Abbas Z, Gazder DP, Hyder Z, Qadeer MA, Abbas M. Serum protein induced by vitamin K absence or antagonist-II predicts aggressive tumor biology in alpha-fetoprotein-normal hepatocellular carcinoma. World J Gastrointest Oncol 2026; 18(2): 113673 [DOI: 10.4251/wjgo.v18.i2.113673]
Corresponding Author of This Article
Zaigham Abbas, AGAF, FACG, FACP, FRCP, Head, Professor, Department of Hepatogastroenterology, Dr. Ziauddin University Hospital Clifton, 4/B Shahrah-e-Ghalib, Block 6, Clifton, Karachi 75600, Sindh, Pakistan. drzabbas@gmail.com
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Gastroenterology & Hepatology
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Retrospective Study
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Feb 15, 2026 (publication date) through Feb 3, 2026
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World Journal of Gastrointestinal Oncology
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1948-5204
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Abbas Z, Gazder DP, Hyder Z, Qadeer MA, Abbas M. Serum protein induced by vitamin K absence or antagonist-II predicts aggressive tumor biology in alpha-fetoprotein-normal hepatocellular carcinoma. World J Gastrointest Oncol 2026; 18(2): 113673 [DOI: 10.4251/wjgo.v18.i2.113673]
World J Gastrointest Oncol. Feb 15, 2026; 18(2): 113673 Published online Feb 15, 2026. doi: 10.4251/wjgo.v18.i2.113673
Serum protein induced by vitamin K absence or antagonist-II predicts aggressive tumor biology in alpha-fetoprotein-normal hepatocellular carcinoma
Zaigham Abbas, Darayus P Gazder, Zeeshan Hyder, Muhammad Ali Qadeer, Minaam Abbas
Zaigham Abbas, Darayus P Gazder, Muhammad Ali Qadeer, Minaam Abbas, Department of Hepatogastroenterology, Dr. Ziauddin University Hospital Clifton, Karachi 75600, Sindh, Pakistan
Zeeshan Hyder, Department of Hepatobiliary Surgery and Liver Transplantation, Dr. Ziauddin University Hospital Clifton, Karachi 75600, Sindh, Pakistan
Minaam Abbas, Department of Medicine, University of Cambridge, Cambridge CB2 1QN, United Kingdom
Author contributions: Abbas Z designed the study; Abbas Z and Gazder DP acquired the data; Abbas Z, Gazder DP, Hyder Z, and Qadeer MA contributed to the multidisciplinary evaluation of patients; Abbas M analyzed the data; Abbas Z and Abbas M wrote and critically revised the manuscript; and all authors read and approved the final manuscript.
Institutional review board statement: This study was approved by the Ethics Review Committee of Ziauddin University (Reference Code: 10310425ZAGE). The study was conducted in compliance with the Declaration of Helsinki.
Informed consent statement: The Ethics Review Committee of Ziauddin University approved a waiver of informed consent due to retrospective design.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: Data available on request from the corresponding author and the Ethics Review Committee of the hospital.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Zaigham Abbas, AGAF, FACG, FACP, FRCP, Head, Professor, Department of Hepatogastroenterology, Dr. Ziauddin University Hospital Clifton, 4/B Shahrah-e-Ghalib, Block 6, Clifton, Karachi 75600, Sindh, Pakistan. drzabbas@gmail.com
Received: September 1, 2025 Revised: November 3, 2025 Accepted: December 10, 2025 Published online: February 15, 2026 Processing time: 155 Days and 8.6 Hours
Abstract
BACKGROUND
Patients with hepatocellular carcinoma (HCC) beyond the Milan criteria or with portal vein tumor thrombosis are often excluded from the transplant list owing to aggressive biology and recurrence risk. While high alpha-fetoprotein (AFP) signals aggressiveness, the behavior of normal AFP HCC with elevated protein induced by vitamin K absence/antagonist-II (PIVKA-II) is less defined.
AIM
To assess the prognostic value of PIVKA-II in normal AFP HCC.
METHODS
Retrospective cohort of 113 patients with normal AFP and normal or elevated PIVKA-II. “Aggressive” tumors were defined as beyond Milan and/or portal vein tumor thrombosis (n = 63); others were non-aggressive (n = 50). Receiver operating characteristic curve analysis identified PIVKA-II cut-offs.
RESULTS
This study included 78 men and 35 women; mean age 58.4 ± 11.1 years; 62.8% with decompensated cirrhosis. PIVKA-II was higher in aggressive tumors: Median 2785 mAU/mL (interquartile range: 222-8152) vs 239 mAU/mL (interquartile range: 55-727), P < 0.001. Area under receiver operating characteristic curve 0.756 (95% confidence interval: 0.669-0.844). The Youden-optimized cut-off for aggressive HCC was 1609.5 mAU/mL [sensitivity: 0.54, specificity: 0.94; positive predictive value (PPV): 0.919]. A sensitivity-oriented cut-off of 400 mAU/mL gave sensitivity 0.69 and specificity 0.64 (PPV: 0.71). Regression analysis showed that PIVKA-II > 400 mAU/mL was strongly associated with aggressive tumor phenotype (adjusted odds ratio = 5.16, P = 0.001). All the 29 patients with ≥ 4000 mAU/mL were in the aggressive group (PPV: 1.0). All thresholds were dataset-derived.
CONCLUSION
In normal AFP HCC, PIVKA-II discriminates aggressive biology. A cut-off of 1609.5 mAU/mL balances sensitivity and specificity; 400 mAU/mL favors sensitivity; ≥ 4000 mAU/mL delineates an ultra-high-risk subgroup. Findings support the incorporation of PIVKA-II into risk stratification.
Core Tip: Alpha-fetoprotein (AFP) often underperforms as a biomarker for hepatocellular carcinoma (HCC). Our study shows that protein induced by vitamin K absence/antagonist-II (PIVKA-II) better indicates aggressive disease when AFP is normal. In normal AFP HCC, PIVKA-II ≥ 400 mAU/mL is linked to high-risk features, and ≥ 4000 mAU/mL identifies an especially aggressive group. Using PIVKA-II in surveillance and treatment planning could improve early detection and outcomes, particularly for AFP-negative patients. Transplant choices may change: Low PIVKA-II, even with large tumors, may suggest slower disease, while very high PIVKA-II within size limits signals higher post-transplant recurrence risk. These findings support updating HCC management guidelines and practice.
