eMedicine Specialties > Obstetrics and Gynecology > Gynecologic Oncology

Gestational Trophoblastic Neoplasia

Enrique Hernandez, MD, FACOG, FACS, Chairman, Department of Obstetrics and Gynecology, Director of Gynecologic Oncology, Abraham Roth Professor of Obstetrics, Gynecology and Reproductive Science, Professor of Pathology, Temple University Hospital, Temple University School of Medicine

Updated: Sep 24, 2008

Introduction

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 GTN. While invasive mole and choriocarcinoma are malignant, a hydatidiform mole can behave in a malignant or benign fashion.

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.

Pathophysiology

A hydatidiform mole is considered malignant when the serum hCG levels plateau or rise during the follow-up period and an intervening pregnancy is excluded. This occurs in 15-20% of hydatidiform moles.^1,2,3

A hydatidiform mole with a fetus or fetal tissue and a triploid karyotype is known as a partial or incomplete mole. Partial moles also have malignant potential, but only 2-3% become malignant.^4,5,6 Cases of partial hydatidiform moles with lung metastasis have been reported and at least one case of choriocarcinoma on a biopsy from a vaginal metastasis has been reported in a patient being observed for a partial hydatidiform mole.^7,8

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, 3% by ectopic pregnancy, and the other 22% by a full-term pregnancy.¹ Choriocarcinoma has also been associated with ectopic pregnancy with a theoretic incidence of 1 in 5333 ectopic pregnancies.⁹

Placental site trophoblastic tumor is a rare form of gestational trophoblastic neoplasia, with slightly more than 200 cases reported in the literature.^10,11 In patients with PSTT, intermediate trophoblasts are found infiltrating the myometrium without causing tissue destruction. The intermediate trophoblasts contain human placental lactogen (hPL).¹² These patients have persistent low levels of serum hCG (100-1000 mIU/mL). However, serum hCG levels as high as 108,000 mIU/mL have been reported in patients with PSTT.¹³ The treatment of PSTT is hysterectomy with ovarian conservation.¹⁴ If the tumor recurs or metastases are present at initial diagnosis, chemotherapy is administered with variable results.^15,16 Radiation therapy may provide local control.

In this microphotograph of a choriocarcinoma metastatic to the brain, the neuropil is seen on the right and the biphasic (2 cell populations) choriocarcinoma is seen to the left with hemorrhage at the left border of the photograph (H&E stain).

Frequency

United States

Gestational trophoblastic neoplasia is diagnosed in 15-20% of patients with a complete hydatidiform mole and 2% of partial hydatidiform moles. Lung metastases are found in 4-5% of patients with complete hydatidiform moles and rarely in cases of partial hydatidiform moles.

Choriocarcinoma occurs in 1 out of 40 hydatidiform moles and in 1 out of 20,000-40,000 pregnancies.^1,17 However, only 1 out of 160,000 term pregnancies is followed by a choriocarcinoma.¹⁸

International

The international rate of choriocarcinoma has been reported to be as high as 1 in 500-600 pregnancies in India to 1 in 50,000 pregnancies in Mexico, Paraguay, and Sweden.^17,19,20 These differences are probably due to differences in methodology (eg, identification of cases, accuracy of denominator).^17,19

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.² The criteria for high-risk metastatic gestational trophoblastic neoplasia include hepatic or brain metastasis, serum hCG levels 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%.²¹
• 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%.^2,22

Race

• Little information is available on international ethnic or racial differences of the incidence of choriocarcinoma. In Singapore, Malaysians have the highest incidence.¹⁹
• In the United States, African Americans have the highest incidence of choriocarcinoma and the lowest survival rates.²³

Sex

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

Age

The incidence of choriocarcinoma increases with age and is 5-15 times higher in women 40 years and older than in younger women.¹⁹

Clinical

History

Most cases of gestational trophoblastic neoplasia are diagnosed when the serum hCG levels plateau or rise in patients being observed after the diagnosis of hydatidiform mole. If metastases are present, signs and symptoms associated with the metastatic disease, such as hemoptysis, abdominal pain, hematuria, and neurologic symptoms, may be present.

