GTG# 38 Management of Gestational Trophoblastic Disease

This post is the summary of green-top guideline GTG 38 “Management of Gestational Trophoblastic Disease” which was published in September 2020.  The new version of the guideline has some changes, so it is important to cover it. There are some important numbers which are tested repeatedly in exams. It is strongly encouraged to go through the original guideline to make sure that no point is missed. 

I hope this post is helpful. Suggestions to improve future posts are welcome.

To Download the Guideline 38: Click Here

All GreenTop Guidelines: Click Here

Definitions

Gestational trophoblastic disease (GTD) is a group of disorders ranging from premalignant (complete & partial mole also called hydatidiform mole) to malignant (invasive mole, choriocarcinoma, placental site specific trophoblastic tumour (PSTT) and epithelium trophoblastic tumour (ETT)

Gestational trophoblastic neoplasia (GTN): persistence of GTD after primary treatment (persistent elevation of HCG)

Histological confirmation for diagnosis

• Required for complete/partial mole
• Not required for GTN

Introduction & Background

Molar pregnancy subdivided into complete and partial mole 

Complete Mole	Partial Mole
Diploid & androgenic in origin	Triploid 90% Tetraploid or mosaic occasionally
No fetal tissue	Fetus or fetal RBCs present
75-80% arise due to duplication of single sperm after fertilisation of an ‘empty’ ovum	2 sets of paternal haploid & 1 set of maternal haploid chromosomes
20-25% due to dispermic fertilization of an ‘empty ovum’	Not all triploid or tetraploid pregnancies are partial moles Must have histopathological evidence of trophoblast hyperplasia for dx

GTD (Hydatidiform mole, Invasive mole, Choriocarcinoma, PSTT)

• Uncommon in UK
• Incidence 1 in 714 live births
• Ethnic variation Asian 1 in 387 live births Non-Asian 1 in 752 live births
• Associated with age at conception, higher in extremes of age
• <15 yrs 1 in 500 pregnancies >50 yrs 1 in 8 pregnancies 

GTN 

• May develop after molar/non-molar pregnancy or a live birth
• 1 in 50 000 after live birth 
• On average, a consultant O &G will deal with one new case every 2 years

Registration & Treatment Program UK

• Effective with cure rates of 98-100% 
• Chemotherapy Needed in 
• 0.5-1.0% after partial mole 
• 13-16% after complete mole
• Registration with GTD is a minimum standard of care

Presentation of Molar Pregnancy

• Most common presentation is irregular vaginal bleeding (60%), positive pregnancy test & supporting USG evidence (12%)
• Less common hyperemesis, excessive uterine enlargement, hyperthyroidism, early-onset pre-eclampsia (PET) & abdominal dissension due to theca lutein cysts
• Very rarely: haemoptysis or seizures— metastasis in lungs or brain

Role of USG

• USG use has lead to earlier diagnosis of molar. Reduction in mean gestation age of diagnosis from 16 to 9 weeks (over 1988- 2013)
• Majority of histologically proven molar → associated with USG diagnosis of delayed miscarriage or an-embryonic pregnancy
• Pre-removal accuracy of diagnosis increases with gestational age 
• 35-40% before 14wks
• 60% after 14 wks 
• USG correctly identified 56% of molar pregnancies with suspected missed miscarriage
• Unrecognised GTD prior to removal → 2.7%
• USG features suggestive of 
• Complete mole: polyploid mass b/w 5-7 wks and thicker cystic villous tissue after 8 wks with no identifiable gestational sac (95% sensitivity 40% PPV)
• Partial mole: enlarged placenta or cystic changes within decidual reaction with either empty sac or delayed miscarriage (20% sensitivity 22% PPV)
• USG correctly identifies: complete mole  88%    partial mole 56%

Diagnosis of Molar Pregnancies

• Definitive diagnosis:  Histological Examination
• Features of complete mole: no fetal tissue, hydropic changes to villi & excess trophoblast proliferation
• Features of partial mole: fetal tissue present, focal hydropic changes to villi & some excess trophoblast proliferation
• To distinguish complete from partial: ploidy status & immunohistochemistry staining for p57 helpful

Removal of a Molar Pregnancy

Best Method of Removal

Complete Mole 

• Suction curettage method of choice irrespective of uterine size
• Avoid medical removal as 16x increased risk of GTN & need of chemotherapy
• Higher rate of incomplete removal with medial methods
• USG guidance during procedure useful to decrease chance of perforation & to ensure maximum tissue removed

