Gestational trophoblastic tumors (GTTs)

ALSO KNOWN AS: Gestational trophoblastic neoplasia (GTN), gestational trophoblastic disease (GTD), metastasizing mole, invasive mole, chorioadenoma destruens

RELATED CONDITIONS: Hydatidiform mole (H. mole), molar pregnancy, placental site trophoblastic tumor (PSTT), choriocarcinoma

DEFINITION: Gestational trophoblastic tumors (GTTS) are a group of benign tumors and malignant cancers in the uterus originating from the trophoblast layer that develops after conception and forms the embryonic placenta. GTTs are classified as hydatidiform mole (complete or partial molar pregnancy), invasive mole (chorioadenoma destruens), choriocarcinoma, placental site trophoblastic tumor (PSTT), or epithelioid trophoblastic tumor (ETT). Some 60 percent of gestational trophoblastic tumors are persisting hydatidiform moles. Although hydatidiform moles are classified as benign and invasive, choriocarcinoma, PSTTs, and ETTs are classified as malignant, their real-life behavior may be similar, especially when aggressive benign tumors mimic malignant ones.

Risk factors: Several factors may contribute to a woman’s susceptibility to developing gestational trophoblastic tumors. All women of childbearing age are at risk, with women under age twenty and over age thirty-five being more prone than others. Women who have had a prior miscarriage, have blood type A or AB (rather than B or O), or have used birth control pills have a higher risk of developing a gestational trophoblastic tumor. In addition, a woman who has previously had a molar pregnancy has a 1 percent risk in any subsequent pregnancy. In comparison, more than one previous molar pregnancy increases that risk drastically to approximately 25 percent.

Etiology and the disease process: A hydatidiform mole arises from the fusion of an ovum with one or more sperm. The trophoblast, a layer of cells surrounding the embryo, produces finger-like villi that attach to the uterus. In a hydatidiform mole, the villi swell and grow in clusters to resemble bunches of grapes.

One of three scenarios is possible in the creation of a hydatidiform mole. The first involves the union of the ovum (unfertilized egg) with two sperm instead of one. The second scenario may involve a single sperm whose complement of 22 chromosomes and one sex chromosome (23 total) is duplicated. These moles contain fetal material and are known as partial moles. Only about 2 percent of partial moles become malignant. The third scenario involves the union of an ovum without a nucleus with one or two sperm. This is known as a complete mole. No fetal tissue is present in a complete molar pregnancy.

Invasive moles (chorioadenoma destruens) are hydatidiform moles, most commonly complete moles, that have invaded the myometrium (muscular wall of the uterus). Some 20 percent of women who have had a complete mole removed by scraping the uterus develop invasive moles. These moles usually must be treated with chemotherapy and sometimes spread to other organs such as the lungs or brain.

Choriocarcinomas are malignant tumors, about half developing from complete hydatidiform moles. Approximately one-quarter form after a normal pregnancy and delivery, while another quarter form after a miscarriage, abortion, or ectopic pregnancy. This type of cancer often spreads past the uterus.

A placental site trophoblastic tumor (PSTT) is a rare form of gestational trophoblastic tumor. It develops after a normal pregnancy or abortion in which the placenta attaches to the uterus. This type of tumor tends to be confined to the uterus and is usually removed by surgery, as it does not respond to chemotherapy.

Epithelioid trophoblastic tumors (ETTs) are even rarer than PSTTs. Previously called atypical choriocarcinomas, they have since been reclassified as a distinct category of the tumor, and their progression is more similar to that of PSTTs than of choriocarcinomas.

Incidence: Global gestational trophoblastic disease rates vary greatly. In India, the disease occurs in one out of 500 to 600 pregnancies, while Mexico, Paraguay, and Sweden report incidence rates of one in 50,000. In the United States, gestational trophoblastic tumors occur in approximately 15 to 20 percent of patients with hydatidiform moles. Gestational choriocarcinomas are rare, occurring in 1 out of 20,000 to 40,000 women in the United States, and PSTTs and ETTs are even rarer.

