You are on page 1of 13

2/19/2015

Sexcordstromaltumorsoftheovary:Granulosastromalcelltumors

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.
http://www.uptodate.com/contents/sexcordstromaltumorsoftheovarygranulosastromalcelltumors?source=machineLearning&search=granulosa+

1/13

2/19/2015

Sexcordstromaltumorsoftheovary:Granulosastromalcelltumors

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].
http://www.uptodate.com/contents/sexcordstromaltumorsoftheovarygranulosastromalcelltumors?source=machineLearning&search=granulosa+

2/13

2/19/2015

Sexcordstromaltumorsoftheovary:Granulosastromalcelltumors

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
http://www.uptodate.com/contents/sexcordstromaltumorsoftheovarygranulosastromalcelltumors?source=machineLearning&search=granulosa+

3/13

2/19/2015

Sexcordstromaltumorsoftheovary:Granulosastromalcelltumors

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
http://www.uptodate.com/contents/sexcordstromaltumorsoftheovarygranulosastromalcelltumors?source=machineLearning&search=granulosa+

4/13

2/19/2015

Sexcordstromaltumorsoftheovary:Granulosastromalcelltumors

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
http://www.uptodate.com/contents/sexcordstromaltumorsoftheovarygranulosastromalcelltumors?source=machineLearning&search=granulosa+

5/13

2/19/2015

Sexcordstromaltumorsoftheovary:Granulosastromalcelltumors

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
http://www.uptodate.com/contents/sexcordstromaltumorsoftheovarygranulosastromalcelltumors?source=machineLearning&search=granulosa+

6/13

2/19/2015

Sexcordstromaltumorsoftheovary:Granulosastromalcelltumors

[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.)
http://www.uptodate.com/contents/sexcordstromaltumorsoftheovarygranulosastromalcelltumors?source=machineLearning&search=granulosa+

7/13

2/19/2015

Sexcordstromaltumorsoftheovary:Granulosastromalcelltumors

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.)
http://www.uptodate.com/contents/sexcordstromaltumorsoftheovarygranulosastromalcelltumors?source=machineLearning&search=granulosa+

8/13

2/19/2015

Sexcordstromaltumorsoftheovary:Granulosastromalcelltumors

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.
REFERENCES
1. YoungRH.Sexcordstromaltumorsoftheovaryandtestis:theirsimilaritiesanddifferenceswith
considerationofselectedproblems.ModPathol200518Suppl2:S81.
2. QuirkJT,NatarajanN.OvariancancerincidenceintheUnitedStates,19921999.GynecolOncol2005
97:519.
3. SegalR,DePetrilloAD,ThomasG.Clinicalreviewofadultgranulosacelltumorsoftheovary.Gynecol
Oncol199556:338.
4. LackEE,PerezAtaydeAR,MurthyAS,etal.Granulosathecacelltumorsinpremenarchalgirls:a
clinicalandpathologicstudyoftencases.Cancer198148:1846.
5. BoyceEA,CostagginiI,VitonisA,etal.Theepidemiologyofovariangranulosacelltumors:acase
controlstudy.GynecolOncol2009115:221.
6. YoungR,ClementPB,ScullyRE.Theovary.In:SurgicalPathology,SternbergSS(Ed),RavenPress,
NewYork1989.p.1687.
7. McCluggageWG.Recentadvancesinimmunohistochemistryinthediagnosisofovarianneoplasms.J
ClinPathol200053:327.
8. MovahediLankaraniS,KurmanRJ.Calretinin,amoresensitivebutlessspecificmarkerthanalpha
inhibinforovariansexcordstromalneoplasms:animmunohistochemicalstudyof215cases.AmJSurg
Pathol200226:1477.
9. MatiasGuiuX,PonsC,PratJ.Mllerianinhibitingsubstance,alphainhibin,andCD99expressioninsex
cordstromaltumorsandendometrioidovariancarcinomasresemblingsexcordstromaltumors.Hum
Pathol199829:840.
10. HildebrandtRH,RouseRV,LongacreTA.Valueofinhibinintheidentificationofgranulosacelltumorsof
theovary.HumPathol199728:1387.
11. ZhaoC,VinhTN,McManusK,etal.Identificationofthemostsensitiveandrobust
immunohistochemicalmarkersindifferentcategoriesofovariansexcordstromaltumors.AmJSurg
Pathol200933:354.
12. ShahSP,KbelM,SenzJ,etal.MutationofFOXL2ingranulosacelltumorsoftheovary.NEnglJMed
2009360:2719.
13. KbelM,GilksCB,HuntsmanDG.AdulttypegranulosacelltumorsandFOXL2mutation.CancerRes
200969:9160.
14. EvansAT3rd,GaffeyTA,MalkasianGDJr,AnnegersJF.Clinicopathologicreviewof118granulosaand
82thecacelltumors.ObstetGynecol198055:231.
15. AdamianRT.[Hyperplasticprocessesandendometrialcancerinpatientswithhormoneproducing
ovariantumors].VoprOnkol199137:48.
16. BerekJS,HackerNF.Nonepithelialovarianandfallopiantubecancers.In:PracticalGynecologic
Oncology,3rd,BerekJS,HackerNF(Eds),LippincottWilliams&Wilkins,Philadelphia2000.p.539.
http://www.uptodate.com/contents/sexcordstromaltumorsoftheovarygranulosastromalcelltumors?source=machineLearning&search=granulosa+