Partial Mole

• Suction curettage method of choice EXCEPT if fetal parts size deters its use THEN may use medical removal 

Anti-D prophylaxis recommended AFTER removal of molar (either type for practical reasons)

Twin with one normal & other molar (or demise of coexisting twin) and woman decides for termination of pregnancy medical removal may be used

Safety of cervical preparation 

• Safe to prepare cervix before evacuation using dilators or prostaglandins
• No increased risk of GTN or needing chemotherapy

Use of oxytocin infusion

• Not recommended to use oxytocin infusion PRIOR to completion of removal 
• Excessive vaginal bleeding is an issue & must involve experienced clinician 
• If excessive bleeding prior to or during removal→ expedite the surgical removal & may use oxytocin after weighing up risks vs benefits

Indications and timing of repeat surgical removal

URGENT repeat surgical management 

• May be done in women having heavy or persistent vaginal bleeding leading to acute haemodynamic compromise
• Delay may be harmful
• Consider balloon tamponade & UAE to reduce risk of hysterectomy

Role for second removal if HCG <5000 u/l.

• Phase II trial indicated 40% avoided chemotherapy
• 3/34 had different histological findings on second removal

Histological Examination for Diagnosis

After Miscarriage

• Recommended to have histological assessment of material obtained in ALL medical/surgical miscarriages if no fetal parts identified at any stage of pregnancy
• If no tissue sent for histopathology → Urine Pregnancy test after 3 wks
• UPT positive @ 3wks → track serum levels to ensure its falling
• If HCG levels not falling→ arrange an USG (for pregnancy tissue). Send all tissue for pathology

After Abortion

• No need to routinely send pregnancy tissue after therapeutic abortion (provided fetal parts identified at USG or surgical removal)
• If medical abortion→ urine pregnancy test 3 wks after procedure
• Risk of GTN after confirmed therapeutic abortion: 1 in 20 000

Management of elevated HCG after a possible pregnancy event

• Consider Referral to GTD centre if persistently increased HCG 
• either after ectopic excluded or 
• after 2 consecutive t/m with methotrexate for PUL
• Reasons for Low level of HCG elevation (10-200 IU/L): malignant female germ cell tumours; any epithelial cancers like bladder, breast, lung, gastric & colorectal; presence of HCG or human anti-mouse antibodies. These women have periods & can conceive

Whom to Investigate for GTN after a non-molar pregnancy

• Incidence of choriocarcinoma 1 in 50 000 pregnancies
• Vaginal Bleeding is most common presenting symptom of GTN after miscarriage, therapeutic abortion or postpartum
• If persistent or irregular vaginal bleeding >8wks after pregnancy event→ perform urine HCG in ALL women
• <1% women develop GTN if HCG returns to normal after 8 wks of pregnancy event
• worse prognosis after a non-molar pregnancy GTN due to delayed diagnosis or advanced disease at presentation

Management of suspected ectopic molar pregnancy

• Manage as any other case of ectopic pregnancy
• If local tissue diagnosis of ectopic molar send tissue to appropriate centre for pathological review

Management of twin with a viable and presumptive coexistent molar pregnancy 

• Refer to regional fetal medicine centre & GTD centre if combined molar pregnancy & viable twin or if diagnostic doubt
• Twin pregnancy with one viable and other molar
• Counsel regarding increased risk of perinatal morbidity & GTN outcome
• Consider prenatal invasive testing for fetal karyotype if unclear whether it partial or complete mole and in cases of abnormal placenta (suspected mesenchymal hyperplasia)
• If a woman wishes to continue pregnancy
• Increase monitoring for PET and fetomaternal wellbeing 
• Risks: Increased early fetal loss 40% premature birth 36% PET 4-20%
• If birth after 26 wks → 51% babies survive
• Recommend histopathology of placenta and 
• Register all confirmed GTD cases with GTD centre

Management of placental site trophoblastic tumour(PSTT) or epitheloid trophoblastic tumours (ETT)

• ALL women with PSTT & ETT to be registered and cared for in GTD centre
• If localised disease → hysterectomy is curative
• Distant +/— extensive metastasis or long interval to antecedent pregnancy → chemotherapy 
• Atypical PSN may progress to PSTT or ETT in 15%
• Atypical PSN or uncertain local pathology provide central review→ discuss existing data, perform staging investigations & decide further management
• Typical PSN  no need for central review

Registration at GTD Centre

• ALL women with diagnosed GTD to be provided written information about condition & need of referral for follow-up by GTD centre
• Better outcomes with ongoing care from GTD centres 
• Registration with GTD is a minimum standard of care

