Objective Hepatocellular adenomas (HCAs) classically develop in women who are taking oral contraceptives and have a risk of malignant transformation into hepatocellular carcinoma (HCC). HCA with malignant transformation is, however, an ill-defined entity thought to be an anecdotic pathway to HCC. The objective of this study was to characterise malignancy occurring within HCA.

Design, setting and patients A series of histology proven HCAs managed between 1993 and 2008 in a tertiary hepato-biliary centre (218 patients, 184 women and 34 men) were screened to identify HCA with malignant transformation.

Main outcome measures The incidence of HCA with malignant transformation was analysed through the study period and associated conditions were retrieved. They were sub-typed according to their molecular features and the malignant compartment was mapped.

Results Areas of HCC within HCA were observed in 23 patients and the risk of malignant transformation was 4% in women and 47% in men. The number of women whose HCA had malignant changes has remained stable during the study period and oral contraception was the only associated condition. The number of men with such transformation has markedly increased since 2000 and the metabolic syndrome has become the most frequent associated condition. Two-thirds of HCAs with malignant transformation were β-catenin activated and one-third displayed cell atypias. Both features were more prevalent in men. The median diameter of HCA with malignancy was 10 cm and only three were 5 cm or less.

Conclusion Prevalence of malignancy within HCA is 10 times more frequent in men than in women and management of HCA should primarily be based on gender. Whereas oral contraception is a classical cause of HCA in women but a marginal cause of HCC, the metabolic syndrome appears as an emerging condition associated with malignant transformation of HCA in men, and is the likely predisposing condition for HCC in this setting.