Physical

• Metastasis to the lower genital tract present as purple to blue-black papules or nodules. These are extremely vascular and might bleed profusely if biopsied.²⁴
• Abdominal tenderness may be present if  liver or gastrointestinal metastases have occurred.
• Abdominal guarding and rebound tenderness may be present if a hemoperitoneum has occurred due to bleeding from an abdominal metastasis. Bleeding from a metastasis could also result in signs and symptoms of hemorrhagic shock.^25,26
• Neurologic deficits, from lethargy to coma, can be encountered if brain metastasis has occurred.
• Jaundice may be present if liver metastasis causes biliary obstruction.

Causes

Why some hydatidiform moles become malignant and others do not is unknown. However, mounting evidence shows different molecular profiles between nonmalignant and malignant gestational trophoblastic disease.^27,28,29

Differential Diagnoses

Other Problems to Be Considered

• The differential diagnosis will depend on whether or not metastasis has occurred and to what organs.
• In the absence of an identifiable preceding pregnancy, the possibility of an hCG-secreting germ cell tumor needs to be entertained. In the presence of stable low levels of serum hCG, the differential diagnosis includes a false positive or "phantom" hCG, pituitary hCG, or quiescent gestational trophoblastic disease.^30,31,32
• A normal intrauterine pregnancy needs to be excluded if the serum hCG levels start to rise in a patient being observed after evacuation of a hydatidiform mole.

Workup

Laboratory Studies

• Serum hCG is used to assess response to therapy and disease status. 
• A CBC may help detect anemia secondary to bleeding.
• Liver enzymes may become elevated in the presence of metastasis to the liver.

Imaging Studies

• Pelvic ultrasonography: This may show persistent molar tissue in the uterus.
• Chest radiograph: This test is recommended because the lung is the most frequent site of metastasis.
• CT scan of the chest (optional): Micrometastases are present in approximately 40-45% of women with nonmetastatic gestational trophoblastic neoplasia (GTN) who have normal chest radiograph findings.^33,34 The significance of this is not clear. However, having metastasis elsewhere is extremely rare if pulmonary or lower genital tract metastases has not occurred. If metastases are found on chest CT and not on chest radiograph, they cannot be used for purpose of staging.^1,2,35
• 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 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

• Suction and sharp curettage could be performed in patients being observed for a hydatidiform mole who have persistent vaginal bleeding and tissue within the endometrial cavity on pelvic ultrasonography.
• A uterine dilatation and curettage (D&C) performed in a woman with abnormal vaginal bleeding and a positive pregnancy test result may reveal a choriocarcinoma.
• A D&C may be part of the evaluation of a patient with an elevated serum hCG levels of unknown origin
  • The tissue is sent for histopathologic examination.
  • Examination may reveal a hydatidiform mole (complete or partial) or a choriocarcinoma.
• Rarely is a histopathologic diagnosis of an invasive mole made on a D&C specimen because this requires the identification of destructive invasion of the myometrium by the trophoblasts. Typically, scant or no myometrium is recovered on a D&C specimen.
• Rarely is the diagnosis of placental site trophoblastic tumor (PSTT) made on a D&C specimen since this usually presents as intermediate trophoblasts infiltrating the myometrium.
• In a patient with GTN, a hysterectomy will reduce the total number of chemotherapy cycles required to achieve a remission.^36,37
• A hysterectomy is the treatment of choice for PSTT; the ovaries do not need to be removed if the patient is premenopausal.¹⁴

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 placental site trophoblastic tumor (PSTT), intermediate trophoblasts are found between myometrial fibers, without tissue necrosis.

Staging

The official International Federation of Gynecology and Obstetrics staging of gestational trophoblastic neoplasia is as follows:^1,35

• 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 6 or less, the substage is A (eg, IIIA is equal to lung metastasis with a prognostic score of 6 or less). If the prognostic score is 7 or greater, the substage is B.³⁸

