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European Journal of -18-0296 of AIto4.4%inradiologicalseriescomparedautopsy Advances in imaging techniques raised the prevalence syndromesareoutsideofthis definition. or hereditary detected onscreeningimagingforpatientswithcancer performed forsuspectedadrenaldisease( in diameterdiscoveredincidentallyonimagingnot Adrenal incidentaloma(AI)isamasslargerthan1 Introduction is focusedonthedifferential diagnosis,investigationandtreatmentofbilateralAIs. as recommendedinunilateralAI,butdiagnosisofCAHandadrenalinsufficiency shouldalsobeexcluded.Thisreview investigation ofbilateralincidentalomasincludesthesamehormonalevaluationtoexcludeexcesshormonesecretion with secondarybilateraladrenalhyperplasia,primarymalignancies,myelolipomas,infectionsorhemorrhage.The bilateral ,congenitaladrenalhyperplasia(CAH),Cushing’s diseaseorectopicACTHsecretion primary bilateralmacronodularadrenalhyperplasiaandcorticaladenomas.Lessfrequentetiologiesare have beenlessfrequentlydiscussed.Thedifferential diagnosisofbilateralincidentalomasincludesmetastasis, last decades.Whilebilateraladrenalincidentalomasrepresentabout15%of(AIs),they The investigationandmanagementofunilateraladrenalincidentalomashavebeenextensivelyconsideredinthe Abstract Montréal (CRCHUM),UniversitédeMontréal,Canada Division ofEndocrinology, DepartmentofMedicine,Centrederechercheduhospitalierl’Université Isabelle Bourdeau, NadaEl Ghorayeb,NadiaGagnon therapy ofbilateraladrenal incidentalomas Differential diagnosis,investigationand MANAGEMENT OFENDOCRINEDISEASE https://doi.org/ www.ej Review Review development genetics ofadrenaltumors and theroleofWnt/beta-cateninsignalinginadrenocortical tumor scientist sheperformstranslational research inadrenal diseases.Herresearch interestsinclude Delegate/PI for Canada of the American-Australian-Asian Adrenal Alliance(A5).Asa clinician- she establishedanewclinicfocusingongeneticsofadrenal tumorsatCHUM.SheistheNational de l’UniversitéMontréal(CHUM)andresearcher atCHUMresearch centersince2004.In2005, Isabelle Bourdeau Invited Author’s profile e-online.org 10.1530/EJE . -18-0296

is ProfessorofMedicineintheDivisionEndocrinology atCentrehospitalier 2 © 2018EuropeanSociety ofEndocrinology I Bourdeauandothers 1 ). Adrenallesions Printed inGreatBritain cm and be estimatedto0.3–0.6%inthegeneralpopulation. of cases( are unilateraltumorsbilateralAIsfoundinupto15% old( than 70 years increasing with age reaching 7–10% in individuals older patients withobesity, diabetesorhypertension ( data (1–8.7%)( André Lacroix incidentalomas Bilateral adrenal Published byBioscientifica Ltd. 10 , 11 ). Thus,theprevalenceofbilateralAIcan 1 , 2 7 , , 3 8 , , 4 Downloaded fromBioscientifica.com at09/29/202106:39:32PM 9 , ). AlthoughthemajorityofAIs 5 ). Theprevalenceishigherin (2018) Endocrinology European Journal of umontreal.ca isabelle.bourdeau@ Email to IBourdeau should beaddressed Correspondence 179 179 :2 , R57–R67

R57 6 ) andis –R67 via freeaccess European Journal of Endocrinology www.eje-online.org Adrenal hemorrhage Amyloidosis Infiltrative Blastomycosis Histoplasmosis Tuberculosis Infections Myelolipomas Lymphoma Metastases Non-adrenal tumors Cushing’s disease Adenomas Adrenal tumorsandhyperplasias Tumoral Adrenal lesions Extra adrenal lesions bilateral adrenalincidentalomas. Table 1 bilateralmacronodular AI weremetastasis,primary patients foundthatthemostcommoncausesofbilateral that ofunilateralAI;twostudiesincluding887and202 summarized in describe belowvariousetiologiesofbilateralAIsthatare represent morethan80–85%ofAI( referred toendocrinology;benignnon-secretingtumors carcinomas and0.2–2.2% formetastasisintrueAIbeing malignancy rateislowbeing0.6–1.4%foradrenocortical the conclusions of a meta-analysis demonstrating that the realprevalenceofmalignancy. Arecentstudyconfirmed tumors areoverrepresentedleadingtooverestimationof from surgicalserieswhereadrenalcancersandsecreting whether recruitment was from endocrinology clinics or depending The causesofunilateralorbilateralAIvary Etiologies AI focusingonadultpopulation. etiologies, theinvestigationandmanagementofbilateral was devotedtobilateralAI.We willreviewherethe in thepasttwodecades( Approach tounilateralAIhasbeendiscussedextensively ACTH-dependent Congenital adrenalhyperplasia Adrenocortical carcinoma Bilateral macronodularadrenalhyperplasia Technical artifacts Kidney, pancreasandspleenlesions Review Ectopic ACTHCushing’s syndrome Glucocorticoid resistancesyndrome The distributionofetiologiesbilateralAIdiffersfrom Differential diagnosisofmostcommoncauses Table 1 . 