9/13

2/19/2015

Sexcordstromaltumorsoftheovary:Granulosastromalcelltumors

17. SchumerST,CannistraSA.Granulosacelltumoroftheovary.JClinOncol200321:1180.
18. ZanagnoloV,PasinettiB,SartoriE.Clinicalreviewof63casesofsexcordstromaltumors.EurJ
GynaecolOncol200425:431.
19. NakashimaN,YoungRH,ScullyRE.Androgenicgranulosacelltumorsoftheovary.Aclinicopathologic
analysisof17casesandreviewoftheliterature.ArchPatholLabMed1984108:786.
20. NorrisHJ,TaylorHB.Virilizationassociatedwithcysticgranulosatumors.ObstetGynecol196934:629.
21. CastroCY,MalpicaA,HearneRH,SilvaEG.Androgenicadultgranulosacelltumorina13yearold
prepubertalpatient:acasereportandreviewoftheliterature.IntJGynecolPathol200019:266.
22. LapphnRE,BurgerHG,BoumaJ,etal.Inhibinasamarkerforgranulosacelltumors.NEnglJMed
1989321:790.
23. JoblingT,MamersP,HealyDL,etal.Aprospectivestudyofinhibiningranulosacelltumorsofthe
ovary.GynecolOncol199455:285.
24. BoggessJF,SoulesMR,GoffBA,etal.Seruminhibinanddiseasestatusinwomenwithovarian
granulosacelltumors.GynecolOncol199764:64.
25. HealyDL,BurgerHG,MamersP,etal.Elevatedseruminhibinconcentrationsinpostmenopausal
womenwithovariantumors.NEnglJMed1993329:1539.
26. GustafsonML,LeeMM,ScullyRE,etal.Mllerianinhibitingsubstanceasamarkerforovariansexcord
tumor.NEnglJMed1992326:466.
27. RobertsonDM,StephensonT,PruysersE,etal.Characterizationofinhibinformsandtheir
measurementbyaninhibinalphasubunitELISAinserumfrompostmenopausalwomenwithovarian
cancer.JClinEndocrinolMetab200287:816.
28. MomCH,EngelenMJ,WillemsePH,etal.Granulosacelltumorsoftheovary:theclinicalvalueof
seruminhibinAandBlevelsinalargesinglecentercohort.GynecolOncol2007105:365.
29. RobertsonDM,StephensonT,PruysersE,etal.Inhibins/activinsasdiagnosticmarkersforovarian
cancer.MolCellEndocrinol2002191:97.
30. ReyRA,LhommC,MarcillacI,etal.Antimllerianhormoneasaserummarkerofgranulosacell
tumorsoftheovary:comparativestudywithserumalphainhibinandestradiol.AmJObstetGynecol
1996174:958.
31. LaneAH,LeeMM,FullerAFJr,etal.DiagnosticutilityofMllerianinhibitingsubstancedeterminationin
patientswithprimaryandrecurrentgranulosacelltumors.GynecolOncol199973:51.
32. ChangHL,PahlavanN,HalpernEF,MacLaughlinDT.SerumMllerianInhibitingSubstance/anti
Mllerianhormonelevelsinpatientswithadultgranulosacelltumorsdirectlycorrelatewithaggregate
tumormassasdeterminedbypathologyorradiology.GynecolOncol2009114:57.
33. MillerBE,BarronBA,WanJY,etal.Prognosticfactorsinadultgranulosacelltumoroftheovary.
Cancer199779:1951.
34. BrownJ,SoodAK,DeaversMT,etal.Patternsofmetastasisinsexcordstromaltumorsoftheovary:
canroutinestaginglymphadenectomybeomitted?GynecolOncol2009113:86.
35. AbuRustumNR,RestivoA,IvyJ,etal.Retroperitonealnodalmetastasisinprimaryandrecurrent
granulosacelltumorsoftheovary.GynecolOncol2006103:31.
36. NationalComprehensiveCancerNetwork(NCCN).NCCNClinicalpracticeguidelinesinoncology.
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp(AccessedonApril01,2014).
37. GershensonDM.Managementofearlyovariancancer:germcellandsexcordstromaltumors.Gynecol
Oncol199455:S62.
38. ZhangM,CheungMK,ShinJY,etal.Prognosticfactorsresponsibleforsurvivalinsexcordstromal
tumorsoftheovaryananalysisof376women.GynecolOncol2007104:396.
39. SchneiderDT,CalaminusG,WessalowskiR,etal.Ovariansexcordstromaltumorsinchildrenand
adolescents.JClinOncol200321:2357.
40. YoungRH,ScullyRE.OvarianSertoliLeydigcelltumors.Aclinicopathologicalanalysisof207cases.
AmJSurgPathol19859:543.
41. YoungRH,DickersinGR,ScullyRE.Juvenilegranulosacelltumoroftheovary.Aclinicopathological
analysisof125cases.AmJSurgPathol19848:575.
42. CalaminusG,WessalowskiR,HarmsD,GbelU.Juvenilegranulosacelltumorsoftheovaryin
childrenandadolescents:resultsfrom33patientsregisteredinaprospectivecooperativestudy.Gynecol
Oncol199765:447.
http://www.uptodate.com/contents/sexcordstromaltumorsoftheovarygranulosastromalcelltumors?source=machineLearning&search=granulosa

