CLINICALGUIDELINES DANISHMEDICALJOURNAL

GestationalTrophoblasticDiseases
Clinicalguidelinesfordiagnosis,treatment,fol
lowup,andcounselling
IsaNiemann,LarsO.Vejerslev,LigitaFrding,JanBlaakr,LisaLethMaroun,EstridSthrHansen,
AnniGrove,HelleLund,HanneHavsteen&LoneSunde


Clinically,distinctionismadedependingonwhetherthelesions
TheguidelinehasbeenapprovedbytheSocietyofDanishGynecologicCancerGroup
(DGCG)02.03.2015 requiretreatmentsuchaschemotherapyorsurgeryorwhether
onlyfollowupisneededafterprimaryevacuation.
Correspondence:IsaNiemann,Departmentofgynecologyandobstetrics,Aarhus Byfarthemostcommontrophoblasticdiseaseishydatidiform
UniversityHospital,PalleJuulJensensBoulevard99,8200AarhusN.Denmark.
Email:isanie@rm.dk
mole.Hydatidiformmoleisahistopathologicdiagnosisbasedon
thepresenceinplacentaltissueofoedematous,abnormalvilli
plustrophoblastichyperplasia.Histologically,hydatidiformmole

isclassifiedaspartialorcomplete.Hydatidiformmolehasauni
DanMedJ2015;62(11):C5082
quegeneticconstitutionbecauseregardlessofwhetheritisdip

Introduction
In2009,aworkingcommitteewasestablishedundertheDanish
GynecologicCancerGroup(DGCG)withthepurposeofimple
mentingregistrationofgestationaltrophoblasticdiseasesinthe
DGCGdatabase.ThisguidelinerepresentstheDanishGynecologic
CancerGroupsnationalguidelinesanno2014.
Definition
Gestationaltrophoblasticdiseasesisaunifyingtermforaspec
trumofdiseasesfromabnormalproliferationofplacentaltro
phoblasts,asseeninhydatidiformmole,toneoplastictrophoblas
ticdiseases.
loidortriploiditmostoftencontainstwosetsofchromosomes
fromthefather.
Hydatidiformmoleisseenwithafrequencyofapproximately1
caseper1000pregnanciesintheWesternworld(2,3);inDen
markthiscorrespondstoabout80to100casesayear.
Boththepartialandthecompleteformsofhydatidiformmoleare
primarilybenignbutcandevelopintopersistenttrophoblastic
disease(PTD),invasivehydatidiformmole,choriocarcinomaand
PSTT/ETTthatrequirechemotherapy.InDenmarkabout10wo
menayeararetreatedwithchemotherapyafteramolarpreg
nancyandsurvivaliscloseto100%.
Thefrequencyofchoriocarcinomais1per2040,000pregnan
cies,whereasPSTT/ETTisevenrarerandcomprisesabout0.2%of

Limitationofsubject thetotalnumberofcasesoftrophoblasticdiseases(2).Halfof
Theseclinicalguidelinesdealwiththeworkup,diagnosis,differ theseariseafteranormalpregnancy.
entialdiagnosticconsiderations,treatment,monitoring,and TrophoblastictumoursarecharacterisedbythesecretionofhCG,
counsellingofpatientswithgestationaltrophoblasticdiseases. andthereisacloserelationbetweenhCGconcentrationinthe
serumandtheamountoflivingtrophoblasttissue.

Background
Abbreviations
Gestationaltrophoblasticdiseasesincludehydatidiformmoleand
PSTT Placentalsitetrophoblastictumour
nonmolartrophoblasticdiseases,thelatterofwhichcanbe
ETT Epithelioidtrophoblastictumour
dividedintoneoplasticandnonneoplasticconditions(1).
EPS Exaggeratedplacentalsite
Hydatidiformmoleisdividedmorphologicallyintocompleteand
partialhydatidiformmole.Bothcandevelopintoinvasivehy CC Choriocarcinoma
datidiformmoleorpersistingtrophoblasticdisease(PTD).The PSN Placentalsitenodule
latterismuchmorecommonwithcompletehydatidiformmole. PMD Placentalmesenchymaldysplasia
Nonmolarlesionsderivedfromtheplacentaincludemesenchy hCG humanchorionicgonadotropin
PTD Persistenttrophoblasticdisease
malplacentaldysplasia(MPD),placentalsitenodule(PSN)and
MTX Methotrexate
exaggeratedplacentalsite,whicharenonneoplastic.Neoplastic
ActD ActinomycinD
diseasesarisingfromtheplacentaincludechoriocarcinoma(CC),
BEP BleomycinEtoposidePaclitaxel
placentalsitetrophoblastictumour(PSTT)andepithelioidtro
EMACO EtoposideMethotrexateActDCarboplatin
phoblastictumour(ETT).

