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OfficialreprintfromUpToDate
www.uptodate.com2015UpToDate

Sexcordstromaltumorsoftheovary:Granulosastromalcelltumors
Author
DavidMGershenson,MD

SectionEditors
BarbaraGoff,MD
RochelleLGarcia,MD

DeputyEditor
SandyJFalk,MD,FACOG

Disclosures:DavidMGershenson,MDGrant/Research/ClinicalTrialSupport:NCI(ovariancancer).Employment:The
UniversityofTexasMDAndersonCancerCenter.EquityOwnerShip/StockOptions:Johnson&JohnsonProcter&Gamble.
BarbaraGoff,MDNothingtodisclose.RochelleLGarcia,MDNothingtodisclose.SandyJFalk,MD,FACOGEmployeeof
UpToDate,Inc.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvetting
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
throughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.
Literaturereviewcurrentthrough:Jan2015.|Thistopiclastupdated:Oct03,2014.
AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

INTRODUCTIONOvariansexcordstromaltumorsareaheterogeneousgroupofbenignormalignant
tumorsthatdevelopfromthedividingcellpopulationthatwouldnormallyproducecellsthatsupportand
surroundtheoocytes,includingthecellsthatproduceovarianhormones(thenongermcellandnonepithelial
componentsofthegonads)(figure1)[1].Ovariansexcordstromaltumorsarerare,comprisingonly1.2percent
ofallprimaryovariancancers[2].
Incontrastwithepithelialovariancancer,mostpatientswithmalignantsexcordstromaltumorsarediagnosed
withearlystagediseasethetumorsaregenerallyconsideredtobelowgrademalignancies.
Sexcordstromaltumorsincludegranulosacelltumors(whichdifferentiatetowardfemalecharacteristics),
fibromathecomas,andSertoliLeydigcelltumors(whichdifferentiatetowardmalecharacteristics).Granulosa
stromalcelltumorsincludegranulosacelltumors,thecomas,andfibromas[3].Theyaccountfor70percentof
ovariansexcordstromaltumors.Amonggranulosastromalcelltumors,fibromasarethemostcommon
histology.Thesetumorsoccurwithequalfrequencyamongpreandpostmenopausalwomen.
Granulosacell,thecacell,andmixedtumorsareusuallyhormonallyactive,incontrasttofibromas,whichdo
notproducehormones.Granulosacelltumorsaremoreoftenmalignantthanthecomasorfibromas,whichare
mostoftenbenign.
Ovariansexcordstromaltumorsofthegranulosastromalcelltype(granulosacelltumors,fibromas,and
thecomas)arereviewedhere.Anoverviewofsexcordstromaltumorsandothertypesofsexcordstromal
tumorsoftheovary(SertolistromalcelltumorsandtumorswithgranulosaandSertoliLeydigelements),as
wellasepithelialovariancancer,arediscussedseparately.(See"Overviewofsexcordstromaltumorsofthe
ovary"and"Sexcordstromaltumorsoftheovary:Sertolistromalcelltumors"and"Sexcordstromaltumorsof
theovary:TumorswithgranulosaandSertoliLeydigelements"and"Epithelialcarcinomaoftheovary,fallopian
tube,andperitoneum:Histopathology"and"Epithelialcarcinomaoftheovary,fallopiantube,andperitoneum:
Clinicalfeaturesanddiagnosis".)
GRANULOSACELLTUMORGranulosacelltumorshavemalignantpotential(ie,theabilityto
metastasize).Theyarethemostcommontypeofpotentiallymalignantovariansexcordstromaltumorthey
comprise2to5percentofallovarianmalignancies[1].
Therearetwosubtypes,adultandjuvenile.Theadultsubtype,whichoccursmostcommonlyinmiddleaged
andolderwomen(medianage50to54years),comprises95percentoftheseneoplasms.
Thejuveniletypecomprises5percentofallgranulosacelltumors[4].Theytypicallydevelopbeforepuberty,
andthus,aremorecommonamongchildrenandyoungwomen.Thissubtypetendstohaveahigher
proliferativeratethantheadulttypeandalowerriskforlaterecurrences.
Thediscussionbelowrelatesmainlytotheadultsubtype.
Granulosacelltumorsappeartobemorecommoninwomenwhoarenonwhite,obese(bodymassindex>30),
andhaveafamilyhistoryofbreastorovariancancer[5].Theriskappearstobedecreasedinwomenwhoare
currentorpastsmokersorusersoforalcontraceptivepills,andinthosewhoareparous.
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HistopathologyThegrossappearanceofgranulosacelltumorsisvariable.Theneoplasmsareusually
largeandunilateral,andcanbesoftorfirmdependingupontherelationshipsofstroma,particularlycollagento
neoplasticcells.Theyareoftenmulticysticandmayresembleamucinouscystadenomaorbefilledwith
serousfluidorclottedblood.Accumulationoflipidsresultsinyellowcolor.
