Gestational Trophoblastic Neoplasia - Epidemiology, Clinical Features, Diagnosis, Staging, and Risk Stratification

2/4/2015
Gestationaltrophoblasticneoplasia:Epidemiology,clinicalfeatures,diagnosis,staging,andriskstratification
Officialreprintfrom UpToDate
www.uptodate.com 2015UpToDate
Gestationaltrophoblasticneoplasia:Epidemiology,clinicalfeatures,diagnosis,staging,andrisk
stratification
Authors
RossSBerkowitz,MD
DonaldPeterGoldstein,
MD
NeilSHorowitz,MD
SectionEditor
BarbaraGoff,MD
DeputyEditors
SandyJFalk,MD,FACOG
DonSDizon,MD,FACP
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jan2015.|Thistopiclastupdated:Dec23,2014.
INTRODUCTIONGestationaltrophoblasticneoplasia(GTN)referstoagroupofmalignantneoplasmsthat
consistofabnormalproliferationoftrophoblastictissue,andmayfollowahydatiformmoleoranonmolar
pregnancy.GTNiscomprisedofthefollowinghistologictypes:
Invasivemole
Choriocarcinoma
Placentalsitetrophoblastictumor(PSTT)
Epithelioidtrophoblastictumor(ETT)
Invasivemoleandchoriocarcinomaarecharacterizedbyhighlevelsofhumanchorionicgonadotropin(hCG),
whilePSTTandETTtypicallyhavelowhCGlevels.
PriortothedevelopmentofeffectivechemotherapyforGTN,themajorityofpatientswithdiseaselocalizedtothe
uteruswerecuredwithhysterectomy,butmetastaticdiseasewasalmostuniformlyfatal[1].Withtheuseof
sensitivequantitativeassaysforhCGandappropriatemanagementwithhighlyeffectivechemotherapy,most
womenwithGTNcanbecuredandtheirreproductivefunctionpreserved[2].
Theclinicalmanifestations,diagnosis,staging,andriskstratificationofGTNarereviewedhere.Treatmentof
GTNandmolarpregnancyarediscussedseparately:
(See"Initialmanagementoflowriskgestationaltrophoblasticneoplasia"and"Initialmanagementofhigh
riskgestationaltrophoblasticneoplasia".)
(See"Gestationaltrophoblasticdisease:Pathology".)
(See"Hydatidiformmole:Epidemiology,clinicalfeatures,anddiagnosis".)
(See"Hydatidiformmole:Management".)
TERMINOLOGY
Gestationaltrophoblasticdisease(GTD)Lesionscharacterizedbyabnormalproliferationoftrophoblastof
theplacenta.Thiscategoryiscomprisedofbenign,nonneoplasticlesions,includingplacentalsitenodule,
exaggeratedplacentalsite,andhydatidiformmole.
Gestationaltrophoblasticneoplasia(GTN)Gestationalneoplasmsinclude:choriocarcinoma,placental
sitetrophoblastictumor(PSTT),epithelioidtrophoblastictumor(ETT),andinvasivemole.Intheabsenceof
tissueforadefinitivehistopathologicdiagnosis,diseasediagnosedasaresultofpersistentelevationof
humanchorionicgonadotropin(hCG)afterevacuationofamolarpregnancyistermedGTN.
EPIDEMIOLOGYTheincidenceofgestationaltrophoblasticneoplasia(GTN)isdifficulttoestablishwith
certaintybecausedataregardingtheincidenceofpregnanciesandsubsequenttrophoblasticeventsarenot
availableinmostcountries.However,representativeestimatesareasfollows:
Approximately50percentofcasesofGTNarisefrommolarpregnancy,25percentfrommiscarriagesor
tubalpregnancy,and25percentfromtermorpretermpregnancy[3,4].
http://www.uptodate.com/contents/gestationaltrophoblasticneoplasiaepidemiologyclinicalfeaturesdiagnosisstagingandriskstratification?topicKey=
1/25
2/4/2015
WhenGTNdevelopsafteramolarpregnancy,itmayhavethehistologyofeithermolartissueor
choriocarcinoma,andrarely,placentalsitetrophoblastictumor(PSTT)orepithelioidtrophoblastictumor
(ETT).Approximately15percentofpatientsaftercompletehydatidiformmolewilldeveloplocalinvasion
and5percentwilldevelopmetastaticdisease.GTN,usuallynonmetastatic,occursin1to5percentof
patientsafterpartialhydatidiformmole[2].
GTNafteranonmolarpregnancy,usuallychoriocarcinomabutrarelyPSTTorETT,occursin
approximately2to7per100,000pregnanciesinEuropeandNorthAmerica,whereasinSoutheastAsia
andJapan,theincidenceishigherat5to200per100,000pregnancies,respectively[5,6].
TheincidenceofGTNafterspontaneousmiscarriageisestimatedat1in15,000pregnancies,whilethe
incidenceafteratermpregnancyisestimatedat1per150,000pregnancies.TheoverallincidenceofGTN
followingalltypesofpregnanciesisestimatedat1in40,000pregnancies[36].
RISKFACTORSThemainriskfactorsforthedevelopmentofgestationaltrophoblasticdisease(GTD)are
priormolarpregnancy,advancedmaternalage(>40years),andAsian,AmericanIndian,andAfricanancestry
[710].Theriskfactorsformolarpregnancyarediscussedindetailseparately.(See"Hydatidiformmole:
Epidemiology,clinicalfeatures,anddiagnosis",sectionon'Epidemiology'and"Hydatidiformmole:
Management",sectionon'Gestationaltrophoblasticneoplasia'.)
CLASSIFICATIONANDCLINICALBEHAVIORThereareseveralhistologictypesofgestational
trophoblasticneoplasia(GTN).GTNhistopathologyisdiscussedindetailseparately.(See"Gestational
trophoblasticdisease:Pathology".)
InvasivemoleInvasivemoledevelopsafteramolarpregnancyandischaracterizedbythepresenceof
edematouschorionicvilliwithtrophoblasticproliferationinvadingthemyometrium.(See"Gestational
trophoblasticdisease:Pathology",sectionon'Invasivemole'.)
PostmolarGTNdevelopsinapproximately15to20percentofpatientsfollowingcompletehydatidiformmoleand
in1to5percentofpatientsfollowingpartialhydatidiformmole[4,11].Incompletemole,postmolarGTNoccurs
morefrequently(40to50percent)inpatientswithoneormorehighriskfeatures,including[12,13]:
Preevacuationuterinesizelargerthandates
Humanchorionicgonadotropin(hCG)levels>100,000mIU/mL
BilateralovarianenlargementcausedbyexcesshCGstimulation(thecaluteincysts)
Approximately15percentofinvasivemolesremainlocalizedtotheuterus,and5percentaremetastatic[2,13].
Deepmyometrialinvasionmayoccur,andmolarvillimaybeobservedontheuterineserosa.Uterineruptureand
severeintraperitonealhemorrhagemayoccurifdeepmyometrialinvasionisleftuntreated.
Metastasesofinvasivemolesspreadhematogenouslythelungsandvaginaarethemostcommonsites[14].
ChoriocarcinomaChoriocarcinomaconsistsofinvasive,highlyvascular,andanaplastictrophoblastictissue
madeupofcytotrophoblastsandsyncytiotrophoblastswithoutvilli.(See"Gestationaltrophoblasticdisease:
Pathology",sectionon'Choriocarcinoma'.)
Choriocarcinomacanfollowanytypeofpregnancy:
Followingamolarpregnancy,choriocarcinomaismorecommonafteracompletemoleratherthanapartial
mole.
Followinganonmolarpregnancy,choriocarcinomaisthemostcommontypeofGTNplacentalsite
trophoblastictumor(PSTT)orepithelioidtrophoblastictumor(ETT)makesuponly1to2percentofGTN
followingnonmolarpregnancy[2,4,15,16].Diagnosisisoftendelayedfollowinganonmolarpregnancyand
thus,metastasesaremorecommonthanafteramolarpregnancy[17].
ChoriocarcinomaisthemostaggressivehistologictypeofGTNandischaracterizedbyearlyvascularinvasion
andwidespreadmetastases.Theclinicalpresentationofchoriocarcinomadependsuponextentofdiseaseand
locationofmetastases.Choriocarcinomametastasizeshematogenously.Theclinicalpresentationisoftendue
tobleedingfromametastaticsite[18].
2/25
2/4/2015
PlacentalsitetrophoblastictumorPSTTsaremalignantanddevelopfromextravillous,intermediate
trophoblast.Theyareusuallydiploidandmonomorphic.Microscopically,thesetumorsshownochorionicvilli
andarecharacterizedbyaproliferationofmononuclearintermediatetrophoblastcellswithovalnucleiand
abundanteosinophiliccytoplasm.(See"Gestationaltrophoblasticdisease:Pathology",sectionon'Placental
sitetrophoblastictumors'.)
PSTToccursmostcommonlyafteranonmolarabortionorpregnancy,althoughitcanalsooccurafteramolar
gestation.APSTTmaybediagnosedseveralmonthsorevenyearsafterthepregnancy[19].
AkeydifferencebetweenPSTTandinvasivemoleorchoriocarcinomaisthatitsecretesverylowlevelsofhCG.
PSTTisassociatedwithlessvascularinvasion,necrosis,andhemorrhagethanchoriocarcinoma.Inaddition,
unlikechoriocarcinoma,PSTTtendstoremainlocalizedintheuterusforlongperiodsbeforemetastasizingto
regionallymphnodesorothermetastaticsites[2022].Approximately30percentofpatientspresentwith