DANISH MEDICAL JOURNAL 1


EPIDEMIOLOGYANDCLINICALFINDINGS
HYDATIDIFORMMOLE
Hydatidiformmoleisknowntoappearwithafrequencyofabout
1per1000pregnanciesintheWesternworld.IDenmark,during
theperiod1999to2010,130to140caseswerediagnosedyearly,
whichisalittlehigherthanexpected(4).Thetruedistributionof
completeandpartialhydatidiformmoleisnotknown;manyhave
reportedthatpartialaremorecommenthancompletemoles(2).
Atpresent,thetwotypesappeartobeequallycommoninDen
mark(4).
Riskfactors
Thetwomostimportantriskfactorsformolarpregnancyarethe
patientsageandpreviousmolarpregnancy(3).Attheextremes,
bothlowandhigh,inmaternalage,thereisasignificantlyin
creasedriskformolarpregnancyandespeciallyforcom
plete/diploidhydatidiformmole(5,6).Theriskincreasesmark
edlyforwomenover40yearsofage,wheretheriskforcomplete
hydatidiformmoleis7.5timesgreaterthaninwomenbetween
21and35yearsofage(3).Previousspontaneousabortionsare
seenmorecommonlyinwomenwithmolarpregnancy(7).Ac
cordingtoaBritishcasecontrolstudy,theriskfortrophoblastic
diseaseisnotincreasedafterfertilitytreatment(8).However,
50%oftwinpregnancieswithhydatidiformmoleandanormal
foetusareprecededbyfertilitytreatment.Itisnotknown
whetherthisisbecauseofthestimulationtherapyoranunderly
ingimpairedfertilityinthewoman(9).Afteronemolarpreg
nancy,theriskforanewmolarpregnancyincreases1%to2%,
andaftertwomolarpregnancies,theriskforathirdis15%to
20%(10).MolarpregnanciesaremorecommoninAsiancoun
tries,andheredietisthoughttoplayarole(2).
Symptoms
Thefourmostcommongynaecologicsymptomsofmolarpreg
nancyarevaginalbleeding(69%89%),uteruslargerthanex
pectedforgestationalage(withcompletehydatidiformmole)
(28%33%),hyperemesis(8%22%)andpreeclampsiaorhyper
tension(1%3%)(3,11,12,13,14,15).Generally,thesymptoms
withpartialhydatidiformmolearelesspronouncedthanthose
withcompletehydatidiformmole(11,15,16).Completehydatidi
formmoledebutssymptomaticallyabout3weeksbeforepartial
hydatidiformmole.Inwomenwithhyperemesis,asonogram
shouldbetakentoruleoutmolarpregnancy.
Sinceultrasoundscanninginthefirsttrimesterisnowroutine,up
to40%ofmolarpregnanciesarefoundtodayatthe12week
scan,andthusoftenwhilethewomenarestillasymptomatic
(6,17).
Diagnosis
Ultrasound
Theclassicalsonographicpictureofacompletehydatidiform
moleisdescribedasasnowstorm,meaningacomplexecho
patternwithmultipleanechoicspacesthatfilltheuterinecavity.
Inpartialhydatidiformmole,cysticspacesareseeninthepla
centatogether,attimes,withadeadfoetusseldomaliving
foetus.Inpartialhydatidiformmole,foetaldevelopmentappears
delayed,andthefoetusmaybemalformed(18,19).Thusif,there
isalivingfoetuswithbiometriescorrespondingtogestational
age,oneshouldsuspectatwinpregnancyconsistingofahydatidi
formmoleandanormalfoetuswithitsownnormalappearing
placenta.
Today,ultrasoundscanningisroutinelyperformedearlyinpreg
nancy,whichhasresultedinthediagnosisofhydatidiformbeing
madeearlierthanpreviously(17,20).However,only4060%ofall
molarpregnanciesaresuspectedonroutineultrasoundscanning,
andthedetectionrateisbetterforcompletehydatidiformmole
(79%)thanforpartialhydatidiformmole(29%),andbestafterthe
14thgestationalweek(21).Thesensitivityofanultrasound
suspicionofhydatidiformmoleis48%,whichmeansthatasus
picionofahydatidiformmoleonultrasoundislaterconfirmed
histologicallyinoneofeverytwocases(22).Inordernottoover
lookamolarpregnancy,evacuatedmaterialfrompathological
pregnanciesshouldbesentforhistopathologicandgeneticeva
luation.(23,24,25).
shCG
Humanchorionicgonadotropinisapregnancyhormonesecreted
bytrophoblastcellsthatisusedasaspecificmarkerfortro
phoblasticdiseases.hCGcanbemeasuredinurineandblood,and
thelevelofhCGcorrelateswiththevolumeoftrophoblasttissue.
InDenmark,quantitativemeasurementofurinehCGisnotdone.
Atdiagnosis,serumhCGisoftenhigherinmolarpregnancythan
innormalpregnancy,andincompletehydatidiformmole,serum
hCGissignificantlyhigherthaninpartialhydatidiformmole.In
completehydatidiformmole,serumhCGisoften>100,000IU/L
(6,11).Inpartialhydatidiformmole,serumhCGis>100,000IU/L
inlessthan10%ofcases(3).
Surgicaltreatment
Uterineevacuation
Priortouterineevacuation,serumhCG,haemoglobin,andblood
typeandcrossmatchtest,shouldatminimumbedetermined.
Regularsurgicaluterineevacuationwithsuctionfollowedbyblunt
curettageisrecommended(26).Regardlessofgestationalageand
typeofhydatidiformmole,amolarpregnancycanoftenbeeva
cuatedwitha12mmsuctioncatheter.Ultrasonographically
guidedbluntcurettageshouldbedonemeticulouslybutcarefully
becauseoftheriskofuterineperforationtoassurecomplete
emptyingoftheuterinecavity.AdministrationofIVsyntocinonis
recommendedwiththeprocedure(3).Medicalevacuationis
contraindicatedbecauseoftheincreasedriskofsubsequentneed
forchemotherapy(RR1.7)(27).Pretreatmenttoassurecervical
ripeningbeforesurgicalevacuationdoesnotincreasetheriskfor
laterchemotherapy(28).
Itisimportanttobeawareoftheincreasedriskofbleedingwith
thesurgicaltreatmentofhydatidiformmole;ultrasoundwith
colourDopplercangiveindicatehypervascularareasinthemyo
metrium.PatientswhoareRhnegativearegivenimmunoglobu
linsaccordingtonormalinstructions.
Hysterectomy
Asanalternativetouterineevacuation,hysterectomycanbe
consideredinthosewomenwhodonotwishtoretaintheirfertil
ity.Thistreatmentdoesnot,however,eliminatetheriskofPTD
(35%),andthereforepatientsafterhysterectomyshouldbe
followupwithmeasurementofhCGaccordingtothesameprin
ciplesasthoseafteruterineevacuation(3).
Followupaftersurgicaltreatmentofhydatidiformmole
Becauseoftheriskofpersistenttrophoblasticdisease(PTD)after
amolarpregnancy,serumhCGshouldbemeasuredweeklyafter
uterineevacuation.ItisimportantthataninitialserumhCGvalue
DANISH MEDICAL JOURNAL 2
ismeasuredimmediatelybefore(oratamaximumof24hours
after)evacuation.Morethanhalfthepatientswillhaveanunde
tectableserumhCGinthecourseof2months.Itisimportantthat
thepatientusessafecontraceptionduringthewholefollowup
period;birthcontrolpillscanberecommendedanddonotin
creasetheriskofPTD(3).
Amarkedreductioninthelengthofthefollowupperiodhas
takenplaceduringthelastfewyearsbecausetheriskofrelapse
afterundetectableserumhCGlevelshavebeenattainedhasbeen
showntobeverylow.ThelatestfindingsfromCharingCross
Hospital,London,showthattheriskofrelapseaftercomplete
hydatidiformmoleis1/400,butonly1/1500ifserumhCGnor
maliseswithin56days(29).Theriskofrelapseafterpartialhy
datidiformmoleis1/3000.
Giventhatthepatientisinformedofthisrisk,thefollowingfol
lowupprogrammesarerecommended:
Indiploidhydatidiformmole,andinhydatidiformmole(complete
andpartial)withoutploidydetermination:
WeeklymeasurementofserumhCGuntilserumhCGisundetect
ableintwoconsecutivemeasurements.HereafterserumhCGis
measuredonceamonth.IfserumhCGbecamenormalwithin56
daysafterevacuation,thepatientcanbedischargedfromfollow
upafter4months.Ifnot,thepatientisfollowedupwithmeas
urementofserumhCGonceamonthfor6months.
Intriploidhydatidiformmole:
WeeklyserumhCGmeasurementuntiltwoconsecutiveunde
tectablevalues.Hereafterthepatientcanbedischargedfrom
followup.
Ifdivergentobservationsareseen,thelengthofthefollowup
periodshouldbedeterminedatamultidisciplinaryconference
withparticipationofpathologist,gynaecologist,oncologistand
geneticist(e.g.ifthehistopathologicdiagnosisiscompletehy
datidiformmoleandgeneticstudiesshowtriploidy,orifthe
diagnosisiscompletehydatidiformmoleand/ordiploidytogether
withpositiveimmunostainingforp57KIP2).
Followupafterfuturepregnancies
Patientsshouldbemonitoredafterlaterpregnanciesbymeas
urementofserumhCG8weekspostpartum.IfhCGisnotunde
tectable,thepatientshouldbediscussedatamultidisciplinary
conference.
PTD(PERSISTENTTROPHOBLASTICDISEASE)
Upto20%ofpatientswithamolarpregnancysubsequentlyde
velopPTDandaretreatedwithchemotherapytoachieveremis
sion(12,25,30).InthemedicalliteratureinEnglish,theexpression
gestationaltrophoblasticneoplasia,GTN,isoftenused.
PTDisdiagnosedaccordingtothefollowingcriteria(thehCG
criteriapresupposethatserumhCGlevelsaremeasureoncea
week):
PersistentshCG
shCGincreasesduring2weeks/threemeasurements
shCGdecresaseslessthan10%during3weeks/fourmeasure
ments(plateau)
shCGpersistswithpositivemeasurementsformorethan6
monthsafterevacuation
ThereisatendencytobelessstrictregardingthethirdhCGcrite
rion(elevatedserumhCG>6months);followupcan,however,
becontinuediftheserumhCGislowandcontinuestofallbe
causesomepatientsareslowtoexcretehCG.Inordernotto
overlooktruePTD,anultrasoundscanoftheuterusandpossibly
achestxrayorPET/CTshouldbeperformed.
Invasivehydatidiformmole
Invasivehydatidiformmoleisaclinicaldiagnosisbasedonmetas
tasesorinvasionofthemyometrium.Invasivehydatidiformmole
isthuseitherdiagnosedwithultrasound,CTorMR,whenpulmo
naryorhepaticmetastasesarevisualized,orhistologicallyif
hydatidiformmoletissuehasinvadedthemyometrium.Invasive
hydatidiformmolecangiverisetoheavybleedingorpulmonary
symptoms.Ifthereissuspicionofinvasionintothemyometrium,
uterineevacuationandbiopsyofhydatidiformmoletissueare
contraindicated.Thediagnosisisconfirmedusingdiagnostic
imagingandserumhCG.
Chemotherapyisprimarytreatment.Somerecommendhysterec
tomyasfirstchoiceinpatientswhodonotwishtoretainfertility
(31,32).Hysterectomycanalsobeperformedbecauseofuncon
trollablevaginalorintraabdominalbleedingandlocalisedchemo
therapyresistantdisease(33).
SymptomsofPTD
PTDisusuallydiagnosedonthebasisofaninsufficientfallin
serumhCGafteramolarpregnancy,butinrarecases,molar
pregnancyhasnotbeendiagnosedupfront.Irregularpersistent
bleedingafterspontaneousabortionorbirthcanraisesuspicion
oftrophoblasticdisease,andoneshouldalwaysmeasureserum
hCGinthesepatients.Thefirstsymptomsofchoriocarcinomaand
PSTT/ETTcanbefrommetastases,intheformofheavyvaginal
bleeding,intestinalbleeding,increasedintracranialpressure
becauseofintracranialbleedingorbleedingfromothersites.
Respiratorysymptomslikedyspnoeaorchestpainbecauseof
pulmonarymetastasescanalsobeseen.
RiskfactorsforPTD
Maternalfactors
Patientsolderthan3540yearshaveanincreasedriskofPTD
(3,13,25).Somestudieshaveshownanincreased(OR2.64.6)
riskforPTDincasesofrepeatedhydatidiformmole,whereas
othershavenotbeenabletoconfirmthis(7,14).
Pregnancyrelatedfactors
ThemajorityofstudieshavefoundanincreasedriskforPTDifthe
initialserumhCG>100,000IU/l(13,34).
Morphology
ThefrequencyofPTDaftercompletehydatidiformmoleisre
portedtobe1828%(2,35,36).Afterpartialhydatidiformmole,
thefrequencyis05%(2,37,38).InDenmark,PTDwasobserved
in16%(16/118)ofpatientswithcompletehydatidiformmoleand
in5%(7/140)withpartialhydatidiformmole(25).
Ploidy
TheriskofPTDafterdiploidhydatidiformmoleisreportedtobe
1825%(39,40).InDenmarkitis18%(25).
Infourprospectivestudiesinwhichploidywasdeterminedusing
appropriatetechniques,nocasesofPTDwereseenafter258
triploidhydatidiformmoles(0%,95%CI:01.4%)(4145).There
are,however,casereportsofchoriocarcinomaafterverified
triploidhydatidiformmoles(46,47,132).
DANISH MEDICAL JOURNAL 3
TheriskofPTDaftertetraploidhydatidiformmoleisunknown,
but,asthemorphologicdiagnosisoftenisacompletehydatidi
formmole,theriskofPTDaftertetraploidhydatidiformmole
shouldbeconsideredtobethesameriskasafteradip
loid/completehydatidiformmole(48).
Parentaloriginofthegenome
TheriskofPTDafterdiploidandrogenetichydatidiformmoleis
approximately18%.(25,39).Insomestudies,suspicionofan
increasedriskofPTDhasbeenraisedafterandrogenetichydatidi
formmolewhentwodifferentpaternalgenomesareinvolved
(P1P2)(40,49).CasesofPTDafterdiploidbiparentalhydatidiform
mole(PM)(50)andafterhydatidiformmolewithmosaicismbe
tweenadiploidandrogeneticandadiploidbiparentalcellline
(PP/PM)havebeenobservated,seethesectionongenetics
(25,51).
UterinereevacuationonsuspicionofPTD
UterinereevacuationinwomenwithPTDinthehopeofreducing
subsequentneedofchemotherapyisstillcontroversial(2).Ina
Dutchstudy,10%ofpatientswithPTD(diagnosedonthebasisof
aninsufficientfallinhCG)werecuredbyreevacuation,andthe
remaining90%neededlesschemotherapythanthecontrolgroup
toachieveremission(52).In5%ofthereevacuatedpatients,
therewerematernalcomplications,mostcommonlyperforation
andinfection.Theseresultsweresupportedbyamorerecent
Dutchretrospectivestudyof29patientswithPTD,inwhichthe
reevacuatedpatientshadasignificantlylesserneedforsubse
quentchemotherapy(53).InaBritishstudy,60%ofpatients
diagnosedwithPTDachievedremissionafteruterinere
evacuation;78%oftheprocedureswereundertakenduetoa
dualindication(e.g.bleeding),andmaternalcomplicationswere
notmentioned(54).Thesuccessrateforremissionwasgreatestif
theserumhCGwas<1500IU/l.Inanotherstudy,uterinere
evacuationisadvisedagainstbecauseofthelowchanceofremis
sionandtheincreasedriskforthepatient(55).Studiesfrom
CharingCrossHospital,UK,indicatethatreevacuationinpatients
withserumhCG>5000IU/lshouldbeavoidedbecausethesub
sequentneedforchemotherapyisnotsubstantiallyreducedand
theriskofsideeffectsshouldbeconsidered.(2).
AphaseIIstudyundertheauspicesoftheAmericanGynaecologic
OncologyGroupiscurrentlyunderwaywiththeobjectiveofeva
luationthevalueofuterinereevacuationinpatientswithPTD
(56).
Atpresent,reevacuationisnotrecommendedasstandardpro
cedure.
TWINPREGNANCYWITHHYDATIDIFORMMOLEANDANORMAL
FOETUS
Atwinpregnancyinvolvingahydatidiformmoleandanormal
foetusisextremelyrareandisseenin1:20,000120,000preg
nancies(57,58).Onultrasoundscan,acysticplacentaandanor
malappearingfoetuswithanormalplacentaareseen(59).Often,
butnotalways,thetwoplacentasappearastwoseparateenti
ties.
About50%ofthesepregnanciestakeplaceafterpreviousfertility
treatment(9).Twinpregnanciescanbedifficulttodistinguish
frompartialhydatidiformmole,andthusploidyandparental
originofthegenomeshouldbedeterminedinplacentalbiopsies
ifthepregnancyisallowedtocontinue.
Aprominentprobleminthesepregnanciesistheevaluation
regardingthechanceofobtaininganormalchildversustheriskof
PTD.OnelargeBritishstudyfoundthatthechanceofobtaininga
normalchildwas38%,andanotherwiththelargestnumberof
cases(90)todatereportedthattherewasa57%chanceofob
taininganormalchild(57,58).Themediangestationalageatbirth
was34+1weeks,andslightlymorethanhalfofthechildrenwere
deliveredbycaesareansection.Becausethereisanincreasedrisk
ofbleeding,preeclampsiaandlatespontaneousabortion,these
pregnanciesareanobstetricchallenge(58,59,60).Carefullyin
formationoftherisksinvolvedismandatory,andthepregnancy
mustbecloselymonitoredwithmonthlymeasurementofserum
hCGandultrasoundscans.
Intwinpregnancieswithdiploidhydatidiformmoleandanormal
foetus,theriskofdevelopingPTDis26%(58,61).Theriskappears
tobegreatestinthosepregnanciesthatareabortedorcease
duringthefirsttrimester.Thereisnoindicationthattheriskof
PTDincreasesinrelationtothelengthofgestation(57,58,62).
REPETITIVEHYDATIDIFORMMOLE
Repetitivehydatidiformmoleisseenin12%ofthosewhobe
comepregnantagainafteramolarpregnancy,correspondingtoa