1 , 9 , 12 , I Bourdeauandothers 13 , 14 ), butnoattention 11 , 15 ). We will pointing totheadrenalglands. well-defined fatattenuatingin thelesions.Thearrowsare 3.9 Bilateral adrenalmyelolipomas (right:10.7 findings ofbilateralmacronodular adrenalhyperplasia.(B) CT scanimagingofbilateraladrenallesions.(A)Classical Figure 1 hepatocellular carcinoma and bladdercancer. also described in melanoma,thyroidcancer, sarcomatoid breast cancers( kidney, bronchogeniccarcinoma, colon,stomachand leading toadrenalmetastasesinthisstudyincluded had bilateraladrenallesions( had metastatic adrenal lesions and among them ten 172 unilateralAIand36bilateralAI,19(9%)patients In astudyinvolving208patientswithAIincluding Adrenal metastasisormalignancies ( bilateraladrenalhyperplasia secretion withsecondary hyperplasia (CAH),Cushing’s diseaseorectopicACTH bilateral pheochromocytomas( adenomas ( adrenal hyperplasia (BMAH) ( metastasis werereportedinpatientswithrenalcell cancer ( glands as described in patients with small-cell lung insufficiency due toneoplastic infiltration of the adrenal of 100% ( adrenal biopsyformalignancy is of87%withaspecificity synchronous ormetachronous.Theoverallsensitivityof rarelybilateraladrenalmetastasesthatmaybe or very patients, theymaypresentwithonlydistantunilateral recurrences most frequently occur locoregionally, in few be indicated for stagingwork-up. Moreover, although who areathighriskformalignancy, adrenalbiopsymay Bilateral adrenalincidentalomas 17 × , Very rare casereports of bilateral For patientswithadrenallesionsmalignancyor

18 4.3 , cm) showingclassicalfeatures of myelolipomaswith 22 19 ). , 14 20 16 ). Bilateral metastasis may lead to adrenal ) ( , 17 Table 1 21 ). OthercausesofbilateralAIinclude ). Bilateraladrenalmetastaseswere ). Downloaded fromBioscientifica.com at09/29/202106:39:32PM Fig. 1A 21 Fig. 2 ). The primary cancers ). Theprimary ) and bilateral cortical ), congenitaladrenal 179 × :2 m n left: and 9.5cm R58 via freeaccess European Journal of Endocrinology adrenal hyperplasia in approximately 60% ofcases as they to bilateral aldosteronism, which is secondary primary in thisreview. Similarly, wewillnotdiscussextensively usually presentasAI,andit willnotbefurtherdiscussed except forrarecases( often notassociatedwithdominantadrenalnodules pigmented nodularadrenaldisease(PPNAD)thatismost < macronodular (nodules Bilateral adrenalhyperplasiacaneitherpresent as Bilateral macronodular adrenal hyperplasia as theyaretreatedwithsystemicchemotherapy. with adrenal lymphoma do not undergo adrenalectomy 11 patients(73%)withbilaterallymphoma( levels. Importantly, adrenalinsufficiencywasfoundin8of such asincreasedLDH,ß2microglobulin,CRPorferritin associated with classical biological features of lymphoma a worsening general state, weight loss and abdominal pain adrenal lymphoma of 71% ( adrenal lymphomareportedaprevalenceofbilateral lymphoma. ArecentFrenchcohortof28patientswith include therarebilateraladrenocorticalcarcinomas and adrenal hormonalfunctionwerereported( partial adrenalectomyonthecontralateralsidetopreserve adrenalectomies andtotaladrenalectomy on onesideand therapeutic option forthesepatients.Both bilateral carcinoma. Surgicalresection ofmetastasesistheonly 1 Review cm). The micronodular form includes primary cm). The micronodular form includes primary Other lessfrequentneoplasticcausesofbilateralAI 26 ). Forthisreason,PPNADdoes not > 1 cm) or micronodular (nodules 25 ). The initial symptoms were I Bourdeauandothers 23 25 , 24 ). Patients ). Attenuation higher than 10 HU was also described ( adrenal enlargementwithout nodulesisalsoseen. usually withmultiplenodules ( of BMAHregulatingcortisol production( of paracrine and autocrine production of ACTHin tissues cortisol secretion was challenged after the demonstration in those patients ( of mutationsinthecatalyticsubunitPKA( hypercortisolism ( frequent inpatientswithunilateraladenomasandovert 31 the highestnumberofaberrantresponses vasopressin andserotoninbeingthestimulileading to were