metastaticdisease[23].
EpithelioidtrophoblastictumorETTisararevariantofPSTT.Itdevelopsfromneoplastic
transformationofchorionictypeextravilloustrophoblast[24].ETTtypicallypresentsasadiscrete,hemorrhagic,
solid,andcysticlesionthatislocatedeitherinthefundus,loweruterinesegment,orendocervix.LikePSTT,it
formstumornodulesinthemyometrium.Microscopically,thetumoriscomposedofarelativelyuniform
populationofmononucleateintermediatetrophoblasticcellsformingnestsandsolidmasses.(See"Gestational
trophoblasticdisease:Pathology",sectionon'Epithelioidtrophoblastictumor'.)
TheclinicalbehaviorofETTissimilartoPSTT.Diagnosisistypicallylateinthecourseofdiseaseduetoslow
growth,paucityofsymptoms,andloworabsenthCGproduction[24,25].Duetolatediagnosis,approximately
50percentofpatientswithETTpresentwithmetastaticdisease[26].ETTcellsshowdiffuseexpressionof
immunohistochemicalmarkers,includingcytokeratinandinhibina.CyclinEstainingishigherinETTthan
placentalsitenodules,whichcanhelpdifferentiatebetweenthetwo[27,28].
MetastaticsitesTheriskofmetastasesvariesdependingonthehistologictypeandthedurationofdisease.
TheclinicalbehaviorofeachtypeofGTNisdescribedabove.(See'Classificationandclinicalbehavior'above.)
Ingeneral,thesitesofGTNmetastasesandtherateofspreadtoeachsite(amongpatientswithmetastases)
include[11,29,30]:
Pulmonary(80percent)(image1)
Vagina(30percent)(picture1)
Centralnervoussystem(CNS)metastases(10percent)areusuallyinthebrainand,rarely,inthe
meninges(image2).VirtuallyallpatientswithCNSmetastaseshaveconcurrentpulmonaryand/orvaginal
involvement.
Hepatic(10percent)(image3)
Othersites(kidney,gastrointestinaltract(picture2),spleen)
OVERVIEWOFDIAGNOSTICAPPROACHGestationaltrophoblasticneoplasia(GTN)hasavaried
presentationdependingupontheantecedentpregnancy,extentofdisease,andhistopathology.GTNmayfollow
amolarpregnancy(completeorpartial)oranyotherpregnancyevent(miscarriage,inducedabortion,pretermor
termpregnancy).
GTNmostcommonlypresentsfollowingevacuationofacompletehydatidiformmole,withthefollowing
characteristics:preevacuationuterinesizeislargerthangestationalageandhumanchorionicgonadotropin
(hCG)level>100,000mIU/mL.BilateralovarianenlargementisfrequentlypresentwhenthehCGlevelis
markedlyelevated.SignssuggestiveofGTNaftercompletemolarpregnancyareanenlargeduterus,abnormal
uterinebleeding(AUB),andpersistentbilateralenlargedovaries.Rarely,ametastaticnodulewillbepresentin
thevagina,whichcanbleedvigorously,particularlyifbiopsied[13,14].
Incontrast,clinicalsignsandsymptomsofGTNfollowingapartialhydatidiformmoleincludepersistentAUB
andaboggy,butnotsignificantlyenlargeduterus,withoutevidenceofbilateralenlargedovaries.Metastatic
3/25
2/4/2015
diseaseisrareafterpartialmole[13,14,31].
GTNfollowingatermorpretermgestationmaypresentwithamenorrhea,butusuallypresentswithAUBdueto
invasionofuterinetumororbleedingfromametastaticsite.Bleedingfromuterineperforationormetastatic
lesionsmayresultinabdominalpain,hemoptysis,ormelena.Patientswithcentralnervoussystem(CNS)
metastasesoftenexhibitevidenceofincreasedintracranialpressurefromintracerebralhemorrhage,leadingto
headaches,dizziness,seizures,orhemiplegia.Patientswhodevelopextensivepulmonarymetastasesmay
presentwithdyspnea,cough,orchestpain[17].Rapidgrowth,widespreaddissemination,andahigh
propensityforhemorrhagemakesthistumoramedicalemergency.
Placentalsitetrophoblastictumors(PSTT)andepithelioidtrophoblastictumors(ETT)almostalwayscause
irregularbleedingoramenorrhea,frequentlylongaftertheantecedentpregnancy.Therearerarereportedcases
ofnephroticsyndromeandvirilizingsyndromeassociatedwiththeseconditions[16,25].Followinganonmolar
antecedentpregnancy,choriocarcinomaisthemostcommonhistopathologictypeofGTNthatdevelops.
Choriocarcinomamaypresentwithnonspecificsignsandsymptoms,makingthediagnosisdifficult.This
frequentlyaccountsforadelayindiagnosis,whichoftenadverselyaffectsprognosis.Patientswhodevelop
risinghCGvaluesfollowinganonmolarpregnancyshouldbeconsideredtohavechoriocarcinomauntilproven
otherwise.However,serumhCGlevelsareroutinelymonitoredinwomenwhohaveapreviousmolarpregnancy,
butnotinotherwomen(exceptfollowingectopicpregnancies).Thus,apersistentlyelevatedhCGdoesnot
generallycometomedicalattentionunlessitismeasuredtoevaluatesymptoms(eg,AUB)[2].
PSTTandETTalmostalwayscauseAUBoramenorrhea,frequentlylongaftertheantecedentpregnancy.
TherearerarereportedcasesofnephroticsyndromeandvirilizingsyndromeassociatedwithGTN[16,25,32].
AnyreproductiveagewomanwithunexplainedpersistentlyelevatedorrisinghCGlevelsshouldbeconsideredto
potentiallyhaveGTN.OthersourcesofpersistentlevelsofhCGshouldbeexcluded,suchasnormalpregnancy,
pituitaryhCG,phantomhCG,andectopichCGproductionfromothertumors.(See'Differentialdiagnosis'below
and"Humanchorionicgonadotropin:Testinginpregnancyandgestationaltrophoblasticdiseaseandcausesof
lowpersistentlevels".)
WhenthediagnosisofGTNismade,patientsmustbeevaluatedforextentofdisease.Allpatientsshouldhave
achestradiographandpelvicexaminationtoidentifypossiblelungandvaginalinvolvement.Intheabsenceof
lungandvaginalmetastases,involvementofothermetastaticsitesisuncommon.
CLINICALPRESENTATIONGestationaltrophoblasticneoplasia(GTN)hasavariedclinicalpresentation
dependingupontheantecedentpregnancy,extentofdisease,andhistologictype.
Elevatedhumanchorionicgonadotropin(hCG)AnelevatedhCGiswhatbringsGTNtomedicalattention
aftermolarpregnancy.Thisistrueforpatientswithapriormolarpregnancy,inwhomweeklyhCGmeasurement
ispartofposttreatmentsurveillance.AnhCGlevelthatdoesnotreturntoundetectablesuggeststhe
developmentofGTN.(See"Hydatidiformmole:Management",sectionon'SerialhCG'and'hCG'below.)
Forwomenwithnohistoryofmolarpregnancy,anelevatedhCGismostoftennotedaspartoftheevaluationfor
otherpresentingsymptoms.
hCGstimulationeffectsPatientswithGTN,particularlyinvasivemoleorchoriocarcinoma,mayhave
highhCGlevels.Atlevels>100,000mIU/mL,hCGstimulationeffectsmaydevelop.Theymaydevelopendocrine
symptoms.Theseincludesymptomsorfindingsofhyperthyroidism,ovarianthecaluteincysts,andrarely,
hyperemesisorpreeclampsia.(See"Diagnosisofhyperthyroidism",sectionon'Symptoms'and"Approachto
thepatientwithanadnexalmass",sectionon'Medicalhistory'and"Clinicalfeaturesandevaluationofnausea
andvomitingofpregnancy"and"Preeclampsia:Clinicalfeaturesanddiagnosis",sectionon'Clinical
presentation'.)
AbnormaluterinebleedingoramenorrheaAbnormaluterinebleeding(AUB)maybepartoftheclinical
presentationafteramolarornonmolarpregnancy.ForGTNafteranonmolarpregnancy,AUBoramenorrheais
oftenthepresentingsymptom.
Insomecases,uterinebleedingfromGTNcanbesevereandmayrequireresectionofdisease.Ifsurgeryis
4/25
2/4/2015
plannedinthissituation,selectiveangiographymaybeutilizedtolimitbloodlossandallowtheextentof
diseasetobeevaluated.Alternatively,selectiveangiographyandembolizationmaybeemployedasan
alternativetotumorresectiontocontrolbleeding[3335].(See"Managinganepisodeofsevereorprolonged
uterinebleeding",sectionon'Therapeuticmeasures'.)
PelvicpainorpressureIfanenlargeduterusorovariancystsarepresent,thepatientmayreportpelvic
painorpressure.(See'Physicalexamination'below.)
Symptomsofmetastases
PulmonaryDyspnea,chestpain,cough,orhemoptysismayoccurduetolungmetastases.Theextent
ofandseverityofsymptomsduetopulmonarymetastasesmayvarysubstantially,dependinguponwheninthe
courseofthediseasethemetastasesaredetected.Inourpractice,theNewEnglandTrophoblasticDisease
Center(NETDC),wegenerallydetectpulmonarymetastasesradiographically,beforerespiratorysymptoms
develop.Incontrast,forpatientswhodonotpresenttoatrophoblasticdiseasecenter,detectionmaybe