10to20foldincreasedriskrelativetowomenwithoutprevious
molarpregnancy(63,64).Theempiricalriskaftertwohydatidi
formmolesisevenhigher(1023%).Onestudyhasshownthat
womenwithrepeathydatidiformmolemostoftenhavemolar
pregnanciesofthesamehistologicsubtype(complete/partial)
(10).
Aftertwomolarpregnancies,between42%and67%ofwomen
haveanormalpregnancy(63,65,66,67).
Womenwithrepetitivehydatidiformmolecanbedividedinto
twosubgroups(10):
Patientswithdiploidandrogeneticortriploidhydatidiformmole
andnormalreproductiveability
Patientswithdiploidbiparentalhydatidiformmoleandreduced
reproductiveability
Diploidbiparentalhydatidiformmoleshavebeendescribedmost
lyinwomenwithrepetitivemolarpregnanciesand/orinfamilies
inwhichasisterhashadahydatidiformmole(50,68,69,70,71).
Diploidbiparentalhydatidiformmoleisthereforeapredictorfora
markedlyincreasedriskofrepeathydatidiformmole.Twogenes
havebeenidentifiedthatinmutatedformgiveriseinwomento
anautosomalrecessivehereditarydispositiontorepetitivehy
datidiformmole:NLRP7(72)andKHDC3L(73).
Afteronemolarpregnancy,thewomanshouldbeinformedabout
theincreasedriskofrepetitivehydatidiformmole,butalsothat
thereisa98%chanceofanormalpregnancy(63).Sheshouldbe
offeredearlyultrasoundinvestigationinallsubsequentpregnan
cies.
Womenwithrepeatmolesshouldbeofferedageneticworkup
andcounselling.
QUIESCENTHYDATIDIFORMMOLEANDFALSELYINCREASEDHCG
Inafewpatients,serumhCGdoesnotfalltoanundetectable
levelbutremainsatalowvalue(10200IU/l)formonthsor
yearsafteramolarpregnancy.Possibleexplanationscanbefalse
positivevalues,PTDorquiescenthydatidiformmole(74).To
ruleoutfalsepositivehCGvalues,urinehCGshouldbeanalysed,
aserumsamplesenttoalaboratorythatusesadifferenthCG
assay,oraseriesofdilutionsbemadesothatfalselyincreased
hCGvaluesduetobindingofheterophileantibodiesorLHcanbe
ruledout.
Inrarecases,physiologicallysecretionofasmallamountofhCG
fromthepituitaryglandisresponsible,whichceasesaftertreat
mentwithbirthcontrolpills(75).
DANISH MEDICAL JOURNAL 4
Iftheabovementionedsourcesoferrorcanbeeliminatedand
thelowserumhCGvaluesareareality,thereasonmaybethe
presenceofaquiescenthydatidiformmole.AnAmericancentre
suggestsmeasurementofhyperglycosylatedhCG(HhCG),which
issecretedfrominvasivetrophoblasttissueandcanthusbea
markerformalignancy.IftheconcentrationofHhCGislow,the
trophoblasttissueisrefractorytochemotherapy,andthepatient
shouldnotbetreated.Because10%25%ofwomenwithquies
centhydatidiformmoleatsomepointwillrequiretreatment,
thesewomenshouldbefollowedupforalongperiod,evenfor
life,butfirsttreatedifhCGorHhCGbeginstoraise,asignof antofneoplastictrophoblasticdiseaseandwasdescribedforthe
tissueinvasion(76).MeasurementofHhCGasadiagnosticmea
sureandasanindicationfortreatmentis,however,controversial
andisnotdoneinEurope.
NONHYDATIDIFORMMOLETROPHOBLASTICDISEASES
Choriocarcinoma(CC)
Choriocarcinomaisamalignanttrophoblasticdiseasewitha
frequencyof1:40,000pregnancies,correspondingto1to2pa
tientsayearinDenmark.Fiftypercentofcasesareprecededbya
molarpregnancy,whereas25%areseenafteraspontaneous
abortionand25%afteranormalpregnancyandbirth.Therisk
factorsforCCarehighageandpreviousmolarpregnancies(2,3).
Thetumourishighlyvascularisedandthefirstsymptomcanbe
heavyvaginalbleedingorbleedingfromorinotherorgans(intes
tine,nose,throat,lungs,liver,brain).SerumhCGshouldtherefore
alwaysbemeasuredincasesofunexplainedbleeding.Patients
areoftenacutelyillbecauseofmetastasestootherorgans.
Thetreatmentisprimarilychemotherapyandreliefofsymptoms.
Adjuvanthysterectomyandresectionofmetastasescanbenec
essary(30).
Placentalsitetrophoblastictumour(PSTT)
Placentalsitetrophoblastictumourisaveryseldomlyoccurring
variantofneoplastictrophoblasticdiseasethatarisesfrominter
mediatetrophoblasticcells.Itsactualincidencehasnotbeen
established,butPSTTmakesupabout0.2%ofallcasesoftro
phoblasticdiseases,correspondingtoonecaseevery5yearsin
Denmark(2).Thediseaseischaracterisedbybeingabletooccur
severalyearsafterapriorpregnancy.PSTTcandevelopafterboth
normalandmolarpregnancies.Itisaslowlygrowingtumourthat
metastasiseslateandoftentolymphnodes.TheserumhCGlevel
islowinrelationtothelevelseenintheothergestationaltro
phoblasticdiseases.Incontrasttotheothertrophoblasticdis
eases,theserumhCGlevelinPSTTdoesnotcorrelatewithtu
mourloadoraggressiveness.
PSTTusuallypresentswithirregularvaginalbleeding(80%)or
alternativelyamenorrhoea.Thediagnosiscannotwithcertainty
bemadebyultrasoundscan,butascanmayshowinhomogene
ousareasinthemyometrium.OnsuspicionofPSTT,MRor
PET/CTscanningcanbedone,butthesensitivityisnotknown.
About1%ofpatientshavelymphnodemetastasesatthetimeof
diagnosis(77).PSTToftenalsometastasisestothelungs.
PSTTisprimarilytreatedsurgicallywithhysterectomyandreten
tionofnormalovariesandinsomecaseswithresectionoflymph
nodes.(2,78,79).Ifthewomanisyoung,wedgedissectionofthe
uteruscanbeconsideredinordertoretainfertility,butone
shouldbeawareoftheriskofmicroscopicmultifocaldisease.
Adjuvantchemotherapyisnotgivenwithdiseaseinstage1.
Indisseminateddisease,multidrugchemotherapyisgiven(e.g.
EMAEPorEP),butPSTTislesssensitivetochemotherapythan
theothertrophoblastictumours.
Thebestprognosticfactoristhetimeintervalfromtherespon
siblepregnancy(whichisnotalwaysthelatest).Inastudyof62
cases,itwasshownthatallinwhomtherewasatimeinterval
longerthan48monthsdiedofthedisease,whereas98%witha
timeintervallessthan48monthssurvived(80).
AftertreatmentforPSTT,patientsshouldbefollowedupwith
lifelongmeasurementofserumhCG,seebelow.
Epithelioidtrophoblastictumour(ETT)
Epithelioidtrophoblastictumour(ETT)isanevenmorerarevari
firsttimein1998(81).Clinicallyandhistopathologically,ETTis
similartoPSTT,andbotharederivedfromtheintermediarytro
phoblast.ETTpresentswithamenorrhoeaorirregularbleeding
afterapregnancyandserumhCGisslightlyelevated.ETTisoften
locatedinthecervixandcanbemisdiagnosedasplanocellular
carcinoma.Thediseaseusuallyoccursbeforetheageof50,and
theclinicalpictureisoneofirregularbleedingandelevatedhCG.
Inthelargestandonlyanalysis(78cases),themedianshCGwas
665IU/latthetimeofdiagnosis(82).Theantecedentpregnancy
wasaspontaneousabortionin50%,hydatidiformmolein35%,
termbirthin10%andectopicpregnancyin5%.Theonlyprognos
ticfactorwastheFIGOstage.Thuspatientswithstage1disease
didmuchbetterthanpatientswithstageIItoIVdisease.Incon
trasttoPSTT,thetimeintervalfromtheantecedentpregnancyis
notaprognosticfactorforETT.Therewasnoincreasedsurvivalin
patientstreatedwithadjuvantchemotherapy.Longtermsurvival
forallstagesisreportedasbeingabout40%.
ThetreatmentforETTisthesameasforPSTT.
Followupandstaging
FollowupaftertreatmentforPSTTandETTshouldbelifelong
andconsistofregularmeasurementofserumhCG,everymonth
thefirstyeardecreasingtoonceayearafter5years.
WhenPSTTorETTisacoincidentalpostoperativefinding,staging
isrecommendedwithuseofMRIofthecerebrumandpelvis
togetherwithCTofthethoraxandupperabdomen.
PATHOLOGICANATOMY
Thepurposeofthepathologicevaluationistoconfirmthediag
nosisofgestationaltrophoblasticdisease,cf.theWHOclassifica
tion.Thetypeoftumourisdeterminedinthecaseofneoplastic
lesions,andifhysterectomyisperformed,thedegreeofanylocal
spreadingtothemyometrialserosa,parametriumandcervixis
described.
Thepathologicdiagnosisofgestationaltrophoblasticdiseasesisa
challengeandsubjecttoconsiderableuncertainty(83,84,85).This
isduetoseveralfactors(seeTabel1).Theextravilloustro
phoblasthasitselfinvasivecharacteristics,anditisdifficultmor
phologicaltodeterminewhethertheinvasioniscontrolled,
physiologicalorneoplastic.Suspicionofhydatidiformmoleoften
arisesearlyinpregnancy,atatimewhenthehistologiccharacter
isticsarenotsowelldevelopedandthemorphologicoverlapis
great.
Inpracticethedifferentialdiagnosticproblemsareamongothers:
1)Hydatidiformmolevs.abortionwithhydropicdegeneration.
2)Earlycompletevs.partialhydatidiformmole.
3)Twinpregnancywithnormalconceptionand(complete)hy
datidiformmolevs.partialhydatidiformmole.
4)Othergeneticabnormalitieswithhydropicchangesinthe
placenta(e.g.BeckwithWiedemannsyndromeandchromosome
abnormalities)vs.hydatidiformmole.
DANISH MEDICAL JOURNAL 5
5)Normalimplantationsiteandbenigntrophoblasticlesionsvs.
trophoblastictumour.
6)Choriocarcinomavs.extravillous/intermediarytrophoblastic
tumour(PSTTandETT).
7)PSTTvs.ETT.
8)Trophoblastictumourvs.carcinoma/sarcoma.
PATHOLOGICDEFINITIONANDCLASSIFICATION
(1)
Gestationaltrophoblasticdiseasecanbedividedintothree
groups:
1.Nonmolar,nonneoplastictrophoblasticlesions(onlydifferen
tialdiagnosticrelevance)
Exaggeratedplacentalsite
Placentalsitenodule
Mesenchymalplacentaldysplasia
2.Hydatidiformmole:Abnormalproductsofconceptioncharac
terisedbydysmorphichydropicchorionicvilliandabnormaltro
phoblastproliferation
Completehydatidiformmole
Partialhydatidiformmole
Invasiveormetastatichydatidiformmole
3.Trophoblastictumours:Neoplasticlesionsarisingfromthe
trophoblast
Choriocarcinoma
Placentalsitetrophoblastictumour(PSTT)
Epithelioidtrophoblastictumour(ETT)
N.B.Persistenttrophoblasticdisease(PTD)isnotapathologic
diagnosisbutsolelyaclinicaldiagnosischaracterisedbystaticor
risingserumhCGvaluesafteramolarpregnancy,seesectionon
PTD.
Macroscopicevaluation
Evacuatedmaterial:Inpractice,mainlyrelevantforearlyproducts
ofconception.Thetotalamountofevacuatedmaterialisgivenin
ml.Itisinvestigatedmacroscopicallyforthepresentofspongy
placentaltissue(chorionicvilli),membranes,umbilicalcordand
foetalparts.Visiblecystsarementioned.Ifcystsarepresent,the
largestandsmallestsizesarenoted,andtheirnumberortheir
proportionofthetotalplacentaltissueisgiven.Itisnoted
whetherthecysticmaterialislocalizedordiffuselypresent.Any
suspicionoftwinpregnancyismentioned.Ifthereisclinical,
macroscopicorhistologicsuspicionofhydatidiformmole,repre
sentativetissueisembeddedinatleastfivecapsules.
Hysterectomy:Uterusremovedduetosuspicionofinvasivehy
datidiformmoleortrophoblastictumouristreatedaccordingto
DanishGynaecologicCancerDatabasesguidelinesforcorpus
utericancer.
Histologicevaluation
(1,8486)
Exaggeratedplacentalsite(EPS)
Afloridandexaggeratedimplantationsitereactioncharacterised
byextensiveinfiltrationintotheendoandmyometriumofextra
villousintermediarytrophoblastcells,severalofwhicharemulti
nuclear.Thecellshaveabundanteosinophiliccytoplasmand
irregularhyperchromaticcellnuclei.Necrosisisnotseen.TheKi
67indexisverylow(<1%).Oftenseenincompletehydatidiform
mole.Probablyrepresentsanormalphysiologicconditionandhas
noclinicalrelevanceifhydatidiformmoleisnotpresent.
Placentalsitenodule(PSN)
Little(114mm)welldefinednodularlesionintheendometrium
orcervixmadeupofextravillousintermediarytrophoblastcellsin
awelldefinedeosinophilicmatrix(attimesmultifocal)Thecells
areseeninarandompattern,singularly,insmallgroupsor
strings,sometimesdiffuselydistributed.Mostofthecellshave
smalluniformnucleiwithglycogencontainingcytoplasm.Afew
cellshavelargeirregularhyperchromaticnucleiwithabundant
eosinophiliccytoplasm.Thereisnorealcellatypiaandnomito
ses.TheKi67indexislow(<8%).Oftenanincidentalfindinginthe
uterinecorpusorcervixsmearthatcanbeseenuptoseveral
yearsafterthelastpregnancy.Requiresnofurthertreatmentor
followup.ThetermatypicalPSNcanbeusedforlesionsthatare
larger,morecellular,withmorecellatypiaand/oranincreased
proliferationsindex,butthesefindingsarenotdiagnosticforETT
(86).
Completehydatidiformmole(CHM)
Abnormalproductofconceptioncharacterisedbythefollowing:
Presenceofacellularcisterns(vesicles/cysts),oftenvisiblemacro
scopically.
Thechorionicvilliareplumporpolypous,oftencauliflowerlike.
Noorfewtrophoblasticinclusions.
Abundantatypicalvilloustrophoblastproliferation,nonpolar,
focal,multifocalorcircumferential(involvetheentireperiphery
ofthevillus).
Thestromaofthevillusismyxoid(bluish)withkaryorrhexis(nu
cleardebris),fewvesselswithnofoetalredbloodcellsandplump
stromalcells.
Thevilliarediffuselyinvolved.
Nofoetalpartsoramnion(exceptintwinpregnancywithanor
maltwinandinsomecaseswithmosaicismPP/PM,seegenetic
section).
Immunostaining:Ki67indexhighinthevillousstromaandtro
phoblasts.p57KIP2oftennegative(orfocalandweak)inthe
villousstromaandvillouscytotrophoblasts(positivecontrolin
intermediarycytotrophoblast).
Partialhydatidiformmole(PHM)
Abnormalproductofconceptioncharacterisedbythefollowing:
Presenceofacellularcisterns(vesicles/cysts),oftenvisiblemac
roscopically.
Someofthechorionicvilliarelargeandirregularwithclefts,deep
invaginationsandtrophoblasticinclusionsinthestroma.
Slightfocaltrophoblasticproliferationwithoutatypia,attimes
withfibrinoiddegeneration.
Thevilliarefocallyinvolved,i.e.therearetwovilluspopulations:
ahydropicandanormal.
Vesselswithfoetalredbloodcellsandsometimesfoetalparts
and/oramnionarepresent.
Immunostaining:Ki67indexlowinthevillousstromaandtro
phoblasts.p57KIP2oftenpositiveinvillousstromaandvillous
cytotrophoblastsasitisinhydropicabortion.
Invasive/metastatichydatidiformmole
Invasivehydatidiformmole:Thisdiagnosiscanusuallyonlybe
madeafterhysterectomy.Villiwithchangesasinhydatidiform
moleareseeninthemyometriumand/orinthevesselsofthe
myometrium.
DANISH MEDICAL JOURNAL 6
Metastatichydatidiformmole:Pathologicinvestigationisrare. Tabel1.Characteristicsofcompleteandpartialhydatidiform
Extrauterinemolarvilliareseeninbloodvesselsortissue,often mole
vaginaorlung. Characteristics Complete Partial
Ploidy Mostoftendiploid Mostoften
Choriocarcinoma(CC) triploid
Malignanttumourconsistingoflayersofbiphasicatypicaltro Foetalparts/amnion Absent Usuallypresent
phoblastpredominantlyofvilloustypewithoutchorionicvilli. Formofvilli Plump Cleftsand
Mixtureofatypicalsyncytiotrophoblastsandcytotrophoblastsas formationof
singlecells,groupsorislands.Avaryingnumberofintermediary fjords
trophoblastcellsareseen.Bleedingisoftenpresent(characteris Stromalapoptosisin Prominent Limited
tic),necrosisandinvasionofvessels.Nostromaandnochorionic villi
villi(exceptinintraplacentalCC).Immunostainingshowsmore Hydropicchangesand Pronounced,obvious Focal,less
hCGexpressionthanhPLexpression. cisterns cisterns pronounced
Intraplacentalchoriocarcinoma:Rare.Biphasictumourtissuelike cisterns
thatmentionedabovegrowingoutofthestemvilliisseeninthe Trophoblasticprolif Circumferential, Focalandmini
placenta.Thetumourissharplydefinedhistologically,andthe eration oftenmarked mal
surroundingvilliarenormal. Trophoblasticatypia Often Absent
Implantationsite Exaggerated MostOften
Placentalsitetrophoblastictumour(PSTT)
normal
Monophasictumourcomposedofextravillousintermediarytro
p57KIP2 Mostoftennegative Mostoften
phoblastsofimplantationsitetype.Mediumtolargemononu
immunostaining diffuselyposi
clearandmultinuclearcellswithslighttomoderatecellatypia,
tive
prominentnuclei,eosinophilicorpalecytoplasm,scatteredmito