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

Treatment

Medical Care

• Patients with 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 in noncompliant patients.^39,40 However, observing patients with weekly serum hCG levels is preferable, and only patients with rising or plateauing titers, as occurs in patients with gestational trophoblastic neoplasia (GTN), should be treated with chemotherapy.¹
• Patients with nonmetastatic GTN or metastatic low-risk GTN are treated with single-agent chemotherapy.^{41,42,43,44,45,46} Many in the United States prefer methotrexate. However, actinomycin D can be used in patients with poor liver function. During treatment, the serum hCG levels are monitored every week. One additional course of chemotherapy is administered after a normal serum hCG level. After 3-4 normal serum hCG levels, the levels are observed once per month for 1 year. A switch from methotrexate to actinomycin D is made if the patient receiving methotrexate for nonmetastatic or metastatic low-risk GTN develops rising or plateauing serum hCG levels.
• A randomized clinical trial comparing 30 mg/m² methotrexate given weekly to patients with low-risk GTN versus 1.25 mg/m² of actinomycin D given every other week showed a higher complete response rate with actinomycin D.⁴⁷
• Patients with high-risk metastatic GTN are subdivided into 2 groups: those with a WHO score of less than 7 and those with a score of 7 or higher and who are at high risk of therapy failure.  
  • Patients with a WHO score of less than 7 can be treated with single-agent chemotherapy (methotrexate or actinomycin) because their chances of achieving a cure are high.³⁸ The authors have treated patients with high-risk metastatic disease, based on the clinical classification, and a WHO score of less than 7 with a combination of methotrexate, actinomycin D, and cyclophosphamide. 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.^2,48 In patients with a low WHO score, one additional course of chemotherapy is administered after a normal serum hCG level.
  • Patients with WHO scores of 7 or higher are treated with a combination of etoposide, methotrexate, and actinomycin D administered in the first week of a 2-week cycle and cyclophosphamide and vincristine (Oncovin) administered in the second week.^49,50,51 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.⁵² 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 level. Patients with metastasis to the brain receive whole brain irradiation (3000 cGy) in combination with chemotherapy.^53,54,55 Corticosteroids (dexamethasone) with systemic effect are administered to reduce brain edema. Patients with liver metastasis are considered for liver irradiation (2000 cGy).⁵⁶
  • After achieving 3-4 consecutive weekly normal serum hCG levels, patients with stage IV GTN are observed with monthly serum hCG levels for 2 years. If the levels begin to rise during follow-up, the patient is evaluated for possible intervening pregnancy, or persistent or recurrent disease.

Surgical Care

• A hysterectomy may be necessary in case of uncontrolled vaginal bleeding. Hysterectomy may reduce the total number of chemotherapy cycles needed to achieve remission.^36,37
• Uterine or hypogastric artery ligation or embolization of feeding vessels may be needed to control hemorrhage. Hepatic artery embolization has been used successfully to control hemorrhage from hepatic metastases.²⁵
• A repeat D&C in the presence of persistent tissue on pelvic ultrasonography may reduce the number of chemotherapy cycles needed to achieve remission.⁵⁷
• Craniotomy may be needed to control bleeding and provide decompression.^58,50
• Resection of solitary metastasis (eg, thoracotomy) or disease within the myometrium may help achieve a remission.^59,60,61

Consultations

A gynecologic oncologist experienced in managing GTN should be consulted.

Diet

No restrictions

Activity

No restrictions

Medication

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

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.

Methotrexate (Folex PFS, Rheumatrex)

Used both as single agent and in multiagent regimens for the treatment of malignant GTN.

Dosing

Adult

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
30-50 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

Children: Not established
Adolescents: Administer as in adults

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

Contraindications

Documented hypersensitivity; hepatic insufficiency

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

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

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.

Dosing

Adult

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, 1.25 mg/m² every other week in patients with on-metastatic GTN or low-risk metastatic GTN. 0.5 mg IV on days 1 and 2 in EMA-CO regimen

Pediatric

<6 months: Not recommended
>6 months: Administer as in adults

Interactions

Concurrent use with liver irradiation or MTX increases risk of developing hepatic toxicity

Contraindications

Documented hypersensitivity; herpes zoster; chickenpox

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

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.

Dosing

Adult

5 mg/kg IV 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

Administer as in adults

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

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

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

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.

Dosing

Adult

100 mg/m² IV on days 1 and 2 of EMA-CO regimen and on day 8 of EMA-CE regimen

Pediatric

Children: Not established
Adolescents: Administer as in adults

Interactions

May prolong effects of warfarin and increase clearance of MTX

Contraindications

Documented hypersensitivity; intrathecal administration may cause death

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

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

Vincristine (Oncovin, Vincasar PFS)

Blocks mitosis; one of the drugs included in multiagent chemotherapy regimens used to treat patients with high-risk metastatic GTN.

