Advertisement

Benign liver lesions 2022: Guideline for clinical practice of Associazione Italiana Studio del Fegato (AISF), Società Italiana di Radiologia Medica e Interventistica (SIRM), Società Italiana di Chirurgia (SIC), Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB), Associazione Italiana di Chirurgia Epatobilio-Pancreatica (AICEP), Società Italiana Trapianti d'Organo (SITO), Società Italiana di Anatomia Patologica e Citologia Diagnostica (SIAPEC-IAP) – Part II - Solid lesions

Published:September 08, 2022DOI:https://doi.org/10.1016/j.dld.2022.08.031

      Abstract

      Benign liver lesions are increasingly diagnosed in daily clinical practice due to the growing use of imaging techniques for the study of the abdomen in patients who have non-specific symptoms and do not have an increased risk of hepatic malignancy. They include simple or parasitic hepatic cysts and solid benign tumors which differ widely in terms of prevalence, clinical relevance, symptoms and natural history and often lead to significant clinical problems relating to diagnosis and clinical management. Following the need to have updated guidelines on the management of benign focal liver lesions, the Scientific Societies mainly involved in their management have promoted the drafting of a new dedicated document. This document was drawn up according to the present Italian rules and methodologies necessary to produce clinical, diagnostic, and therapeutic guidelines based on evidence. Here we present the second part of the guideline, concerning the diagnosis and clinical management of hemangioma, focal nodular hyperplasia, and hepatocellular adenoma.

      Keywords

      1. Introduction

      This report is a summary of Clinical Practice Guidelines for the management of benign liver lesions promoted by the following scientific societies: Associazione Italiana Studio del Fegato (AISF), Società Italiana di Radiologia Medica e Interventistica (SIRM), Società Italiana di Chirurgia (SIC), Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB), Associazione Italiana di Chirurgia Epatobilio-Pancreatica (AICEP), Società Italiana Trapianti d'Organo (SITO), Società Italiana di Anatomia patologica e Citologia Diagnostica (SIAPEC-IAP).
      Current knowledge on diagnosis and management of benign liver lesions is translated into relevant practical recommendations following the rules and the methodology suggested in Italy by the Centro Nazionale per l'Eccellenza delle cure (CNEC) and Istituto Superiore di Sanità (ISS).

      1.1 Methods for developing the guideline

      The above-mentioned scientific societies, whose members are primarily involved in the management of benign liver lesions, selected a committee of experts to draw up the guideline. This document was prepared according to the rules of the National center for clinical excellence, quality and safety of care (Centro Nazionale per l'Eccellenza Clinica, la Qualità e la Sicurezza delle Cure - CNEC), [
      CNEC - Centro Nazionale per l'Eccellenza delle Cure
      Manuale metodologico per la Produzione di Linee Guida di Pratica Clinica.
      ]. The committee defined the objectives and key issues. The most relevant questions were developed following the PICO format (Population, Intervention, Comparison, Outcomes), selected by discussion and voted by the whole committee. For each of the PICO questions, the literature on the MEDLINE database was systematically searched with both pertinent string and free text. A further hand-search was performed on previously published guidelines. The evidence profiles were developed applying the GRADE Evidence to Decision (EtD) framework [

      GRADEpro GDT [Computer program] McMaster University (developed by Evidence Prime) GRADEpro GDT. Version accessed 5 November 2021. Hamilton (ON): McMaster University (developed by Evidence Prime). Available at gradepro.org

      ] according to the CNEC manual [
      CNEC - Centro Nazionale per l'Eccellenza delle Cure
      Manuale metodologico per la Produzione di Linee Guida di Pratica Clinica.
      ,
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • et al.
      GRADE guidelines: 2. Framing the question and deciding on important outcomes.
      . All aspects concerning the questions, assessment of evidence, and conclusions were discussed among panel members and voted. The online GRADEpro GDT tool was used to develop questions and make decisions [
      • Moberg J.
      • Oxman A.D.
      • Rosenbaum S.
      • et al.
      The GRADE Evidence to Decision (EtD) framework for health system and public health decisions.
      ]. The quality of the studies was assessed applying the Quality Assessment of Diagnostic Accuracy Studies version 2 (QUADAS-2) checklist for diagnostic accuracy questions [
      • Whiting P.F.
      • Rutjes A.W.
      • Westwood M.E.
      • et al.
      QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies.
      ], the revised tool for Risk of Bias in randomized trials (RoB 2) [
      • Sterne J.A.C.
      • Savovic J.
      • Page M.J.
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      ], and the Risk Of Bias in Non-randomized Studies - of interventions (ROBINS-I) tool [
      • Sterne J.A.
      • Hernan M.A.
      • Reeves B.C.
      • et al.
      ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.
      ] for randomized clinical trials and non-randomized studies, where applicable.

      2. Hemangioma

      Hemangioma is the most common benign liver tumor [
      • Ishak K.G.
      • Rabin L.
      Benign tumors of the liver.
      ,
      • Choy B.Y.
      • Nguyen MH.
      The diagnosis and management of benign hepatic tumors.
      . The prevalence ranges from 2% to 5% in series with imaging techniques but raises up to 20% in autopsy series [
      • Ishak K.G.
      • Rabin L.
      Benign tumors of the liver.
      ,
      • Colombo M.
      • Forner A.
      • Ijzermans
      • et al.
      EASL Clinical Practice Guidelines on the management of benign liver tumours.
      ,
      • Karhunen PJ.
      Benign hepatic tumours and tumour like conditions in men.
      ,
      • Vilgrain V.
      • Boulos L.
      • Vullierme M.P.
      • et al.
      Imaging of atypical hemangiomas of the liver with pathologic correlation.
      ,
      • Bahirwani R.
      • Reddy KR.
      Review article: the evaluation of solitary liver masses.
      ,
      • Horta G.
      • Lopez M.
      • Dotte A.
      • et al.
      Benign focal liver lesions detected by computed tomography: review of 1,184 examinations.
      ]. Hemangiomas are more common in females (female/male ratio 3:1 to 6:1), at age between 30 and 50 years [
      • Bahirwani R.
      • Reddy KR.
      Review article: the evaluation of solitary liver masses.
      ,
      • Trotter J.F.
      • Everson GT.
      Benign focal lesions of the liver.
      . They may occur as solitary (with sizes ranging from a few millimeters to 20 cm) or multiple, and rarely concur with focal nodular hyperplasia nodules. Formerly, they were classified as “giant” when > 4 cm, more recently only when >10 cm [
      • Ishak K.G.
      • Rabin L.
      Benign tumors of the liver.
      ,
      • Di Carlo I.
      • Koshy R.
      • Al Mudares S.
      • et al.
      Giant cavernous liver hemangiomas: is it the time to change the size categories?.
      ,
      • Farges O.
      • Daradkeh S.
      • Bismuth H.
      Cavernous hemangiomas of the liver: are there any indications for resection?.
      .
      The diagnosis is usually incidental, and rarely associated with symptoms. In very large hemangiomas, symptoms are related to compression of adjacent organs with abdominal pain or vomit, or to the occurrence of systemic inflammatory response syndrome. Kasabach-Merritt syndrome is characterized by thrombocytopenia and coagulopathy [
      • Bahirwani R.
      • Reddy KR.
      Review article: the evaluation of solitary liver masses.
      ,
      • O'Rafferty C.
      • O'Regan G.M.
      • Irvine A.D.
      • et al.
      Recent advances in the pathobiology and management of Kasabach-Merritt phenomenon.
      . The etiology of hemangiomas is unclear. They are considered vascular malformations or hamartomas rather than true neoplasms. Despite a possible hormonal influence, estrogen receptors have never been demonstrated and hemangiomas grow even in subjects not taking oral contraceptive pills (OCP) [
      • Bahirwani R.
      • Reddy KR.
      Review article: the evaluation of solitary liver masses.
      ,
      • Giannitrapani L.
      • Soresi M.
      • La Spada E.
      • et al.
      Sex hormones and risk of liver tumor.
      ,
      • Jing L.
      • Liang H.
      • Caifeng L.
      • et al.
      New recognition of the natural history and growth pattern of hepatic hemangioma in adults.
      . During pregnancy, a volumetric increase may be observed, but complications have been rarely reported [
      • Cobey F.C.
      • Salem R.R.
      A review of liver masses in pregnancy and a proposed algorithm for their diagnosis and management.
      ].
      In 40–60% of cases, hemangiomas’ volume may increase over time with a variable, usually slow, rate. Factors determining growth are not completely clear: size (the largest ones increase faster) and age (the growth rate is higher in subjects below 30 years and slower in those over 50) have been implicated [
      • Jing L.
      • Liang H.
      • Caifeng L.
      • et al.
      New recognition of the natural history and growth pattern of hepatic hemangioma in adults.
      ,
      • Hasan H.Y.
      • Hinshaw J.L.
      • Borman E.J.
      • et al.
      Assessing normal growth of hepatic hemangiomas during long-term follow-up.
      . The main complication of hemangiomas, especially giant and pedunculated ones, is rupture with possible hemoperitoneum [
      • Liu X.
      • Yang Z.
      • Tan H.
      • et al.
      Location affects the management of liver haemangioma: a retrospective cohort study.
      ].
      PICO 1 - a. In adult patients diagnosed with hemangioma, should imaging surveillance be indicated? b. If surveillance is required, what imaging technique should be used?
      Studies assessing the natural course of hemangioma are mainly retrospective [
      • Hasan H.Y.
      • Hinshaw J.L.
      • Borman E.J.
      • et al.
      Assessing normal growth of hepatic hemangiomas during long-term follow-up.
      ,
      • Liu X.
      • Yang Z.
      • Tan H.
      • et al.
      Location affects the management of liver haemangioma: a retrospective cohort study.
      ,
      • Etemadi A.
      • Golozar A.
      • Ghassabian A.
      • et al.
      Cavernous hemangioma of the liver : factors affecting disease progression in general hepatology practice.
      ,
      • Yedibela S.
      • Alibek S.
      • Müller V.
      • et al.
      Management of hemangioma of the liver: surgical therapy or observation?.
      ,
      • Liu X.
      • Yang Z.
      • Tan H.
      • et al.
      Patient age affects the growth of liver haemangioma.
      ,
      • Glinkova V.
      • Shevah O.
      • Boaz M.
      • et al.
      Hepatic haemangiomas: possible association with female sex hormones.
      ,
