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Gestational Trophoblastic Disease

By Pedro T. Ramirez, MD, Professor, Department of Gynecologic Oncology and Reproductive Medicine, David M. Gershenson Distinguished Professor in Ovarian Cancer Research, and Director of Minimally Invasive Surgical Research and Education, The University of Texas MD Anderson Cancer Center ; David M. Gershenson, MD, Professor and Chairman, Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center ; Gloria Salvo, MD, Rotating Research Resident, Department of Gynecologic Oncology and Reproductive Medicine, MD Anderson Cancer Center

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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 Conception and Prenatal Development : Amniotic sac and placenta). This 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.

Some forms of gestational trophoblastic disease are malignant; others are benign but behave aggressively.

Pathology

Gestational trophoblastic disease may be classified as

  • Hydatidiform mole, which may be complete or partial

  • Gestational trophoblastic neoplasia, which includes chorioadenoma destruens (invasive mole), choriocarcinoma, placental site trophoblastic tumor (very rare), and epithelioid trophoblastic tumor (extremely rare)

Gestational trophoblastic disease may also be classified morphologically:

  • Hydatidiform mole: In this abnormal pregnancy, villi become edematous (hydropic), and trophoblastic tissue proliferates.

  • Invasive mole: The myometrium is invaded locally by a hydatidiform mole.

  • Choriocarcinoma: This invasive, usually widely metastatic tumor is composed of malignant trophoblastic cells and lacks hydropic villi; most of these tumors develop after a hydatidiform mole.

  • Placental site trophoblastic tumor: This rare tumor consists of intermediate trophoblastic cells that persist after a term pregnancy; it may invade adjacent tissues or metastasize.

  • Epithelioid trophoblastic tumor: This rare variant of placental site trophoblastic tumor consists of intermediate trophoblastic cells. Like placental site trophoblastic tumors, it may invade adjacent tissues or metastasize.

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.

Symptoms and Signs

Initial manifestations of a hydatidiform mole suggest early pregnancy, but the uterus often becomes larger than expected within 10 to 16 wk 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:

  • Uterine infection

  • Sepsis

  • Hemorrhagic shock

  • Preeclampsia

Placental site trophoblastic tumors tend to cause bleeding.

Choriocarcinoma usually manifests with symptoms due to metastases.

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

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.

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).

Staging

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).

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, with or without genital tract involvement

IV

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

Based on the International Federation of Gynecology and Obstetrics (FIGO) Committee on Gynecologic Oncology: Current FIGO staging for cancer of the vagina, fallopian tube, ovary, and gestational trophoblastic neoplasia. International Journal of Gynaecology and Obstetrics 105 (1):3–4, 2009.

Prognosis

In metastatic disease, the 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*

Prognostic Factor

Description

Score

Age (yr)

< 40

0

40

1

Preceding pregnancy

Mole

0

Abortion

1

Term

2

Interval (mo)

< 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

GI 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 the International Federation of Gynecology and Obstetrics (FIGO) Oncology Committee: FIGO staging for gestational trophoblastic neoplasia 2000. International Journal of Gynaecology and Obstetrics 77(3):285–287, 2002 and the American Joint Committee on Cancer (AJCC), AJCC Cancer Staging Manual, ed. 7. New York, Springer, 2010.

Poor prognosis is also suggested by the following (National Institutes of Health [NIH] criteria):

  • Urinary hCG excretion > 100,000 IU in 24 h

  • Duration of disease > 4 mo (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

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 wk, 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-wk intervals are normal. Pregnancy should be prevented for 6 mo 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 mo; 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 or multidrug chemotherapy. High-risk metastatic disease requires aggressive multidrug chemotherapy. Cure rates are 90 to 95% for low-risk and 60 to 80% for high-risk disease.

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 mo.

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