Gestational trophoblastic diseases (GTD) are a unique spectrum of diseases that originate in the placenta or afterbirth.
After conception, the cell formed from the union of an egg and a sperm normally divides and, after repeated division, forms a healthy placenta and membranes around a developing baby (foetus). The cells of the placenta and membranes, containing the fluid in which the foetus grows, are called trophoblastic cells. These structures make the vital connection between mother and baby for the exchange of oxygen and nutrients, and the removal of the baby’s waste products. They form the afterbirth (placenta) that is delivered after a baby is born.
The most common examples of GTD are hydatidiform moles. Most moles go into spontaneous remission. If GTDs persist or spread to other organs (metastasise), they are designated gestational trophoblastic neoplasms. The latter include invasive moles and choriocarcinomas.
Nearly all GTDs produce a hormonal substance called human chorionic gonadotropin (hCG), which can be measured in the blood. hCG is a very sensitive marker for these tumours and can be used to diagnose them and show how well they are responding to treatment. Gestational trophoblastic neoplasms are mostly very responsive to chemotherapy and if these cancers have spread to other organs such as lungs, they are mostly still curable. The only other gynaecological cancers that are so responsive to chemotherapy are germ cell tumours of the ovary, and some of them also produce hCG.
Less than 300 Australian women are diagnosed with GTD each year. These are rare tumours.
GTD is typically highly responsive to treatment and likely to be cured. However even when curable, it still causes much anxiety and discomfort. Its impact is greatest on women in their childbearing years, when they should be healthy and highly productive. If GTD is suspected and if hCG and other appropriate testing is done in a timely fashion, its impact is minimised. A woman should expect hCG testing:
- After any pregnancy, whenever she has persistent abnormal vaginal bleeding or acute persisting respiratory symptoms e.g. cough or new neurological symptoms e.g. headache.
- 6 weeks after the end of all subsequent pregnancies if she has had a previous GTD. Rarely previous GTD may be reactivated after a subsequent pregnancy, even after several years.
Awareness campaigns aimed at spreading this advice could mean that women with GTD and their doctors more often suspect and make the correct diagnosis when the risk is still low. Research to determine the optimal use of hCG testing and chemotherapy would also make a valuable contribution to women’s health.
About 80% of GTD are hydatidiform moles, which may be complete or partial. Moles form in about 1 in every 1500 pregnancies among women in Australia. There are about 300,000 pregnancies resulting in live births in Australia every year. There are also about 60,000 other pregnancies, including ectopic pregnancies, and pregnancies that result in therapeutic termination or miscarriage. About 240 of these pregnancies result in benign or malignant gestational trophoblastic disease.
There is a much higher rate of molar pregnancy among Asian women. Asian women who migrate have a similar rate so presumably the risk is genetic. Molar pregnancies occur more frequently in women younger than 20 years and in those older than 40 years.
A hydatidiform mole begins as an abnormal conception which implants in a woman’s uterus and continues growing there. If it is a complete hydatidiform mole, it will have masses of rapidly growing abnormal cells but no foetus. If it is a partial hydatidiform mole, it will have an abnormal non-viable foetus and placenta. In either type, the mole is a non-malignant tumour and will grow only in the space inside the uterus. Very rarely a molar pregnancy will be twinned with an otherwise normal pregnancy.
Often a woman with a hydatidiform mole is initially thought to have a healthy pregnancy after her menstruation ceases and her pregnancy test is positive. However she typically will develop vaginal bleeding. The bleeding is usually painless. She may be more nauseous than expected and may have high blood pressure and protein in her urine detected at antenatal check-ups. She is about 50% likely to have a uterus that is bigger than expected, based on the time since her last menstruation. hCG levels in her blood will be much higher than expected and the hydatidiform mole will usually be diagnosed with reasonable confidence by ultrasonic imaging.
A mole must be evacuated under anaesthesia, using a suction curette. Examination of the tissues removed will confirm the diagnosis.
The outcome after this treatment is usually excellent but it is not possible to be confident that the hydatidiform mole has been completely removed by this procedure. A woman who has had a hydatidiform mole evacuated must be monitored with weekly blood levels of hCG until she has had 3 consecutive negative levels. Her levels should steadily decline to normal within 12 to 16 weeks.
If the molar pregnancy has been a complete one and the hCG results are normal by 8 weeks, the follow up can be stopped. If hCG levels remain high beyond 8 weeks then become normal, monthly hCG tests should be done for 12 months and pregnancy needs to be avoided during this time. Pregnancies cause hCG to rise, and this would make it impossible to detect persistent trophoblastic disease using this test. Persistent trophoblastic disease would require treatment with chemotherapy that would not be compatible with continued pregnancy.
Once the hCG levels reach normal following a partial mole, the follow up can be stopped and she can then get pregnant.
Abnormal hCG results after 16 weeks require further investigation.
Fertility is seldom harmed by this condition and future healthy pregnancies can be expected to follow her full recovery. Only approximately 2% of subsequent pregnancies will be molar.
