Wang XM, Li HG, Xu JX, Wu X, Li H. Protein induced by vitamin K absence or antagonist-II in hepatocellular carcinoma with normal alpha-fetoprotein: Current advances and controversies. World J Gastrointest Oncol 2026; 18(5): 118297 [DOI: 10.4251/wjgo.v18.i5.118297]
Corresponding Author of This Article
Hong Li, MD, Full Professor, Li Huili Hospital Affiliated to Ningbo University, No. 57 Xingning Road, Yinzhou District, Ningbo 315000, Zhejiang Province, China. lihong196311@163.com
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Gastroenterology & Hepatology
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Opinion Review
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May 15, 2026 (publication date) through May 14, 2026
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World Journal of Gastrointestinal Oncology
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Wang XM, Li HG, Xu JX, Wu X, Li H. Protein induced by vitamin K absence or antagonist-II in hepatocellular carcinoma with normal alpha-fetoprotein: Current advances and controversies. World J Gastrointest Oncol 2026; 18(5): 118297 [DOI: 10.4251/wjgo.v18.i5.118297]
World J Gastrointest Oncol. May 15, 2026; 18(5): 118297 Published online May 15, 2026. doi: 10.4251/wjgo.v18.i5.118297
Protein induced by vitamin K absence or antagonist-II in hepatocellular carcinoma with normal alpha-fetoprotein: Current advances and controversies
Xi-Ming Wang, Hui-Gang Li, Jin-Xin Xu, Xiang Wu, Hong Li
Xi-Ming Wang, School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou 310053, Zhejiang Province, China
Hui-Gang Li, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang Province, China
Jin-Xin Xu, The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
Xiang Wu, Hong Li, Li Huili Hospital Affiliated to Ningbo University, Ningbo 315000, Zhejiang Province, China
Co-first authors: Xi-Ming Wang and Hui-Gang Li.
Co-corresponding authors: Xiang Wu and Hong Li.
Author contributions: Wang XM contributed to the conceptualization, formal analysis, and drafting of the original manuscript; Li HG and Xu JX contributed to investigation and formal analysis; Wu X contributed to manuscript writing, review, and editing, methodology, and funding acquisition; Li H contributed to manuscript writing, review, and editing, supervision, resources, methodology, investigation, formal analysis, and funding acquisition.
Conflict-of-interest statement: The authors declare that they have no conflict of interest to disclose.
Corresponding author: Hong Li, MD, Full Professor, Li Huili Hospital Affiliated to Ningbo University, No. 57 Xingning Road, Yinzhou District, Ningbo 315000, Zhejiang Province, China. lihong196311@163.com
Received: December 30, 2025 Revised: January 17, 2026 Accepted: February 24, 2026 Published online: May 15, 2026 Processing time: 135 Days and 17.5 Hours
Core Tip
Core Tip: Alpha-fetoprotein (AFP)-normal hepatocellular carcinoma is a clinically challenging subgroup in which conventional biomarker-driven surveillance and risk assessment often underperform. Current evidence indicates that protein induced by vitamin K absence/antagonist-II (PIVKA-II) can supplement AFP for detection, provide information on tumor aggressiveness and microvascular invasion, and contribute to recurrence risk stratification after resection, locoregional therapy, and liver transplantation. At the same time, major controversies remain around assay harmonization, cut-off selection, regional generalizability, vitamin K-related confounding, and the incremental value of PIVKA-II relative to modern multi-marker panels and imaging-based models. Our perspective is that PIVKA-II is most promising when treated as a context-dependent component of integrated risk modelling rather than as a binary standalone test.
