Giant angiomyolipoma in a tuberous sclerosis patient and review of the literature

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African

Journal

of

Urology

Official

journal

of

the

Pan

African

Urological

Surgeon’s

Association

web

page

of

the

journal

www.ees.elsevier.com/afju www.sciencedirect.com

Uro-oncology

Case

report

Giant

angiomyolipoma

in

a

tuberous

sclerosis

patient

and

review

of

the

literature

J.T.M.

Mensink

a,∗

,

M. Locketz

b

,

J. Lazarus

a

a_Department_of_Urology,_Main_Rd,_Observatory,_Cape_Town,_7925,_South_Africa

b_Department_of_Anatomical_pathology,_Main_Rd,_Observatory,_Cape_Town,_7925,_South_Africa

Received26January2018;receivedinrevisedform11May2018;accepted3June2018;Availableonline11August2018

KEYWORDS Renalangiomyolipoma; Giantrenal angiomyolipoma; Tuberoussclerosis complex; Nephrectomy; Mammaliantargetof rapamycin Abstract

Introduction: About20%ofrenalangiomyolipomas(RAML)areassociatedwithtuberoussclerosis com-plex(TS).About34–80%ofpatientswithTSpresentwithRAML.RAMLsassociatedwithTSareathigher riskofpotentiallylife-threateninghemorrhageandhypovolemicshock.Onlyafewcasereportsofgiant RAML,definedaslargerthan10cmindiameter,anditsmanagement,havebeenreported.

Observation:Wepresenta21yearoldwomanwithabdominaldistensionoverthelast2years.A contrast-enhancedCTscanrevealedagiantRAMLontheleftside.Basedonthepresenceofatleast3majorfeaturesof theclinicaldiagnosticcriteriaoftuberoussclerosiscomplex,thediagnosiswasmade.Anopennephrectomy wasperformed.Therapeuticoptionsdescribedinliteratureareconservativemanagement,medicaltreatment withmTORinhibitors,arterialembolization,radioablationandpartialortotalnephrectomy.

Conclusion:IngiantTS-associatedRAMLtotalnephrectomy,ratherthanconservativetreatment,isthe treatmentofchoiceinordertoreducetheriskofpotentiallylife-threateningbleeding.

Introduction

Renalangiomyolipomas(RAML)arerare,benigntumors consist-ingofvascularelements,smoothmuscleandadiposetissue.About

∗_{Corresponding}_author._Present_address:_Erasmus_Medical_Center

Rotter-dam.DoctorMolewaterplein403015GD,Rotterdam,TheNetherlands. E-mailaddress:j.t.m.mensink@umcutrecht.nl(J.T.M.Mensink).

PeerreviewunderresponsibilityofPanAfricanUrologicalSurgeons’ Association.

20%of themoccurin patientswith thetuberous sclerosis com-plex(TSC)[1–3].Inthepresenceofbilaterallesions,oneshould considera diagnosis of this neurocutaneous condition that also causesbenigntumorsinthebrain,heart,eyes,lungandskin[1]. SmallerRAMLsareoftenincidentallyfoundonradiological exam-ination,whereas RAMLs larger than 4cm are at higher risk of bleeding[1,3].RAMLassociatedwithTSaremorelikelytolead to potentiallylife-threatening retroperitoneal hemorrhage due to theirsize,andmultifocalandbilateralnature[1–3].Embolization, partialortotalnephrectomyas treatmentoflargerRAMLshave

https://doi.org/10.1016/j.afju.2018.06.003

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Figure1 A.Facialangiofibromas.B.Hypomelanoticmaculeontheleftchest>5mm.

beendescribed[3]. OnlyafewcasereportsaboutgiantRAML, whichisdefinedaslargerthan10cmindiameter,andits manage-ment,havebeenpublished[4].WepresentacaseofgiantRAML inayoungwomanwhopresentedwithleftabdominalpainandin whomthediagnosisoftuberoussclerosiswasmade.

