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

Background: Previous survival studies on hepatocellular carcinoma (HCC) by etiology are limited to hospital-based series, restricted cohorts, and monolithic etiological 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), non-alcoholic fatty liver disease (NAFLD), and dual etiology HCV&HBV, HCV&ALD, and HBV&ALD-accounting for clinical and socio-demographic characteristics.

Methods: All HCC cases diagnosed during 2005-2018 from the Florida Cancer Registry were linked for etiology using statewide discharge and viral hepatitis data. We performed 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%). Five-year adjusted survival was low, 17.6% overall and <22% across all HCC etiologies; yet ALD-related etiologies [ALD only (14.4%; 95%CI:12.7-16.0), HCV&ALD (10.2%; 95%CI:8.7-11.7), 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 socio-demographic 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 to those with HCV only-HCC.

Conclusions: ALD only and dual etiologies involving ALD show worse prognosis for HCC, compared to 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.