sesandintranuclearinclusions.Tumourcellsinvadethemyo

metriumandgrowintothespiralarterieswheretheyinduce
p57KIP2immunostaining:p57KIP2isanuclearstainthatcanhelp
fibrinoidnecrosis(asinnormalimplantationsites).Cytokeratin
identifycellswithonlyapaternalgenome(PP)(seeninsectionon
andhPLarepositive,onlyfocalhCGpositivity.Ki67ispositivein>
genetics).Inhydropicabortionandtriploidhydatidiformmoles,
10%ofcells.
thevillousstromaandvillouscytotrophoblastsarealmostalways

positive.Indiploidandrogenetichydatidiformmoles,thevillous
Epithelioidtrophoblastictumour(ETT)
stromaandthecytotrophoblastsaremostoftennegativeoronly
Monophasictumourcomposedofextravillousintermediarytro
weaklyfocallypositive.Anegativep57KIP2thusstronglysuggests
phoblastsofchorionlaevetype(thefreemembranes).Thetu
completehydatidiformmole.Extravillousintermediarytro
mourisrareandisconsideredbysometobeasubtypeofPSTT
phoblastsintrophoblasticcolumnsareapositivecontrolinall
andbyotherstobeamalignantcounterpartofPSN.Thetumour
cases.
cellsaremonomorphic,smallerthanandnotasatypicalasthe
Ifdeterminationofploidyhasnotbeenundertakeninnonfixed
tumourcellsinPSTT.Theygrownodularly,thehyalinematrixis
tissue,aFISHanalysisorflowcytometryforploidyonformalin
abundant,andsometimesplacentalsitenodulesareseennearby,
fixedparaffinembeddedtissuecanbeconsidered;theresults
sometimeswithcellatypia.Calcificationsareoftenseen.Ki67is
are,however,lesscertainthanthoseundertakeninnonfixed
positivein>12%ofcells.
tissue.

