Gestational Trophoblastic Neoplasia

Synonyms and related keywords: gestational trophoblastic disease, gestational trophoblastic tumors, GTD, GTN



INTRODUCTION

Background: Gestational trophoblastic neoplasia (GTN) can be benign or malignant. Histologically, it is classified into a hydatidiform mole, an invasive mole (chorioadenoma destruens), choriocarcinoma, and a placental site trophoblastic tumor (PSTT). Hydatidiform mole is the most common form of GTN. 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 GTN 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.

PSTT is a rare form of GTN, 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 cases of PSTT. The treatment of PSTT 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 GTN are the lungs, lower genital tract, brain, liver, kidney, and gastrointestinal tract.

Frequency:

• In the US: Hydatidiform moles occur in 1 in 2000 deliveries, or 1 in 1200 to 1 in 1300 pregnancies.

• Internationally: 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 GTN 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 GTN following a term pregnancy.

• Patients with malignant nonmetastatic or metastatic low-risk GTN have an almost 100% probability of cure with chemotherapy. The probability of cure after chemotherapy for patients with metastatic high-risk GTN 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 GTN.

• In the United States, race does not appear to be a risk factor.

Sex:

• GTN affects women during their reproductive years. However, PSTTs 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

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.

• A history of amenorrhea exists. 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 also is 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 GTN when a positive pregnancy test 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

Abortion
Ectopic Pregnancy

Other Problems to be Considered:

Intrauterine pregnancy
Tubal pregnancy

WORKUP

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 neoplasia (GTN).

• 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.

• Ovarian theca lutein cysts are observed in 20% of patients with hydatidiform mole.

• Chest x-ray: This test is recommended because the lung is the most frequent site of metastasis.

• CT scan of the head, abdomen, and pelvis with contrast

• This is recommended if the patient has malignant GTN (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.

• This exhibits 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 PSTT, intermediate trophoblasts are found between myometrial fibers, without tissue necrosis.

TREATMENT

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 neoplasia (GTN) 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 GTN, should be treated with chemotherapy.

• Patients with malignant nonmetastatic GTN or metastatic low-risk GTN 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 GTN develops rising or plateauing serum HCG titers.

• Patients with high-risk metastatic GTN 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 21 days 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 number 10 or 12F.

Consultations: An obstetrician and gynecologist may be consulted.

MEDICATION

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 Name	Methotrexate (Folex PFS, Rheumatrex) -- Used both as single agent and in multiagent regimens for the treatment of malignant GTN.
Adult Dose	0.4 mg/kg IV/IM qd for 5 d when used as single agent (not to exceed 30 mg) 0.3 mg/kg IV/IM qd for 5 d when used in MAC regimen (not to exceed 15 mg); may repeat 14-16 d after last dose 50 mg/m2 IV/IM every week is alternative single-agent regimen 100 mg/m2 IV as 12-h infusion on day 1 of EMA-CO regimen
Pediatric Dose	Children: Not established Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity; hepatic insufficiency
Interactions	Salicylates, procarbazine, sulfonamides, and NSAIDs may increase effects and toxicity; folic acid and its derivatives contained in some vitamins may decrease response to MTX; may increase plasma levels of thiopurines; coadministration with etretinate may increase hepatotoxicity of MTX
Pregnancy	X - Contraindicated in pregnancy
Precautions	Monitor liver enzymes and CBC; most common adverse effects are hematologic and gastrointestinal; may cause oral mucositis and hepatic toxicity; liver irradiation can increase hepatotoxicity

Drug Name	Actinomycin D (Dactinomycin) -- Intercalates between guanine and cytosine base pairs, inhibiting DNA and RNA synthesis and protein synthesis. Use as single agent or as part of multiagent regimen for treatment of malignant GTN.
Adult Dose	0.01 mg/kg IV qd for 5 d as part of MAC regimen or as single agent (not to exceed 0.5 mg); repeat 14-16 d after last dose Alternatively, 0.5 mg IV on days 1 and 2 in EMA-CO regimen
Pediatric Dose	less than 6 months: Not recommended >6 months: Administer as in adults
Contraindications	Documented hypersensitivity; herpes zoster; chickenpox
Interactions	Concurrent use with liver irradiation or MTX increases risk of developing hepatic toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Infusion must be IV because it is a vesicant; monitor CBC and liver enzymes (can cause bone marrow depression and hepatotoxicity); premedicate against nausea; unsafe to use in normal pregnancies, especially in first trimester; use as antineoplastic in second and third trimester of pregnancy should be under the supervision of a qualified oncologist and qualified obstetrician after proper patient counseling