Histologically,granulosacellsoftheadultsubtypeappearround,pale,withscantcytoplasm,andclassic
"coffeebean"groovednucleiatypiaandmitosesaretypicallynotfrequent,butdooccur(picture1).Thecells
mayarrangethemselvesinsmallclustersorrosettesaroundacentralcavity.Thesearrangements,whichare
termed"CallExnerbodies",resembleprimordialfolliclesand,whendiffuselypresent,constitutea
microfollicularpattern[6].LackofCallexnerbodiesisnotinfrequent.
Incontrast,thejuvenilesubtypehasamacrofollicularorcysticpatternandiscomprisedofimmaturegranulosa
cellswithfrequentmitosesCallExnerbodiesandcoffeebeangroovednucleiarenotfrequent.
Whilethebetterdifferentiatedgranulosacelltumorsmayhavevariouspatterns,includingmicrofollicular,
macrofollicular,trabecular,solidtrabecular,andinsular,lesswelldifferentiatedtumorshaveamorediffuse
pattern,designatedassarcomatoid.Otherpatterntypesarediffuse,cylindroid,pseudoadenomatous,ormixed,
dependinguponthepredominanthistologicalelements.Thesevariouspatternsarenotparticularlyimportant,
butcanrenderrecognitionasgranulosacelltumordifficult.
Thecacells,whichareluteinizedcellswithinthestroma,arepresentinabout70percentofcases.Thecacells
produceandrostenedione,aweakandrogen,andgranulosacellsconverttheandrostenedionetoestradiol.
Significanthormoneproductionisresponsiblefortheclinicalphenotypeassociatedwiththeneoplasm.(See
'Clinicalfeatures'below.)
Thehistologicdiagnosisisfacilitatedbyimmunohistochemicalstaining(IHC)usingantibodiesagainstmarkers
ofsexcordstromaldifferentiation.Inhibinisthemostsensitiveandspecific[7,8].Calretininistypically
positive,butisnotspecificforsexcordstromaldifferentiation.Othermarkers,includingCD99,mllerian
inhibitingsubstance,vimentin,WT1,SF1,cytokeratin,S100protein,andsmoothmuscleactin,arenot
specificandarenotparticularlyhelpfulindistinguishingbetweengranulosacelltumoranditsmimics[911].
However,evenpositivityforinhibinisnotabsolutelyspecificforanovariansexcordtumor,assexcord
stromaldifferentiationcanbeseeninotherneoplasms.Asanexample,inonereport,positiveIHCforinhibin
waspresentin94percentofgranulosacelltumorsandin10to20percentofovarianendometrioidtumorsand
metastaticcarcinomastotheovary(althoughwithsignificantlyweakerstainingintensity)[10].
Inthefuture,moleculartestingformutationsintheFOXL2genemayimprovediagnosticaccuracyinpatients
withsexcordstromaltumors.Somaticmutationsinthisgene,whichplayaroleinthedevelopmentofnormal
granulosacells,havebeenidentifiedin97percentofadulttypegranulosacelltumors[12,13].Incontrast,the
mutationwasidentifiedinonly1of10juveniletypegranulosacelltumorsand3of14thecomas(21percent),
whileitwasabsentinsexcordstromaltumorsofothertypesandinotherovarianneoplasms.
ClinicalfeaturesGranulosacelltumorstypicallypresentaslargemassesthemeandiameteris12cm.
Womenmaypresentwithanasymptomaticmassnotedonabdominalorpelvicexamination.
Granulosacelltumorsoftenproduceestrogenand/orprogesteroneconsequently,symptomsrelatedto
hyperestrogenismarecommonatdiagnosis.Inareviewof118patientswithgranulosacelltumors,55percent
hadhyperestrogenicfindings,includinghyperplasticendometriumandabnormaluterinebleeding[14].Increased
productionofestrogenmayalsocausebreasttenderness,postmenopausalbleeding,menstrualabnormalities,
and,inchildren,sexualprecocity.(See"Definition,etiology,andevaluationofprecociouspuberty".)
Thereisawelldocumentedassociationbetweengranulosacelltumorsandendometrialneoplasms(complex
endometrialhyperplasiaandadenocarcinoma)[15].Forthisreason,asnotedinaprecedingsection,
preoperativeendometrialbiopsyissuggestedinallwomenwithabnormaluterinebleeding,allpostmenopausal
womenwithanadnexalmassandathickened(5mm)endometrialstripe,andintheoccasionalpatientwho
hasapreoperativediagnosisofovariangranulosacelltumor.Endometrialbiopsywilldetectendometrial
hyperplasia/intraepithelialneoplasiain25to50percentofwomenwithgranulosacelltumorsandcarcinomain
5to10percent[1618].Theendometrialadenocarcinomasthatareassociatedwithgranulosastromalcell
tumorsareusuallyearlystageandwelldifferentiated[14].