demonstratedinhalfofthepatientswithBMAH: ( 80% ofpatientswithovertormildhypercortisolism of steroidogenicfactors.GPCRswereidentifiedin ACTH receptorconsequentlyleadingtothetranscription pathway inasimilarfashiontotheactivatedby activation ofcyclicAMP/proteinkinaseA(PKA)signaling glucagon andangiotensinII( chorionic gonadotropin, for vasopressin,serotonin,luteinizinghormone/human receptors (GPCRs) in zona fasciculata cells including those the expressionof multiple aberrantGprotein-coupled overnight test.Cortisolsecretionisinpartregulatedby with incompletesuppressionto1 rarely investigatedinthecourseofevaluationAIs( may have normal-appearing adrenal glands onCT and are Bilateral adrenalincidentalomas 28 , ). Severalsimultaneousaberrantreceptorresponses 32 On unenhancedCT, bothadrenalglandsareenlarged BMAH issuspectedwhentherebilateralAI , 33 ). Thepresenceofaberrantresponseswasless 34 29 pathology afterbilateraladrenalectomies. pheochromocytomas wasconfirmedat adrenal gland.Diagnosisofbilateral MIBG waspositiveonlyontheright right sideand4.6ontheleftside.(D) FDG-PET withaSUVmaxof5.4onthe Both adrenallesionsshoweduptakeat hyperintensity onT2-weightedimages.(C) and inbothlesions,thereareareasof are hypointenseonT1-weightedimage, 2.9 4.7 28-year-old woman.(A)MRIshowinga Bilateral pheochromocytomasina Figure 2 ). The concept of ACTH-independent ) probablyduetothehighfrequency × ×

2.9 leftadrenalmass(B).Themasses 4.4 Downloaded fromBioscientifica.com at09/29/202106:39:32PM cm rightadrenalmassanda β -adrenergic agonists,GIP, 28 Figs 1A ). TheseGPCRsledtothe 179 mg dexamethasone and www.eje-online.org :2 35 in vivo 3 , ), butdiffuse 36 ). PRKACA) ( 29 R59 , 27 37 30 via freeaccess ). ). ,

European Journal of Endocrinology www.eje-online.org dexoxy-D glucosepositron emissiontomography/CT images ( on T1-weightedimagesand hyperintense onT2-weighted MR, relativetotheliver, glandsareusually hypointense possible and may be confused with a unilateral disease. On oftheglands.Anasymmetricappearance is periphery enhancement, and there might be enhancement of the In contrast-enhancedimaging,nodulescanhavemarked hyperplasia. supporting thediagnosisofbilateralmacronodularadrenal overproduction ofserumcortisoland17-hydroxyprogesterone suppression test.The250 investigation wasnormal.Includingthe1 nodules werestableinsizefrom2006to2017.Thehormonal the rightadrenalglandhasanoduleof1.8 nodular lesionsof3 bilateral incidentalomas.Theleftadrenalglandhastwo Adrenal CTscanofa69-year-old manwhopresentedwith Figure 3 Review In limitedstudiesusing 2-(fluorine 18)fluoro-2- 38 ). × m n 1.6 and 2cm µg cosyntropintestshowed × U, whereas (11 HU), 1.3cm I Bourdeauandothers mg dexamethasone × m All 0.8cm. unilateral pheochromocytomas( causecomparedto likely associatedtoahereditary Bilateral adrenalpheochromocytomasaremore Pheochromocytomas These findingsneedtobeconfirmedinlargerseries. although BMAHiswellrecognizedasabenigndisease. susceptibility gene, recently, germlinemutationsofthetumorsuppressor patients withneurofibromatosistype 1aswell( Hippel–Lindau syndromeandhavebeenreportedin multiple endocrineneoplasiatype2Aand2B,von pheochromocytomas maybefoundinassociationwith reaching levelusuallyseeninmalignanttumors( standardized uptakevalue(SUVmax) glands ofBMAHwashigherthantheliver, withmaximum (PET/CT) imaging, uptake inthemacronodular adrenal of 15%bilateralAI( CAH, whichismuchhigher thantheexpectedprevalence in the subgroup of patients with genetically confirmed had bilateralAIandthisfrequency wasincreasedto50% predict CAH;one-thirdofbiochemically confirmedCAH CAH and adrenal tumors suggested that bilateral AI may respectively ( frequency withaprevalenceof16.1%and21.1% with unilateralAIandbilateralwasfoundatsimilar 21-hydroxylase-gene mutation (CYP21)inpatients to adrenal tumors in 82% of cases. The occurrence of In patients with CAH, chronic elevation of ACTH leads Congenital adrenal hyperplasia T2-weighted images( gadolinium andclassicallytheyarehyperintenseon they showhyperenhancementfollowinginjectionof during thearterialphaseofCTscan.Similarly, inMRI, are hypervascular, thentheyhaveintenseenhancement unilateral pheochromocytoma.Pheochromocytomas identify agermlinegeneticcauseishigherthanthatin pheochromocytomas knowingthattheprobabilityto a geneticcounselingtopatientswithbilateral look forunderlyinggenetic syndromes andoffering pheochromocytomas ( germline ( and paragangliomaswithaprevalenceof1.12% were identifiedinalargecohortofpheochromocytomas Bilateral adrenalincidentalomas 42 ). Amongthe19patientsharboringapathogenic MAX 44 mutations,11haddevelopedbilateral ). Ameta-analysesof36publicationson 43 MAX 45 ). Downloaded fromBioscientifica.com at09/29/202106:39:32PM 42 ). Nodularadrenalhyperplasia ). Thus,caregiversshould (MYC-associatedfactorX), 40 179 ). Bilateraladrenal > 3.1 (3.3–8.9),thus :2 41 ). More 37 R60 , 39 via freeaccess ) European Journal of Endocrinology lesions secreteexcesshormones? 