Following to be registered and need follow up in GTD centre

• Complete/Partial mole
• Twin with complete or partial mole
• Limited microscopic/macroscopic molar change (early complete/partial mole/choriocarcinoma)
• PSTT or ETT
• Atypical PSN

Optimum follow-up after diagnosis of GTD

Complete Mole

• If HCG revert to normal within 56 days → follow-up for 6 months from date of uterine removal
• If HCG does not revert to normal in 56 days → follow-up for 6 months from date of normalisation

Partial Mole

• Conclude follow-up once HCG returns to normal on 2 samples at least 4 weeks apart

If no chemotherapy received

• incidence of GTD in subsequent pregnancy 1:4011
• no need to check HCG in any subsequent pregnancy

Optimum treatment for GTN

• May be treated with single-agent or multi-agent chemotherapy
• Use FIGO 2000 scoring system for assessment 

Ref: GTG

• Score ≤6 low risk 
• single-agent IM methotrexate, alternating daily with folinic acid for 1 wk followed by 6 rest days
• Score ≥7 high risk 
• IV multi-agent chemotherapy including combinations of methotrexate, dactinomycin, etoposide, cyclophosphamide and vincristine
• Continue treatment until HCG returns to normal and further 6 consecutive weeks 
• Score ≥13
• higher risk of early death (within 4 weeks ) due to bleeding into organs or multi-drug resistant disease

Cure rates: Score ≤6  almost 100% Score ≥7  94%

Suspected choriocarcinoma

• more extensive investigations in specialist centre like Contrast CT chest, abdomen or Contrast MRI pelvis & head, in addition to Doppler USG of pelvis and HCG

PSTT & ETT

• 0.2% of all GTD 
• Produce less HCG, confined to uterus for longer, more often involve lymphatic, more chemoresistant
• Not managed according to FIGO score
• Most important prognostic factor for adverse outcome → interval to presentation from last known and presumed causative pregnancy
• >48 month 100% death rates
• <48 months nearly all long-term survivors even if extensive t//m given >50% die
• Independent poor prognostic factor → stage IV disease
• Surgery plays a vital role
• stage I hysterectomy mainstay 
• intense platinum-based combination agent chemotherapy only required if interval >48 months

Recommended interval between complete or partial molar pregnancy and conception / pregnancy monitoring after a previous molar pregnancy / outcome of subsequent pregnancy

• Advised not to conceive until follow-up is complete
• If chemotherapy
• do not conceive for 1 year after completion of treatment
• If conceived within 12 months of chemotherapy 
• Increased risk of miscarriage
• higher rate of abortion if received multi-agent chemotherapy 
• Congenital abnormality 1.8% (regardless of type of chemo)
• If previous molar pregnancy 
• Risk of further mole → <1% (more with complete)
• Previous molar pregnancy + not needed treatment no need to send post-pregnancy HCG sample 
• Previous molar pregnancy + now normal pregnancy → no need for placental tissue histology
• No increased risk of maternal complication
• increased risk of preterm birth 25% in index pregnancy
• at least one birth between mole and index pregnancy  increased risk of LGA (1.35) & stillbirth (1.81)

Long-term Outcome for women treated for GTN

• Overall cure rates close to 100%
• 83% conceive after chemo ( regardless of single or multi agent)
• Menses stop during treatment but nearly always restart within a few weeks to months after chemo completion
• No overall increased risk of second cancers if treated methotrexate or EMA/CO
• Increased risk of premature menopause with combination agent chemo 
• 13% by 40 years 36% by 45 years
• Advice for near 40 years
• Warn of potential negative impact on fertility if high-dose chemotherapy given
• Unlikely to regain ovarian function
• AMH can be misleading 

Safe contraception and its timing

• No pregnancy until HCG follow-up completed
• Refer to FSRH guideline “Contraception after pregnancy” Click here 
• To access ALL FSRH guidelines : Click Here

ART & HRT after GTD

• Once HCG returns to normal
• Exogenous estrogens & other fertility drugs may be used
• HRT may be used
• No effects on outcome of GTN

Impact of diagnosis on women & their families

• GTD centres provide individualised support 
• Dedicated GTD nurse specialists and advisors
• Can be access in centre or via phone or both
• Online support groups (molarpregnancy.co.uk)

GTD Treatment Centres UK 

• Charing Cross Hospital Trophoblastic Tumour Screening and Treatment Centre
• Sheffield Trophoblastic Disease Centre
• Hydatidiform Mole Follow-up (Scotland) Dundee

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