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Nonspecificsymptomsorsignsassociatedwiththeseneoplasmsincludeascites,increasingabdominalgirth,
abdominalpainduetotorsion,intraneoplasmalhemorrhage,ortumorruptureandhemoperitoneum.
DiagnosisDiagnosisofagranulosacelltumorismadebyhistologyatthetimeofsurgicalexcision.
Preoperatively,agranulosacelltumorshouldbesuspectedbaseduponthepresenceofalargeadnexalmass,
ifaccompaniedbythesignsofhyperestrogenismdescribedintheprecedingsection.Ultrasonographicfindings
(anechogenic,septatedcysticorsolidmassrelatedtotheovary)aretypicallynonspecific.Surgeryisrequired
forhistologicdiagnosisaswellasstaging(stagingisthebestdeterminationofpotentialmalignantbehavior)
andtreatment.
Thedifferentialdiagnosisofawomanwhopresentswithbothanadnexalmassandabnormalvaginalbleeding
shouldalsoincludeovarianmetastasisfromaprimaryuterinecancer,anendometrialmetastasisfroma
primaryovarianmalignantneoplasm,andseparateprimaryovarianandendometrialcarcinomas.
Thehormonalactivityofgranulosacelltumorspermitstheuseofavarietyofserumtumormarkersinthe
diagnosticevaluation(table1).Thesemarkersinclude[1821]:
InhibinClinically,themostusefulserummarkerforgranulosacelltumorsisinhibin,apeptidethatis
producedbytheovariesinresponsetofolliclestimulatinghormoneandluteinizinghormone.Inhibin
usuallybecomesundetectableaftermenopause,unlessproducedbycertainovariantumors,mostly
mucinousepithelialovariancarcinomasandgranulosacelltumors[2227].
Inhibinexistsastwodifferentisoforms,inhibinAandinhibinB.Bothisoformsconsistofadimeroftwo
subunits,thealphaandbetasubunits.Thealphasubunitisthesameforbothisoforms,whilethebeta
subunitsdiffer(betaAandbetaB)theyshowabout64percenthomology.Thethreesubunits(alpha,
betaA,betaB)areproducedonseparategeneslocatedonchromosomes2(alphaandbetaBsubunit)
and7(betaAsubunit).
Ingeneral,bothinhibinAandinhibinBshouldbeordered,ifpossible,whenfollowingpatientswith
granulosacelltumors.AlthoughmostcommerciallaboratoriesonlyprovideassaysforinhibinA,serum
levelsofinhibinBseemtobemorefrequentlyelevated[28].Thefreealphasubunitcanalsobemeasured
[29].
Thediagnosticperformanceofinhibinlevelsispoor.Anelevatedinhibinlevelinapremenopausalwoman
presentingwithamenorrheaandinfertilityorinapostmenopausalwomanissuggestiveofthepresenceof
agranulosacelltumor,butnotspecific.Conversely,bothinhibinAandBmaybenegativeinpatients
withactivegranulosacelltumors.
Estradiolwasoneofthefirstmarkersidentifiedintheserumofpatientswithgranulosacelltumors.In
general,however,estradiolisnotasensitivemarkerforthepresenceofagranulosacelltumor.
Approximately30percentoftheseneoplasmsdonotproduceestradiol,perhapsrelatedtothelackof
thecacells,whichproduceandrostenedione,anecessaryprecursorforestradiolsynthesis.
Mllerianinhibitingsubstance(MIS),whichisproducedbygranulosacellsinthedevelopingfollicles,has
emergedasapotentialtumormarkerforgranulosacelltumors.Aswithinhibin,MISistypically
undetectableinpostmenopausalwomen.AlthoughanelevatedMISlevelappearstobehighlyspecificfor
ovariangranulosacelltumors[3032],thistestisnotavailableforclinicaluse.
Management
SurgicalstagingandtreatmentGranulosacelltumorsarestagedsurgicallyaccordingtothe
InternationalFederationofGynecologyandObstetrics(FIGO)ovariancancerstagingsystem(table2).Atotal
abdominalhysterectomyandbilateralsalpingooophorectomyisrecommendedforwomenwhoaredonewith
childbearing.Assessmentofstageisthemostimportantfactorindeterminingprognosisandtoguide
postoperativetreatmentrecommendations[33].
Therarityoflymphnodemetastasisatinitialdiagnosissuggeststhatpelvicandparaaorticlymphadenectomy
maybeomittedaspartofsurgicalstagingfortheseneoplasms[34,35].However,thisisdependentupon
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whetheranintraoperativediagnosisofagranulosacelltumorcanbemade,sincethediagnosismaynothave
beenmadepreoperativelyandisdifficulttoconfirmduringsurgery.
