AUTHOR AND EDITOR INFORMATION

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• Follow-up
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INTRODUCTION

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Background

Gestational trophoblastic disease (GTD) can be benign or malignant. Histologically, it is classified into hydatidiform mole, invasive mole (chorioadenoma destruens), choriocarcinoma, and placental site trophoblastic tumor (PSTT). Those that invade locally or metastasize are collectively known as gestational trophoblastic neoplasia (GTN). Hydatidiform mole is the most common form of gestational trophoblastic neoplasia (see Image 1). While invasive mole and choriocarcinoma are malignant, a hydatidiform mole can behave in a malignant or benign fashion.

No methods exist to accurately predict the clinical behavior of a hydatidiform mole by histopathology. The clinical course is defined by the patient's serum human chorionic gonadotropin (HCG) curve after evacuation of the mole. In 80% of patients with a benign hydatidiform mole, serum HCG titers steadily drop to normal within 8-12 weeks after evacuation of the molar pregnancy. In the other 20% of patients with a malignant hydatidiform mole, serum HCG titers either rise or plateau.

The official International Federation of Gynecology and Obstetrics staging of gestational trophoblastic neoplasia is as follows:

• Stage I – Confined to the uterus
• Stage II – Limited to the genital structures
• Stage III – Lung metastases
• Stage IV – Other metastases

Each stage is subclassified further according to a prognostic scoring index. If the risk factors are unknown, no substage is assigned. If the prognostic score is 7 or less, the substage is A (eg, IIIA is equal to lung metastasis with a prognostic score of 7 or less). If the prognostic score is 8 or greater, the substage is B.

The currently used prognostic scoring index is a modification of the World Health Organization (WHO) classification. It provides points for the presence of a number of prognostic factors, as follows:

• Age 40 years or older = 1 point
• Antecedent pregnancy terminated in abortion = 1 point
• Antecedent full-term pregnancy = 2 points
• Interval of 4 months to less than 7 months between antecedent pregnancy and start of chemotherapy = 1 point
• Interval of 7-12 months between antecedent pregnancy and start of chemotherapy = 2 points
• Interval of more than 12 months between antecedent pregnancy and start of chemotherapy = 4 points
• Beta-HCG level in serum is 1000 mIU/mL but less than 10,000 mIU/mL = 1 point
• Beta-HCG level in serum is 10,000 mIU/mL but less than 100,000 mIU/mL = 2 points
• Beta-HCG level in serum is 100,000 mIU/mL or greater = 4 points
• Largest tumor is 3 cm but less than 5 cm = 1 point
• Largest tumor is 5 cm or greater = 2 points
• Site of metastases is spleen or kidney = 1 point
• Site of metastases is gastrointestinal tract = 2 points
• Site of metastases is brain or liver = 4 points
• Number of metastases is 1-4 = 1 point
• Number of metastases is 5-8 = 2 points
• Number of metastases is more than 8 = 4 points
• Prior chemotherapy with single drug = 2 points
• Prior chemotherapy with multiple drugs = 4 points

Pathophysiology

Histologically, hydatidiform moles look like placental tissue, but edema of the villi demonstrates varying sizes. Proliferation of the trophoblast occurs, and fetal blood vessels are lacking or are scarce.

If a fetus or fetal parts are present, this is known as a partial or incomplete mole. Partial moles also have malignant potential, but only 2% become malignant. An invasive mole has the same histopathologic characteristics of a hydatidiform mole, but invasion of the myometrium with necrosis and hemorrhage occurs or pulmonary metastases are present. Histologically, choriocarcinomas have no villi, but they have sheets of trophoblasts and hemorrhage.

Choriocarcinomas are aneuploid and can be heterozygous, depending on the type of pregnancy from which the choriocarcinoma arose. If a hydatidiform mole preceded the choriocarcinoma, the chromosomes are of paternal origin. Maternal and paternal chromosomes are present if a term pregnancy precedes the choriocarcinoma. Of choriocarcinomas, 50% are preceded by a hydatidiform mole, 25% by an abortion, and the other 25% by a full-term pregnancy.

Placental site trophoblastic tumor is a rare form of gestational trophoblastic neoplasm, with slightly more than 200 cases reported in the literature. In patients with PSTT, intermediate trophoblasts are found infiltrating the myometrium without causing tissue destruction. The intermediate trophoblasts contain human placental lactogen (HPL). These patients have persistent low levels of serum HCG (100-1000 mIU/mL). However, serum HCG titers as high as 58,000 mIU/ml have been reported in patients with placental site trophoblastic tumors. The treatment of placental site trophoblastic tumors is hysterectomy with ovarian conservation. If the tumor recurs or metastases are present at initial diagnosis, chemotherapy is administered with variable results. Radiation therapy may provide local control.

