Gestational trophoblastic disease (GTD) forms a group of disorders which range from complete and partial molar pregnancies to malignant conditions such as invasive mole, choriocarcinoma and placental site trophoblastic tumour (PSTT). If there is any evidence of persistence of GTD, usually defined as persistent elevation of beta human chorionic gonadotrophin (beta hCG), the condition is referred to as gestational trophoblastic neoplasia (GTN).¹

Gestational trophoblastic tumours are rare but very curable. They arise from the products of conception in the uterus. The most common preceding pregnancy is a hydatidiform mole, which is usually a genetic disorder of pregnancy in which only placental-like tissue is present.

Choriocarcinoma most often follows a molar pregnancy but can follow a normal pregnancy, ectopic pregnancy or abortion, and should always be considered when a patient has continued vaginal bleeding after the end of a pregnancy.²

Molar pregnancies can be subdivided into complete and partial moles based on genetic and histopathological features:¹

• Complete moles:
  • Are diploid and androgenic in origin, with no evidence of fetal tissue.
  • Usually arise as a consequence of duplication of a single sperm following fertilisation of an 'empty' ovum.
  • May also arise after dispermic fertilisation of an 'empty' ovum.
• Partial moles:
  • Usually evidence of a fetus or fetal red blood cells.
  • Are usually triploid in origin, with two sets of paternal haploid genes and one set of maternal haploid genes.
  • Almost always occur following dispermic fertilisation of an ovum.
  • 10% of partial moles represent tetraploid or mosaic conceptions.

Hydatidiform mole (molar pregnancy)

• Hydatidiform moles are abnormal conceptions with excessive placental, and little or no fetal development.
• They affect 1-3 in every 1,000 pregnancies.
• Hydatidiform moles affect women throughout the reproductive age range but women aged under 16 have a six times higher risk of developing the disease than those aged 16-40, and women who conceive when aged 50 or more have a one in three chance of having a molar pregnancy.
  They can also rarely develop (1/100,000 pregnancies) as part of twin or multiple gestations.
• 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.
• About 10% of hydatidiform moles transform into one of the malignant forms of GTD.

Malignant GTD

• In benign disease, human chorionic gonadotrophin (hCG) concentrations spontaneously return to normal but, in women who develop malignant forms, the concentration plateaus or rises.
• The risk of malignancy after a complete or partial hydatidiform mole is 15% and 0.5%, respectively. This is identified in almost all cases by regularly measuring hCG with an assay that detects all the different forms of the hormone seen in cancer, with a sensitivity and specificity of virtually 100%.
• In malignant GTD, which is highly vascular, biopsy is contra-indicated because it may cause life-threatening haemorrhage.
• To ensure reliable monitoring of hCG concentrations after a molar pregnancy, all patients in the UK are registered with one of three centres: Ninewells Hospital (Dundee), Weston Park Hospital (Sheffield), and Charing Cross Hospital (London).
• At Charing Cross Hospital, the hormone is measured in serum and urine, then for several months in urine only, once values are normal.
• Molar disease may occasionally be reactivated after a subsequent pregnancy, even several years later, so hormone concentrations should be monitored at six and 10 weeks after any further pregnancy ends.
• Following a molar pregnancy, the risk of the next gestation being a hydatidiform mole rises to 1 in 80. Thus most women can expect to have a normal pregnancy.

Epidemiology

• Gestational trophoblastic disease (GTD) 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 in 50,000.

Risk factors

• Molar pregnancies may occur at any age but are more common in women aged 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.

Clinical presentation of gestational trophoblastic disease³

Most affected women in the UK develop vaginal bleeding in the first trimester and undergo uterine evacuation at about 10 weeks' gestation. It is most often diagnosed on an early dating scan but features include:

• Irregular vaginal bleeding.
• Hyperemesis.
• Persistent vaginal bleeding after a miscarriage or pregnancy. Any woman who develops persistent vaginal bleeding after a pregnancy event is at risk of having gestational trophoblastic neoplasia (GTN).¹
• Excessive uterine enlargement.
• Rarer presentations include hyperthyroidism, early-onset pre-eclampsia or abdominal distension due to theca lutein ovarian cysts.
• Metastatic disease very rarely presents with dyspnoea or abnormal neurology, including seizures.

Women with persistent abnormal vaginal bleeding after a non-molar pregnancy should undergo a pregnancy test to exclude persistent GTN, which should also be considered in any woman developing acute respiratory or neurological symptoms after any pregnancy.