Casepresentation

A21yearoldwoman wasreferredtothe urologydepartmentof GrooteSchuurHospitalinCapeTown(SouthAfrica)inNovember 2017because of weightloss and progressive abdominal disten-sionoverthelasttwoyears.Norelevantmedicalorfamilyhistory wasreported.Anultrasoundofthekidneyswhichwasdoneatthe referringhospitalreportedabigsolidmassontheleftsideofthe abdomen.

Skininspectionshowedmultiple(>10)facialangiofibromasand4 hypopigmentedmaculesonthechest,lowerbackandrightbuttock (Fig.1).Multipleskinlesionswitha‘confetti’appearancewereseen onbotharmsandlegs.Nootherdermatologicordentalfeatures ofTSwere seen.Inspection ofthe abdomenshowedabdominal distensionontheleftside.Alargenon-tendermasswaspalpatedin theleftupperquadrantextendingbeyondthemidline.

Laboratoryresultsshowedanemia(Hbof9,4g/dl)andmicroscopic hematuria.AcontrastenhancedCT-scanoftheabdomenrevealeda heterogeneousleftrenalmasswithareasofsofttissueandfat compo-nents(Hounsfieldunitsof−68,97),measuring123,0×159,4mm (Fig.2).Therightkidneyshowedmultiplecorticalhypodensities withthelargestmeasuring11mm.Bothlesionswerereportedas suspiciousforangiomyolipoma(AML).

Blood transfusion with 2 units of packed cells was given.

A left radical nephrectomy was performed through a chevron incision under general anesthesia. A mass with a diameter of 290mm×215mm×120mmandaweightof3,58kgwasremoved (Fig.3).Theprocedurewascomplicatedintraoperativelyby pan-creatictailinjuryrequiringdistalpancreatectomy.Shedevelopeda pancreaticleakwhichrequiredastayintheIntensiveCareUnit.The leakresolvedspontaneously.Thepatientwasdischarged3weeks aftersurgery.

Figure2 Axialimagefromacontrastenhancedcomputed tomog-raphy(CT)shows aprimarily fat containingmassarisingfromthe leftkidneysuggestiveofagiantangiomyolipoma(Hounsfieldunitsof −68,97).

Figure3 Excisedtumorof3,58kg,showingamixtureofmature adiposetissueandthickwalledbloodvessels.

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Figure4 A.Histopathologicalexaminationdemonstratedsmoothmuscle,matureadiposetissueandthickwalledbloodvessels(hematoxylinand eosinstain,magnification×40).B.Epithelioidsmoothmusclecellsemanatingfrombloodvesselwalls(haematoxylinandeosinstain,magnification ×200).

Figure5 AxialMagneticresonanceimaging(MRI)(T2weighted)ofthebrain,demonstratingwhitematterhyperintensitiesandrightventricular smallsubependymalnodule(indicatedbywhitearrowsandblackarrows,respectively).

Histopathologyof the mass confirmedanangiomyolipoma con-sistingofacombinationofspindledsmoothmusclecells,mature adiposetissueandthickwalledbloodvessels.Smoothmusclecells whichemanatedfromthewallsofthebloodvesselsfrequentlyhad anepithelioidmorphology(Fig.4).Afewofthemanylymphnodes submittedcontainedacombinationofbothsmoothmuscleand adi-posetissuecomponentsofangiomyolipoma.Immunohistochemical stainingwasnotrequired.

FurtherinvestigationwithMRIbrainshowedmultiplecorticaland subcorticalT2weightedwhitematterhyperintensitiesandmultiple predominantlyrightventricularsmallsubependymalnodules.No subependymalgiantcellastrocytomawasseen(Fig.5).Expectative managementwasperformedsinceneurologicalinvestigationwas negativeformentalretardationorepilepsy.

Ophthalmologicconsultrevealednolesionsindicativeofaretinal hamartoma.Electrocardiogramdidnotshowanycardiac arrhyth-mias therefore, echocardiography was not performed. Genetic screeningunfortunatelycouldnotbedoneduetonon-availability oftheservice.