      • Gandolfi L.
      • Leo P.
      • Solmi L.
      • et al.
      Natural history of hepatic haemangiomas: clinical and ultrasound study.
      ] and at high-risk of bias for patients’ selection and missing data. The diagnosis is almost always obtained by ultrasound (US), less frequently by computed tomography (CT) or magnetic resonance imaging (MRI), and rarely by scintigraphy or angiography. The follow-up is variable, preventing any comparison. No study compared imaging surveillance to no surveillance and only the number of complications detected during surveillance can be assessed. Most studies report size changes, especially in hemangiomas > 4-5 cm. A study, using CT or MRI, showed in 40% of hemangiomas a volume increase during a follow-up of 3.7 years, with a growth rate of 17.4%/year [
      • Hasan H.Y.
      • Hinshaw J.L.
      • Borman E.J.
      • et al.
      Assessing normal growth of hepatic hemangiomas during long-term follow-up.
      ]. Complications (ruptures, hemorrhages) have been demonstrated mainly in hemangiomas larger than 5-10 cm [
      • Yedibela S.
      • Alibek S.
      • Müller V.
      • et al.
      Management of hemangioma of the liver: surgical therapy or observation?.
      ]. Glinkova estimated an odds ratio for enlargement of 3.02 (95% CI 0.99–9.12) without complications [
      • Glinkova V.
      • Shevah O.
      • Boaz M.
      • et al.
      Hepatic haemangiomas: possible association with female sex hormones.
      ]. Yedibela reported an increased risk of complications and recommended follow-up in patients with hemangiomas > 10 cm [
      • Yedibela S.
      • Alibek S.
      • Müller V.
      • et al.
      Management of hemangioma of the liver: surgical therapy or observation?.
      ]. Further studies should assess the outcome of asymptomatic large volume hemangiomas > 10 cm, using US in view of non-invasiveness, low costs, and absence of biological risk. In case of giant hemangiomas >15 cm, the repeatability of US may be an issue and MRI may be more accurate [
      • Hasan H.Y.
      • Hinshaw J.L.
      • Borman E.J.
      • et al.
      Assessing normal growth of hepatic hemangiomas during long-term follow-up.
      ].
      Recommendation
      • a.
        In patients with asymptomatic hemangioma <10 cm we suggest no follow-up. In symptomatic patients or with hemangiomas > 10 cm we suggest follow-up, due to possible complications. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      • b.
        When indicated, follow-up should be performed with ultrasound in view of non-invasiveness, low costs, and absence of biological risk. In hemangiomas >15 cm, due to the difficulty of assessing dimensional variations by means of ultrasound, we suggest using magnetic resonance. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 2 - In patients with hemangioma, should ultrasound surveillance be indicated during pregnancy?
      The higher prevalence of hemangiomas in women [
      • Gandolfi L.
      • Leo P.
      • Solmi L.
      • et al.
      Natural history of hepatic haemangiomas: clinical and ultrasound study.
      ,
      • Trotter J.F.
      • Everson GT.
      Benign focal lesions of the liver.
      raises the question if estrogens may be responsible for their development, and if pregnancy plays a role in growth or in complications occurrence. Complications such as bleeding or Kasabach-Merritt syndrome are very rarely reported [
      • Schwartz S.I.
      • Husser WC.
      Cavernous hemangioma of the liver. A single institution report of 16 resections.
      ]. Cobey reports volume increase without any complication after pregnancy in four women with hemangiomas larger than 5 cm, [
      • Cobey F.C.
      • Salem R.R.
      A review of liver masses in pregnancy and a proposed algorithm for their diagnosis and management.
      ]. Etemadi found that 14 out of 38 cases increased in size during pregnancy without any complication [
      • Etemadi A.
      • Golozar A.
      • Ghassabian A.
      • et al.
      Cavernous hemangioma of the liver : factors affecting disease progression in general hepatology practice.
      ].
      Recommendation
      In patients with asymptomatic hemangiomas we suggest no ultrasound surveillance during pregnancy. Ultrasound surveillance during pregnancy might be required in women with giant hemangiomas. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 3 – Do patients with symptomatic giant hepatic hemangiomas show better outcomes if treated surgically rather than with conservative loco-regional methods?
      Treatment should be considered in cases of symptomatic hemangiomas (pain, sense of heaviness), Kasabach-Merritt syndrome (bulky hemangioma associated with severe thrombocytopenia, microangiopathic-hemolytic anemia, and consumption coagulopathy), or in presence of pedunculated hemangiomas at risk of rupture. Surgical treatment is a well-established option, and a recent meta-analysis shows that resection with enucleation is preferable to anatomical resection reducing the duration of surgery, blood loss, and postoperative complications [
      • Cheng W.L.
      • Qi Y.Q.
      • Wang B.
      • et al.
      Enucleation versus hepatectomy for giant hepatic haemangiomas: a meta-analysis.
      ]. Beside surgical procedures, other therapeutic options are interventional radiology techniques such as trans-arterial embolization (TAE) and thermal ablation; the latter can also support surgery in selected cases (e.g., laparoscopic/laparotomic thermal ablation) [
      • Wang S.
      • Gao J.
      • Yang M.
      Intratumoral coagulation by radiofrequency ablation facilitated the laparoscopic resection of giant hepatic hemangioma: a surgical technique report of two cases.
      ]. Ablation techniques should be considered a therapeutic option especially in patients with lesions < 10 cm refusing surgical treatment or at high surgical risk [
      • Dong W.
      • Qiu B.
      • Xu H.
      • et al.
      Invasive management of symptomatic hepatic hemangioma.
      ,
      • Sakamoto Y.
      • Kokudo N.
      • Watadani T.
      • et al.
      Proposal of size-based surgical indication criteria for liver hemangioma based on a nationwide survey in Japan.
      . Percutaneous radiofrequency ablation (RFA) has an effectiveness higher than 80% for complete hemangioma ablation [
      • Wu S.
      • Gao R.
      • Yin T.
      • Zhu R.
      • et al.
      Complications of radiofrequency ablation for hepatic hemangioma: a multicenter retrospective analysis on 291 cases.
      ,
      • Gao J.
      • Ding X.
      • Ke S.
      • et al.
      Radiofrequency ablation in treatment of huge hepatic hemangiomas: a comparison of multi-tined and internally cooled electrodes.
      ,
      • Park S.Y.
      • Tak W.Y.
      • Jung M.K.
      • et al.
      Symptomatic-enlarging hepatic hemangiomas are effectively treated by percutaneous ultrasonography-guided radiofrequency ablation.
      ], with a complications rate (bleeding, rupture, injury to adjacent organs) of 5.5% for lesions between 5.5 and 9.9 cm, and of 13.2% for lesions ≥ 10 cm [
      • Wu S.
      • Gao R.
      • Yin T.
      • Zhu R.
      • et al.
      Complications of radiofrequency ablation for hepatic hemangioma: a multicenter retrospective analysis on 291 cases.
      ]. Contraindications to RFA include lesions in subcapsular space, close to vascular structures greater than 4 mm in caliber or close to perihepatic viscera. In case of proximity to viscera or subcapsular locations, RFA can be safely performed using the laparoscopic approach. Percutaneous or laparoscopic microwave ablation (MWA) can also be used. In comparison to conventional open resection, laparoscopic MWA is associated with reduced blood loss, shorter operative time and post-operative hospital stay, with the same risk of long-term complications [
      • Chen L.
      • Zhang L.
      • Tian M.
      • et al.
      Safety and effective of laparoscopic microwave ablation for giant hepatic hemangioma: a retrospective cohort study.
      ]. Finally, a systematic review including 18 studies and 1,284 patients, reported that TAE of hemangiomas was associated to volume reduction in 89.9% of cases and an improvement or disappearance of symptoms in 98.5%. Grade 3 complications were found in 2.9% of patients, and failure of the procedure with need of surgery, in 2.7% [
      • Furumaya A.
      • van Rosmalen B.V.
      • Takkenberg R.B.
      • et al.
      Transarterial (Chemo-) embolization and lipiodolization for hepatic haemangioma.
      ].
      Recommendation
      • a.
        In patients with symptomatic hemangiomas (Kasabach-Merritt syndrome or bulk symptoms) or pedunculated hemangiomas or hemangiomas with a diameter of 10 cm or more, we suggest surgical treatment. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      • b.
        Symptomatic hemangiomas less than 10 cm may be initially approached with locoregional ablation techniques. In case of unfavorable clinical evolution or volume increase after treatment we suggest resection with radical intent. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 4 - Do patients with severely symptomatic hemangioma or multiple hemangiomas show better outcomes with liver transplant compared to conservative therapeutic approach?
      Liver transplantation is rarely an option for hepatic hemangiomas due to their benign nature. It is indicated in symptomatic patients with bilobar multiple hemangiomas, complicated hemangiomas, or with Kasabach-Merritt syndrome, when intra-arterial embolization is ineffective and surgical resection is unfeasible. In the European Liver Transplantation Registry, 71 patients underwent liver transplant for single or multiple hemangiomas from 1988 to 2016, with a 1-year and 5-year survival rate of 80% and 77%, respectively [
      • Adam R.
      • Karam V.
      • Cailliez V.
      • et al.
      Annual report of the European Liver Transplant Registry (ELTR) - 50-year evolution of liver transplantation.
      ]. According to the United Network for Organ Sharing (UNOS), 23 patients received liver transplant for hemangioma from 1988 to 2013, with a 1-year and 5-year survival rate of 87.8% and 74.8%, respectively [
      • Sundar Alagusundaramoorthy S.
      • Vilchez V.
      • Zanni A.
      • et al.
      Role of transplantation in the treatment of benign solid tumors of the liver: a review of the United Network of Organ Sharing data set.
      ]. A recent systematic review showed an overall transplant-related morbidity of 31%; surgical complications were recorded in 2/16 patients (one bleeding and one hyperacute rejection requiring re-transplantation) whereas medical complications (acute cellular rejections) were observed in 3/16 patients [
      • Prodromidou A.
      • Machairas N.
      • Garoufalia Z.
      • et al.
      Liver transplantation for giant hepatic hemangioma: a systematic review.
      ].
      Recommendation
      In symptomatic patients with unresectable giant hepatic hemangioma or multiple hemangiomas, we suggest liver transplantation as a feasible treatment. Very low quality of evidence (D); strength of recommendation 2 (conditional)

