Gestational Gestational Trophoblastic DiseaseTrophoblastic Disease

Current managementCurrent management

BackgroundBackgroundIncidence – Incidence – U.S. and Europe 1/1500U.S. and Europe 1/1500

South East Asia 1/150South East Asia 1/150 ((↓↓ Carotene, animal fat and Carotene, animal fat and Vit. A)Vit. A)

Can follow any gestational event – abortion, miscarriage, ectopic, normal Can follow any gestational event – abortion, miscarriage, ectopic, normal pregnancypregnancy

Curable in vast majority – chemotherapy 1956Curable in vast majority – chemotherapy 1956

Complete & partial moleComplete & partial moleInvasive moleInvasive molePlacental-site trophoblastic tumourPlacental-site trophoblastic tumourChoriocarcinoma ( always if follows term pregnancy 1/50,000 )Choriocarcinoma ( always if follows term pregnancy 1/50,000 )

Latter 3 Latter 3 usuallyusually derive from molar pregnancy derive from molar pregnancy

Complete MoleComplete MolePathology:Pathology: Generalized hydatidiform swelling and trophoblastic hyperplasiaGeneralized hydatidiform swelling and trophoblastic hyperplasia

fetal/embryonic tissue absentfetal/embryonic tissue absent

Karyotype:Karyotype: 90% 46XX haploid sperm fertilizes ovum and duplicates90% 46XX haploid sperm fertilizes ovum and duplicatesovum nucleus either absent or inactivatedovum nucleus either absent or inactivated

10% 46XY10% 46XY

Clinical:Clinical: Vaginal bleedingVaginal bleeding 95% 95% (prune juice, anaemia)(prune juice, anaemia)Enlarged uterusEnlarged uterus 50%50%Theca lutein cystsTheca lutein cysts 50% 50% (often >6cm.- may take 3 months)(often >6cm.- may take 3 months)HyperemesisHyperemesis 25%25%PETPET 25%25% (no reported case of eclampsia)(no reported case of eclampsia)HyperthyroidismHyperthyroidism 5% 5% (if free T4(if free T4↑ - B-blockade)↑ - B-blockade)Trophoblastic emboli 2%Trophoblastic emboli 2%

Diagnosis:Diagnosis: U/S usually very sensitive – generalized swelling (snow-storm )U/S usually very sensitive – generalized swelling (snow-storm )

Complete MoleComplete Mole

Complete Mole HistologyComplete Mole Histology

Partial MolePartial MoleTriploid karyotype – extra haploid set paternalTriploid karyotype – extra haploid set paternalSometimes fetus present – usually triploid Sometimes fetus present – usually triploid growth restricted / multiple anomaliesgrowth restricted / multiple anomalies

Pathology differs from complete:Pathology differs from complete: focal hydatidiform swellingfocal hydatidiform swellingvarying size of chorionic villivarying size of chorionic villimarked villous scallopingmarked villous scallopingfocal trophoblastic hyperplasiafocal trophoblastic hyperplasiaidentifiable embryonic or fetal tissuesidentifiable embryonic or fetal tissues

Clinical:Clinical: Usually as a regular incomplete or missed abortionUsually as a regular incomplete or missed abortionExcessive uterine enlargement / PET very rareExcessive uterine enlargement / PET very rareNo hyperemesis / hyperthyroidism / theca-lutein cystsNo hyperemesis / hyperthyroidism / theca-lutein cysts

Diagnosis: Diagnosis: U/S may detect focal cystic spaces of varying diameterU/S may detect focal cystic spaces of varying diameterDiagnosis on histology of curettingsDiagnosis on histology of curettings

Partial Mole HistologyPartial Mole Histology

ManagementManagementPre-operative assessment – medical complications / CXRPre-operative assessment – medical complications / CXR

Evacuation -Evacuation - oxytocin infusion after curettageoxytocin infusion after curettageheavy bleeding should not deter from cervical dilatationheavy bleeding should not deter from cervical dilatationsuction curettage (fundal massage)suction curettage (fundal massage)uterus usually dramatically reduces in size / bleeding controlleduterus usually dramatically reduces in size / bleeding controlledcomplete with sharp curettagecomplete with sharp curettageHistological evaluation of all tissueHistological evaluation of all tissue