2)Aretheymalignant AI andisbasedontwomain clinicalquestions;1)dothese The initialwork-upforbilateral AIissimilartounilateral Hormonal work-upfor bilateralAIs to eliminateunderlyingadrenaltumorallesions. adrenal enlargement.Follow-upinthesecasesisessential recognized innoncontrastCTshowinghyperdense ( and stress as surgery meningococcemia (Waterhouse–Friderichsen syndrome) therapy, antiphospholipidsyndrome,sepsis suchas Predisposing factorsincludetrauma,anticoagulation adrenalinsufficiency ( may resultinacuteprimary bilateral adrenallesionsthatmaybefoundincidentally. amyloidosis are part of the differential diagnosis of and adrenalinsufficiency. Infiltrativediseasessuchas term infectionmayleadtoadrenalglandsdestruction adrenal enlargement has been reported ( infections inimmunocompetentindividualsandbilateral most commonsitesinvolvedindisseminatedhistoplasma and blastomycosis.Theadrenalglandsareamongthe include infectionssuchastuberculosis, histoplasmosis hemorrhage ( ( for secretingmyelolipomasandorthoselargerlesions reported sofar( 40 cases of bilateral adrenal myelolipomas have been but ofvariableintensityonT2signal( images, whereas the marrow elements are T1 hypointense macroscopic fatappearshyperintenseonT1-weighted of 130–23 characteristics atnoncontrastCTwithhypoattenuation tumor inthesameadrenal.Myelolipomasshowspecific if thereisacompoundassociatedhormone-secreting effect symptomsorrarelyhormonal-secreting tissue. Theymaybediagnosedincidentally, duetomass composed of mature adiposecells and hematopoietic lesions areadrenalmyelolipoma( Among the less frequent causes of bilateral adrenal Other causesofbilateralAI standing disease( particularly inolderpatientsandthosewithalonger occurs inACTH-dependentCushing’s syndrome > Review 6–7 Adrenal hemorrhagemaybefoundbilaterallyand Non-tumoral causesofbilateraladrenalenlargement cm) that may cause pain or be prone to rupture of HU containingmacroscopicfat( 48 , 48 49 46 ). Surgical removal should be reserved ). Surgicalremovalshouldbereserved ). ). 51 , 52 ). Adrenal hemorrhage is I Bourdeauandothers Fig. 1B ), benigntumors 43 47 ). Lessthan 50 ). AtMRI, ). Long- 51 ). after 15 hypokalemia arepresent,plasmaaldosteroneandrenin rest insupineposture( metanephrines andnormetanephrinesafter30 catecholamines orbymeasuringfreeplasmalevelsof collectionof metanephrines and fractionated urinary of catecholaminesexcessisperformedeitherbya24-h 8 24 DST requirestaking1 a 1 Cortisol excess should be excluded in all patients with be excluded specifically for patients with bilateral AI. to unilateralAI,adrenalinsufficiencyandCAHsshould adrenal hormoneexcess( The investigationshouldbeabletoidentifyevenmild to assessthesignsofadrenalhormonesoversecretion. questionnaire andphysicalexaminationofthepatients masses? Theassessmentshouldincludeadetailed deficiency withmodestrise in17-hydroxyprogesterone test forCAHdiagnosisconfirmation. Amildenzymatic and CYP21A2mutationanalyses willbethemostreliable CAH with17-hydroxyprogesterone maylackspecificity deficiency in21-hydroxylase. However, screeningfor > test of17-hydroxyprogesterone(17-hydroxyprogesterone Increased levelsofbasalandpost250 the requirementformineralocorticoidsreplacement. renin insittingpositionarethenindicatedtoevaluate levels arehigh.Samplesofplasmaaldosteroneand depending themethodofmeasurement)andbasalACTH when cortisolincreaseisincomplete( at 30and60 of cortisol and 17-hydroxyprogesterone are measured by stimulationwith250 morning anddependingontheresultsmaybefollowed 17-hydroxyprogesterone andACTHareobtainedearly adulthood. For this fasting blood samples for cortisol, 21-hydroxylase deficiency)maybediagnosedlatein insufficiency. Second,late-onsetformsofCAH(specially 