Immunohistochemistry
3)PHMversustwinpregnancywithamolarandanormalproduct
Alltrophoblastictumours(CC,PSTTandETT)andtheothertro
ofconceptionversusmosaicismPP/PM
phoblasticlesionsarepositiveforlowmolecularweightcy
Intwinpregnancy,asharpmacroscopicorhistologicdivisionis
tokeratin(e.g.CK18)andHLAG.TheyarefocallypositiveforhPL
seenbetweenareaswithhydatidiformmolechangesintheform
andhCG(syncytiotrophoblast).hCG,hPL,CD146,P63,Ki67and
ofeitherCMHorPMHandareaswithnormaltissue.Ifthehy
cyclinEcanbeuseddifferentialdiagnostically(seetable1).(84
datidiformmolehasonlyapaternallyimprintedgenome(whichis
87)
oftenthecasewithCHM),immunostainingwithp57KIP2can

clearlydifferentiatebetweenthedifferentareas.Inmosaicism
Differentialdiagnosticconsiderations
betweenadiploidandrogeneticcelllineandadiploidbiparental
1)Hydropicabortionversushydatidiformmole
(normal)cellline(PP/PM),areaswithhydatidiformmolechanges
Inabortedtissuewithhydropicdegenerativechanges,uniform,
andnormaltissuecanbeseeninlocalisedareas,orthetwotypes
plumpvilliwithanoedematoushypocellularstromaareoften
oftissuecanbeseendiffuselyscatteredamongsteachother.
seen.Inthestroma,collapsedvesselsarealsooftenseen.True
Immunostainingofp57KIP2cangivevaryingresultsdependingon
trophoblastichyperplasiaisnotseen,butsmalltrophoblastic
thedistributionandtypeofcellswithparentaltypesPPandPM.
budsandpseudoinclusionscanbeenseen.Thereactionfor

p57KIP2isoftenretainedinthevillousstromaandcytoplasm.
4)Othergeneticabnormalitiescausingchangesintheproductof

conceptionversushydatidiformmole
2)CHMversusPHM
InBeckwithWiedemannsyndrome(BWS)cysticchanges(mesen

