Gestational trophoblastic disease (GTD)

Persistent gestational trophoblastic disease may develop after a molar pregnancy, a non-molar pregnancy or a live birth. Hydatidiform mole (molar pregnancy) is disease limited to the uterine cavity. Invasive mole (chorioadenoma destruens) is a locally invasive, rarely metastatic lesion.

• Hydatidiform mole can be subdivided into complete and partial mole based on genetic and histopathological features:
  • Complete moles are diploid and androgenetic in origin, with no evidence of fetal tissue.
  • Partial moles are triploid in origin with two sets of paternal haploid genes and one set of maternal haploid genes. There is usually evidence of a fetus or fetal red blood cells.
• Choriocarcinoma
  • Most commonly follows a molar pregnancy but can follow a normal pregnancy, ectopic pregnancy, or abortion.
  • The most common sites for metastases are the lungs and brain.

• Gestational trophoblastic neoplasia (hydatidiform mole, invasive mole, choriocarcinoma, placental site trophoblastic tumour) is rare in the UK, with a calculated incidence of 1 in 714 live births.¹
• This may be less than the true incidence of the disease because of problems with reporting, particularly partial moles.
• The incidence after a live birth is estimated at 1/50,000.

Risk Factors

• Molar pregnancies may occur at any age but are more common in women over 40 years or under 15 years.
• There is also an increased risk with multiple pregnancy and previous molar pregnancy.
• There is evidence of ethnic variation, with women from Asia having a higher incidence compared with non-Asian women.

• Most often diagnosed on an early dating scan but features include:
  • Large for dates and the uterus feels 'doughy' in all forms of gestational trophoblastic disease.
  • Vaginal bleeding, possibly with vesicles.
  • Early pre-eclampsia.
  • Thyrotoxicosis - rare.
• Presentation with hyperemesis, early severe pre-eclampsia and hyperthyroidism is very rare.
• Women with persistent abnormal vaginal bleeding after a non-molar pregnancy should undergo a pregnancy test to exclude persistent gestational trophoblastic neoplasia, which should also be considered in any woman developing acute respiratory or neurological symptoms after any pregnancy.

• Ultrasound:
  • Typical snow storm appearance.
  • Ultrasound has limited value in detecting partial molar pregnancies.
  • When there is diagnostic doubt about the possibility of a combined molar pregnancy with a viable fetus then ultrasound examination should be repeated before intervention.
• Human chorionic gonadotrophin (HCG) levels may be of value in diagnosing molar pregnancies but are far more important in disease follow-up.
• Chest x-ray is appropriate to diagnose lung metastases. Lung CT may be used but does influence the score.²
• CT scanning or by ultrasound for liver metastases.
• MRI or CT scanning for brain metastases.
• CT scanning is preferable for intra-abdominal metastases.

Registration of any molar pregnancy is essential. Women with the following molar pregnancies should be registered and require follow up for 6-24 months as determined by the screening centre¹:

• Complete hydatidiform mole
• Partial hydatidiform mole
• Twin pregnancy with complete or partial hydatidiform mole
• Limited macroscopic or microscopic molar change suggesting possible partial or early complete molar change
• Choriocarcinoma
• Placental site trophoblastic tumour

The FIGO staging system is as follows:²

• Stage I: disease confined to the uterus.
• Stage II: Extends outside the uterus but is limited to the genital structures (adnexa, vagina, broad ligament).
• Stage III: Extends to the lungs with or without genital tract involvement.
• Stage IV: All other metastatic sites.

Twin pregnancies with a viable fetus and a molar pregnancy

• The pregnancy should be allowed to proceed if the mother wishes, following appropriate counselling.
• The probability of achieving a viable baby is 40% and there is a risk of complications such as pulmonary embolism and pre-eclampsia.
• There is no increased risk of developing persistent GTN (for definition see Further Treatment section below) after such a twin pregnancy and outcome after chemotherapy is unaffected.