      3. Focal nodular hyperplasia

      Focal nodular hyperplasia (FNH) is the second most common benign tumor of the liver and is generally detected incidentally during US. In non-selected autopsy series, the prevalence was 0.4–3% [
      • Rubin R.A.
      • Mitchell DG.
      Evaluation of the solid hepatic mass.
      ,
      • Marrero J.A.
      • Ahn J.
      • Rajender Reddy K.
      • et al.
      ACG clinical guideline: the diagnosis and management of focal liver lesions.
      . FNH is mainly diagnosed in reproductive-aged women (up to 90%, age 35-50 years), is usually solitary and less than 5 cm in diameter, multiple in 20–30% of cases, and associated with hepatic hemangiomas in about 20% of cases [
      • Nguyen B.N.
      • Flejou J.F.
      • Terris B.
      • et al.
      Focal nodular hyperplasia of the liver: a comprehensive pathologic study of 305 lesions and recognition of new histologic forms.
      ,
      • Vilgrain V.
      • Uzan F.
      • Brancatelli G.
      • et al.
      Prevalence of hepatic hemangioma in patients with focal nodular hyperplasia: MR imaging analysis.
      . FNH is considered a hyperplastic-proliferative cell response to vascular malformations [
      • Bioulac-Sage P.
      • Cubel G.
      • Balabaud C.
      • et al.
      Revisiting the pathology of resected benign hepatocellular nodules using new immunohistochemicalmarkers.
      ]. This hypothesis is supported by absence of somatic mutations, deregulation of genes involved in vascular remodeling [
      • Paradis V.
      • Benzekri A.
      • Dargere D.
      • et al.
      Telangiectatic focal nodular hyperplasia: a variant of hepatocellular adenoma.
      ], and association with other intrahepatic arterial injuries such as hereditary hemorrhagic telangiectasia [
      • Buscarini E.
      • Danesino C.
      • Plauchu H.
      • et al.
      High prevalence of hepatic focal nodular hyperplasia in subjects with hereditary hemorrhagic telangiectasia.
      ], or exposure to oxaliplatin in adults [
      • Furlan A.
      • Brancatelli G.
      • Dioguardi Burgio M.
      • et al.
      Focal nodular hyperplasia after treatment with oxaliplatin: a multiinstitutional series of cases diagnosed at MRI.
      ]. Pregnancy and OCP showed no role in the development or progression of FNH [
      • Rifai K.
      • Mix H.
      • Krusche S.
      • et al.
      No evidence of substantial growth progression or complications of large focal nodular hyperplasia during pregnancy.
      ,
      • D'Halluin V.
      • Vilgrain V.
      • Pelletier G.
      • et al.
      Natural history of focal nodular hyperplasia. A retrospective study of 44 cases.
      .
      FNH is generally stable, only occasionally a mild volume increase has been reported, with rare complications [
      • D'Halluin V.
      • Vilgrain V.
      • Pelletier G.
      • et al.
      Natural history of focal nodular hyperplasia. A retrospective study of 44 cases.
      ,
      • Perrakis A.
      • Demir R.
      • Muller V.
      • et al.
      Management of the focal nodular hyperplasia of the liver: evaluation of the surgical treatment comparing with observation only.
      . Macroscopically, a star-shaped scar, centrally located with radiating fibrous septa containing large-sized artery and veins, is the typical form. Histologically, it is composed of benign hepatocytes arranged in nodules partially surrounded by fibrous septa, with ductular proliferation and inflammatory cells. Several atypical forms are recognized, including FNH without a central scar (the most common atypical form, particularly in <3 cm lesions) and FNH with steatosis [
      • Ronot M.
      • Paradis V.
      • Duran R.
      • et al.
      MR findings of steatotic focal nodular hyperplasia and comparison with other fatty tumours.
      ]. Molecular analysis identified up-regulation of extracellular matrix genes, associated with activation of the transforming-growth factor beta-pathway, and overexpression of Wnt/b-catenin target genes, including glutamate ligase, coding for glutamine synthase (GS) [
      • Rebouissou S.
      • Couchy G.
      • Libbrecht L.
      • et al.
      The beta-catenin pathway is activated in focal nodular hyperplasia but not in cirrhotic FNH-like nodules.
      ,
      • Bioulac-Sage P.
      • Laumonier H.
      • Rullier A.
      • et al.
      Over-expression of glutamine synthetase in focal nodular hyperplasia: a novel easy diagnostic tool in surgical pathology.
      .
      PICO 5 - a. In asymptomatic adults with focal nodular hyperplasia should imaging surveillance be indicated? b. If surveillance is required, what imaging technique should be used?
      In patients with FNH no algorithm supporting surveillance is currently available. Although large FNHs can be associated with symptoms due to compression, almost all FNHs remain stable without complications, such as hemorrhage and rupture [
      • Terkivatan T.
      • de Wilt J.H.W.
      • de Man R.A.
      • et al.
      Indications and long-term outcome of treatment for benign hepatic tumors.
      ,
      • Campos Amico E.
      • de Souza I.K.
      • Grigório Trigueiro J.R.
      • et al.
      Should focal nodular hyperplasia still be operated upon? Analysis of a case series.
      . In a retrospective study including 96 patients with FNH, symptoms worsened in 13% and FNH increased only in 4%, during imaging surveillance (with US or MRI) [
      • Perrakis A.
      • Vassos N.
      • Grützmann R.
      • et al.
      what is changing in indications and treatment of focal nodular hyperplasia of the liver. is there any place for surgery?.
      ]; no major complications and no increased disease-related mortality were reported in patients refusing resection despite symptoms. However, albeit rare, some cases of rupture, often with hemoperitoneum, are reported [
      • Hardwigsen J.
      • Pons J.
      • Veit V.
      • et al.
      A life-threatening complication of focal nodular hyperplasia.
      ,
      • Bathe O.F.
      • Mies C.
      • Franceschi D.
      • et al.
      Massive hemorrhage and infarction complicating focal nodular hyperplasia of the liver.
      ,
      • Chang S.K.
      • Chung Y.F.
      • Thng C.H.
      • et al.
      Focal nodular hyperplasia presenting as acute abdomen.
      ,
      • Rahili A.
      • Cai J.
      • Trastour C.
      • et al.
      Spontaneous rupture and hemorrhage of hepatic focal nodular hyperplasia in lobus caudatus.
      ,
      • Demarco M.P.
      • Shen P.
      • Bradley R.F.
      • et al.
      Intraperitoneal hemorrhage in a patient with hepatic focal nodular hyperplasia.
      ,
      • Li T.
      • Qin L.X.
      • Ji Y.
      • et al.
      Atypical hepatic focal nodular hyperplasia presenting as acute abdomen and misdiagnosed as hepatocellular carcinoma.
      ,
      • Kinoshita M.
      • Takemura S.
      • Tanaka S.
      • et al.
      Ruptured focal nodular hyperplasia observed during follow-up: a case report.
      ]. In particular, large lesions, localized in the subcapsular region, appear at higher risk of rupture. Accordingly, imaging surveillance might be proposed for selected patients refusing treatment despite large and/or located in the subcapsular or pericaval region FNHs. MRI, with hepato-specific contrast agents, is more accurate than US and CT, in differentiating adenoma from FNH, with 91%-100% sensitivity and 93%–100 specificity [
      • Grazioli L.
      • Bondioni M.P.
      • Haradome H.
      • et al.
      Hepatocellular adenoma and focal nodular hyperplasia: value of gadoxetic acid-enhanced MR imaging in differential diagnosis.
      ,
      • McInnes M.D.
      • Hibbert R.M.
      • Inácio J.R.
      • et al.
      Focal nodular hyperplasia and hepatocellular adenoma: accuracy of gadoxetic acid-enhanced MR imaging–a systematic review [published correction appears in radiology. 2015 Dec;277(3):927].
      ,
      • Grazioli L.
      • Morana G.
      • Kirchin M.A.
      • et al.
      Accurate differentiation of focal nodular hyperplasia from hepatic adenoma at gadobenate dimeglumine-enhanced MR imaging: prospective study.
      ,
      • Grieser C.
      • Steffen I.G.
      • Seehofer D.
      • et al.
      Histopathologically confirmed focal nodular hyperplasia of the liver: gadoxetic acid-enhanced MRI characteristics.
      ,
      • Nault J.C.
      • Zucman Rossi J.
      Molecular classification of hepatocellular adenomas.
      ]. However, most studies overestimated the MRI accuracy failing to classify hepatocellular adenoma (HCA) subtypes with possible misclassification of inflammatory adenomas as telangiectatic FNH [
      • McInnes M.D.
      • Hibbert R.M.
      • Inácio J.R.
      • et al.
      Focal nodular hyperplasia and hepatocellular adenoma: accuracy of gadoxetic acid-enhanced MR imaging–a systematic review [published correction appears in radiology. 2015 Dec;277(3):927].
      ]. When surveillance is required, US could be used for single small lesion, and MRI with hepato-specific contrast agent for multiple, atypical, or very large lesions.
      Recommendation
      • a.
        In asymptomatic adults with focal nodular hyperplasia not localized in the subcapsular or pericaval region, we suggest not performing imaging surveillance. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      • b.
        In symptomatic patients with pain or compression symptoms, refusing treatment, and in patients with lesions located in the subcapsular or pericaval region, we suggest ultrasound or magnetic resonance surveillance. Very low quality of evidence (D); strength of recommendation 2 (conditional). We suggest referring patients with lesions undefined by imaging techniques as focal nodular hyperplasia to a tertiary reference center. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 6 - In patients, with focal nodular hyperplasia and on treatment with oral contraceptives, should discontinuation of therapy be indicated?
      The largest study reports data from 216 women diagnosed with FNH, enrolled between 1989 and 1998, and grouped according to the use of OCP: 28 non-users, 46 on high-dose OCP therapy, 98 on low-dose therapy, 33 on high-dose and then on low-dose therapy, and 11 on therapy with progestinic only. No difference was found between the five groups in number and size of FNH. In addition, 136 of these patients were kept under surveillance: a change in size was detected only in 2.9%, without difference according to the use of OCP [
      • Mathieu D.
      • Kobeiter H.
      • Maison P.
      • et al.
      Oral contraceptive use and focal nodular hyperplasia of the liver.
      ]. In another study, FNHs grew in 4 of 44 cases regardless of the use of OCP [
      • D'Halluin V.
      • Vilgrain V.
      • Pelletier G.
      • et al.
      Natural history of focal nodular hyperplasia. A retrospective study of 44 cases.
      ]. On the contrary, a case-control study suggested that the prolonged use of OCP in 23 women could be a risk factor for developing FNH [
      • Scalori A.
      • Tavani A.
      • Gallus S.
      • et al.
      Oral contraceptives and the risk of focal nodular hyperplasia of the liver: a case-control study.
      ].
      Recommendation
      In patients with focal nodular hyperplasia, we suggest not discontinuing oral contraceptives, that show no role in the development and evolution. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 7 – In symptomatic adults with focal nodular hyperplasia, is surgical treatment associated with better outcomes compared to follow-up?
      Several studies showed that surgery is effective for symptoms relief and low recurrences in symptomatic adults with FNH [
      • Shen Y.H.
      • Fan J.
      • Wu Z.Q.
      • et al.
      Focal nodular hyperplasia of the liver in 86 patients.
      ,
      • Fioole B.
      • Kokke M.
      • van Hillegersberg R.
      • Rinkes IH.
      Adequate symptom relief justifies hepatic resection for benign disease.
      ,
      • Hau H.M.
      • Atanasov G.
      • Tautenhahn H.M.
      • et al.
      The value of liver resection for focal nodular hyperplasia: resection yes or no?.
      ]. Moreover, TAE proved to be safe and effective as an alternative to surgery, with long-term control of symptoms and significant lesions downsize [
      • Zhang G.
      • Wang M.
      • Duan F.
      • et al.
      Transarterial embolization with bleomycin for symptomatic hepatic focal nodular hyperplasia.
      ,
      • Birn J.
      • Williams T.R.
      • Croteau D.
      • et al.
      Transarterial embolization of symptomatic focal nodular hyperplasia.
      . However, in absence of randomized clinical trials, the therapeutic algorithm remains controversial [
      • Perrakis A.
      • Demir R.
      • Muller V.
      • et al.
      Management of the focal nodular hyperplasia of the liver: evaluation of the surgical treatment comparing with observation only.
      ,
      • Terkivatan T.
      • de Wilt J.H.W.
      • de Man R.A.
      • et al.
      Indications and long-term outcome of treatment for benign hepatic tumors.
      ,
      • Perrakis A.
      • Vassos N.
      • Grützmann R.
      • et al.
      what is changing in indications and treatment of focal nodular hyperplasia of the liver. is there any place for surgery?.
      ,
      • Shen Y.H.
      • Fan J.
      • Wu Z.Q.
      • et al.
      Focal nodular hyperplasia of the liver in 86 patients.
      ,
      • Hsee L.C.
      • McCall J.L.
      • Koea J.B.
      Focal nodular hyperplasia: what are the indications for resection?.
      ,
      • Descottes B.
      • Glineur D.
      • Lachachi F.
      • et al.
      Laparoscopic liver resection of benign liver tumours.
      ,
      • Mezhir J.J.
      • Fourman L.T.
      • Do R.K.
      • et al.
      Changes in the management of benign liver tumours: an analysis of 285 patients.
      ]. Perrakis retrospectively analyzed two groups of patients with FNH, 93 underwent surgery and 96 remained in follow-up. Indications for surgery were abdominal discomfort (68), tumor growing (16) and uncertain diagnosis (15). Symptoms’ relief occurred in 92% of surgically treated patients. In the untreated group, 13% reported additional symptoms and 4% showed increased volume [
      • Perrakis A.
      • Demir R.
      • Muller V.
      • et al.
      Management of the focal nodular hyperplasia of the liver: evaluation of the surgical treatment comparing with observation only.
      ]. It is currently accepted that surgery is indicated in symptomatic patients with FNH in case of uncertain diagnosis or in case of marked increase in size of the lesion [
      • Perrakis A.
      • Demir R.
      • Muller V.
      • et al.
      Management of the focal nodular hyperplasia of the liver: evaluation of the surgical treatment comparing with observation only.
      ,
      • Hau H.M.
      • Atanasov G.
      • Tautenhahn H.M.
      • et al.
      The value of liver resection for focal nodular hyperplasia: resection yes or no?.
      ,
      • Hsee L.C.
      • McCall J.L.
      • Koea J.B.
      Focal nodular hyperplasia: what are the indications for resection?.
      ,
      • Descottes B.
      • Glineur D.
      • Lachachi F.
      • et al.
      Laparoscopic liver resection of benign liver tumours.
      ,
      • Mezhir J.J.
      • Fourman L.T.
      • Do R.K.
      • et al.
      Changes in the management of benign liver tumours: an analysis of 285 patients.
      ,
      • Pain J.A.
      • Gimson A.E.
      • Williams R.
      • et al.
      Nodular hyperplasia of the liver: results of treatment and options in management.
      ].
      Recommendation
      In symptomatic adults with focal nodular hyperplasia, we suggest surgical treatment of the lesion, as it might improve the quality of life. However, follow-up does not appear associated with the occurrence of major complications. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 8 - In patients with focal nodular hyperplasia, should ultrasound surveillance be indicated during pregnancy?
      The largest published study reports data from 216 women with FNH enrolled between 1989 and 1998: 136 were maintained in surveillance and 12 had at least one pregnancy during the study. The lesions size did not change, and no complications occurred during pregnancy and after delivery [
      • Mathieu D.
      • Kobeiter H.
      • Maison P.
      • et al.
      Oral contraceptive use and focal nodular hyperplasia of the liver.
      ]. Two other studies confirmed these findings [
      • Rifai K.
      • Mix H.
      • Krusche S.
      • et al.
      No evidence of substantial growth progression or complications of large focal nodular hyperplasia during pregnancy.
      ,
      • D'Halluin V.
      • Vilgrain V.
      • Pelletier G.
      • et al.
      Natural history of focal nodular hyperplasia. A retrospective study of 44 cases.
      .
      Recommendation
      In patients with focal nodular hyperplasia, we suggest not performing surveillance during pregnancy that does not play a role in the development and evolution of the lesion. Very low quality of evidence (D); strength of recommendation 2 (conditional)