Drug Name	Cyclophosphamide (Cytoxan, Neosar) -- Chemically related to nitrogen mustards. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. Part of multiagent chemotherapy regimens used to treat high-risk metastatic GTN.
Adult Dose	5 mg/kg qd for 5 d as part of MAC regimen (not to exceed 250 mg) Course is repeated 14-16 d after last dose 600 mg/m2 IV on day 8 of EMA-CO regimen
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; severely depressed bone marrow function
Interactions	Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects of cyclophosphamide; may reduce digoxin serum levels and antimicrobial effects of quinolones; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity of cyclophosphamide; thiazide diuretics may prolong cyclophosphamide-induced leukopenia; potentiates effect of succinylcholine
Pregnancy	D - Unsafe in pregnancy
Precautions	Preinfusion and postinfusion hydration prevents hemorrhagic cystitis; monitor CBC; premedicate against nausea; regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis

Drug Name	Etoposide (Toposar, VePesid) -- Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in late S or early G2 portion of cell cycle. One of the drugs in multiagent chemotherapy regimens used to treat patients with high-risk metastatic GTN.
Adult Dose	100 mg/m2 IV on days 1 and 2 of EMA-CO regimen and on day 8 of EMA-CE regimen
Pediatric Dose	Children: Not established Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity; intrathecal administration may cause death
Interactions	May prolong effects of warfarin and increase clearance of MTX
Pregnancy	D - Unsafe in pregnancy
Precautions	Mix in 500 mL of isotonic sodium chloride solution and infuse over 1 h to prevent hypotension; monitor CBC (can cause severe myelosuppression); premedicate against nausea

Drug Name	Vincristine (Oncovin, Vincasar PFS) -- Blocks mitosis; one of the drugs included in multiagent chemotherapy regimens used to treat patients with high-risk metastatic GTN.
Adult Dose	1 mg/m2 IV on day 8 of EMA-CO regimen (not to exceed 2 mg)
Pediatric Dose	Children: Not established Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity; patients with demyelinating form of Charcot-Marie-Tooth syndrome
Interactions	Concurrent use with itraconazole can cause earlier onset and/or increase severity of adverse neuromuscular effects; acute pulmonary reaction may occur when administered concurrently with mitomycin-C
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution with severe cardiopulmonary or hepatic impairment and preexisting neuromuscular disease; administration must be IV

Drug Name	Cisplatin (Platinol) -- Inhibits DNA synthesis and, thus, cell proliferation, by causing DNA cross-links and denaturation of double helix. Effective antineoplastic used in patients with chemotherapy-resistant malignant GTN.
Adult Dose	75-80 mg/m2 IV on day 8 of EMA-CE regimen
Pediatric Dose	Children: Not established Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity; preexisting renal insufficiency
Interactions	May cause decrease in plasma levels of anticonvulsants
Pregnancy	D - Unsafe in pregnancy
Precautions	Can cause nephrotoxicity and neurotoxicity; monitor serum creatinine and electrolytes; administer prechemotherapy and postchemotherapy hydration; potent emetic; premedicate with combination of antiemetics; hydroxylated cisplatinum is more nephrotoxic than chlorinated cisplatinum; should be mixed in isotonic sodium chloride solution or hypertonic saline for infusion

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.

Drug Name	Leucovorin; folinic acid (Wellcovorin) -- Used to prevent toxicity from high doses of MTX.
Adult Dose	15 mg PO/IM q12h for 4 doses starting 24 h after administration of MTX as part of EMA-CO and EMA-CE regimens
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	At high doses, may counteract effect of some anticonvulsants (phenobarbital, phenytoin, primidone); increases 5-fluorouracil toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Do not administer intrathecally or intraventricularly; not to be used for treatment of megaloblastic anemia secondary to vitamin B-12 deficiency

FOLLOW-UP

Further Outpatient Care:

• In patients with benign gestational trophoblastic neoplasia (GTN), such as those not requiring 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 GTN 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 GTN 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 persistent GTN with or without metastasis.

Prognosis:

• Nonmetastatic GTN has a cure rate with chemotherapy of close to 100%.

• Metastatic low-risk GTN has a cure rate with chemotherapy of close to 100%.

• Metastatic high-risk GTN has a cure rate with chemotherapy of approximately 75%.

• After 12 months of normal HCG titers, less than 1% of patients with malignant GTN 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 GTN should have a pelvic ultrasound early during the pregnancy to confirm that the pregnancy is normal.

MISCELLANEOUS

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