Abstract
Hepatocellular carcinoma (HCC) is unique among solid tumors in being routinely diagnosed without histological confirmation, based instead on dynamic imaging criteria-namely arterial phase hyperenhancement (APHE) and venous washout-in at-risk populations. This noninvasive approach has improved diagnostic efficiency and safety but is not without limitations. Indeterminate imaging findings are common, particularly for small lesions or in noncirrhotic livers, increasing the risk of misclassification and treatment delays. Moreover, the advent of precision oncology has renewed interest in biopsy to enable molecular profiling and clinical trial eligibility. However, tissue biopsy carries important risks. Complications such as bleeding, though rare, are potentially serious; sampling errors may lead to false negatives; and needle-tract seeding, while now reduced to <1% with modern techniques, remains a critical concern-especially in transplant candidates, where extrahepatic spread may compromise eligibility. Observational studies further suggest that biopsy might negatively influence long-term outcomes through microscopic dissemination. Current guidelines recommend avoiding biopsy when imaging is definitive, but endorse its use in indeterminate nodules, noncirrhotic presentations, or when histology informs treatment selection. Emerging tools such as liquid biopsy and radiomics may reduce the need for invasive sampling in the future. This review critically examines the evolving role of tissue biopsy in HCC diagnosis and management, balancing its risks and benefits, and offers a practical framework to guide hepatologists, surgeons, and oncologists in making evidence-based, individualized decisions on when biopsy is warranted-and when it can safely be avoided.