What's on this Page
Gestational Trophoblastic Disease
Gestational trophoblastic disease (GTD) refers to a spectrum of neoplastic conditions that arise from abnormal proliferation of trophoblastic cells (cells that ultimately form the placenta).
Gestational trophoblastic neoplasia (GTN) specifically refers to GTD with the potential for tissue invasion and metastases.
GTN is a clinical and laboratory diagnosis and is characterized by a plateaued, rising, or prolonged persistence of elevated human chorionic gonadotropin (HCG) levels after evacuation of a mole; histologic diagnosis of choriocarcinoma, invasive mole, placental site trophoblastic tumor (PSTT), or epithelioid trophoblastic tumor (ETT); or evidence of metastatic disease after evacuation of a mole.
Synonym
- Gestational trophoblastic neoplasia
Incidence
In North America and Europe the incidence of GTD is approximately 1 to 2 per 1000 deliveries. The incidence of molar pregnancies in the United States is 1 in 1500 pregnancies.
On a global scale, the incidence is thought to be less than 1 in 1000 pregnancies. From 15% to 20% of patients develop GTN after complete mole (CM) evacuation and 1% to 5% after partial mole (PM).
Predominant Gender and Age
There appears to be bimodal distribution in the incidence of molar pregnancy with a significantly higher incidence in women younger than 15 yr and older than 40 yr of age.
Risk Factors
- •Extremes of reproductive age (younger than 15 and older than 40 yr of age)
- •Personal history of GTD increases the risk of a subsequent molar pregnancy 10-fold
- •A history of prior unsuccessful pregnancies increases the risk of GTD
- •High HCG levels before evacuation, uterine size larger than dates, and theca-lutein cysts increase the risk of developing postmolar GTN
Physical Findings & Clinical Presentation
- •Vaginal bleeding is typically the hallmark symptom of hydatidiform mole. Patients usually have delayed or irregular menses.
- •Patients usually present with vaginal bleeding in the first trimester that spans from spotting to hemorrhage potentially requiring blood transfusion.
- •Other clinical manifestation of GTD can vary depending on whether the molar pregnancy is complete or partial.
- •CM may present with excessive uterine size for dates, theca-lutein cysts, preeclampsia, hyperthyroidism, or respiratory problems.
- •Presentation of patients with GTN is highly variable. Many are asymptomatic. If metastatic, GTN most commonly spreads to the lungs, vagina, pelvis, liver, and brain. Therefore patients may present with symptoms related to the site of spread.View full size
Risk Factors for Trophoblastic Neoplasia
From Crum CP: Diagnostic gynecologic and obstetric pathology, ed 3, Philadelphia, 2018, Elsevier.
| Factor | Qualifier | Relative Risk |
|---|---|---|
| Maternal age | <20 yr | 1.5 |
| >40 | 5.2 | |
| Prior SAB | 1.9-3.3 | |
| Parity | >1 | 0.4 |
| Vitamin A | Median consumption | 0.6 |
| Incidence | ||
| Race | Indonesia | 1:85 |
| Japan | 1:522 | |
| Sweden | 1:1560 | |
| United States | 1:1724 | |
| Socioeconomic status | Philippines (wealthy) | 1:2000 |
| Philippines (poor) | 1:200 | |
| Prior molar pregnancy | 1 | 1:100 |
| >1 | 1:6 to 1:4 | |
| Trend | ||
| Smoking | >15 cigarettes/day | Increasing |
| Infertility | Increasing | |
| Theca-lutein cyst | >6 cm by ultrasound | Increasing (GTD subsequently develops in up to 50%) |
GTD, Gestational trophoblastic disease; SAB, spontaneous abortion.
Clinico-Radiologic and Gross Pathologic Presentation of Trophoblastic Neoplasia
From Crum CP: Diagnostic gynecologic and obstetric pathology, ed 3, Philadelphia, 2018, Elsevier.