delayed.Asanexample,inonestudyof79womenwithGTNandwithpulmonarymetastases,33percent
displayed>50percentopacificationoftheirlungatpresentation,48percenthadevidenceofaprominentpleural
effusion,and11percentdevelopedrespiratoryfailure[36].
Trophoblasticembolimaycausepulmonaryarterialocclusionleadingtorightheartstrainandpulmonary
hypertension,whichmayleadtoafalsediagnosisofprimarypulmonarydisease[37].Thisisespeciallytrueif
theantecedentpregnancyisremoteandthegynecologicsymptomsareminimaltoabsent.
VaginalVaginalmetastasestypicallypresentwithvaginalbleedingorpurulentvaginaldischarge.
CentralnervoussystemCentralnervoussystem(CNS)involvementmaybeasymptomaticinitially,but
asthediseaseprogresses,patientsdevelopneurologicsignsandsymptomsduetoincreasedintracranial
pressureorhemorrhage,including:headache,neuropathy,dizziness,nausea,slurredspeech,visual
disturbances,and/orhemiparesis[38,39].Neurologicsymptomsarereportedtooccurin87to100percentof
patientswithbrainmetastases[4042].
HepaticJaundice,epigastric,orbackpainmayoccurinpatientswithlivermetastases,butfewerthan
onethirdofpatientswithlivermetastasesaresymptomatic[43].
Patientswithlivermetastasesmaybeatriskforintraabdominalhemorrhageifthetumorsrupture,which
representsamedicalemergency[43].Hepaticlesionsshouldnotbebiopsiedbecauseofriskofhemorrhage.
OtherGTNisrarelyassociatedwithnephroticsyndromeorvirilization[16,25].Virilizationmaybedueto
longstandingstimulationofovarybyhCG,causingthecacellhyperplasiawithsubsequentelevated
testosteronelevels[32].
DIAGNOSTICEVALUATIONThekeyelementsofthediagnosticevaluationaretoconfirmanelevated
humanchorionicgonadotropin(hCG)andevaluateformetastaticdiseaseorhCGstimulationeffects.Themost
commonmetastaticsiteisthevaginaorlungs.Uterinecurettageorotherbiopsieshavealimitedroleinthe
diagnosisofgestationaltrophoblasticneoplasia(GTN),becauseofriskofhemorrhageandbecauseGTNisa
clinicaldiagnosis.(See'Metastaticsites'aboveand'Diagnosis'below.)
HistorySymptomsassociatedwithgestationaltrophoblasticneoplasia(GTN)shouldbeelicited.(See
'Clinicalpresentation'above.)
Anobstetrichistoryistaken.Theobstetrichistoryshouldincludethedates,duration,andoutcomeofall
pregnancies.Ahistoryofamolarpregnancyis,ofcourse,themostimportantriskfactorforgestational
trophoblasticneoplasia(GTN),particularlyinvasivemole.Asnoted,however,GTNmayoccurafterany
pregnancy,includingspontaneousorinducedabortion,pretermdelivery,ortermdelivery.
Amedical,gynecologic,andsurgicalhistoryshouldalsobetaken.
PhysicalexaminationAcompletepelvicexaminationshouldbeperformedaswellasafocusedgeneral
physicalexaminationtoevaluateformetastases.
Onspeculumexamination,thevaginashouldbeexaminedformetastases.Thesearegenerallyidentifiableasa
5/25
2/4/2015
vascularimplant(picture1),mostcommonlylocatedinthesuburethralareaorfornices.Theselesionsshould
notbebiopsiedbecausetheyareextremelyvascular,andhemorrhagemayoccur.
Onbimanualexamination,theuterusmaybeenlargedduetothepresenceoftumoraswellashCGstimulation.
Uterineenlargementoccursinmanyconditions(eg,normalpregnancy,uterineleiomyomas,otheruterine
malignancies),andimagingisrequiredforfurtherevaluation.Theuterusisusuallymobileratherthanfixed.
BilateraladnexalmassesmaybepresentifovarianthecaluteincystshavedevelopedduetohCGstimulation.A
unilateraladnexalmasssuggestsanothertypeofadnexalmass.
Ageneralphysicalexaminationwithafocusonlikelysiteofmetastasesshouldbeperformed(ie,lungs,liver,
centralnervoussystem[CNS]).
Rarely,GTNisassociatedwithvirilization,whichmayincludemalepatternhairgrowthonthebodyorhead,
deepeningofthevoice,orclitoromegaly[16,25].
Laboratoryevaluation
hCGAnelevatedhumanchorionicgonadotropin(hCG)isoftenthefirstevidenceofpossibleGTN.A
serumquantitativehCGshouldbedrawninallpatientswithsuspectedGTN,includingwomenwithapriormolar
pregnancy,nonmolarpregnancy,noknownhistoryofpregnancy,andanywomanofreproductiveagewith
evidenceofmetastaticdiseasewithoutanobviousprimarysiteofmalignancy.
Forwomenwithapriormolarpregnancy,serialmeasurementofhCGispartofposttreatmentsurveillance,
andanelevation,plateau,orpersistenceofhCGsuggeststhedevelopmentofGTN.(See'Followinga
molarpregnancy'below.)
Forwomenwithnopriorhistoryofamolarpregnancy,anelevatedhCGmaybeinitiallypresumedtobea
normalpregnancy.GTNmaybesuspectedifpelvicultrasounddoesnotconfirmanonmolarpregnancy
(viableintrauterinepregnancy,spontaneousabortion,orectopicpregnancy),orinsomecases,ifthe
patientiscertainthatshehasnotconceivedrecently.
PatientswithanelevatedhCGshouldbeevaluatedwithultrasound.ForhCGlevelsbelowthe
discriminatoryzone(levelabovewhichagestationalsacshouldbevisualizedbytransvaginalultrasoundif
anintrauterinepregnancyispresent1500or2000mIU/mLinmostinstitutions),agestationwillnotbe
visualized,andthepatientshouldbeevaluatedagainbasedupontheclinicalsetting.SerialhCGlevels
shouldbedeterminedat48to72hourintervalsuntilitisdeterminedthatthepregnancyiseithernormalor
abnormal.IfthehCGlevelsorultrasoundsuggestthatthepregnancyisabnormal,furtherevaluationshould
becarriedouttoexcludeGTN.Otherlaboratorytestsorimagingstudiesshouldbeperformedtoassess
formetastaticdisease.(See'Liverfunctiontests'belowand'Otherimagingstudies'below.)
Thediagnosisofanormalpregnancyandevaluationofpatientsforearlypregnancycomplicationsisdiscussed
indetailseparately.(See"Clinicalmanifestationsanddiagnosisofearlypregnancy"and"Overviewofthe
etiologyandevaluationofvaginalbleedinginpregnantwomen"and"Spontaneousabortion:Riskfactors,
etiology,clinicalmanifestations,anddiagnosticevaluation"and"Ectopicpregnancy:Clinicalmanifestationsand
diagnosis".)
ThelevelofserumhCGvariesacrosshistologictypesofGTN:
Invasivemoleandchoriocarcinomadevelopfromthecytoandsyncytialcellsofthevilloustrophoblast.
TheseneoplasmsproduceabundantamountsofhCG,whichcantypicallyrangefrom100toover100,000
mIU/mLdependingontheextentofdisease.hCGlevelsareparticularlyhighinpatientswithanonmolar
antecedentpregnancyduetodelaysindiagnosis,whereastheytendtobelowerfollowingmolar
evacuationwhenGTNisusuallydiagnosedearlyduetopostmolarhCGmonitoring.Forthesehistologies,
hCGservesasatumormarkerfordiagnosis(evenintheabsenceofhistologicconfirmation),aswellasfor
monitoringtreatmentresponse,andposttreatmentsurveillance[17].
Placentalsitetrophoblastictumors(PSTT)andepithelioidtrophoblastictumors(ETT)originatefromthe
intermediatecellsofextravilloustrophoblast,ratherthanthesyncytiotrophoblast,andproducelowlevelsof
hCG,makingtheuseofhCGasatumormarkerlessreliable[4446].hCGlevelsinthesepatientsare
6/25
2/4/2015
usually<1000mIU/mLandareinfrequentlyundetectable.Asanexample,inonereportofpatientswith
PSTT,serumlevelsofhCGwereraisedinallpatients,butin41of62(69percent),thelevelwasonly
moderatelyincreased(<1000mIU/mL)[44].
InwomenwithPSTT,measurementofthefreebetasubunitofhCGmaybeusefultoestablishthe
diagnosis.AssaysforthefreebetasubunitofhCGmeasurethebetachainofhCGwithoutthealphachain
andcarbohydratemoiety.PSTTmaybecharacterizedbyanelevatedfreebetasubunittototalhCGratio
orpercent.Asanexample,inaretrospectivestudyof13casesofPSTTand12nontrophoblastic
malignancies,anhCGfreebetasubunitpercent>35percenthada100percentsensitivityandspecificity
forPSTT[47].FurtherstudyisneededtoevaluatetheperformanceofanhCGfreebetasubunitpercentas
adiagnostictestforPSTT.Atthistime,anassayforfreebetasubunitisnotcommerciallyavailable.
Onrareoccasionsfollowingmolarevacuation,thehCGlevelwillfailtonormalizeandremainelevatedat
lowlevels(<200mIU/mL).Onecauseofpersistent(presentforatleastthreemonths)lowlevelhCGis
quiescentGTNthatmostcommonlyfollowsacompletemole.QuiescentGTNisthoughttobeduetothe
presenceofhighlydifferentiated,noninvasivesyncytiotrophoblastcells[48].(See"Hydatidiformmole:
Management",sectionon'PersistentlowhCG(quiescentGTN)'.)
ThephysiologyofhCGandtheevaluationofwomenwithpersistentlowhCGlevelsisdiscussedindetail
separately.(See"Humanchorionicgonadotropin:Testinginpregnancyandgestationaltrophoblasticdisease
andcausesoflowpersistentlevels",sectionon'Gestationaltrophoblasticdisease'.)
ThyroidfunctiontestsThyroidfunctiontestsshouldbeorderedifthehCGlevelis>100,000mIU/mLto
determineifthepatientmaybehyperthyroid.Thisisparticularlyimportantinpatientswithunevacuatedmolar
pregnancywhoareabouttoundergoanesthesiabecauseoftheriskofthyroidstorm.
LiverfunctiontestsAlanineaminotransferase(ALT)andaspartateaminotransferase(AST)shouldbe
drawntoassessformetastases.
RenalfunctiontestsRenalfunctiontestsshouldalsobedeterminedpriortoinitiationofchemotherapy.
Also,inrarecases,PSTTorETTisassociatedwithnephroticsyndrome[16,25].(See"Overviewofheavy
proteinuriaandthenephroticsyndrome".)
OthertestsVirilization,whileinfrequent,canoccurinpatientswithGTN.Ifpresent,serumtestosterone
levels(freeandtotal)shouldbemeasured[16,25,32].(See"Overviewofandrogendeficiencyandtherapyin
women".)
ImagingstudiesApelvicultrasoundisperformedinallwomenwithsuspectedGTN.Achestradiographis
alsoorderedbecausethelungsarethemostcommonsiteofmetastases.Otherimagingstudiesareperformed
ifthechestradiographorvaginalexaminationshowsevidenceofmetastaticdisease,orifothermetastaticsites
aresuspectedbaseduponsymptomsorlaboratoryfindings.
PelvicultrasoundPelvicultrasoundistheimagingmodalityusedtoevaluatetheuterusandadnexaif
GTNissuspected[49].SonographicfindingsinwomenwithGTNinclude:
InvasivemoleInvasivemoletypicallyappearsasoneormorepoorlydefinedmassesintheuteruswith
anechoicareas.ColorDoppleroftheanechoicareasrevealshighvascularflow.Invasionintothe
myometriummaybevisualized.
ChoriocarcinomaChoriocarcinomaappearsasamassenlargingtheuterus,withaheterogeneous
appearancethatcorrelateswithareasofnecrosisandhemorrhage(image4).Thetumorisusually
markedlyhypervascularoncolorDoppler(image5).Thetumormayextendintotheparametrium.
PlacentalsitetrophoblastictumorPSTTalsoappearsasahyperechoicintrauterinemass,usuallywith
lesshemorrhagethanobservedwithchoriocarcinoma.Bothcysticandsolidlesionscanbepresent,with
orwithoutacentralcomponent.Themassusuallyinvadesthemyometrialwall.
EpithelioidtrophoblastictumorEarlyinthecourseofthedisease,transvaginalultrasoundreveals
irregularecholucentlacunaewithinthemyometrium,someofthemfilledwithlowresistance,turbulent
bloodflowonDopplerexamination,suggestiveofthediagnosisofgestationaltrophoblasticdisease(GTD).
7/25
2/4/2015
Lateinthecourseofthedisease,transvaginalultrasoundrevealsawellcircumscribedechogeniclesionin
theuterinefundus,frequentlywithnodetectablebloodflowonDopplerimaging.Mostreportedcasesof
ETTshowsolitarynoduleswithsharpmarginsonultrasound.Ultrasoundmaybehelpfulindifferentiating
ETTfromPSTT,whichshowsinfiltrativegrowthinsinuatingbetweenmusclefibers[50].
ChestimagingAllpatientsshouldhaveabaselinechestradiographtoevaluateforlungmetastases
(image1)ratherthanchestcomputedtomography(CT),sinceachestradiograph,notCT,isthebasisfor
InternationalFederationofGynecologyandObstetrics(FIGO)staging.Inaddition,althoughmicrometastases
aredetectedin40percentofchestCTscansperformedonpatientswithanegativechestradiograph,theydo
notappeartoaffectoutcomeandarenotconsideredtobeariskfactorforresistancetochemotherapy[51,52].
ChestCTorpositronemissiontomography(PET)CTmaybeusefulinpatientswithchemotherapyresistanceto
helpidentifysitesofresistanttumor[33,51,52].(See'Stagingandriskassessment'below.)
Onchestimaging,fourprincipalpulmonaryradiographicpatternsareseeninpatientswithGTN:1)discrete
roundeddensities2)analveolaror"snowstorm"pattern3)pleuraleffusionor4)embolicpatterncausedby
pulmonaryarterialocclusion[5356].
OtherimagingstudiesForpatientswithnovaginalmetastasesonexamination,anormalchest
radiograph,andnormalliverfunctiontests,additionalimagingisnotnecessarysincedistantmetastasesare
unlikely.
Ifthereisevidenceofmetastaticdiseaseoninitialevaluation,theevaluationshouldbeexpandedtoincludeone
ormoreofthefollowingstudies:
CToftheabdomenandpelvis(image3).Alternatively,wholebody18fluorodeoxyglucosepositron
emissiontomography(18FDGPET)scancanbeused(image6)[33].
Magneticresonanceimaging(MRI)orCTscanofthebrain(withandwithoutcontrast)(image2)[4042].If
brainimagingisequivocalornegativeandthepatientssymptomsarehighlysuspiciousofbrain
involvement,alumbarpuncturemaybeindicatedinordertomeasuretheplasmatocerebrospinalfluid
hCGratio(normal=<60:1)toruleoutoccultcerebralormeningealdisease[57,58].
Imagingofthepelvis,abdomen,andheadshouldalsobeperformedinpatientswithsymptomssuggestiveof
metastasesatthesesites(eg,neurologicsymptoms)orinpatientswithhistologicevidenceofchoriocarcinoma,
sincethelikelihoodofmetastasesishighinthistypeofGTN.(See'Metastaticsites'above.)
UterinecurettageUterinecurettagehasalimitedroleintheevaluationofGTN.Itsusehasgenerallybeen
reservedforpatientswhopresentwithpostpartumorpostabortalbleedingandanelevatedhCGlevelto
determinewhetherthediagnosisisGTNorretainedproductsofconception.Otherindicationsincludeaclinical
presentationthatincludesuterineenlargementoruterinediseaseonpelvicimaging.
HistopathologiccriteriaforthediagnosisofGTNarediscussedindetailseparately.(See"Gestational
trophoblasticdisease:Pathology",sectionon'Gestationaltrophoblasticneoplasia'.)
TheroleofuterinecurettageinthemanagementofGTNisalsolimited.Thisisdiscussedseparately.(See
"Initialmanagementoflowriskgestationaltrophoblasticneoplasia",sectionon'Persistentuterinebleeding'.)
DIAGNOSISGestationaltrophoblasticneoplasia(GTN)isaclinicaldiagnosismadebaseduponelevationof
serumhumanchorionicgonadotropin(hCG),afteranonmolarpregnancyandotheretiologiesofanelevatedhCG
havebeenexcluded.ImagingfindingsofuterineenlargementorpathologyconsistentwithGTN,bilateralovarian
thecaluteincysts,ormetastaticdiseasesupportthediagnosis.Unlikeothersolidtumors,atissuediagnosisis
notrequiredpriortotreatment.
TheinterpretationofhCGlevelsisbaseduponwhetherthepatienthashadapriormolarpregnancy.
FollowingamolarpregnancyFollowingevacuationofacompleteorpartialmolarpregnancy,serialserum
hCGlevelsaremeasured,typicallyonaweeklyschedule,untilanundetectablelevelisreached.IfhCGlevels
riseorremainelevatedoverseveralweeks,thediagnosisofpostmolarGTNisbaseduponthefollowing
InternationalFederationofGynecologyandObstetrics(FIGO)criteria[5961]:
8/25
2/4/2015
WeeklyhCGlevelsplateau(remainwithin10percentofthepreviousresult)overathreeweekperiod
hCGlevelincreases>10percentacrossthreevaluesrecordedoveratwoweekduration
PersistenceofdetectableserumhCGformorethansixmonthsaftermolarevacuation
TheabovecriteriaareinternationallyacceptedtomakethediagnosisofGTNforwomenwhohadapriormolar
pregnancy.However,FIGOalsoacceptsthediagnosisofGTNbasedonahistologicdiagnosisof
choriocarcinomaorinvasivemole(eg,madebyexaminationofuterinecurettings)and/ortheidentificationof
clinicalorradiologicalevidenceofmetastases(table1).
FollowinganonmolarpregnancySerumhCGmonitoringisnotroutinelyperformedafternonmolar
pregnancies.Forthisreason,womenwhodevelopGTNafteranonmolarpregnancytypicallyundergoevaluation
withserumhCGandultrasoundonlyaftertheybecomesymptomatic.Thismaybeweeksormonthsafterthe
antecedentpregnancyormonthsoryearsinthecaseofplacentalsitetrophoblastictumor(PSTT)and
epithelioidtrophoblastictumor(ETT).
ThediagnosisismadebaseduponanelevatedhCG,withtheexclusionofanyotherexplanationthan
GTN.Thisissufficientfordiagnosisevenifthereisnouterineenlargementandnoevidenceofmetastatic
disease.Itiscriticaltoexcludeanormalviablepregnancyandabnormalpregnancies(eg,spontaneous
