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UterineCancer
Author:JingWangChiang,MDChiefEditor:WarnerKHuh,MDmore...
Updated:May13,2016

Background
Uterinecancerisdefinedasanyinvasiveneoplasmoftheuterinecorpus.Invasive
neoplasmsofthefemalepelvicorgansaccountforalmost15%ofallcancersin
women.Themostcommonofthesemalignanciesisuterinecancer.An
estimated54,870casesarediagnosedannually,leadingto10,170deaths.Itisthe
fourthmostcommoncancer,accountingfor7%offemalecancers,followingbreast,
lung,andcolorectalcancer.Endometrialadenocarcinomaisthemostcommon
gynecologicmalignancyintheUnitedStates.However,ithasafavorableprognosis
becausethemajorityofpatientspresentatanearlystage,resultinginonly4%of
cancerdeathsinwomen. [1]Uterinesarcomascomprise<9%ofcancersofuterine
corpus,howeverisassociatedwithmoreaggressivebehaviorandapoorer
prognosis. [2]

HistoryoftheProcedure
Canceroftheuterinecorpusisthemostcommonpelvicgynecologicmalignancyin
theUnitedStatesandinmostdevelopedcountrieswithaccesstosufficienthealth
care.Approximately95%ofthesemalignanciesarecarcinomasofthe
endometrium.Themostcommonsymptomin90%ofwomenispostmenopausal
(PMP)bleeding.Mostwomenrecognizetheneedforpromptevaluation,although
only1020%ofwomenwithpostmenopausalvaginalbleedinghaveagynecologic
malignancy.Becauseofthispromptevaluation,7075%ofwomenarediagnosed
withsurgicalstageIdisease.
Currently,noscreeningtestsforcanceroftheuterusarerecommendedfor
asymptomaticwomen.Noevidencesuggeststhatroutineendometrialsamplingor
transvaginalsonographytoevaluatetheendometrialstripeinasymptomaticwomen
hasaroleinearlydetectionofuterinecancer,eveninwomenwhotaketamoxifen
afterbreastcancerorhasacancersyndrome.Theearlydetection,presenting
symptoms,andhighersurvivalratemakeitunlikelythatscreeningwillhavea
successfulimpactonimprovingsurvivalrates.
Approximatelyeightypercentofendometrialcarcinomasareendometrioid
adenocarcinomas.Otherhistologicsubtypesincludeadenosquamous,clearcell,
andpapillaryserouscarcinomas. [3]Sarcomasmakeupabout<9%ofuterinecorpus
malignancies,includingcarcinosarcomasormixedhomologousmlleriantumors,
4850%leiomyosarcomas(LMSs),3840%andendometrialstromalsarcomas
(EESs),810%.Theremainingsarcomasaremadeupofheterologoustumors
tumorsthatcontainhistologiccomponentsforeigntotheuterus,suchas
rhabdomyosarcomas,osteosarcomas,andchondrosarcomas.Thisarticlediscusses
endometrialcanceranduterinesarcomas.Seetheimagebelow.

Adenocarcinomaoftheendometrium.Thistumor,whichoccupiesasmalluterinecavity,grows
primarilyasafirmpolypoidmass.CourtesyofTELEPATH,ArmedForcesInstituteofPathology
(AFIP).