      4. Hepatocellular adenoma

      HCA is a rare epithelial benign tumor that usually develops in a healthy liver, mainly in young women. In 70–80% of cases HCAs are solitary and vary widely in size (from 1 to 30 cm). Symptoms are more frequent in larger lesions [
      • Grazioli L.
      • Federle M.P.
      • Brancatelli G.
      • et al.
      Hepatic adenomas: imaging and pathologic findings.
      ]. Complications, such as hemorrhage and malignant transformation, may occur. The major risk factors for developing HCA include OCP and anabolic steroids, obesity, metabolic syndrome, and alcohol abuse. Other associated conditions are glycogen-storage diseases (types 1 and 3), galactosemia, tyrosinemia, familial polyposis coli, polycystic-ovary syndrome, and β-thalassemia. The recent increase in HCA prevalence seems related to the increased prevalence of obesity and metabolic syndrome [
      • Bioulac-Sage P.
      • Sempoux C.
      • Balabaud C.
      Hepatocellular adenoma: classification, variants and clinical relevance.
      ,
      • Sherlock S.
      Hepatic adenomas and oral contraceptives.
      ,
      • Klatskin G.
      Hepatic tumors: possible relationship to use of oral contraceptives.
      ,
      • Baum J.K.
      • Bookstein J.J.
      • Holtz F.
      • Klein EW.
      Possible association between benign hepatomas and oral contraceptives.
      ,
      • Edmondson H.A.
      • Henderson B.
      • Benton B.
      Liver-cell adenomas associated with use of oral contraceptives.
      ].
      HCAs were rarely diagnosed before the advent of the OCPs [
      • Baum J.K.
      • Bookstein J.J.
      • Holtz F.
      • Klein EW.
      Possible association between benign hepatomas and oral contraceptives.
      ,
      • Edmondson H.A.
      Tumors of the liver and intrahepatic bile ducts.
      and their development correlates with the dose and duration of hormonal therapy [
      • Edmondson H.A.
      • Henderson B.
      • Benton B.
      Liver-cell adenomas associated with use of oral contraceptives.
      ,
      • Rooks J.B.
      • Ory H.W.
      • Ishak K.G.
      • et al.
      Epidemiology of hepatocellular adenoma. The role of oral contraceptive use.
      ,
      • Nime F.
      • Pickren J.W.
      • Vana J.
      • et al.
      The histology of liver tumors in oral contraceptive users observed during a national survey by the American college of surgeons commission on cancer.
      ,
      • Rosenberg L.
      The risk of liver neoplasia in relation to combined oral contraceptive use.
      ,
      • Søe K.L.
      • Søe M.
      • Gluud C.
      Liver pathology associated with the use of anabolic-androgenic steroids.
      ]. The annual incidence is 1/1,000,000 in women never using OCPs, and 30–40/1,000,000 in women on OCPs [
      • Rooks J.B.
      • Ory H.W.
      • Ishak K.G.
      • et al.
      Epidemiology of hepatocellular adenoma. The role of oral contraceptive use.
      ,
      • Reddy K.R.
      • Schiff ER.
      Approach to a liver mass.
      . The risk is greater in women > 30 years assuming high-estrogen OCP for > 25 months [
      • Rooks J.B.
      • Ory H.W.
      • Ishak K.G.
      • et al.
      Epidemiology of hepatocellular adenoma. The role of oral contraceptive use.
      ,
      • Cherqui D.
      • Rahmouni A.
      • Charlotte F.
      • et al.
      Management of focal nodular hyperplasia and hepatocellular adenoma in young women: a series of 41 patients with clinical, radiological, and pathological correlations.
      . The introduction of low-estrogen OCP may have reduced the HCA incidence [
      • Cherqui D.
      • Rahmouni A.
      • Charlotte F.
      • et al.
      Management of focal nodular hyperplasia and hepatocellular adenoma in young women: a series of 41 patients with clinical, radiological, and pathological correlations.
      ,
      • Benhamou J.P.
      Diagnostic approach to a liver mass: diagnosis of an asymptomatic liver tumor in a young woman.
      . OCP use affects the HCA natural course with more numerous and larger and more likely to bleed lesions [
      • Klatskin G.
      Hepatic tumors: possible relationship to use of oral contraceptives.
      ,
      • Søe K.L.
      • Søe M.
      • Gluud C.
      Liver pathology associated with the use of anabolic-androgenic steroids.
      ,
      • Shortell C.K.
      • Schwartz SI.
      Hepatic adenoma and focal nodular hyperplasia.
      ,
      • Meissner K.
      Hemorrhage caused by ruptured liver cell adenoma following long-term oral contraceptives: a case report.
      . Volume reduction or complete regression were observed discontinuing OCP, with relapses in patients resuming therapy or during pregnancy [
      • Rooks J.B.
      • Ory H.W.
      • Ishak K.G.
      • et al.
      Epidemiology of hepatocellular adenoma. The role of oral contraceptive use.
      ,
      • Edmondson H.A.
      • Reynolds T.B.
      • Henderson B.
      • et al.
      Regression of liver cell adenomas associated with oral contraceptives.
      ,
      • Kawakatsu M.
      • Vilgrain V.
      • Erlinger S.
      • Nahum H.
      Disappearance of liver cell adenoma: CT and MR imaging.
      ,
      • Aseni P.
      • Sansalone C.V.
      • Sammartino C.
      • Benedetto F.D.
      • Carrafiello G.
      • Giacomoni A.
      • Osio C.
      • Vertemati M.
      • Forti D.
      Rapid disappearance of hepatic adenoma after contraceptive withdrawal.
      ,
      • Norris S.
      Drug- and Toxin-Induced Liver Injury.
      ,
      • Cohen C.
      • Lawson D.
      • DeRose P.B.
      Sex and androgenic steroid receptor expression in hepatic adenomas.
      ,
      • Masood S.
      • West A.B.
      • Barwick KW.
      Expression of steroid hormone receptors in benign hepatic tumors. An immunocytochemical study.
      ]. HCA development is also associated with the administration of anabolic steroids, mainly 17-alpha-alkylated steroids, in patients with aplastic anemia or Fanconi's syndrome, in body-builders, and in transgender people [
      • Nakao A.
      • Sakagami K.
      • Nakata Y.
      • et al.
      Multiple hepatic adenomas caused by long-term administration of androgenic steroids for aplastic anemia in association with familial adenomatous polyposis.
      ,
      • Resnick M.B.
      • Kozakewich H.P.
      • Perez-Atayde AR.
      Hepatic adenoma in the pediatric age group. Clinicopathological observations and assessment of cell proliferative activity.
      ,
      • Touraine R.L.
      • Bertrand Y.
      • Foray P.
      • et al.
      Hepatic tumours during androgen therapy in Fanconi anaemia.
      ,
      • Coombes G.B.
      • Reiser J.
      • Paradinas F.J.
      Burn I. An androgen-associated hepatic adenoma in a trans-sexual.
      ,
      • Norris S.
      Drug- and Toxin-Induced Liver Injury.
      . Androgens induce the development of multiple HCA, and regression is frequently observed after discontinuation [
      • Resnick M.B.
      • Kozakewich H.P.
      • Perez-Atayde AR.
      Hepatic adenoma in the pediatric age group. Clinicopathological observations and assessment of cell proliferative activity.
      ,
      • Carrasco D.
      • Prieto M.
      • Pallardó L.
      • et al.
      Multiple hepatic adenomas after long-term therapy with testosterone enanthate. Review of the literature.
      . HCAs are described in type I (51%) and III (25%) glycogen storage disease; they are often multiple, more frequently found in males and usually seen before the age of 20. Regression has been occasionally described after protracted nocturnal gastric drip feeding and correction of insulin, glucose, and glucagon levels [
      • Shortell C.K.
      • Schwartz SI.
      Hepatic adenoma and focal nodular hyperplasia.
      ,
      • Fujiyama S.
      • Sato K.
      • Sakai M.
      • et al.
      A case of type Ia glycogen storage disease complicated by hepatic adenoma.
      ,
      • Alshak N.S.
      • Cocjin J.
      • Podesta L.
      • et al.
      Hepatocellular adenoma in glycogen storage disease type IV.
      ,
      • Labrune P.
      • Trioche P.
      • Duvaltier I.
      • et al.
      Hepatocellular adenomas in glycogen storage disease type I and III: a series of 43 patients and review of the literature.
      ,
      • Leese T.
      • Farges O.
      • Bismuth H.
      Liver cell adenomas. A 12-year surgical experience from a specialist hepato-biliary unit.
      ,
      • Talente G.M.
      • Coleman R.A.
      • Alter C.
      • et al.
      Glycogen storage disease in adults.
      ].
      Hepatocellular adenomatosis was described in 1985 and defined as the presence of 10 or more adenomas. Initially considered as a pathological entity distinct from HCA, it is now considered part of the spectrum of HCA. Indeed, it has been observed that HCA could be solitary, multiple < 10 or multiple > 10 in all hepatocellular subtypes and in particular etiologies such as glycogenosis and male hormone administration [
      • Ribeiro A.
      • Burgart L.J.
      • Nagorney D.M.
      • et al.
      Management of liver adenomatosis: results with a conservative surgical approach.
      ,
      • Flejou J.F.
      • Barge J.
      • Menu Y.
      • et al.
      Liver adenomatosis. An entity distinct from liver adenoma?.
      ,
      • Howell R.R.
      • Stevenson R.E.
      • Ben-Menachem Y.
      • et al.
      Hepatic adenomata with type 1 glycogen storage disease.
      ,
      • Chen K.T.
      • Bocian J.J.
      Multiple hepatic adenomas.
      ].
      HCA histotype and size seem to correlate with outcomes. Hemorrhage is particularly common in HCA > 4 cm located in the subcapsular region. Bleeding is more frequent in patients with adenomatosis than with single HCA (62% vs 26%) (114). Malignant transformation was reported in a small case-series of adenomatosis (2/15 patients) [
      • Grazioli L.
      • Federle M.P.
      • Ichikawa T.
      • et al.
      Liver adenomatosis: clinical, histopathologic, and imaging findings in 15 patients.
      ] and in case reports relating to patients with single HCA or with adenomatosis [
      • Kwok W.Y.
      • Hagiwara S.
      • Nishida N.
      • et al.
      Malignant transformation of hepatocellular adenoma.
      ,
      • González-Lara M.F.
      • Córdova-Ramón J.C.
      • Gamboa-Domínguez A.
      • et al.
      Hepatocellular carcinoma arising in a telangiectatic hepatocellular adenoma.
      ,
      • Mouhoub M.
      • Miry A.
      • Haloui A.
      • et al.
      Malignant transformation of hepatocellular adenoma: report of a case.
      ,
      • Timothy L.D.
      • Lehrke H.D.
      • Chandan V.S.
      • et al.
      Diffuse adenomatosis and hepatocellular carcinoma treated with liver transplantation in an adolescent female with kabuki syndrome with a novel KMT2D gene mutation.
      ]. A study including 40 patients with adenomatosis showed a 3% risk of malignant transformation and a 15% risk of bleeding at a 11-years follow-up [
      • Barbier L.
      • Nault J.C.
      • Dujardin F.
      • et al.
      Natural history of liver adenomatosis: a long term observational study.
      ].
      The Bordeaux Classification identifies six major subgroups of HCAs: HNF1-alpha mutated, inflammatory, beta-catenin-activated mutated in exon 3 and in exon 7–8, sonic hedgehog (SH), and unclassified HCA [
      • Nault J.C.
      • Couchy G.
      • Balabaud C.
      • et al.
      Molecular classification of hepatocellular adenoma associates with risk factors, bleeding, and malignant transformation.
      ,
      • Sala M.
      • Gonzales D.
      • Leste-Lasserre T.
      • et al.
      ASS1 overexpression: a hallmark of sonic hedgehog hepatocellular adenomas; recommendations for clinical practice.
      ,
      • Bioulac Sage P.
      • Sempoux C.
      • Frulio N.
      • et al.
      Snapshot summary of diagnosis and management of hepatocellular adenoma subtypes.
      ,
      • Haring M.P.D.
      • Vriesendorp T.M.
      • Klein Wassink-Ruiter J.S.
      • et al.
      Diagnosis of hepatocellular adenoma in men before onset of diabetes in HNF1A-MODY: watch out for winkers.
      ,
      • Calderaro J.
      • Labrune P.
      • Morcrette G.
      • et al.
      Molecular characterization of hepatocellular adenomas developed in patients with glycogen storage disease type I.
      ,
      • Longerich T.
      • Endris V.
      • Neumann O.
      • et al.
      RSPO2 gene rearrangement: a powerful driver of ß-catenin activation in liver tumours.
      ]. HNF1-alpha mutated HCAs (30-40%) are characterized by marked steatosis with clear cells. Cyto-architectural atypia is rare and inflammation usually absent. The main risk factors are estrogens, familial liver adenomatosis, and maturity onset diabetes of the young (MODY) [
      • Haring M.P.D.
      • Vriesendorp T.M.
      • Klein Wassink-Ruiter J.S.
      • et al.
      Diagnosis of hepatocellular adenoma in men before onset of diabetes in HNF1A-MODY: watch out for winkers.
      ]. Inflammatory HCAs (40-55%) are characterized by marked sinusoidal dilation, inflammatory infiltrate, dystrophic arteries with thickened walls and pseudo portal tracts, and increased cytoplasmic expression of C-reactive protein and serum amyloid A protein. They are mainly related to obesity, alcohol abuse, and glycogen storage disease [
      • Calderaro J.
      • Labrune P.
      • Morcrette G.
      • et al.
      Molecular characterization of hepatocellular adenomas developed in patients with glycogen storage disease type I.
      ]. The risk for HCC transformation is generally low but increased by concurrent beta-catenin activation. Beta-catenin mutated HCAs represent 10-20% of HCAs; those mutated in exon 7-8 have no specific risk factor, whereas those mutated in exon 3 are more frequent in males, sensitive to androgenic stimulation, and characterized by cyto-architectural atypia, with pseudo-gland formation. Beta catenin exon 3 (Bex3) mutated HCAs show high risk of malignant transformation. They are also observed in combination with vascular liver diseases and type 1 glycogen-storage disease [
      • Longerich T.
      • Endris V.
      • Neumann O.