chymaldysplasia)areseenintheplacenta,butthechangesin

volvestemvilli,whichcontainfoetalstemvillousvesselsandnot

distalvilli.Inchromosomeabnormitiessuchastrisomy,hydatidi

formmolelikevillouschangescanbeseen,buttheseareusually

DANISH MEDICAL JOURNAL 7

notasprominentandcharacteristicasthoseseeninhydatidiform
mole.Demonstrationofaneuploidydoesnotruleoutthediagno
sisofhydatidiformmole,becauseseveralexamplesareknownof
hydatidiformmoleswithadditionalabnormalities,e.g.diploid
androgeneticgenome(PP)andtrisomy(seesectionongenetics).
5)Normalimplantationsiteandbenigntrophoblasticlesionsvs.
trophoblastictumour
Thisisaveryimportantdifferentiationthat,likeasmearwiththe
presenceofatypicaltrophoblasts,canbeverydifficulttomake.In
benignlesionstherearenomitosesornecrosis,andimmu
nostainingforKi67showsalowproliferationindex(<1%inEPS,
<8%inPSN).Inneoplastictrophoblastictumours,theKi67index
ishigh(>10%inPSTT,>12%inETT)(86).Alwayscollatewith chromosomesarelost(25,43,93).
clinicaldataregardingserumhCG,PTDandtimeintervalfrom
latestpregnancy.Thelongerthetimeinterval,thegreatertherisk
oftrophoblastictumour.
6)Choriocarcinoma(CC)vs.intermediarytrophoblastictumour
(PSTTandETT)
CCrespondswelltochemotherapy,whereasPSTTandETTre
spondpoorly,andthusdifferentiationhasdecisivetherapeutic
importance.CCconsistsmacroscopicallyofhaemorrhagictissue
andismicroscopicallybiphasicofthevilloustrophoblasttype
(withavaryingnumberofextravillousintermediarytrophoblast
cells)withextensivebleedingandnecrosisandahighhCGlevel,
whereasPSTTandETTaremonophasictumoursofextravillous
intermediarytypewithlessbleedingandnecrosisandalower
hCGlevel.PSTTissimilartoimplantationsiteandETTtochorion
laeve.Immunostainingisoflimitedhelp(seetable1).Thebest
approachisathoroughinvestigationofalltissueafterstaining
withhaematoxylin&eosinforthepresenceofsyncytiotro
phoblastsinCC.InpredominantlymononuclearCC,whichisseen
especiallyafterchemotherapy,thedifferentialdiagnosiscanbe
extremelydifficult.MixedtumourswithbothCCandextravillous
intermediarytrophoblastictumourareseen.
7)PSTTvs.ETT
PSTTandETTaretreatedinthesamewaybuthavedifferent
prognosesdependingonthetimeintervalfromtheantecedent
pregnancy.Canbereportedasextravillous/intermediarytro
phoblastictumour.ImmunostainingforhPLandp63canbeused,
seetable1.
8)Trophoblastictumourvs.carcinomaorsarcoma
Trophoblastictumoursandbenigntrophoblasticlesionsare
stronglypositiveforcytokeratin.Poorlydifferentiatedcarcinomas
typicallyshowweakerkeratinstainingthantrophoblastictu
mours.TrophoblastictumoursarealsostronglypositiveforHLAG
andmaybepositiveforinhibin,melCAM,hPLandhCG(syncyti
otrophoblast).Theyarenegativeforp16(cervixcancer),actinand
vimentin(sarcoma)(83,88).
Inthepathologyreportofhydatidiformmole,acomprehensive
diagnosisisgivenbasedonthemorphologicpicture,immu
nostainingwithp57KIP2andpossibleploidydetermination.The
resultsofindividualinvestigationshouldbeevidentinthereport.
ThereportissubsequentlyenteredintotheDGCDdatabase.
Ifthereislackofagreementbetweenthepathologicandthe
geneticfindings(e.g.p57KIP2andFISH),thedisagreementshould
bedescribedinthereportandbeexpressedintheconclusion.In
suchcasesthereportstates:hydatidiformmole,uncertain
whethercompleteorpartial.
GENETICS
HYDATIDIFORMMOLE
Approximatelyhalfofhydatidiformmolesarediploid,halfare
triploidand<1%aretetraploid(25,48).
Diploidhydatidiformmole
Diploidhydatidiformmolesaremostoftenandrogeneticand
homozygous.Apossiblemechanismisthatanovumbecomes
fertilisedbyaspermatozoonafterwhichthespermatozoons
chromosomesdoubleandthematernalchromosomesarelost
(89,90,91).About10%ofthediploidandrogenetichydatidiform
molesareheterozygous(43,92);apossiblemechanismisthatan
ovumisfertilisedbytwoseparatespermatozoaandthematernal
Sevenpercentofhydatidiformmolesare(near)diploidandhave
amorecomplicatedgeneticconstitution(25,91,94,134).About
3%ofcasesaremosaicscomprisinganandrogeneticandadiploid
biparentalcellline(PP/PM).Inabout2%ofcases,atwinpreg
nancyexistsinwhichtheoneconceptionhasadiploidandroge
neticgenome(hydatidiformmole)andtheotherhasadiploid
biparentalgenome(normalpregnancy)(PP+PM).Inabout1%of
cases,aneuploidyexists,e.g.diploidandrogenesis(PP)andtriso
myinvolvingoneormoresupernumerarychromosomes(e.g.
47,XX,+8).In<1%ofcasesallthecellshaveadiploidbiparental
genome(PM).
Somewomenwithbiparentaldiploidhydatidiformmoleshavea
recessivehereditarydispositiontohydatidiformmole,inthat
theyhaveinheritedamutationinbothalleles1ofthegeneNLRP7
(72)orofgeneKHDC3L(73).Inalmostallreportedpregnanciesin
thesewomen,hydatidiformmoleshavebeenseen.Itispossible
thatoocytesmaturinginwomenwithmutationinbothallelesof
NLRP7areabnormallyimprintedandthatthisisthereasonfor
thehydatidiformmolephenotypeintheirconceptions(95).Nor
malpregnancieshavebeendescribedinthesewomenafteregg
donation(96).
MutationinNLRP7andKHDL3Cgenesdoesnothavephenotypi
calconsequencesforthewomenthemselves.Menwithamuta
tioninbothalleleshaveneitheraffectedphenotypenorfertility.
Ithasbeensuggestedthatwomenwhoareheterozygotefora
mutationinthesegenescouldhavereducedfertility(97),butto
datethereisnoconvincingevidenceforthis(94,98).
Triploidhydatidiformmole
Triploidhydatidiformmolescontainonechromosomesetinher
itedfromthemotherandtwochromosomessetsfromthefather
(PPM).Themostlikelymechanismisfertilisationofaneggcell
withtwoseparatespermatozoa(19,45,99).Triploidconceptions
withtwosetsofmaternalchromosomesarenothydatidiform
moles(19,100).
Tetraploidhydatidiformmole
Tetraploidhydatidiformmolesusuallycontainamaternalchro
mosomesetandthreechromosomessetsinheritedfromthe
father(48,92,101,102).
1
Allele=copyofagene.Womenhavetwoallelesofallgenes
becausetheyhaveinheritedacopyofallgenesfromtheirmother
andfromtheirfather.Menhaveallelesofgenesonchromosomes
122andonealleleofgenesontheXandYchromosomes.
DANISH MEDICAL JOURNAL 8
Gestationaltrophoblasticneoplasia(GTN)
Gestationalchoriocarcinoma,PSTTandETTcanallariseonthe
basisofamolarpregnancyandanonmolarpregnancy.Even
thoughthereareoften(always?)somaticgenomicaberrationsin
neoplasticcells,theoverallgeneticconstitutioninaGTNisidenti
calwiththeconstitutionintheoriginalpregnancy.Thismeans
thatthegeneticconstitutioninGTNthatarisesfromadiploid
androgenetichydatidiformmolewillbediploidandrogeneticand
thatthegeneticconstitutioninaGTNthatarisesfromanon
molarpregnancywillbediploidbiparental.Inthesameway,the
overallgeneticconstitutioninanongestationaltrophoblastic
tumourinwomenwillbeidenticalwiththewomensowngenetic
constitution.
Sincetreatmentandprognosisdiffersbetweengestationaland
nongestationalGTN,andbetweengestationalGTNwithbiparen
talandpaternalgenomes,itisimportanttogenotypethesetu
mors.
GENETICANALYSES
Determinationofploidy
Ploidy(numberofchromosomesets)canbedeterminedinsev
eralways:
Karyotypingoflivingcells
Flowcytometryonnonfixedtissuewithexternalcontrolcells
Flowcytometryonfixedtissue
FISH
Therearevariouslimitationsregardingtheuseoftechniquesto
determineploidyonfixedtissue.Inflowcytometryonfixedtis
sue,thereisnopossibilityofincludingvalidcontrolcells.Byflow
cytometryoffreshcontraformalinfixed,paraffinembedded
specimensofthesametissue,conflictingresultswereobtainedin
4/30cases(14%)(103).InFISHonfixedtissue,thecellnucleiwill
becutthrough.InDNApurificationinfixedtissue,itcanbediffi
culttoobtainDNAofadequatequality,andtherewilloftenbe
contaminationwithmaternalDNA
Ploidyisoptimallydeterminedwhenunfixedcellsareused,e.g.
withkaryotyping,flowcytometry(withadditionoftwodifferent
typesofcontrolcellswithknownDNAcontents),orFISHonwho
lecellnuclei.Careshouldbetakenintheuseofinformation
regardingploidydeterminedonfixedtissue.
Determinationoftheparentaloriginofthegenome
Theparentaloriginofthegenomeinahydatidiformmoleor
othergestationaltrophoblasticdiseaseisdeterminedbypurifying
DNAfromthehydatidiformmole/trophoblasticlesionandthe
mother/womanandcomparingthepolymorphicDNAmarkers.
OftenitishelpfultoincludeDNAfromthefather/man.
ItisoftenpossibletopurifyDNAfromformalinfixed,paraffin
embeddedtissue.Buttherateofsuccessisgreaterandtheriskof
maternalcontaminationoftissuefromthehydatidiformmo
le/trophoblasticlesionlessifanunfixedsampleisusedthatcan
bedissectedfreeofmaternaltissue.Fromthemother/women
(andfather/man)abloodsampleisoptimal.
DeterminationofwhichpregnancywastheoriginoftheGTNand
studyofGTNvs.nongestationaltrophoblasticdisease
PolymorphicDNAmarkersintheindexGTNarecomparedwith
markersinpreviouspregnancies/childrenofboththewomanand
theman.Thesametechniqueasfordeterminationoftheparen
taloriginofthegenomeisused.
GENETICSCOMPAREDWITHOTHERANALYSES
Geneticsandmorphology
Molarpregnanciescanbeclassifiedmorphologicallyorgeneti
cally.Howgreatistheagreementbetweenthesetwoclassifica
tions?
Mostcompletehydatidiformmolesarediploidandrogenetic;
partialhydatidiformmolesaremostlytriploid.
Correspondingly,diploidandrogenetichydatidiformmolesare
usuallycomplete,triploidhydatidiformmolesareusuallypartial
(19,25,89,104107),whereasmosttetraploidhydatidiformmoles
aredescribedascompleteandafewaspartial(48).Amongthese
classicalhydatidiformmoles",thegreatestvariabilityinmor
phologyappearstobeamongthetriploidhydatidiformmoles,
rangingfromcompletehydatidiformmoletohydropicdegenera
tion/nonhydatidiformmole(19,25,100,108,109).
Variousdifferentmorphologieshavebeendescribedindiploid
biparentalhydatidiformmoleinwomenwithmutationsinNLRP7,
evenamonghydatidiformmolesinthesamewoman
(72,110,111).Amongthefewcasesofdiploidbiparentalhydatidi
formmoleinwomenwithmutationsinKHDC3Lthathavebeen
described,thephenotypeappearstobemainlycompletehy
datidiformmole(73,112).
InmosaicismPP/PM,itcanbeexpectedthatthemorphologyof
thepregnancyvariesdependingontheprevalenceofcellswith
androgeneticandbiparentalgenomesanddependentofwhich
celltypes(e.g.trophoblastsvs.mesenchymalcells)havebiparen
talandandrogeneticgenomes(91,113)anddependingon
whetherandrogeneticcellsarepresentinanyfoetaltissue.Living
childrenhavebeenbornafterpregnancieswithmosaicismPP/PM
(114).
Inatwinpregnancymadeupofahydatidiformmoleandanor
malpregnancy,themixtureoftissuesfrombothconceptionscan
beconfusing.Andinbothmultiplepregnancyandinmosaicism,
thecorrectdiagnosisisdependentonwhetheranadequately
largeandrepresentativesampleissentforgeneticand/orpatho
logicevaluation.
Geneticsandimmunochemicalstainingforp57KIP2
ThegeneCDKN1C,locatedonchromosome11,isparentally
imprinted2incytotrophoblastsandvillousstromalcells;onlythe
maternalalleleisexpressed.ThegeneproductofCDKN1C
(p57KIP2)canbedemonstratedwithimmunostaining.Cytotro
phoblastsandvillousstromalcellsthatarestainedwiththeanti
bodyagainstp57KIP2maythereforebeconsideredtocontain(at
least)onlymaternallyinheritedcopyofthegeneCDKN1C.Inmost
diploidandrogenetichydatidiformmoles,thecytotrophoblasts
andvillousstromalcellsdonotstainwiththeantibodyagainst
p57KIP2,whereasthesecellswillbestainedinmosttriploidand
tetraploidhydatidiformmoles.Somecasesinwhichthispredic
tionhasnotheldtruecanbeexplainedbythepresenceofa
maternalchromosome11inanotherwisediploidandrogenetic
hydatidiformmoleorlossofthematernalchromosome11in
triploidortetraploidhydatidiformmoles(115).Insomebiparen
2
Parentalimprintedgenesaregeneswhoseexpression(use)is
differentfromtheallelethatisinheritedfromthefatherandthe
allelethatisinheritedfromthemother.Insomegenes,onlythe
alleleinheritedfromthemotherisexpressed,inothergenes,only
thealleleinheritedfromthefather.Imprintingcan,e.g.,consistof
the presence or absence of a methyl group in certain cytosine
basesinornearthegeneinquestion.
DANISH MEDICAL JOURNAL 9
taldiploidhydatidiformmoles,absenceofp57KIP2hasbeen
seen,probablyasaconsequenceofabnormalimprinting(116).
Interpretationoftheimmunostainingofp57KIP2molarpreg
nancywithmosaicismisataskforanexpert(51,113).Thevalue
ofimmunostainingofp57KIP2asapredictorforPTDhasnotbeen
systematicallyevaluated.
GENETICEVALUATION/WORKUPANDCOUNSELLING
Women/coupleswiththefollowinghistory/orfamilyhistory
shouldbeofferedevaluationataclinicalgeneticsunit:
thewomen/couplehavehadtwohydatidiformmoles
thewomen/couplehavehadhydatidiformmoleandthreespon
taneousabortions
thewomanhashadahydatidiformmoleandafamilyhistorythat
suggestsautosomalrecessivehereditarydispositiontohydatidi
formmole
thewomanhashadahydatidiformmoleandhasconsanguine
parents
thewomen/couplehavehadadiploid,biparentalhydatidiform
mole
thewomanhasarelativewithmutationinNLRP7orKHDC3L.
Theworkupconsistsof:
Personalhistoryandfamilyhistory(pedigree)
Determinationofploidyandtheparentaloriginofthegenomein
theabnormalpregnanciesthewomen/coupleandanyaffected
relativesmayhavehad
Ifindicated,mutationanalysisofNLRP7andKHDC3L
Ifindicated,chromosomestudyofthewomanandthepartner
IfmutationsaredetectedinbothallelesofNLRP7orKHDC3Lin
thewoman:
Theprobabilitythatapregnancyofthewomanwillresultina
viablechildismostoftensmall,butdependsonthetypeofmuta
tion.Eggdonationshouldbediscussed.
Thereisindicationforqualifiedultrasoundexaminationofthe
pregnancy,bothincaseofeggdonationandincaseofspontane
ouspregnancy.Itisunlikelythatchangeinpartnerordonorin
seminationwillchangetheriskofrecurrence.Prenatalgenetic
diagnosticsarenotpossible.
Thewomansrelativesshouldbeofferedgeneticcounsellingand
genetictesting.
Ifthehistoryandfamilyhistorysuggestsautosomalrecessive
inheritance,butnomutationinNLRP7orKHDC3Lcanbedemon
stratedinthewoman:
Thecertaintywithwhichapregnancyinwomenwillresultina
livingchildshouldbedeterminedbasedonthewomanshistory.
Eggdonationcanbediscussed,keepinginmindthatthereisonly
indirectevidenceforitsrationality.Qualifiedultrasonicmonitor
ingduringthepregnancyisindicated,bothaftereggdonationand
ifspontaneouspregnancyoccurs.Itisunlikelythatchangein
partnerordonorinseminationwillchangetheriskofrecurrence.
Prenatalgeneticdiagnosticsarenotpossible.
Thewomansrelativesshouldbeofferedgeneticcounselling.
Ifabiparentaldiploidhydatidiformmoleisfoundbutthereisno
informationonadditionalcasesofabortionorhydatidiformmole
inthewomenorherfamily,andnomutationisdemonstratedin
NLRP7orKHDC3L:
Themorphologicobservationsregardingthehydatidiformmole
shouldberevised.Isitpossiblethatthereisnohydatidiform
mole?
Thegeneticobservationsregardingthehydatidiformmoleshould
berevised:Ismosaicismpossiblypresentwithoftwodifferent
celllines?Couldtherebeastructuralchromosomalabnormality
inthegenomeofthehydatidiformmole?
Ifthediagnosisofbiparentaldiploidhydatidiformmoleismain
tained,theriskofrecurrenceisunknown,butprobablylower
thaninthosewomeninwhomthereisevidenceofautosomal
recessiveinheritance.
ONCOLOGICTREATMENT
InDenmark,approximately10patientsayeardevelopgestational
trophoblasticdiseasethatrequireschemotherapy.Theobjective
ofcytostatictreatmentistocurethepatientandatthesame
timeretainfertilitywithoutriskofsecondarymalignancyorearly
menopause.
INDICATIONSFORTREATMENT
PTD(hCGcriterion:increasing,plateau)
Invasivehydatidiformmole/metastatichydatidiformmole
Choriocarcinoma
Intermediarytrophoblastictumour(PSTT/ETT)(notaccessibleto
surgicaltherapy)
Persistentheavyvaginalbleedinginapatientwithtrophoblastic
disease
WORKUPBEFORECHEMOTHERAPY
InaccordancewithFIGO,thefollowingarerequiredinthewor
kup:chestxray,ultrasoundscanofabdomenandpelvis,serum
hCG,gynaecologicandphysicalexamination,CTisnotarequire
mentbutisrecommended.
CTcandetectpulmonarymetastasesinupto40%ofthexray
negativepatients(117)andisthereforerecommended.Ultra
soundscanningcanbeusedtodiagnosediseaseinandoutside
theuterus(118).CNSmetastasescanbedetectedwithCTorMR,
andwithaspinaltap,hCGcanbemeasuredinthecerebrospinal
fluid.Aratioofover1:60intheconcentrationofhCGinthespinal
fluid:serumisdiagnosticforCNSmetastasis(35).Ifapatienthas
pulmonarymetastases,diagnosticworkupforbrainmetastases
shouldbeconsidered(119).
CHEMOTHERAPY
Almostallforeigncentresclassifypatientsbasedontheprognos
ticparametersinFIGOsscoringsystem(120)intohighandlow
riskgroups.Patientsinthehighriskgroupsaretreatedwith
highlyintensivecombinationregimes.Thetreatmentoflowrisk
patientsisalsomoreintensivethaninDenmark(132,136).In
Denmark,however,aresponseadaptiveregimeisused,inwhich
allpatientsregardlessofriskfactorsareinitiallytreatedwith
methotrexate(MTX).
ByusingMTXasinitialtherapy,agoodresponseisseeninpa
tients(alsoinhighriskdisease),andtheriskofsuddenlife
threateningbleeding,whichcanbeseenatthestartoftreatment,
isreducedtoaminimum.Thepatientcanbesustainedthrough
theacutephaseandafterwardstreatedmoreintenselyifMTX
resistancedevelops.
ThisregimehasbeenusedinDenmarkformorethan30years,
andarecentreviewof71patientstreatedforposthydatidiform
moleswithPTDshoweda100%response,norecurrencesanda
lowincidenceofsideeffects(121).Bycomparison,therateof
recurrenceintheU.K.is23%,andseveralcasesofacute,life
threateningbleedingareseen(2).
Gestationaltrophoblastictumoursarehighlysensitivetochemo
therapy,andresponseadaptivechemotherapyconsistsofthree
lines.Primarytherapy(lstline)isoralMTXorI.V.MTX.Ifresis
DANISH MEDICAL JOURNAL 10
tancedevelops,I.V.actinomycinDisaddedas2ndlinetherapy,
orMTXisreplacedwithactinomycinD.Ifthepatientdoesnot
respond,shiftismadetoamoreintensiveregime(3rdline),often
BEPorEP.
TheresponseratetotheinitialoralMTXtherapyis50%,while
37%arecuredwith2ndlinetherapy.Only13%ofpatientshave
tobetreatedwithhighdosecombinationtherapytobecured
(121).Oneconsolidationtreatmentisgivenaftertherapyhasled
toundetectableserumhCGvalues.
Chemotherapeuticregimes
1stlinetherapy
MTXcanbegiveneitherorallyorintravenously.Fororaltreat
ment,2.5mgx4dailyfor5days/every3rdweekwithleucovorin
rescuetherapyconsistingof1mlcalciumfolinategivenorally.If
I.V.MTXisused,thedoseis250mg/m2perweek.Ifthereisa
highriskofbleeding,givingthefirsttherapysessionduringhospi
talizationmaybeconsidered.Ifthereareproblemswithcompli
ance,I.V.orI.M.MTXcanbegiveninsteadoforaltherapy.
2ndlinetherapy
IfkineticresistanceagainstMTXdevelops,i.e.serumhCGde
creasesaftereachseriesbutincreasesorstagnatesbeforethe
nextseries,actD0.5mgisgivendailyfor5daysevery3rdweek. alwaysdevelopresistancetoMTXandtreatmentthereforecon
IfMTXintoleranceorresistantdevelops,patientsaretreatedwith
actDalone.
3rdlinetherapy
Combinationtherapywithbleomycin(30,000IUI.V.days2,9,
16),etoposid(100mg/m2I.V.days15)andcisplatin(20mg/m2
I.V.days15)everythirdweek(BEP),orpossiblyonlyetoposid
andcisplatin(EP).
Otherchemotherapeuticregimes
EMACO
EMACO(etoposid,MTX,actinomycinDalternatingeveryweek
withOncovorinandcyclophosphamide)isusedinpatientsinthe
highriskgroupandpatientswhorelapsewhileonMTXand/or
actinomycinD.NormalisationofhCGisseenin98%ofpatients,
butthetreatmentisintensiveandtoxic(122)
EMAEP
EMAEP(etoposid,MTX,actinomycinD,alternatingeveryweek
withetoposidandcisplatin)isatoxicandresourcedemanding
treatment.InpatientswithhighriskGTN(PSTT,ETTandchorio
carcinomasareoftenrefractorytoEMACO)EMAEPhasbeen
showntoresultinaresponsein100%andpersistentremissionin
75%(78).
Taxans
Taxanshavebeenshowntohaveaneffectinpreviouslyintensely
treatedpatients,withpersistentcompleteremissioninmost.This
informationis,however,basedoncasereports(137,138).
Acutesideeffectsofchemotherapy
SeveresideeffectsareusuallynotseenwithMTX,butkidney
functionmustbemonitoredbecauseMTXisexcretedrenallyand
cancauseuncontrollabletoxicityinthepresenceofrenalinsuffi
ciency.InadditionsomepatientsarepoorexcretesofMTX.Hepa
tocellulartoxicityisseenintreatmentregimeswithoutfolinic
acid.
ActinomycinDmoreoftenthanMTXcauseshairloss,nauseaand
vomiting,myelosuppressionandstomatitis(123).
CombinationregimeslikeEMACOandespeciallyEMAEPare
markedlymoretoxic,withgrades3and4toxicityinupto50%
(78).
BEPcancausetransientmyelosuppression,tinnitus,lossofhear
ing,paraesthesiasinfingersandtoesaswellasskinandlung
toxicity.Ifbleomycinisnotincluded,EPdoesnotcauseskinand
lungtoxicity.
Sequelaetochemotherapy
MTXassingledrugdoesnotincreasetheriskofsecondarymalig
nancy,butcombinationtherapyincreasetheriskofsecondary
malignancybyafactorof1.5andforacutemyeloidleukaemia
andbreastcancerwithfactorsof16and6,respectively(124).
Afteruseofcombinationchemotherapy,menopauseappearson
average2yearsearlierthanafterMTXalone(133).
Medicaltreatmentofraretrophoblasticdiseases
Choriocarcinoma
PatientswithchoriocarcinomaareseldomcuredwithMTXalone,
andtheprimarytreatmentconsistsofetoposidandcisplatin
possiblyalsowithbleomycin.Inordertoavoidbleedingcomplica
tionsinthesepatients,theycaninitiallybetreatedwithMTX
aloneorincombinationwithactinomycinD(139).Patientsalmost
tinueswithetoposid,cisplatinandpossiblybleomycin(135).
Placentalsitetrophoblastictumour(PSTT)
PSTTmetastasiseslaterthandoeschoriocarcinoma,buttumour
spreadintheuteruscanbeextensive.SerumhCGisnormallyonly
slightlyelevated,whereasserumhumanplacentallactogenhor
mone(serumhPL)isusuallyelevated.Thetumourislesssensitive
tochemotherapythanothertrophoblasticdiseases,andifpossi
ble,surgeryshouldbethefirsttreatment(125).
Epithelioidtrophoblastictumour(ETT)
Thecourseisoftenbenign,but25%ofpatientscanhavemetas
tasesand10%dieofthedisease.Theresultsofcytostatictherapy
areverysparselydescribed,butaswithPSTT,sensitivitytoche
motherapyappearstobepoor,andforthisreasonlocaltreat
ment(suchashysterectomyandresectionofpulmonarymetasta
ses)shouldbechosen(81).
Complications
Trophoblastictumoursarehighlyvascularised,whichmaycause
bleedingafterbiopsyorstartofchemotherapy(35),andmassive
pulmonaryemboliofnecrotictumourtissuemaybeseenafter
startoftreatment.Biopsyofanymetastasesisnotnecessaryto
makethediagnosisandshouldbeavoided.Pulmonarymetasta
sescancausedyspnoea,cough,haemoptysisandpulmonary
hypertension(126128).Inrarecases,intubationorextracorpo
realventilationcanbenecessary.Theprognosisisextremely
poor,butcurativetreatmentshouldbeattempted.
ThehCGmoleculecancrossreactwiththeTSHreceptorand
causethyrotoxicosis,whichimproveswhenthepatientistreated
forthemalignantdisease(127).
Monitoringoftheeffectoftreatment
Theeffectoftreatmentismonitoredbyregularmeasurementof
hCGinserum,andinthecaseofCNSdisease,inthespinalfluid.
TheserumhCGlevelisproportionatewiththeamountofthe
disease,andregulardiagnosticimagingisnormallynotnecessary.
Theconcentrationofhumanplacentallactogenhormone(hPL)in
theserumcansupplementserumhCGinmonitoringtheeffectof
DANISH MEDICAL JOURNAL 11
thetreatmentofPSTTandETT.Heretoo,diagnosticimagingis
notindicated.
Followupaftermedicaltreatment
Aftercompletionofcytostatictherapyfortrophoblastictumour,
thepatientshouldbefollowedupfor1yearwithserumhCG(12 (B).
timesamonthforthefirst3months,thenevery2nddto3rd 3rdlinechemotherapyisBEPorEP,alternativelyEMACO(B).
month).Patientsareadvisednottobecomepregnancyduringthe
followupperiod.Gynaecologicexaminationanddiagnosticimag
ingarenotnecessary.
Atanylaterpregnancy,serumhCGshouldbemeasured8weeks
afterterminationofpregnancy.
TreatmentofresidualdiseaseinpatientswithnormalisedhCG
TwostudiesshowthatpatientstreatedformetastaticGTN(gesta
tionaltrophoblasticneoplasia)withresidualinfiltratesinthe
lungsafternormalisationofhCGcanbeobservedwithoutaddi
tionaltreatmentandthatsurvivalisthesameasinpatientswith
outresidualinfiltrates.Suchinfiltratesprobablyconsistofnon
vitaltumourtissue.(129,130).
RadiotherapyofCNSdisease
LocalcontrolofthewholeCNSisobtainedwithradiotherapyin
91%withdosesof2236GYandin24%withdoseslessthan22 toredandultrasoundscansregularlypreformed,andpossible
GY(131).Thedownsideistransienthairlossandmyelosuppres
sion.MTXgiveintrathecallyorinhighI.V.doseshasthesame
effectasradiotherapyandcanberecommended(124).
SUMMARY
Hydatidiformmoleistreatedwithsurgicaluterineevacuation
withsuctionandbluntcurettage(D).
Medicaluterineevacuationshouldnotbeused(C).
Onclinicalsuspicionofhydatidiformmole,onerepresentative
sampleoftheevacuatedtissueisfixedforhistopathologicinves
tigationandoneisforwardedunfixedforgeneticanalysis(D).
SerumhCGismeasuredonsuspicionofhydatidiformmole.Atthe
timeoftheuterineevacuation,theinitialhCGismeasured(A).
Afterahydatidiformmolethatisbothtriploidandpartial,serum
hCGismeasuredweeklyuntiltherearetwoconsecutiveunde
tectablevalues(<1or<2),afterwhichthepatientcanbedis
chargedfromfollowup(C).
Afteradiploidhydatidiformmole,acompletemole,orahydatidi
formmolewithoutvalidploidydetermination,serumhCGis
measuredweeklyuntilthevalueisundetectable(<1or<2).If
serumhCGisundetectablewithin56daysafterevacuation,the
patientcanbedischargedfromfollowupafteranadditional4
monthlymeasurements.IfserumhCGisfirstnormalisedafter56
days,thepatientisfollowupwithmonthlyserumhCGmeasure
mentfor6months.
Safecontraceptionshouldbeusedduringthefollowupperiod
(A).
IfhCGstagnates(lessthan10%falloverthreemeasurements),
increases,orifhCGcanbedemonstratedforlongerthan6
months,thepatientbydefinitionhaspersistenttrophoblastic
disease(PTD).Achestxrayshouldbetakenandagynaecologic
ultrasoundscanningperformed.Thepatientisreferredtoon
cologictreatment(A).
UterinereevacuationasatreatmentforPTDcan,ingeneral,not
berecommendedbecausetherateofremissionislow,andthere
istheriskofperforationoftheuterus(C).
Inallfollowingpregnancies,thewomanisofferedanearlyultra
soundscan,e.g.ingestationalweek8(D).
8weeksafterterminationofallfuturepregnancies,serumhCGis
measured(D).
InPTDandinvasivehydatidiformmole,theprimarytreatmentis
MTX,eitherorallyevery3rdweekorI.V.everyweek(B).
InMTXresistantPTD,I.V.actDisadded(orreplacestheMTX)
Choriocarcinomaisprimarilytreatedwithchemotherapy.Hyster
ectomyand/orresectionofmetastasesarepossibletreatments
(A).
Placentalsitetrophoblastictumour(PSTT)andepithelioidtro
phoblastictumour(ETT)areprimarilytreatedwithhysterectomy.
Inthecaseofdisseminateddisease,chemotherapyisconsid
ered(A).
Theriskofreoccurrenceaftertrophoblasticdiseasetreatedwith
chemotherapyisapproximately3%.Mostreoccurrencesareseen
within12months,andforthisreasonmonitoringofhCGisrec
ommendedfor1year,thefirst3monthsonceortwiceamonth,
thereafterevery2ndto3rdmonth.
PatientswithPSTTandETTaremonitoredwithmeasurementof
hCGthroughouttheirlifetimes(C).
Ingeneticallyverifiedtwinpregnancywithhydatidiformmoleand
alivingfoetus,thepregnancycancontinueifserumhCGismoni
obstetriccomplicationsdealtwith(C).
Inthecaseofrecurrenthydatidiformmoleand/orfamilialhy
datidiformmole,patientsshouldbereferredtogeneticworkup
andcounselling(C).
Womenwithahereditarydispositiontohydatidiformmolebe
causeofamutationinNLRP7shouldbeinformedofthepossibil
ityofbecomingpregnantviaeggdonation(C).
REFERENCES
1.ShihIM.Gestationaltrophoblasticneoplasiapathogenesis
andpotentialtherapeutictargets.LancetOncol2007;8:64250.
2.SecklMJ,SebireNJ,BerkowitzRS.Gestationaltrophoblastic
disease.Lancet2010;376:71729.
3.LurainJR.GestationaltrophoblasticdiseaseI:epidemiology,
pathology,clinicalpresentationanddiagnosisofgestationaltro
phoblasticdisease,andmanagementofhydatidiformmole.AJOG
2010:5319.
4.LundH,GroveA,VybergM,SundeL.Incidenceofhydatidiform
moleinDenmark19992010.OralpresentationatISSTD2013.
5.SebireNJ,FoskettM,FisherRA,ReesH,SecklM,NewlandsE.
Riskofpartialandcompletehydatidiformmolarpregnancyin
relationtomaternalage.BJOG2002;109:99102.
6.NiemannI,PetersenLK,HansenES,SundeL.Differencesin
currentclinicalfeaturesofdiploidandtriploidhydatidiformmole.
BJOG2007;114:12737.
7.ParazziniF,MangiliG,LaVecchiaCetal.Riskfactorsforgesta
tionaltrophoblasticdisease:aseparateanalysisofcompleteand
partialhydatidiformmoles.ObstetGynecol1991;78:103945.
8.BatesM,EveradJ,WallL,HorsmanJM,HancockB.Istherea
relationshipbetweentreatmentforinfertilityandgestational
trophoblasticdisease?HumReprod2004;19:3657.
DANISH MEDICAL JOURNAL 12