abortion,ectopicpregnancy,ectopichCGproductionbyanontrophoblastictumor,orothercausesof
persistentlowlevelhCG)[62].(See'Differentialdiagnosis'below.)
Iftherearefindingsonexaminationorimagingthatsuggestmetastaticdisease,thissupportsthe
diagnosis.BiopsiesshouldnotbeperformedbecauseGTNlesionsarehighlyvascularandmaycause
vigorousbleeding.Thus,hemorrhageiscommon,particularlyfromtheuterusduetorepeatedtraumaby
dilationandcurettage.Lifethreateninghemorrhagemaynecessitateembolizationorresectionofthe
affectedorgan[35].Unlikeothertumors,histologicconfirmationisnotnecessaryfordiagnosis,although
onrareoccasions,abiopsymaybeneededifthereissignificantquestionaboutthediagnosisofGTN.
Anotherexceptiontoobtainingahistologicdiagnosisisinpatientswhopresentwithpostpartumor
postabortalbleeding,uterineenlargement,orevidenceofuterinediseaseonimaging.Inthesepatients,a
uterinecurettagemaybeperformedandthediagnosiscanbeconfirmedbaseduponthepathology
evaluationofthecurettagespecimen.(See'Uterinecurettage'above.)
Followinganonmolarpregnancy,themostcommonhistologictypeofGTNischoriocarcinoma,andthisshould
bepresumedtobethediagnosis,unlessprovenotherwise.(See'Choriocarcinoma'above.)
DIFFERENTIALDIAGNOSISThedifferentialdiagnosisforgestationaltrophoblasticneoplasia(GTN)depends
uponthehistoryandclinicalpresentation.Thekeyissueistodeterminewhethertheantecedentpregnancywas
amolarpregnancyornonmolarpregnancy,andwhenthatpregnancyterminated.Followingamolarpregnancy,
thediagnosisofGTNisusuallyclearlyestablishedbydoingweeklyhumanchorionicgonadotropin(hCG)
monitoring.Followinganonmolarpregnancy,however,thedifferentialdiagnosisofGTNismorechallenging.
PregnancyorothersourcesofhCGmustbeexcluded.(See"Hydatidiformmole:Epidemiology,clinical
features,anddiagnosis".)
TheobstetricdifferentialdiagnosisofelevatedhCGincludesnormalpregnancy,spontaneousabortion,and
ectopicpregnancy.Duringanonmolargestation,anatypicallyhighlevelofhCGmaybeduetomultiple
gestation.Thediagnosisofanormalpregnancyandevaluationofpatientsforearlypregnancycomplicationsis
discussedindetailseparately.(See"Clinicalmanifestationsanddiagnosisofearlypregnancy"and"Overviewof
theetiologyandevaluationofvaginalbleedinginpregnantwomen"and"Spontaneousabortion:Riskfactors,
etiology,clinicalmanifestations,anddiagnosticevaluation"and"Ectopicpregnancy:Clinicalmanifestationsand
diagnosis".)
AnelevatedhCGlevelintheabsenceofapregnancymayoccurduetootherneoplasms.Theseconditionsmay
alsohavemetastaticdisease,similartoGTN:
AnhCGproducinggermcelltumoroftheovary(See"Ovariangermcelltumors:Pathology,clinical
manifestations,anddiagnosis".)
9/25
2/4/2015
EctopicallyproducedhCGfromnontrophoblastictumorshasbeendescribedinconnectionwithawide
varietyofneoplasms,includingstomach,liver,pancreas,breast,aswellasmyelomaandmelanoma[63].
(See"Serumtumormarkersintesticulargermcelltumors"and"Intracranialgermcelltumors"and
"Extragonadalgermcelltumorsinvolvingthemediastinumandretroperitoneum"and"Pinealgland
masses",sectionon'Germcelltumors'.)
OtheretiologiesofanelevatedhCGintheabsenceofpregnancyincludepituitaryhCGorafalsepositivetest
(phantomhCG).(See"Humanchorionicgonadotropin:Testinginpregnancyandgestationaltrophoblastic
diseaseandcausesoflowpersistentlevels",sectionon'Causesandevaluationofpersistentlowlevelsof
hCG'.)
RegardingotherclinicalsignsandsymptomsofGTN:
Anenlargeduterusmaybeduetobenignormalignantpathology,includingleiomyomas,adenomyosis,or
uterinemalignancy.(See"Epidemiology,clinicalmanifestations,diagnosis,andnaturalhistoryofuterine
leiomyomas(fibroids)"and"Uterineadenomyosis"and"Endometrialcarcinoma:Clinicalfeaturesand
diagnosis"and"Uterinesarcoma:Classification,clinicalmanifestations,anddiagnosis".)
Ovarianthecaluteincystsmayalsooccurinovarianhyperstimulationsyndromeduringovulationinduction
forassistedreproduction.(See"Pathogenesisofovarianhyperstimulationsyndrome".)
Hyperthyroidismsymptomsshouldbeevaluatedandtheetiologydetermined.(See"Diagnosisof
hyperthyroidism".)
PRETREATMENTEVALUATIONPatientsdiagnosedwithgestationaltrophoblasticneoplasia(GTN)should
undergoevaluationpriortotreatmenttoassessstageandabilitytotoleratechemotherapyformanypatients,
thesetestswillhavebeenperformedduringthediagnosticevaluation(see'Diagnosticevaluation'above):
Completehistoryandphysicalexamination.
Baselinelaboratorytesting,includingapretreatmentbaselinequantitativeserumhumanchorionic
gonadotropin(hCG),completebloodcount,andhepatic,renal,andthyroidfunctiontests.
PelvicultrasoundThisisimportanttoensurethatthepatientisnotpregnant,toobtainmeasurementsof
theuterinesizeandvolume,toevaluatethedegreeofpelvicspread,andtoseeifthereisevidenceof
retainedtumororinvasion.TheuseoftransvaginalultrasoundandcolorflowDopplerisparticularlyuseful
whentheuterusisenlargedtoidentifypatientsatriskofperforationorwhomightbecandidatesfor
hysterectomytoreducetumorburden(image4andimage5)[6470].
ChestradiographAplainfilmofthechestratherthanchestcomputedtomography(CT)isthebasisfor
InternationalFederationofGynecologyandObstetrics(FIGO)staging(image1).
ReviewofavailablepathologyspecimensAlthoughhistologicconfirmationisnotrequiredfortreatmentof
GTN,ifauterinecurettageorotherbiopsyspecimenisavailable,itshouldbereviewedpriortotreatment.
Thismaybeusefulindeterminingtheapproachtotreatment.Pathologycandifferentiatebetweeninvasive
mole,choriocarcinoma,placentalsitetrophoblastictumor(PSTT),andepithelioidtrophoblastictumor
(ETT).ThemanagementofPSTTandETTdifferssignificantlyfromthemanagementofinvasivemoleor
choriocarcinoma.(See"Initialmanagementoflowriskgestationaltrophoblasticneoplasia"and"Initial
managementofhighriskgestationaltrophoblasticneoplasia".)
STAGINGANDRISKASSESSMENTForpatientswithgestationaltrophoblasticneoplasia(GTN),botha
stageandariskscoreareassignedpriortotreatment.ThisstagingsystemisacombinationoftheInternational
FederationofGynecologyandObstetrics(FIGO)stagingsystemandtheWorldHealthOrganization(WHO)
PrognosticScoringSystem,whichtakesintoaccounteightriskfactorsthathavebeenshowntopredictthe
potentialforthedevelopmentofresistancetosingleagentchemotherapywithmethotrexate(MTX)and
actinomycinD(ActD)(table1).
StageIPersistentlyelevatedhumanchorionicgonadotropin(hCG)levelstumorconfinedtotheuterine
corpus
10/25
2/4/2015
StageIITumoroutsideoftheuterus,butlocalizedtothepelvisand/orvagina
StageIIIPulmonarymetastasesonchestradiograph,withorwithoututerine,pelvic,orvaginal
involvement
StageIVMetastaticdiseaseoutsideofthelungsandpelvisand/orvagina
IntheWHOPrognosticScoringSystem,theFIGOstageisfollowedbythemodifiedWHOScoredesignatedby
anArabicnumberseparatedbyacolon(eg,II:6)[5961,7173].Theriskscoreisbasedonthefollowing
variables(table1):
Age
Antecedentpregnancy
Intervalfromlastpregnancy
PretreatmentserumhCGlevel
Largesttumor(includinguterine)
Siteofmetastases
Numberofmetastases
Priorchemotherapytreatment
TheuseoftheWHOPrognosticScoringSystemismorepredictiveofclinicaloutcomethantheuseofindividual
riskfactors[7478]:
Ascoreof0to6suggestslowriskofresistancetosingleagentchemotherapy
Ascoreof7predictsahighriskofresistancetomonotherapyandrequirescombinationchemotherapy
Theprognosticsignificanceofthissystemwasshowninasmallstudythatincluded21patientswithaWHO
score7[78,79].Allpatientsattainedacompleteremissiontochemotherapy,with67percent(n=14)doingso
withmonotherapy.Patientswithaprognosticscoreof5and6areathigherriskofresistancetosingleagent
chemotherapy,andabout70percentofthesepatientswillrequirecombinationchemotherapytoachieve
remission[80,81].
ThebenefitofusingthemodifiedWHOPrognosticScoringsystemappliesprimarilytoFIGOstagesIIandIII,