Investigations

A urine pregnancy test should be performed in all cases of persistent or irregular vaginal bleeding after a pregnancy event. Definitive diagnosis is made by histological examination of the products of conception.¹

• Ultrasound:
  • The grape-like or hydropic change most commonly found occurs mainly in the second trimester, and ultrasound shows a classic snowstorm-like appearance.
  • Two recent retrospective studies identified molar pregnancy by ultrasonography in the first and early second trimester in only 40-60% of cases.³
  • 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.
• Levels of hCG may be of value in diagnosing molar pregnancies but are far more important in disease follow-up.
• Chest X-ray or lung CT scan to diagnose lung metastases.⁴
• CT scanning is preferable for liver or other intra-abdominal metastases.
• MRI or CT scanning for brain metastases.
• Histology:
  • The histological assessment of material obtained from the medical or surgical management of all failed pregnancies is recommended to exclude trophoblastic neoplasia.¹
  • There is no need routinely to send products of conception for histological examination following therapeutic termination of pregnancy, provided that fetal parts have been identified on prior ultrasound examination.¹
  • If a diagnosis is not made, malignant change will not subsequently be monitored and women will have a significantly increased risk of life-threatening complications, such as uterine perforation and severe haemorrhage.

Staging

The staging system of the International Federation of Gynecology and Obstetrics (FIGO) is as follows:⁴

• 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.

Management^1,3

• Suction curettage is the method of choice of evacuation for complete molar pregnancies.
• Suction curettage is the method of choice of evacuation for partial molar pregnancies except when the size of the fetal parts deters the use of suction curettage and then medical evacuation can be used.
• A urinary pregnancy test should be performed 3 weeks after medical management of failed pregnancy if products of conception are not sent for histological examination.
• Anti-D prophylaxis is required following evacuation of a molar pregnancy.
• Preparation of the cervix immediately prior to evacuation is safe.
• Excessive vaginal bleeding can be associated with molar pregnancy and a senior surgeon directly supervising surgical evacuation is advised.
• The use of oxytocic infusion prior to completion of the evacuation is not recommended.
• If the woman is experiencing significant haemorrhage prior to evacuation, surgical evacuation should be expedited and the need for oxytocin infusion weighed up against the risk of tumour embolisation.

Management of hydatidiform moles

• Suspected cases are initially managed with suction uterine evacuation (sharp curettage is avoided to minimise the risk of uterine perforation).
• 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
• Initial evacuation usually removes most molar material and residual tissue involutes.
• Sometimes the first evacuation is incomplete, with molar material left behind in the uterine cavity; further evacuation within the next few days may help reduce symptoms and prevent the need for chemotherapy.
• If little residual material is left after the initial procedure, the guidelines do not recommend further evacuation for persistent disease, at least until after consultation with a specialist centre.¹

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 GTD after such a twin pregnancy and outcome after chemotherapy is unaffected.

UK (Charing Cross Hospital) protocol for surveillance after hydatidiform mole

• Two-weekly serum and urine samples until hCG concentrations are normal.
• Then when hormone concentrations are normal:
  • If 56 or fewer days after evacuation, measure urine concentrations monthly for six months from the evacuation date.
  • If more than 56 days after evacuation, measure urine concentrations monthly for six months after values become normal.

Indications for chemotherapy in GTD

• Histological evidence of choriocarcinoma.
• Evidence of metastases in the brain, liver, or gastrointestinal (GI) tract, or radiological opacities >2 cm on chest X-ray.
• Pulmonary, vulval, or vaginal metastases unless hCG concentrations are falling.
• Heavy vaginal bleeding or evidence of GI or intraperitoneal haemorrhage.
• Rising hCG concentrations in two consecutive samples or plateaued concentrations in three consecutive samples after evacuation.
• Serum hCG greater than 20,000 IU/L more than four weeks after evacuation, because of the risk of uterine perforation with further evacuation attempts.
• Raised hCG concentrations six months after evacuation, even if still falling.

Chemotherapy regimes

Women with evidence of persistent GTD should undergo assessment of their disease followed by chemotherapy. Disease risk is scored according to the FIGO staging for GTD.⁴

© Royal College of Obstetricians and Gynaecologists; reproduced with permission.

Chemotherapy regimen for low-risk patients with GTD

• Methotrexate 50 mg intramuscularly; repeated every 48 hours (total of four doses) - courses are repeated every two weeks.
• Calcium folinate (folinic acid) 15 mg orally 30 hours after each injection of methotrexate.

