Gestational Trophoblastic Disease


Malignant disease- Gestational trophoblastic neoplasia (GTN)



Gestational trophoblastic diseases (GTD) are a group of 5 inter-related disorders of trophoblast epithelium of the placenta leading to placental tumors. Of the 5 forms of GTD, two forms, complete hydatidiform mole (Figure 1) and partial hydatidiform mole tend to have a benign course and are cured in the majority of cases by evacuating the uterus with a suction dilation and curettage. Three forms of GTD are malignant: invasive mole, choriocarcinoma and placenta site trophoblastic tumor. Malignant forms of GTD are referred to as gestational trophoblastic neoplasia (GTN) and are typically treated with chemotherapy and hysterectomy if appropriate. Malignant forms of GTD most commonly arise from the malignant transformation of a complete hydatidiform mole, but they may occur following any type of gestation including term pregnancy, ectopic pregnancy or spontaneous abortion. Malignant GTD is curable in most cases.
Hydatidiform mole, which may be complete or partial is the most common type of GTD and represents over 80% of all cases. This chapter will focus on these two presentations of the disease. Malignant GTD will be reviewed briefly at the end of the chapter.

Gestational trophoblastic disease (GTD)-Hydatidiform Mole


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All hydatidiform moles have abnormal DNA complements which are the result of abnormal fertilization of an oocyte. (Table 1) In the case of complete hydatidiform mole, an empty oocyte is fertilized by a sperm that duplicates its chromosome material, or less commonly by fertilization of an empty oocyte by two sperm. A partial mole arises from the fertilization of an oocyte by two sperm resulting in triploidy.

Diagnosis and Initial Monitoring of Disease Activity

In countries where diagnostic ultrasound is widely available, most hydatidiform moles are diagnosed by this technique in the first trimester of pregnancy. Almost all women with hydatidiform mole present with first trimester uterine bleeding. Due to the bleeding, pelvic ultrasound is routinely obtained to assess the status of the pregnancy. Complete hydatidiform mole is diagnosed when the ultrasound demonstrates the characteristic “snow storm” of multiple small cystic structures which is the ultrasound presentation of multiple swollen villi (Figure 2). Partial hydatidiform mole typically are thought to be missed abortions on ultrasound, but when the uterus is evacuated, full pathological analysis demonstrates the presence of a mole. Women with suspected molar pregnancy should have a suction dilatation and curettage to obtain placental tissue for final pathologic diagnosis. In 80% of cases of complete hydatidiform mole, suction dilatation and curettage cures the disease. In 20% of cases the disease persists requiring later chemotherapy. In 98% of cases of partial hydatidiform mole, suction dilatation and curettage cures the disease.

After dilatation and curettage, serum hCG levels are followed weekly. An hCG level that reaches < 5 mIU/ml indicates that the disease is cured. Following evacuation of a complete or partial hydatidiform mole, on average it takes 100 days and 60 days respectively for the hCG to reach < 5 mIU/ml. (After a normal pregnancy hCG levels return to normal after 4 weeks.) An hCG level that does not decrease (plateau of hCG for 3 weeks), or increases by 10%, or remains > 5 mIU/ml after 26 weeks of measurement indicates the presence of persistent hydatidiform mole. (1) In this situation 75% of the cases represent an invasive mole and 25% represent choriocarcinoma.


Complete hydatidiform moles are characterized by diffuse and marked swelling of the villi. Partial hydatidiform moles are characterized by focal swelling of the villi and the presence of embryonic tissue. (2) (Table 1.)

Prevalence, Epidemiology

About 1 in 1000 pregnancies are complicated by hydatidiform mole. In Asia and Latin America, higher rates of mole have been reported. The two main risk factors are a history of a previous GTD pregnancy (1% risk of recurrence) and maternal age < 20 years or > 35 years. Other minor risk factors are cigarette smoking, nulliparity and history of infertility.