Granulosacelltumorsaregenerallyconfinedtooneovary.ForwomenwithstageIdiseasewhowishto
preservefertilityoravoidexogenoushormonereplacement,aunilateralsalpingooophorectomyanduterine
preservationwithotherproceduresforcompletesurgicalstagingareappropriate(table3)[36].Retrospective
studiessuggestanequivalentcurerateforearlystagediseasewhethertreatedbyunilateralsalpingo
oophorectomyorbilateralsalpingooophorectomy[37,38].Thecontralateralovaryshouldbecarefullyinspected
biopsyisnecessaryonlyifanabnormalityisfound.
Duetotheriskofendometrialneoplasia,ifanendometrialbiopsywasnotperformedpreoperatively,adilation
andcurettageshouldbeperformedduringsurgery.
AdjuvanttherapySurgeryaloneisacceptabletreatmentformostwomenwithgranulosacelltumors,
sincethemajorityarestageIAandconfinedtooneovaryatthetimeofdiagnosis(table2)[37].Longterm
diseasefreesurvivalratesareapproximately90percent.
OutcomesarelessfavorableforwomenwithhigherstagediseaseandforthosewithstageIdiseasewhose
tumorhasruptured,hasnuclearatypia,orahighmitoticindex.Thereareconflictingreportsregardingthe
prognosticinfluenceofotherfactorssuchaspositivecytology,tumorsize,ovariansurfaceinvolvement,and
ploidystatus.Furtherstudiesareneededinthisarea.(See'Prognosisandfollowup'below.)
Althoughpostoperativeoradjuvanttherapyisoftenconsideredforsuchpatients,therarityoftheseneoplasms
makesitdifficulttoconductwelldesignedrandomizedstudiestodefinethevalueofanysuchstrategy.Asa
result,thebenefitofpostoperativetreatmentforwomenwithstageIBtoIVdiseaseisunclear,andpracticeis
variable.SomecentersrecommendadjuvanttherapyforallwomenwithstageICtoIVdisease,others
recommendadjuvanttherapyonlyforwomenwithresidualdiseaseaftersurgery,andstillothersdonot
recommendadjuvanttherapyforanystageofdisease,treatingonlyatthetimeofarecurrence.
Thefollowingrepresentstherangeoffindingsregardingthebenefitofadjuvanttherapyfromobservational
studies:
Forchildrenwithadvancedstagejuvenilegranulosacelltumors,adjuvantchemotherapyappearsto
contributetolonglastingcompleteremissionandisusuallyrecommendedforthosewithstageIC
diseaseandahighmitoticindex(20per10highpowerfields[HPF]),aswellasthosewithmore
advancedstagedisease[3945].However,itisdifficulttoextrapolatetheseresultstoadulttypetumors,
whichhaveadifferentbiology(ie,lowerproliferativerateandgreaterriskoflaterecurrences)thanthe
juveniletype.
Someretrospectiveseriesofadultswithgranulosacelltumorsuggestthatwomenwithadvanced(stage
III/IV)diseasewhoreceivepostoperativechemotherapyhavealongerprogressionfreeintervalthanthose
whodonot[46].However,othershavefailedtoshowthattheuseofchemotherapyisassociatedwith
bettersurvival[18,47,48].
Nevertheless,despitetheabsenceofdatasupportingasurvivalbenefit,someexpertsrecommend
postoperativechemotherapyforwomenwithresectedstageICtoIVdiseasebecauseofthehighriskof
diseaseprogression(table4)andthepotentialforlongtermsurvivalinwomenwithadvanceddiseasewho
receivemodernplatinumbasedchemotherapy[17,39,4953].(See'Metastaticorrecurrentdisease'below.)
Somereservethisrecommendationforwomenovertheageof40atdiagnosis,who,inoneearlyseries,hada
higherriskofdiseaserecurrencescomparedtoyoungerwomen[54].However,otherreportshavefailedto
confirmtheadverseimpactofolderageonoutcomes[14,5560].
GuidelinesfromtheNationalComprehensiveCancerNetwork(NCCN)recommendplatinumbased
chemotherapy(orradiationtherapy[RT]forlimiteddisease,seebelow)inwomenwithstageIItoIVovarian
stromaltumorsandthattheseoptionsbe"considered"inwomenwithhighriskstageIdisease(ie,ruptured
stageICtumors)[36].
Themostcommonlyusedregimenisacombinationofbleomycin,etoposide,andcisplatin(BEP)(table4)asis
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usedfortesticularandovariangermcelltumors[17].(See"Initialriskstratifiedtreatmentforadvanced
testiculargermcelltumors"and"Treatmentofmalignantgermcelltumorsoftheovary".)
Alternativechemotherapyoptionsincludeetoposidepluscisplatin(EP)cyclophosphamide,doxorubicinand
cisplatin(CAP)paclitaxelandcarboplatinoraplatinumagentalone.TheGynecologicOncologyGroupis
currentlyconductingarandomizedphaseIItrialofBEPversusthecombinationofpaclitaxelandcarboplatinfor
patientswithnewlydiagnosedandchemonaiverecurrentmetastaticsexcordstromaltumorsoftheovary.