Dosing

Adult

1 mg/m² IV on day 8 of EMA-CO regimen (not to exceed 2 mg)

Pediatric

Children: Not established
Adolescents: Administer as in adults

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

Contraindications

Documented hypersensitivity; patients with demyelinating form of Charcot-Marie-Tooth syndrome

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution with severe cardiopulmonary or hepatic impairment and preexisting neuromuscular disease; administration must be IV

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.

Dosing

Adult

75-80 mg/m² IV on day 8 of EMA-CE regimen

Pediatric

Children: Not established
Adolescents: Administer as in adults

Interactions

May cause decrease in plasma levels of anticonvulsants

Contraindications

Documented hypersensitivity; preexisting renal insufficiency

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

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

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.

Leucovorin; folinic acid (Wellcovorin)

Used to prevent toxicity from high doses of MTX.

Dosing

Adult

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

Administer as in adults

Interactions

At high doses, may counteract effect of some anticonvulsants (phenobarbital, phenytoin, primidone); increases 5-fluorouracil toxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

Patients with gestational trophoblastic neoplasia (GTN) should have follow-up serum hCG levels measured once per week until 4 normal values are obtained. Then, hCG levels should be obtained once per month for 1 year. Patients with stage IV disease are observed with monthly serum hCG level monitoring for 2 years after 3-4 consecutive weekly normal levels. Patients should use a reliable method of contraception.

Inpatient & Outpatient Medications

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 levels are critical in monitoring the status of the disease, and a normal intrauterine pregnancy interferes with this critical monitoring tool.

Transfer

Patients with resistant disease may benefit from consultation at a regional trophoblastic disease center.

Deterrence/Prevention

• The early diagnosis of GTN by the close follow-up of serum hCG levels after the evacuation of a hydatidiform mole results in therapeutic intervention prior to the development of high-risk disease.
• In patients with a history of gestational trophoblastic disease (GTD), measuring serum hCG levels 6 weeks after any subsequent pregnancy should be strongly considered to exclude occult GTN.

Complications

• Plateauing or rising serum hCG levels during the period of follow-up care may indicate a normal intrauterine pregnancy or GTN with or without metastasis.
• Etoposide is associated with an increased risk of developing leukemia. It should be used only in patients with high-risk disease.⁶²
• The rate of abnormal pregnancies (spontaneous abortions, stillbirths, repeat GTD) is higher if a subsequent pregnancy occurs within 6 months of completing chemotherapy, compared with pregnancies that occur after 12 months.⁶³

Prognosis

• Nonmetastatic GTN has a cure rate of close to 100% with chemotherapy treatment.
• Metastatic low-risk GTN has a cure rate of close to 100% with chemotherapy treatment.
• Metastatic high-risk GTN has a cure rate of approximately 75% with chemotherapy treatment.
• After 12 months of normal hCG levels, less than 1% of patients with GTN have recurrences.

Patient Education

• The pregnancy rate after chemotherapy with methotrexate and cyclophosphamide is 80%. Of women treated with EMA-CO, 46% have had at least 1 live birth after chemotherapy.^64,65
• Patients who become pregnant after treatment for GTN should have pelvic ultrasonography early during the pregnancy to confirm that the pregnancy is normal.
• A serum hCG level should be obtained 6 weeks after delivery of a subsequent pregnancy to exclude repeat GTN.

Miscellaneous

Medicolegal Pitfalls

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

Special Concerns

The salvage rate of patients who relapsed after chemotherapy with EMA/CO is very high. Other chemotherapy protocols with or without surgery can be tried.^66,48 This includes high-dose chemotherapy with peripheral stem cell transplant.⁶⁷

Multimedia

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.

Media file 2: In this microphotograph of a choriocarcinoma metastatic to the brain, the neuropil is seen on the right and the biphasic (2 cell populations) choriocarcinoma is seen to the left with hemorrhage at the left border of the photograph (H&E stain).

References

1. Smith HO, Kohorn E, Cole LA. Choriocarcinoma and gestational trophoblastic disease. Obstet Gynecol Clin North Am. Dec 2005;32(4):661-84. [Medline].