90% ofthecortexbothglandsmayleadtoadrenal should be ruled out because destruction of more than specifically inbilateralAI.First,adrenalinsufficiency carcinoma. of hirsutism/virilization or suspicion of adrenocortical and DHEAS,totaltestosterone,SHBGinthepresence including estrogensinthepresenceofgynecomastia samplings shouldbedoneaccordingtoclinicalsuspicion aldosteronism.Additionalspecific to detectprimary Bilateral adrenalincidentalomas mlL ( 43 nmol/L) h–9 h thenmeasuringcortisollevelthenextmorningat Two additionalinvestigationsshouldbeperformed mg dexamethasonesuppressiontest(1 h; normallevelsshouldbe minutes ofsittingpositionshouldbeperformed min later. Adrenalinsufficiencyispresent 55 ) could reveal a partial congenital mg oraldexamethasoneat23 54 Downloaded fromBioscientifica.com at09/29/202106:39:32PM ). Whenarterialhypertensionor μ 1 g ofACTH1–24wherelevels , 10 , 12 < mlL Evaluation 50 nmol/L. , µg ACTHstimulation 179 14 < www.eje-online.org , :2 430–550 nmol/L 53 ). Incontrast minutes of mg DST). R61 h or via freeaccess European Journal of Endocrinology www.eje-online.org an adenomawithlowHUand lower SUVmax(SUVmax3.8). FDG-PET anda2.7 adrenocortical carcinoma(36 scan showedaright5.9 referred forbilateraladrenocortical carcinomas.RevisedCT Cushing’s syndromeandhyperandrogenism.Shewasinitially Bilateral adrenallesionsina78-year-old womanwith Figure 4 not high enough to result in classical clinical stigmata to 25%ofAI( termed subclinicalCushingsyndrome)arefoundinup adenomas withmodestcortisolsecretion(previously symptoms rarely presents as an AI (0.8%) ( A cortisol-secretingadenomawithovertCushing unilateral AIs frequent inbilateralAIsthan Modest secretion ofcortisolismore on theotherside( secreting adrenallesionononesideandanon-secreting adrenal lesionsmaybedifferentinthetwosideswitha should bekeptinmindthatthenatureofbilateral deficiency of21hydoxylaseexpression( the massofhyperplasticadrenalglandswithrelative cortisol and17-hydroxyprogesteronelevelsreflect 250 usually inBMAH.InpatientswithBMAH,followinga ACTH levelsarewithinorbelowthenormallimitvalues discriminate betweenCAH(increasedACTH),whereas In thesecases,weshouldexpectthatACTHlevelscould is alsofrequentlyfoundinadenomasandBMAH( Review µg cosyntropintest,anoverproductionofplasma 13 × ,

Fig. 4 2.1 56 cm leftadrenalmasscompatible with × ). Modestcortisolsecretionthatis

7.7 ). cm lesionsuggestingan HU) withSUVmaxof9.5at I Bourdeauandothers 31 ) ( 11 i. 3 Fig. ) while ). It 31 ). pituitary axis wasdisturbedinpatientswithbilateralAI; pituitary group suggesting that the regulation of hypothalamic– stimulation comparedtounilateral AIandtoacontrol AI duringthecombined test ofDSTfollowedbyCRH response ofcortisolandACTH inpatientswithbilateral AI ( was presentin21.7%bilateralAIvs6.2%ofunilateral 112 unilateralAIand23bilateralAI,mildcortisolexcess groups ( type2anddyslipidemiawerecomparableinboth patients withunilateralAI( 35.1% ofpatientswithbilateralAI,butonlyin17.9% of 74 bilateralAI,wheremildcortisolexcesswaspresent in confirmed ina prospective study of 224 unilateral AI and than patientswithunilateralAI( aldosterone secretionandglucosemetabolismalterations with bilateral AI have more pronounced cortisol and study in2011byAndroulakis AI withaprevalenceof41.5%vs12.2%( excess wasmorefrequentinbilateralAIvsunilateral cohort ofadrenalincidentalomasthatmildcortisol were morefrequentinpatientswithbilateralAI( comparable betweenthetwogroups,whereasfractures , diabetes type 2 anddyslipidemia were to 38 bilateral AI; the prevalence of mild cortisol excess, ( were ageandmeanconcentrationofcortisolpostDST adrenal masses ( ( lower inpatientswithabnormalsuppressionto1 rates for all-cause mortality were and found thatsurvival et al for age,gender and BMI( complications comparedtocontrolpatientsmatched risk ofosteoporotic,metabolicandcardiovascular anincreased secreting mildcortisolexcessmightcarry cortisol secretionforhighervalues.Nevertheless,patients possible autonomous cortisol secretion and autonomous post dexamethasone between 51 and 140 nmol/L for diagnostic criteria( authors andtodate,thereisstillnoconsensusonits secretion ( autonomous (for non-ACTH-dependent) cortisol- of Cushingsyndromewasrecentlytermed(possible) increasing post-dexamethasoneserumcortisollevel( causes) with due