Гестаційна трофобластична хвороба

Initial manifestations of a hydatidiform mole suggest early pregnancy, but the uterus often becomes larger than expected within 10 to 16 weeks gestation. Commonly, women test positive for pregnancy and have vaginal bleeding and severe nausea and vomiting (hyperemesis gravidarum) and fetal movement and fetal heart sounds are absent. Vaginal passage of grapelike tissue strongly suggests the diagnosis.

Complications, such as the following, may occur:

• Severe bleeding, with possible hemorrhagic shock

• Preeclampsia

• Ovarian theca lutein cysts

Less common complications include uterine infection and sepsis.

Placental site trophoblastic tumors tend to cause bleeding.

Choriocarcinoma usually manifests with symptoms due to lung, liver, or brain metastases.

Hyperthyroidism is more common among women with gestational trophoblastic disease than in those without. Symptoms can include tachycardia, warm skin, sweating, heat intolerance, and mild tremors.

Gestational trophoblastic disease does not impair subsequent fertility or predispose to prenatal or perinatal complications (eg, congenital malformations, spontaneous abortions) in subsequent pregnancies.

• Serum beta subunit of human chorionic gonadotropin (beta-hCG)

• Pelvic ultrasonography

• Pathology evaluation of evacuated uterine contents or endometrial biopsy

Gestational trophoblastic disease is suspected in women with a positive pregnancy test and any of the following:

• Unexpectedly high levels of beta-hCG detected during pregnancy testing (except for placental site trophoblastic tumor and epithelioid trophoblastic tumor, which result in low beta-hCG levels)

• Uterine size much larger than expected for dates

• Symptoms or signs of preeclampsia in 1st or 2nd trimester

• Vaginal passage of grapelike tissue

• Suggestive findings (eg, mass containing multiple cysts, absence of a fetus and amniotic fluid) seen during ultrasonography done to evaluate pregnancy

• Unexplained metastases in women of child-bearing age with an unknown primary tumor

Postmolar gestational trophoblastic neoplasia is most frequently diagnosed based on hCG levels and should be excluded if abnormal uterine bleeding occurs after any pregnancy.

If gestational trophoblastic disease is suspected, testing includes measurement of serum beta-hCG and, if not previously done, pelvic ultrasonography. Findings (eg, very high beta-hCG levels, classic ultrasonographic findings) may suggest the diagnosis, but the diagnosis must be histologically confirmed through pathology evaluation of evacuated uterine contents or endometrial biopsy. Typically, beta-hCG levels are high in patients with invasive mole or choriocarcinoma and low in those with placental site trophoblastic tumor or epithelioid trophoblastic tumor.

Invasive mole and choriocarcinoma are suspected if biopsy findings suggest invasive disease or if beta-hCG levels remain higher than expected after treatment for hydatidiform mole (see below).

Thyroid function tests are done if the beta-hCG level is > 100,000 mIU/mL (> 100,000 IU/L) to check for hyperthyroidism.

When gestational trophoblastic neoplasia is diagnosed, clinicians should check for metastases. CT of the chest, abdomen, and pelvic area should be done. Pelvic ultrasonography or MRI may be helpful if better visualization of the uterine tumor is needed or if there are ovarian theca lutein cysts. Metastases to other sites usually occur only after metastases to the lungs are established.

• Tumor removal by suction curettage or hysterectomy (if fertility is not desired, especially if women > 40 years)

• Further evaluation for persistent disease and spread of tumor

• Chemotherapy for persistent disease

• Posttreatment contraception for persistent disease

(See also National Comprehensive Cancer Network (NCCN): NCCN Clinical Practice Guidelines in Oncology: Gestational Trophoblastic Neoplasia.)

Usually, any type of gestational trophoblastic disease can be successfully diagnosed and treated and fertility can be preserved. Desire to preserve fertility should be discussed when planning treatment for gestational trophoblastic disease.

Hydatidiform mole, invasive mole, placental site trophoblastic tumor, and epithelioid trophoblastic tumor are evacuated by suction curettage. Alternatively, if childbearing is not planned, hysterectomy may be done.

A chest x-ray is taken. Serum beta-hCG is measured serially. Effective contraception is recommended while hCG is being monitored. If the beta-hCG level does not normalize within 10 weeks, the disease is classified as persistent. Persistent disease requires CT of the brain, chest, abdomen, and pelvis. Results dictate whether disease is classified as nonmetastatic or metastatic.

Persistent disease is usually treated with chemotherapy. Treatment is considered successful if at least 3 consecutive serum beta-hCG measurements at 1-week intervals are normal. Pregnancy should be prevented for 6 months after treatment because pregnancy would increase beta-hCG levels, making it difficult to determine whether treatment has been successful. Typically, oral contraceptives are given for 6 months; alternatively, any effective contraceptive method can be used.

For most types of gestational trophoblastic neoplasia, chemotherapy is the primary treatment.

Low-risk metastatic disease can be cured, often with a single chemotherapy agent (eg, methotrexate, actinomycin D [dactinomycin]). Multidrug chemotherapy is an acceptable alternative.