Natural history:Natural history: Complete - 15% local uterine invasionComplete - 15% local uterine invasion 4% metastatic disease4% metastatic disease

High risk - hCG > 100000High risk - hCG > 100000(40%)(40%) large uterus large uterus 30% local invasion30% local invasion

theca lutein cysts > 6cm. theca lutein cysts > 6cm. 9% metastases9% metastases

Partial mole - Partial mole - 4% local uterine persistence/no cases choriocarcinoma4% local uterine persistence/no cases choriocarcinomaMany centres have abandoned follow-upMany centres have abandoned follow-up

Follow upFollow upWeekly Weekly -hCG (syncytiotrophoblast) -hCG (syncytiotrophoblast) levelslevels until untilnormal for 3 consecutive weeksnormal for 3 consecutive weeksCan take 12-14 weeksCan take 12-14 weeks

Then monthly until normalThen monthly until normalfor 6 monthsfor 6 months

Contraception:Contraception: ImmediateImmediate

Oral / barrier / permanentOral / barrier / permanent

No IUCD until hCG normal (perforation)No IUCD until hCG normal (perforation)

No No persistent disease on OCP and persistent disease on OCP and regression time not influencedregression time not influenced

GTN Follow-upGTN Follow-up

WHO Prognostic ScoringWHO Prognostic Scoring

Original assessment and scoring system 1984 changed in 2000Original assessment and scoring system 1984 changed in 2000

Metastatic disease occurs in 4% patients with molar pregnancyMetastatic disease occurs in 4% patients with molar pregnancy

Plateau:Plateau: 4 values over 3 weeks4 values over 3 weeks

Rise:Rise: 10% for 3 values over 2 weeks 10% for 3 values over 2 weeks

Clinical examination – especially pelvis, vagina and vulvaClinical examination – especially pelvis, vagina and vulva

U/S to exclude pregnancyU/S to exclude pregnancy

Brain – MRI superior to CT scanBrain – MRI superior to CT scan

Chest – CXR adequate for counting metastases / CT scan also acceptableChest – CXR adequate for counting metastases / CT scan also acceptable

Abdomen – CT scanAbdomen – CT scan

WHO Prognostic ScoringWHO Prognostic ScoringPrognostic scorePrognostic score

Prognostic factorPrognostic factor 00 11 22 4 4AgeAge <39<39 >39 >39Antecedent pregnancyAntecedent pregnancy MoleMole Abortion Abortion Term pregnancyTerm pregnancyInterval (months)Interval (months) 44 4-6 4-6 7-127-12Pre-treatment Pre-treatment -hCG (log)-hCG (log) <3<3 <4 <4 <5<5 >5 >5Largest tumourLargest tumour 3-4 3-4 5 5Site of metastasesSite of metastases Spleen GI tract Spleen GI tract Brain Brain

KidneyKidney Liver LiverNumber of metastasesNumber of metastases 1-4 1-4 5-85-8 >8 >8Previous Chemo. FailedPrevious Chemo. Failed Single drug 2 or moreSingle drug 2 or more

Changes: Changes: ABO group deleted, Liver mets score upgraded, no medium risk groupABO group deleted, Liver mets score upgraded, no medium risk group

Low risk = Low risk = 6 6 single agent chemotherapy single agent chemotherapyHigh risk = High risk = 7 7 combination chemotherapy combination chemotherapy

FIGO StagingFIGO Staging

Stage 1Stage 1 Tumour confined to uterusTumour confined to uterus

Stage 2Stage 2 Tumour confined to pelvisTumour confined to pelvis

Stage 3Stage 3 Metastases to lung ( with/without pelvic metastases )Metastases to lung ( with/without pelvic metastases )

Stage 4Stage 4 Distant organ metastases ( with/without lung metastases )Distant organ metastases ( with/without lung metastases )

ChemotherapyChemotherapyLow-riskLow-risk If non-metastatic - always curable ( Hysterectomy if chemo fails) If non-metastatic - always curable ( Hysterectomy if chemo fails)

Methotrexate:Methotrexate:Many regimesMany regimesI.M. Methotrexate 1mg/Kg days 1,3,5,7I.M. Methotrexate 1mg/Kg days 1,3,5,7I.M./ P.O. Folinic acid 0.1mg/Kg days 2,4,6,8I.M./ P.O. Folinic acid 0.1mg/Kg days 2,4,6,8