to circulatory or respiratory/infectious rate(deathsweremainly a significantdecreaseinsurvival a retrospectivecohortof206patientswithAIs.Therewas Bilateral adrenalincidentalomas 60 > 50 ). Similarly, in2014,Debono In 2011,Vassiliadi Morelli 66 . studiedaretrospectivecohortofpatientswithAIs nmol/L) comparedtopatientswithnon-secreting ). Vassiliadi 65 ). More recently, in a surgical series including 14 et al ). Its biochemical definition varied among . comparedprospectively175unilateralAI 60 ). Factors associated with mortality t al et 14 , t al et Downloaded fromBioscientifica.com at09/29/202106:39:32PM 57 . demonstrated an exaggerated 2 ) exceptforaserumcortisol , . reportedinaretrospective 58 65 et al , ). However, hypertension, 59 et al ). In2014, Di Damalzi . showedthatpatients 64 . assessed survival in . assessedsurvival 179 ). Thesedatawere :2 63 ). Another 62 mg DST ). R62 61 via freeaccess ). European Journal of Endocrinology numerous medications( improved healthandreduced needforlong-term reversibility ofmetabolicmorbidities withsignificantly the adrenalBMAHtissues ledtocompleteorpartial or specificdrugstargeting the aberrantreceptorswithin genetic screening( had unsuspectedBMAHbeforesystematicclinicaland excess mainlyobesity, hypertensionand diabetes and previously wereaffectedbyvariousdegreesofcortisol Several individualsfromBMAHfamiliesdescribed agermline mutation.relatives ofindividualswhocarry should beofferedandthenavailabletofirst-degree for specializedgeneticcounseling.Genetictesting should include a detailed family history, and a reference syndromes.Evaluationof BMAHpatientsof hereditary be awarethatpatientsmaydevelopBMAHinthecontext dominant modeoftransmission;thus,cliniciansshould 76 (FH) BMAH suchasinthemenin( a likelypathogenic patients includedintheirstudy, onlyonepatientcarried discovered bilateraladrenalnodules( mutations playaroleinthedevelopmentofincidentally Very recently, Emms genotype–phenotype correlationswereidentified( genetic alterations described in BMAH, no clear ARMC5 Although possibility ofanewmultipleneoplasiasyndrome( of othertumorssuchasmeningiomassuggestingthe association betweenthesemutationsandthepresence has beendescribed( mutations and the expression of aberrant receptors ( for the formation of different macronodules necessary diffuse hyperplasia and additional somatic mutations are ( mutations iscloserto25%basedonlargerrecentstudies with Cushing’s syndrome( the firstseriesof33apparentlysporadiccasesBMAH containing 5( Inactivating germlinemutationsofArmadillorepeat BMAH and this group( nevertheless, thediagnosisofBMAHwasnotexcludedin 68 34 Review , , , 77 In allcases,thesegenemutationshaveanautosomal Other geneticalterationscouldbeassociatedwith and adenomatosis polyposis coli 69 70 ). , 70 ). Thepossibleassociationbetween ). Thegermlinemutationisresponsibleforthe ARMC5 67 ). ARMC5 ARMC5 mutationsare the mostcommon 69 ARMC5 et al. , ) genewereidentifiedin55%of 68 71 genemutations 71 , ). Inthesecases,surgicaland/ investigatedwhether mutation( ). 70 68 , MEN1) ). Theprevalenceofthese 71 I Bourdeauandothers , 72 , fumaratehydratase (APC) 74 74 ) aswellthe ) Amongthe39 ). genes ( ARMC5 ARMC5 33 , 72 73 75 ). ). ) ,

the treatmentofchoice. with mineralocorticoidsreceptors antagonistsremains confirmed byadrenalvenous sampling,medicaltreatment patient preference( importantly general condition and comorbidities and very based onageofthepatients,degreecortisolexcess, adrenalectomy ofthedominantlesionmaybeconsidered Society suggestedthatinselectedpatients,aunilateral volume ( to improvethedeterminationofremnantgland volumetric measurementbeforepartialadrenalectomy a patientwithBMAHusing3Dadrenalglandprintingand and contralateral partial adrenalectomy was performed in hormonal replacement,concomitanttotaladrenalectomy improved themetaboliccomplications( adenoma reducedcortisolexcessinasignificantwayand AI and mild cortisolsecretion, resection of the largest cases inaFrenchseries( detect adrenalinsufficiencythatwaspresentin40%of poorly defined). Post-operative follow-upisessential to (selectivity criteriausingfreemetanephrinesremain others relyontheresultsofadrenalvenoussampling (yet limitedavailabilitydependingoncenters),whereas or theonewithhighestuptakeofiodo-cholesterol some choosetoremovetheadrenalwithlargestsize