Gestational Trophoblastic Neoplasia

Updated: Apr 08, 2021
  • Author: Enrique Hernandez, MD, FACOG, FACS; Chief Editor: Leslie M Randall, MD, MAS, FACS  more...
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Practice Essentials

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, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT).

Histologic section of a complete hydatidiform mole 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.

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 [1]

  • 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

Imaging studies

  • 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 GTN are subdivided into 2 groups: those with a WHO score of less than 7 (low-risk) and those with a score of 7 or higher and who are at high risk of therapy failure. Patients with nonmetastatic GTN or metastatic low-risk GTN are treated with single-agent chemotherapy, as follows [6, 7, 8, 9, 10, 11] [12] :

  • 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 and the WHO score remains less than 7

 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-EP regimen – Cisplatin and etoposide are substituted for cyclophosphamide and vincristine during the second week [17] ; sometimes reserved for patients in whom EMA-CO fails

  • At least 6 weeks of maintenance EMA-CO or EMA-EP are administered after a normal serum hCG level

  • Patients with liver metastasis are considered for liver irradiation (2000 cGy) [18]

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, [22] 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 [222]

  • In patients not receiving whole brain irradiation, the dose of methotrexate on day 1 of the EMA-CO or EMA-EP regimen is increased to 1000 mg/m2

  • 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

Surgical care

  • 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 [2]

  • 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 complete response (normalization of serum hCG) occurs in 30-40% of patients with newly diagnosed low-risk non-metastatic GTN who undergo a repeat D&C

  • Hysterectomy, [26, 27] or a repeat D&C in patients with persistent tissue on pelvic ultrasonography, may reduce the number of chemotherapy cycles needed to achieve remission [28]

  • A hysterectomy is the treatment of choice for PSTT; the ovaries do not need to be removed if the patient is premenopausal [29]

See Treatment and Medication for more detail.



Gestational trophoblastic disease (GTD) can be benign or malignant. Histologically, it is classified into hydatidiform mole, invasive mole (chorioadenoma destruens), choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). 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 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.

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. [31]

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. [4] Choriocarcinoma has also been associated with ectopic pregnancy with a theoretic incidence of 1 in 5333 ectopic pregnancies. [38]

Placental site trophoblastic tumor is a rare form of gestational trophoblastic neoplasia. [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). [41] 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. [42] The treatment of PSTT is hysterectomy with ovarian conservation. [29] 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.

Like PSTT, epithelioid trophoblastic tumor (ETT) is comprised of intermediate trophoblasts, but they have an epithelioid appearance. [39] The monomorphic epithelioid cells form nests or cords. ETT frequently involves the lower uterine segment and endocervix, which could be misdiagnosed as a squamous cell carcinoma. When the ETT replaces the endocervical glands it could be confused with high grade squamous cervical intraepithelial neoplasia. ETT stains focally for hCG and human placental lactogen (hPL).  Serum levels of hCG are usually less than 1000 mIU/ml. Measuring serum levels hPL is not clinically useful. Similar to PSST the treatment is surgical with total hysterectomy with ovarian preservation in young women if the ovaries are not involved.

Both PSST and ETT may be diagnosed years after the antecedent pregnancy. They are characterized by slow growth and remain at stage I for a long time. The WHO score is not as useful as in other types of GTN in determining prognosis. Factors associated with poor prognosis include time from antecedent pregnancy, deep myometrial invasion, tumor necrosis, and mitotic count >6/10 high power fields. The prognosis is worse when the interval from the antecedent pregnancy is >4 years. Chemotherapy is administered to patients with metastatic disease or high risk factors. EMA-EP seems to be the most effective regimen.

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

In this microphotograph of a choriocarcinoma metas 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).


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. [4, 45] However, only 1 out of 160,000 term pregnancies is followed by a choriocarcinoma. [46]


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. [49]

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. [47]



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.

Currently, prognosis and treatment is decided using the WHO prognostic score. Patients with a WHO score of 6 or less have excellent prognosis and are initially treated with single agent chemotherapy. Patients with WHO score >6 have a prognosis similar to that of patients previously classified as having metastatic high-risk disease. These patients with high-risk disease are treated initially with multiagent chemotherapy. Patients with WHO score of 5-6 have a higher probability of failing initial single agent chemotherapy but a complete response is usually achieved when switching to the alternate agent if the serum hCG is below 300 IU//L. [50]

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. Prior to the WHO scoring system as revised by FIGO in 2000, patients who had metastases were classified as high-risk or low-risk according to the National Institutes of Health (NIH) classification. [30] The NIH criteria for high-risk metastatic gestational trophoblastic neoplasia included 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%. [51]  The WHO score as modified by FIGO 2000 classifies patients into low risk if the score is 6 or less and high-risk if the score is >6. The reported cure rate for patients with low-risk disease (WHO score of 6 or less) is almost 100%. [52] The survival of patients with high-risk disease (score >6) treated aggressively at specialized centers is better than 90%. [53, 54, 55]

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, 56]

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. [57]

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. [58]