Journal of Liver Cancer

Original Article

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.

Review Articles

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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607 Downloads
9 Web of Science
9 Citations

Abstract PDF

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.

Citations

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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”
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Journal of Liver Cancer.2026; 26(1): 83. CrossRef
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K. Luo, S. Liu, Y. Liu
Clinical Oncology.2026; 54: 104157. CrossRef
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Yifan Zhang, Yiquan Lu, Nan Wang, Fengjie Hao, Yongjun Chen, Xiaochun Fei, Junqing Wang
Scientific Reports.2025;[Epub] CrossRef
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International Journal of Molecular Sciences.2025; 26(19): 9584. CrossRef
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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

Disease modifiers and novel markers in hepatitis B virus-related hepatocellular carcinoma: Lung-Yi Mak; J Liver Cancer. 2024;24(2):145-154. Published online August 5, 2024; DOI: https://doi.org/10.17998/jlc.2024.08.03

13,978 Views
218 Downloads
6 Web of Science
7 Citations

Abstract PDF

Chronic hepatitis B (CHB) infection is responsible for 40% of the global burden of hepatocellular carcinoma (HCC) with a high case fatality rate. The risk of HCC differs among CHB subjects owing to differences in host and viral factors. Modifiable risk factors include viral load, use of antiviral therapy, co-infection with other hepatotropic viruses, concomitant metabolic dysfunctionassociated steatotic liver disease or diabetes mellitus, environmental exposure, and medication use. Detecting HCC at early stage improves survival, and current practice recommends HCC surveillance among individuals with cirrhosis, family history of HCC, or above an age cut-off. Ultrasonography with or without serum alpha feto-protein (AFP) every 6 months is widely accepted strategy for HCC surveillance. Novel tumor-specific markers, when combined with AFP, improve diagnostic accuracy than AFP alone to detect HCC at an early stage. To predict the risk of HCC, a number of clinical risk scores have been developed but none of them are clinically implemented nor endorsed by clinical practice guidelines. Biomarkers that reflect viral transcriptional activity and degree of liver fibrosis can potentially stratify the risk of HCC, especially among subjects who are already on antiviral therapy. Ongoing exploration of these novel biomarkers is required to confirm their performance characteristics, replicability and practicability.

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Direct Viral Mechanisms Underlying the Onset of HBV-Related Hepatocellular Carcinoma and Implications for Therapeutic Strategies
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Viruses.2026; 18(2): 185. CrossRef
Superior Efficacy of Besifovir in Reducing Hepatocellular Carcinoma Risk Compared to Tenofovir in Chronic Hepatitis B Patients: A Nationwide Cohort Study
Yoon E Shin, Jae Young Kim, Hyuk Kim, Jeong Ju Yoo, Sang Gyune Kim, Young Seok Kim
Journal of Korean Medical Science.2026;[Epub] CrossRef
Predictors of HBV-associated hepatocarcinoma: a scientific review
M. A. Lobanova, N. E. Danilova, S. S. Sleptsova, S. S. Sleptsov
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Reply to: Comment on “Lower Incidence of Hepatocellular Carcinoma with Tenofovir Alafenamide in Chronic Hepatitis B: Evidence from a Large-Scale Cohort”
Jisoo Lee, Jae-Young Kim, Jeong-Ju Yoo, Hye Won Lee, Sang Gyune Kim, Young Seok Kim
JHEP Reports.2025; : 101371. CrossRef
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Original Articles

The diagnostic value of circulating tumor DNA in hepatitis B virus induced hepatocellular carcinoma: a systematic review and meta-analysis: Young Chang, Soung Won Jeong, Jae Young Jang, Hyuksoo Eun, Young‑Sun Lee, Do Seon Song, Su Jong Yu, Sae Hwan Lee, Won Kim, Hyun Woong Lee, Sang Gyune Kim, Seongho Ryu, Suyeon Park; J Liver Cancer. 2022;22(2):167-177. Published online September 29, 2022; DOI: https://doi.org/10.17998/jlc.2022.09.19

