Comparative Prognostic Value of AFP, PIVKA-II, and GPC-3 in Hepatocellular Carcinoma: A Real-World Multicenter Cohort Study

Background/Objectives: The current cornerstone for prognostic hepatocellular carcinoma (HCC) stratification is the Barcelona Clinic Liver Cancer (BCLC) score, which integrates tumor and liver function staging but lacks tumor biology parameters. Serum tumor biomarkers, such as alpha-fetoprotein (AFP), protein induced by vitamin K absence-II (PIVKA-II), and glypican-3 (GPC-3), may improve prognostic assessment. We evaluated their prognostic value in this multicenter retrospective study. Methods: Serum AFP, PIVKA-II, and GPC-3 levels were measured (as continuous and categorical variables: >20 ng/mL, >200 mAU/mL, and >150 pg/mL, respectively) at baseline in 605 consecutive patients newly diagnosed with HCC at two tertiary Italian centers (2010–2024). The correlation between tumor stage, liver function, tumor marker levels, and overall survival (OS) was analyzed using Kaplan–Meier and Cox proportional hazards models. Results: Tumor marker levels increased stepwise across BCLC stages. Median OS was 29.0 months, declining from 47.9 months (BCLC-0) to 10.7 months (BCLC-C; p < 0.001). In univariate analysis, shorter OS was significantly (p < 0.001) associated with elevated serum levels of all tumor markers, higher ALBI grade, presence of ascites, and portal hypertension. On multivariate analysis, BCLC stage, ascites (hazard ratio [HR] 2.19, p < 0.001), ALBI grade 2–3 (HR 1.36, p = 0.009), and PIVKA-II > 200 mAU/mL (HR 1.56, p < 0.001) were independently associated with OS, whereas GPC-3 showed a borderline association (HR 1.27, p = 0.058), but not AFP (HR 0.88; p = 0.306). Conclusions: In this multicenter retrospective cohort study, PIVKA-II was the only serum biomarker independently associated with OS after adjusting for BCLC stage and liver function. These findings support further prospective evaluation of whether PIVKA-II provides clinically meaningful incremental prognostic information beyond established BCLC-based assessment.