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Epidemiology
Frequency
Approximately54,870womenwerepredictedtodevelopthisformofmalignancyin
2015intheUnitedStates.Afterdoublingintheearly1970s,theincidenceof
uterinecancerhasremainedfairlyconstant.In2015,10,170deathswere
predicted.Awoman'slifetimeriskisapproximately2.7%. [1]
Whileendometrialcanceraffectsreproductiveageaswellaspostmenopausal
women,75%ofendometrialcancersoccurinpostmenopausalwomen,withthe
meanageofdiagnosisat61years.Premenopausalwomenareatincreasedriskif
theyhavecertainriskfactors. [4]Themostcommonlowgradeendometrioid
endometrialcancershavebeenassociatedwithobesity,nulliparity,anovulatory
menstrualcycles,diabetes,andhypertension.Inaddition,theseyoungerwomen
areathigherriskforasynchronousprimaryovariancancer,witharateupto19
25%. [4,5]
Anothergroupofwomenatincreasedriskofpremenopausalendometrialcancerare
thosewithLynchIIsyndrome,alsoknownashereditarynonpolyposiscolorectal
cancer(HNPCC).ThisisanautosomallydominantgermlinemutationinDNA
mismatchrepair(MMR)genes(MSH1,MSH2,MSH6)andaccountsfor9%of
patientsyoungerthan50yearswithendometrialcancer.Thesemutationsleadto
microsatelliteinstabilityin90%ofcoloncancersand75%ofendometrialcancers.
Besidescoloncancer,womenaffectedhavea4060%riskofendometrialcancerby
age70years,comparedtoabaselinepopulationriskof1.5%atthesameage.
Fiftyonepercentofwomenhadendometrialorovariancancerdiagnosedfirstas
thesentinelcancer.Thesewomenarealsoatincreasedriskforcanceroftheovary,
stomach,smallbowel,hepatobiliarysystem,pancreas,brain,breast,andureteror
kidney. [6,7]
IncidenceofendometrialcancerishigheramongCaucasianscomparedwithAsian
orblackwomenhowever,mortalityishigheramongblacks.Thisisthoughttobe
duetopooraccesstocareandpresentationatmoreadvancedstages.
Uterinesarcomas,regardlessofthehistologicsubtype,aremorecommoninblack
women.Leiomyosarcoma(LMS)tendstooccurmoreofteninwomenaged3050
yearscomparedwithcarcinosarcomasandendometrialstromalsarcomas(EES),
whichhaveamuchhigherincidenceinwomenolderthan50years.Recentmeta
analysisfoundestimatedrateofleiomyosarcomastobe1in2000uteriremovedfor
presumedbenignfibroids.Alargehealthcaresystemfoundanincidenceof3.6
occultuterinesarcomasper1000hysterectomiesforfibroids. [8,9]

Etiology
Endometrioidadenocarcinomacanbeduetoexcessestrogenfromvarioussources,
eitherexogenousorendogenous.Exogenoussourceshaveincludedunopposed
estrogenreplacementtherapyortamoxifenuse.Tamoxifenincreasesendometrial
cancerriskbyitsagonistactivityontheestrogenreceptorsontheendometrial
lining.Endogenousestrogensourcesincludeobesityandpolycysticovarysyndrome
(PCOS)withanovulatorycycles,orestrogensecretingtumorssuchasgranulose
celltumors.Increasingbodymassindexhasbeenassociatedwithincreasingriskof
endometrialcancer. [10]Researchhasfoundarelativeriskof3inwomen2150lb
overweightandrelativeriskover10inwomenmorethan50lboverweight.
Androstenedioneisconvertedtoestrone,andandrogensarearomatizedtoestradiol
intheadiposetissue,leadingtohigherlevelsofunopposedestrogeninobese
women.SeeTable1.
Table1.FactorsContributingtoEndometrialCancer(OpenTableinanewwindow)
RiskFactor

NumberofFoldsIncreased
Risk

Estrogenonlyhormonereplacementtherapy
(HRT)

210

Obesity

220

PCOS,chronicanovulation

Tamoxifen

23

Nulliparity

23

Earlymenarche,latemenopause

23

Hypertension,diabetes

23

Theotherfactorsassociatedwithincreasingonesriskofendometrialcancerare
believedtoberelatedtothesamemechanismofincreasedlevelsofunopposed
estrogen.Nulliparityandinfertilityarelikelyrelatedtochronicanovulation.
Increasedalcoholusecanelevateestrogenlevels.Latemenopauseandearly
menarchecanbeassociatedwithmoreanovulatorycyclesandthusmore
unopposedestrogen.
Whilethereisnoevidencethatscreeningforendometrialcancerinhighrisk
populations,suchaspatientsontamoxifenorpatientswhohaveHNPCCsyndrome,
decreasesmortality,somesocietiesadvocatescreeningwithendometrialbiopsies
startingatage35yearsinpatientswithHNPCC.