History, Physical examination and laboratory studies

Most women with complete hydatidiform mole present with vaginal bleeding in the first trimester of pregnancy. Diagnostic ultrasound is ordered to evaluate the source of bleeding and the diagnosis is made. The increasing availability of high-quality ultrasound imaging and the wide-spread use of this technology in pregnancy has resulted in a marked change in the initial presentation of the disease. Prior to the availability of ultrasound, the diagnosis of GTD was typically made at 16 weeks gestation, early in the second trimester. In the past, an enlarged uterus (50% of cases), theca lutein cysts, anemia (50% of cases), hyperthyroidism (7% of cases) and preeclampsia (27% of cases) were common findings in women with GTD. In the modern era, with wide availability of high-quality sonography, the diagnosis of GTD is typically made at about 10 weeks gestation (3). With early diagnosis, the only symptom may be first trimester vaginal bleeding. In the modern era it is unusual to see a patient with GTD present with hyperthyroidism or preeclampsia (<1% of cases). Early in the first trimester it is more difficult to identify cases of GTD by ultrasound. This means that highly experienced sonologists who focus on obstetrical and gynecological imaging are more likely to make an early diagnosis. Partial hydatidiform moles typically present as missed abortions. Evacuation of the uterus results in pathological identification of the partial mole.


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As noted above, the treatment of both complete and partial hydatidiform moles is evacuation of the uterus with suction dilatation and curettage. Following suction dilatation and curettage, serum hCG is measured weekly. In 80% of cases of complete hydatidiform mole this results in cure of the disease as represented by an hCG < 5 mIU/ml. Once the hCG reaches < 5 mIU/ml, it is uncommon for the hCG to increase above 5 mIU/ml (4) (Box 1). In 20% of cases, hCG levels do not decrease to < 5 mIU/ml. Following dilatation and curettage, 98% of cases of partial hydatidiform mole are cured. Prior to suction dilatation and curettage, a complete blood count, renal, liver and thyroid function tests are obtained to assess for systemic manifestation of the disease. A type and screen is obtained to facilitate the availability of red blood cells if needed for transfusion. Routine imaging of the liver, chest and brain are not necessary. In order to prevent another pregnancy during the initial interval of weekly hCG measurements, a highly effective contraceptive should be recommended, such as an oral contraceptive. (5)

In 20% of cases, hCG levels do not decrease to < 5 mIU/ml and chemotherapy is given to eradicate the persistent disease. In general, women with persistent disease should be referred to a trophoblast disease center. Women with persistent disease should have a thorough evaluation for the presence of detectable metastatic disease including pelvic ultrasound and computerized tomography of the thorax. If either of these studies demonstrate metastatic or persistent tumor, imaging of the brain and liver is indicated. In most cases if pelvic sonography and computerized tomography of the thorax are negative for metastases, then brain and liver imaging will also be negative. In women with known choriocarcinoma, complete imaging of the pelvis, thorax, liver and brain should be obtained before treatment. In women who have completed their family, hysterectomy may be a useful adjuvant to single agent chemotherapy in order to reduce the bulk of residual and invasive disease. (6)

Staging of GTN is based on the International Federation of Gynecologists and Obstetricians system: Stage I- persistently elevated hCG levels and tumor confined to the uterus, Stage II- tumor outside of the uterus, but limited to vagina or pelvic, Stage III- pulmonary metastases, Stage IV- metastatic disease at non-pulmonary sites such as brain, liver and kidneys.

