Gestational Trophoblastic Neoplasia
- Author: Enrique Hernandez, MD, FACOG, FACS; Chief Editor: Warner K Huh, MD more...
Gestational trophoblastic neoplasia (GTN) is a collective term for gestational trophoblastic diseases that invade locally or metastasize. Hydatidiform mole is the most common form of GTN (see the image below); others are invasive mole (chorioadenoma destruens), choriocarcinoma, and placental site trophoblastic tumor (PSTT).
Signs and symptoms
Most cases of GTN are diagnosed when the serum hCG levels plateau or rise in patients being observed after the diagnosis of hydatidiform mole. If metastases have developed, the following signs and symptoms may be noted:
Metastasis to the lower genital tract presents as purple to blue-black papules or nodules, which are extremely vascular and may bleed profusely if biopsied 
Abdominal tenderness, if liver or gastrointestinal metastases have occurred
Abdominal guarding and rebound tenderness, 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 [2, 3]
Neurologic deficits, from lethargy to coma, if brain metastasis has occurred
Jaundice, if liver metastasis causes biliary obstruction
See Clinical Presentation for more detail.
Laboratory studies used in the diagnosis of GTN are as follows:
Serum quantitative hCG – To assess response to therapy and disease status
CBC – May help detect anemia secondary to bleeding
Liver enzymes – May become elevated in patients with metastasis to the liver
Pelvic ultrasonography – May show persistent molar tissue in the uterus
Chest radiograph – Recommended because the lung is the most frequent site of metastasis
CT scan of the chest (optional)
CT scan of the abdomen and pelvis with contrast
MRI of the head (preferable to CT)
CT and MRI are recommended if the patient has hydatidiform mole with metastasis to the lungs, choriocarcinoma, or persistent hydatidiform mole. The lungs, lower genital tract, brain, liver, kidney, and gastrointestinal tract are common sites of metastases.
Suction and careful 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
Uterine dilatation and curettage (D&C) performed in a woman with abnormal vaginal bleeding and a positive pregnancy test result may reveal a choriocarcinoma
Features of a D&C are as follows:
A D&C may be part of the evaluation of a patient with an elevated serum hCG level 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 PSTT made on a D&C specimen, since this usually presents as intermediate trophoblasts infiltrating the myometrium
Staging and prognostic scoring
The official International Federation of Gynecology and Obstetrics staging of gestational trophoblastic neoplasia is as follows[4, 5] :
Stage I – Confined to the uterus
Stage II – Limited to the genital structures
Stage III – Lung metastases
Stage IV – Other metastases
The currently used prognostic scoring index is a modification of the World Health Organization (WHO) classification. Scores are determined by adding up points from a list of 19 prognostic factors.
See Workup for more detail.
Patients with nonmetastatic GTN or metastatic low-risk GTN are treated with single-agent chemotherapy, as follows[6, 7, 8, 9, 10, 11] :
Methotrexate is preferred by many US specialists, but actinomycin D can be used in patients with poor liver function
During treatment, the serum hCG levels are monitored every week
Six weeks of maintenance 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 serum hCG levels rise or plateau
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 D). Six weeks of maintenance chemotherapy is administered after a normal serum hCG level is achieved.
