Liver International
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.
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.
Liver International. 2021;41(10):2474-2484. © 2021 Blackwell Publishing
Table 1. Baseline characteristics of patients with a final diagnosis of HCA, uncertain HCA/HCC and HCC
Total (n = 66)
HCA (n = 20)
Uncertain (n = 26)
HCC (n = 20)
Age in years (mean, SD) 45.0 (21.6) 40 37.4 (18.0) 17 43.7 (23.0) 14 61.4 (18.3) 9 . 021
BMI in kg/m2 (mean, SD) 25.8 (5.6) 32 24.5 (4.8) 14 25.8 (6.7) 12 28.9 (4.1) 6 .289
Tumour size in cm (mean, SD) 6.1 (3.9) 39 6.3 (3.9) 18 6.6 (4.6) 13 4.7 (2.7) 8 .524
Hormone use (n, %) 2 (4.9) 41 1 (5.6) 18 0 (0) 14 1 (11) 9 .693
Underlying liver disease (n, %) 18 (44) 41 6 (33) 18 10 (71) 14 2 (22) 9 . 035
Solitary tumours (n, %) 19 (46) 41 9 (50) 18 5 (36) 14 5 (56) 9 .666
Values in bold indicate statistically significant results (P < .05).
Abbreviations: HCA, hepatocellular adenoma; HCC, hepatocellular carcinoma; Uncertain, uncertain HCA/HCC.
Table 2. Treatment and outcomes of patients with a final diagnosis of HCA, uncertain HCA/HCC and HCC
Follow-up in months (mean, SD) 53 (47) 41 45 (36) 18 50 (50) 14 71 (61) 9 .416
Treatment with curative intent (n, %) 34 (83) 41 15 (83) 18 11 (79) 14 8 (89) 9 1.000
Recurrence or metastasis (n, %) 6 (15) 41 0 (0) 18 3 (21) 14 3 (33) 9 . 023
All-cause mortality (n, %) 10 (24) 41 1 (5.6) 18 5 (36) 14 4 (44) 9 . 031
Table 3. Description of 14 patients with recurrence, metastasis or death in clinical follow-up, according to final diagnosis
Age (y)
Underlying liver disease
Recurrence or metastasis
Death (time after diagnosis)
1 38 M 38 Peliosis hepatis LTx No Because of LTx (1.5 y)
Uncertain HCA/HCC
1 63 M 37 No TAE R: time unknown Cause unknown (4 y)
M: time unknown, to lymph nodes
2 70 S 65 No No N/A Because of HCC (unknown)
3 45 S 22 Cirrhosis, hepatitis C No N/A Because of sepsis (2.5 y)
4 62 S 34 No No N/A Because of heart attack (2 wk)
5 26 S 20 Cirrhosis, hepatitis B RFA No Cause unknown (1 y)
6 72 M 50 Hepatitis B RFA and open resection R: 6 mo after surgery No
MT: 5.5 y after surgery, to thoracic wall
7 70 S 120 NASH Sorafenib and open resection MT: 2 y after surgery, to lung No
1 69 M 20 Cirrhosis, hepatitis C RFA R: 10 mo after diagnosis Because of HCC (3.5 y)
2 62 M NA No LTx No Because of HCC (unknown)
3 76 S 59 No Open resection No Cause unknown (>5 y)
4 79 S 85 No Open resection No Cause unknown (unknown)
5 35 M 70 No Laparoscopic resection and TAE R: 5 y after surgery, treated by LTx No
MT: 10 y after surgery, to peritoneum
6 69 S 51 No Open resection R: 8 y after surgery No
Abbreviations: HCA, hepatocellular adenoma; HCC, hepatocellular carcinoma; LTx, liver transplantation; M, multiple; MT, metastasis; N/A, not applicable; NASH, non-alcohol steatohepatitis; R, recurrence; RFA, radiofrequency ablation; S, solitary; S/M, solitary or multiple tumours; TAE, transarterial embolization; wk, weeks; y, years.
Belle V. van Rosmalen1*, Alicia Furumaya1*, Anne J. Klompenhouwer2, Maarten E. Tushuizen3, Andries E. Braat4, Roy J. Reinten5, Marjolein A. P. Ligthart6, Martijn P. D. Haring7, Vincent E. de Meijer7, Theo van Voorthuizen8, R. Bart Takkenberg9, Cornelis H. C. Dejong6,10, Robert A. de Man2, Jan N. M. IJzermans11, Michail Doukas12†, Thomas M. van Gulik1† and Joanne Verheij5†, on behalf of the Dutch Benign Liver Tumor Group and the PALGA group
1Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
2Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
3Department of Gastroenterology and Hepatology, LUMC, Leiden University, Leiden, the Netherlands
4Department of Surgery, LUMC, Leiden University, Leiden, the Netherlands
5Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
6Department of Surgery and School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands
7Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
8Department of Oncology, Rijnstate hospital, Arnhem, the Netherlands
9Department of Gastroenterology and Hepatology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
10Department of Surgery, Universitätsklinikum Aachen, Aachen, Germany
11Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
12Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
Belle Vivica van Rosmalen, Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. Email: b.v.vanrosmalen@gmail.com
*Shared first authorship.
†Shared senior authorship.
BVvR, AJK, RAdM, JNMIJ, MD, TMvG and JV conceived the ideas or experimental design of the study; BVvR, AF, AJK, MET, AEB, RJR, MAPL, MPDH, VEdM, TvV, RBT, CHCD, RAdM, JNMIJ, MD, TMvG and JV performed data collection; BVvR, AF, RJR, MD and JV performed data analyses and interpretation; BVvR, AF, AJK, RJR, MD, TMvG and JV drafted the paper; BVvR, AF, AJK, MET, AEB, RJR, MAPL, MPDH, VEdM, TvV, RBT, CHCD, RAdM, JNMIJ, MD, TMvG and JV provided revisions to scientific content to the manuscript and gave final approval of the version to be published.
Lay Summary
In the tissue of 66 Dutch male patients with potential HCA, we demonstrated that a histopathological diagnosis of HCA in male patients is difficult. Expert pathology revision, additional stainings and NGS are very helpful. NGS may be more important than indicated in current guidelines, especially to identify B-catenin activated HCA.
HCA in men without malignant features and favourable clinical outcomes may exist.
Expert revision according to international guidelines aids adequate diagnosis.
Next generation sequencing improves identification of high risk (B-catenin activated) subtypes.
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