Gestational trophoblastic disease includes a spectrum of proliferative disorders ranging from nonneoplastic hydatiform moles to malignant neoplastic disorders. These disorders originate from the trophoblastic layer of the embryo, which surrounds the blastocyst and develops into the chorion and amnion (see figure Placenta and embryo at about 11 4/7 weeks gestation Amniotic sac and placenta For conception (fertilization), a live sperm must unite with an ovum in a fallopian tube with normally functioning epithelium. Conception occurs just after ovulation, about 14 days after a menstrual... read more ).
Gestational trophoblastic disease can occur during or after an intrauterine or ectopic pregnancy. Risk is increased in pregnancies in women at the extremes of reproductive life, especially after age 45 years. During a pregnancy, disease typically results in spontaneous abortion, eclampsia, or fetal death.
Gestational trophoblastic disease is classified as hydatiform moles or gestational trophoblastic neoplasias:
Hydatiform moles are benign placental tumors with malignant potential. They consist of proliferations of villous trophoblasts. They are further classified as complete or partial moles.
Gestational trophoblastic neoplasias are malignant placental tumors. These tumors include postmolar gestational trophoblastic neoplasia (gestational trophoblastic neoplasia that develops after a molar pregnancy), placental-site trophoblastic tumor, epithelioid trophoblastic tumor, choriocarcinoma, and invasive mole.
Hydatidiform moles are most common among women < 17 or > 35 and those who have previously had gestational trophoblastic disease. In the US, hydatiform moles occur in 1 of 1000 to 1200 pregnancies and in 1 of 600 induced abortions ( 1 General references Gestational trophoblastic disease is proliferation of trophoblastic tissue in pregnant or recently pregnant women. Manifestations may include excessive uterine enlargement, vomiting, vaginal... read more , 2). They are usually diagnosed during the first half of pregnancy.
There are two types of molar pregnancy:
Complete mole: The placental tissue is abnormal, and fetal tissue does not form. Complete moles are diploid. Most are 46XX and result from fertilization by a single sperm that then duplicates; the ovum nucleus is either absent or inactivated. However, some result from dispermic fertilization and can be 46 XY.
Partial mole: A partial molar pregnancy may contain normal placental tissue with abnormal placental tissue. A fetus may develop but is not able to survive; miscarriage usually occurs early in the pregnancy. Partial moles are triploid, resulting from fertilization by two sperm or a diploid sperm.
Most (> 80%) hydatidiform moles are benign. In patients with a prior partial or complete mole, incidence of a second mole in subsequent pregnancies is 1 to 2%. Patients who have had a mole require ultrasonography early in subsequent pregnancies, and the placenta should be sent for pathology evaluation. Patients with consecutive molar pregnancies require germline genetic testing for mutations in NLRP7 and KHDC3L.
Choriocarcinoma develops after 2 to 3% of hydatidiform moles, more commonly after a complete than a partial mole. After a complete hydatidiform mole, about 15 to 20% of patients are treated for gestational trophoblastic neoplasia. Invasive mole occurs in 15% of cases, and metastatic disease occurs in 5%. After a partial mole, local invasion occurs in up to 3 to 5%, and metastatic disease is rare ( 3 General references Gestational trophoblastic disease is proliferation of trophoblastic tissue in pregnant or recently pregnant women. Manifestations may include excessive uterine enlargement, vomiting, vaginal... read more ).
Overall incidence of gestational trophoblastic neoplasia is about 1/40,000 pregnancies ( 4 General references Gestational trophoblastic disease is proliferation of trophoblastic tissue in pregnant or recently pregnant women. Manifestations may include excessive uterine enlargement, vomiting, vaginal... read more ). Risk of postmolar gestational trophoblastic neoplasia is increased if patients are > 40 years or have pre-evacuation hCG > 100,000 mIU/mL, excessive uterine enlargement, or theca lutein cysts > 6 cm.