The most frequent sites of metastases of malignant gestational trophoblastic neoplasm are the lungs, lower genital tract, brain, liver, kidney, and gastrointestinal tract.

Frequency

United States

Hydatidiform moles occur in 1 in 2000 deliveries, or 1 in 850 to 1 in 1300 pregnancies.

International

In Mexico, an incidence of 1 in 200 deliveries is reported, while an incidence of 1 in 120 deliveries is reported in Taiwan. Some believe these international differences are due to differences in diet. However, in some countries, these differences are due to poor recording of the total number of deliveries, especially if deliveries are normal and do not occur in a hospital.

Mortality/Morbidity

Patients who have a malignant hydatidiform mole, an invasive mole, or a choriocarcinoma should undergo a systematic search for metastases. Patients who have metastases are classified as high-risk or low-risk according to the National Institutes of Health classification. The criteria for high-risk metastatic gestational trophoblastic neoplasia include hepatic or brain metastasis, serum HCG titers greater than 40,000 mIU/mL prior to the initiation of chemotherapy, duration of disease longer than 4 months, prior unsuccessful chemotherapy, and malignant gestational trophoblastic neoplasia following a term pregnancy.

• Patients with malignant nonmetastatic or metastatic low-risk gestational trophoblastic neoplasia have an almost 100% probability of cure with chemotherapy. The probability of cure after chemotherapy for patients with metastatic high-risk gestational trophoblastic neoplasia is approximately 75%.
• The probability of a late recurrence after the patient has been in remission (normal serum beta-HCG titers) for 1 year is less than 1%.

Race

• International reports are conflicting as to whether ethnicity is an independent risk factor for the development of gestational trophoblastic neoplasia.
• In the United States, race does not appear to be a risk factor.

Sex

• Gestational trophoblastic neoplasia affects women during their reproductive years. However, placental site trophoblastic tumors have been diagnosed when patients were postmenopausal.

Age

• Hydatidiform mole is more frequent in teenagers and in women older than 40 years. The potential for malignant change is higher when a hydatidiform mole occurs in a woman older than 40 years.

CLINICAL

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History

• Patients with a hydatidiform mole present with signs and symptoms of pregnancy.
• • The most frequent symptom of gestational trophoblastic neoplasia (GTN) is abnormal uterine bleeding.
  • Patients have a history of amenorrhea. Occasionally, the typical hydatid vesicles (edematous villi) are passed through the vagina.
• Signs and symptoms of preeclampsia occur in up to one third of patients.
• Prolonged hyperemesis gravidarum is also common.
• Hyperthyroidism is found in up to 3% of patients. This is due to the production of human molar thyrotropin by the molar tissue and the similarities between HCG and thyroid-stimulating hormone (TSH).
• If metastases exist, signs and symptoms associated with the metastatic disease, such as hematuria, hemoptysis, abdominal pain, and neurologic symptoms, may be present.
• The more frequent use of early obstetrical ultrasound has resulted in the earlier diagnosis of hydatidiform mole prior to the onset of the above signs and symptoms.

Physical

• Suspect gestational trophoblastic neoplasia when a positive pregnancy test result occurs in the absence of a fetus.
• Uterine size could be larger, smaller, or equal to the estimated gestational age.
• The identification of hydatid vesicles in the vagina is diagnostic for hydatidiform mole.
• Enlarged ovaries secondary to theca lutein cysts are found in up to 20% of patients with hydatidiform mole.
• • These cysts are the result of stimulation of the ovaries by the high circulating levels of HCG.
  • The cysts regress after evacuation of the hydatidiform mole, but this process can take as long as 12 weeks.

Causes

• A hydatidiform mole occurs when a haploid sperm fertilizes an egg that has no maternal chromosomes and then duplicates its chromosomal complement.
• • Most complete hydatidiform moles are 46,XX, and all the chromosomes come from the male.
  • Of hydatidiform moles, 10-15% are 46,XY. This occurs when 2 sperm, 1 carrying an X and the other carrying a Y, fertilize an "empty" egg.
• Partial moles are 69,XXY, and 2 sets of chromosomes are of paternal origin.

DIFFERENTIALS

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Other Problems to be Considered

Intrauterine pregnancy
Tubal pregnancy

WORKUP

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Lab Studies

• Serum HCG is elevated and frequently higher than expected for the estimated gestational age. A serum HCG greater than 100,000 mIU/mL should raise the concern of gestational trophoblastic disease (GTD).
• A CBC count may help detect anemia secondary to vaginal bleeding.
• Liver enzymes may become elevated in the presence of metastasis to the liver.