2. Soper JT. Gestational trophoblastic disease. Obstet Gynecol. Jul 2006;108(1):176-87. [Medline].

3. Yuen BH, Cannon W. Molar pregnancy in British Columbia: estimated incidence and postevacuation regression patterns of the beta subunit of human chorionic gonadotropin. Am J Obstet Gynecol. Feb 1 1981;139(3):316-9. [Medline].

4. Goto S, Yamada A, Ishizuka T, et al. Development of postmolar trophoblastic disease after partial molar pregnancy. Gynecol Oncol. Feb 1993;48(2):165-70. [Medline].

5. Hancock BW, Tidy JA. Current management of molar pregnancy. J Reprod Med. May 2002;47(5):347-54. [Medline].

6. Watson EJ, Hernandez E, Miyazawa K. Partial hydatidiform moles: a review. Obstet Gynecol Surv. Sep 1987;42(9):540-4. [Medline].

7. Cheung AN, Khoo US, Lai CY, et al. Metastatic trophoblastic disease after an initial diagnosis of partial hydatidiform mole: genotyping and chromosome in situ hybridization analysis. Cancer. Apr 1 2004;100(7):1411-7. [Medline].

8. Menczer J, Girtler O, Zajdel L, et al. Metastatic trophoblastic disease following partial hydatidiform mole: case report and literature review. Gynecol Oncol. Aug 1999;74(2):304-7. [Medline].

9. Lurain JR, Sand PK, Brewer JI. Choriocarcinoma associated with ectopic pregnancy. Obstet Gynecol. Aug 1986;68(2):286-7. [Medline].

10. Baergen RN, Rutgers JL, Young RH, et al. Placental site trophoblastic tumor: A study of 55 cases and review of the literature emphasizing factors of prognostic significance. Gynecol Oncol. Mar 2006;100(3):511-20. [Medline].

11. Tsuji Y, Tsubamoto H, Hori M, et al. Case of PSTT treated with chemotherapy followed by open uterine tumor resection to preserve fertility. Gynecol Oncol. Dec 2002;87(3):303-7. [Medline].

12. Nigam S, Singhal N, Kumar Gupta S, et al. Placental site trophoblastic tumor in a postmenopausal female--a case report. Gynecol Oncol. May 2004;93(2):550-3. [Medline].

13. Hassadia A, Gillespie A, Tidy J, et al. Placental site trophoblastic tumour: clinical features and management. Gynecol Oncol. Dec 2005;99(3):603-7. [Medline].

14. Berkowitz BJ, Jones JG, Merkatz IR, et al. Ovarian conservation in placental site trophoblastic tumor. Gynecol Oncol. May 1990;37(2):239-43. [Medline].

15. Zhao J, Xiang Y, Wan XR, et al. Clinical and pathologic characteristics and prognosis of placental site trophoblastic tumor. J Reprod Med. Dec 2006;51(12):939-44. [Medline].

16. Papadopoulos AJ, Foskett M, Seckl MJ, et al. Twenty-five years' clinical experience with placental site trophoblastic tumors. J Reprod Med. Jun 2002;47(6):460-4. [Medline].

17. Grimes DA. Epidemiology of gestational trophoblastic disease. Am J Obstet Gynecol. Oct 1 1984;150(3):309-18. [Medline].

18. McDonald TW, Ruffolo EH. Modern management of gestational trophoblastic disease. Obstet Gynecol Surv. Feb 1983;38(2):67-83. [Medline].

19. Palmer JR. Advances in the epidemiology of gestational trophoblastic disease. J Reprod Med. Mar 1994;39(3):155-62. [Medline].

20. Chakrabarti BK, Mondal NR, Chatterjee T. Gestational trophoblastic tumor at a tertiary level cancer center: a retrospective study. J Reprod Med. Nov 2006;51(11):875-8. [Medline].

21. Soper JT, Evans AC, Conaway MR, et al. Evaluation of prognostic factors and staging in gestational trophoblastic tumor. Obstet Gynecol. Dec 1994;84(6):969-73. [Medline].

22. Mutch DG, Soper JT, Babcock CJ, et al. Recurrent gestational trophoblastic disease. Experience of the Southeastern Regional Trophoblastic Disease Center. Cancer. Sep 1 1990;66(5):978-82. [Medline].