| Disorder | Clinico-Radiologic Features | Beta–Human Chorionic Gonadotropin | Endometrial Curettings/Hysterectomy (Gross) | Exclude |
|---|---|---|---|---|
| PHM | 11-25 wk gestation ± fetal cardiac activity Vaginal bleeding Missed/incomplete pregnancy loss | Variable | Moderate amount of tissue Hydropic and normal villi Sac/membranes ± fetal parts (esp. syndactyly) | SAB CHM Aneuploid gestation (e.g., trisomy 13) |
| CHM | “Snowstorm” U/S Vaginal bleeding Toxemia Hyperemesis Thyrotoxicosis | High (>100K mIU/mL) | Voluminous grapelike, transparent vesicles Ectopic pregnancy Mild diffuse swelling under dissecting microscope (early CHM) | SAB PHM |
| Persistent GTD/invasive mole | Vaginal bleeding Prior CHM or PHM | Plateau (<10% drop in 14 days) or rising (>10% increase × 3 wk) | Minimal residual villous tissue Subtle, sometimes hemorrhagic myometrial nodule | Choriocarcinoma Unsuspected degenerating IUP |
| Choriocarcinoma | Irregular/severe bleeding Recent CHM or normal pregnancy Pulmonary, neurologic, or gastrointestinal symptoms | Rising, 2 wk after delivery After CHM: Plateau (<10% drop in 14 days) or rising (>10% incr. × 3 wk) | Hemorrhagic tumor nodules in endomyometrium | Persistent mole PSTT Unsuspected degenerating IUP |
| PSTT | Irregular vaginal bleeding Pregnancy months to years earlier | Persistent, low (50 mU/mL) | Discrete or infiltrative, polypoid or endophytic, tan, fleshy mass in endomyometrium | Exaggerated implantation site Placental site nodule Ectopic pregnancy Unsuspected IUP |
| ETT | Irregular vaginal bleeding Pregnancy months to years earlier | Persistent low (<150 mU/mL) | Expansile mass, may be centered in cervix or lower uterine segment | Squamous cell carcinoma Placental site nodule Ectopic pregnancy PSTT |
| Spontaneous pregnancy loss/SAB | Vaginal bleeding, first/second trimester | Declining | Minimal villous edema (not typically grossly evident; by dissecting microscope or histology usually) | CHM PHM Ectopic pregnancy |
β-hCG, Beta–human chorionic gonadotropin; CHM, complete hydatidiform mole; ETT, epithelioid trophoblastic tumor; GTD, gestational trophoblastic disease; IUP, intrauterine pregnancy; PHM, partial hydatidiform mole; PSTT, placental site trophoblastic tumor; SAB, spontaneous abortion; U/S, ultrasound.
a With first-trimester ultrasound screening and quantitative β-hCG, complete hydatidiform moles are most often diagnosed before clinical manifestations are evident.
Clinical Classification System for Patients with Malignant Gestational Trophoblastic Neoplasia
From Disaia PJ et al: Clinical gynecologic oncology, ed 9, Philadelphia, 2018, Elsevier.
| Category | Criteria |
|---|---|
| Nonmetastatic GTN | No evidence of metastases; not assigned to prognostic category |
| Metastatic GTN | Any extrauterine metastases |
| Good-prognosis metastatic GTN | Short duration (<4 mo) |
| No brain or liver metastases | |
| Pretherapy hCG <40,000 mIU/mL | |
| No antecedent term pregnancy | |
| No prior chemotherapy | |
| Poor-prognosis metastatic GTN | Any one risk factor: Long duration (>4 mo) |
| Pretherapy hCG >40,000 mIU/mL | |
| Brain or liver metastases | |
| Antecedent term pregnancy | |
| Prior chemotherapy |
GTN, Gestational trophoblastic neoplasia; hCG, human chorionic gonadotropin.
What causes Gestational Trophoblastic Disease?
- •Complete moles have a diploid karyotype; 85% to 90% of cases are 46,XX. The chromosomes, however, are entirely of paternal origin. In 46,XX cases a haploid sperm duplicates its own chromosomes after meiosis. Dispermic fertilization of an ovum is possible and produces a 46,XY karyotype.
- •Partial moles have a triploid karyotype, 69,XXX, 69,XXY, or less commonly 69,XYY. Composed of one maternal and two paternal haploid sets of chromosomes.
Differential Diagnosis
- •Vaginal bleeding in women of reproductive age includes gynecologic causes as well as complications of first-trimester pregnancy.
- •Malignant GTN should be considered in a woman of reproductive age who presents with metastatic disease from an unknown primary site or cerebral hemorrhage.
How is Gestational Trophoblastic Disease diagnosed?
- •Full patient history
- •Past pregnancy history specifically asking about miscarriages, terminations, prior molar pregnancies
- •Physical exam
- •Blood work
Diagnosis and Evaluation of Gestational Trophoblastic Neoplasia
From Disaia PJ et al: Clinical gynecologic oncology, ed 9, Philadelphia, 2018, Elsevier.
| Diagnosis of GTN |
| After molar evacuation: Four values or more of plateaued hCG (±10%) over at least 3 wk: Days 1, 7, 14, and 21 |
| After molar evacuation: A rise of hCG of 10% or greater for three values or more over at least 2 wk: Days 1, 7, and 14 |
| After molar evacuation: Persistence of hCG beyond 6 mo |
| The histologic diagnosis of choriocarcinoma, invasive mole, or PSTT |
| Metastatic disease without established primary site with elevated hCG (pregnancy has been excluded) |
| Evaluation of GTN |
| Complete physical and pelvic examination; baseline hematologic, renal, and hepatic functions |
| Baseline quantitative hCG level |
| Chest radiograph or CT scan of chest |
| Brain MRI |
| CT or MRI scan of abdomen and pelvis |
CT, Computed tomography; GTN, gestational trophoblastic neoplasia; hCG, human chorionic gonadotropin; MRI, magnetic resonance imaging; PSTT, placental site trophoblastic tumor.
