Protein induced by vitamin K absence or antagonist-II in hepatocellular carcinoma with normal alpha-fetoprotein: Current advances and controversies

Abstract

A recent retrospective study evaluated the prognostic value of protein induced by vitamin K absence/antagonist-II (PIVKA-II) in patients with hepatocellular carcinoma (HCC) who have normal alpha-fetoprotein (AFP) levels. The study demonstrated that, among AFP-normal HCC patients, PIVKA-II exhibits a stratification threshold for invasive tumors and can serve as a supplementary indicator for risk stratification beyond AFP. Although this study suggests a potential correlation between elevated PIVKA-II levels and invasive tumor phenotypes, the predictive stability and generalizability of PIVKA-II for tumor recurrence still require further validation due to the limited clinical database and insufficient external verification. Future studies should be conducted in multiple prospective cohorts, with an expanded sample size and extended follow-up duration. In addition, the current study only included patients who had undergone PIVKA-II testing, which may introduce selection bias, thus limiting its general applicability. Finally, greater attention should be paid to the dynamic changes of PIVKA-II, and its predictive value for disease progression or treatment response should be evaluated by combining it with imaging and clinical variables. In this paper, we evaluate the strengths and limitations of this study and propose future research directions to refine the research model and deepen the understanding of the role of PIVKA-II in the invasive biology of AFP-normal HCC.

Keywords: Hepatocellular carcinoma; Alpha-fetoprotein; Protein induced by vitamin K absence/antagonist-II; Des-gamma carboxy prothrombin; Aggressive tumor

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.