Symptoms: Patients often complain of delayed menses, and gestational trophoblastic tumors can mimic a pregnancy. However, abnormalities such as painless uterine bleeding during the first trimester or the passing of grapelike material from deformed chorionic villi through the vagina suggest the presence of a gestational trophoblastic tumor. The condition may also mimic preeclampsia (elevated blood pressure, swelling, headache, blurring of vision) and persisting hyperemesis gravidarum (frequent bouts of nausea and vomiting initially associated with rapidly rising hormone levels). Hyperthyroidism symptoms (palpitations, diarrhea, heat intolerance, sweating, tremors, nervousness/irritability) may also occur due to a molar analog of thyroid-stimulating hormone (human molar thyrotropin) or direct stimulation by beta-human chorionic gonadotropin (β-HCG).

Symptoms of metastasis develop according to the involved organs. On physical examination, a disparity between gestational age and fundal height (length of uterus along its long axis) of four or more weeks is suggestive. A screening β-HCG of more than 100,000 million international units per milliliter (mIU/ml) suggests neoplasia.

Screening and diagnosis: No specific screening is recommended. The single most important laboratory test for diagnosis of GTT is a quantitative assay of human chorionic gonadotropin (HCG), particularly β-HCG, and all its subcomponents. Diagnosis is confirmed by pelvic ultrasound, where the grapelike vesicles may be seen, and partial moles may be found by the absence of a fetal heart and blood flow. A “snowstorm” appearance also may be described. Other imaging studies include a chest X-ray and computed tomography (CT) scan or magnetic resonance imaging (MRI) of the head, abdominal, and pelvic regions to find evidence of metastases.

The International Federation of Gynecology and Obstetrics (FIGO) has created the following staging system:

• Stage I: Gestational trophoblastic tumors strictly confined to the uterine corpus
• Stage II: Tumors extending to the adnexa or vagina but limited to the genital structures
• Stage III: Tumors extending to the lungs, with or without genital tract involvement
• Stage IV: All other metastases

The World Health Organization (WHO) created a prognostic scoring system that is used to further classify the stages used by FIGO into high and low risk. Point values are assigned to various factors present at the time of diagnosis. Prognostic factors include:

• Age: Being over forty, 1 point
• Prior pregnancy: Hydatidiform mole, 0 points; abortion, 1 point; full-term pregnancy, 2 points
• Time from pregnancy to manifestation of the tumor: Less than four months, 0 points; four to six months, 1 point; seven to twelve months, 2 points; more than twelve months, 4 points
• HCG levels in blood (mIU/ml): Less than 1,000, 0 points; 1,000 to 9,999, 1 point; 10,000 to 100,000, 2 points; more than 100,000, 4 points
• Tumor size: Less than 3 centimeters (cm), 0 points; 3 to 4 cm, 1 point; 5 cm or more, 2 points
• Site of metastases: Lung, 0 points; spleen or kidney, 1 point; gastrointestinal tract, 2 points; brain or liver, 4 points
• Number of metastases: One to four, 1 point; five to eight, 2 points; more than eight, 4 points
• Earlier failed chemotherapy: Single drug, 2 points; multiple drugs, 4 points

Low-risk patients have a WHO score of seven or less. High-risk patients have a score of eight or more. This stratification determines the best treatment course. Metastasis to only the lungs with a disease duration of less than four months can be considered low risk.

Treatment and therapy: Treatment includes evacuation of the uterus by suction dilation and curettage, along with monitoring of HCG with the overall goal of achieving undetectable levels. A hysterectomy is avoided unless extensive invasion is present. Metastatic lesions are resected if possible. Evacuation is usually followed by chemotherapy according to risk stratification. Low-risk patients undergo single-drug therapies, which may use methotrexate with or without leucovorin rescue or actinomycin-D given as intramuscular or intravenous injections at regular intervals. High-risk patients are given combination chemotherapy. The main regimen, the EMA-CO protocol, uses etoposide, methotrexate, and actinomycin-D, given before cyclophosphamide and vincristine (Oncovin). Resistant disease utilizes the EMA-EP protocol, in which EMA alternates with etoposide and cisplatin (EP). Other drugs used include paclitaxel (Taxol), 5-fluorouracil (FU), or vinblastine in various combinations with EP. Levels of HCG are monitored after treatment, with two additional chemotherapy sessions after reaching undetectable levels. A minimum of twelve disease-free months is recommended before pregnancy, after which early monitoring is complete.

Prognosis, prevention, and outcomes: Surgery, followed by chemotherapy, has excellent cure rates, approaching 100 percent in low-risk patients and 75 to 90 percent for high-risk patients. Recurrence rates are low, at less than 1 percent.

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