Aswithchemotherapy,therearenoprospectiverandomizedtrialsthatdefinethevalueofpostoperativeRT.
GranulosacelltumorsareradioresponsiveinthatRTcaninduceclinicalresponsesandoccasionallongterm
remissioninpatientswithpersistentorrecurrentgranulosacelltumors.(See'Metastaticorrecurrentdisease'
below.)
Intheadjuvantsetting,anolderretrospectiveseriesisoftenquotedassupportingbenefitfromradiotherapy
[56].However,insufficientdatawereprovidedtodeterminewhetherthedifferencesinoutcomebetween
irradiatedandnonirradiatedwomenwereattributabletotherapy.Severallaterobservationalseriesfailtoshow
anybenefitfromadjuvantradiation[14,51,55,57,61].
Insummary,beyondprimarysurgery,thereisnostandardforpostoperativetherapy.ForpatientswithstageIA
granulosacelltumor,surgeryaloneisthepreferredtreatment.ForwomenwithstageICtoIVdisease,some
groupsdonotrecommendpostoperativetherapy,whileothersrecommendplatinumbasedchemotherapy,most
frequentlyBEP[16,62].Asnotedabove,NCCNguidelinesrecommendplatinumbasedchemotherapy(orRT
forlimiteddisease,seebelow)inwomenwithstageIItoIVovarianstromaltumorsandthattheseoptionsbe
"considered"inwomenwithhighriskstageIdisease(ie,rupturedstageICtumors)[36].
MetastaticorrecurrentdiseaseAcommonsiteofrecurrenceisthepelvis,althoughtheretroperitoneum
andupperabdomenmaybeinvolved,aswell[35].
Thereisnostandardapproachtothemanagementofadvancedunresectableorrelapseddisease.Complete
resectionmayprovidelongtermdiseasecontroliftheneoplasmislocalized[60],butdiffuseintraabdominal
diseaseisdifficulttotreateffectively.
RTcaninduceclinicalresponsesandoccasionallongtermremissioninwomenwithpersistentorrecurrent
granulosacelltumors,particularlyifthediseaseissurgicallycytoreduced[17,51,63].Inonereviewof34
patientstreatedatasinglecenterovera40yearperiodwithradiationalone,3ofthe14whoweretreatedfor
measurablediseasewerealivewithoutprogression10to21yearsfollowingtreatment[63].
Forpatientswithmetastaticorsuboptimallycytoreduceddisease,chemotherapyregimenssimilartothose
usedforgermcelltumors(eg,bleomycinetoposidecisplatinor(table4))areactive,producingoverallresponse
ratesof58to84percent(table4)[50,52,64].Inonestudy,14of38patients(37percent)undergoingsecond
looklaparotomyfollowingfourcoursesofBEPhadnegativefindings[50].Themediansurvivalofpatientswho
hadacompleteclinicalresponse(n=6)wasovertwoyears.
Unfortunately,themajorityofpatientswithadvanceddiseasedonothavedurableremissions[50,64].Ina
combinedseriesofpatientstreatedwithBEPforsexcordstromaltumors,onlyoneofsevenwomenwith
metastaticdiseasehadadurableremission[64].Furthermore,treatmentrelatedtoxicity(especiallyfrom
bleomycin)maybeprominent[52].(See"Bleomycininducedlunginjury".)
Otherchemotherapeuticregimenswithreportedtherapeuticefficacyincludedoxorubicinalone[65]carboplatin
plusetoposide[66]cisplatin,vinblastine,plusbleomycin(PVBorVBP)[3]andcyclophosphamide,
doxorubicin,pluscisplatin(CAP)[6769].Noneoftheseregimenshaveproducedconsistentlybetterresults
thanseenwithBEP,butmaybeconsideredforsecondlinetherapy.Thevalueoftaxanes,particularlyin
combinationwithcisplatin,isunderactiveinvestigation[7073].
Experimentaldataandsmallclinicalseriessuggestthathormonalagentssuchasluteinizinghormonereleasing
hormoneagonists(eg,leuprolide)mighthavebeeneffectivethroughthesuppressionofgonadotropinsecretion
[7478].However,othershavefailedtodocumentefficacy[51,79].
Treatmentofrecurrentdiseasewithtamoxifenalone,progesteronealone,oracombinationofthetwoagents
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occasionallyyieldslongtermclinicalresponses.Inonecasereport,acompleteclinicalresponseinapatient
withrecurrentgranulosacelltumorwasachievedusingalternatingbiweeklycyclesofmegestrol40mgtwice
dailyfortwoweeks,alternatingwithtwoweekcoursesoftamoxifen10mgtwicedaily[78].
