Hepatocellular carcinoma in patients without cirrhosis

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, the sixth most common cancer worldwide, and the third leading cause of cancer-related death. Cirrhosis is the predominant risk factor for HCC, driven by major etiologies including hepatitis B and C, excessive alcohol consumption, and metabolic dysfunction-associated steatotic liver disease (MASLD). While approximately 80% of HCC cases occur in patients with cirrhosis, its incidence among individuals without cirrhosis has significantly increased, particularly in developed countries, driven by the rising prevalence of MASLD. The prevalence of patients with non-cirrhotic HCC varies geographically, yet data on this subgroup remain limited. Consequently, screening and clinical management guidelines for patients with non-cirrhotic HCC are underdeveloped. Current surveillance is typically not recommended for non-cirrhotic populations, except for individuals with hepatitis B, and diagnostic criteria like Liver Imaging Reporting and Data System are designed explicitly for cirrhotic or hepatitis B-associated HCC. Furthermore, treatment strategies for non-cirrhotic HCC are often extrapolated from studies focused on patients with cirrhosis, leading to gaps in knowledge regarding treatment efficacy, survival outcomes, and etiological variability in non-cirrhotic cohorts. Thus, emerging evidence must be reviewed to guide the development of enhanced diagnostic and therapeutic strategies for patients with non-cirrhotic HCC. To address these gaps, we comprehensively reviewed the epidemiology, clinical and genetic characteristics, diagnostic modalities, and therapeutic approaches for patients with non-cirrhotic HCC.