      • et al.
      RSPO2 gene rearrangement: a powerful driver of ß-catenin activation in liver tumours.
      ]. In about 4% of cases, HCAs are characterized by activation of the sonic-hedgehog (sH) pathway due to small somatic deletions of INHBE, leading to the fusion of INHBE and GLI1. shHCAs, involving overweight women with fatty liver and using OCP show risk of spontaneous bleeding even in HCAs<5 cm [
      • Nault J.C.
      • Couchy G.
      • Balabaud C.
      • et al.
      Molecular classification of hepatocellular adenoma associates with risk factors, bleeding, and malignant transformation.
      ,
      • Sala M.
      • Gonzales D.
      • Leste-Lasserre T.
      • et al.
      ASS1 overexpression: a hallmark of sonic hedgehog hepatocellular adenomas; recommendations for clinical practice.
      ,
      • Bioulac Sage P.
      • Sempoux C.
      • Frulio N.
      • et al.
      Snapshot summary of diagnosis and management of hepatocellular adenoma subtypes.
      ]. The risk of symptomatic bleeding is also higher than in other HCA subtypes (71% vs. 14%) [
      • Nault J.C.
      • Couchy G.
      • Balabaud C.
      • et al.
      Molecular classification of hepatocellular adenoma associates with risk factors, bleeding, and malignant transformation.
      ] and the rate of emergency hospitalization for acute bleeding is particularly high [
      • Sala M.
      • Gonzales D.
      • Leste-Lasserre T.
      • et al.
      ASS1 overexpression: a hallmark of sonic hedgehog hepatocellular adenomas; recommendations for clinical practice.
      ].
      To note, HCA transformation into HCC can be observed almost exclusively in the Bex3 mutated subtype, rarely in the HNF1-alpha mutated, and never in the inflammatory subtype in the absence of beta-catenin mutation. In glycogen storage disease type I, HCAs show 10% risk of malignant transformation [
      • Calderaro J.
      • Labrune P.
      • Morcrette G.
      • et al.
      Molecular characterization of hepatocellular adenomas developed in patients with glycogen storage disease type I.
      ].
      PICO 9 - In adults with hepatocellular adenoma and with histological subtype not classifiable with imaging, is biopsy of the lesion useful for histopathological and biomolecular typing and for assessing the risk of malignant transformation?
      The European Association for the Study of the Liver (EASL) [
      • Colombo M.
      • Forner A.
      • Ijzermans
      • et al.
      EASL Clinical Practice Guidelines on the management of benign liver tumours.
      ], the American College of Gastroenterology (ACG) [
      • Marrero J.A.
      • Ahn J.
      • Rajender Reddy K.
      • et al.
      ACG clinical guideline: the diagnosis and management of focal liver lesions.
      ], and the Brasilian Society of Gastroenterology (BSG) [
      • Strauss E.
      • Ferreira Ade S.
      • França A.V.
      • et al.
      Diagnosis and treatment of benign liver nodules: Brazilian Society of Hepatology (SBH) recommendations.
      ] guidelines, and a recent review [
      • Haring M.P.D.
      • Cuperus F.J.C.
      • Duiker E.W.
      • de Haas R.J.
      • de Meijer VE.
      Scoping review of clinical practice guidelines on the management of benign liver tumours.
      ], suggest using MRI for the identification of HNF1-alpha mutated HCA (sensitivity 87-90%; specificity 89-100%) and of inflammatory HCA (sensitivity 85%-88%; specificity 88%–100%), while underlining that the identification of the beta-catenin mutation subtype is impossible. Moreover, about 10% of the inflammatory HCA have a mixed, inflammatory beta-catenin mutated phenotype, which cannot be identified by imaging techniques [
      • Henriet E.
      • Abou Hammoud A.
      • Dupuy J.W.
      • et al.
      Argininosuccinate synthase 1 (ASS1): a marker of unclassified hepatocellular adenoma and high bleeding risk.
      ,
      • Ronot M.
      • Bahrami S.
      • Calderaro J.
      • et al.
      Hepatocellular adenomas: accuracy of magnetic resonance imaging and liver biopsy in subtype classification.
      ,
      • Bise S.
      • Frulio N.
      • Hocquelet A.
      • et al.
      New MRI features improve subtype classification of hepatocellular adenoma.
      ,
      • Auer T.A.
      • Fehrenbach U.
      • Grieser C.
      • et al.
      Hepatocellular adenomas: is there additional value in using Gd-EOB-enhanced MRI for subtype differentiation?.
      ]. Broker et al reported that the findings of CEUS and MRI with hepatospecific contrast showed fair agreement for the differential diagnosis between HCA and FNH, but MRI is more accurate in cases with discordant findings [
      • Bröker M.E.E.
      • Taimr P.
      • de Vries M.
      • et al.
      Performance of contrast-enhanced sonography versus MRI with a liver-specific contrast agent for diagnosis of hepatocellular adenoma and focal nodular hyperplasia.
      ]. A recent study reported that hepato-specific MRI contrast agent might be used as a marker of beta-catenin mutated forms [
      • Reizine E.
      • Ronot M.
      • Ghosn M.
      • et al.
      Hepatospecific MR contrast agent uptake on hepatobiliary phase can be used as a biomarker of marked β-catenin activation in hepatocellular adenoma.
      ]. A systematic review of image-guided liver biopsy reported a percentage of major complications between 0.1% and 4.6%. The risk factors for bleeding were related to patient characteristics (>50 years or <2 years, inpatient status, comorbidities), coagulation status (INR >1.5), and biopsy technique [
      • Midia M.
      • Odedra D.
      • Shuster A.
      • et al.
      Predictors of bleeding complications following percutaneous image-guided liver biopsy: a scoping review.
      ]. The risk of complications related to percutaneous biopsy of HCA is currently considered acceptable (no mortality, 2% of major and 10% of minor complications) [
      • Doolittle D.E.
      • Atwell T.D.
      • Sanchez W.
      • et al.
      Safety and outcomes of percutaneous biopsy of 61 hepatic adenomas.
      ].
      Recommendation
      In adults with hepatocellular adenoma and histological subtype not classifiable with imaging techniques, we suggest biopsying the lesion to identify the beta-catenin mutated adenoma (exon 3), the subtype with highest risk of malignant transformation, and the sonic hedgehog adenoma subtype associated with a high risk of spontaneous bleeding. The risk of complications of percutaneous biopsy of adenomas is considered low. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 10 - In female patients with hepatocellular adenoma in surveillance, what imaging technique should be used and how long the follow-up intervals should be?
      Observational studies document that discontinuation of OCP reduces the HCA volume [
      • Klompenhouwer A.J.
      • Bröker M.E.E.
      • Thomeer M.G.J.
      • et al.
      Retrospective study on timing of resection of hepatocellular adenoma.
      ,
      • Haring M.P.D.
      • Gouw A.S.H.
      • de Haas R.J.
      • et al.
      The effect of oral contraceptive pill cessation on hepatocellular adenoma diameter: a retrospective cohort study.
      , that the risk of neoplastic transformation is 4.2% and is very rare in HCA < 5 cm [
      • Stoot J.H.
      • Coelen R.J.
      • De Jong M.C.
      • et al.
      Malignant transformation of hepatocellular adenomas into hepatocellular carcinomas: a systematic review including more than 1600 adenoma cases.
      ], and that MRI is the most used imaging technique during follow-up [
      • Vernuccio F.
      • Ronot M.
      • Dioguardi Burgio M.
      • et al.
      Long term evolution of hepatocellular adenoma at MRI follow up.
      ,
      • Shao N.
      • Pandey A.
      • Ghasabeh M.A.
      • et al.
      Long-term follow-up of hepatic adenoma and adenomatosis: analysis of size change on imaging with histopathological correlation.
      . The ACG [
      • Marrero J.A.
      • Ahn J.
      • Rajender Reddy K.
      • et al.
      ACG clinical guideline: the diagnosis and management of focal liver lesions.
      ], BSG [
      • Strauss E.
      • Ferreira Ade S.
      • França A.V.
      • et al.
      Diagnosis and treatment of benign liver nodules: Brazilian Society of Hepatology (SBH) recommendations.
      ], and EASL [
      • Colombo M.
      • Forner A.
      • Ijzermans
      • et al.
      EASL Clinical Practice Guidelines on the management of benign liver tumours.
      ] guidelines, and a recent review [
      • Haring M.P.D.
      • Cuperus F.J.C.
      • Duiker E.W.
      • de Haas R.J.
      • de Meijer VE.
      Scoping review of clinical practice guidelines on the management of benign liver tumours.
      ], suggest using MRI as for the follow-up after discontinuation of OCPs.
      Recommendation
      In women with adenoma in follow-up who discontinued oral contraceptives, we suggest a magnetic resonance re-evaluation at six months. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      If the adenoma is unchanged or is reduced to less than 5 cm, we suggest a re-evaluation at one year. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      After the first 18 months of follow-up, if the adenoma is unchanged, we suggest continuing the follow-up with annual ultrasound examination which is accurate to evaluate the lesion size, safe and cheap. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 11 - In female patients with hepatocellular adenoma > 5 cm does surgical resection offer better results than follow-up?
      Malignant transformation is reported in 4.2% of HCAs and is the main factor supporting surgical resection. The highest risk of malignancy is observed in males with Bex3 mutated HCA, in patients on androgen treatment, and, more controversially, in lesions ≥ 5 cm [
      • Stoot J.H.
      • Coelen R.J.
      • De Jong M.C.
      • et al.
      Malignant transformation of hepatocellular adenomas into hepatocellular carcinomas: a systematic review including more than 1600 adenoma cases.
      ]. In women with Bex3mutated HCA, available data do not allow stratification based on lesions’ size. Currently, surgery is indicated for Bex 3mutated HCA, regardless the tumor size, and when malignant degeneration cannot be ruled out [
      • Krause K.
      • Tanabe K.K.
      A shifting paradigm in diagnosis and management of hepatic adenoma.
      ,
      • Herman P.
      • Fonseca G.M.
      • Kruger J.A.P.
      • et al.
      Guidelines for the treatment of hepatocellular adenoma in the era of molecular biology: an experience-based surgeons' perspective.
      .
      Recommendation
      In female patients with hepatocellular adenomas that, 6 months after discontinuation of oral contraceptives, remain equal to or greater than 5 cm, or with malignant features on imaging or with histologically proven beta catenin mutation we suggest surgical resection. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 12 - In male patients with diagnosis of hepatocellular adenoma does surgical resection offer better results than follow-up?
      Male sex is one of the main risk factors for malignant transformation [
      • Fuchs J.
      • Warmann S.W.
      • Urla C.
      • et al.
      Management of benign liver tumors.
      ]. In a series of 218 HCAs, it was observed in 23 patients. The risk of malignancy was 4% in women and 47% in men. Two-thirds of HCAs transformed were beta-catenin activated and one-third displayed cell atypia. The median diameter of the transformed HCAs was 10 cm and only three were ≤ 5 cm [
      • Farges O.
      • Ferreira N.
      • Dokmak S.
      • et al.
      Changing trends in malignant transformation of hepatocellular adenoma.
      ]. In a study including patients with biopsy-confirmed HCA, men had a 10-year cumulative HCC risk > 60.0% (95%CI 15.3%-87.0%) [
      • Bossen L.
      • Gronbaeck H.
      • Eriksen P.L.
      • et al.
      Men with biopsy confirmed hepatocellular adenoma have a high risk of progression to hepatocellular carcinoma: a nationwide population study.
      ]. In a cross-sectional study, male and tumor size > 10 cm were the main risk factors (RR 11.6) [
      • Laurent A.
      • Dokmak S.
      • Nault J.C.
      • et al.
      European experience of 573 liver resections for hepatocellular adenoma: a cross-sectional study by the AFC-HCA-2013 study group.
      ]. In a review [
      • Tsilimigras D.I.
      • Rahnemai-Azar A.A.
      • Ntanasis-Stathopoulos I.
      • et al.
      Current approaches in the management of hepatic adenomas.
      ], malignant transformation was reported in 4.2%: the most important risk factors were male sex (8-10 times higher than in females), lesion size (>5 cm), and the beta-catenin-activated subtype. Another review [
      • Stoot J.H.
      • Coelen R.J.
      • De Jong M.C.
      • et al.
      Malignant transformation of hepatocellular adenomas into hepatocellular carcinomas: a systematic review including more than 1600 adenoma cases.
      ] reported malignant transformation in 4.2% and only three cases (4.4%) with tumors < 5 cm. A retrospective study involving 66 male patients with HCA, showed that, after expert revision of histological material and new generation genetic tests, the diagnosis was changed in 50% of cases (33/66), and four beta-catenin-mutated HCA were further identified. Accordingly, the systematic application of next generation genetic tests is suggested in males with HCA for a more precise definition of beta-catenin-mutated forms [
      • van Rosmalen B.V.
      • Furumaya A.
      • Klompenhouwer A.J.
      • et al.
      Hepatocellular adenoma in men: a nationwide assessment of pathology and correlation with clinical course.
      ].
      Recommendation
      In male patients with hepatocellular adenoma, we suggest surgical resection regardless of the size of the lesion. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 13 - In patients with hepatocellular adenoma does laparoscopic resection offer better results than laparotomy?
      Available studies show an advantage of laparoscopy over laparotomy in terms of quality of life and operative outcomes [