For women with Stage I disease who are at low risk, single agent chemotherapy with methotrexate or dactinomycin are used to treat persistent disease. Risk can be assessed using a complex scoring system that the assesses points for the following factors: patient age, type of antecedent pregnancy, interval between pregnancy and start of chemotherapy, pretreatment hCG level, size of largest tumor, site of metastases, number of metastases and history of prior chemotherapy. (1) Methotrexate is commonly administered as an intramuscular injection once weekly with or without leucovorin rescue. Normal cells can be rescued from the toxic effects of methotrexate on folate metabolism by leucovorin (folinic acid). In contrast gestational trophoblast tumor cells accumulate large quantities of methotrexate metabolites and cannot be easily rescued by leucovorin from the toxic effects of methotrexate. Dactinomycin is as effective as methotrexate but associated with more side effects such as nausea and vomiting. After chemotherapy, hCG levels are monitored weekly and should decrease rapidly. Multiple courses of single agent therapy may be given to achieve an hCG <5 mIU/mL. Over 80% of women with persistent disease will be cured by a single agent regimen. In cases where multiple courses of single agent chemotherapy does not result in normalization of the hCG, multiagent chemotherapy is administered (see section on GTN below)

False Positive Serum hCG Measurements

The treatment regimen recommended above is highly dependent on the monitoring of serum hCG to determine if persistent disease is present. In rare circumstances laboratories will report a serum hCG value > 5 mIU/ml, but further testing will demonstrates that there is no hCG in the serum. These false positive laboratory results are thought to be due to antibodies in the patient’s serum that interfere with the hCG assay. Interfering antibodies are present in low concentration in the urine. If a false-positive serum hCG is suspected, a simultaneous urine assay for hCG should be performed. A positive serum hCG and a negative urine hCG should prompt additional testing with highly reliable and specific hCG assays. In normal sera that does not contain interfering antibodies, sequential dilution of the sera should result in an appropriate sequential decrease in the measured hCG. For example, diluting the serum 1:1 with control sera should result in a 50% decrease in measured hCG. Diluting the serum 1:3 should result in a 75% in measured hCG. In sera that contain interfering antibodies, sequential dilution does not result in the expected decrease in measured hCG. (7) (8)

Malignant disease- Gestational trophoblastic neoplasia (GTN)

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Three forms of GTD are malignant: invasive mole, choriocarcinoma and placenta site trophoblastic tumor (PSTT). These malignant forms of GTD are referred to as gestational trophoblastic neoplasia (GTN). As indicated by the terminology, invasive mole is characterized by invasion of trophoblastic tissue into the myometrium of the uterus. Choriocarcinoma is characterized by sheets of anaplastic cytotrophoblasts and syncytiotrophoblasts without chorionic villi. (9)

GTN occurs following about 20% of the cases of complete hydatidiform mole and less than 5% of cases of partial hydatidiform mole. If histological samples are available, persistent disease following a complete hydatidiform mole demonstrates invasive mole in 75% of cases and choriocarcinoma in 25% of cases. Persistent trophoblastic disease following a spontaneous abortion, ectopic pregnancy or term pregnancy is always caused by choriocarcinoma or PSTT. Choriocarcinoma occurs in approximately 1 in 30,000 pregnancies. PSTT is very rare and is managed with hysterectomy with chemotherapy if indicated. (10) All women with malignant gestational trophoblastic disease should be referred to a center specializing in this disease.

Treatment. Persistent GTD that is resistant to single agent chemotherapy and high-risk malignant gestational trophoblastic neoplasia is typically treated with multiagent chemotherapy. A commonly used multiagent regimen includes etoposide, methotrexate with leucovorin rescue, and dactinomycin on days 1 and 2 followed by cyclophosphamide and vincristine on day 8 (EMA/CO therapy). Therapy is repeated every 2 weeks until hCG is < 5 mIU/ml and all radiographic evidence of active malignant disease has resolved. Therapy is then continued for another 3 cycles to consolidate the cure. Using this regimen the overall 5 year survival rate is about 90% (11).

Molar pregnancy was reported by ancient Greek physicians based on the visual identification of the grossly swollen placental villi (“cluster of grapes”). In the modern era, molar pregnancy is diagnosed based on ultrasound findings. The first trimester diagnosis of molar pregnancy has dramatically altered the presentation of the disease, with most patients presenting with no systemic symptoms. In most cases, the disease resolves following evacuation of the uterus.