1. Seckl MJ, Sebire NJ, Berkowitz RS: Gestational trophoblastic disease. Lancet 376 (9742):717–729, 2010. doi: 10.1016/S0140-6736(10)60280-2 Epub 2010 Jul 29.
2. Lurain JR: Gestational trophoblastic disease I: Epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole. Am J Obstet Gynecol 203 (6):531–539, 2010. doi: 10.1016/j.ajog.2010.06.073 Epub 2010 Aug 21.
3. Goldstein DP, Berkowitz RS: Current management of gestational trophoblastic neoplasia. Hematol Oncol Clin North Am 26 (1):111–131, 2012. doi: 10.1016/j.hoc.2011.10.007
4. Smith HO: Gestational trophoblastic disease epidemiology and trends. Clin Obstet Gynecol (3):541–556, 2003. doi: 10.1097/00003081-200309000-00006
Symptoms and Signs of Gestational Trophoblastic Disease
Initial manifestations of a hydatidiform mole suggest early pregnancy, but the uterus often becomes larger than expected within 10 to 16 weeks gestation. Commonly, women test positive for pregnancy and have vaginal bleeding and severe nausea and vomiting ( hyperemesis gravidarum Hyperemesis Gravidarum Hyperemesis gravidarum is uncontrollable vomiting during pregnancy that results in dehydration, weight loss, and ketosis. Diagnosis is clinical and by measurement of urine ketones, serum electrolytes... read more ) and fetal movement and fetal heart sounds are absent. Vaginal passage of grapelike tissue strongly suggests the diagnosis.
Complications, such as the following, may occur:
Ovarian theca lutein cysts
Less common complications include uterine infection Postpartum Endometritis Postpartum endometritis is uterine infection, typically caused by bacteria ascending from the lower genital or gastrointestinal tract. Symptoms are uterine tenderness, abdominal or pelvic pain... read more and sepsis Sepsis and Septic Shock Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection. In septic shock, there is critical reduction in tissue perfusion; acute failure... read more .
Placental site trophoblastic tumors tend to cause bleeding.
Choriocarcinoma usually manifests with symptoms due to lung, liver, or brain metastases.
Hyperthyroidism is more common among women with gestational trophoblastic disease than in those without. Symptoms can include tachycardia, warm skin, sweating, heat intolerance, and mild tremors.
Gestational trophoblastic disease does not impair subsequent fertility or predispose to prenatal or perinatal complications (eg, congenital malformations, spontaneous abortions) in subsequent pregnancies.
Diagnosis of Gestational Trophoblastic Disease
Serum beta subunit of human chorionic gonadotropin (beta-hCG)
Pathology evaluation of evacuated uterine contents or endometrial biopsy
Gestational trophoblastic disease is suspected in women with a positive pregnancy test and any of the following:
Unexpectedly high levels of beta-hCG detected during pregnancy testing (except for placental site trophoblastic tumor and epithelioid trophoblastic tumor, which result in low beta-hCG levels)
Uterine size much larger than expected for dates
Symptoms or signs of preeclampsia in 1st or 2nd trimester
Vaginal passage of grapelike tissue
Suggestive findings (eg, mass containing multiple cysts, absence of a fetus and amniotic fluid) seen during ultrasonography done to evaluate pregnancy
Unexplained metastases in women of child-bearing age with an unknown primary tumor
Postmolar gestational trophoblastic neoplasia is most frequently diagnosed based on hCG levels and should be excluded if abnormal uterine bleeding occurs after any pregnancy.
Pearls & Pitfalls
If gestational trophoblastic disease is suspected, testing includes measurement of serum beta-hCG and, if not previously done, pelvic ultrasonography. Findings (eg, very high beta-hCG levels, classic ultrasonographic findings) may suggest the diagnosis, but the diagnosis must be histologically confirmed through pathology evaluation of evacuated uterine contents or endometrial biopsy. Typically, beta-hCG levels are high in patients with invasive mole or choriocarcinoma and low in those with placental site trophoblastic tumor or epithelioid trophoblastic tumor.
