Etiologic profile and prognostic patterns of hepatocellular carcinoma in a Southern European population - Madeira, Portugal: Insight into a preventable cancer

Abstract

Background: Liver cancer is the sixth most common and third deadliest cancer worldwide. In Portugal, it remains highly lethal, with 1740 new cases and 1611 deaths estimated in 2022. Hepatocellular carcinoma (HCC) is the main histological type and exhibits variation in risk factors and outcomes. Unlike many malignancies, HCC arises predominantly in chronically diseased tissues and is largely attributable to four modifiable etiologies: hepatitis B (HBV) and C viruses (HCV), alcohol-associated liver disease (ALD), and metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to characterize HCC etiology-specific incidence and prognostic patterns in the Madeira islands, Portugal.

Methods: All HCC cases diagnosed between 2010 and 2023 were identified through the Madeira Cancer Registry. Etiologies and risk factors were assigned using clinical records, serological markers, and ICD-coded discharge data. Age-standardized incidence rates (ASIRs) were computed using the world and the 2000 U.S. standard population. Survival outcomes were assessed with Kaplan-Meier curves and Cox proportional hazards models.

Results: Among 240 HCC cases, the leading etiology was ALD (50.0 %), followed by MASLD (17.1 %), HBV (16.5 %), and HCV (11.9 %). Male incidence was nearly 8-fold higher than female incidence (ASIR: 6.9 vs. 0.9 per 100,000), with ALD dominating among men and MASLD among women. No significant temporal change in HCC incidence was observed. Most patients (63.8 %) were diagnosed at advanced stages. The age-adjusted 5-year survival was 5.6 %, and median survival was 6 months. Cancer stage was the strongest prognostic factor, while HCC etiology was not independently associated with survival.

Conclusions: HCC in Madeira presents a distinct etiologic and prognostic pattern, marked by a high ALD burden among men, a MASLD burden among women, and poor survival due to late-stage diagnosis. These findings highlight the urgency of expanding liver cancer surveillance, integrating metabolic risk management, and targeting alcohol misuse through population-level interventions, especially among males and older patients.

Keywords: Etiology; Hepatocellular carcinoma; Incidence; Liver cancer; Risk factors.