FIGO staging for Gestational Trophoblastic Neoplasia
Modified from Kohorn EI: The new FIGO 2000 staging and risk factor scoring system for gestational trophoblastic disease: description and critical assessment, Int J Gynecol Cancer 2000;11:73.
| Stage | Criteria |
|---|---|
| I | Disease confined to the uterus |
| II | Disease outside of the uterus but is limited to the genital structures |
| III | Disease extends to the lungs with or without known genital tract involvement |
| IV | All other metastatic sites |
FIGO, International Federation of Gynecology and Obstetrics.
Scoring system for Gestational Trophoblastic Neoplasia
From Kohorn EI: The new FIGO 2000 staging and risk factor scoring system for gestational trophoblastic disease: description and critical assessment, Int J Gynecol Cancer 2000;11:73.
| FIGO Score | 0 | 1 | 2 | 4 |
|---|---|---|---|---|
| Age (years) | <40 | ≥40 | ||
| Antecedent pregnancy | Hydatidiform mole | Abortion | Term pregnancy | |
| Interval from index pregnancy (months) | <4 | 4-6 | 7-12 | ≥13 |
| Pretreatment HCG | <1000 | 1000-<10,000 | 10,000-100,000 | ≥100,000 |
| Largest tumor size including uterus (cm) | <3 | 3-5 | ≥5 | |
| Site of metastases | Lung | Spleen, kidney | Gastrointestinal | Brain, liver |
| Number of metastases | 1-4 | 5-8 | >8 | |
| Previous failed chemotherapy | Single drug | ≥2 drugs |
FIGO, International Federation of Gynecology and Obstetrics; HCG, human chorionic gonadotropin.
∗Total score for a patient is obtained by adding the individual scores for each prognostic factor. Total score 0-6= low risk; >7= high risk.
Laboratory Tests
- •Urine β-HCG
- •Serum β-HCG levels
- •CBC
- •CMP
- •Type and Rh
- •Thyroid function tests
- •Histopathologic evaluation of any products of conception, uterine curettings, etc.
Imaging Studies
- •Transvaginal ultrasound
- •If there is concern for GTN, chest radiograph (CXR) should be obtained to look for metastasis
- •Chest computed tomography (CT) and magnetic resonance (MR) imaging of the brain should be performed if lesions are seen in CXR
Treatment
- •Suction dilation and evacuation (D&E) is the preferred treatment, especially when future fertility is desired. Hysterectomy in selected patients, however, may be considered.
- •Chemotherapy is the mainstay of treatment for malignant GTN.
- •The below table summarizes the management and outcome of trophoblastic neoplasia.View full size
Management and Outcome of Trophoblastic Neoplasia
From Crum CP: Diagnostic gynecologic and obstetric pathology, ed 3, Philadelphia, 2018, Elsevier.
| Disorder | Therapy | Risk of Progression | Comments/Caveats |
|---|---|---|---|
| PHM | 1.Suction curettage2.Follow β-hCG every week until <5 mIU/mL × 3 wk, then every month × 6 mo, then every year × 1-3 yr3.Contraception × 1 yr | Persistent GTD = 4%-15% (often as retained products of conception with no or minimal proliferation) ChorioCa = essentially 0% | Confusion with a twin complete and normal gestation (rare) |
| CHM | Low-risk; same as PHM High-risk; chemoprophylaxis | Persistent GTD = 10%-30% Invasive mole = 15% ChorioCa: 2%-3% | If persistently elevated β-hCG: 75% have persistent GTD; 25% risk of ChorioCa |
| Persistent invasive mole | 1.Evaluate for metastatic disease2.Single-agent chemo until β-hCG <5 mIU/mL3.Contraception for 1 yr4.Hysterectomy for local control (optional) or bleeding complications | “Persistent GTD” is a clinical diagnosis applied to persistently elevated serum β-hCG following molar pregnancy and often treated empirically without pathologic sampling to distinguish persistent/invasive mole versus ChorioCa | |
| Choriocarcinoma | 1.Evaluate for metastatic disease2.Single-agent chemo if low risk3.Multiagent chemo if high risk4.Hysterectomy for local control (optional) | Based on FIGO staging and WHO score Remission: No metastases = 80% Metastases = 67% Overall disease-free survival with single-agent chemo = 87% | |
| PSTT and ETT | 1.Hysterectomy (therapy of choice) 2.Evaluate for metastatic disease 3.Multiagent chemo | Nonmetastatic disease: Cured by surgery Metastases = >30% at diagnosis Recurrence = 30% Mortality: 21%-36% | Poor prognosis: >5 mitoses/10 HPFs (recurrence), pulmonary metastases, antecedent pregnancy >4 yr prior |
β-hCG, Beta–human chorionic gonadotropin; chemo, chemotherapy; CHM, complete hydatidiform mole; ChorioCa, choriocarcinoma; ETT, epithelioid trophoblastic tumor; FIGO, International Federation of Gynecology and Obstetrics; GTD, gestational trophoblast disease; HPF, high-power field; PHM, partial hydatidiform mole; PSTT, placental site trophoblastic tumor; WHO, World Health Organization.
