Liver parenchymal quality stratifies outcomes after hepatic resection for hepatocellular carcinoma

Background: Hepatic resection (HR) and liver transplantation (LT) are curative-intent treatments for hepatocellular carcinoma (HCC). Patients without cirrhosis are typically analyzed as a single group, obscuring potentially important differences between those with histologically normal liver and those with non-cirrhotic parenchymal disease. We aimed to characterize long-term outcomes following HR stratified by underlying parenchymal quality, with a contemporary LT cohort as an external benchmark. Methods: Retrospective cohort study of 662 adults undergoing curative-intent surgery for HCC at two tertiary centers (2010–2024). Resection patients (n=380) were stratified by non-tumor parenchymal histology into HR-Normal (n=84), HR-Diseased non-cirrhotic (n=159), and HR-Cirrhotic (n=137). 282 LT recipients served as an external reference but were not entered into comparative models. Overall survival (OS) was analyzed by Kaplan–Meier and multivariable Cox regression and recurrence by Fine–Gray competing-risks regression. Results: Ninety-day mortality was low across resection strata (1.2–3.2%). OS differed significantly across parenchymal groups (log-rank p =0.01), driven by superior outcomes in HR-Normal patients compared with both HR-Cirrhotic ( p =0.008) and HR-Diseased ( p =0.005). HR-Cirrhotic and HR-Diseased did not differ ( p =0.97). Five-year OS was 77.0%, 76.2%, and 64.1%, respectively. On multivariable Cox regression, both cirrhosis (HR 2.03, 95% CI 1.16–3.54, p =0.01) and diseased non-cirrhotic parenchyma (HR 2.04, 95% CI 1.21–3.43, p =0.008) independently predicted death versus normal liver. Fine–Gray analysis confirmed higher recurrence risk in cirrhotic (sHR 2.09, p =0.01) and diseased non-cirrhotic (sHR 1.80, p =0.04) groups. The LT benchmark cohort achieved 5-year OS of 84.6%. Conclusions: Histologically normal liver identifies a distinct HR subgroup with favorable oncologic outcomes. The conventional cirrhotic/non-cirrhotic dichotomy underestimates the prognostic impact of underlying parenchymal disease.