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Factorsthatdecreaseunopposedestrogenareassociatedwithdecreasedriskof
endometrialcancers.Theuseofcombinationoralcontraceptivepillsfor12months
decreasestheriskofendometrialcancerbymorethan40%. [11]Similarly,
postmenopausalwomentakingthecombinedestrogenandprogesteronehormone
replacementtherapyhavealsobeenfoundtodecreasetheirrateofendometrial
cancer. [12]Smokingisthoughttodecreasetheriskofendometrialcancerby
decreasingestrogenlevelsaswellasleadingtoearliermenopause.
Thefollowinghavebeenidentifiedasriskfactorsforthevariousuterinesarcomas.
Riskfactorsforuterineleiomyosarcomasmayincludeearlymenarche,late
menopause,andAfricanAmericanrace.Womenwithahistoryofpelvicradiation
areatgreatestriskforcarcinosarcomasandleiomyosarcomas.Nulliparouswomen
maybeatgreaterriskforbothtypesofsarcomas.Tamoxifenusealsoincreases
theriskofendometrialcarcinomaaswellasuterinesarcomas.

Pathophysiology
Fibroblastgrowthfactorreceptor2(FGFR2)isatyrosinekinasereceptorinvolvedin
manybiologicalprocesses.MutationsinFGFR2havebeenreportedinupto10
12%ofendometrialcarcinomas.InhibitionofFGFR2couldbeanewtherapeutic
targetinendometrialcarcinoma.GatiusetalsuggestthatFGFR2hasadualrolein
theendometrium,inhibitingcellproliferationinnormalendometriaduringthe
menstrualcyclebutactingasanoncogeneinendometrialcarcinoma. [13]
Endometrialcancersaredividedinto2classes,eachwithdifferingpathophysiology
andprognosis.
Morethan80%ofendometrialcarcinomasaretypeIandareduetounopposed
estrogenstimulation,resultinginalowgradehistology.Itisoftenfoundin
associationwithatypicalendometrialhyperplasia,whichisthoughttobeaprecursor
lesion.TypeIIendometrialcancersarethoughttobeestrogenindependent,
occurringinolderwomen,withhighgradehistologiessuchasuterinepapillary
serousorclearcell.
Endometrialcancermayoriginateinasmallarea(eg,withinanendometrialpolyp)
orinadiffusemultifocalpattern.Earlytumorgrowthischaracterizedbyan
exophyticandspreadingpattern.Thisgrowthischaracterizedbyfriabilityand
spontaneousbleeding,evenatearlystages.Latertumorgrowthischaracterizedby
myometrialinvasionandgrowthtowardthecervix.Fourroutesofspreadoccur
beyondtheuterus:
Direct/localspreadaccountsformostlocalextensionbeyondtheuterus.
Lymphaticspreadaccountsforspreadtopelvic,paraaortic,and,rarely,
inguinallymphnodes.
Hematologicspreadisresponsibleformetastasestothelungs,liver,bone,
andbrain(rare).
Peritoneal/transtubalspreadresultsinintraperitonealimplants,particularly
withuterinepapillaryserouscarcinoma(UPSC),similartothepattern
observedinovariancancer.
Endometrioidadenocarcinomaoftheendometrium,themostcommonhistology,is
usuallyprecededbyadenomatoushyperplasiawithatypia.Ifleftuntreated,simple
andcomplexendometrialhyperplasiawithatypiaprogresstoadenocarcinomain8%
and29%ofcases,respectively.Withoutatypia,simpleandcomplexhyperplasia
progresstocancerinonly1%and3%ofcases,respectively.Seetheimagebelow.

Typicalhistologicpattern,specificallycribriformglandularappearance,ofendometrioid
adenocarcinomaoftheendometrium.Increasednuclearatypiaandmitoticfiguresarepresent.