Accordingtotherecommendationsofthe2012International Tuber-ousSclerosisComplex Consensus(ITSCC) our patientmeets 4

majorcriteriatoconfirmthediagnosisofTSC:>2 angiomyolipo-mas,>3facialangiofibromas,4hypopigmentedmacules(>5mm diameter)andsubependymalnodulesinthebrain[5](Table1).

Discussion

TSisanautosomaldominantdisease,mostoftencausedbya muta-tionoftheTSC1orTSC2gene,withincompletepenetrance,which affectsmultipleorgansystems.Prevalenceintheliteraturevaries from 1/6000 to 1/12000 individuals [1,6–8]. About 34–80% of patientswithTSpresentwithrenalangiomyolipoma(RAML)and about20–30%ofRAMLcasesareassociatedwithTS[9].RAML associatedwithTStypicallymanifestatayoungerage,are bilat-eralandmultifocal,growwithtime,and aremorelikelyto lead topotentiallylifethreateninghemorrhage[10].GiantRAMLsare definedaslargerthan10cmindiameter[4].Verylittleliterature iswrittenaboutgiantRAMLs.Ourpatientpresentedwith abdom-inaldistensionfor2years,andpainintheabdomenandbackfor 3months,withoutsignsofhypovolemicshock.Shedidnothave anyurinarysymptoms.PatientswithTS-associatedgiantRAMLs asreportedbyLinetal.,Katzetal.andTsutsumietal.presented withcyclicleftflankpain,generalfatigue,andepigastricfullness

[2,11,12].About10%ofpatientswithRAMLpresentwithacute flankpain,haematuria,andsignsofinternalbleedingwhichis

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char-Table1 ClinicaldiagnosticcriteriaofTSC.

Tuberoussclerosiscomplexdiagnosticcriteriaupdate: recommendationsofthe2012InternationalTuberousSclerosis ComplexConsensusConference

Majorfeatures

1.Hypomelanoticmacules(≥3,atleast5-mmdiameter) 2.Angiofibromas(≥3)orfibrouscephalicplaque 3.Ungualfibromas(≥2)

4.Shagreenpatch

5.Multipleretinalhamartomas 6.Corticaldysplasias* 7.Subependymalnodules

8.Subependymalgiantcellastrocytoma 9.Cardiacrhabdomyoma

10.Lymphangioleiomyomatosis(LAM)† 11.Angiomyolipomas(≥2)†

Minorfeatures 1.“Confetti”skinlesions 2.Dentalenamelpits(>3) 3.Intraoralfibromas(≥2) 4.Retinalachromicpatch 5.Multiplerenalcysts 6.Nonrenalhamartomas

Definitediagnosis:Twomajorfeaturesoronemajorfeaturewith≥2 minorfeatures

acteristicof ‘WünderlichSyndrome’;aurologicalemergencyof retroperitonealhemorrhagewhichmanifestsashypovolemicshock. Thepresenceofintratumoralaneurysms>5mmintumors>4cmhas alsobeenreportedasariskfactorforspontaneousretroperitoneal hemorrhage[13].

TreatmentoptionsforRAMLdescribedin the literatureinclude activesurveillance with reimaging, partial/total/radical

nephrec-tomy, radiofrequency- or cryoablation and selective mTOR

inhibitorssuchaseverolimus.

Ingeneral,indicationsforinterventionforrenalAMLarethe pres-enceofsymptoms,highriskofbleedingandsize(>4cm),evenwhen asymptomatic[14].However,theindicationoftumorsizehasbeen questionedrecently.Kuusketal.showedthatonlytumors>6cmare atahigherriskforbleedingwhileChronopoulosetal.showedthat eventumors<8cmtendtobeasymptomatic[4,15].

Active surveillance seems to be appropriate for tumors smaller than4cmonly[16,17].Onthecontrary,Ouzaidetal.statedthat activesurveillancecanalsobeanoptionin tumors>4cm.They suggestthatthehistoricallyquotedthresholdof4cmmayleadto overtreatment[18].

