Comprehensive Radiopathological and Molecular Review of HCC: Expanding on the WHO, 6th Edition

Hepatocellular carcinoma (HCC) exhibits substantial molecular and morphological heterogeneity. The recently updated 6th edition of the World Health Organization Classification of Digestive Tumours recognizes nine specific HCC subtypes, each characterized by distinct morphomolecular and clinical profiles. Although these subtypes account for approximately 35% of all HCC cases, the remaining 65% are classified as conventional HCCs. These subtypes are categorized based on their prognostic implications: the unfavorable prognosis group comprises macrotrabecular-massive, sarcomatoid, and neutrophil-rich HCCs; the comparable prognosis group includes steatohepatitic, fibrolamellar, and chromophobe HCCs; and the favorable prognosis group consists of lymphocyte-rich and clear cell HCCs. By contrast, scirrhous HCC is associated with various clinical outcomes. Furthermore, this classification includes two newly recognized patterns: vessels encapsulating tumor clusters and CTNNB1-mutated HCC. The imaging features of HCC are significantly correlated with its molecular-pathological characteristics. In particular, aggressive subtypes frequently present with specific imaging hallmarks such as rim arterial phase hyperenhancement, diffuse arterial phase hypo-enhancement, and intratumoral necrosis on T2-weighted imaging, which serve as critical noninvasive predictors of clinical outcomes. However, a definitive diagnosis of specific subtypes based solely on imaging remains challenging. This review provides a comprehensive overview of the molecular, pathological, and radiological characteristics of HCC subtypes and patterns, emphasizing that a detailed understanding of these features is essential for informed therapeutic decision-making and accurate prognostic assessment.