Endometrialadenocarcinomaishistologicallycharacterizedbycribriformglands(or
glandularcrowding)withlittle,ifany,stromaltissuebetweentheglands.Nuclear
atypia,variationinglandsize,andincreasedmitosesarecommonin
adenocarcinoma.Welldifferentiatedtumorsmaybeconfusedwithcomplex
hyperplasiawithatypiahistologically.Likewise,poorlydifferentiatedtumorsmight
beconfusedwithsarcomashistologically.Allpapillaryserousandclearcell
histologiesareconsideredgrade3.Thedifferentiationofendometrialcancersisone
ofthemostimportantprognosticfactors.Grade1,2,and3tumorsmakeup
approximately45%,35%,and20%,respectively,ofadenocarcinomasofthe
endometrium.The5yearsurvivalrateofclinicalstageIcancersis94%,88%,and
79%forgrade1,2,and3tumors,respectively.Thedegreeofhistologic

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differentiationofadenocarcinomaoftheendometriumasdefinedbythe
InternationalFederationofGynecologyandObstetrics(FIGO)isasfollows:
FIGOgrade15%orlessofsolid/nonglandularareas
FIGOgrade2650%ofsolid/nonglandularareas
FIGOgrade3Morethan50%ofsolid/nonglandularareas
Lesshistologicdifferentiationisassociatedwithahigherincidenceofdeep
myometrialinvasionandlymphnodemetastases.Subsequently,thedepthof
myometrialinvasionandpresenceoftumorinthelymphnodesisdirectlyrelatedto
recurrenceratesand5yearsurvivalrates.

Histologicalvariants
Themostcommonhistologicsubtypeofendometrialcancerisendometrioid
adenocarcinoma,accountingforabout7580%ofendometrialcancers.Less
commonhistologiesincludeadenosquamous(2%)andmucinous(2%).When
correctedforgrade,however,thepresenceofsquamouscomponentshasnotbeen
demonstratedtocauseasignificantdifferenceinprognosiscomparedtopure
adenocarcinomas.PTENmutationisthoughttobeanearlyeventinlowgrade
endometrialcancersandisfoundin55%ofhyperplasiaand85%ofcancers,
whereasitisnotfoundinbenignendometrium.
Approximately1520%ofendometrialcancersaretypeIIcancerswithpapillary
serousorclearcellhistologies.Papillaryseroushistologyrepresents510%and
clearcellhistologyrepresentslessthan5%ofendometrialcancers.Theyare
consideredhighgradewithpoorprognosis.Theyhaveapropensityforearlynodal
orupperabdominalspreadevenwithminimalornomyometrialinvasion.Thep53
mutationismorecommoninhighgradetumors,andERBB2(HER2/neu)
mutationiscommonintypeIIcancers.EvenwithsurgicalstageIcancer,the5year
survivalrateis60%.Histologically,uterinepapillaryserouscarcinoma(UPSC)
resemblespapillaryserouscarcinomaoftheovary.Althoughadjuvantchemotherapy
ishelpful,UPSCdoesnothavethesamedurationofresponsetocytotoxicagents
(eg,paclitaxel,carboplatin)asitsovariancounterpart.
Carcinosarcomasormalignantmixedmlleriantumors(MMMT)are
typicallycomprisedofahighgradeepithelialcarcinomaandstromalsarcoma.The
sarcomatousportionofthetumormayexhibitanendometrialstromalsarcoma
(ESS)pattern,ifdifferentiated.TheMMMTisconsideredhomologousifthe
sarcomatoustissuetypesarenativetotheuterus.MMMTsaretermed
heterologousonlyifidentifiableextrauterinehistologyisdemonstrated,suchas
rhabdomyosarcoma,chondrosarcoma,osteosarcoma,orliposarcoma.MMTsare
characterizedbyearlyextrauterinespreadandlymphnodemetastases.Extrauterine
diseaseandlymphnodemetastasesaredirectlyrelatedtodepthofmyometrial
invasionandthepresenceofcervicaldisease.Thepresenceofheterologous
elementsdoesnotseemtoaffectprognosisintermsoftheinitialextentofdisease.
NewevidencepointstoasubstantialexpressionofckitreceptorsinMMMTs.
Thehistopathologicdiagnosisofuterinesarcomascanbeunclearuntilthetimeof
definitivesurgery.Diagnosisofleiomyosarcomaisdependentonthenumberof
mitosesandthedegreeofcellularatypia.Thediagnosisofleiomyosarcomaversus
leiomyomaandleiomyomawithhighmitoticactivityoruncertainmalignantpotential
isbasedonthemetastaticpotentialofthetumor.Themitoticcountandcellular
atypiacorrelatestothismetastaticpotential.Althoughcontroversycontinuesto
existregardingthediagnosisofleiomyosarcoma,severalstudiessupportthetheory
thatifthemitoticcountislessthan5per10highpoweredfields(HPF),thetumor
isaleiomyomawithnegligiblemetastaticpotentialregardlessofthepresenceof
anycellularatypia.Likewise,thetumorhasahighmetastaticpotentialandis
consideredanleiomyosarcoma,regardlessofthedegreeofcellularatypia,ifthe
mitoticcountisgreaterthan10per10HPF.Somebelievethatmitoticcountalone
isnotagoodindicatorofmetastaticpotential.
EndometrialStromalSarcomas(ESS)areatypeofuterinecancerarisingfromthe
uterinemesenchymaltissue.ESScanbedividedinto2categories:lowgrade
ESS(LGESS)andhighgradeorundifferentiatedESS(HGESS).LGESSis
characterizedbyfewerthan510mitosesper10HPFandminimalcellularatypia.
Thesetumorscanhavearecurrencerateofupto50%butdemonstrateindolent
growthandlaterecurrences.HGESShaveagreatermitoticcountanddegreeof
cellularatypiawithassociatednecrosisandinvasion.Riskofrecurrenceinboth
LGESSandHGESSisdeterminednotonlybyhistologicalcharacteristicsbutalso
bysurgicalstageandextentofdisease.
Uterineadenosarcomasarecomprisedofmixedepithelialandmesenchymal
tissues.Theyarerareandusuallydiagnosedwithdiseaseconfinedtotheuterus.