Antiangiogenictherapyalsoappearspromising.Inanearlyreportofeightpatientswithgranulosacelltumors,
bevacizumab,amonoclonalantibodydirectedagainstthevascularendothelialgrowthfactor(VEGF),induceda
completeclinicalresponseinonepatient,partialresponsesintwo,andstablediseaseintwoothers[80].The
GynecologicOncologyGroupiscurrentlyconductingaphaseIItrialofbevacizumabforwomenwithrecurrent
sexcordstromalovariantumors.
PrognosisandfollowupTheprognosisofovariangranulosacelltumordependsuponthestageofdisease
atdiagnosisandthepresenceofresidualdiseaseaftersurgery(table5)[17,48,61,8183].
FiveyearsurvivalratesforcompletelyresectedstageIdiseaseareapproximately90percent[48,49,61],but
outcomestendtobelessfavorableinthepresenceofalargetumorsize(10to15cm)or(inmanybutnotall
series[60])tumorrupture[14,57,58,61,84].
Anumberofhistologicfeatureshavealsobeenexaminedfortheirprognosticsignificance.Inadultneoplasms,
cellularatypia,highmitoticindex(4to10mitosesper10HPF),andtheabsenceofCallExnerbodiesarethe
onlysignificanthistologicpredictorsofearlyrecurrence[33,60,61].Abnormalkaryotype,p53overexpression,
andploidydonotappeartobeofprognosticvalue[85,86].
Ovariangranulosacelltumorshavemetastaticpotentialandatendencyforlaterelapse.Inonereportof37
womenwithstageIdisease,survivalratesat5,10,and20yearswere94,82,and62percent,respectively
[49].Themediantimetorelapseisapproximatelyfourtosixyearsafterinitialdiagnosishowever,late
recurrenceshavebeenreportedafterasmanyas40years[14,33,49,61,87,88].Thus,prolongedsurveillance
withserialphysicalexaminationsandserumtumormarkers(particularlyinhibin)[36]shouldbeperformed.
Afterprimarytherapy,prolongedsurveillancewithserialphysicalexaminationsandserumtumormarkerlevels
isindicatedbecauseoftheindolentgrowthpatternoftheseneoplasms.Thereisnoconsensusonthe
frequencyofpostoperativesurveillance.Ingeneral,wefollowpatientswithpelvicexaminationsandserum
inhibinlevelseverythreemonthsforthefirsttwoyears,everyfourtosixmonthsduringyearsthreetofive,and
yearlythereaftersincerecurrencescanoccurmanyyearsafterinitialdiagnosis.Inaddition,followingserum
estradiollevelspostoperativelymaybeusefulfordetectingrecurrenceofanestradiolsecretingneoplasm
[3,14].
Radiographicimagingstudiessuchascomputedtomography(CT)orchestradiographsareperformedonlyif
clinicallyindicated(eg,evaluationofspecificsymptomsoranelevatedinhibinlevel),butarenotrecommended
forroutinefollowup[17,89].
Anoverviewofposttreatmentsurveillanceforsexcordstromaltumorscanbefoundseparately.(See
"Overviewofsexcordstromaltumorsoftheovary",sectionon'Posttreatmentsurveillance'.)
FIBROMAFibromasarethemostcommonofthesexcordstromaltumors.Purefibromasarebenignsolid
neoplasms,usuallyunilateral,thatprimarilyoccurinpostmenopausalwomen.Theyarenothormonallyactive.
Cellularfibromasarecharacterizedbymildlyincreasedcellulardensity,mildnuclearatypia,andanaverageof
threeorfewermitoticfiguresper10highpowerfields(HPF).Incontrast,fibrosarcomas(whichhavefouror
moremitoticfiguresper10HPFplusmarkedcellulardensityandnuclearatypia)areveryraremalignant
ovariansarcomaswhoseaggressivenesscorrelateswiththenumberofmitosesandthedegreeofanaplasia.
Onultrasoundexamination,anovarianfibromamayappearasamassthatiseitherhyperorhypoechoic,
whichmaybecalcifiedand/orexhibitcysticdegeneration[90].Ascitesispresentin10to15percentofcases
andhydrothoraxin1percent,especiallywithlargerlesions.
Theassociationofovarianfibromawithascitesand/orpleuraleffusionistermedMeigs'syndrome[91].Fluid
accumulationisprobablyrelatedtosubstanceslikevascularendothelialgrowthfactor(VEGF)thatraise
capillarypermeability[24,88].Removaloftheneoplasmresultsineliminationofascitesandpleuraleffusion
[92].SeveralcasesofMeigs'syndromehavebeenreportedinassociationwithelevatedserumCA125levels
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[93].Thus,neitherascitesorpleuraleffusion,noranelevatedCA125isnecessarilyindicativeofanadvanced
epithelialovariancarcinomainawomanwithapelvicmass.