Chemotherapy regimen for high-risk patients with GTD

• The following two regimens alternate each week:
  • Regimen 1:
    • Day 1: etoposide, dactinomycin and methotrexate
    • Day 2: etoposide, dactinomycin and folinic acid rescue (starting 24 hours after beginning the methotrexate infusion)
  • Regimen 2:
    • Day 8: vincristine and cyclophosphamide (on day 8 only)

There is no strong evidence to determine the best combination chemotherapy regimen for high-risk gestational trophoblastic tumour.⁶ A recent Cochrane review found that "pulsed" dactinomycin was superior to weekly parenteral methotrexate.⁷

Follow-up after chemotherapy¹

• Follow-up after GTD is increasingly individualised.
• If hCG has reverted to normal within 56 days of the pregnancy event then follow-up will be for 6 months from the date of uterine evacuation.
• If hCG has not reverted to normal within 56 days of the pregnancy event then follow-up will be for 6 months from normalisation of the hCG level.
• All women should notify the screening centre at the end of any future pregnancy, whatever the outcome of the pregnancy. Levels of hCG are measured 6-8 weeks after the end of the pregnancy to exclude disease recurrence.

Women should be advised not to conceive until their follow-up is complete. Women who undergo chemotherapy are advised not to conceive for 1 year after completion of treatment.¹

Future pregnancy

• 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.
• However, of 1,708 patients with gestational trophoblastic neoplasia (GTN) at Charing Cross Hospital, including women presenting after non-molar pregnancies, the overall relapse rate was 3.5%, and most relapses occurred in the first year after treatment.
• 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

Contraception and hormone replacement therapy¹

• Women with gestational trophoblastic disease (GTD) should be advised to use barrier methods of contraception until hCG levels revert to normal. Once hCG levels have normalised, the combined oral contraceptive pill (COCP) may be used.
• There is no evidence as to whether single-agent progestogens have any effect on gestational trophoblastic neoplasia (GTN).
• There is no evidence of risk that the use of hormone replacement therapy (HRT) affects the outcome of GTN.
• If oral contraception has been started before the diagnosis of GTD was made, the woman can be advised to remain on oral contraception but she should be advised that there is a potential but low increased risk of developing GTN.
• Intrauterine contraceptive devices should not be used until hCG levels are normal in order to reduce the risk of uterine perforation.
• The COCP and HRT are safe to use after hCG levels have reverted to normal.¹
• 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.

Prognosis

• The need for chemotherapy following a complete mole is 15% and is 0.5 % after a partial mole. Persistent gestational trophoblastic disease (GTD) requiring chemotherapy after other pregnancies is rare.
• Women who receive chemotherapy for gestational trophoblastic neoplasia (GTN) are likely to have an earlier menopause. The age at menopause for women who receive single-agent chemotherapy is advanced by 1 year and by 3 years if they receive multi-agent chemotherapy.
• Women with high-risk GTN who require multi-agent chemotherapy which includes etoposide should be advised that they may be at increased risk of developing secondary cancers.
• Good-prognosis metastatic gestational trophoblastic tumours:²
  • Last pregnancy less than four months ago.
  • Low hCG titre.
  • No liver or brain metastases.
  • No previous chemotherapy.
• Poor-prognosis metastatic gestational trophoblastic tumours¹:
  • Last pregnancy more than four months ago.
  • High hCG titre.
  • Liver or brain metastases.
  • Previous chemotherapy.
  • Occurrence after a full-term pregnancy.

Document references

1. Management of Gestational Trophoblastic Disease, Royal College of Obstetricians and Gynaecologists (February 2010)
2. National Cancer Institute (US); Gestational trophoblastic tumors
3. Sebire NJ, Seckl MJ; Gestational trophoblastic disease: current management of hydatidiform mole. BMJ. 2008 Aug 15;337:a1193. doi: 10.1136/bmj.a1193.
4. Kohorn EI; The new FIGO 2000 staging and risk factor scoring system for gestational trophoblastic disease: description and critical assessment. Int J Gynecol Cancer. 2001 Jan-Feb;11(1):73-7. [abstract]
5. Hydatidiform Mole and Choriocarcinoma UK Information and Support Service.
6. Deng L, Yan X, Zhang J, et al; Combination chemotherapy for high-risk gestational trophoblastic tumour. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD005196. [abstract]
7. Alazzam M, Tidy J, Hancock BW, et al; First line chemotherapy in low risk gestational trophoblastic neoplasia. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD007102. [abstract]

Internet and further reading

• International Society for the Study of Trophoblastic Diseases
• Hernandez E; Gestational Trophoblastic Neoplasia, eMedicine, Mar 2010

Acknowledgements