      • van Rosmalen B.V.
      • de Graeff J.J.
      • van der Poel M.J.
      • et al.
      Impact of open and minimally invasive resection of symptomatic solid benign liver tumours on symptoms and quality of life: a systematic review.
      ]. The minimally invasive approach was associated with lower intra-operative blood loss (93 vs 196 ml), reduced need for transfusion (8 vs. 24 red blood cells units), and shorter hospital stay (5 vs.7 days) [
      • Landi F.
      • De’ Angelis N.
      • Scatton O.
      • et al.
      Short-term outcomes of laparoscopic vs. open liver resection for hepatocellular adenoma: a multicenter propensity score adjustment analysis by the AFC-HCA-2013 study group.
      ]. A Dutch nationwide retrospective study examined 415 patients undergoing laparoscopic (230 pts) or laparotomic (185 pts) resection for benign liver tumors (HCA in 59%). Comparison of the two surgical techniques, adjusted with propensity score matching, showed a shorter hospital stay and reduced overall post-operative morbidity with laparoscopy [
      • Elfrink A.K.E.
      • Haring M.P.D.
      • de Meijer V.E.
      • et al.
      Surgical outcomes of laparoscopic and open resection of benign liver tumours in the Netherlands: a nationwide analysis.
      ].
      Recommendation
      In patients with hepatocellular adenoma, we suggest laparoscopic surgical resection as it may provide better outcomes than laparotomy in terms of postoperative complications, quality of life, and length of hospital stay. Low quality of evidence (C); strength of recommendation 2 (conditional)
      PICO 14 - In female patients with hepatic adenoma in follow-up, should discontinuation of oral contraceptives be indicated?
      There are no randomized clinical trials evaluating the outcome of HCA in women on treatment with OCPs versus women discontinuing OCPs. Only data from small case-series, case–control studies, and case reports are available. Epidemiological studies suggest a higher (40-fold) incidence in women on long-time OCP treatment. The risk is higher in women > 30 years on OCP for > 25 months, (particularly with high estrogen content) [
      • Rosenberg L.
      The risk of liver neoplasia in relation to combined oral contraceptive use.
      ,
      • Cherqui D.
      • Rahmouni A.
      • Charlotte F.
      • et al.
      Management of focal nodular hyperplasia and hepatocellular adenoma in young women: a series of 41 patients with clinical, radiological, and pathological correlations.
      . Discontinuation of OCP may result in an HCA reduction/regression [
      • Aseni P.
      • Sansalone C.V.
      • Sammartino C.
      • Benedetto F.D.
      • Carrafiello G.
      • Giacomoni A.
      • Osio C.
      • Vertemati M.
      • Forti D.
      Rapid disappearance of hepatic adenoma after contraceptive withdrawal.
      ] and a recent cross-sectional study, including 48 post-menopausal women, suggests that for lesions < 5 cm, no further follow-up would be necessary; in fact, after a median time of 60.5 months, 43.5% of the lesions were undetectable, 32.6% were stable, and 19.6% became smaller [
      • Klompenhouwer A.J.
      • Sprengers D.
      • Willemssen F.E.
      • et al.
      Evidence of good prognosis of hepatocellular adenoma in post-menopausal women.
      ]. In another retrospective study including 78 HCA patients, 37.2% of HCA showed ≥30% regression, 5.1% complete regression, 56.4% stability of the lesion, and 1.3% progression, after discontinuation [
      • Haring M.P.D.
      • Gouw A.S.H.
      • de Haas R.J.
      • et al.
      The effect of oral contraceptive pill cessation on hepatocellular adenoma diameter: a retrospective cohort study.
      ]. A recent publication of the American Association for the Study of Liver Disease (AASLD), strongly recommends discontinuing OCPs in women with adenoma [
      • Sarkar M.
      • Brady C.W.
      • Fleckenstein J.
      • et al.
      Reproductive health and liver disease: practice guidance by the American association for the study of liver diseases.
      ].
      Recommendation
      In female patients with hepatocellular adenoma on follow-up, we recommend discontinuing oral contraceptives. Low quality of evidence (C); strength of recommendation 1 (strong)
      PICO 15- Should periodical ultrasound surveillance be indicated in patients with hepatocellular adenoma during pregnancy?
      The EASL [
      • Colombo M.
      • Forner A.
      • Ijzermans
      • et al.
      EASL Clinical Practice Guidelines on the management of benign liver tumours.
      ], ACG [
      • Marrero J.A.
      • Ahn J.
      • Rajender Reddy K.
      • et al.
      ACG clinical guideline: the diagnosis and management of focal liver lesions.
      ], and BSG [
      • Strauss E.
      • Ferreira Ade S.
      • França A.V.
      • et al.
      Diagnosis and treatment of benign liver nodules: Brazilian Society of Hepatology (SBH) recommendations.
      ] guidelines, and a recent review [
      • Haring M.P.D.
      • Cuperus F.J.C.
      • Duiker E.W.
      • de Haas R.J.
      • de Meijer VE.
      Scoping review of clinical practice guidelines on the management of benign liver tumours.
      ], recommend monitoring during pregnancy and post-partum all women with HCA, indicating US as the imaging technique of choice. Several HCAs growths and ruptures during pregnancy are reported, with high risk of maternal/fetal mortality (59% and 62%, respectively) [
      • Kent D.R.
      • Nissen E.D.
      • Nissen S.E.
      • et al.
      Effect of pregnancy on liver tumor associated with oral contraceptives.
      ,
      • Bis K.A.
      • Waxman B.
      Rupture of the liver associated with pregnancy: a review of the literature and report of 2 cases.
      . The most recent literature, suggests “watching-and-waiting", particularly in women with HCA < 5 cm. In a study, 17 pregnancies in 12 women with HCA were followed; in 4 cases, HCAs grew during pregnancy, requiring a caesarean section in one patient (two pregnancies) at 36 and 34 weeks because of a presumed high risk of rupture. In one case radiofrequency ablation therapy was applied in the first trimester for treating a hormone sensitive HCA with high risk of growth later in pregnancy. No intervention was performed in the other 14 pregnancies which had an uneventful course [
      • Noels J.E.
      • van Aalten S.M.
      • van der Windt D.J.
      • et al.
      Management of hepatocellular adenoma during pregnancy.
      ]. In another prospective study of 48 women with HCA < 5 cm, followed during 51 pregnancies, only in one case the growth of the lesion was significant (> 7 cm) requiring embolization. Median increase of 14 mm was seen in 25.5% of cases and pregnancies proceeded without any risk for mother and child. Accordingly, authors suggest a conservative approach and surveillance with US performed at 14-20-26-32-38 weeks of pregnancy and at 6-12 weeks postpartum, combining MRI in case of increased lesion size [
      • Gaspersz M.P.
      • Klompenhouwer A.J.
      • Broker M.E.E.
      • et al.
      Growth of hepatocellular adenoma during pregnancy: a prospective study.
      ]. In a single-center retrospective study of 11 patients (4 with HCA > 5 cm), only two patients showed lesion growth and there were no hemorrhages during 34 months of follow-up. A systematic review of the literature including 33 studies was also performed; 39 lesions remained stable (53.4%), 11 regressed (15.1%), and 23 (31.5%) progressed. Overall, 15 HCA-related hemorrhages occurred in lesions measuring 6.5-17 cm in diameter (8 during pregnancy, 2 during labor, and 5 postpartum). The Authors conclude that HCA hemorrhage, although rare and only reported in HCA ≥ 6.5 cm, can be fatal, and suggest close surveillance in pregnancy and postpartum [
      • Haring M.P.D.
      • Spijkerboer C.S.
      • Cuperus F.J.C.
      • et al.
      Behavior and complications of hepatocellular adenoma during pregnancy and puerperium: a retrospective study and systematic review.
      ]. The guidelines of the ACG on liver disease and pregnancy [
      • Tran T.T.
      • Ahn J.
      • Reau N.S.
      ACG clinical guideline: liver disease and pregnancy.
      ] and the recent AASLD position-paper (157) reaffirm the need to monitor HCA with US during pregnancy.
      Recommendation
      In pregnant women with hepatocellular adenoma, we suggest ultrasound surveillance to identify adenoma growth. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      The suggested surveillance timing is at 14-20-26-32-38 weeks of pregnancy and at 6-12 weeks post-partum. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 16 - In patients with hepatocellular adenoma on follow-up, planning medically assisted procreation procedures, should ultrasound surveillance be indicated?
      No randomized clinical trial nor observational studies evaluated HCA patients on hormonal therapy for medically assisted procreation. Data may be extrapolated from studies evaluating patients with adenoma during pregnancy (a physiologically similar condition) [
      • Noels J.E.
      • van Aalten S.M.
      • van der Windt D.J.
      • et al.
      Management of hepatocellular adenoma during pregnancy.
      ,
      • Gaspersz M.P.
      • Klompenhouwer A.J.
      • Broker M.E.E.
      • et al.
      Growth of hepatocellular adenoma during pregnancy: a prospective study.
      ,
      • Haring M.P.D.
      • Spijkerboer C.S.
      • Cuperus F.J.C.
      • et al.
      Behavior and complications of hepatocellular adenoma during pregnancy and puerperium: a retrospective study and systematic review.
      ]. In addition, a study reported three cases of HCA after treatment with norethindrone acetate for endometriosis [
      • Brady P.C.
      • Missmer S.A.
      • Laufer M.R.
      Hepatic adenomas in adolescents and young women with endometriosis treated with norethindrone acetate.
      ], another one reported a case of malignant transformation of HCA during ovulation induction [
      • Glinka J.
      • Clariá R.S.
      • Fratanons E.
      • et al.
      Malignant transformation of hepatocellular adenoma in a young female patient after ovulation induction fertility treatment: a case report.
      ], and another documented one case of HCA in 60 patients on long-term methyltestosterone therapy [
      • Westaby D.
      • Ogle S.J.
      • Paradinas F.J.
      • et al.
      Liver damage from long-term methyltestosterone.
      ].
      Recommendation
      In patients with hepatocellular adenoma on hormonal therapy for medically assisted procreation, we suggest ultrasound surveillance. Very low quality of evidence (D); strength of recommendation 2 (conditional).
      Similarly to pregnancy, ultrasound may be suggested every 6 weeks during therapy, and at 6 and 12 weeks after discontinuation. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 17 - In adults with multiple hepatocellular adenomas (≥10) does surgical resection offer better results than follow-up?
      EASL guidelines recommend management based on the size of the largest tumor, because the clinical presentation and risk of bleeding and malignant transformation in patient with multiple HCAs do not differ from those with a single HCA [
      • Colombo M.
      • Forner A.
      • Ijzermans
      • et al.
      EASL Clinical Practice Guidelines on the management of benign liver tumours.
      ]. However, the natural course of liver adenomatosis is poorly described. A study demonstrated that, during a follow-up up of 26 years, 23% of patients with adenomatosis presented a new lesion or increased size of preexisting lesions. Surgery was performed in 4 patients (10%) due to a change in size or in number of tumors [
      • Barbier L.
      • Nault J.C.
      • Dujardin F.
      • et al.
      Natural history of liver adenomatosis: a long term observational study.
      ].
      Recommendation
      In adults with multiple hepatocellular adenomas, we suggest surgical resection in case of malignant degeneration or bleeding of one or more lesions. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 18 – In adults with multiple hepatocellular adenomas (≥ 10) does liver transplantation offer better results than surgical resection?
      A list of major and minor criteria indicating liver transplantation was proposed [
      • Chiche L.
      • David A.
      • Adam R.
      • et al.
      Liver transplantation for adenomatosis: European experience.
      ]. Proof of malignant transformation in one or more HCAs is sufficient to justify liver transplantation and represents a major criterion. Other clinical or pathological parameters (minor criteria) include: more than two serious hemorrhages, more than two previous liver resections, presence of beta-catenin mutated or inflammatory adenomas, underlying liver disease (severe steatosis or vascular abnormalities), age > 30 years. Using these criteria to support the decision-making process, liver transplant is indicated in patients with the major criterion or at least 3 minor criteria [
      • Chiche L.
      • David A.
      • Adam R.
      • et al.
      Liver transplantation for adenomatosis: European experience.
      ]. In a retrospective study including five patients with type I glycogen storage disease who underwent liver transplantation for prevention of HCC, multiple HCAs with focal hemorrhage and necrosis without evidence of malignancy were identified in all explanted specimens. The authors suggest that transplant could provide a definitive prevention against HCC in this clinical context by removing all HCAs and correcting the metabolic derangements [
      • Reddy S.K.
      • Austin S.L.
      • Spencer-Manzon M.
      • et al.
      Liver transplantation for glycogen storage disease type Ia.
      ].
      Recommendation
      In adults with multiple hepatocellular adenomas (≥10), liver transplantation is suggested in case of malignant degeneration, and might be considered in patients at high risk of liver functional decompensation after resection and in symptomatic massive forms. Very low quality of evidence (D); strength of recommendation 2 (conditional)