23. Smith HO, Qualls CR, Prairie BA, et al. Trends in gestational choriocarcinoma: a 27-year perspective. Obstet Gynecol. Nov 2003;102(5 Pt 1):978-87. [Medline].

24. Yingna S, Yang X, Xiuyu Y, et al. Clinical characteristics and treatment of gestational trophoblastic tumor with vaginal metastasis. Gynecol Oncol. Mar 2002;84(3):416-9. [Medline].

25. Grumbine FC, Rosenshein NB, Brereton HD, et al. Management of liver metastasis from gestational trophoblastic neoplasia. Am J Obstet Gynecol. Aug 15 1980;137(8):959-61. [Medline].

26. Soper JT, Mutch DG, Chin N, et al. Renal metastases of gestational trophoblastic disease: a report of eight cases. Obstet Gynecol. Nov 1988;72(5):796-8. [Medline].

27. Fulop V, Mok SC, Berkowitz RS. Molecular biology of gestational trophoblastic neoplasia: a review. J Reprod Med. Jun 2004;49(6):415-22. [Medline].

28. Fong PY, Xue WC, Ngan HY, et al. Mcl-1 expression in gestational trophoblastic disease correlates with clinical outcome: a differential expression study. Cancer. Jan 15 2005;103(2):268-76. [Medline].

29. Kim SJ, Park SE, Lee C, et al. Altered imprinting, promoter usage, and expression of insulin-like growth factor-II gene in gestational trophoblastic diseases. Gynecol Oncol. Mar 2003;88(3):411-8. [Medline].

30. Olsen TG, Barnes AA, King JA. Elevated HCG outside of pregnancy--diagnostic considerations and laboratory evaluation. Obstet Gynecol Surv. Oct 2007;62(10):669-74; quiz 691. [Medline].

31. Olsen TG, Hubert PR, Nycum LR. Falsely elevated human chorionic gonadotropin leading to unnecessary therapy. Obstet Gynecol. Nov 2001;98(5 Pt 1):843-5. [Medline].

32. Khanlian SA, Cole LA. Management of gestational trophoblastic disease and other cases with low serum levels of human chorionic gonadotropin. J Reprod Med. Oct 2006;51(10):812-8. [Medline].

33. Ngan HY, Chan FL, Au VW, et al. Clinical outcome of micrometastasis in the lung in stage IA persistent gestational trophoblastic disease. Gynecol Oncol. Aug 1998;70(2):192-4. [Medline].

34. Gamer EI, Garrett A, Goldstein DP, et al. Significance of chest computed tomography findings in the evaluation and treatment of persistent gestational trophoblastic neoplasia. J Reprod Med. Jun 2004;49(6):411-4. [Medline].

35. Kohorn EI. Negotiating a staging and risk factor scoring system for gestational trophoblastic neoplasia. A progress report. J Reprod Med. Jun 2002;47(6):445-50. [Medline].

36. Hammond CB, Weed JC Jr, Currie JL. The role of operation in the current therapy of gestational trophoblastic disease. Am J Obstet Gynecol. Apr 1 1980;136(7):844-58. [Medline].

37. Suzuka K, Matsui H, Iitsuka Y, et al. Adjuvant hysterectomy in low-risk gestational trophoblastic disease. Obstet Gynecol. Mar 2001;97(3):431-4. [Medline].

38. Ngan HY, Odicino F, Maisonneuve P, et al. Gestational trophoblastic neoplasia. FIGO 6th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. Nov 2006;95 Suppl 1:S193-203. [Medline].

39. Kashimura Y, Kashimura M, Sugimori H, et al. Prophylactic chemotherapy for hydatidiform mole. Five to 15 years follow-up. Cancer. Aug 1 1986;58(3):624-9. [Medline].

40. Massad LS, Abu-Rustum NR, Lee SS, et al. Poor compliance with postmolar surveillance and treatment protocols by indigent women. Obstet Gynecol. Dec 2000;96(6):940-4. [Medline].

41. Soper JT, Clarke-Pearson DL, Berchuck A, et al. 5-day methotrexate for women with metastatic gestational trophoblastic disease. Gynecol Oncol. Jul 1994;54(1):76-9. [Medline].

42. Foulmann K, Guastalla JP, Caminet N, et al. What is the best protocol of single-agent methotrexate chemotherapy in nonmetastatic or low-risk metastatic gestational trophoblastic tumors? A review of the evidence. Gynecol Oncol. Jul 2006;102(1):103-10. [Medline].