7,841 Views
122 Downloads
6 Citations

Abstract PDF Supplementary Material

Background/Aim
New biomarkers are urgently needed to aid in the diagnosis of early stage hepatocellular carcinoma (HCC). We performed a meta-analysis on the diagnostic utility of circulating tumor DNA (ctDNA) levels in patients with hepatitis B virus-induced HCC.
Methods
We retrieved relevant articles from PubMed, Embase, and the Cochrane Library up to February 8, 2022. Two subgroups were defined; one subset of studies analyzed the ctDNA methylation status, and the other subset combined tumor markers and ctDNA assays. Pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic curve (AUC) were analyzed.
Results
Nine articles including 2,161 participants were included. The overall SEN and SPE were 0.705 (95% confidence interval [CI], 0.629-0.771) and 0.833 (95% CI, 0.769-0.882), respectively. The DOR, PLR, and NLR were 11.759 (95% CI, 7.982-17.322), 4.285 (95% CI, 3.098- 5.925), and 0.336 (0.301-0.366), respectively. The ctDNA assay subset exhibited an AUC of 0.835. The AUC of the combined tumor marker and ctDNA assay was 0.848, with an SEN of 0.761 (95% CI, 0.659-0.839) and an SPE of 0.828 (95% CI, 0.692-0.911).
Conclusions
Circulating tumor DNA has promising diagnostic potential for HCC. It can serve as an auxiliary tool for HCC screening and detection, especially when combined with tumor markers.

Citations

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Harnessing viral footprints in circulating free DNA (cfDNA) for early cancer detection: A focus on liquid‐biopsy‐based screening
Richard Donkor Amponsah, Emmanuel Addai Gyabaah, Moro Amidu, Zhao Cheng, Fazlur Rahman Talukdar
International Journal of Cancer.2026; 158(3): 511. CrossRef
Development and validation of a high-confidence diagnostic model integrating ctDNA methylation and serum biomarkers for early-stage hepatocellular carcinoma detection
Han Wu, Mingda Wang, Zhiyi Wan, Lanqing Yao, Shuang Zhou, Hui Wang, Guoyue Lv, Nanya Wang, Fengmei Wang, Jiahao Xu, Xinfei Xu, Chao Li, Yongkang Diao, Timohty M. Pawlik, Rui Liu, Feng Shen, Tian Yang
Molecular Biomedicine.2026;[Epub] 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
Current Tools to Diagnose and Predict Hepatocellular Carcinoma: Relevance to HIV and Hepatitis B Virus Coinfection
Edwin Wilbur Woodhouse, Tzu-Hao Lee, Susanna Naggie
Current HIV/AIDS Reports.2025;[Epub] CrossRef
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Chan Jin Yang, Ju Sun Song, Jeong-Ju Yoo, Keun Woo Park, Jina Yun, Sang Gyune Kim, Young Seok Kim
Medicina.2024; 60(2): 289. CrossRef
Methylated circulating tumor DNA in hepatocellular carcinoma: A comprehensive analysis of biomarker potential and clinical implications
Qian Zhu, Jiaqi Xie, Wuxuan Mei, Changchun Zeng
Cancer Treatment Reviews.2024; 128: 102763. CrossRef

Diagnostic performance of serum exosomal miRNA-720 in hepatocellular carcinoma: Jeong Won Jang, Ji Min Kim, Hye Seon Kim, Jin Seoub Kim, Ji Won Han, Soon Kyu Lee, Heechul Nam, Pil Soo Sung, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon; J Liver Cancer. 2022;22(1):30-39. Published online March 21, 2022; DOI: https://doi.org/10.17998/jlc.2022.02.25