9.PetignatP,VassilakosP,CampanaA.Arefertilitydrugsarisk
factorforpersistenttrophoblastictumour?HumReprod
2002;17:161015.
10.SebireNJ,FisherRA,FoskettM,ReesH,SecklMJ,Newlands
ES.Riskofrecurrenthydatidiformmoleandsubsequentpreg
nancyoutcomefollowingcompleteorpartialhydatidiformmolar
pregnancy.BJOG2003;110:226.
11.HancockBW,TidyJA.Currentmanagementofmolarpreg
nancy.JReprodMed2002;47:34754.
12.CurrySL,HammondCB,TyreyL,CreasmanWT,ParkerRT.
Hydatidiformmole:diagnosis,management,andlongtermfol
lowupof347patients.ObstetGynecol1975;45:18.
13.FelembanAA,BakriYN,AlkharifHA,AltuwaijriSM,ShalhoubJ,
BerkowitzRS.Completemolarpregnancy.ClinicaltrendsatKing
FahadHospital,Riyadh,KingdomofSaudiArabia.JReprodMed
1998;43:113.
14.MunganT,KuscuE,DabakogluT,SenozS,UgurM,Cobanoglu
O.Hydatidiformmole:clinicalanalysisof310patients.IntJGy
naecolObstet1996;52:23336.
15.BerkowitzRS,GoldsteinDP,BernsteinMR.Naturalhistoryof
partialmolarpregnancy.ObstetGynecol1985;66:67781.
16.SzulmanAE,SurtiU.Theclinicopathologicprofileofthepar
tialhydatidiformmole.ObstetGynecol1982;59:597602.
17.SzulmanASotoWrightV,BernsteinM,GoldsteinDP,Berko
witzRS.Thechangingclinicalpresentationofcompletemolar
pregnancy.ObstetGynecol1995;86:7759.
18.JauniauxE,NicolaidesKH.Earlyultrasounddiagnosisand
followupofmolarpregnancies.UltrasoundObstetGynecol
1997;9:1721.
19.JoergensenMW,NiemannI,RasmussenAA,HindkjaerJ,
AgerholmI,BolundL,KolvraaS,SundeL.Triploidpregnancies,
geneticandclinicalfeaturesof158cases,aretrospectiveanalysis
.Underreview
20.CoukosG,MakrigiannakisA,ChungJ,RandallTC,RubinSC,
BenjaminI.Completehydatidiformmole.Adiseasewithachang
ingprofile.JReprodMed1999;44:698704.
21.FowlerDJ,LindsayI,SecklMJ,SebireNJ.Routinepre
evacuationultrasounddiagnosisforhydatidiformmole:experi
enceofmorethan1000casesfromaregionalreferralcenter.
UltrasoundObstetGynecol2006;27:5660.
22.KirkE,PapageorghiouAT,CondousG,BottomleyC,BourneT.
Theaccuracyoffirsttrimesterultrasoundinthediagnosisof
hydatidiformmole.UltrasoundObstetGynecol2007;29:7075.
23.LindholmH,FlamF.Thediagnosisofmolarpregnancyby
sonographyandgrossmorphology.ActaObGynScan1999;78:6
9.
24SebireNJ,ReesH,ParadinasF,SecklM,NewlandsE.Thediag
nosticimplicationsofroutineultrassoundexaminationinhis
tologicallyconfirmedearlymolarpregnancies.UltrasoundObstet
Gynecol2001;18:6625.
25.NiemannI,HansenES,SundeL.Theriskofpersistenttro
phoblasticdiseaseafterhydatidiformmoleclassifiedbymorphol
ogyandploidy.GynecolOncol2007Feb;104:4115.
26.BerkowitzRS,GoldsteinDP.Clinicalpractice:Molarpreg
nancy.NEnglJMed2009;360:163945.
27.TidyJA,GillespieAM,BrightN,RadstoneCR,ColemanRE,
HancockBW.Gestationaltrophoblasticdisease:astudyofmode
ofevacuationandsubsequentneedfortreatmentwithchemo
therapy.GynecolOncol2000;78:30912.
28.FlamF,LundstrmV,PetterssonF.Medicalinductionpriorto
surgicalevacuationofhydatidiformmole:isthereagreaterriskof
persistenttrophoblasticdisease?EurJObstetGynecolReprod
Biol1991;42:5760.
29.CoyleC,ShortD,DayalL,HorsleyL,SebireN,KaurB,Harvey
R,SavageP,SecklM.TimetohCGnormalisationinpatientswith
hydatidiformmolarpregnancy(HM)andriskofpersistentgesta
tionaltrophoblasticdisease(PTD).OralpresentationattheISSTD
2013conference.
30.LurainJR.Managenmentofhighriskgestationaltrophoblastic
disease.JReprodMed1998;43:4452.
31.SchorgeJO,GoldsteinDP,BersteinMR,BerkowitzRS.Gesta
tionalTrophoblasticDisease.CurrTreatOptionsOncol
2000;1:16975.Review.
32.IlancheranA,Optimaltreatmentingestationaltrophoblastic
disease.AnnAcadMedSingapore1998;27:698704.Review.
33.PisalN,NorthC,TidyJ,HancockB.Roleofhysterectomyin
managementofgestationaltrophoblasticdisease.GyncolOncol
2002;87:1902.
34.AyhanA,TuncerZS,HalilzadeH,KckALIT.Predictorsof
persistentdiseaseinwomenwithcompletehydatidiformmole.J
ReprodMed1996;41:5914.
35.BerkowitzRS,GoldsteinDP.Chorionictumors.NEnglJMed
1996;335:17408.
36.WolfbergAJ,BerkowitzRS,GoldsteinDP,FeltmateC,Lieber
manE.PostevacuationhCGlevelsandriskofgestationaltro
phoblasticneoplasiainwomenwithcompletemolarpregnancy.
ObstetGynecol2005;106:54852.
37.WolfbergAJ,GrowdonWB,FeltmateCM,GoldsteinDP,Ge
nestDR,ChinchillaME,etal.Lowriskofrelapseafterachieving
undetectableHCGlevelsinwomenwithpartialmolarpregnancy.
ObstetGynecol2006;108:3936.
38.WielsmaS,KerkmeijerL,BekkersR,PymanJ,TanJ,QuinnM.
Persistenttrophoblastdiseasefollowingpartialmolarpregnancy.
AustN.ZJObstetGynaecol2006;46:119123.
DANISH MEDICAL JOURNAL 13
39.LawlerSD,FisherRA.Geneticstudiesinhydatidiformmole
withclinicalcorrelations.Placenta1987;8:7788.
40.WakeN,FujinoT,HoshiS,ShinkaiN,SakaiK,KatoH,etal.The 54.PezeshkiM,HancockBW,SilcocksP,EverardJE,ColemanJ,
propensitytomalignancyofdispermicheterozygousmoles.Pla
centa1987;8:319326.
41.NiemannI,PetersenLK,HansenES,SundeL.Predictorsoflow
riskofpersistenttrophoblasticdiseaseinmolarpregnancies.
ObstetGynecol2006;107:100611.
42.KanekiE,KobayashiH,hirakawaT,MatsudaT,KatoH,Wake
N.Incidenceofpostmolargestationaltrophoblasticdiseasein
androgeneticmolesandthemorphologicalfeaturesassociated
withlowriskpostmolargestationaltrophoblasticdisease.Cancer
Sci2010;101:171721.
43.LawlerSD,FisherRA,DentJ.Aprospectivegeneticstudyof
completeandpartialhydatidiformmoles.AmJObstetGynecol
1991;164:12707.
44.OhamaK,UedaK,OkamotoEetal.Cytogeneticandclinicopa
thologicstudiesofpartialmoles.ObstetGynecol1986:68:25962.
45.ScholzN,BolundL,NyegaardM,FaaborgL,JoergensenM,
LundH,NiemannI,SundeL.Triploidconceptuseswithmolar
morphologygeneticsandriskofgestationaltrophoblasticneo
plasia.Inprep2015
46.VejerslevLO,LarsenG,JacobsenM.Partialhydatidiformmole
withsubsequenttrophoblastictumor;acasereport.EurJObstet
GynecolReprodBiol1991;40(1):737.
47.SecklMJ,FisherRA,SalernoG,ReesH,ParadinasFJ,Foskett
M,etal.Choriocarcinomaandpartialhydatidiformmoles.Lancet
2000;356:369.
48.SundvallL,LundH,NiemannI,JensenUB,BolundL,SundeL.
Tetraploidyinhydatidiformmoles.HumReprod.2013
Jul;28(7):201020.
49.BaasanjavB,UsuiH,KiharaM,KakuH,NakadaE,TateS,
MitsuhashiA,MatsuiH,ShozuM.Theriskofpostmolargesta
tionaltrophoblasticneoplasiaishigherinheterozygousthanin
homozygouscompletehydatidiformmoles.HumReprod
2010;25:11831191.
50.FisherRA,HodgesMD,NewlandsES.Familialrecurrenthy
datidiformmole:areview.JReprodMed.2004Aug;49(8):595
601.
51.SurtiU,HoffnerL,KolthoffM,DunnJ,HuntJ,SniezekL,etal. 19651992.JReprodMed1994;39:22832.
Persistentgestationaltrophoblasticdiseaseafteranandroge
netic/biparentalfetalchimera:acasereportandreview.IntJ
GynecolPathol2006;25(4):36672.
52.vanTrommelNE,MassurgerLF,VerheijenRH,SweepFC,
ThomasCM.Thecurativeeffectofasecondcurettageinpersis
tenttrophoblasticdisease:aretrospectivecohortsurvey.Gynecol
Oncol2005;99:613.
53.HemidaRA,TosonE,VanDoornHC.Theimpactofuterinere
curettage,preevacuationandweekonelevelofhCGonthe
numberofchemotherapycoursesintreatmentofpostmolar
GTN.JExpTherOncol2011;9:21720.
GillespieAM,TidyJ,ColemanRE.Theroleofrepeatuterineeva
cuationinthemanagementofpersistentgestationaltrophoblas
ticdisease.GynecolOncol2004;95:4239.
55.SchlaerthJB;MorrowCP,RodriguezM.Diagnosticandthera
peuticcurettageingestationaltrophoblasticdisease.AmJObstet
Gynecol1990;162:146570.
56.OsborneRFVSDetal.Theroleofsecondcurettageinthe
primarymanagementofpersistentgestationaltrophoblastic
neoplasia;aGynecologicOncologyGroupstudy.
57.SebireNJ,FoskettM,ParadinasFJ,FisherRA,FrancisRJ,Short
Detal.Outcomeoftwinpregnancieswithcompletehydatidiform
moleandhealthycotwin.Lancet2002;359:21656.
58.NiemannI,FisherR,SebireN,WellsM,ShortD,TidyJ,Han
cockB,ColemanR,SavageP,SecklM.UpdateonUKoutcomes
forwomenwithtwinpregnanciescomprisingacompletehy
datidiformmoleandnormalcotwin.OralpresentationatISSTD
2013.
59.StellerMA,GenestDR,BernsteinMR,LageJM,GoldsteinDP,
BerkowitzRS.Clinicalfeaturesofmultipleconceptionswithpar
tialorcompletemolarpregnancyandcoexistingfetuses.JReprod
Med1994;39:14754.
60.MatsuiH,IitsukaY,IshiiJ,OsadaH,SekiK,SekiyaS.Androge
neticcompletemolecoexistentwithatwinlive
fetus.GynecolOncol1999;74:21721.
61.NiemannI,SundeL,PetersenLK.Evaluationoftheriskof
persistenttrophoblasticdiseaseaftertwinpregnancywithhy
datidiformmoleandcoexistingnormalfetus.AmJObstetGyncol
2007;1997:45.
62.SecklMJ,DhillonT,DanceyG,FoskettM,ParadinasFJ,Rees
HC,etal.Increasedgestationalageatevacuationofacomplete
hydatidiformmole:doesitcorrelatewithincreasedriskofrequir
ingchemotherapy?JReprodMed2004;49:52730.
63.SandPK,LurainJR,BrewerJ.Repeatgestationaltrophoblastic
disease.ObstetGynecol1984;63:1404.
64.BerkowitzRS,BernsteinMR,LabordeO,GoldsteinDP.Subse
quentpregnancyexperienceinpatientswithgestationaltro
phoblasticdisease.NewEnglandTrophoblasticDiseaseCenter,
65.BerkowitzRS,ImSS,BernsteinMR,GoldsteinDP.Gestational
trophoblasticdisease.Subsequentpregnancyoutcome,including
repeatmolarpregnancy.JReprodMed1998;43(1):816.
66.YaparEG,AyhanA,ErgeneliMH.Pregnancyoutcomeafter
hydatidiformmole,initialandrecurrent.JReprodMed
1994;39:2979.
DANISH MEDICAL JOURNAL 14
67.RiceLW,LageJM,BerkowitzRS,GoldsteinDP,BernsteinMR.
Repetitivecompleteandpartialhydatidiformmole.ObstetGyne
col1989;74:2179.
68.VejerslevLO,SundeL,HansenBF,LarsenJK,ChristensenIJ,
LarsenG.Hydatidiformmoleandfetuswithnormalkaryotype:
supportofaseparateentity.ObstetGynecol1991;77:86874.
69.SundeL,VejerslevLO,JensenMP,PedersenS,HertzJM,Bo
lundL.Geneticanalysisofrepeated,biparental,diploid,hydatidi
formmoles.CancerGenetCytogenet1993;66:1622.
70.HelwaniMN,SeoudM,ZahedL,ZaatariG,KhalilA,SlimR.A
familialcaseofrecurrenthydatidiformmolarpregnancieswith
biparentalgenomiccontribution.HumGenet1999;105:1125.
71.SensiA,GualandiF,PittalisMC,CalabreseO,FalcianoF,
MaestriI,etal.Molemakerphenotype:possiblenarrowingofthe
candidateregion.EurJHumGenet2000;8:6414.
72.MurdochS,DjuricU,MazharB,SeoudM,KhanR,KuickR,et
al.MutationsinNALP7causerecurrenthydatidiformmolesand
reproductivewastageinhumans.NatGenet2006;38(3):3002.
73.ParryDA,LoganCV,HaywardBE,ShiresM,LandolsiH,Diggle
C,CarrI,RittoreC,TouitouI,PhilibertL,FisherRA,FallahianM,
HuntrissJD,PictonHM,MalikS,TaylorGR,JohnsonCA,Bonthron
DT,SheridanEG.MutationsCausingFamilialBiparentalHydatidi
formMoleImplicateC6orf221asaPossibleRegulatorofGenomic
ImprintingintheHumanOocyte.AmJHumGen201189,4518.
74.KhanlianSA,SmidthHO,ColeLA.Persistentlowlevelsof
humanchorionicgonadotropin:Apremalignantgestationaltro
phoblasticdisease.AmJObstetGynecol2003;188:12549.
75.ColeLA,KhanlianSA.Inappropiatemanagementofwomen
withpersistentlowhCGresults.JReprodMed2004;49:42332.
76.ColeLA,ButlerSA,KhanlianSA,GiddingsA,MullerCY,Seckl
MJ,KohornEI.Gestationaltrophoblasticdiseases:2.Hypergly
cosolatedhCGasareliablemarkerofactiveneoplasia.Gynecol
Oncol2006;102:1519.
77.BetashN,ZarchiMK.Placentalsitetrophoblastictumor.J
CancerResClinOncol2008;134:16.
78.NewlandsES,MulhollandPJ,HoldenL,SecklMJ,RustinGJS.
EtoposideandCisplatin/Etoposide,Methotrexate,andActinomy
cinD(EMA)chemotherapyforpatientswithhighriskgestational
trophoblastictumorsrefractorytoEMA/cyclophosphamideand
vincristinechemotherapyandpatientspresentingwithmetastatic
placentalsitetrophoblastictumors.JClinOncol2000;18:8549.
79.PapadopoulosAJ,FoskettM.SecklMj,MCNeishI,Paradinas
FJ,ReesH,NewlandsES.Twentyfiveyearsexperiencewith
placentalsitetrophoblastictumors.JReprodMed2002;47:4604.
80.SchmidP,NagaiY,AgarwalRetal.Prognosticmarkersand
longtermoutcomeofplacentalsitetrophoblastictumours:a
retrospectiveobservationalstudy.Lancet2009;374:4855.
81.ShihIM,KurmanRJ.EpithelioidtrophoblastictumorAneo
plasmdistinctfromchoriocarcinomaandplacentalsitetro
phoblastictumorsimulatingcarcinoma.AmJSurg
Pathol1998;22:1393403.
82.ZhangX,LuW,LuB.EpithelioidTrophoblasticTumorAn
outcomebasedliteraturereviewof78reportedcases.IntJGyne
colCancer2013;23:13348.
83.WellsM:Thepathologyofgestationaltrophoblastic:recent
advances.Pathology2007;39:8896.
84.SebireNJ,LindsayI:Currentissuesinthehistopathologyof
gestationaltrophoblastictumors.FetalPediatrPathol.
2010;29(1):3044.
85.SebireNJ.Histopathologicaldiagnosisofhydatidiformmole:
contemporaryfeaturesandclinicalimplications.FetalPediatr
Pathol2010;29:116.
86.ShihIM,MazurMT,KurmanRJ.Gestationaltrophoblastic
tumorsandrelatedtumorlikelesions.In:KurmanRJ,EllensonLH,
RonnettBM,eds.Blausteinspathologyofthefemalegenital
tract.Springer;2010:10751135.
87.ShihIM.Gestationaltrophoblasticlesions.In:NucciMR,Oliva
E,eds.Gynecologicpathology.ChurchillLivingstoneElsevier;
2009:645665.
88.DeaversMG,KalhorN,SilvaE:Diagnosticproblemswith
trophoblasticlesions.ArchpatholLabMed2008;132:16874.
89.KajiiT,OhamaK.Androgeneticoriginofhydatidiformmole.
Nature1977;268(5621):6334.
90.JacobsPA,HuntPA,MatsuuraJS,WilsonCC,SzulmanAE.
CompleteandpartialhydatidiformmoleinHawaii:cytogenetics,
morphologyandepidemiology.BrJObstetGynaecol.
1982;89(4):25866.
91.SundeL,NiemannI,HansenES,HindkjaerJ,DegnB,Jensen
UB,BolundL.Mosaicsandmoles.EurJHumGenet.2011
Oct;19(10):102631
92.SundeL.Geneticanalysesinhydatidiformmolewithconcep
tualandpracticalimplications.PhDthesis1990.
93.OhamaK,OkamotoE,NomuraK,FujiwaraA,FukudaY.Ge
neticstudiesofhydatidiformmolewith46,XYkaryotype(author's
transl).NipponSankaFujinkaGakkaiZasshi1981;33:16648.
94.AndreasenL,BolundL,NiemannI,HansenES,SundeL.Mosaic
molesandnonfamilialbiparentalmolesarenotcausedbymuta
tionsinNLRP7,NRPL2orC6orf221.MolHumReprod.2012
Dec;18(12):5938.
95.DiasRP,MaherER.Genes,assistedreproductivetechnology
andtransillumination.Epigenomics(2013)5(3),33140.
96.FisherRA,LaverySA,CarbyA,AbuHayyehS,SwinglerR,
SebireNJ,SecklMJ.Whatadifferenceaneggmakes.Lancet
2011;378:1974
DANISH MEDICAL JOURNAL 15
97.SlimR,WallaceEP.NLRP7andthegeneticsofhydatidiform
moles:recentadvancesandnewchallenges.FrontiersinImmu
nology20August2013doi:10.3389/fimmu.2013.00242
98.AndreasenL,ChristiansenOB,NiemannI,BolundL,SundeL.
NLRP7orKHDC3Lgenesandtheetiologyofmolarpregnancies
andrecurrentmiscarriage.MolHumReprod.2013Sep1.[Epub
aheadofprint]
99.ScholzNB,BolundL,NyegaardM,FaaborgL,JoergensenMW,
LundH,NiemannI,SundeL.Triploidyobservationsin154dian
driccases.Inprepaug2015.
100.ZaragozaMV,SurtiU,RedlineRW,MillieE,ChakravartiA,
HassoldTJ.Parentaloriginandphenotypeoftriploidyinsponta
neousabortions:predominanceofdiandryandassociationwith
thepartialhydatidiformmole.AmJHumGenet2000;66:180720.
101.SurtiU,SzulmanAE,WagnerK,LeppertM,O'BrienSJ.Te
traploidpartialhydatidiformmoles:twocaseswithatriplepater
nalcontributionanda92,XXXYkaryotype.HumGenet
1986;72:1521.
102.VejerslevLO,FisherRA,SurtiU,WalkeN.Hydatidiformmole:
cytogeneticallyunusualcasesandtheirimplicationsforthepre
sentclassification.AmJObstetGynecol1987;157:1804.
103.FriersonHF.FlowCytometricanalysisofploidyinsolidneo
plasms:Comparisonoffreshtissueswithformalinfixedparaffin
embeddedspecimens.HumPathol1988;19:2904.
104.VassilakosP,KajiiT.Letter:Hydatidiformmole:twoentities.
Lancet1976;1(7953):259.
105.VassilakosP,RiottonG,KajiiT.Hydatidiformmole:two
entities.Amorphologicandcytogeneticstudywithsomeclinical
consideration.AmJObstetGynecol1977;127(2):16770.
106.WakeN,TakagiN,SasakiM.Androgenesisasacauseof
hydatidiformmole.JNatlCancerInst1978;60(1):517.
107.SzulmanAE,SurtiU.Thesyndromesofhydatidiformmole.I.
Cytogeneticandmorphologiccorrelations.AmJObstetGynecol
1978;131(6):66571.
108.ParadinasFJ.Thediagnosisandprognosisofmolarpreg
nancy:theexperienceoftheNationalReferralCentreinLondon.
IntJGynaecolObstet1998;60Suppl1:S5764.
109.FukunagaM.Earlypartialhydatidiformmole:prevalence,
histopathology,DNAploidy,andpersistencerate.VirchowsArch.
2000;437(2):1804.
110.UlkerV,GurkanH,TozkirH,KaramanV,OzgurH,Numanoglu
C,GedikbasiA,AkbayirO,UygunerZO.NovelNLRP7mutationsin
familialrecurrenthydatidiformmole:areNLRP7mutationsarisk
forrecurrentreproductivewastage?EurJObstetGynecolReprod
Biol2013;170:18892.
111.SebireNJ,SavagePM,SecklMJ,FisherRA.Histopathological
featuresofbiparentalcompletehydatidiformmolesinwomen
withNLRP7mutations.Placenta2013Jan;34(1):506.
112.ReddyR,AkouryE,NguyenNMPetal.Reportoffournew
patientswithproteintruncatinmutationsinC6orf221/KHDCL3
andcolocalizationinNLRP7.EurJHumGenet2013Sep;21:957
64.
113.LewisGH,DeScipioC,MurphyKM,HaleyL,BeierlK,Mosier
S,TandyS,CohenDS,LytwynA,ElitL,VangR,RonnettBM.Char
acterizationofandrogenetic/biparentalmosaic/chimericconcep
tions,includingthosewithamolarcomponent:Morphology,p57
Immnohistochemistry,MolecularGenotyping,andRiskofPersis
tentGestationalTrophoblasticDisease.IntJGynPat2013
32:199214
114.KalishJM,ConlinLK,BhattiTR,DubbsHA,HarrisMC,IzumiK,
MostoufiMoabS,MulchandaniS,SaittaS,StatesLJ,SwarrDT,
WilkensAB,ZackaiEH,ZelleyK,BartolomeiMS,NicholsKE,Pal
ladinoAA,SpinnerNB,DeardorffMA.2013.Clinicalfeaturesof
threegirlswithmosaicgenomewidepaternaluniparentaliso
disomy.AmJMedGenetPartA161A:192939.
115.BanetN,DeScipioC,MurphyKM,BeierlK,AdamsE,VangR,
RonnettBM.Characteristicsofhydatidiformmoles:analysisofa
prospectiveserieswithp57immunohistochemistryandmolecular
genotyping.ModernPathologyadvanceonlinepublication,26
July2013;doi:10.1038/modpathol.2013.143
116.FisherRA,HodgesMD,ReesHC,SebireNJ,SecklMJ,New
landsES,etal.Thematernallytranscribedgenep57(KIP2)
(CDNK1C)isabnormallyexpressedinbothandrogeneticand
biparentalcompletehydatidiformmoles.HumMolGenet
2002;11:326772.
117.MutchDG,SoperJT,BakerME,BandyLC,CoxEB,Clarke
PearsonDL,HammondCB.Roleofcomputedtomographyofthe
chestinstagingpatientswithnonmetastaticgestationaltro
phoblasticdisease.ObstetGynecol1986Sep;68:34852.
118.SecklMJ,NewlandsES.Treatmentofgestationaltrophoblas
ticdisease.GenDiagnPathol1997Nov;143:15971.
119.McNeishIA,StricklandS,HoldenL,RustinGJS,FoskettM,
SecklMJ,NewlandsES.Lowriskpersistentgestationaltro
phoblasticdisease:outcomeafterinitialtreatmentwithlowdose
methotrexateandfolinicacidfrom1992to2000.JClinOncol
2002;20:183844.
120.KohornEI.Dynamicstagingandriskfactorscoringforgesta
tionaltrophoblasticdisease.IntJGynecolCancer2007;17:1124
30.
121.LarsenLF.Responseadaptedchemotherapyinthetreatment
ofpersistenttrophoblasticdiseasea30yearexperienceat
AarhusUniversityHospital.Health,AarhusUniversity,Denmark,
April2013.
122.BowerM,NewlandsES,HoldenL,ShortD,BrockC,Rustin
GJ,BegentRH,BagshaweKD.EMA/COforhighriskgestational
trophoblastictumors:resultsfromacohortof272patients.JClin
Oncol1997;15(7):263643.
123.CovensA,FiliaciVL,BurgerRA,OsborneR,ChenMD.PhaseII
trialofpulsedactinomycinassalvagetherapyforfailedlowrisk
DANISH MEDICAL JOURNAL 16
gestationaltrophoblasticneoplasia.AGynecologicOncology
GroupStudy.Cancer2006;107:12806.
124.RustinGJ,NewlandsES,LutzJM,HoldenL,BagshaweKD,
HiscoxJG,FoskettM,FullerS,ShortD.Combinationbutnotsin
gleagentmethotrexatechemotherapyforgestationaltro
phoblastictumorsincreasestheincidenceofsecondtumors.
JournalofClinicalOncology1996;14:276973.
125.FinklerNJ.Placentalsitetrophoblastictumour.Diagnosis,
clincalbehaviorandtreatment.JReprodMed1991Jan;36:2730.
126.BerkowitzRS,GoldsteinDP,JonesMA,MareanAR,Bernstein
MR.Methotrexatewithcitrovorumfactorrescue:reducedche
motherapytoxicityinthemanagementofgestationaltrophoblas
ticneoplasms.Cancer1980;45(3):4236.
127.BerkowitzRS,GoldsteinDP,BernsteinMR.Methotrexate
withCitrovorumFactorRescueasPrimaryTherapyforGestational
TrophoblasticDisease.Cancer1982;50:20247.
128.BerkowitzRS,GoldsteinDP,BernsteinMR.Methotrexate
infusionandfolinicacidintheprimarytherapyofnonmetastatic
gestationaltrophoblastictumors.GynecolOncol1990;36(1):569.
129.PowlesT,SavageP,ShortD,YoungA,PappinC,SecklMJ.
Residuallunglesionsaftercompletionofchemotherapyforgesta
tionaltrophoblasticneoplasia:shouldweoperate?BritishJournal
ofCancer2006;94:514.
130.YangJ,XiangY,WanX,YangX.Theprognosisofgestational
trophoblasticneoplasiapatientwithresiduallungtumorafter
completingtreatment.GynecolOncol2006;103:47982.
131.AbroRA,deAndradeJM,TiezziDG,MaranaHR,Candido
dosReisFJ,ClagnanWS.Treatmentforlowriskgestationaltro
phoblasticdisease:comparisonofsingleagentmethotrexate,
dactinomycinandcombinationregimens.GynecolOncol2008
Jan;108(1):14953.
132.BagshaweKD,LawlerSD,ParadinasFJ,DentJ,BrownP,
BoxerGM.Gestationaltrophoblastictumoursfollowinginitial
diagnosisofpartialhydatidiformmole.Lancet1990;335:10746.
133.BowerM,RustinGJ,NewlandsES,HoldenL,ShortD,Foskett
M,BagshaweKD.Chemotherapyforgestationaltrophoblastic
tumourshastensmenopauseby3years.EurJCancer
1998;34:12047.
134.FisherRA,KhatoonR,ParadinasFJ,RobertsAP,NewlandsES.
Repetitivecompletehydatidiformmolecanbebiparentalinorigin
andeithermaleorfemale.HumReprod2000;15:5948.
135.GersonR,SerranoA,DelCarmenBelloM,LazaroM,etal.
Responseofchoriocarcinomatopaclitaxel.Casereportandre
viewofresistance.EurJGynaecolOncol1997;18(2):10810.
136.HomesleyHD,BlessingJA,SchlaerthJ,RettenmaierM,Major
FJ.Rapidescalationofweeklyintramuscularmethotrexatefor
nonmetastaticgestationaltrophoblasticdisease:aGynecologic
OncologyGroupstudy.GynecolOncol1990;39(3):3058.
137.JonesWB,SchneiderJ,ShapiroF,LewisJ.Treatmentof
ResistantGestationalChoriocarcinomawithTaxol:AReportof
TwoCases.GynecolOncol1996;61:12630.
138.JoshuaAM,CarterJR,BealeP.Theuseoftaxanesinchorio
carcinoma;acasereportandreviewoftheliterature.Gynecol
Oncol2004;94:5813.
139.McNallyOM,TranM,FortuneD,QuinnMA.Successful
treatmentofmotherandbabywithmetastaticchoriocarcinoma.
IntJGynaecolCancer2002;12(4):3948.
140.ShihIM.Trophogram,animmunohistochemistrybased
algorithmicapproach,inthedifferentialdiagnosisoftrophoblastic
tumorsandtumorlikelesions.AnnDiagPatholJune;11(3);
2007:228234.
APPENDIX
EVIDENCE
TheprevalenceofPTDafterdiploidhydatidiformmoleis18%,
aftertriploidhydatidiformmole0%(95%confidenceinterval:0
1.4%)(EvidenceIIa)
Classificationofhydatidiformmoleaccordingtoploidy(dip
loid/triploid)comparedtormorphology(complete/partial)givesa
betterdiscriminationbetweenhydatidiformmoleswithhighrisk
andhydatidiformmoleswithlowriskofPTD(EvidenceIIa)
Patientsover40yearswithamolarpregnancyhaveanincreased
riskofPTD(EvidenceIIa)
IftheinitialserumhCGisgreaterthan100,000IU/L,theriskof
PTDisincreased(EvidenceIII)
10%ofhydatidiformmolepatientswithaninsufficientfallin
serumhCGcanexpectremissionafteruterinereevacuation
alone(EvidenceIII)
Theincidenceoftwinpregnancieswithhydatidiformmoleand
normalfoetusis1:20,000120,000pregnancies,correspondingto
0.53%ofregisteredtrophoblasticdiseases(EvidenceIIa)
TheriskofPTDafteratwinpregnancywithhydatidiformmole
andanormalfoetusisapproximately25%anddoesnotdeviate
significantlyfromtheriskassociatedwithasingletonhydatidi
formmole(EvidenceIII)
About60%ofwomenwithatwinpregnancywithhydatidiform
molewillproducealivingbaby:medianlengthofgestationis34
weeks(EvidenceIII)
Thefrequencyofhydatidiformmoleamongwomenwhohave
previouslyhadonehydatidiformmoleandlaterbecomepregnant
is12%(EvidenceIIa)
Theempiricalriskofanewmolarpregnancyaftertwohydatidi
formmolesis1023%.(EvidenceIIa)
DANISH MEDICAL JOURNAL 17
Thegroupofwomenwithtwoormorehydatidiformmolesis
heterogeneous.Someprobablyhavealowriskofrecurrence;
othershaveahereditaryveryhighriskofrecurrence(EvidenceIII)
WomenwithmutationinbothallelesofNLRP7orbothallelesof
KHDC3Lhaveanautosomalrecessivehereditarydispositionto
hydatidiformmolewithahighpenetrance(EvidenceIII)
WomenwithmutationinbothallelesofNLRP7canachievea
normalpregnancyusingeggdonation(EvidenceIII)
50%ofpatientswithPTDcanbecuredwithMTXalone(Evidence
IIa)
In75%ofpatientswithMTXresistance,hCGnormalisesonactin
omycinDtherapy(EvidenceIIa)
Menopauseoccurs2yearsearlierinwomengivencombination
chemotherapycomparedwiththosethatreceiveMTXalone
(EvidencegradeIIa)
Combinationregimes(EMACOandespeciallyEMAEP)cause
grades3and4toxicityinupto50%(EvidenceIIa)
Thereisnotcompleteagreementbetweentheresultsofploidy
determinationwithflowcytometryonfixedandonunfixedtissue
(EvidenceIII)
Thereisnotcompleteagreementbetweenthehistopathologic
andthegeneticclassificationofhydatidiformmole(EvidenceIIa)