Molar pregnancies

• Surgical evacuation of molar pregnancies is advisable. Routine repeat evacuation after the diagnosis of a molar pregnancy is not warranted.¹
• Suction curettage is the method of choice of evacuation for complete molar pregnancies.
• Medical termination of complete molar pregnancies, including cervical preparation prior to suction evacuation, should be avoided where possible. There is theoretical concern over the potential for inducing embolism and metastatic disease in the lung.¹
• Medical termination can be used for partial molar pregnancies. There may be an increased risk of requiring treatment for persistent trophoblastic neoplasia, but the proportion of women with partial molar pregnancies needing chemotherapy is very low.¹
• All products of conception obtained after evacuation (medical or surgical) should undergo histological examination. Products of conception from therapeutic terminations of pregnancy should be examined if there is no evidence of fetal tissue.¹
• In cases where there are persisting symptoms, such as vaginal bleeding, after initial evacuation, consultation with a screening centre should be sought before surgical intervention.¹

• Following initial treatment, patients should be monitored with serum beta HCG to document its return to normal.
• Monitoring should be weekly until less than 100 mIU/mL and then every two weeks.³
• Once the titre of serum BHCG has fallen to normal levels, BHCG titers need to be repeated every 2 weeks for 3 months, then monthly for 3 months, then every 2 months for 6 months, then every 6 months for 3 years.³

• Criteria for the diagnosis of post hydatidiform mole trophoblastic neoplasia (GTN):²
  • The plateau of human chorionic gonadotropin (hCG) lasts for 4 measurements over a period of 3 weeks or longer.
  • There is a rise of hCG on three consecutive weekly measurements, over a period of two weeks or longer.
  • Histologic diagnosis of choriocarcinoma.
  • Beta hCG level remains elevated for 6 months or more.
• There is no clinical indication for the routine use of a second uterine evacuation in the management of molar pregnancies. Uterine evacuation may be recommended, in selected cases, by the screening centre as part of the management of persistent trophoblastic neoplasia.
• Women with evidence of persistent GTN should undergo assessment of their disease followed by chemotherapy. Disease risk is scored according to the FIGO staging for GTN.²
• Women scoring six or less (low risk) receive intramuscular methotrexate on alternate days, followed by six rest days, with each course consisting of four injections. Women who develop resistance to methotrexate are treated with a combination of intravenous dactinomycin and etoposide.
• Women scoring seven or more (high risk) receive combination chemotherapy:
  • At the Charing Cross Hospital, London, the treatment is intravenous etoposide, methotrexate, dactinomycin for two days followed by vincristine and cyclophosphamide (EMA-CO) one week later. The course is then repeated after six days.
  • At Weston Park Hospital, Sheffield, the treatment is intravenous methotrexate followed by dactinomycin and etoposide one week later. The course is then repeated after one week.
  • Treatment is continued, in all cases, until the hCG level has returned to normal and then for a further six consecutive weeks.
• Chemotherapy regimens for high-risk gestational trophoblastic tumour include methotrexate, actinomycin D and cyclophosphamide (MAC), methotrexate, actinomycin D, cyclophosphamide, doxorubicin, melphalan, hydroxyurea and vincristine (CHAMOC), etoposide, methotrexate and actinomycin (EMA) plus cyclophosphamide and vincristine (CO) (EMA-CO), etoposide, methotrexate and actinomycin (EMA) plus etoposide and cisplatin(EP) (EMA-EP). There is no strong evidence to determine the best combination chemotherapy regimen for high-risk gestational trophoblastic tumour.⁴

• Women should be advised not to conceive until their hCG levels have been normal for six months.¹
• The risk of a further molar pregnancy is low and more than 98% of women who become pregnant following a molar pregnancy will not have a further mole or be at increased risk of obstetric complications.
• If a further molar pregnancy does occur, it will be of the same histological type in 68-80% of cases.¹
• Women who undergo chemotherapy are advised not to conceive for one year after completion of treatment.¹

• The combined oral contraceptive pill and hormone replacement therapy are safe to use after hCG levels have reverted to normal.¹
• The combined oral contraceptive pill, if taken while hCG levels are raised, may increase the need for treatment.
• Other forms of hormonal contraception do not appear to be linked to an increased need for treatment.
• The small potential risk of using emergency hormonal contraception, in women with raised hCG levels, is outweighed by the potential risk of pregnancy to the woman.¹

• The need for chemotherapy following a complete mole is 15% and is 0.5 % after a partial mole. Persistent GTN requiring chemotherapy after other pregnancies is rare.
• Good-prognosis metastatic gestational trophoblastic tumours:³
  • Last pregnancy less than 4 months ago.
  • HCG titre low
  • No liver or brain metastases.
  • No prior chemotherapy.
• Poor-prognosis metastatic gestational trophoblastic tumours¹:
  • Last pregnancy more than 4 months ago.
  • HCG titre high.
  • Liver or brain metastases.
  • Prior chemotherapy.
  • Occurrence after a full-term pregnancy.