43. Roberts JP, Lurain JR. Treatment of low-risk metastatic gestational trophoblastic tumors with single-agent chemotherapy. Am J Obstet Gynecol. Jun 1996;174(6):1917-23; discussion 1923-4. [Medline].

44. Matsui H, Suzuka K, Yamazawa K, et al. Relapse rate of patients with low-risk gestational trophoblastic tumor initially treated with single-agent chemotherapy. Gynecol Oncol. Mar 2005;96(3):616-20. [Medline].

45. Kohorn EI. Is lack of response to single-agent chemotherapy in gestational trophoblastic disease associated with dose scheduling or chemotherapy resistance?. Gynecol Oncol. Apr 2002;85(1):36-9. [Medline].

46. Homesley HD, Blessing JA, Schlaerth J, et al. Rapid escalation of weekly intramuscular methotrexate for nonmetastatic gestational trophoblastic disease: a Gynecologic Oncology Group study. Gynecol Oncol. Dec 1990;39(3):305-8. [Medline].

47. Osborne R, Filiaci V, Schink J, et al. A randomized phase III trial comparing weekly parenteral methotrexate and "pulsed" dactinomycin as primary management for low-risk gestational trophoblastic neoplasia: A Gynecologic Oncology Group study. Gynecol Oncol. 2008;108:S2-S3.

48. Lurain JR. Advances in management of high-risk gestational trophoblastic tumors. J Reprod Med. Jun 2002;47(6):451-9. [Medline].

49. Lurain JR, Singh DK, Schink JC. Primary treatment of metastatic high-risk gestational trophoblastic neoplasia with EMA-CO chemotherapy. J Reprod Med. Oct 2006;51(10):767-72. [Medline].

50. Lehman E, Gershenson DM, Burke TW, et al. Salvage surgery for chemorefractory gestational trophoblastic disease. J Clin Oncol. Dec 1994;12(12):2737-42. [Medline].

51. Escobar PF, Lurain JR, Singh DK, et al. Treatment of high-risk gestational trophoblastic neoplasia with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine chemotherapy. Gynecol Oncol. Dec 2003;91(3):552-7. [Medline].

52. Xiang Y, Sun Z, Wan X, et al. EMA/EP chemotherapy for chemorefractory gestational trophoblastic tumor. J Reprod Med. Jun 2004;49(6):443-6. [Medline].

53. Yordan EL Jr, Schlaerth J, Gaddis O, et al. Radiation therapy in the management of gestational choriocarcinoma metastatic to the central nervous system. Obstet Gynecol. Apr 1987;69(4):627-30. [Medline].

54. Cagayan MS, Lu-Lasala LR. Management of gestational trophoblastic neoplasia with metastasis to the central nervous system: A 12-year review at the Philippine General Hospital. J Reprod Med. Oct 2006;51(10):785-92. [Medline].

55. Schechter NR, Mychalczak B, Jones W, et al. Prognosis of patients treated with whole-brain radiation therapy for metastatic gestational trophoblastic disease. Gynecol Oncol. Feb 1998;68(2):183-92. [Medline].

56. Barnard DE, Woodward KT, Yancy SG, et al. Hepatic metastases of choriocarcinoma: a report of 15 patients. Gynecol Oncol. Sep 1986;25(1):73-83. [Medline].

57. van Trommel NE, Massuger LF, Verheijen RH, et al. The curative effect of a second curettage in persistent trophoblastic disease: a retrospective cohort survey. Gynecol Oncol. Oct 2005;99(1):6-13. [Medline].

58. Soper JT, Spillman M, Sampson JH, et al. High-risk gestational trophoblastic neoplasia with brain metastases: individualized multidisciplinary therapy in the management of four patients. Gynecol Oncol. Mar 2007;104(3):691-4. [Medline].

59. Rojas-Espaillat L, Houck KL, Hernandez E, et al. Fertility-sparing surgery for persistent gestational trophoblastic neoplasia in the myometrium: a case report. J Reprod Med. May 2007;52(5):431-4. [Medline].