Imaging Studies

• Pelvic ultrasound
• • In the presence of an elevated serum HCG titer, the absence of a fetus, and the characteristic sonographic appearance ("snowstorm pattern"), a hydatidiform mole is diagnosed.
  • The ultrasound helps identify the fluid-filled vesicles within the uterine cavity (see Image 2).
  • Ovarian theca lutein cysts are observed in up to 20% of patients with hydatidiform mole.
• Chest radiograph: This test is recommended because the lung is the most frequent site of metastasis.
• CT scan of the abdomen and pelvis with contrast and MRI of the head (preferable to CT)
• • CT and MRI are recommended if the patient has malignant gestational trophoblastic neoplasia (hydatidiform mole with metastasis to the lungs, choriocarcinoma, or persistent hydatidiform mole).
  • The lungs, lower genital tract, brain, liver, kidney, and gastrointestinal tract are frequent sites of metastases.

Procedures

• Evacuation of the uterus is performed with suction and sharp curettage.
• • The tissue is sent for histopathologic examination.
  • Examination reveals a hydatidiform mole (complete or partial) or a choriocarcinoma.
• Rarely is a histopathologic diagnosis of an invasive mole made on a dilation and curettage (D&C) specimen because this requires the identification of destructive invasion of the myometrium by the trophoblasts. Scant or no myometrium is recovered on a D&C specimen.

Histologic Findings

Complete hydatidiform moles have edematous placental villi, hyperplasia of the trophoblasts, and lack or scarcity of fetal blood vessels.

In the incomplete or partial hydatidiform mole, scalloping of the villi and trophoblastic inclusions occur within the villi. Fetal blood vessels are present.

In a hydropic degeneration of a normal pregnancy, edema of the villi is present, but no trophoblastic hyperplasia. Ghost villi may be observed.

The invasive mole has the same appearance as the hydatidiform mole, but the myometrium is invaded with the presence of hemorrhage and tissue necrosis.

Although the choriocarcinoma has no chorionic villi, it has sheets of trophoblasts, hemorrhage, and necrosis. In the placental site trophoblastic tumors, intermediate trophoblasts are found between myometrial fibers, without tissue necrosis.

TREATMENT

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Medical Care

• Emergency department care involves starting intravenous (IV) fluids (crystalloids) and sending blood for type and antibody screen. Rh-negative patients should receive anti–RhD immune globulin, such as RhoGAM, if not already immunized.
• Patients with benign gestational trophoblastic disease (GTD) do not require medical therapy. Because 20% of patients with hydatidiform mole develop malignant disease, such as persistent hydatidiform mole with or without metastasis, some have suggested the use of a prophylactic dose of methotrexate (MTX) in noncompliant patients. However, observing patients with weekly serum HCG titers is preferable, and only patients with rising or plateauing titers, as occurs in patients with malignant gestational trophoblastic neoplasia (GTN), should be treated with chemotherapy.
• Patients with malignant nonmetastatic gestational trophoblastic neoplasia or metastatic low-risk gestational trophoblastic neoplasia are treated with single-agent chemotherapy. Many in the United States prefer MTX. However, actinomycin D can be used in patients with poor liver function. During treatment, the serum HCG titers are monitored every week. One additional course of chemotherapy is administered after a normal serum HCG titer. After 3-4 normal serum HCG titers, the titers are followed once per month for 1 year. A switch from MTX to actinomycin D is made if the patient receiving MTX for nonmetastatic or metastatic low-risk gestational trophoblastic neoplasia develops rising or plateauing serum HCG titers.
• Patients with high-risk metastatic gestational trophoblastic neoplasia are subdivided into 2 groups: those with a WHO score of less than 8 and those with a score of 8 or higher and a high risk of therapy failure.
• • In patients with a WHO score of less than 8, a combination of MTX, actinomycin D, and cyclophosphamide can be used. This is known as the MAC regimen. This chemotherapeutic regimen is administered every 19-21 days (from day 1 of the previous chemotherapy cycle) until the serum HCG titers normalize. In patients with a low WHO score, one additional course of MAC is administered after a normal serum HCG titer. Some prefer to treat these patients with single-agent chemotherapy (MTX or actinomycin) because their chances of achieving a cure are high.
  • Patients with WHO scores of 8 or higher are treated with a combination of etoposide, MTX, and actinomycin D administered in the first week of a 2-week cycle and cyclophosphamide and vincristine (Oncovin) administered in the second week. This is known as the EMA-CO regimen. Some substitute cisplatin and etoposide for cyclophosphamide and vincristine during the second week. This is known as the EMA-CE regimen. Some reserve the EMA-CE regimen for patients in whom EMA-CO fails. Two additional courses of EMA-CO or EMA-CE are administered after a normal serum HCG titer in very high-risk patients. Patients with metastasis to the brain receive whole brain irradiation (3000 cGy) in combination with chemotherapy. Corticosteroids (Decadron) with systemic effect are administered to reduce brain edema. Patients with liver metastasis are considered for liver irradiation (2000 cGy).