10/13

2/19/2015

Sexcordstromaltumorsoftheovary:Granulosastromalcelltumors

43. SchneiderDT,CalaminusG,WessalowskiR,etal.Therapyofadvancedovarianjuvenilegranulosacell
tumors.KlinPadiatr2002214:173.
44. SchneiderDT,JnigU,CalaminusG,etal.Ovariansexcordstromaltumorsaclinicopathologicalstudy
of72casesfromtheKielPediatricTumorRegistry.VirchowsArch2003443:549.
45. PlantazD,FlamantF,VassalG,etal.[Granulosacelltumorsoftheovaryinchildrenandadolescents.
Multicenterretrospectivestudyin40patientsaged7monthsto22years].ArchFrPediatr199249:793.
46. UygunK,AydinerA,SaipP,etal.Clinicalparametersandtreatmentresultsinrecurrentgranulosacell
tumoroftheovary.GynecolOncol200388:400.
47. AlBadawiIA,BrasherPM,GhatageP,etal.Postoperativechemotherapyinadvancedovariangranulosa
celltumors.IntJGynecolCancer200212:119.
48. ChanJK,ZhangM,KalebV,etal.Prognosticfactorsresponsibleforsurvivalinsexcordstromaltumors
oftheovaryamultivariateanalysis.GynecolOncol200596:204.
49. LauszusFF,PetersenAC,GreisenJ,JakobsenA.Granulosacelltumoroftheovary:apopulationbased
studyof37womenwithstageIdisease.GynecolOncol200181:456.
50. HomesleyHD,BundyBN,HurteauJA,RothLM.Bleomycin,etoposide,andcisplatincombination
therapyofovariangranulosacelltumorsandotherstromalmalignancies:AGynecologicOncologyGroup
study.GynecolOncol199972:131.
51. SavageP,ConstenlaD,FisherC,etal.Granulosacelltumoursoftheovary:demographics,survivaland
themanagementofadvanceddisease.ClinOncol(RCollRadiol)199810:242.
52. ColomboN,SessaC,LandoniF,etal.Cisplatin,vinblastine,andbleomycincombinationchemotherapy
inmetastaticgranulosacelltumoroftheovary.ObstetGynecol198667:265.
53. ZambettiM,EscobedoA,PilottiS,DePaloG.cisplatinum/vinblastine/bleomycincombination
chemotherapyinadvancedorrecurrentgranulosacelltumorsoftheovary.GynecolOncol199036:317.
54. SchwartzPE,SmithJP.Treatmentofovarianstromaltumors.AmJObstetGynecol1976125:402.
55. OhelG,KanetiH,SchenkerJG.GranulosacelltumorsinIsrael:astudyof172cases.GynecolOncol
198315:278.
56. PankratzE,BoyesDA,WhiteGW,etal.Granulosacelltumors.Aclinicalreviewof61cases.Obstet