Invasive mole and choriocarcinoma are suspected if biopsy findings suggest invasive disease or if beta-hCG levels remain higher than expected after treatment for hydatidiform mole (see below).
Thyroid function tests are done if the beta-hCG level is > 100,000 mIU/mL (> 100,000 IU/L) to check for hyperthyroidism.
When gestational trophoblastic neoplasia is diagnosed, clinicians should check for metastases. CT of the chest, abdomen, and pelvic area should be done. Pelvic ultrasonography or MRI may be helpful if better visualization of the uterine tumor is needed or if there are ovarian theca lutein cysts. Metastases to other sites usually occur only after metastases to the lungs are established.
Before gestational trophoblastic disease is treated, it is assigned the following:
A stage based on the 2000 International Federation of Gynecology and Obstetrics (FIGO) staging system (see table FIGO Anatomic Staging of Gestational Trophoblastic Neoplasia FIGO Anatomic Staging of Gestational Trophoblastic Neoplasia )
A risk score based on the modified World Health Organization [WHO] prognostic scoring system (see table WHO Scoring System in Metastatic Gestational Trophoblastic Disease )
Both systems correlate with clinical outcomes and identify patients at risk of treatment failure.
Prognosis for Gestational Trophoblastic Disease
In metastatic disease, the World Health Organization (WHO) prognostic scoring system for metastatic gestational trophoblastic disease can help predict prognosis, including risk of death (see table WHO Scoring System in Metastatic Gestational Trophoblastic Disease WHO Scoring System in Metastatic Gestational Trophoblastic Disease* ). A WHO risk score of ≤ 6 is classified as low risk, and scores > 6 are classified as high risk.
Poor prognosis is also suggested by the following (National Institutes of Health [NIH] criteria):
Urinary hCG excretion > 100,000 IU in 24 hours
Duration of disease > 4 months (interval since prior pregnancy)
Brain or liver metastases
Disease after full-term pregnancy
Serum hCG > 40,000 mIU/mL
Unsuccessful prior chemotherapy
WHO score > 6
Treatment of Gestational Trophoblastic Disease
Tumor removal by suction curettage or hysterectomy (if fertility is not desired, especially if women > 40 years)
Further evaluation for persistent disease and spread of tumor
Chemotherapy for persistent disease
Posttreatment contraception for persistent disease
(See also National Comprehensive Cancer Network (NCCN): NCCN Clinical Practice Guidelines in Oncology: Gestational Trophoblastic Neoplasia.)
Usually, any type of gestational trophoblastic disease can be successfully diagnosed and treated and fertility can be preserved. Desire to preserve fertility should be discussed when planning treatment for gestational trophoblastic disease.
Hydatidiform mole, invasive mole, placental site trophoblastic tumor, and epithelioid trophoblastic tumor are evacuated by suction curettage. Alternatively, if childbearing is not planned, hysterectomy may be done.
A chest x-ray is taken. Serum beta-hCG is measured serially. Effective contraception is recommended while hCG is being monitored. If the beta-hCG level does not normalize within 10 weeks, the disease is classified as persistent. Persistent disease requires CT of the brain, chest, abdomen, and pelvis. Results dictate whether disease is classified as nonmetastatic or metastatic.
Persistent disease is usually treated with chemotherapy. Treatment is considered successful if at least 3 consecutive serum beta-hCG measurements at 1-week intervals are normal. Pregnancy should be prevented for 6 months after treatment because pregnancy would increase beta-hCG levels, making it difficult to determine whether treatment has been successful. Typically, oral contraceptives are given for 6 months; alternatively, any effective contraceptive method can be used.
For most types of gestational trophoblastic neoplasia, chemotherapy is the primary treatment.
Low-risk metastatic disease can be cured, often with a single chemotherapy drug (eg, methotrexate, actinomycin D [ dactinomycin]). Multidrug chemotherapy is an acceptable alternative. Primary remission rates for these regimens range from
Actinomycin D regimens: 69 to 94%
5-day methotrexate regimens: 87 to 94%
8-day methotrexate-folate regimens: 74 to 93%
The National Comprehensive Cancer Network guidelines (NCCN) recommends multiday methotrexate or methotrexate/folate regimens. If patients have contraindications to methotrexate regimens, actinomycin D regimens are recommended. Serum hCG levels are monitored during chemotherapy and after normalization of hCG levels. Usually, additional cycles of consolidation therapy are given.
