LAUSR

Simple Summary In clinical settings, some cases with hepatocellular carcinoma (HCC) demonstrate negativity in both alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP). Most are small and early-stage hepatocellular carcinomas (HCCs). This study aimed to investigate the characteristics and prognosis of AFP (<20 ng/mL) and DCP (<40 mAU/ml) double-negative HCC (DNHC) in higher BCLC stages. We confirmed that 120 of 374 patients (32.1%) were DNHC, and 17 (14.7%) were in higher stages (BCLC-B, C, and D). In higher-stage HCC, there was no difference in BCLC staging; however, there were significantly more cases under TNM Stage III in DNHC (71.0% vs. 41.4%, p = 0.026). This is due to the tumor size, which can influence treatment. Curative locoregional therapy was dominantly applied in DNHC (p = 0.022). Therefore, survival was significantly better in DNHC (p = 0.027). Abstract Alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP) are widely used as tumor markers to diagnose hepatocellular carcinoma (HCC). Some advanced HCCs demonstrate neither AFP nor DCP. This study investigated the characteristics and prognosis of AFP (<20 ng/mL) and DCP (<40 mAU/ml) double-negative HCC (DNHC) in higher-stage HCC. Between April 2012 and March 2022, 419 consecutive patients were enrolled with newly diagnosed HCC and 372 patients were selected that were diagnosed by histopathology and/or imaging. AFP-negative, DCP-negative, and double-negative HCC were identified in 262 patients (70.4%), 143 patients (38.2%), and 120 patients (32.3%), respectively. In higher-BCLC stages (BCLC-B, C, and D), 17 patients (14.7%) were DNHC. Although there was no difference in BCLC staging, there were more cases under TNM Stage III in DNHC (71.0% vs. 41.4%, p = 0.026). The median maximum tumor diameter was smaller in DNHC [3.2 (1.8–5.0) vs. 5.5 (3.5–9.0) cm, p = 0.001] and their median survival time was significantly better, even in higher-stage HCC [47.0 (24.0–84.0) vs. 19.0 (14.0–30.0) months, p = 0.027). DNHC in higher-BCLC stage HCC is independent of BCLC staging, characterized by a tumor diameter < 5 cm, and is treatable with a good prognosis.