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Gestational Trophoblastic Disease

By

Pedro T. Ramirez

, MD, The University of Texas MD Anderson Cancer Center;


Gloria Salvo

, MD, MD Anderson Cancer Center

Last full review/revision Sep 2020| Content last modified Sep 2020
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Gestational trophoblastic disease is proliferation of trophoblastic tissue in pregnant or recently pregnant women. Manifestations may include excessive uterine enlargement, vomiting, vaginal bleeding, and preeclampsia, particularly during early pregnancy. Diagnosis includes measurement of the beta subunit of human chorionic gonadotropin, pelvic ultrasonography, and confirmation by biopsy. Tumors are removed by suction curettage. If disease persists after removal, chemotherapy is indicated.

Gestational trophoblastic disease is a tumor originating from the trophoblast, which surrounds the blastocyst and develops into the chorion and amnion (see page Placenta and embryo at about 11 4/7 weeks gestation).

Gestational trophoblastic disease can occur during or after an intrauterine or ectopic pregnancy. If the disease occurs during a pregnancy, spontaneous abortion, eclampsia, or fetal death typically occurs; the fetus rarely survives.

Gestational trophoblastic disease may be

  • Benign: These tumors include placental site nodule and hydatidiform mole.

  • Gestational trophoblastic neoplasms: These malignant tumors include 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. They occur in about 1/2000 gestations in the US. For unknown reasons, incidence in Asian countries approaches 1/200.

Most (> 80%) hydatidiform moles are benign. The rest may persist, tending to become invasive; 2 to 3% of hydatidiform moles are followed by choriocarcinoma.

Overall incidence of gestational trophoblastic neoplasia is about 1/40,000 pregnancies (1, 2).

Half of gestational trophoblastic neoplasms develop from a molar pregnancy, 25% from miscarriages or tubal pregnancy, and 25% from a term or preterm pregnancy (3). After a molar pregnancy, trophoblastic neoplasms usually develop as molar tissue or choriocarcinoma or, rarely, a placental site trophoblastic tumor or epithelioid trophoblastic tumor.

There are two types of molar pregnancy:

  • Complete:The placental tissue is abnormal and fetal tissue does not form.

  • Partial: In a partial molar pregnancy, there may be normal placental tissue with abnormal placental tissue. A fetus may develop but is not able to survive and is usually miscarries early in the pregnancy.

After a complete hydatidiform mole, local invasion 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

  • 1. Smith HO: Gestational trophoblastic disease epidemiology and trends. Clin Obstet Gynecol (3):541–556, 2003. doi: 10.1097/00003081-200309000-00006.

  • 2. Ngan S, Seckl MJ: Gestational trophoblastic neoplasia management: an update. Curr Opin Oncol 19 (5):486–491, 2007. doi: 10.1097/CCO.0b013e3282dc94e5.

  • 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.

Symptoms and Signs

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 vomiting, and fetal movement and fetal heart sounds are absent. Passage of grapelike tissue strongly suggests the diagnosis.

Complications, such as the following, may occur during early pregnancy:

Placental site trophoblastic tumors tend to cause bleeding.

Choriocarcinoma usually manifests with symptoms due to metastases.

Hyperthyroidism is more common among women with gestational trophoblastic disease than in those without. Symptoms can include a tachycardia, warm skin, sweating, heat intolerance, and mild tremors.

Gestational trophoblastic disease does not impair fertility or predispose to prenatal or perinatal complications (eg, congenital malformations, spontaneous abortions) in subsequent pregnancies.

Diagnosis

  • Serum beta subunit of human chorionic gonadotropin (beta-hCG)

  • Pelvic ultrasonography

  • Biopsy

Gestational trophoblastic disease is suspected in women with a positive pregnancy test and any of the following:

  • Uterine size much larger than expected for dates

  • Symptoms or signs of preeclampsia

  • 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

  • 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)

  • Unexplained complications of pregnancy

Pearls & Pitfalls

  • Do ultrasonography during early pregnancy if uterine size is much larger than expected for dates, if women have symptoms or signs of preeclampsia, or if beta-hCG levels are unexpectedly high.

