Hepatocellular Adenoma in Men

A Nationwide Assessment of Pathology and Correlation With Clinical Course

Belle V. van Rosmalen; Alicia Furumaya; Anne J. Klompenhouwer; Maarten E. Tushuizen; Andries E. Braat; Roy J. Reinten; Marjolein A. P. Ligthart; Martijn P. D. Haring; Vincent E. de Meijer; Theo van Voorthuizen; R. Bart Takkenberg; Cornelis H. C. Dejong; Robert A. de Man; Jan N. M. IJzermans; Michail Doukas; Thomas M. van Gulik; Joanne Verheij


Liver International. 2021;41(10):2474-2484. 

In This Article

Abstract and Introduction


Background & Aims: Hepatocellular adenomas (HCA) rarely occur in males, and if so, are frequently associated with malignant transformation. Guidelines are based on small numbers of patients and advise resection of HCA in male patients, irrespective of size or subtype. This nationwide retrospective cohort study is the largest series of HCA in men correlating (immuno)histopathological and molecular findings with the clinical course.

Methods: Dutch male patients with available histological slides with a (differential) diagnosis of HCA between 2000 and 2017 were identified through the Dutch Pathology Registry (PALGA). Histopathology and immunohistochemistry according to international guidelines were revised by two expert hepatopathologists. Next generation sequencing (NGS) was performed to confirm hepatocellular carcinoma (HCC) and/or subtype HCA. Final pathological diagnosis was correlated with recurrence, metastasis and death.

Results: A total of 66 patients from 26 centres fulfilling the inclusion criteria with a mean (±SD) age of 45.0 ± 21.6 years were included. The diagnosis was changed after expert revision and NGS in 33 of the 66 patients (50%). After a median follow-up of 9.6 years, tumour-related mortality of patients with accessible clinical data was 1/18 (5.6%) in HCA, 5/14 (35.7%) in uncertain HCA/HCC and 4/9 (44.4%) in the HCC groups (P = .031). Four B-catenin mutated HCA were identified using NGS, which were not yet identified by immunohistochemistry and expert revision.

Conclusions: Expert revision with relevant immunohistochemistry may help the challenging but prognostically relevant distinction between HCA and well-differentiated HCC in male patients. NGS may be more important to subtype HCA than indicated in present guidelines.


Hepatocellular adenoma (HCA) is a benign liver tumour, occurring predominantly in females, but sporadically in males. The incidence of HCA in females who use oral contraceptives is estimated at 3–4 per 100 000 females.[1] Ten percent of all HCAs occur in men.[2–4] Over the past decades, however, the incidence of HCA in males appears to be rising mainly because of an increase in HCA-related risk factors, such as the use of anabolic steroids, and the prevalence of obesity and metabolic syndrome.[5–11]

HCA in general features different pathomolecular subtypes: inflammatory adenoma (I-HCA, 30% of all HCA), HNF-1a (hepatocyte nuclear factor-1 alpha) inactivated adenoma (H-HCA, 34%), B-catenin activated adenoma with CTNNB1 exon 3 mutation (Bex3HCA, 8%), B-catenin activated adenoma with CTNNB1 exon 7/8 mutation (Bex7,8HCA, 4%), B-catenin activated inflammatory adenoma with CTNNB1 exon 3 mutation (Bex3IHCA, 8%), B-catenin activated inflammatory adenoma with CTNNB1 exon 7/8 mutation (Bex7,8IHCA, 5%) and sonic hedgehog adenoma (sh-HCA, 4%).[12] When no known mutation is found, an HCA is termed unclassified (U-HCA, <7% of all HCA).[13,14]

The overall reported risk of malignant transformation of HCA is estimated at 4.2%.[15] Malignant transformation generally occurs in Bex3(I)HCA, with an odds ratio of 9.3 in the total, predominantly female, population.[12,13] Cases of malignant transformation of Bex7,8(I)HCA have also been reported.[16] There appears to be an overrepresentation of the Bex3(I)HCA subtype among men.[12] In males, up to 47% of HCA are described as having undergone malignant transformation into hepatocellular carcinoma (HCC).[13,17,18]

According to European (European Association for the Study of the Liver, EASL) guidelines, HCA in men calls for different management as compared to HCA in females. In females with HCA, treatment including resection is only advocated in case of B(I)HCA and in HCA >5 cm that do not adequately regress after cessation of oral contraceptives.[3,12] In males with HCA, however, resection is advised irrespective of molecular subtype or tumour size. Although this recommendation is based on a limited number of patients and the precise definition of malignant transformation remains debatable,[19–25] the recommendation to always resect HCA in males is generally accepted based on the high risk of and challenging differentiation with HCC.[3,17,18] The aim of the current study is to provide a nationwide overview of diagnosis and management of HCA in men in the Netherlands, correlating histopathological, immunohistochemical and molecular findings with the clinical course of the disease, thus providing one of the largest series of HCA in men to date.