Hepatocellular Carcinoma Etiology Drives Survival Outcomes: A Population-Based Analysis

Abstract Background: Previous survival studies on hepatocellular carcinoma (HCC) by etiology are limited to hospital-based series, restricted cohorts, and monolithic etiologic categories. We studied population-based survival by seven mutually exclusive HCC etiologic groups—standalone hepatitis-C virus (HCV), hepatitis-B virus (HBV), alcohol-related liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), and dual etiology HCV–HBV, HCV–ALD, and HBV–ALD—accounting for clinical and sociodemographic characteristics. Methods: All HCC cases diagnosed during 2005 to 2018 from the Florida Cancer Registry were linked for etiology using statewide discharge and viral hepatitis data. We performed a cause-specific survival analysis including Cox regression for the matched 15,616 cases by HCC etiology. Results: The leading etiology was HCV only (n = 4,983; 31.9%); the leading dual etiology was HCV–ALD (n = 2,552; 16.3%). The five-year adjusted survival was low—17.6% overall and 22% across all HCC etiologies. ALD-related etiologies ALD only (14.4%; 95% confidence interval (CI), 12.7–16.0), HCV–ALD (10.2%; 95% CI, 8.7–11.7), and HBV–ALD (8.2%; 95% CI, 2.2–14.1) showed lower survival than non-ALD causes—HCV only, HBV only, and NAFLD only. After adjustment for clinical and sociodemographic covariates, ALD and HBV–ALD HCC had 1.20 (95% CI, 1.13–1.27) and 1.28 (95% CI, 1.06–1.54) times higher risk of death compared with those with HCV-only HCC. Conclusions: ALD only and dual etiologies involving ALD show worse prognosis for HCC compared with viral etiology alone. To increase survival, improved screening and treatment are needed for patients with multiple HCC risk factors. Impact: Understanding US disparities in HCC survival by etiology can help guide the identification of etiologically specific biomarkers and potential therapeutic targets and inform public health measures.