The choice of which adrenal to remove remains uncertain: size ( (ULN) with both adrenals having relatively symmetrical levels arehigherthan3–4timestheupperlimitofnormal cortisol adrenalectomy maybeconsideredifurinary of patientswithmildcortisolsecretion.Bilateral to dexamethasonetendsinfluenceourmanagement of patients with abnormal cortisol suppression survival controversial ( secretion, theindicationforadrenalectomyremains clear consensus on the criteria defining abnormal cortisol of thetumorsisnotacriterionforsurgery. Asthereisno management isquitedifferentinBMAHbecausethesize or catecholamines)( with clearovert hormonal secretion (cortisol, aldosterone aswellfortumors certain lesionslargerthan4–6 cm, AI withsuspiciousmalignantlesionsonimaging,orfor Unilateral adrenalectomyisrecommendedforunilateral Management ofbilateralAI reaching 97%witharecurrencerateof23%( combined datashowaremissionrateofhypercortisolism and modestcortisolsecretion( adrenalectomy insmallseriesofpatientswithBMAH Bilateral adrenalincidentalomas For AIwithbilateralsecretion ofaldosterone 28 ). Manygroupsreportedthebenefitsofunilateral 82 ). Very recently, theexpertsfromEuropean 14 ); however, recentdataondecreased 14 ). 1 Downloaded fromBioscientifica.com at09/29/202106:39:32PM , 80 10 ). In14patientswithbilateral , 12 < 2–3 timesULN):their , 179 53 ). However, the www.eje-online.org :2 81 ). To avoid 78 , 79 R63 , 80 via freeaccess ). European Journal of Endocrinology www.eje-online.org without clinicalCushing'ssigns ( with hypertensionand/or biologicalhypercortisolism overninght 1-mgdexamethasone test.Thiswasassociated incomplete suppression ofcortisol and ACTHafter particularly ifbilateralcharacterized byelevatedUFC, mutations) inpatientswithadrenalincidentalomas, glucocorticoid resistance (heterozygous NR3C1 A recentstudyrevealedanincidenceof5%mild Note addedinproof with BMAH. hypercortisolism after unilateral adrenalectomy in cases the evolutionofbilateralAIandriskrecurrence of Long-term prospective studies are neededtodetermine diagnosis andallowearliertherapyofaffectedindividuals. biochemical andradiologicalinvestigationsrequiredfor improve itsearlymoleculardiagnosisandabolishthe counseling. BetterknowledgeofBMAHgeneticswill pheochromocytomas orCAHshouldbeofferedgenetic Patients withbilateraldiseaseinthecontextofBMAH, cortisol excess, bilateral pheochromocytomas and CAH. a predominanceofmetastases,BMAHwithmild of etiologies is quite different from unilateral AI with of malignancyandlevelsecretion.Thedistribution case, taking into consideration many factors such asrisk diagnostic andtherapeuticapproachesadaptedtoeach pathology thatrequiresconductionofthorough therapeutic strategiesarelacking. AI andstudiesevaluatingcost/benefitofdiagnostic Cushing’s syndrome,( of consensusforthedefinitionmildcortisolexcess management ofbilateralAIremainscarce, ( ( management ofbilateraladrenalincidentalomas: Overall, physiciansfacemanyuncertaintiesforthe Conclusion appropriately. Infection-causing adrenalenlargementshouldbetreated low( where theriskofmalignanttumorsisvery the setting of genetic syndromes such as VHL and MEN2A tumor resectionsparingtheadrenalcortexparticularlyin replacement haveledcertaingroupstoperformpartial insufficiency andthesideeffectsofglucocorticoids pheochromocytomas; however, theriskofadrenal 1 ) studiesemittingguidelinesforthework-upand Review Nonetheless, bilateral AI represents a frequent Bilateral adrenalectomyissuggestedforbilateral 3 ) data on natural history ofbilateral ) dataonnaturalhistory I Bourdeauandothers 84 ) 2 ) absence 83 ). References (FRQS) toIB. This workwassupportedinpartbyFondsdeRechercheduQuébec-Santé Funding perceived asprejudicingtheimpartialityofthisreview. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest

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77 76 75 74 73 72 71 70 Review De Venanzi A, Alencar GA,Bourdeau I,Fragoso MC&Lacroix A. Fragoso MC, Alencar GA,Lerario AM,Bourdeau I,Almeida MQ, Mazzuco TL, Durand J,Chapman A,Crespigio J&Bourdeau I. Emms H, Tsirou I, Cranston T, Tsagarakis S &Grossman AB.Do Elbelt U, Trovato A, Kloth M,Gentz E,Finke R,Spranger J,Galas D, Albiger NM, Regazzo D,Rubin B,Ferrara AM,Rizzati S,Taschin E, Bourdeau I, Oble S,Magne F, Levesque I,Caceres-Gorriti KY, Correa R, Zilbermint M,Berthon A,Espiard S,Batsis M, Primary bilateralmacronodularadrenalhyperplasia. Primary (https://doi.org/10.1530/JOE-14-0568) adrenal hyperplasia. macronodular Mendonca BB &Lacroix A.Geneticsofprimary 2265.2012.04403.x) Endocrinology Genetic aspectsofadrenocorticaltumoursandhyperplasias. s12020-016-0988-4) hyperplasia? represent anearlyformofARMC5-mediatedbilateralmacronodular patients withincidentallydiscoveredbilateraladrenalnodules jc.2014-2648) and Metabolism adrenal hyperplasiaandmeningioma. macronodular somatic mutationsareassociatedwithbothprimary an ARMC5tumorsyndrome:concurrentinactivatinggermlineand Weber S, Wolf C, Konig K (https://doi.org/10.1007/s12020-016-0956-z) characterization toclinicalphenotype. bilateralmacronodularadrenalhyperplasia:fromgenetic primary experience ontheprevalenceofARMC5mutationsinpatientswith Ceccato F, Arnaldi G,PecoriGiraldi F, Stigliano A 85–96. adrenal hyperplasia. beta-adrenergic/vasopressin responsivebilateralmacronodular mutations inalargeFrench–Canadianfamilywithcortisol-secreting Nolet S, Awadalla P, Tremblay J, Hamet P, Fragoso MC 0205) Endocrinology macronodular adrenocorticalhyperplasia. The ARMC5geneshowsextensivegeneticvarianceinprimary Papadakis GZ, Xekouki P, Lodish MB,Bertherat J,Faucz FR (https://doi.org/10.1530/EJE-15-0642) 2012 2015 Endocrine 2015 77 173 Journal ofEndocrinology Journal ofEndocrinology European Journal 100 1–10. 2016 435–440. E119–E128. et al 53 (https://doi.org/10.1111/j.1365- . Molecularandclinicalevidencefor 801–808. (https://doi.org/10.1530/EJE-15- I Bourdeauandothers (https://doi.org/10.1210/ Journal ofClinicalEndocrinology Journal Endocrine (https://doi.org/10.1007/ European Journal of European Journal 2015 2017 et al 224 Current Opinion 2016 . Amulticenter R31–R43. et al 55 959–968. . ARMC5 et al 174 Clinical .

Accepted 10May2018 Received 19April2018

83. Castinetti F, Taieb D, Henry JF, Walz M, Guerin C,Brue T, Conte- Bilateral adrenalincidentalomas 82 81 80 79 78 84 Srougi V, Rocha BA,Tanno FY, Almeida MQ, Baroni RH, Perogamvros I, Vassiliadi DA, Karapanou O,Botoula E,Tzanela M Debillon E, Velayoudom-Cephise FL, Salenave S,Caron P, Xu Y, Rui W, Qi Y, Zhang C,Zhao J,Wang X, Wu Y, Zhu Q,Shen Z, Albiger NM, Ceccato F, Zilio M,Barbot M,Occhi G,Rizzati S, Vitellius G,Trabado S,HoeffelC,BouligandJ,BennetA, 4417–4424. Mendonca BB, Srougi M,Fragoso MC&Chambo JL.Theuseof 2015 bilateral adrenalincidentalomas. adrenalectomy inpatientswithsubclinicalhypercortisolism and & Tsagarakis S. Biochemicalandclinicalbenefitsofunilateral hyperplasia. bilateralmacronodularadrenal syndrome inpatientswithprimary et al Chaffanjon P, Wagner T, Massoutier M,Lambert B,Benoit M,Young J 2059-9) Surgery independent bilateraladrenocorticalhyperplasias. Ning G org/10.1111/cen.12763) experience. due tobilateralmacronodularadrenalhyperplasia:asingle-centre different therapeuticoptionsinpatientswithCushing’s syndrome Fassina A, Mantero F, Boscaro M,Iacobone M org/10.1097/MED.0000000000000061) in Endocrinology, DiabetesandObesity Endocrinology hyperplasia: resultsoftheFrenchMUTA-GR Study. of NR3C1mutationsinincidentallydiscoveredbilateraladrenal B, andinvestigatorsoftheMUTA-GR Study. Significantprevalence Castinetti F, DecoudierB,Guiochon-MantelA,LombesM,Delemer R9–R18. pheochromocytoma. inheritable DISEASE: outcomeofadrenalsparingsurgery Devolx B, Neumann HP&Sebag F. MANAGEMENTOFENDOCRINE urology.2015.11.043) resection limits. three-dimensional printersforpartialadrenalectomy:estimatingthe . Unilateraladrenalectomyasafirst-linetreatmentofCushing’s 173 2013 et al 719–725. . Theroleofunilateraladrenalectomyincorticotropin- Clinical Endocrinology (https://doi.org/10.1210/jc.2015-2662) 2018 Journal ofClinicalEndocrinologyand Metabolism Journal 37 1626–1632. Urology

178 (https://doi.org/10.1530/EJE-15-0566) European Journal ofEndocrinology European Journal 411–423. 2016 Downloaded fromBioscientifica.com at09/29/202106:39:32PM (https://doi.org/10.1007/s00268-013- 90 217–220. (https://doi.org/10.1530/EJE-17-1071) 2015 European Journal ofEndocrinology European Journal 2014 82 808–815. 21 (https://doi.org/10.1016/j. 179 177–184. et al www.eje-online.org :2 European Journal of of European Journal . Ananalysisof World of Journal (https://doi. 2016 (https://doi. 2015 174 R67

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