Gynecol197852:718.
57. BjrkholmE,SilfverswrdC.Prognosticfactorsingranulosacelltumors.GynecolOncol198111:261.
58. StenwigJT,HazekampJT,BeechamJB.Granulosacelltumorsoftheovary.Aclinicopathologicalstudy
of118caseswithlongtermfollowup.GynecolOncol19797:136.
59. FoxH,AgrawalK,LangleyFA.Aclinicopathologicstudyof92casesofgranulosacelltumorofthe
ovarywithspecialreferencetothefactorsinfluencingprognosis.Cancer197535:231.
60. SehouliJ,DrescherFS,MusteaA,etal.Granulosacelltumoroftheovary:10yearsfollowupdataof65
patients.AnticancerRes200424:1223.
61. MalmstrmH,HgbergT,RisbergB,SimonsenE.Granulosacelltumorsoftheovary:prognostic
factorsandoutcome.GynecolOncol199452:50.
62. GershensonDM,HartmannLC,YoungRH.Ovariansexcordstromaltumors.In:PrinciplesandPractice
ofGynecologicOncology,WJ,YoungRC,MarkmanM,PerezCA,BarakatR,RandallM(Eds),
LippincottWilliams&Wilkins,Philadelphia2005.p.1011.
63. WolfJK,MullenJ,EifelPJ,etal.Radiationtreatmentofadvancedorrecurrentgranulosacelltumorof
theovary.GynecolOncol199973:35.
64. GershensonDM,MorrisM,BurkeTW,etal.Treatmentofpoorprognosissexcordstromaltumorsofthe
ovarywiththecombinationofbleomycin,etoposide,andcisplatin.ObstetGynecol199687:527.
65. DisaiaP,SaltzA,KaganAR,RichW.Atemporaryresponseofrecurrentgranulosacelltumorto
adriamycin.ObstetGynecol197852:355.
66. PowellJL,OtisCN.Managementofadvancedjuvenilegranulosacelltumoroftheovary.GynecolOncol
199764:282.
67. MuntzHG,GoffBA,FullerAFJr.Recurrentovariangranulosacelltumor:roleofcombination
chemotherapywithreportofalongtermresponsetoacyclophosphamide,doxorubicinandcisplatin
regimen.EurJGynaecolOncol199011:263.
68. GershensonDM,CopelandLJ,KavanaghJJ,etal.Treatmentofmetastaticstromaltumorsoftheovary
withcisplatin,doxorubicin,andcyclophosphamide.ObstetGynecol198770:765.
69. PectasidesD,AlevizakosN,AthanassiouAE.Cisplatincontainingregimeninadvancedorrecurrent
http://www.uptodate.com/contents/sexcordstromaltumorsoftheovarygranulosastromalcelltumors?source=machineLearning&search=granulosa