      Declaration of Competing Interest

      The Authors declare no conflict of interest.

      References

        • CNEC - Centro Nazionale per l'Eccellenza delle Cure
        Manuale metodologico per la Produzione di Linee Guida di Pratica Clinica.
        ISS - Istituto Superiore di SanitàAvailable at:, Roma2020
      1. GRADEpro GDT [Computer program] McMaster University (developed by Evidence Prime) GRADEpro GDT. Version accessed 5 November 2021. Hamilton (ON): McMaster University (developed by Evidence Prime). Available at gradepro.org

        • Guyatt G.H.
        • Oxman A.D.
        • Kunz R.
        • et al.
        GRADE guidelines: 2. Framing the question and deciding on important outcomes.
        J Clin Epidemiol. 2011; 64: 395-400
        • Moberg J.
        • Oxman A.D.
        • Rosenbaum S.
        • et al.
        The GRADE Evidence to Decision (EtD) framework for health system and public health decisions.
        Health Res Policy Syst. 2018; 16: 45https://doi.org/10.1186/s12961-018-0320-2
        • Whiting P.F.
        • Rutjes A.W.
        • Westwood M.E.
        • et al.
        QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies.
        Ann Intern Med. 2011; 155: 529-536
        • Sterne J.A.C.
        • Savovic J.
        • Page M.J.
        • et al.
        RoB 2: a revised tool for assessing risk of bias in randomised trials.
        BMJ. 2019; 366: l4898
        • Sterne J.A.
        • Hernan M.A.
        • Reeves B.C.
        • et al.
        ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.
        BMJ. 2016; 355: i4919
        • Ishak K.G.
        • Rabin L.
        Benign tumors of the liver.
        Med Clin N. Am. 1975; 59: 995-1013
        • Choy B.Y.
        • Nguyen MH.
        The diagnosis and management of benign hepatic tumors.
        J Clin. Gastroenterol. 2005; 39: 401-412
        • Colombo M.
        • Forner A.
        • Ijzermans
        • et al.
        EASL Clinical Practice Guidelines on the management of benign liver tumours.
        J Hepatol. 2016; 65: 386-398
        • Karhunen PJ.
        Benign hepatic tumours and tumour like conditions in men.
        J Clin Pathol. Feb 1986; 39: 183-188
        • Vilgrain V.
        • Boulos L.
        • Vullierme M.P.
        • et al.
        Imaging of atypical hemangiomas of the liver with pathologic correlation.
        Radiographics. 2000; 20: 379-397
        • Bahirwani R.
        • Reddy KR.
        Review article: the evaluation of solitary liver masses.
        Aliment Pharmacol Ther. 2008; 28: 953-965
        • Horta G.
        • Lopez M.
        • Dotte A.
        • et al.
        Benign focal liver lesions detected by computed tomography: review of 1,184 examinations.
        Rev Med Chil. 2015; 143: 197-202
        • Trotter J.F.
        • Everson GT.
        Benign focal lesions of the liver.
        Clinics in Liver Disease. 2001; 5: 17-42
        • Di Carlo I.
        • Koshy R.
        • Al Mudares S.
        • et al.
        Giant cavernous liver hemangiomas: is it the time to change the size categories?.
        Hepatobiliary Pancreat Dis Int. 2016; 15: 21-29
        • Farges O.
        • Daradkeh S.
        • Bismuth H.
        Cavernous hemangiomas of the liver: are there any indications for resection?.
        World J Surg. Jan-Feb 1995; 19: 19-24
        • O'Rafferty C.
        • O'Regan G.M.
        • Irvine A.D.
        • et al.
        Recent advances in the pathobiology and management of Kasabach-Merritt phenomenon.
        Br J Haematol. 2015; 171: 38-51
        • Giannitrapani L.
        • Soresi M.
        • La Spada E.
        • et al.
        Sex hormones and risk of liver tumor.
        Ann N Y Acad Sci. 2006; 1089: 228-236
        • Jing L.
        • Liang H.
        • Caifeng L.
        • et al.
        New recognition of the natural history and growth pattern of hepatic hemangioma in adults.
        Hepatology Research. 2016; 46: 727-733
        • Cobey F.C.
        • Salem R.R.
        A review of liver masses in pregnancy and a proposed algorithm for their diagnosis and management.
        Am. J Surg. 2004; 187: 181-191
        • Hasan H.Y.
        • Hinshaw J.L.
        • Borman E.J.
        • et al.
        Assessing normal growth of hepatic hemangiomas during long-term follow-up.
        JAMA Surg. 2014; 149: 1266-1271
        • Liu X.
        • Yang Z.
        • Tan H.
        • et al.
        Location affects the management of liver haemangioma: a retrospective cohort study.
        Int J Surg. Dec 2017; 48: 110-115
        • Etemadi A.
        • Golozar A.
        • Ghassabian A.
        • et al.
        Cavernous hemangioma of the liver : factors affecting disease progression in general hepatology practice.
        Eur J Gastroenterol Hepatol. Apr 2011; 23: 354-358
        • Yedibela S.
        • Alibek S.
        • Müller V.
        • et al.
        Management of hemangioma of the liver: surgical therapy or observation?.
        World J Surg. Jun 2013; 37: 1303-1312
        • Liu X.
        • Yang Z.
        • Tan H.
        • et al.
        Patient age affects the growth of liver haemangioma.
        HPB (Oxford). Jan 2018; 20: 64-68
        • Glinkova V.
        • Shevah O.
        • Boaz M.
        • et al.
        Hepatic haemangiomas: possible association with female sex hormones.
        Gut. Sep 2004; 53: 1352-1355
        • Gandolfi L.
        • Leo P.
        • Solmi L.
        • et al.
        Natural history of hepatic haemangiomas: clinical and ultrasound study.
        Gut. Jun 1991; 32: 677-680
        • Schwartz S.I.
        • Husser WC.
        Cavernous hemangioma of the liver. A single institution report of 16 resections.
        Ann Surg. 1987; 205: 456-465
        • Cheng W.L.
        • Qi Y.Q.
        • Wang B.
        • et al.
        Enucleation versus hepatectomy for giant hepatic haemangiomas: a meta-analysis.
        Ann R Coll Surg Engl. Mar 2017; 99: 237-241
        • Wang S.
        • Gao J.
        • Yang M.
        Intratumoral coagulation by radiofrequency ablation facilitated the laparoscopic resection of giant hepatic hemangioma: a surgical technique report of two cases.
        Oncotarget. Jul 5 2017; 8: 52006-52011
        • Dong W.
        • Qiu B.
        • Xu H.
        • et al.
        Invasive management of symptomatic hepatic hemangioma.
        Eur J Gastroenterol Hepatol. Sep 2019; 31: 1079-1084
        • Sakamoto Y.
        • Kokudo N.
        • Watadani T.
        • et al.
        Proposal of size-based surgical indication criteria for liver hemangioma based on a nationwide survey in Japan.
        J Hepatobiliary Pancreat Sci. Jul 2017; 24: 417-425
        • Wu S.
        • Gao R.
        • Yin T.
        • Zhu R.
        • et al.
        Complications of radiofrequency ablation for hepatic hemangioma: a multicenter retrospective analysis on 291 cases.
        Front Oncol. Jul 28 2021; 11706619
        • Gao J.
        • Ding X.
        • Ke S.
        • et al.
        Radiofrequency ablation in treatment of huge hepatic hemangiomas: a comparison of multi-tined and internally cooled electrodes.
        J Clin Gastrol. 2014; 48: 540-547
        • Park S.Y.
        • Tak W.Y.
        • Jung M.K.
        • et al.
        Symptomatic-enlarging hepatic hemangiomas are effectively treated by percutaneous ultrasonography-guided radiofrequency ablation.
        J Hepatol. 2011; 54: 559-565
        • Chen L.
        • Zhang L.
        • Tian M.
        • et al.
        Safety and effective of laparoscopic microwave ablation for giant hepatic hemangioma: a retrospective cohort study.
        Ann Med Surg (Lond). 2019 Feb 5; 39: 29-35
        • Furumaya A.
        • van Rosmalen B.V.
        • Takkenberg R.B.
        • et al.
        Transarterial (Chemo-) embolization and lipiodolization for hepatic haemangioma.
        Cardiovasc Intervent Radiol. Jun 2019; 42: 800-811
        • Adam R.
        • Karam V.
        • Cailliez V.
        • et al.
        Annual report of the European Liver Transplant Registry (ELTR) - 50-year evolution of liver transplantation.
        Transpl Int. Dec 2018; 31: 1293-1317
        • Sundar Alagusundaramoorthy S.
        • Vilchez V.
        • Zanni A.
        • et al.
        Role of transplantation in the treatment of benign solid tumors of the liver: a review of the United Network of Organ Sharing data set.
        JAMA Surg. Apr 2015; 150: 337-342
        • Prodromidou A.
        • Machairas N.
        • Garoufalia Z.
        • et al.
        Liver transplantation for giant hepatic hemangioma: a systematic review.
        Transplant Proc. Mar 2019; 51: 440-442
        • Rubin R.A.
        • Mitchell DG.
        Evaluation of the solid hepatic mass.
        Med Clin North Am. 1996; 80: 907-928
        • Marrero J.A.
        • Ahn J.
        • Rajender Reddy K.
        • et al.
        ACG clinical guideline: the diagnosis and management of focal liver lesions.
        Am J Gastroenterol. 2014; 109: 1328-1348
        • Nguyen B.N.
        • Flejou J.F.
        • Terris B.
        • et al.
        Focal nodular hyperplasia of the liver: a comprehensive pathologic study of 305 lesions and recognition of new histologic forms.
        Am J Surg Pathol. 1999; 23: 1441-1454
        • Vilgrain V.
        • Uzan F.
        • Brancatelli G.
        • et al.
        Prevalence of hepatic hemangioma in patients with focal nodular hyperplasia: MR imaging analysis.
        Radiology. 2003; 229: 75-79
        • Bioulac-Sage P.
        • Cubel G.
        • Balabaud C.
        • et al.
        Revisiting the pathology of resected benign hepatocellular nodules using new immunohistochemicalmarkers.
        Semin Liver Dis. 2011; 31: 91-103
        • Paradis V.
        • Benzekri A.
        • Dargere D.
        • et al.
        Telangiectatic focal nodular hyperplasia: a variant of hepatocellular adenoma.
        Gastroenterology. 2004; 126: 1323-1329
        • Buscarini E.
        • Danesino C.
        • Plauchu H.
        • et al.
        High prevalence of hepatic focal nodular hyperplasia in subjects with hereditary hemorrhagic telangiectasia.
        Ultrasound Med Biol. 2004; 30: 1089-1097
        • Furlan A.
        • Brancatelli G.
        • Dioguardi Burgio M.
        • et al.
        Focal nodular hyperplasia after treatment with oxaliplatin: a multiinstitutional series of cases diagnosed at MRI.
        AJR Am J Roentgenol. Apr 2018; 210: 775-779
        • Rifai K.
        • Mix H.
        • Krusche S.
        • et al.
        No evidence of substantial growth progression or complications of large focal nodular hyperplasia during pregnancy.
        Scand J Gastroenterol. 2013; 48: 88-92
        • D'Halluin V.
        • Vilgrain V.
        • Pelletier G.
        • et al.
        Natural history of focal nodular hyperplasia. A retrospective study of 44 cases.
        Gastroenterol Clin Biol. 2001; 25: 1008-1010
        • Perrakis A.
        • Demir R.
        • Muller V.
        • et al.
        Management of the focal nodular hyperplasia of the liver: evaluation of the surgical treatment comparing with observation only.
        Am J Surg. 2012; 204: 689-696
        • Ronot M.
        • Paradis V.
        • Duran R.
        • et al.
        MR findings of steatotic focal nodular hyperplasia and comparison with other fatty tumours.
        Eur Radiol. 2013; 23: 914-923
        • Rebouissou S.
        • Couchy G.
        • Libbrecht L.
        • et al.
        The beta-catenin pathway is activated in focal nodular hyperplasia but not in cirrhotic FNH-like nodules.
        J Hepatol. 2008; 49: 61-71
        • Bioulac-Sage P.
        • Laumonier H.
        • Rullier A.
        • et al.
        Over-expression of glutamine synthetase in focal nodular hyperplasia: a novel easy diagnostic tool in surgical pathology.
        Liver Int. 2009; 29: 459-465
        • Terkivatan T.
        • de Wilt J.H.W.
        • de Man R.A.
        • et al.
        Indications and long-term outcome of treatment for benign hepatic tumors.
        Arch Surg. 2001; 136: 1033-1038
        • Campos Amico E.
        • de Souza I.K.
        • Grigório Trigueiro J.R.
        • et al.
        Should focal nodular hyperplasia still be operated upon? Analysis of a case series.
        Dig Dis. 2019; 37: 309-314
        • Perrakis A.
        • Vassos N.
        • Grützmann R.
        • et al.
        what is changing in indications and treatment of focal nodular hyperplasia of the liver. is there any place for surgery?.
        Ann Hepatol. 2017; 16: 333-341
        • Hardwigsen J.
        • Pons J.
        • Veit V.
        • et al.
        A life-threatening complication of focal nodular hyperplasia.
        J Hepatol. 2001; 35: 310-312
        • Bathe O.F.
        • Mies C.
        • Franceschi D.
        • et al.
        Massive hemorrhage and infarction complicating focal nodular hyperplasia of the liver.
        HPB. 2003; 5: 123-126
        • Chang S.K.
        • Chung Y.F.
        • Thng C.H.
        • et al.
        Focal nodular hyperplasia presenting as acute abdomen.
        Singap Med J. 2005; 46: 90-92
        • Rahili A.
        • Cai J.
        • Trastour C.
        • et al.
        Spontaneous rupture and hemorrhage of hepatic focal nodular hyperplasia in lobus caudatus.
        J Hepatobiliary Pancreat Surg. 2005; 12: 138-142
        • Demarco M.P.
        • Shen P.
        • Bradley R.F.
        • et al.
        Intraperitoneal hemorrhage in a patient with hepatic focal nodular hyperplasia.
        Am Surg. 2006; 72: 555-559
        • Li T.
        • Qin L.X.
        • Ji Y.
        • et al.
        Atypical hepatic focal nodular hyperplasia presenting as acute abdomen and misdiagnosed as hepatocellular carcinoma.
        Hepatol Res. 2007; 37: 1100-1105
        • Kinoshita M.
        • Takemura S.
        • Tanaka S.
        • et al.
        Ruptured focal nodular hyperplasia observed during follow-up: a case report.
        Surg Case Rep. Dec 2017; 3: 44
        • Grazioli L.
        • Bondioni M.P.
        • Haradome H.
        • et al.
        Hepatocellular adenoma and focal nodular hyperplasia: value of gadoxetic acid-enhanced MR imaging in differential diagnosis.
        Radiology. 2012; 262: 520-529
        • McInnes M.D.
        • Hibbert R.M.
        • Inácio J.R.
        • et al.
        Focal nodular hyperplasia and hepatocellular adenoma: accuracy of gadoxetic acid-enhanced MR imaging–a systematic review [published correction appears in radiology. 2015 Dec;277(3):927].