sinceessentiallyallpatientswithFIGOStageIGTNarelowrisk,and>90percentachieveremissionwith
singleagentchemotherapy.Furthermore,patientswithFIGOstageIVdiseasehavehighriskscores,which
indicateprobableresistancetosingleagentchemotherapyandtheneedforprimarytreatmentwithmultiagent
chemotherapytooptimizeoutcomes.Unfortunately,themodifiedWHOPrognosticScoringSystemisnot
particularlyusefulforpatientswithplacentalsitetrophoblastictumor(PSTT)andepithelioidtrophoblastictumor
(ETT),andtherefore,treatmentisbasedontheFIGOStagealone[82].
INDICATIONSFORREFERRALGestationaltrophoblasticneoplasia(GTN)isararedisease,andpatients
shouldbemanagedbyagynecologiconcologistand/ormedicaloncologistexperiencedwithGTN.Ideally,
patientsshouldbereferredtoatrophoblasticdiseasecenterwheneverpossible.Thesecentersprovidesufficient
clinicalexperiencetoallowopportunitiesforresearchandimprovedoutcomes.
SUMMARYANDRECOMMENDATIONS
Gestationaltrophoblasticneoplasia(GTN)referstoagroupofmalignantneoplasmsthatconsistof
abnormalproliferationoftrophoblastictissue,andmayfollowahydatiformmoleoranonmolarpregnancy.
GTNiscomprisedofthefollowinghistologictypes:invasivemole,choriocarcinoma,placentalsite
trophoblastictumor(PSTT),andepithelioidtrophoblastictumor(ETT).(See'Introduction'above.)
Approximately50percentofcasesofGTNarisefrommolarpregnancy,25percentfrommiscarriagesor
tubalpregnancy,and25percentfromtermorpretermpregnancy.TheestimatedincidenceofGTNaftera
termpregnancyis1per150,000pregnanciesandafteraspontaneousmiscarriageis1in15,000
pregnancies.(See'Epidemiology'above.)
ThemainriskfactorsforthedevelopmentofGTNarepriormolarpregnancy,advancedmaternalage(>40
years),andAsian,AmericanIndian,andAfricanancestry.(See'Riskfactors'above.)
11/25
2/4/2015
PresentingsymptomsandsignsofGTNdependuponwhethertheantecedentpregnancywasmolaror
nonmolar.Theclinicalpresentationmayinclude:elevatedserumhumanchorionicgonadotropin(hCG),
hyperthyroidism,ovarianthecaluteincysts,abnormaluterinebleeding,pelvicpainorpressure,or
symptomsofmetastaticdisease.(See'Clinicalpresentation'above.)
ThekeyelementsofthediagnosticevaluationaretoconfirmanelevatedhCGandevaluateformetastatic
diseaseorhCGstimulationeffects.Thevaginaandlungsarethemostcommonmetastaticsites.Uterine
curettageorotherbiopsieshavealimitedroleinthediagnosisofGTN.(See'Diagnosticevaluation'above
and'Metastaticsites'above.)
Allpatientsshouldhaveachestimagingtoevaluateforlungmetastases.Wesuggestachestradiograph
(image1)ratherthanchestcomputedtomography(CT).Achestradiograph,notCT,isthebasisfor
InternationalFederationofGynecologyandObstetrics(FIGO)staging,andadditionalfindingsonCTdo
typicallycontributetotreatmentplanning.(See'Chestimaging'above.)
GTNisaclinicaldiagnosismadebaseduponelevationofserumhCG,afteranonmolarpregnancyand
otheretiologiesofanelevatedhCGhavebeenexcluded.Imagingfindingsofuterineenlargementor
pathologyconsistentwithGTN,bilateralovarianthecaluteincysts,ormetastaticdiseasesupportthe
diagnosis.Unlikeothersolidtumors,atissuediagnosisisnotrequiredpriortotreatment.(See'Diagnosis'
above.)
TheGTNstagingandriskstratificationsystemisacombinationoftheFIGOstagingsystemandthe
WorldHealthOrganization(WHO)PrognosticScoringSystem(table1).(See'Stagingandrisk
assessment'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
REFERENCES
1. BrewerJI,EckmanTR,DolkartRE,etal.Gestationaltrophoblasticdisease.Acomparativestudyofthe
resultsoftherapyinpatientswithinvasivemoleandwithchoriocarcinoma.AmJObstetGynecol1971
109:335.
2. GoldsteinDP,BerkowitzRS.Currentmanagementofgestationaltrophoblasticneoplasia.HematolOncol
ClinNorthAm201226:111.
3. HertigAT,MansellH.Tumorsofthefemalesexorgans.Part1.Hydatidiformmoleandchoriocarcinoma.
In:AtlasofTumorPathology(1stseries),ArmedForcesInstituteofPathology,Washington,DC1956.
Fascicle33.
4. NganS,SecklMJ.Gestationaltrophoblasticneoplasiamanagement:anupdate.CurrOpinOncol2007
19:486.
5. BrintonLA,BrackenMB,ConnellyRR.ChoriocarcinomaincidenceintheUnitedStates.AmJEpidemiol
1986123:1094.
6. SmithHO.Gestationaltrophoblasticdiseaseepidemiologyandtrends.ClinObstetGynecol200346:541.
7. AltieriA,FranceschiS,FerlayJ,etal.Epidemiologyandaetiologyofgestationaltrophoblasticdiseases.
LancetOncol20034:670.
8. MoodleyM,TunkyiK,MoodleyJ.Gestationaltrophoblasticsyndrome:anauditof112patients.ASouth
Africanexperience.IntJGynecolCancer200313:234.
9. MesserliML,LilienfeldAM,ParmleyT,etal.Riskfactorsforgestationaltrophoblasticneoplasia.AmJ
ObstetGynecol1985153:294.
10. BerkowitzRS,CramerDW,BernsteinMR,etal.Riskfactorsforcompletemolarpregnancyfromacase
controlstudy.AmJObstetGynecol1985152:1016.
11. GoldsteinDP,BerkowitzRS.GestationalTrophoblasticNeoplasms:ClinicalPrinciplesofDiagnosisand
Management,WBSaunders,Philadelphia1982.
12. SotoWrightV,BernsteinM,GoldsteinDP,BerkowitzRS.Thechangingclinicalpresentationofcomplete
molarpregnancy.ObstetGynecol199586:775.
12/25
2/4/2015
13. BerkowitzRS,GoldsteinDP.Clinicalpractice.Molarpregnancy.NEnglJMed2009360:1639.
14. BerkowitzRS,GoldsteinDP.Gestationaltrophoblasticdiseases.In:PrinciplesandPracticeof
GynecologicOncology,3rded,HoskinsWJ,PerezCA,YoungRD(Eds),WilliamsandWilkins,
Philadelphia2000.p.1127.
15. SecklMJ,SebireNJ,BerkowitzRS.Gestationaltrophoblasticdisease.Lancet2010376:717.
16. FeltmateCM,GenestDR,WiseL,etal.Placentalsitetrophoblastictumor:a17yearexperienceatthe
NewEnglandTrophoblasticDiseaseCenter.GynecolOncol200182:415.
17. BerkowitzRS,GoldsteinDP.Chorionictumors.NEnglJMed1996335:1740.
18. LurainJR.GestationaltrophoblasticdiseaseI:epidemiology,pathology,clinicalpresentationand
diagnosisofgestationaltrophoblasticdisease,andmanagementofhydatidiformmole.AmJObstet
Gynecol2010203:531.
19. OsborneR,DodgeJ.Gestationaltrophoblasticneoplasia.ObstetGynecolClinNorthAm201239:195.
20. FoxH,SebireNJ.Pathologyoftheplacenta,3rded,Elsevier,Philadelphia2007.
21. BaergenRN,RutgersJL,YoungRH,etal.Placentalsitetrophoblastictumor:Astudyof55casesand
reviewoftheliteratureemphasizingfactorsofprognosticsignificance.GynecolOncol2006100:511.
22. HassadiaA,GillespieA,TidyJ,etal.Placentalsitetrophoblastictumour:clinicalfeaturesand
management.GynecolOncol200599:603.
23. LanC,LiY,HeJ,LiuJ.Placentalsitetrophoblastictumor:lymphaticspreadandpossibletarget
markers.GynecolOncol2010116:430.
24. ShihIM,KurmanRJ.Epithelioidtrophoblastictumor:aneoplasmdistinctfromchoriocarcinomaand
placentalsitetrophoblastictumorsimulatingcarcinoma.AmJSurgPathol199822:1393.
25. AllisonKH,LoveJE,GarciaRL.Epithelioidtrophoblastictumor:reviewofarareneoplasmofthe
chorionictypeintermediatetrophoblast.ArchPatholLabMed2006130:1875.
26. ZhangX,LW,LB.Epithelioidtrophoblastictumor:anoutcomebasedliteraturereviewof78reported
cases.IntJGynecolCancer201323:1334.
27. MaoTL,SeidmanJD,KurmanRJ,ShihIeM.CyclinEandp16immunoreactivityinepithelioid
trophoblastictumoranaidindifferentialdiagnosis.AmJSurgPathol200630:1105.
28. BambergerAM,AupersS,MildeLangoschK,LningT.Expressionpatternofthecellcyclepromoter
cyclineinbenignextravilloustrophoblastandgestationaltrophoblasticlesions:correlationwith
expressionofKi67.IntJGynecolPathol200322:156.
29. BerkowitzRS,GoldsteinDP.Pathogenesisofgestationaltrophoblasticneoplasms.PathobiolAnnu1981
11:391.
30. BerkowitzRS,GoldsteinDP.Currentmanagementofgestationaltrophoblasticdiseases.GynecolOncol
2009112:654.
31. BerkowitzRS,GoldsteinDP,BernsteinMR.Naturalhistoryofpartialmolarpregnancy.ObstetGynecol
198566:677.
32. RajatanavinR,ChuahirunS,ChailurkitL,etal.Virilizationassociatedwithchoriocarcinoma.JEndocrinol
Invest199518:653.
33. DhillonT,PalmieriC,SebireNJ,etal.Valueofwholebody18FDGPETtoidentifytheactivesiteof
gestationaltrophoblasticneoplasia.JReprodMed200651:879.