Treatment in patients with WHO scores of 7 or higher is as follows:
EMA-CO regimen – 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 [13, 14, 15, 16]
EMA-CE regimen – Cisplatin and etoposide are substituted for cyclophosphamide and vincristine during the second week  ; sometimes reserved for patients in whom EMA-CO fails
At least 6 weeks of maintenance EMA-CO or EMA-CE are administered after a normal serum hCG level
Patients with liver metastasis are considered for liver irradiation (2000 cGy) 
Brain metastasis treatment
Whole brain irradiation (3000 cGy) is given in combination with chemotherapy [19, 20, 21] ; dexamethasone is administered to reduce brain edema (most common approach in US)
Early neurosurgical intervention for solitary lesions or stereotactic radiotherapy for multiple lesions or solitary lesions in locations at high risk for surgical morbidity,  followed by moderate- and high-dose intravenous methotrexate and, at some centers, intrathecal methotrexate (approach used in selected institutions)
A therapeutic level of methotrexate is achieved in the cerebrospinal fluid at IV doses of >600 mg/m 2
In patients not receiving whole brain irradiation, the dose of methotrexate on day 1 of the EMA-CO or EMA-CE regimen is increased to 1000 mg/m 2
Instead of 4 doses of folinic acid (15 mg every 12 hours), 12 doses (15 mg every 6 hours) are given, starting 24 hours after the initiation of methotrexate infusion
Stage IV GTN
Patients with stage IV GTN are most often treated with multiagent chemotherapy, even when the WHO score is less than 7, which is uncommon
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
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 
A hysterectomy may be necessary in case of uncontrolled vaginal bleeding
Craniotomy may be needed to control bleeding and provide decompression [15, 22]
Resection of solitary metastasis (eg, thoracotomy) or disease within the myometrium may help achieve a remission [23, 24, 25]
A hysterectomy is the treatment of choice for PSTT; the ovaries do not need to be removed if the patient is premenopausal 
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.
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 levels 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 levels either rise or plateau.[4, 30]
The International Federation of Gynecology and Obstetrics considers an elevated serum hCG level 6 or more months after evacuation of a hydatidiform mole to be diagnostic of malignancy (ie, GTN). However, serum hCG levels spontaneously return to normal without chemotherapy in most patients with elevated but still declining serum hCG levels 6 months after diagnosis of a hydatidiform mole. Therefore, continuing to follow these patients is reasonable as long as the hCG levels do not rise or plateau.
For more information on hydatidiform mole, see the Medscape Reference article Hydatidiform Mole.
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.[4, 30, 32]
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.[33, 34, 35] 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.[36, 37]
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. Choriocarcinoma has also been associated with ectopic pregnancy with a theoretic incidence of 1 in 5333 ectopic pregnancies.
Placental site trophoblastic tumor is a rare form of gestational trophoblastic neoplasia, with slightly more than 200 cases reported in the literature.[39, 40] 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 levels as high as 108,000 mIU/mL have been reported in patients with 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.[43, 44] Radiation therapy may provide local control.
The most frequent sites of metastases of malignant gestational trophoblastic neoplasia are the lungs, lower genital tract, brain, liver, kidney, and gastrointestinal tract.
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.
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.[45, 47, 48] These differences are probably due to differences in methodology (eg, identification of cases, accuracy of denominator).[45, 47]
Race-, sex-, age-related demographics
Little information is available on international ethnic or racial differences of the incidence of choriocarcinoma. In the United States, African Americans have the highest incidence of choriocarcinoma and the lowest survival rates.
Gestational trophoblastic neoplasia affects women during their reproductive years. However, placental site trophoblastic tumors have been diagnosed when patients were postmenopausal.
The incidence of choriocarcinoma increases with age and is 5-15 times higher in women 40 years and older than in younger women.
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.
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 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.
As noted above, 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%.[30, 51]
See Prognosis section for more information on recurrence rate.
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.
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.
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|Age ≥40 y||1|
|Antecedent pregnancy terminated in abortion||1|
|Antecedent full-term pregnancy||2|
|Interval of 4-7 mo between antecedent pregnancy and start of chemotherapy||1|
|Interval of 7-12 mo between antecedent pregnancy and start of chemotherapy||2|
|Interval of more than 12 mo between antecedent pregnancy and start of chemotherapy||4|
|Beta-hCG level in serum is 1,000 to < 10,000 mIU/mL||1|
|Beta-hCG level in serum is 10,000 to < 100,000 mIU/mL||2|
|Beta-hCG level in serum is ³100,000 mIU/mL||4|
|Largest tumor is 3 cm to < 5 cm||1|
|Largest tumor is ³5 cm||2|
|Site of metastases is spleen or kidney||1|
|Site of metastases is gastrointestinal tract||2|
|Site of metastases is brain or liver||4|
|Number of metastases is 1-4||1|
|Number of metastases is 5-8||2|
|Number of metastases is >8||4|
|Prior chemotherapy with single drug||2|
|Prior chemotherapy with multiple drugs||4|