11/13

2/19/2015

Sexcordstromaltumorsoftheovary:Granulosastromalcelltumors

granulosacelltumoursoftheovary.AnnOncol19923:316.
70. TresukosolD,KudelkaAP,EdwardsCL,etal.Recurrentovariangranulosacelltumor:acasereportofa
dramaticresponsetoTaxol.IntJGynecolCancer19955:156.
71. BrownJ,ShvartsmanHS,DeaversMT,etal.Theactivityoftaxanesinthetreatmentofsexcord
stromalovariantumors.JClinOncol200422:3517.
72. BrownJ,ShvartsmanHS,DeaversMT,etal.Theactivityoftaxanescomparedwithbleomycin,
etoposide,andcisplatininthetreatmentofsexcordstromalovariantumors.GynecolOncol2005
97:489.
73. PowellJL,ConnorGP,HendersonGS.Managementofrecurrentjuvenilegranulosacelltumorofthe
ovary.GynecolOncol200181:113.
74. EmonsG,SchallyAV.Theuseofluteinizinghormonereleasinghormoneagonistsandantagonistsin
gynaecologicalcancers.HumReprod19949:1364.
75. MartikainenH,PenttinenJ,HuhtaniemiI,KauppilaA.Gonadotropinreleasinghormoneagonistanalog
therapyeffectiveinovariangranulosacellmalignancy.GynecolOncol198935:406.
76. FishmanA,KudelkaAP,TresukosolD,etal.Leuprolideacetatefortreatingrefractoryorpersistent
ovariangranulosacelltumor.JReprodMed199641:393.
77. BriasoulisE,KaravasilisV,PavlidisN.Megestrolactivityinrecurrentadulttypegranulosacelltumourof
theovary.AnnOncol19978:811.
78. HardyRD,BellJG,NicelyCJ,ReidGC.Hormonaltreatmentofarecurrentgranulosacelltumorofthe
ovary:casereportandreviewoftheliterature.GynecolOncol200596:865.
79. MaxwellGL,SoissonAP,MilesP.Failureofgonadotropinreleasinghormonetherapyinpatientswith
metastaticovariansexcordstromaltumors.Oncology199451:356.
80. TaoX,SoodAK,DeaversMT,etal.Antiangiogenesistherapywithbevacizumabforpatientswith
ovariangranulosacelltumors.GynecolOncol2009114:431.
81. CronjHS,NiemandI,BamRH,WoodruffJD.Reviewofthegranulosathecacelltumorsfromtheemil
Novakovariantumorregistry.AmJObstetGynecol1999180:323.
82. UygunK,AydinerA,SaipP,etal.Granulosacelltumoroftheovary:retrospectiveanalysisof45cases.
AmJClinOncol200326:517.
83. LeeYK,ParkNH,KimJW,etal.Characteristicsofrecurrenceinadulttypegranulosacelltumor.IntJ
GynecolCancer200818:642.
84. AuranenA,SundstrmJ,IjsJ,GrnmanS.Prognosticfactorsofovariangranulosacelltumor:astudy
of35patientsandreviewoftheliterature.IntJGynecolCancer200717:1011.
85. AlaFossiSL,MenpJ,AineR,etal.Prognosticsignificanceofp53expressioninovariangranulosa
celltumors.GynecolOncol199766:475.
86. RoushGR,elNaggarAK,AbdulKarimFW.Granulosacelltumorofovary:aclinicopathologicandflow
cytometricDNAanalysis.GynecolOncol199556:430.
87. CrewKD,CohenMH,SmithDH,etal.Longnaturalhistoryofrecurrentgranulosacelltumoroftheovary
23yearsafterinitialdiagnosis:acasereportandreviewoftheliterature.GynecolOncol200596:235.
88. IshikoO,YoshidaH,SumiT,etal.Vascularendothelialgrowthfactorlevelsinpleuralandperitoneal
fluidinMeigs'syndrome.EurJObstetGynecolReprodBiol200198:129.
89. StuartGC,DawsonLM.Updateongranulosacelltumoursoftheovary.CurrOpinObstetGynecol2003
15:33.
90. ChechiaA,AttiaL,TemimeRB,etal.Incidence,clinicalanalysis,andmanagementofovarianfibromas
andfibrothecomas.AmJObstetGynecol2008199:473.e1.
91. BrunJL.Demonssyndromerevisited:areviewoftheliterature.GynecolOncol2007105:796.
92. MEIGSJV.FibromaoftheovarywithascitesandhydrothoraxMeigs'syndrome.AmJObstetGynecol
195467:962.
93. TimmermanD,MoermanP,VergoteI.Meigs'syndromewithelevatedserumCA125levels:twocase
reportsandreviewoftheliterature.GynecolOncol199559:405.
94. PepariniN,ChirlettiP.Ovarianmalignancieswithcytologicallynegativepleuralandperitonealeffusions:
demons'ormeigs'pseudosyndromes?IntJSurgPathol200917:396.
95. TsujiT,CatasusL,PratJ.Islossofheterozygosityat9q22.3(PTCHgene)and19p13.3(STK11gene)
involvedinthepathogenesisofovarianstromaltumors?HumPathol200536:792.
96. DiSaiaPJ,CreasmanWT.Germcell,stromalandotherovariantumors.In:ClinicalGynecologic
http://www.uptodate.com/contents/sexcordstromaltumorsoftheovarygranulosastromalcelltumors?source=machineLearning&search=granulosa