About 20% of moles undergo malignant transformation and start spreading more widely. These tumours can grow by invasion into the underlying uterine muscle, and their malignant cells can also get into the blood stream and spread to the lungs or to other organs, lodging there, dividing and creating metastatic tumours. Malignant forms of GTD are known as GTN. They include invasive mole, choriocarcinoma and placental site trophoblastic tumour.
Invasive moles are diagnosed when molar tumours invade into uterine muscle or spread more widely. When tissue from them is examined under the microscope, it has the characteristics of a hydatidiform mole. Invasive moles are typically detected when hCG levels in the blood start to rise after evacuation of complete hydatidiform moles. For about 1 in 12 women diagnosed with an invasive mole after a complete mole, their tumour has spread more widely, particularly to their lungs and sometimes to their vaginas. But only about 1 in 500 women who have had partial moles develop invasive moles. Spread of tumour to lungs is rare in this group.
Choriocarcinomas are the most aggressively malignant form of GTN. Of these tumours:
- 50% follow hydatidiform moles, 1 out of 40 hydatidiform moles.
- 22% follow full-term pregnancies, 1 out of 60,000 term pregnancies, sometimes years later.
- 25% follow miscarriages or a therapeutic termination of pregnancy, a rare complication.
- 3% follow ectopic pregnancies, 1 in 5000 ectopic pregnancies.
The incidence of choriocarcinoma increases with age and is 5-15 times higher in women who have reached 40 than in younger women. Cells from choriocarcinomas tend to get into the blood stream early in the development of the disease and these cells spread (metastasise) to the lungs, vagina, brain, liver, kidneys, or bowel, forming secondary tumours, i.e. metastatic disease.
Most choriocarcinomas are diagnosed after women develop symptoms of metastatic disease. Tumour deposits in lungs may cause coughing of blood or shortness of breath. Brain tumours may cause headaches, dizzy spells, or blackouts. Bowel tumours may cause rectal bleeding or dark stools. Abnormal vaginal bleeding is common, either due to uterine choriocarcinoma tumours or vaginal metastatic tumours.
Placental site trophoblastic tumours are exceptionally rare forms of GTN that start growing where placentas were once attached. They typically differ from other GTNs in that their cells secrete human placental lactogen, hPL, rather than hCG. They may also be diagnosed in women after menopause.
Treatment of a GTN is based on assessment of the risk of an undesirable outcome such as progressive disease. Assessment depends on the presence or absence of several prognostic factors. A woman’s invasive mole is considered to be low risk if it has not spread outside her uterus. If it has spread outside her uterus, to be considered low risk, all of the following must apply:
- Her last pregnancy must have been less than four months ago.
- The level of her hCG must be low.
- Her tumour must not have spread to the liver or brain.
- She must not have previously received any chemotherapy.
Otherwise her invasive mole will be considered to be high risk. Choriocarcinoma is always high risk.
A woman with an invasive mole of low risk is treated with single-agent chemotherapy, either methotrexate or actinomycin D. This is usually curative. A woman with high-risk disease always needs combination chemotherapy. In addition to methotrexate and actinomycin D, other drugs may also be given, such as cyclophosphamide, cisplatin, vinblastine and bleomycin. One combination regimen often used is EMACO – etoposide, methotrexate, actinomycin D, cyclosphosphamide and vincristine (Oncovin).
For a woman whose cancer has spread to brain or liver, radiation may be employed to these areas in conjunction with chemotherapy. Surgery is sometimes used to treat a solitary brain metastasis.
Hysterectomy may sometimes be helpful. Placental site trophoblastic tumour will usually be treated by hysterectomy alone, but if it has spread widely it will need treatment by chemotherapy and radiotherapy.
A woman with GTN should use a reliable method of contraception for at least 12 months to limit the risk of adverse effects of chemotherapy on pregnancy and avoid difficulties in interpretation of hCG levels.
A woman with low risk GTN has almost 100% chance of being cured of her disease, even if her cancer had spread to her lungs before it was diagnosed. She should have follow-up serum hCG levels measured once per week until 4 normal values are obtained. Then, hCG levels should be obtained once per month for 1 year. After 12 months of normal hCG levels, she has less than 1% risk of GTN recurrence.
A woman with high-risk GTN has about an 85% chance of cure. She should also have hCG tests weekly until there have been 4 consecutive normal levels, then hCG tests monthly for at least a year. If her GTN has spread to organs other than her lungs, i.e. she has Stage IV disease, monthly testing should continue for 5 years.
Any woman who relapses, as shown by rising hCG levels, should have a full restaging. This will involve imaging tests as originally used to determine the extent of tumour spread and an assessment of her response to previous chemotherapy. Chemotherapy will be restarted with different combinations of drugs than those used initially. This restaging is different from the way other gynaecologic cancers with metastases are typically managed because, even after relapse of GTN, chemotherapy can still be highly effective.