34. GarnerEI,MeyerovitzM,GoldsteinDP,BerkowitzRS.Successfultermpregnancyafterselectivearterial
embolizationofsymptomaticarteriovenousmalformationinthesettingofgestationaltrophoblastictumor.
GynecolOncol200388:69.
35. LimAK,AgarwalR,SecklMJ,etal.Embolizationofbleedingresidualuterinevascularmalformationsin
patientswithtreatedgestationaltrophoblastictumors.Radiology2002222:640.
36. BakriYN,BerkowitzRS,KhanJ,etal.Pulmonarymetastasesofgestationaltrophoblastictumor.Risk
factorsforearlyrespiratoryfailure.JReprodMed199439:175.
37. BagshaweKD,NobleMI.Cardiorespiratoryaspectsoftrophoblastictumours.QJMed196635:39.
38. JonesWB,WagnerReissKM,LewisJLJr.Intracerebralchoriocarcinoma.GynecolOncol199038:234.
39. HongzhaoS,BaozhenW.Brainmetastasisinchoriocarcinomaandmalignantmole:ananalysisof98
cases.ChinMedJ(Engl)197992:164.
13/25
2/4/2015
40. BakriY,BerkowitzRS,GoldsteinDP,etal.Brainmetastasesofgestationaltrophoblastictumor.J
ReprodMed199439:179.
41. AthanassiouA,BegentRH,NewlandsES,etal.Centralnervoussystemmetastasesofchoriocarcinoma.
23years'experienceatCharingCrossHospital.Cancer198352:1728.
42. LiuTL,DeppeG,ChangQT,TanTT.CerebralmetastaticchoriocarcinomainthePeople'sRepublicof
China.GynecolOncol198315:166.
43. BakriYN,SubhiJ,AmerM,etal.Livermetastasesofgestationaltrophoblastictumor.GynecolOncol
199348:110.
44. SchmidP,NagaiY,AgarwalR,etal.Prognosticmarkersandlongtermoutcomeofplacentalsite
trophoblastictumours:aretrospectiveobservationalstudy.Lancet2009374:48.
45. HoekstraAV,KehP,LurainJR.Placentalsitetrophoblastictumor:areviewof7casesandtheir
implicationsforprognosisandtreatment.JReprodMed200449:447.
46. PapadopoulosAJ,FoskettM,SecklMJ,etal.Twentyfiveyears'clinicalexperiencewithplacentalsite
trophoblastictumors.JReprodMed200247:460.
47. ColeLA,KhanlianSA,MullerCY,etal.Gestationaltrophoblasticdiseases:3.Humanchorionic
gonadotropinfreebetasubunit,areliablemarkerofplacentalsitetrophoblastictumors.GynecolOncol
2006102:160.
48. KohornEI.WhatweknowaboutlowlevelhCG:definition,classificationandmanagement.JReprodMed
200449:433.
49. ZhouQ,LeiXY,XieQ,CardozaJD.SonographicandDopplerimaginginthediagnosisandtreatmentof
gestationaltrophoblasticdisease:a12yearexperience.JUltrasoundMed200524:15.
50. OkumuraM,FushidaK,RezendeWW,etal.Sonographicappearanceofgestationaltrophoblastic
diseaseevolvingintoepithelioidtrophoblastictumor.UltrasoundObstetGynecol201036:249.
51. GamerEI,GarrettA,GoldsteinDP,BerkowitzRS.Significanceofchestcomputedtomographyfindingsin
theevaluationandtreatmentofpersistentgestationaltrophoblasticneoplasia.JReprodMed2004
49:411.
52. NganHY,ChanFL,AuVW,etal.ClinicaloutcomeofmicrometastasisinthelunginstageIApersistent
gestationaltrophoblasticdisease.GynecolOncol199870:192.
53. SungHC,WuPC,HuMH,SuHT.Roentgenologicmanifestationsofpulmonarymetastasesin
choriocarcinomaandinvasivemole.AmJObstetGynecol1982142:89.
54. BAGSHAWEKD,GARNETTES.RADIOLOGICALCHANGESINTHELUNGSOFPATIENTSWITH
TROPHOBLASTICTUMOURS.BrJRadiol196336:673.
55. EVANSKT,COCKSHOTTWP,HENDRICKSEPDEV.PULMONARYCHANGESINMALIGNANT
TROPHOBLASTICDISEASE.BrJRadiol196538:161.
56. LibshitzHI,BaberCE,HammondCB.Thepulmonarymetastasesofchoriocarcinoma.ObstetGynecol
197749:412.
57. BakriY,alHawashimN,BerkowitzR.CSF/serumbetahCGratioinpatientswithbrainmetastasesof
gestationaltrophoblastictumor.JReprodMed200045:94.
58. BagshaweKD,HarlandS.Immunodiagnosisandmonitoringofgonadotrophinproducingmetastasesin
thecentralnervoussystem.Cancer197638:112.
59. KohornEI.ThenewFIGO2000stagingandriskfactorscoringsystemforgestationaltrophoblastic
disease:descriptionandcriticalassessment.IntJGynecolCancer200111:73.
60. KohornEI.Negotiatingastagingandriskfactorscoringsystemforgestationaltrophoblasticneoplasia.A
progressreport.JReprodMed200247:445.
61. NganHY,BenderH,BenedetJL,etal.Gestationaltrophoblasticneoplasia,FIGO2000stagingand
classification.IntJGynaecolObstet200383Suppl1:175.
62. HarveyRA,MitchellHD,StenmanUH,etal.Differencesintotalhumanchorionicgonadotropin
immunoassayanalyticalspecificityandabilitytomeasurehumanchorionicgonadotropiningestational
trophoblasticdiseaseandgermcelltumors.JReprodMed201055:285.
63. BraunsteinGD,VaitukaitisJL,CarbonePP,RossGT.Ectopicproductionofhumanchorionic
gonadotrophinbyneoplasms.AnnInternMed197378:39.
64. MutchDG,SoperJT,BakerME,etal.Roleofcomputedaxialtomographyofthechestinstagingpatients
14/25
2/4/2015
withnonmetastaticgestationaltrophoblasticdisease.ObstetGynecol198668:348.
65. BerkowitzRS,BirnholzJ,GoldsteinDP,BernsteinMR.Pelvicultrasonographyandthemanagementof
gestationaltrophoblasticdisease.GynecolOncol198315:403.
66. KohornEI,McCarthySM,TaylorKJ.Nonmetastaticgestationaltrophoblasticneoplasia.Roleof
ultrasonographyandmagneticresonanceimaging.JReprodMed199843:14.
67. KohornEI.Imagingpracticesinthediagnosisandmanagementofgestationaltrophoblasticdisease:an
assessment.JReprodMed201257:207.
68. MangiliG,SpagnoloD,ValsecchiL,MaggiR.Transvaginalultrasonographyinpersistenttrophoblastic
tumor.AmJObstetGynecol1993169:1218.
69. DobkinGR,BerkowitzRS,GoldsteinDP,etal.Duplexultrasonographyforpersistentgestational
trophoblastictumor.JReprodMed199136:14.
70. LongMG,BoultbeeJE,BegentRH,etal.PreliminaryDopplerstudiesontheuterinearteryand
myometriumintrophoblastictumoursrequiringchemotherapy.BrJObstetGynaecol199097:686.
71. FIGOCommitteeonGynecologicOncology.CurrentFIGOstagingforcancerofthevagina,fallopiantube,
ovary,andgestationaltrophoblasticneoplasia.IntJGynaecolObstet2009105:3.
72. PecorelliS,BenedetJL,CreasmanWT,ShepherdJH.FIGOstagingofgynecologiccancer.19941997
FIGOCommitteeonGynecologicOncology.InternationalFederationofGynecologyandObstetrics.IntJ
GynaecolObstet199964:5.
73. GoldsteinDP,ZantenPrzybyszIV,BernsteinMR,BerkowitzRS.RevisedFIGOstagingsystemfor
gestationaltrophoblastictumors.Recommendationsregardingtherapy.JReprodMed199843:37.
74. WorldHealthOrganizationScientificGrouponGestationalTrophoblasticDisease.WHOTechRepSer
1983692:1.
75. LurainJR.Treatmentofgestationaltrophoblastictumors.CurrTreatOptionsOncol20023:113.
76. GordonAN,GershensonDM,CopelandLJ,etal.Highriskmetastaticgestationaltrophoblasticdisease:
furtherstratificationintotwoclinicalentities.GynecolOncol198934:54.
77. MortakisAE,BragaCA."Poorprognosis"metastaticgestationaltrophoblasticdisease:theprognostic
significanceofthescoringsysteminpredictingchemotherapyfailures.ObstetGynecol199076:272.
78. DubucLissoirJ,ZweizigS,SchlaerthJB,MorrowCP.Metastaticgestationaltrophoblasticdisease:a
comparisonofprognosticclassificationsystems.GynecolOncol199245:40.
79. DuBeshterB,BerkowitzRS,GoldsteinDP,etal.Metastaticgestationaltrophoblasticdisease:
experienceattheNewEnglandTrophoblasticDiseaseCenter,1965to1985.ObstetGynecol1987
69:390.
80. SitaLumsdenA,ShortD,LindsayI,etal.Treatmentoutcomesfor618womenwithgestational
trophoblastictumoursfollowingamolarpregnancyattheCharingCrossHospital,20002009.BrJCancer
2012107:1810.
81. McNeishIA,StricklandS,HoldenL,etal.Lowriskpersistentgestationaltrophoblasticdisease:outcome
afterinitialtreatmentwithlowdosemethotrexateandfolinicacidfrom1992to2000.JClinOncol2002
20:1838.
82. YouB,HarveyR,HeninE,etal.Earlypredictionoftreatmentresistanceinlowriskgestational
trophoblasticneoplasiausingpopulationkineticmodellingofhCGmeasurements.BrJCancer2013
108:1810.
Topic95881Version1.0
15/25
2/4/2015
GRAPHICS
Gestationaltrophoblasticneoplasia:Lungmetastases
Chestradiographshowingpulmonaryinfiltratesinpatientwithgestational
trophoblastic neoplasia.
Graphic96988Version1.0
16/25
2/4/2015
Gestationaltrophoblasticneoplasia:Vaginalmetastases
Vaginalmetastasesinapatientwithc horioc arc inoma.