12/13

2/19/2015

Sexcordstromaltumorsoftheovary:Granulosastromalcelltumors

Oncology,7th,MosbyElsevier,2007.p.387.
97. RothLM,CzernobilskyB.Perspectivesonpureovarianstromalneoplasmsandtumorlikeproliferations
oftheovarianstroma.AmJSurgPathol201135:e15.
98. NowakM,PodciechowskiL,KrawczykT,WilczynskiJ.Meigs'syndromeandvirilizingovarian
fibrothecomacomplicatingpregnancy.Acasereportandreviewoftheliterature.NeuroEndocrinolLett
200930:192.
99. ElghororiMR,AlTaherH,RedwoodNF.Ovarianfibrothecoma:abenignneoplasmwithpotential
adverseconsequences.JObstetGynaecol200323:677.
100. LiuH,HaoSH,LiWM.Giantmalignantovarianfibrothecomainvolvedwithretroperitonealstructures
mimickingaretroperitonealsarcoma.ArchGynecolObstet2009279:763.
101. TroianoRN,LazzariniKM,ScouttLM,etal.Fibromaandfibrothecomaoftheovary:MRimaging
findings.Radiology1997204:795.
102. JungSE,RhaSE,LeeJM,etal.CTandMRIfindingsofsexcordstromaltumoroftheovary.AJRAm
JRoentgenol2005185:207.
103. TanakaYO,SaidaTS,MinamiR,etal.MRfindingsofovariantumorswithhormonalactivity,with
emphasisontumorsotherthansexcordstromaltumors.EurJRadiol200762:317.
104. OkajimaY,MatsuoY,TamuraA,etal.Intracellularlipidinovarianthecomasdetectedbydualecho
chemicalshiftmagneticresonanceimaging:reportof2cases.JComputAssistTomogr201034:223.
Topic3234Version16.0

http://www.uptodate.com/contents/sexcordstromaltumorsoftheovarygranulosastromalcelltumors?source=machineLearning&search=granulosa

13/13