However,itmustbenoticedthattheabovestudiesincludedboth spo-radicandTSassociatedRAML.Hence,largerlesionsareathigher riskofbleeding,butthereisnoconsensusonwhatsizeshouldbe usedasthecutoffforintervention.Inthiscase,treatment indica-tionwasclear,sincethepatienthadasymptomaticgiantRAML (290mm×215mm×120mm).Surgicaltreatmentseemstobethe treatmentofchoice inlargerRAML,ifrenalmalignancyis sus-pectedorincasesofhemorrhage[19].SinceRAMLinTSisoften bilateralandmultifocal,andisknowntohaveahigherrecurrence rate,nephronsparingsurgery(NSS)ishighlyrecommendedeither byselectiveembolizationorpartialnephrectomy[15,16,20].

Selec-tivearterialembolization(SAE)isnowafirst-linetreatmentoption inRAMLandparticularlyusedincasesofacutehemorrhageand hemodynamicshock[20].Comparedtosurgicaltreatment,themost importantadvantageissparingoftherenalparenchymaandthe min-imallyinvasivenatureoftheprocedure.However,recurrencerates afterSAEinTSassociatedRAMLvaryfrom11to40%,hence con-tinuousfollow-upisrequired[21].Moreover,inthiscaseselective embolizationwastechnicallyimpossiblesincetheAMLsubstituted themajorityoftheparenchymaoftheleftkidney.Thesametechnical impossibilityappliesforapartialnephrectomy.

ThemostrecentlyintroducedtreatmentoptioninRAMListargeted therapywhichinhibitsthemammaliantargetofrapamycin(mTOR). Theaimofthetreatmentistoreducetumorprogressionandpromote regressionofexistingtumor.AccordingtorecentliteraturemTOR inhibitors are effective and safe in regulating asymptomatic TS associatedRAML>3cmnotamendabletoothertreatment. Addi-tionally,renalparenchymawillbespared inthis treatment[22]. However, Cabrera-Lopezetal.suggest that theeffect of mTOR inhibitorsisunlikelytobedurable[23].Moreover,everolimusfor exampleisassociatedwithstomatitis(48%),nasopharyngitis(24%), acne-likeskin lesions(22%),headache(22%),cough(20%)and hypercholesterolemia(20%).Long-termconsequencesof mTOR toxicityremainunknown[22].Sinceourpatienthadasymptomatic TSassociatedRAML>3cm,treatmentwithmTORinhibitorswas notappropriateinthiscase.However,thispatienthadasymptomatic smallerlesions(biggestlesionwas11mm)intheotherkidneyas well.AtthisstagetreatmentwithmTORinhibitorsfortheright kid-neyisprematuresincethelesionsare<3cm.mTORinhibitorscan beconsideredwhenlesionsare>3cm.Wewillseethepatientat ouroutpatientclinicin6monthsforfollow-up,withaCTscanin advance.

SpecificresearchontreatmentoptionsforgiantRAMLhasnotbeen reportedsofar.OwingtothesizeofthetumoringiantTS-associated RAMLweassumemTORinhibitorsmightpotentiallyplayarole intheirmanagement,alongsidesurgicaltreatment.

Conclusion

The present case report highlights two important aspects for clinicians. First, in giant TS-associated RAML, partial or total nephrectomy,ratherthanconservativetreatment,isthetreatment ofchoiceinordertoreducetheriskofapotentiallylife-threatening bleed.However,inthiscasereportwewouldliketoemphasizethe technicalchallengeofnephronsparingtreatmentingiantRAML. Second, futureresearch isneeded to furtherexplore the role of mTORinhibitorsinthetreatmentofgiantRAML.

Conflictofinterest

Wehavenoconflictofinteresttodeclare.

Authors’contributions

JolienMensink:clinicalexaminationofpatient,collectionofdata, literaturereview,writingofintroduction,casepresentation, discus-sionandconclusion.

MichaelLocketz:selectionofhistopathologyimages,commenton images,reviewofgrammarandspellingofcasereport.

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JohnLazarus:headofdepartment,coordinatorandmainreviewer ofcasereport.

Consentfromthepatient

Awrittenconsentfromthepatientwasobtained.

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