ActinomycinDcausesmoreoftenthanMTXhairloss,nauseaand

vomiting,myelosuppressionandstomatitis(EvidenceIIa)

TABLEOFIMMUNOHISTOCHEMICALCHARACTERISTICSOFGESTATIONALTROPHOBLASTICDISEASES
(ModifiedfromTrophogram,ShihIM,chap.20,BlausteinsPathologyoftheFemaleGenitalTract,Sixthedition)

Tumour Celltype CK18 HLAG Ki67 hCG P63 hPL CD CyclinE
index 146

EPS Intermediarytrophoblast ++ ++ <1% ++ ++ ++
*
PSTT
Intermediarytrophoblast ++ ++ >10% ++ ++ ++
*


PSN Intermediarytrophoblast ++ ++ <8% / ++ /+ /+ /+


ETT Intermediarytrophoblast ++ ++ >12% /+ ++ /+ /+ ++
*

CC Syncytiotrophoblastand ++ ++ >40% ++ /+ /+ /+
cytotrophoblast

Thetablecanbeusedasanalgorithm.First,confirmationofsuspicionoftrophoblasticcellswithstainingforCK18andHLAG.hCG
positivesyncytiotrophoblastcellssuggestchoriocarcinoma.Ifchoriocarcinomaisruledout,P63andhPLareusedtodifferentiatebe
tweentumoursconsistingofintermediarytrophoblastofchoriontypeorimplantationtype.Ki67caninadditiondifferentiatebetween
EPS/PSTTandPSN/ETT.BecausetherangeoftheKi67indexinPSN/ETTisverynarrow,cyclinEcanbeusedforadditionaldiscrimina
tion.
*Positiveinmultinuclearintermediarytrophoblastcells.

DANISH MEDICAL JOURNAL 18


FLOWCHARTINAGYNECOLOGICALSETTING
Ultrasonic suspicion of hydatidiform
mole
Measure serum hCG, haemoglobin,
thrombocytes, and blood type.
Regardless of gestational age,
evacuate ultrasonic-guided with suc-
tion catheter and blunt curettage.
Hydatidiform mole not verified:
Manage according to abortion guide-
lines
After triploid hydatidiform mole: Meas-
ure serum hCG weekly until 2 con-
secutive undetectable values.
Safe contraception, e.g. birth control pills, should be used during the control period.
If serum hCG stagnates (less than 10% fall over 3 measurements), increases, or persists longer than 6 months,
the patient should referred to centralised work up.
Forward unfixed tissue for ploidy de-
termination
Forward fixed tissue for histology
Hydatidiform mole verified:
If valid ploidy determination: Manage in ac-
cordance with ploidy.
If no ploidy determination: Manage as diploid
hydatidiform mole.
Discuss divergent results at MDT conference
After diploid hydatidiform mole and after mole
without known ploidy: Measure
serum hCG weekly until undetectable.
- If serum hCG is un-detectable before
56 days, discarge the patient after 4 undetectable
monthly values.
- If not, follow-up for 6 months
DANISH MEDICAL JOURNAL 19