Temporal Association of Combined AFP-L3 and PIVKA-II with Early Recurrence after Hepatocellular Carcinoma Resection

Background/Aims: agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) independently predicts early recurrence and whether this association is temporally specific. Methods: This retrospective cohort study included 431 patients who underwent curative resection for HCC between 2010 and 2023 at a single tertiary center. Dual positivity was defined as AFP-L3 ≥15% and PIVKA-II ≥100 mAU/mL. The primary outcome was early recurrence-free survival. Late recurrence was assessed using landmark analysis in patients who were recurrencefree at 24 months (n=258). Multivariable Cox proportional hazards regression was performed adjusting for clinical and tumor characteristics. Results: During a median follow-up of 36.0 months, 100 patients (23.2%) developed early recurrence and 73 (16.9%) developed late recurrence. Dual positivity was independently associated with early recurrence (hazard ratio [HR], 2.38; 95% confidence interval [CI], 1.44 to 3.93; p<0.001) but not with late recurrence (HR, 0.92; 95% CI, 0.39 to 2.15; p=0.844). The 24-month cumulative incidence of recurrence was 39.2% for dual-positive patients compared with 19.2% in the low-risk group. This association remained consistent across sensitivity analyses using alternative biomarker cutoffs and across most clinical subgroups. Conclusions: Preoperative dual positivity for AFP-L3 and PIVKA-II was associated with early but not late recurrence after curative resection for HCC, suggesting temporal specificity of this biomarker combination. Prospective validation studies are warranted.