Presentation
Morethan90%ofpatientswithendometrialcancerwillpresentwithabnormal
vaginalbleeding,whetheritismenorrhagia,metrorrhagia,oranyamountof
postmenopausalbleeding.Approximately10%ofpostmenopausalbleedingwilllead
toadiagnosisofendometrialcancer.Advancedcases,especiallypatientswith
uterinepapillaryserousorclearcellhistologiesmaypresentwithabdominalpain
andbloatingorothersymptomsofmetastaticdisease.Otherpresentingsymptoms
mayincludepurulentgenitaldischarge,pain,weightloss,andachangeinbladder
orbowelhabits.Fortunately,mostcasesofendometrialcancerarediagnosedprior
tothisclinicalpresentationbecauseoftherecognitionofpostmenopausalbleeding

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asapossibleearlysymptomofcancer.About5%ofwomenmaybeasymptomatic
anddiagnosedafterworkupofabnormalPapanicolaoutestresults.
Uterinesarcomascanpresentinasimilarfashiontoendometrialcarcinomaswith
vaginalbleeding,andoftenpelvicpressure.Imagingwillrevealauterinemassand
enlargement.Leiomyosarcomamaypresentinwomenearlyinthesixthdecadeof
lifewithirregularmensesorpostmenopausalbleeding.Othersymptomsinclude
pain,pelvicpressure,andarapidlyenlargingpelvicmass.Unfortunately,the
diagnosisisrarelymadepriortodefinitivesurgery.Endometrialstromalsarcoma
(ESS)usuallypresentswithpostmenopausalbleeding,pelvicpain,andanenlarging
mass.Likemixedmlleriantumors(MMT),ESStypicallypresentsintheseventh
decadeoflife.Weightloss,anorexia,andchangeinbowelorbladderhabitsare
signsofadvanceddiseaseinallcasesofuterinecancer.

Indications
Themainstayofprimarytreatmentinendometrialcanceranduterinesarcomasis
surgery.Radiationhasanimportantroleinadjuvanttreatmentofendometrial
cancersandsarcomas.Chemotherapyplaysaroleinadjuvanttherapyforhigh
gradeuterinesarcomas,inadditiontohighgrade,recurrentormetastatic
endometrialcancer.Hormonaltherapyalsohasaroleinadjuvanttherapyin
receptorpositiveuterinecancers.Detailsregardingallofthesetherapiesare
discussedlaterinthisarticle.
Likeendometrialcancer,primarysurgicaltherapyisthefirststepintreatmentof
uterinesarcomas.Infact,thesetumorsareoftenfoundatthetimeofsurgeryfor
benignindicationssuchasuterineleiomyomataanddysfunctionaluterinebleeding.
Oftentheyarefoundincidentallyonpostoperativepathologicalevaluationof
myomectomyorhysterectomyspecimen.