Hysterectomy shortens the duration and amount of chemotherapy needed for remission in patients with low-risk disease. After hysterectomy, patients still require chemotherapy and serum hCG monitoring.
If treatment is successful, hCG levels should decrease by ≥ 10% over three cycles of treatment. An alternative treatment is needed if there is significant toxicity or if hCG levels
Do not decrease as expected.
Increase > 10% over two cycles
For patients previously treated with multiday methotrexate regimens, 5-day actinomycin D is recommended.
All patients with high-risk gestational trophoblastic neoplasia (WHO risk score > 6) should be referred to specialists. High-risk metastatic disease requires aggressive multidrug chemotherapy because patients are likely to develop resistance if a single drug is used. EMA-CO is the most widely used regimen. It consists of etoposide, methotrexate, plus dactinomycin (EMA), alternating with cyclophosphamide plus vincristine (CO). Surgery and/or radiation therapy are often part of primary treatment. Survival rates in specialized centers exceed 86% ( 1 Treatment reference Gestational trophoblastic disease is proliferation of trophoblastic tissue in pregnant or recently pregnant women. Manifestations may include excessive uterine enlargement, vomiting, vaginal... read more ).
Treatment of high-risk gestational trophoblastic neoplasia resistant to initial chemotherapy is difficult. Options include
EMA/EP (etoposide/methotrexate/actinomycin D/etoposide/cisplatin)
Paclitaxel/etoposide alternating with cisplatin/etoposide
Multiday etoposide/cisplatin regimens
High-dose chemotherapy with stem cell support
Programmed death receptor 1 (PD-1) is present in almost all gestational trophoblastic disease lesions. Some patients with drug-resistant gestational trophoblastic neoplasia have been treated with checkpoint inhibitors (pembrolizumab, avelumab) with some benefit.
Cure rates are
Low-risk: 90 to 95%
High-risk: 60 to 80%
Risk of disease progression and resistance to single-drug chemotherapy is determined by the FIGO staging system and the WHO risk scoring system.
Gestational trophoblastic disease is considered low risk if it is one of the following:
FIGO stage I (persistently elevated beta-hCG level and/or tumor confined to the uterus)
FIGO stage II or III with a WHO risk score of ≤ 6
Gestational trophoblastic disease is considered high risk if it is one of the following:
FIGO stages II and III with a WHO risk score of > 6
FIGO stage IV
After remission of gestational trophoblastic neoplasia (normalization of hCG levels), hCG levels should be measured at 2-week intervals during the first 3 months, then at monthly intervals for at least 12 months. After 12 months, risk of recurrence is < 1%; risk is higher for patients with high-risk disease. In patients with high-risk disease, hCG levels should be measured at 6- to 12-month intervals after the first 12 months of remission. Oral contraceptives during chemotherapy and the 12 months after remission are recommended.
Suspect gestational trophoblastic disease during early pregnancy if uterine size is much larger than expected for dates, if beta-hCG levels are unexpectedly high during, if there are symptoms or signs of preeclampsia, or if ultrasonographic findings suggest gestational trophoblastic disease.
Measure beta-hCG level, do pelvic ultrasonography, and if findings suggest gestational trophoblastic disease, confirm the diagnosis by pathology evaluation of evacuated uterine contents or endometrial biopsy.
Remove the tumor (eg, by suction curettage), then classify the tumor based on clinical criteria.
If disease is persistent, treat patients with chemotherapy and prescribe contraception for 12 months.
The following is an English-language resource that may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
National Cancer Institute: Gestational Trophoblastic Disease Treatment: This web site provides information about gestational trophoblastic disease, its classification, staging, and treatment of each type of gestational trophoblastic disease.
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