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 biopsy is required. 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.

Staging

A stage and risk score are assigned before gestational trophoblastic disease is treated.

The International Federation of Gynecology and Obstetrics (FIGO) has developed a staging system for gestational trophoblastic neoplasia (see table FIGO Anatomic Staging of Gestational Trophoblastic Neoplasia).

Table
icon

FIGO Anatomic Staging of Gestational Trophoblastic Neoplasia

Stage

Description

I

Confined to the uterus

II

Extending outside the uterus but limited to genital structures (adnexa, vagina, broad ligament)

III

Extending to the lungs

IV

Spread to all other distant sites (eg, brain, liver, kidneys, gastrointestinal tract)

Adapted from staging established by the International Federation of Gynecology and Obstetrics (FIGO) and American Joint Committee on Cancer (AJCC), AJCC Cancer Staging Manual, ed. 8. New York, Springer, 2017.

Prognosis

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).

Table
icon

WHO Scoring System in Metastatic Gestational Trophoblastic Disease*

Prognostic Factor

Description

Score†

Age (years)

< 40

0

40

1

Preceding pregnancy

Mole

0

Abortion

1

Term

2

Interval (months)‡

< 4

0

4–6

1

7–12

2

> 12

4

Pretreatment serum hCG (IU/mL)

< 1000

0

1,000−< 10,000

1

10,000−< 100,000

2

100,000

4

Largest tumor, including any uterine tumors

3−< 5 cm

1

5 cm

2

Site of metastases

Lungs

0

Spleen, kidneys

1

Gastrointestinal tract

2

Brain, liver

4

Number of metastases identified

1−4

1

5−8

2

> 8

4

Number of chemotherapy drugs used unsuccessfully

1

2

2

4

* Does not apply to placental site trophoblastic disease or epithelioid trophoblastic tumor.

† Total score obtained by adding the score for each prognostic factor:

  • 6 = low risk

  • 7= high risk

‡ Between the end of the preceding pregnancy and the start of chemotherapy.

hCG = human chorionic gonadotropin.

Adapted from AJCC Cancer Staging Manual, ed. 8. New York, Springer, 2017.

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 7

Treatment

  • Tumor removal by suction curettage or hysterectomy

  • 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.)

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.

After tumor removal, gestational trophoblastic disease is classified clinically to determine whether additional treatment is needed. The clinical classification system does not correspond to the morphologic classification system. Invasive mole and choriocarcinoma are classified clinically as persistent disease. The clinical classification is used because invasive mole and choriocarcinoma are treated similarly and because exact histologic diagnosis may require hysterectomy.

A chest x-ray is taken, and serum beta-hCG is measured. 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 (any is acceptable) are given for 6 months; alternatively, any effective contraceptive method can be used.

Nonmetastatic disease can be treated with a single chemotherapy drug (methotrexate or dactinomycin). Alternatively, hysterectomy is considered for patients > 40 or those desiring sterilization and may be required for those with severe infection or uncontrolled bleeding. If single-drug chemotherapy is ineffective, hysterectomy or multidrug chemotherapy is indicated. Virtually 100% of patients with nonmetastatic disease can be cured.

Low-risk metastatic disease is treated with single-drug (eg, methotrexatedactinomycin) chemotherapy preferably or with multidrug chemotherapy. 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).

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 ≥ 7

  • FIGO stage IV

Hydatidiform mole recurs in about 1% of subsequent pregnancies. Patients who have had a mole require ultrasonography early in subsequent pregnancies, and the placenta should be sent for pathologic evaluation.

Key Points

  • Suspect gestational trophoblastic disease if uterine size is much larger than expected for dates, if women have symptoms or signs of preeclampsia, if beta-hCG levels are unexpectedly high during early pregnancy, 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 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 posttreatment contraception for 6 months.

More Information

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.

Click here for Patient Education
NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version
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