Gestational trophoblastic diseases are a group of interrelated diseases that form a spectrum from benign hydatidiform mole to trophoblastic malignancy (placental-site trophoblastic tumor and choriocarcinoma). Malignant forms account for <1% of female gynecologic malignancies and can be cured with appropriate chemotherapy. Deaths from this disease have become rare in the United States.
The incidence is about 1 per 1500 pregnancies in the United States and is nearly tenfold higher in Asia. Maternal age >45 years is a risk factor for hydatidiform mole. A prior history of molar pregnancy is also a risk factor. Choriocarcinoma occurs in ~1 in 25,000 pregnancies or 1 in 20,000 live births. Prior history of hydatidiform mole is a risk factor for choriocarcinoma. A woman with a molar pregnancy is 1000 times more likely to develop choriocarcinoma than a woman with a prior normal-term pregnancy.
Pathology and Etiology
The trophoblastic neoplasms have been divided by morphology into complete or partial hydatidiform mole, invasive mole, placental-site trophoblastomas, and choriocarcinomas. Hydatidiform moles contain clusters of villi with hydropic changes, hyperplasia of the trophoblast, and the absence of fetal vessels. Invasive moles differ only by invasion into the uterine myometrium. Placental-site trophoblastic tumors are predominately made up of cytotrophoblast cells arising from the placental implantation site. Choriocarcinomas consist of anaplastic trophoblastic tissue with both cytotrophoblastic and syncytiotrophoblastic elements and no identifiable villi.
Complete moles result from uniparental disomy in which loss of the maternal genes (23 autosomes plus X) occurs by unknown mechanisms and is followed by duplication of the paternal haploid genome (23 autosomes plus X). Uncommonly (5%), moles result from dispermic fertilization of an empty egg, resulting in either 46XY or 46XX genotype. Partial moles result from dispermic fertilization of an egg with retention of the maternal haploid set of chromosomes, resulting in diandric triploidy.
Molar pregnancies are generally associated with first-trimester bleeding, ectopic pregnancies, or threatened abortions. The uterus is inappropriately large for the length of gestation, and β-hCG7 levels are higher than expected. Fetal parts and heart sounds are not present. The diagnosis is generally made by the passage of grapelike clusters from the uterus, but ultrasound demonstration of the hydropic mole can be diagnostic. Patients suspected of a molar pregnancy require a chest film, careful pelvic examinations, and weekly serial monitoring of β-hCG levels.
Patients with hydatidiform moles require suction curettage coupled with postevacuation monitoring of β-hCG8 levels. In most women (80%), the β-hCG titer progressively declines within 8 to 10 days of evacuation (serum half-life is 24 to 36 h). Patients should be monitored on a monthly basis and should not become pregnant for at least a year. Patients found to have invasive mole at curettage are generally treated with hysterectomy and chemotherapy. Approximately half of patients with choriocarcinoma develop the malignancy after a molar pregnancy, and the other half develop the malignancy after abortion, ectopic pregnancy, or occasionally after a normal full-term pregnancy.
Chemotherapy is generally used for gestational trophoblastic neoplasia and is often used in hydatidiform mole if β-hCG9 levels rise or plateau or if metastases develop. Patients with invasive mole or choriocarcinoma require chemotherapy. Several regimens are effective, including methotrexate at 30 mg/m2 intramuscularly on a weekly basis until β-hCG titers are normal. However, methotrexate (1 mg/kg) every other day for 4 days followed by leukovorin (0.1 mg/kg) intravenously 24 h after methotrexate is associated with a cure rate of ≥90% and low toxicity. Intermittent courses are continued until the β-hCG titer becomes undetectable for 3 consecutive weeks, and then patients are monitored monthly for a year.
Patients with high-risk tumors (high β-hCG10 levels, disease presenting ≥4 months after antecedent pregnancy, brain or liver metastasis, or failure of single-agent methotrexate) are initially treated with combination chemotherapy. EMA-CO (a cyclic non-cross-resistant combination of etoposide, methotrexate, and dactinomycin alternating with cyclophosphamide and vincristine); cisplatin, bleomycin, and vinblastine; and cisplatin, etoposide, and bleomycin are effective regimens. EMA-CO is now the regimen of choice for patients with high-risk disease because of excellent survival rates (>80%) and less toxicity. The use of etoposide carries a 1.5% lifetime risk of acute myeloid leukemia (16-fold relative risk). Because of this problem, etoposide-containing regimens should be reserved for patients with high-risk features. Patients with brain or liver metastases are usually treated with local irradiation to metastatic sites in conjunction with chemotherapy. Long-term studies of patients cured of trophoblastic disease have not demonstrated an increased risk of maternal complications or fetal abnormalities with subsequent pregnancies.
Revision date: June 14, 2011
Last revised: by Jorge P. Ribeiro, MD