References Chapter 50 Gestational Trophoblastic Disease

1. Kohorn EI. The new FIGO 2000 staging and risk factor scoring system for gestational trophoblast disease: description and clinical assessment. Int J Gynecol Cancer 2001; 11: 73-7.

2. Berkowitz RS, Goldstein DP. Chorionic tumors. N Engl J Med 1996; 335: 1740-8.

3. Soto-Wright V, Bernstein M, Goldstein DP, Berkowitz RS. The changing clinical presentation of complete molar pregnancy. Obstet Gynecol 1995; 86: 775-9.

4. Wolfberg AJ, Feltmate C, Goldstein DP, et al. Low risk of relapse after achieving undetectable hCG levels in women with complete molar pregnancy. Obstet Gynecol 2004; 104: 551.

5. Curry SL, Schlaerth JB, Kohorn EI, et al. Hormonal contraception and trophoblastic sequelae after hydatidiform mole. Am J Obstet Gynecol 1989; 160: 805-9.

6. Hammond CB, Weed JC, Currie JL. The role of operation in the current therapy of gestational trophoblastic disease. Am J Obstet Gynecol 1980; 136: 844-58.

7. Cole LA. Phantom hCG and phantom choriocarcinoma. Gynecol Oncol 1998; 71: 325-9.

8. Rotmensch S, Cole LA. False diagnosis and needless therapy of presumed malignant disease in women with false-positive human chorionic gonadotropin concentrations. Lancet 2000; 355: 712-5.

9. Wells M. The pathology of gestational trophoblast disease. Pathology 2007; 39: 88-96.

10. Hassadia A, Gillespie A, Tidy J, Everard RGN, et al. Placental site trophoblastic tumor. Gynecol Oncol 2005; 99: 603-7.

11. Bower M, Newlands ES, Holden L, et al. EMA/CO for high-risk gestational trophoblastic tumors: results from a cohort of 272 patients. J Clin Oncol 1997; 15: 2636.

Table 1. Characteristic features of complete and partial hydatidiform molar pregnancy.

Complete Hydatidiform Mole Partial Hydatidiform Mole
Karyotype 90% of cases 46, XX; 10% of cases 46, XY 90% of cases- Triploid, 69 XXX or 69 XXY
Source of sex chromosomes All sex chromosomes are of paternal origin One set of chromosomes are of maternal origin, and two sets of paternal origin
Villi swelling Diffuse swelling of all villi Focal swelling, scalloped villi
Trophoblast hyperplasia Marked, circumferential around villi Minimal, focal
Fetal tissue None Present
Immunocytochemistry Intense staining for hCG Intense staining for placental alkaline phosphatase
Malignant sequelae About 20% of cases 2% of cases

Box 1 Best Clinical Evidence

For women with complete hydatidiform mole diagnosed by ultrasound, standard treatment is uterine evacuation with suction dilatation and curettage. Following uterine evacuation, serum hCG is measured sequentially. Women are diagnosed as having complete remission of their trophoblast tumor when their hCG level becomes undetectable (< 5 mIU/ml). Historically, women were required to demonstrate an hCG < 5 mIU/ml for 6 months in order to be diagnosed as in complete remission.

However, data from one center indicates that once a woman achieves a single hCG level < 5 mIU/ml it is highly likely that she has entered a complete remission. In this study, the course of 1,029 women with complete hydatidiform mole was analyzed. 15% of the patients developed persistent gestational trophoblastic neoplasia. Of the 85% of patients who entered remission, 99.8% were demonstrated to have entered a complete remission once their hCG level became undetectable. A sensitive hCG assay with a lower limit of sensitivity of 5 mIU/ml had better performance characteristics for determining complete remission than an hCG assay with a lower limit of sensitivity of 10 mIU/ml.

Wolfberg AJ, Feltmate C, Goldstein DP, et al. Low risk of relapse after achieving undetectable hCG levels in women with complete molar pregnancy. Obstet Gynecol 2004; 104: 551.