Association of AFP with Hepatocellular Carcinoma Subtypes

Background/Objectives: Alpha-fetoprotein (AFP) is often elevated in hepatocellular carcinoma (HCC) and has been linked to poor prognosis. Among HCC subtypes, the association is less defined. We aimed to characterize AFP and their association with prognosis for the fibrolamellar, scirrhous, clear-cell, spindle-cell, and pleomorphic subtypes of HCC. Methods: Patients in the National Cancer Database (NCDB) diagnosed with HCC between 1998–2021, including not otherwise specified (NOS), fibrolamellar, scirrhous, clear-cell, spindle-cell, and pleomorphic were included. Elevated AFP was defined as 400 ng/mL or above. Associations between clinical characteristics, including AFP levels, and HCC subtypes were analyzed using two-sample t-test, chi-square, and Fisher exact tests. Survival was assessed using Kaplan–Meier curves with log-rank tests. Results: The study population included 168,470 patients, of which 166,778 (99.0%) were HCC NOS, followed by 872 (0.5%) clear-cell, 417 (0.2%) fibrolamellar, 251 (0.2%) scirrhous, 136 (0.1%) spindle-cell, and 16 (0.01%) pleomorphic. Elevated AFP was highest in the spindle-cell subtype (30.9%), followed by HCC NOS (29.4%), scirrhous (25.1%), clear-cell (23.4%), and fibrolamellar (15.6%) (p < 0.0001). Elevated AFP was significantly different across stage of disease with elevation in 11.9% of fibrolamellar, 6.8% of scirrhous, 35.7% of spindle-cell, 25.2% of clear-cell, and 17.6% of HCC NOS at stage 2; 22.5%, 50%, 33.3%, 28.2%, and 44.2%, respectively at stage 3; and 13.8%, 30.4%, 31.7%, 42.2%, and 53.2%, respectively, at stage 4 (all p < 0.005). Elevated AFP was associated with decreased survival for the fibrolamellar (9.7 months when elevated vs. 39 months when not elevated), scirrhous (3.8 vs. 24.2) and clear-cell (7.2 vs. 25.9) subtypes (p < 0.0001). Conclusions: Elevated AFP is least prevalent for fibrolamellar HCC, including when stratifying by disease stage, though it is associated with worse survival in that population. AFP elevation may offer important prognostic information when rare subtypes are diagnosed.