Both actinomycin D and methotrexate are effective first-line agents with no consensus regarding which agent is more effective and has the least morbidity. A meta-analysis included 1674 patients with low-risk gestational trophoblastic neoplasia and compared these 2 agents. Actinomycin D was associated with a higher complete response (80.2% versus 65.1%; odds ratio 2.15). Nausea, vomiting, and alopecia were more frequent in the group treated with actinomycin D, and there was less liver toxicity in patients treated with methotrexate (1).

The National Comprehensive Cancer Network guidelines (NCCN) recommends multiday methotrexate or methotrexate/folate regimens. If patients have contraindications to methotrexate regimens, actinomycin D regimens are recommended. Serum hCG levels are monitored during chemotherapy and after normalization of hCG levels. Usually, additional cycles of consolidation therapy are given.

Hysterectomy shortens the duration and amount of chemotherapy needed for remission in patients with low-risk disease. After hysterectomy, patients still require chemotherapy and serum hCG monitoring.

If treatment is successful, hCG levels should decrease by ≥ 10% over three cycles of treatment. An alternative treatment is needed if there is significant toxicity or if hCG levels

• Do not decrease as expected.

• Increase > 10% over two cycles

For patients previously treated with multi-day methotrexate regimens, 5-day actinomycin D is recommended.

All patients with high-risk gestational trophoblastic neoplasia (WHO risk score > 6) should be referred to specialists. High-risk metastatic disease requires aggressive multidrug chemotherapy because patients are likely to develop resistance if a single drug is used. EMA-CO is the most widely used regimen. It consists of etoposide, methotrexate, plus dactinomycin (EMA), alternating with cyclophosphamide plus vincristine (CO). Surgery and/or radiation therapy are often part of primary treatment.

Survival rates in specialized centers exceed 86% (2). A meta-analysis included 2276 patients with high-risk gestational trophoblastic neoplasia; treatments included chemotherapy in 99.7%, surgery in 35.8%, and radiation in 4.9%. Complete response to primary chemotherapy was 79.7%, and the mortality rate was 10%. The most frequently used chemotherapy regimens were EMA/CO or EMA/EP, which were associated with lower mortality than other chemotherapy regimens (8.1% versus 12.4%, odds ratio 0.42) and higher likelihood of complete response (75.9% versus 60.7%, odds ratio 2.98). The study concluded that chemotherapy (EMA/CO or EMA/EP) was associated with improved outcomes. Mortality was higher in patients with ultra-high-risk, relapsed, and disease after a term pregnancy (3).

Treatment of high-risk gestational trophoblastic neoplasia resistant to initial chemotherapy is difficult. Options include

• EMA/EP (etoposide/methotrexate/actinomycin D/etoposide/cisplatin)

• Paclitaxel/etoposide alternating with cisplatin/etoposide

• Multi-day etoposide/cisplatin regimens

• High-dose chemotherapy with stem cell support

Programmed death receptor 1 (PD-1) is present in almost all gestational trophoblastic disease lesions. Some patients with drug-resistant gestational trophoblastic neoplasia have been treated with checkpoint inhibitors (pembrolizumab, avelumab) with some benefit.

Cure rates are

• Low-risk: 90 to 95% (4)

• High-risk: 60 to 80% (5)

Risk of disease progression and resistance to single-drug chemotherapy is determined by the FIGO staging system and the WHO risk scoring system.

Gestational trophoblastic disease is considered low risk if it is one of the following:

• FIGO stage I (persistently elevated beta-hCG level and/or tumor confined to the uterus)

• FIGO stage II or III with a WHO risk score of ≤ 6

Gestational trophoblastic disease is considered high risk if it is one of the following:

• FIGO stages II and III with a WHO risk score of > 6

• FIGO stage IV

After remission of gestational trophoblastic neoplasia (normalization of hCG levels), hCG levels should be measured at 2-week intervals during the first 3 months, then at monthly intervals for at least 12 months. After 12 months, risk of recurrence is < 1%; risk is higher for patients with high-risk disease. In patients with high-risk disease, hCG levels should be measured at 6- to 12-month intervals after the first 12 months of remission. Oral contraceptives during chemotherapy and the 12 months after remission are recommended.

In metastatic disease, the World Health Organization (WHO) prognostic scoring system for metastatic gestational trophoblastic disease can help predict prognosis, including risk of death (see table WHO Scoring System in Metastatic Gestational Trophoblastic Disease). A WHO risk score of ≤ 6 is classified as low risk, and scores > 6 are classified as high risk.

Poor prognosis is also suggested by the following (National Institutes of Health [NIH] criteria):

• Urinary hCG excretion > 100,000 IU in 24 hours

• Duration of disease > 4 months (interval since prior pregnancy)

• Brain or liver metastases

• Disease after full-term pregnancy

• Serum hCG > 40,000 mIU/mL

• Unsuccessful prior chemotherapy

• WHO score > 6

The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

1. National Cancer Institute: Gestational Trophoblastic Disease Treatment: This web site provides information about gestational trophoblastic disease, its classification, staging, and treatment of each type of gestational trophoblastic disease.