RelevantAnatomy
Seetheimagesbelowforrelevantsurgicalanatomy.

Typicalhistologicpattern,specificallycribriformglandularappearance,ofendometrioid
adenocarcinomaoftheendometrium.Increasednuclearatypiaandmitoticfiguresarepresent.

Transvaginalultrasonographydemonstratinganenlargedendometrialstripe(EMS=2.4cm).

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Adenocarcinomaoftheendometrium.Thistumor,whichoccupiesasmalluterinecavity,grows
primarilyasafirmpolypoidmass.CourtesyofTELEPATH,ArmedForcesInstituteofPathology
(AFIP).

Workup

ContributorInformationandDisclosures
Author
JingWangChiang,MDClinicalAssociateProfessorofObstetricsandGynecology(Affiliated),Stanford
UniversitySchoolofMedicineChiefofGynecologicOncology,DepartmentofObstetricsandGynecology,Santa
ClaraValleyMedicalCenter
JingWangChiang,MDisamemberofthefollowingmedicalsocieties:AmericanCollegeofObstetriciansand
Gynecologists,SocietyofGynecologicOncology
Disclosure:Nothingtodisclose.
SpecialtyEditorBoard
FranciscoTalavera,PharmD,PhDAdjunctAssistantProfessor,UniversityofNebraskaMedicalCenterCollege
ofPharmacyEditorinChief,MedscapeDrugReference
Disclosure:ReceivedsalaryfromMedscapeforemployment.for:Medscape.
JoriSCarter,MD,MSAssistantProfessor,DivisionofGynecologicOncology,DepartmentofObstetricsand
Gynecology,VirginiaCommonwealthUniversitySchoolofMedicine
JoriSCarter,MD,MSisamemberofthefollowingmedicalsocieties:AlphaOmegaAlpha,AmericanCollegeof
ObstetriciansandGynecologists,SocietyofGynecologicOncology,AssociationofWomenSurgeons,
InternationalSocietyforMagneticResonanceinMedicine,AmericanSocietyofClinicalOncology
Disclosure:Nothingtodisclose.
ChiefEditor
WarnerKHuh,MDProfessor,DepartmentofObstetricsandGynecology,DivisionofGynecologicOncology,
SeniorScientist,ComprehensiveCancerCenter,UniversityofAlabamaSchoolofMedicine
WarnerKHuh,MDisamemberofthefollowingmedicalsocieties:AmericanCollegeofObstetriciansand
Gynecologists,AmericanCollegeofSurgeons,MassachusettsMedicalSociety,SocietyofGynecologic
Oncology,AmericanSocietyofClinicalOncology
Disclosure:Ihavereceivedconsultingfeesfor:MerckTHEVAX.
AdditionalContributors
JohnJKavanagh,Jr,MDChief,Professor,DepartmentofInternalMedicine,SectionofGynecologicaland
MedicalTherapeutics,MDAndersonCancerCenter,UniversityofTexasMedicalSchoolatHouston
JohnJKavanagh,Jr,MDisamemberofthefollowingmedicalsocieties:AmericanAssociationforthe
AdvancementofScience,SocietyofGynecologicOncology,AmericanAssociationforCancerResearch,
AmericanAssociationfortheHistoryofMedicine,AmericanCollegeofPhysicians,AmericanFederationfor
MedicalResearch,AmericanMedicalAssociation,SouthernMedicalAssociation,TexasMedicalAssociation
Disclosure:Nothingtodisclose.
Acknowledgements
TheauthorsandeditorsofMedscapeReferencegratefullyacknowledgethecontributionsofpreviousauthors
WilliamEWinterIII,MD,andJimAGosewehr,MD,tothedevelopmentandwritingofthisarticle.

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