Surgical Care

• The treatment of a hydatidiform mole is evacuation of the uterus by suction and sharp curettage.
• • To avoid excessive bleeding, oxytocin is administered intravenously at the initiation of the suctioning of the uterine contents.
  • The largest possible suction curet is used, usually a 10F or 12F.

Consultations

An obstetrician and gynecologist may be consulted.

MEDICATION

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The goals of pharmacotherapy are to reduce morbidity and to eradicate the neoplasm.

Drug Category: Antineoplastics

Gestational trophoblastic tumors are sensitive to many antineoplastic agents, especially those that act in the S phase or the M phase of the cell cycle.

Drug Category: Vitamins

May be used to alleviate toxic adverse effects of MTX. MTX blocks conversion of uridine to thymidine, one of the building blocks of DNA. Folinic acid provides a methyl group to uridine monophosphate, thus forming thymidine monophosphate, overcoming effects of MTX on tetrahydrofolic acid reductase.

FOLLOW-UP

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Further Outpatient Care

• In patients with benign gestational trophoblastic disease (GTD), who do not require chemotherapy, obtain follow-up serum HCG titers once per week until 3-4 normal values are obtained. Then, obtain them once per month for 6 months. Have patients use reliable contraception, such as oral contraceptives or depot progesterone injections, during the period of follow-up care.
• Patients with malignant gestational trophoblastic neoplasia should have follow-up serum HCG titers once per week until 4 normal values are obtained. Then, obtain them once per month for 1 year. Have patients use a reliable method of contraception.

In/Out Patient Meds

• During the period of follow-up care, patients with gestational trophoblastic disease should use a reliable method of contraception, such as oral contraceptives or depot progesterone.
• The serum HCG titers are critical in monitoring the status of the disease, and a normal intrauterine pregnancy interferes with this critical monitoring tool.

Complications

• Plateauing or rising serum HCG titers during the period of follow-up care may indicate a normal intrauterine pregnancy or gestational trophoblastic neoplasia with or without metastasis.

Prognosis

• Nonmetastatic gestational trophoblastic neoplasia has a cure rate with chemotherapy of close to 100%.
• Metastatic low-risk gestational trophoblastic neoplasia has a cure rate with chemotherapy of close to 100%.
• Metastatic high-risk gestational trophoblastic neoplasia has a cure rate with chemotherapy of approximately 75%.
• After 12 months of normal HCG titers, less than 1% of patients with malignant gestational trophoblastic neoplasia have recurrences.

Patient Education

• The rate of occurrence of a repeat molar pregnancy is approximately 1-2%.
• The rate of occurrence of a repeat molar pregnancy in a patient with a history of 2 previous hydatidiform moles is approximately 10-20%.
• The pregnancy rate after chemotherapy with MTX and cyclophosphamide is 80%. Of women treated with EMA-CO, 46% have had at least 1 live birth after chemotherapy.
• Patients who become pregnant after treatment for gestational trophoblastic neoplasia should have a pelvic ultrasound early during the pregnancy to confirm that the pregnancy is normal.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Failure to perform a systematic search for metastases in patients who have a malignant hydatidiform mole, an invasive mole, or a choriocarcinoma

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Histologic section of a complete hydatidiform mole stained with hematoxylin and eosin. Villi of different sizes are present. The large villous in the center exhibits marked edema with a fluid-filled central cavity known as cisterna. Marked proliferation of the trophoblasts is observed. The syncytiotrophoblasts stain purple, while the cytotrophoblasts have a clear cytoplasm and bizarre nuclei. No fetal blood vessels are in the mesenchyme of the villi.
	View Full Size Image
Media type:  Photo

Media file 2:  Real-time ultrasound image of a hydatidiform mole. The dark circles of varying sizes at the top center are the edematous villi.
	View Full Size Image
Media type:  Image

REFERENCES

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Article Last Updated: Jan 26, 2007