PseudoMeigs'syndrome(aclinicalsyndromeofpleuraleffusion,ascites,andanovarianmassthatisnota
fibromaorfibromalikemass/tumor)hasbeenreportedfromanumberofsources,suchasleiomyomas,struma
ovarii,mucinouscystadenoma,teratoma,andmalignanciesthataremetastatictotheovary(particularly
colorectalcancer)[94].
OvarianfibromasassociatedwithbasalcellcancersarecallednevoidbasalcellcarcinomasyndromeorGorlin
syndrome.Otherassociatedfindingsincludeodontogenickeratocysts,brainneoplasms,andmesentericcysts.
Gorlinsyndromeisinheritedasanautosomaldominanttraitwithhighdegreeofpenetrance(97percent),but
variableexpressivity.WhethertheinheritedgermlineabnormalityresponsibleforGorlinsyndrome(amutationin
thepatchedorPTCH1geneonchromosome9)isrelatedtothedevelopmentofovarianfibromasaswellis
unclear[95].(See"Nevoidbasalcellcarcinomasyndrome".)
Themostcommontreatmentforanovarianfibromaisunilateralsalpingooophorectomy.Forwomenwhodesire
preservationoftheovary,anovariancystectomymaybeperformedwithcompleteexcisionofthefibromatous
tissue.
THECOMAThecomasaresolid,fibromatousneoplasmsandaregenerallybenign.Theyarecomposedof
thecacellsandarisefromtheovarianstroma[96].Thecomasarealmostexclusivelyconfinedtooneovaryand
occurpredominantlyinpostmenopausalwomen(averageage59years).Thecomasmayproduceestrogen,and
upto20percentofpatientspresentwithasynchronousendometrialcancer.
Grossly,theyhaveayellowishappearancefromaccumulatedlipids(alsoseeningranulosacelltumors)and
canbecomeverylarge(upto40cm).Histologically,theyareprimarilycomposedofthecacells,butmayalso
containgranulosacellcomponents.Thetumorsaredesignatedgranulosathecacelltumorsorgranulosacell
tumorsdependingupontherelativeamountofgranulosaversusthecacells[81].Malignantthecomasarerare,
andmaybeinterpretedasfibrosarcomasoradiffuseformofagranulosacelltumor.
Themostcommonsymptomofthecomasisabnormaluterinebleedingasaresultofendometrialstimulation
fromestrogenproducedbythecacells.Endometrialhyperplasiaandcarcinomaarepresentinapproximately15
and25percentofcases,respectively[23].Ascitesisrare.Ultrasoundgenerallyrevealsanonspecificovarian
mass.
Wesuggestthattreatmentofthecomasinwomeninthemenopausaltransitionandpostmenopausalwomen
includeatotalabdominalhysterectomywithbilateralsalpingooophorectomy(TAHBSO).Thisrecommendation
takesintoaccountthepossiblepresenceofasynchronousendometrialmalignancy,aswellastherare
occurrenceofovarianfibrosarcoma,amalignantmixedMllerianneoplasmoftheuterus,orendometrial
stromalsarcoma.
Unilateraloophorectomyisanoptioninyoungwomenwhenpreservationoffertilityoravoidanceofexogenous
hormonereplacementisdesired[37].
Allwomenwithathecomashouldhavepreorintraoperativeendometrialsamplingtoexcludethepresenceof
asynchronousendometrialmalignancy.
FIBROTHECOMAThetermfibrothecomaisusedbysomeexpertstorefertoaneoplasmwithfeaturesthat
areintermediatebetweenafibromaandathecoma[97].Thereisnouniversalagreementonwhichneoplasms
shouldbeclassifiedasafibrothecomaratherthaneitherafibromaorthecomahowever,manyneoplasms
havemixturesofthesecelltypes.
Hormonalactivityoftheseneoplasmsdependsupontheextenttowhichtheyresemblefibromas(lipidpoor,
hormonallyinert)orthecomas(lipidcontaining,hormonallyactive)[97,98].Fibrothecomasmaybeeitherbenign
ormalignant,althoughtheyaremostcommonlybenign[99,100].Theriskofmalignancyisdifficulttopredict
duetoinconsistentclassificationandthepaucityofdataregardingtheseneoplasms.Ofnote,womenwitha
significantamountofhormonallyactivethecomaelementsareatriskforendometrialneoplasia,similartopure
thecomas.(See'Thecoma'above.)
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Pelvicimagingcancertainlynarrowthedifferentialdiagnosisofanadnexalmass,butthereisnothing
pathognomonicabouttheultrasoundormagneticresonanceimaging(MRI)appearanceoffibrothecomas.