60. Jones WB, Romain K, Erlandson RA, et al. Thoracotomy in the management of gestational choriocarcinoma. A clinicopathologic study. Cancer. Oct 1 1993;72(7):2175-81. [Medline].

61. Carlson N, Winter WE 3rd, Krivak TC, et al. Successful management of metastatic placental site trophoblastic tumor with multiple pulmonary resections. Gynecol Oncol. Oct 2002;87(1):146-9. [Medline].

62. Rustin GJ, Newlands ES, Lutz JM, et al. Combination but not single-agent methotrexate chemotherapy for gestational trophoblastic tumors increases the incidence of second tumors. J Clin Oncol. Oct 1996;14(10):2769-73. [Medline].

63. Matsui H, Iitsuka Y, Suzuka K, et al. Risk of abnormal pregnancy completing chemotherapy for gestational trophoblastic tumor. Gynecol Oncol. Feb 2003;88(2):104-7. [Medline].

64. Woolas RP, Bower M, Newlands ES, et al. Influence of chemotherapy for gestational trophoblastic disease on subsequent pregnancy outcome. Br J Obstet Gynaecol. Sep 1998;105(9):1032-5. [Medline].

65. Lok CA, van der Houwen C, ten Kate-Booij MJ, et al. Pregnancy after EMA/CO for gestational trophoblastic disease: a report from The Netherlands. BJOG. Jun 2003;110(6):560-6. [Medline].

66. Matsui H, Iitsuka Y, Suzuka K, et al. Salvage chemotherapy for high-risk gestational trophoblastic tumor. J Reprod Med. Jun 2004;49(6):438-42. [Medline].

67. Knox S, Brooks SE, Wong-You-Cheong J, et al. Choriocarcinoma and epithelial trophoblastic tumor: successful treatment of relapse with hysterectomy and high-dose chemotherapy with peripheral stem cell support: a case report. Gynecol Oncol. Apr 2002;85(1):204-8. [Medline].

Keywords

gestational trophoblastic disease, gestational trophoblastic tumors, GTD, GTN, hydatidiform mole, invasive mole, chorioadenoma destruens, choriocarcinoma, placental site trophoblastic tumor, PSTT, gestational trophoblastic neoplasia, molar pregnancy, uterine cancer, uterine tumor, cancer of the uterus

Contributor Information and Disclosures

Author

Enrique Hernandez, MD, FACOG, FACS, Chairman, Department of Obstetrics and Gynecology, Director of Gynecologic Oncology, Abraham Roth Professor of Obstetrics, Gynecology and Reproductive Science, Professor of Pathology, Temple University Hospital, Temple University School of Medicine
Enrique Hernandez, MD, FACOG, FACS is a member of the following medical societies: Alpha Omega Alpha, American College of Obstetricians and Gynecologists, American College of Surgeons, American Medical Association, American Society for Colposcopy and Cervical Pathology, Association of Professors of Gynecology and Obstetrics, Johns Hopkins Medical and Surgical Association, Pennsylvania Medical Society, Philadelphia County Medical Society, and Society of Gynecologist Oncologists
Disclosure: Nothing to disclose.

Medical Editor

Robert C Shepard, MD, FACP, Associate Professor of Medicine in Hematology and Oncology at University of North Carolina at Chapel Hill; Vice President of Scientific Affairs, Therapeutic Expertise, Oncology, at PRA International
Robert C Shepard, MD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physician Executives, American College of Physicians, American Federation for Clinical Research, American Federation for Medical Research, American Medical Association, American Medical Informatics Association, American Society of Hematology, Association of Clinical Research Professionals, Eastern Cooperative Oncology Group, European Society for Medical Oncology, Massachusetts Medical Society, and Society for Biological Therapy
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

David Chelmow, MD, Professor of Obstetrics and Gynecology, Tufts University School of Medicine; Program Director, Tufts University Affiliated Hospitals Obstetrics/Gynecology Residency Program; Chair, Tufts University Health Sciences Campus Institutional Review Board; Vice Chair for Research and Education, Department of Obstetrics/Gynecology, Tufts Medical Center
David Chelmow, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Medical Association, Association of Professors of Gynecology and Obstetrics, Massachusetts Medical Society, Phi Beta Kappa, Sigma Xi, Society for Gynecologic Investigation, and Society for Medical Decision Making
Disclosure: Nothing to disclose.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)