The Rationale for Tissue Biopsy in the Era of Precision Hepatocellular Carcinoma Management

Hepatocellular carcinoma (HCC) is the most common liver cancer and usually develops on a background of cirrhotic liver. Early and accurate diagnosis enables potentially curative interventions. HCC surveillance, usually offered to patients at risk for HCC, such as those with cirrhosis, chronic hepatitis B infection, and previous diagnosis of HCC, is associated with earlier detection and improved survival. In these patients, the diagnosis can be established non-invasively without histological confirmation when the imaging-based LI-RADS criteria are met. Tissue biopsy is mandatory for establishing diagnosis in patients without cirrhosis or other risk factors for HCC, differentiating HCC from other malignant and non-malignant entities, especially when imaging features are not conclusive. In this review, we discuss the evolving role of tissue biopsy beyond establishing the diagnosis, in providing important prognostic information and enabling precise histopathological classification. Features such as poor differentiation, microvascular invasion, and a pattern of vessels encapsulating tumor clusters are linked to worse prognosis. HCC is characterized by heterogeneity, with different histological subtypes associated with distinct clinical and radiological features and distinct biology. Emerging data from molecular profiling and immune-microenvironment studies enable further classification into proliferative versus non-proliferative molecular subgroups and inflamed versus non-inflamed immune subtypes. This more refined characterization of HCC carries important implications not only for prognostication but also for predicting response to immunotherapy. In the future, the combination of imaging features that correlate with molecular signatures, novel serum biomarkers, and liquid biopsy may provide less invasive tools for early detection, risk stratification, and guide personalized therapeutic strategies.