8,802 Views
183 Downloads
9 Citations

Abstract PDF Supplementary Material

Background/Aim
Hepatocellular carcinoma (HCC) is associated with poor prognosis, largely due to late detection. Highly accurate biomarkers are urgently needed to detect early-stage HCC. Our study aims to explore the diagnostic performance of serum exosomal microRNA (miR)-720 in HCC.
Methods
Exosomal miRNA was measured via quantitative real-time PCR. A correlation analysis of exosomal miR-720 and tumor or clinico-demographic data of patients with HCC was performed. The receiver operating characteristic (ROC) curve was used to assess the diagnostic capacity of serum exosomal miR-720 for HCC, in comparison with α-fetoprotein (AFP) and prothrombin induced by vitamin K absence or antagonist-II (PIVKA-II).
Results
MiR-720 was chosen as a potential HCC marker via miR microarray based on significant differential expression between tumor and non-tumor samples. Serum exosomal miR-720 was significantly upregulated in patients with HCC (n=114) versus other liver diseases (control, n=30), with a higher area under the ROC curve (AUC=0.931) than the other markers. Particularly, serum exosomal miR-720 showed superior performance in diagnosing small HCC (< 5 cm; AUC=0.930) compared with AFP (AUC=0.802) or PIVKA-II (AUC=0.718). Exosomal miR-720 levels showed marginal correlation with tumor size. The proportion of elevated miR-720 also increased with intrahepatic tumor stage progression. Unlike AFP or PIVKA-II showing a significant correlation with aminotransferase levels, the exosomal miR-720 level was not affected by aminotransferase levels.
Conclusions
Serum exosomal miR-720 is an excellent biomarker for the diagnosis of HCC, with better performance than AFP or PIVKA-II. Its diagnostic utility is maintained even in small HCC and is unaffected by aminotransferase levels.

Citations

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The role of exosomal microRNAs in detecting hepatocellular carcinoma: A systematic review and meta-analysis
Zhihua Zuo, Miyuan Yang, Xiushan Yin, Wei Tang, Lijun Du, Yongcan Guo
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Tarek El Hayek, Osama Abdulwahab Alnaser-Almusa, Sulaiman Mamoun Alsalameh, Maya Taofik Alhalabi, Ahmad Nedal Sabbah, Eman Abdullah Alshehri, Tanveer Ahmad Mir, Naresh Kumar Mani, Khaled Al-Kattan, Raja Chinnappan, Ahmed Yaqinuddin
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Gut-microbiome Taxonomic Profiling as Non-invasive Biomarkers for the Early Detection of Alcoholic Hepatocellular Carcinoma: Jun Seok, Ki Tae Suk; J Liver Cancer. 2020;20(1):32-40. Published online March 31, 2020; DOI: https://doi.org/10.17998/jlc.20.1.32

9,633 Views
261 Downloads
8 Citations

Abstract PDF

Background/Aims
Hepatocellular carcinoma (HCC) is a prevalent form of primary liver cancer and the fifth leading cause of worldwide cancer mortality. Though early diagnosis of HCC is important, so far lack of effective biomarkers for early diagnosis of HCC has been a problem. In this study, we searched for potential functional biomarkers of alcoholic HCC by using metagenomics approach.
Methods
Between September 2017 and April 2019, normal control (n=44), alcoholic liver cirrhosis (n=44), and alcoholic HCC (n=13) groups were prospectively enrolled and analyzed. Gut microbiota was analyzed using the 16S-based microbiome taxonomic profiling platform of EzBioCloud Apps and analyzing system.
Results
There was a statistically significant difference among groups in diversity (P<0.05). In the comparison of phylum between cirrhosis and HCC, Proteobacteria were increased and Bacteroidetes were decreased. Firmicutes were not significantly different among the three groups. In the taxonomic profiling, relative abundance of Lactobacillus in the cirrhosis and HCC groups showed richness (P<0.05). In the biomarker analysis between cirrhosis and HCC, obiquinome Fe-S protein 3, global nitrogen regulator, Vesicle-associated membrane protein 7, toxin YoeB, peroxisome-assembly ATPase, and nitrogen oxide reductase regulator were differently expressed (P<0.001).
Conclusions
Alcoholic HCC showed different expressions in the stool taxonomy and biomarker compared with that of cirrhosis and control. Therefore, new biomarkers using stool analysis for alcoholic HCC are necessary.

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