amit Mahipal, Lee M. Ocuin, Seth N. Sclair; J Liver Cancer. 2026;26(1):169-175. Published online December 17, 2025; DOI: https://doi.org/10.17998/jlc.2025.12.09

1,508 Views
71 Downloads

Abstract PDF: Immunoglobulin G4 (IgG4)-related sclerosing cholangitis (IgG4-SC) is a rare condition with symptoms often mimicking malignancy, infection, or other autoimmune diseases. This case report describes the unique case of a 62-year-old male initially diagnosed with IgG4-SC, followed by subsequent diagnosis of cholangiocarcinoma. Biliary tract cancer in the setting of IgG4 related disease has been previously described; however, this patient course is novel as it encompasses the spectrum of challenges in IgG4-SC management, including diagnostic uncertainty, risk of infection with immunosuppressive agents, and development of malignancy diagnosed shortly following IgG4-SC diagnosis. We review the literature of management, outcomes, and malignancy risk and furthermore, highlight a promising recent therapy in treatment of IgG4 related disease, inebilizumab.

Review Article

Exploring single-cell and multi-omics technologies and their role in unraveling tumor heterogeneity of hepatocellular carcinoma: Charmi Jyotishi, Suresh Prajapati, Mansi Patel, Reeshu Gupta; J Liver Cancer. 2026;26(1):104-123. Published online December 17, 2025; DOI: https://doi.org/10.17998/jlc.2025.11.29

2,233 Views
88 Downloads
4 Web of Science
4 Citations

Abstract PDF

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Tumor heterogeneity is a major obstacle to effective treatment and is poorly understood using traditional bulk sequencing methods. This review highlights the transformative role of single-cell and multi-omics technologies in determining the cellular and molecular complexities of HCC. We summarize recent advances in single-cell transcriptomics, epigenomics, multi-omics, and spatial transcriptomics platforms, emphasizing their applications in characterizing tumor subclones, cancer-associated fibroblast-immune interactions, circulating tumor cells, and immune-resistant phenotypes. Spatial approaches have revealed the architecture of cancer stem cell niches and tertiary lymphoid structures, providing unprecedented insights into tumor organization and microenvironmental crosstalk. Although still in their early stages, clinical trials have begun to incorporate these technologies, underscoring their translational potential. Single-cell and spatial omics have reshaped HCC research by enabling high-resolution profiling of tumor ecosystems and driving the discovery of biomarkers, therapeutic targets, and strategies for patient stratification. However, high cost, technical expertise, and limited accessibility, particularly in resource-constrained settings, are major barriers to its widespread adoption. Addressing these challenges is critical for translating these powerful approaches into clinical practice and for advancing precision medicine for the treatment of liver cancer.

Citations

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The lncRNA–DNA Methylation Axis in Hepatocellular Carcinoma: Mechanisms, Epigenetic Plasticity, and Biological Implications
Lingke Meng, Lingzhu Cheng, Yuanyuan Li, Yushan Guo, Na Li
Biology.2026; 15(6): 458. CrossRef
Review Article: Biomarkers in Liver Transplantation for Hepatocellular Carcinoma: Towards Precision Medicine
Yule Ma, Huigang Li, Huan Chen, Jinxin Xu, Ziyi Ye, Yuhang Li, Xiang Wu, Jinyan Chen, Chenghao Cao, Peiru Zhang, Ruijie Zhao, Jun Li, Cheng Zhu, Jianyong Zhuo, Shengjun Xu, Xiao Xu, Di Lu
Alimentary Pharmacology & Therapeutics.2026; 64(4): 441. CrossRef
Development and Validation of a Six-Gene Signature of Myeloid Antigen Presentation Dysfunction Based on Single-Cell and Multi-Cohort Transcriptomics for Predicting Prognosis and Recurrence of Hepatocellular Carcinoma
Ye Tan, Jingxuan Xiang, Zehan Wang, Yu Wang, Aidong Chen, Qiwen Wu
Cancer Informatics.2026;[Epub] CrossRef
Unraveling the regulatory role of intercellular communication in intestinal immune cells mediated by H₂ in sepsis recovery through single-cell RNA sequencing
Yanhua Luo, Yajuan Zhao, Jinfeng Liu, Bin Liu, Zhimei Zhang, Yuan Jiang, Yaopeng Zhang, Xue-ting Wang, Shilong Li, Nian Zhao, Xiaokang Li, Dong Xiong, Xue Zhao, Shaoqiang Wang, Weihang Zhang, Bao Lang
Journal of Translational Medicine.2026;[Epub] CrossRef

Original Article

PNPLA3 I148M is unrelated to HCC occurrence but associates with poorer tumor differentiation in Korean MASLD: a prospective cohort of 562 patients: Jaejun Lee, Dong Yeop Lee, Jung Hoon Cha, Hee Sun Cho, Keungmo Yang, Hyun Yang, Mi Young Byun, Seok Keun Cho, Seong Wook Yang, Si Hyun Bae, Pil Soo Sung; J Liver Cancer. 2026;26(1):147-156. Published online December 4, 2025; DOI: https://doi.org/10.17998/jlc.2025.11.16

1,548 Views
73 Downloads

Abstract PDF Supplementary Material: Backgrounds/Aims
The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M variant has been implicated in metabolic dysfunction-associated steatotic liver disease (MASLD), but its role in hepatocellular carcinoma (HCC) development is unclear. This study examines the association between the PNPLA3 I148M variant and HCC occurrence.
Methods
A total of 562 MASLD patients, with and without HCC, were prospectively and consecutively enrolled at two universityaffiliated hospital between June 2024 and June 2025. Genomic DNA was extracted from buccal swabs or liver biopsy samples, and single nucleotide polymorphism genotyping was performed to determine the rs738409 genotype at codon 148 of PNPLA3. The histological grade of HCC was assessed using the Edmondson-Steiner (ES) grading system in patients who underwent core-needle liver biopsy.
Results
Among 474 non-HCC patients, the GG genotype was found in 39.9%, GC in 37.1%, and CC in 23.0%. In 88 HCC patients, these frequencies were 45.5%, 36.4%, and 18.2%, respectively. No significant differences in GG genotype distribution were observed between HCC and non-HCC groups (P=0.509), nor in subgroups by sex, age, obesity status, cirrhosis status, fibrosis-4 index, or liver stiffness measurement. However, among HCC patients with histological grading, the GG genotype was significantly associated with higher ES grades (P=0.0076).
Conclusions
The PNPLA3 I148M GG genotype was not significantly associated with increased HCC occurrence in Korean MASLD patients within the present cohort. Although the GG genotype is known to play a role in development and progression of MASLD, further studies are warranted to clarify its contribution to tumor initiation and dedifferentiation.

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