17/25
2/4/2015
Gestationaltrophoblasticneoplasia:Brainmetastasison
MRI
18/25
2/4/2015
Gestationaltrophoblasticneoplasia:Livermetastasison
CT
19/25
2/4/2015
Gestationaltrophoblasticneoplasia:Bowel
metastasis
Bowelmetastasisinapatientwithc horioc arc inoma.

20/25
2/4/2015
Ultrasoundchoriocarcinoma
Chorioc arc inoma:Patientwithstage3c horioc arc inomaaftertermpregnanc y.

Theendometrialc avityisfilledwithahyperec hoic massmeasuring3.0x2.9x
2.8c m.
CourtesyofDepartmentofRadiology,SantaClaraValleyMedicalCenter.
21/25
2/4/2015
Dopplerultrasoundchoriocarcinoma
Chorioc arc inoma:Ultrasoundrevealsahyperec hoic massshowing

hypervasc ularityonc olorDoppler.
CourtesyofDepartmentofRadiology,SantaClaraValleyMedicalCenter.
22/25
2/4/2015
Gestationaltrophoblasticneoplasia:Positronemissiontomography
oflivermetastases
23/25
2/4/2015
FIGOStagingofGestationalTrophoblasticNeoplasia(GTN)and
modifiedWHOPrognosticScoringSystemasadaptedbyFIGO
Stage
I
Diseaseconfinedtothe
uterus
Stage
GTNextendsoutsideof
II
Stage
III
Stage
IV
Riskfactor
Score
Age(years)
<40
40
theuterus,butislimited
tothegenitalstructures
Antecedent
Mole
Abortion
Term
GTNextendstothelungs,
with
or
withoutgenitaltract
involvement
Interval
(months)*
4to6
7to
12
>12
Pretreatment
serumhCG
(mIU/mL)
<10 3
10 3to
10 4
10 4
to
10 5
>10 5
Largesttumor
(including
uterus)
<3cm
3to4
cm
5cm
Siteof
metastases
Lung
Spleen,
kidney
GI
tract
Brain,
liver
Numberof
metastases
1to4
5to8
>8
Priorfailed
chemotherapy
Single
drug
2
drugs
Allothermetastaticsites
Thestageshouldbefollowed
bythesumoftheriskfactors
(eg,III:5)
pregnancy
FIGO:InternationalFederationofGynecologyandObstetricsWHO:WorldHealthOrganization
hCG:humanchorionicgonadotropin.
*Interval(inmonths)betweenendofantecedentpregnancyandstartofchemotherapy.
Originalfiguremodifiedforthispublication.BerkowitzRS,GoldsteinDP.Currentmanagementof
gestationaltrophoblasticdiseases.GynecolOncol2009112:654.Tableusedwiththepermissionof
ElsevierInc.Allrightsreserved.
24/25
2/4/2015
Disclosures
Disclosures:RossSBerkow itz,MDNothingtodisclose.DonaldPeterGoldstein,MDNothingto
disclose.NeilSHorow itz,MDNothingtodisclose.BarbaraGoff,MDNothingtodisclose.SandyJ
Falk,MD,FACOGEmployeeofUpToDate,Inc.DonSDizon,MD,FACPEmployeeofUpToDate,Inc.
Contributordisclosuresarereview edforconflictsofinterestbytheeditorialgroup.Whenfound,these
areaddressedbyvettingthroughamultilevelreview process,andthroughrequirementsfor
referencestobeprovidedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofall
authorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy
25/25

Gestational Trophoblastic Neoplasia - Epidemiology, Clinical Features, Diagnosis, Staging, and Risk Stratification

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Gestational Trophoblastic Neoplasia - Epidemiology, Clinical Features, Diagnosis, Staging, and Risk Stratification

Uploaded by

Copyright:

Available Formats

2/4/2015

Vaginalmetastasesinapatientwithc horioc arc inoma.

Bowelmetastasisinapatientwithc horioc arc inoma.

Chorioc arc inoma:Patientwithstage3c horioc arc inomaaftertermpregnanc y.

Chorioc arc inoma:Ultrasoundrevealsahyperec hoic massshowing

You might also like