I.M. Methotrexate 40mg/mI.M. Methotrexate 40mg/m²² weekly weekly

Actinomycin D:Actinomycin D: I.V. push 1.25mg/mI.V. push 1.25mg/m² every 14 days² every 14 days

Follow-up:Follow-up: -hCG, FBC, LFTs and U/Es, creatinine prior to each cycle-hCG, FBC, LFTs and U/Es, creatinine prior to each cycleContinue treatment cycle for 1-3 weeks after normal Continue treatment cycle for 1-3 weeks after normal -hCG-hCGCheck Check -hCG monthly for 12 months, then 2 monthly for 12 months-hCG monthly for 12 months, then 2 monthly for 12 monthsContraception for 12 monthsContraception for 12 months

Complete remission in 85-90% Complete remission in 85-90% 80% require only one course80% require only one course

Toxicity:Toxicity: Thrombocytopenia 2%, neutropenia 6% and hepatotoxicity 14%Thrombocytopenia 2%, neutropenia 6% and hepatotoxicity 14%

High Risk GTNHigh Risk GTNInvasive mole:Invasive mole: invades myometrium / diagnosed at hysterectomy / can metastasizeinvades myometrium / diagnosed at hysterectomy / can metastasize

mets may be choriocarcinomamets may be choriocarcinoma

Placental site trophoblastic tumour: Placental site trophoblastic tumour: Locally invasive composed of cytotrophopblastLocally invasive composed of cytotrophopblast small if any rise in hCG (<3000)small if any rise in hCG (<3000)

vaginal bleeding usually after amenorrhoeavaginal bleeding usually after amenorrhoea Large polypoid tumour / insensitive to Large polypoid tumour / insensitive to

chemotherapychemotherapy Curettage sometimes successful / Curettage sometimes successful / HysterectomyHysterectomy

Choriocarcinoma:Choriocarcinoma: Accounts for majority of metastatic diseaseAccounts for majority of metastatic diseaseEarly vascular invasion and widespread disseminationEarly vascular invasion and widespread disseminationFragile vessels Fragile vessels haemorrhagic complications haemorrhagic complications80% have lung mets – any respiratory symptom80% have lung mets – any respiratory symptom30% have vaginal mets – highly vascular (avoid biopsy)30% have vaginal mets – highly vascular (avoid biopsy)10% have liver mets – usually only with extensive tumour elsewhere10% have liver mets – usually only with extensive tumour elsewhere10% have brain mets – never isolated ( lung / vagina)10% have brain mets – never isolated ( lung / vagina)

Treatment:Treatment: EMA-CO chemotherapy +/- surgical resection / radiotherapyEMA-CO chemotherapy +/- surgical resection / radiotherapyPrognosis:Prognosis: 75% complete response rate75% complete response rate Salvage chemo – BEP varying successSalvage chemo – BEP varying success

Pregnancy After GTNPregnancy After GTN

No evidence of increased congenital anomalies after one year contraceptionNo evidence of increased congenital anomalies after one year contraception

Recent Japanese data – Recent Japanese data – Women who concieved during follow-up period < 1 Women who concieved during follow-up period < 1 yearyear

No adverse effect on anomalies nor preterm No adverse effect on anomalies nor preterm deliverydelivery

Risk of further molar pregnancy:Risk of further molar pregnancy: 0.5-2.5% if one previous molar0.5-2.5% if one previous molar

33% if two previous molar33% if two previous molar

3 molar pregnancies – poor live birth rate3 molar pregnancies – poor live birth rate

Risk of molar pregnancy increases with number of previous spontaneous abortionsRisk of molar pregnancy increases with number of previous spontaneous abortions

Previous term pregnancies reduce risk of GTN Previous term pregnancies reduce risk of GTN

ConclusionsConclusions

GTN is rareGTN is rare

Ultrasound diagnosis becoming more commonUltrasound diagnosis becoming more common

Senior staff should perform ERPC ( suction and sharp curettage)Senior staff should perform ERPC ( suction and sharp curettage)

Follow-up – clinical and serum Follow-up – clinical and serum -hCG measurements in specialized clinics-hCG measurements in specialized clinics

Chemotherapy curative in vast majority low risk patientsChemotherapy curative in vast majority low risk patients