Typically,theyappearasasolidovarianmassandareconsideredworrisomeformalignantneoplasm.The
sonographicappearanceoftheseneoplasmsisusuallynonspecific.OnMRI,fibrothecomastypicallyhavelow
signalintensityonT1weightedimagesandverylowsignalintensityonT2weightedimages[101103].Large
fibrothecomasmayhaveareasofedemaandcysticdegeneration.However,thereisonereportindicatingthat
dualechochemicalshiftMRImaybeausefulmethodfordetectingsmallamountsoflipidinthecomasversus
thefibroustissueinfibromas[104].Butonceagain,stromaltumorsmaycontainboththecomaelementsand
fibromaelements(hence"fibrothecoma"),sothisdistinctionisprobablyofverylimitedclinicalbenefit.
Ultimately,regardlessofimagingfindings,removalofthemassisrequired,sincetheselesionsareneoplastic.
Thediagnosisismadebaseduponhistology.
SUMMARYANDRECOMMENDATIONS
Granulosacelltumor
Granulosacelltumorsaregenerallylargeandunilateralandhavemalignantpotential.Theyare
categorizedintotwosubtypes,adultandjuvenile.Theadultsubtypeismorecommonandoccursmostly
inmiddleagedandolderwomen,whilethejuvenilesubtypeoccursmostlyinchildrenandyoungwomen.
(See'Histopathology'above.)
Theseneoplasmsoftenproduceestrogen(table1).Granulosacelltumorstypicallypresentasalarge
adnexalmassfrequentlywithsignsofhyperestrogenism(abnormaluterinebleeding,endometrial
neoplasia,breasttenderness,and,inchildren,precociouspuberty).Werecommendendometrialsampling
preorintraoperativelytoexcludeasymptomaticendometrialneoplasm(carcinomaoritsprecursor)
(Grade1B).(See'Clinicalfeatures'aboveand'Surgicalstagingandtreatment'above.)
Wesuggesttotalabdominalhysterectomyandbilateralsalpingooophorectomyforwomenwithgranulosa
celltumorswhohavecompletedchildbearing(Grade2B).ForwomenwithstageIdisease(table2)who
wishtopreservechildbearingcapacityoravoidestrogentherapy,wesuggestunilateraloophorectomy
alone(Grade2C).(See'Surgicalstagingandtreatment'above.)
Wesuggestacourseofpostoperativeplatinumbasedchemotherapyforallwomenwithresectedstage
ICtoIVdiseasebecauseofthehighriskofdiseaseprogressionandthepotentialforlongtermsurvivalin
womenwithadvanceddiseasewhoreceivemodernplatinumbasedchemotherapy(Grade2B).However,
othersdisagree,eitherrecommendingchemotherapyonlyforwomenwhoareleftwithmeasurable
residualdiseasefollowingsurgery,orwithholdingadjuvantchemotherapyforallwomenregardlessof
stage,andtreatingonlyatthetimeofrecurrence.(See'Adjuvanttherapy'above.)
Forrecurrentlocalizeddisease,wesuggestsurgicalresection,iffeasible(Grade2B).Wesuggest
chemotherapyratherthansurgeryaloneforpatientswithmetastaticorsuboptimallycytoreduceddisease
(Grade2B).Radiationmaybeappropriateasprimarytreatmentorasanadjunctivetherapyfollowing
surgeryinselectedpatientswithrecurrenceconfinedtothepelvis.(See'Metastaticorrecurrentdisease'
above.)
Afterprimarytherapy,prolongedsurveillancewithserialphysicalexaminationsandserumtumormarker
levels(ifelevated,(table1))isindicatedbecauseoftheindolentgrowthpatternoftheseneoplasms.(See
'Prognosisandfollowup'above.)
Fibroma
Fibromasarethemostcommonofthesexcordstromaltumors.Purefibromasarebenign,solid,usually
unilateralneoplasmsthatprimarilyoccurinpostmenopausalwomen.Theyarenothormonallyactive.
FibromasarerarelyassociatedwithMeigs'syndrome(ie,ovarianfibroma,ascites,pleuraleffusion).
Werecommendoophorectomyfordiagnosisandcureforwomenwithovarianfibromas(Grade1B).(See
'Fibroma'above.)
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Thecoma
Thecomasareusuallybenignneoplasmslikegranulosacelltumors,thecomasmayproduceestrogen
(table1)andusuallypresentasabnormaluterinebleedinginapostmenopausalwoman.
Wesuggestunilateraloophorectomyandendometrialsamplingforwomenwiththecomaswhohavenot
completedchildbearingorwishtoavoidexogenoushormonereplacement(Grade2B).Wesuggesttotal
abdominalhysterectomywithbilateralsalpingooophorectomyforallotherwomen(Grade2B).(See
'Thecoma'above.)
Fibrothecoma
Thetermfibrothecomaisusedbysomeexpertstorefertoaneoplasmwithfeaturesthatareintermediate
betweenafibromaandathecoma.Hormonalactivityoftheseneoplasmsdependsupontheextentto
whichtheyresemblefibromas(lipidpoor,hormonallyinert)orthecomas(lipidcontaining,hormonally
active).Fibrothecomasareusuallybenign.(See'Fibrothecoma'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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