Low Alpha-Fetoprotein in Non-Viral Early-Stage Hepatocellular Carcinoma: Complementary Des-Gamma-Carboxyprothrombin

Alpha-fetoprotein (AFP) is widely used in hepatocellular carcinoma (HCC) surveillance, but its performance may vary with etiology and tumor stage. We assessed etiology-specific AFP and des-gamma-carboxyprothrombin (DCP) positivity at HCC diagnosis, focusing on early-stage disease.

We retrospectively enrolled consecutive adults with newly diagnosed, treatment-naïve HCC at two tertiary centers in Japan (2007-2023). AFP (cutoff ≥ 10 ng/mL) and DCP (≥ 40 mAU/mL) at diagnosis were analyzed overall and by etiology (Hepatitis B virus (HBV), Hepatitis C virus (HCV), sustained virological response [SVR], and non-B/non-C [NBNC]). Early stage was defined as Barcelona Clinic Liver Cancer (BCLC) 0/A and Union for International Cancer Control tumor-node-metastasis (UICC) T1a.

Among 1396 patients, 760 (54.4%) had BCLC 0/A and 278 (19.9%) had T1a tumors. AFP positivity differed by etiology in BCLC 0/A disease (HBV 50.0%, HCV 64.6%, SVR-related 39.0%, NBNC 39.7%; p < 0.001), and in T1a tumors (48.1%, 60.3%, 39.0%, and 34.5%, respectively; p = 0.002). DCP (n = 1364) positivity in BCLC 0/A showed less variability (40.6%, 47.8%, 40.8%, and 58.4%, respectively; p = 0.005). Either-marker positivity in BCLC 0/A increased (64.1%, 80.0%, 59.2%, and 70.6%, respectively); the incremental yield from DCP alone among AFP-negative cases was 21.1% in SVR-related and 30.5% in NBNC early-stage HCC.

AFP positivity at diagnosis was substantially lower in early-stage SVR-related and NBNC HCC than in HCV-related HCC. Adding DCP provides complementary detection, supporting an etiology-aware dual-marker strategy at diagnosis.