        Radiology. 2015; 277: 413-423
        • Grazioli L.
        • Morana G.
        • Kirchin M.A.
        • et al.
        Accurate differentiation of focal nodular hyperplasia from hepatic adenoma at gadobenate dimeglumine-enhanced MR imaging: prospective study.
        Radiology. 2005; 236: 166-177
        • Grieser C.
        • Steffen I.G.
        • Seehofer D.
        • et al.
        Histopathologically confirmed focal nodular hyperplasia of the liver: gadoxetic acid-enhanced MRI characteristics.
        Magn Reson Imaging. 2013; 31: 755-760
        • Nault J.C.
        • Zucman Rossi J.
        Molecular classification of hepatocellular adenomas.
        Int J Hepatol. 2013; 2013315947
        • Mathieu D.
        • Kobeiter H.
        • Maison P.
        • et al.
        Oral contraceptive use and focal nodular hyperplasia of the liver.
        Gastroenterology. 2000; 118: 560-564
        • Scalori A.
        • Tavani A.
        • Gallus S.
        • et al.
        Oral contraceptives and the risk of focal nodular hyperplasia of the liver: a case-control study.
        Am J Obstet Gynecol. 2002; 186: 195-197
        • Shen Y.H.
        • Fan J.
        • Wu Z.Q.
        • et al.
        Focal nodular hyperplasia of the liver in 86 patients.
        Hepatobiliary Pancreat Dis Int. 2007; 6: 52-57
        • Fioole B.
        • Kokke M.
        • van Hillegersberg R.
        • Rinkes IH.
        Adequate symptom relief justifies hepatic resection for benign disease.
        BMC Surg. Apr 1 2005; 5: 7
        • Hau H.M.
        • Atanasov G.
        • Tautenhahn H.M.
        • et al.
        The value of liver resection for focal nodular hyperplasia: resection yes or no?.
        Eur J Med Res. Oct 22 2015; 20: 86
        • Zhang G.
        • Wang M.
        • Duan F.
        • et al.
        Transarterial embolization with bleomycin for symptomatic hepatic focal nodular hyperplasia.
        Diagn Interv Radiol. Jan-Feb 2017; 23: 66-70
        • Birn J.
        • Williams T.R.
        • Croteau D.
        • et al.
        Transarterial embolization of symptomatic focal nodular hyperplasia.
        J Vasc Interv Radiol. Nov 2013; 24: 1647-1655
        • Hsee L.C.
        • McCall J.L.
        • Koea J.B.
        Focal nodular hyperplasia: what are the indications for resection?.
        HPB. 2005; 7: 298-302
        • Descottes B.
        • Glineur D.
        • Lachachi F.
        • et al.
        Laparoscopic liver resection of benign liver tumours.
        Surg Endosc. 2003; 17: 23-30
        • Mezhir J.J.
        • Fourman L.T.
        • Do R.K.
        • et al.
        Changes in the management of benign liver tumours: an analysis of 285 patients.
        HPB. 2013; 15: 156-163
        • Pain J.A.
        • Gimson A.E.
        • Williams R.
        • et al.
        Nodular hyperplasia of the liver: results of treatment and options in management.
        Gut. 1991; 32: 524-527
        • Grazioli L.
        • Federle M.P.
        • Brancatelli G.
        • et al.
        Hepatic adenomas: imaging and pathologic findings.
        Radiographics. 2001; 21: 877-892
        • Bioulac-Sage P.
        • Sempoux C.
        • Balabaud C.
        Hepatocellular adenoma: classification, variants and clinical relevance.
        Semin Diagn Pathol. 2017; 34: 112-125
        • Sherlock S.
        Hepatic adenomas and oral contraceptives.
        Gut. 1975; 16: 753-756
        • Klatskin G.
        Hepatic tumors: possible relationship to use of oral contraceptives.
        Gastroenterology. 1977; 73: 386-394
        • Baum J.K.
        • Bookstein J.J.
        • Holtz F.
        • Klein EW.
        Possible association between benign hepatomas and oral contraceptives.
        Lancet. 1973; 2: 926-929
        • Edmondson H.A.
        • Henderson B.
        • Benton B.
        Liver-cell adenomas associated with use of oral contraceptives.
        N Engl J Med. 1976; 294: 470-472
        • Edmondson H.A.
        Tumors of the liver and intrahepatic bile ducts.
        in: Edmondson H.A. Atlas of tumor pathology. Armed Forces Institute of Pathology, Washington, D.C.1958
        • Rooks J.B.
        • Ory H.W.
        • Ishak K.G.
        • et al.
        Epidemiology of hepatocellular adenoma. The role of oral contraceptive use.
        JAMA. 1979; 242: 644-648
        • Nime F.
        • Pickren J.W.
        • Vana J.
        • et al.
        The histology of liver tumors in oral contraceptive users observed during a national survey by the American college of surgeons commission on cancer.
        Cancer. 1979; 44: 1481-1489
        • Rosenberg L.
        The risk of liver neoplasia in relation to combined oral contraceptive use.
        Contraception. 1991; 43: 643-652
        • Søe K.L.
        • Søe M.
        • Gluud C.
        Liver pathology associated with the use of anabolic-androgenic steroids.
        Liver. 1992; 12: 73-79
        • Reddy K.R.
        • Schiff ER.
        Approach to a liver mass.
        Semin Liver Dis. 1993; 13: 423-435
        • Cherqui D.
        • Rahmouni A.
        • Charlotte F.
        • et al.
        Management of focal nodular hyperplasia and hepatocellular adenoma in young women: a series of 41 patients with clinical, radiological, and pathological correlations.
        Hepatology. 1995; 22: 1674-1681
        • Benhamou J.P.
        Diagnostic approach to a liver mass: diagnosis of an asymptomatic liver tumor in a young woman.
        J Hepatol. 1996; 25: 30-34
        • Shortell C.K.
        • Schwartz SI.
        Hepatic adenoma and focal nodular hyperplasia.
        Surg Gynecol Obstet. 1991; 173: 426-431
        • Meissner K.
        Hemorrhage caused by ruptured liver cell adenoma following long-term oral contraceptives: a case report.
        Hepatogastroenterology. 1998; 45: 224-225
        • Edmondson H.A.
        • Reynolds T.B.
        • Henderson B.
        • et al.
        Regression of liver cell adenomas associated with oral contraceptives.
        Ann Intern Med. 1977; 86: 180-182
        • Kawakatsu M.
        • Vilgrain V.
        • Erlinger S.
        • Nahum H.
        Disappearance of liver cell adenoma: CT and MR imaging.
        Abdom Imaging. 1997; 22: 274-276
        • Aseni P.
        • Sansalone C.V.
        • Sammartino C.
        • Benedetto F.D.
        • Carrafiello G.
        • Giacomoni A.
        • Osio C.
        • Vertemati M.
        • Forti D.
        Rapid disappearance of hepatic adenoma after contraceptive withdrawal.
        J Clin Gastroenterol. 2001; 33: 234-236
        • Norris S.
        Drug- and Toxin-Induced Liver Injury.
        Comprehensive Clinical Hepatology. 2000;
        • Cohen C.
        • Lawson D.
        • DeRose P.B.
        Sex and androgenic steroid receptor expression in hepatic adenomas.
        Hum Pathol. 1998; 29: 1428-1432
        • Masood S.
        • West A.B.
        • Barwick KW.
        Expression of steroid hormone receptors in benign hepatic tumors. An immunocytochemical study.
        Arch Pathol Lab Med. 1992; 116: 1355-1359
        • Nakao A.
        • Sakagami K.
        • Nakata Y.
        • et al.
        Multiple hepatic adenomas caused by long-term administration of androgenic steroids for aplastic anemia in association with familial adenomatous polyposis.
        J Gastroenterol. 2000; 35: 557-562
        • Resnick M.B.
        • Kozakewich H.P.
        • Perez-Atayde AR.
        Hepatic adenoma in the pediatric age group. Clinicopathological observations and assessment of cell proliferative activity.
        Am J Surg Pathol. Oct 1995; 19: 1181-1190
        • Touraine R.L.
        • Bertrand Y.
        • Foray P.
        • et al.
        Hepatic tumours during androgen therapy in Fanconi anaemia.
        Eur J Pediatr. 1993; 152: 691-693
        • Coombes G.B.
        • Reiser J.
        • Paradinas F.J.
        Burn I. An androgen-associated hepatic adenoma in a trans-sexual.
        Br J Surg. 1978; 65: 869-870
        • Carrasco D.
        • Prieto M.
        • Pallardó L.
        • et al.
        Multiple hepatic adenomas after long-term therapy with testosterone enanthate. Review of the literature.
        J Hepatol. 1985; 1: 573-578
        • Fujiyama S.
        • Sato K.
        • Sakai M.
        • et al.
        A case of type Ia glycogen storage disease complicated by hepatic adenoma.
        Hepatogastroenterology. 1990; 37: 432-435
        • Alshak N.S.
        • Cocjin J.
        • Podesta L.
        • et al.
        Hepatocellular adenoma in glycogen storage disease type IV.
        Arch Pathol Lab Med. 1994; 118: 88-91
        • Labrune P.
        • Trioche P.
        • Duvaltier I.
        • et al.
        Hepatocellular adenomas in glycogen storage disease type I and III: a series of 43 patients and review of the literature.
        J Pediatr Gastroenterol Nutr. 1997; 24: 276-279
        • Leese T.
        • Farges O.
        • Bismuth H.
        Liver cell adenomas. A 12-year surgical experience from a specialist hepato-biliary unit.
        Ann Surg. 1988; 208: 558-564
        • Talente G.M.
        • Coleman R.A.
        • Alter C.
        • et al.
        Glycogen storage disease in adults.
        Ann Intern Med. 1994; 120: 218-226
        • Ribeiro A.
        • Burgart L.J.
        • Nagorney D.M.
        • et al.
        Management of liver adenomatosis: results with a conservative surgical approach.
        Liver Transpl Surg. 1998; 4: 388-398
        • Flejou J.F.
        • Barge J.
        • Menu Y.
        • et al.
        Liver adenomatosis. An entity distinct from liver adenoma?.
        Gastroenterology. 1985; 89: 1132-1138
        • Howell R.R.
        • Stevenson R.E.
        • Ben-Menachem Y.
        • et al.
        Hepatic adenomata with type 1 glycogen storage disease.
        JAMA. 1976; 236: 1481-1484
        • Chen K.T.
        • Bocian J.J.
        Multiple hepatic adenomas.
        Arch Pathol Lab Med. 1983; 107: 274-275
        • Grazioli L.
        • Federle M.P.
        • Ichikawa T.
        • et al.
        Liver adenomatosis: clinical, histopathologic, and imaging findings in 15 patients.
        Radiology. 2000; 216: 395-402
        • Kwok W.Y.
        • Hagiwara S.
        • Nishida N.
        • et al.
        Malignant transformation of hepatocellular adenoma.
        Oncology. 2017; 92: 16-28
        • González-Lara M.F.
        • Córdova-Ramón J.C.
        • Gamboa-Domínguez A.
        • et al.
        Hepatocellular carcinoma arising in a telangiectatic hepatocellular adenoma.
        Ann Hepatol. 2013; 12: 626-628
        • Mouhoub M.
        • Miry A.
        • Haloui A.
        • et al.
        Malignant transformation of hepatocellular adenoma: report of a case.
        Pan Afr Med J. Mar 26 2020; 35: 92
        • Timothy L.D.
        • Lehrke H.D.
        • Chandan V.S.
        • et al.
        Diffuse adenomatosis and hepatocellular carcinoma treated with liver transplantation in an adolescent female with kabuki syndrome with a novel KMT2D gene mutation.
        Case Rep Pediatr. 2019; 7983824
        • Barbier L.
        • Nault J.C.
        • Dujardin F.
        • et al.
        Natural history of liver adenomatosis: a long term observational study.
        J Hepatol. 2019; 71: 1184-1192
        • Nault J.C.
        • Couchy G.
        • Balabaud C.
        • et al.
        Molecular classification of hepatocellular adenoma associates with risk factors, bleeding, and malignant transformation.
        Gastroenterology. 2017; 152: 880-894
        • Sala M.
        • Gonzales D.
        • Leste-Lasserre T.
        • et al.
        ASS1 overexpression: a hallmark of sonic hedgehog hepatocellular adenomas; recommendations for clinical practice.
        Hepatol Commun. Apr 11 2020; 4: 809-824
        • Bioulac Sage P.
        • Sempoux C.
        • Frulio N.
        • et al.
        Snapshot summary of diagnosis and management of hepatocellular adenoma subtypes.
        Clinics and research in Hepatol Gastroenterol. 2019; 43: 12-19
        • Haring M.P.D.
        • Vriesendorp T.M.
        • Klein Wassink-Ruiter J.S.
        • et al.
        Diagnosis of hepatocellular adenoma in men before onset of diabetes in HNF1A-MODY: watch out for winkers.
        Liver Int. 2019; 39: 2042-2045
        • Calderaro J.
        • Labrune P.
        • Morcrette G.
        • et al.
        Molecular characterization of hepatocellular adenomas developed in patients with glycogen storage disease type I.
        J Hepatol. 2013; 58: 350-357
        • Longerich T.
        • Endris V.
        • Neumann O.
        • et al.
        RSPO2 gene rearrangement: a powerful driver of ß-catenin activation in liver tumours.
        Gut. 2019; 68: 1287-1296
        • Strauss E.
        • Ferreira Ade S.
        • França A.V.
        • et al.
        Diagnosis and treatment of benign liver nodules: Brazilian Society of Hepatology (SBH) recommendations.
        Arq Gastroenterol. 2015; 52: 47-54
        • Haring M.P.D.
        • Cuperus F.J.C.
        • Duiker E.W.
        • de Haas R.J.
        • de Meijer VE.
        Scoping review of clinical practice guidelines on the management of benign liver tumours.
        BMJ Open Gastroenterol. 2021; 8e000592
        • Henriet E.
        • Abou Hammoud A.
        • Dupuy J.W.
        • et al.
        Argininosuccinate synthase 1 (ASS1): a marker of unclassified hepatocellular adenoma and high bleeding risk.
        Hepatology. 2017; 66: 2016-2028
        • Ronot M.
        • Bahrami S.
        • Calderaro J.
        • et al.
        Hepatocellular adenomas: accuracy of magnetic resonance imaging and liver biopsy in subtype classification.
        Hepatology. 2011; 53: 1182-1191
        • Bise S.
        • Frulio N.
        • Hocquelet A.
        • et al.
        New MRI features improve subtype classification of hepatocellular adenoma.
        Eur Radiol. 2019; 29: 2436-2447
        • Auer T.A.
        • Fehrenbach U.
        • Grieser C.
        • et al.
        Hepatocellular adenomas: is there additional value in using Gd-EOB-enhanced MRI for subtype differentiation?.
        Eur Radiol. 2020; 30: 1-10
        • Bröker M.E.E.
        • Taimr P.
        • de Vries M.
        • et al.
        Performance of contrast-enhanced sonography versus MRI with a liver-specific contrast agent for diagnosis of hepatocellular adenoma and focal nodular hyperplasia.
        AJR Am J Roentgenol. 2020; 214: 81-89
        • Reizine E.
        • Ronot M.
        • Ghosn M.
        • et al.
        Hepatospecific MR contrast