Advances in Hepatocellular Carcinoma: Molecular Insights, Histologic Subtypes, and Differential Diagnosis

Significant advancements over the past 2 decades have reshaped our understanding and diagnostic capabilities for hepatocellular carcinoma (HCC). These advancements span molecular insights into key driver gene mutations and chromosomal aberrations, refined recognition of distinct histologic subtypes, improved differentiation from precursor and benign hepatic lesions, and enhanced strategies for interpreting challenging biopsy samples. The discovery of driver mutations such as TERT promoter, CTNNB1 , and TP53 , along with chromosomal alterations, has provided essential tools for identifying malignancy and understanding tumor behavior. Concurrently, the recognition of distinct morphomolecular HCC subtypes has underscored the importance of integrating histologic and molecular findings for accurate diagnosis and prognostic assessment. In addition, differentiating HCC from dysplastic nodule and hepatocellular adenoma remains a diagnostic challenge, often requiring a combination of morphologic, immunohistochemical, and molecular approaches. Moreover, the interpretation of biopsy samples from borderline hepatocellular neoplasms highlights the limitations of conventional pathology alone and the need for comprehensive diagnostic strategies. This review aims to provide an updated overview of these interconnected aspects, emphasizing their collective role in advancing the precision diagnosis of HCC.