Nonpharmacologic Therapy
- •Following serial dilation of the cervix, the largest cannula that can be introduced throughthe cervix should be used. After complete suction D&E, gentle sharp curettage may be performed. Significant hemorrhage may occur at the time of D&E, therefore various uterotonics should be available at the time of procedure (oxytocin, methylergonovine, misoprostol). Rh immune globulin should be administered to nonsensitized RhD-negative women given the possibility of a partial mole and concomitant fetal tissue. Rh immune globulin can be withheld if complete mole is certain, but a diagnosis is often not known at the time of the procedure.
- •Medical induction of labor with oxytocin or prostaglandin is not recommended given the risk of increased blood loss as well as an increased risk of malignant sequelae when compared with suction D&E.
- •If a patient does not desire future fertility, hysterectomy is an alternative to suction D&E. However, this also increases blood loss and does not eliminate the risk of malignant postmolar GTN sequelae.
Pharmacologic Therapy
Various chemotherapeutic agents including methotrexate, dactinomycin, etoposide, actinomycin, chlorambucil, cyclophosphamide, and vincristine are used in the treatment of malignant GTN. Single- versus multiple-agent treatment depends on the staging of disease. Specifics of chemotherapy treatment are beyond the scope of this chapter, and patients diagnosed with malignant GTN should be referred to a gynecologic oncologist.
Acute General Treatment
- •Expeditious evacuation of suspected molar pregnancy should be performed.
- •Effective contraception during postmolar surveillance is important because an early pregnancy may mask an elevation in HCG caused by GTN.
- •Duration of chemotherapy depends on decrease in β-HCG to normal levels.
Chronic Treatment
- •Following D&E for a mole, close surveillance is necessary to monitor for the development of GTN. HCG levels are obtained every 1 to 2 wk until there are 3 consecutive normal levels and then at monthly intervals until 6 mo after the initial normal value.
- •After 6 mo of surveillance, documenting remission, pregnancy can be recommended and β-HCG monitoring discontinued.
- •No long-term therapy after successful treatment of GTN is needed.
- •Surveillance of remission of GTN is necessary. HCG levels should be obtained every 2 wk for 3 mo, then every month to complete a year of follow-up. Physical exam every 6 to 12 mo for 3 to 5 yr should be performed.
Disposition
- •Cure rates for women with low-risk, nonmetastatic GTN approach 100%.
- •Overall survival for patients with high-risk GTN is 86% to 92%.
- •Overall, pregnancy outcomes in women with a history of molar gestations are similar to those without such a history.
- •Surveillance during and after therapy of gestational trophoblastic neoplasia is summarized in the below table
Surveillance during and after Therapy of Gestational Trophoblastic Neoplasia
From Disaia PJ et al: Clinical gynecologic oncology, ed 9, Philadelphia, 2018, Elsevier.
| Monitor serum quantitative hCG levels every week during chemotherapy:1.Response: >10% decline in hCG during 1 cycle2.Plateau: ±10% change in hCG during 1 cycle3.Resistance: >10% rise in hCG during 1 cycle or plateau for 2 cycles of chemotherapy •Evaluate for new metastases •Consider alternative chemotherapy •Consider extirpation of drug-resistant sites of disease |
| Remission: Three consecutive normal weekly hCG values1.Maintenance chemotherapy |
| Surveillance of remission:1.hCG values every 2 wk × 3 mo2.hCG values every month to complete 1 yr of follow-up3.Physical examination every 6-12 mo for at least 3-5 yr |
Referral
- •Treatment of molar pregnancy and postmolar surveillance can safely be performed by a general OB/GYN.
- •Patients diagnosed with malignant GTN should be referred to a gynecologic oncologist.
Seek Additional Information
- Ngan H.Y., et al.: Update on the diagnosis and management of gestational trophoblastic disease. Int J Gynecol Obstet 2018; 143: pp. 79-85.
