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Practice Guidelines: Gestational Trophoblastic Disease

Practice Guidelines: Gestational Trophoblastic Disease

Gestational trophoblastic disease is a term applied to a rare group of tumors that have several common characteristics: the tumor cells arise in the fetal chorion during pregnancy; the vast majority of the tumors make human chorionic gonadotropin (hCG); the amount of hCG produced is proportional to the amount of viable tumor; and they are sensitive to a variety of cytotoxic chemotherapeutic agents. Histopathologic diagnoses included in this group of tumors are:

  • Hydatidiform mole, complete or partial
  • Gestational choriocarcinoma
  • Placental site trophoblastic tumor

Although they have these common characteristics, they differ in other characteristics: histopathology, type of pregnancy in which the tumor arises, clinical course if untreated with chemotherapy, and likelihood of responding to treatment. Since this group of tumors varies greatly in malignant potential, it is critical that the clinician know enough about the various clinical patterns so that a patient with an essentially benign condition is not overtreated and a patient with a potentially fatal condition can be treated as early and as aggressively as possible.


Although all of these tumors arise in pregnancy, it is only possible in molar pregnancies to know or suspect the type of trophoblastic tumor while the pregnancy is ongoing. Complete hydatidiform moles have characteristics that make them likely to be diagnosed before the uterus is evacuated: the villi are diffusely involved and often quite large (hydropic, “grape-like”); trophoblastic overgrowth is common; uterine size is often in excess of expected size based on dates; theca lutein cysts are common; hCG levels are often greater than expected for corresponding dates of normal pregnancies; and there is no evidence of fetal parts.

With the common practice of routine ultrasonography in the first trimester of pregnancy and the characteristic appearance of the prominent villi on ultrasonographic examination, it is common for complete hydatidiform moles to be diagnosed before there is vaginal spotting or passage of grossly detectable vesicles. The likelihood of there being a need for subsequent chemotherapy after evacuation of the uterus varies from 10% to 25% and depends largely on the criteria the clinician follows to define this need.

Partial hydatidiform moles are much less likely to be diagnosed while still in utero. Much less placenta is involved in hydropic villous change; trophoblastic proliferation is focal and slight; fetal remnants may be seen; the uterus tends to be small; theca lutein cysts are rare; and the hCG level is not excessive. The sonographic findings often fail to result in the correct diagnosis. Although the likelihood of so-called “malignant sequelae” (molar proliferation or transition to choriocarcinoma) is less than that associated with a complete hydatidiform mole, the fact that these have been reported requires that all patients with molar pregnancies undergo the same surveillance. This use of hCG assays will be discussed below.

Gestational choriocarcinoma is the highly malignant form of gestational trophoblastic disease that, unfortunately, can arise in any form of pregnancy. It can follow an apparently normal pregnancy, any type of abortion (spontaneous, ectopic, or elective), and can develop from malignant transition in a molar pregnancy. Because of the rarity of it developing after a term delivery (1/12,000 to 1/40,000), it is not practical to follow patients after term deliveries or even miscarriages with hCG assays to detect malignant disease.

Placental site trophoblastic tumors are the rarest form of gestational trophoblastic disease and were belatedly recognized as a separate histopathologic and clinical entity. They are composed of only one cell type, intermediate trophoblast, and, like gestational choriocarcinoma, they can follow any type of pregnancy. Their clinical course is unpredictable, for they may be cured by a dilation and curettage (D&C) or persist and metastasize. Unfortunately, they respond poorly to chemotherapy and produce hCG unreliably. Early surgery, including hysterectomy, is important. Their rarity is fortunate for we have little control over their clinical outcome if surgery is not successful.


Although the diagnosis of a molar pregnancy identifies a patient who needs follow-up hCG assays to identify those needing further therapy, the early diagnosis of malignant trophoblastic disease following a term pregnancy or abortion often requires suspicion for the diagnosis when a woman of reproductive age presents with an undiagnosed tumor or bleeding from a metastatic site. Some patients will be fortunate enough to have persistent tumor limited to the uterus and have their diagnosis established by D&C, but most will present with metastatic disease. Sites of metastases, in descending order, are lung, vagina, brain, liver, gastrointestinal tract, and kidney. Because the time interval from the antecedent normal pregnancy to the onset of symptoms of metastatic disease can vary from months (usual) to years (rare), clinicians must be aware of the possibility that a malignant trophoblastic tumor may be the cause of abnormal bleeding or an unexplained tumor in virtually any organ. One sensitive hCG assay will determine if the woman has a rare, but highly curable, gestational choriocarcinoma.

Diagnostic procedures that are needed to properly classify patients begin with a chest x-ray to detect pulmonary metastases. If there is no abnormal bleeding or worrisome symptoms from other organs and the chest x-ray is clear, an argument can be made for classifying the patient as having a nonmetastatic tumor. Even though a CT scan might reveal disease detectable by regular x-rays, 40% of patients with suspected malignant gestational trophoblastic disease and a clear chest x-ray will have small metastases detected by CT scans of the lungs.

If pulmonary metastases are detected, CT scans of the brain, abdomen, and pelvis are indicated. In the presence of questionable liver changes on CT scan, a sonogram may be more useful. Similarly, an MRI or serum/cerebrospinal fluid (CSF) ratio of beta hCG may be more sensitive in detecting brain metastases. If there is gastrointestinal (GI) bleeding, upper and lower GI tract endoscopy is indicated. If GI bleeding is heavy, an arteriogram to detect bleeding sites is useful prior to surgery. Hematuria calls for an intravenous pyelogram and cystoscopy.

All of these tests may contribute to the localization of disease and the assignment of proper stage or World Health Organization (WHO) score, but they are not as useful in following response to chemotherapy, as is the weekly assay of hCG levels. A reliable assay of hCG is critical for diagnosis, monitoring of response to therapy, defining complete response, and surveillance for recurrence. None of the x-rays or scans is as reliable for these purposes.

Staging (Classification of Disease)

Unlike all other staging systems for gynecologic malignancies, the two most often used systems for categorizing patients with gestational trophoblastic disease are based on more than histology and location of the disease. There are several reasons for this. The most important reason is that the two most commonly used staging classifications, the National Institutes of Health (NIH) clinical classification (Table 1) and the Bagshawe/WHO system (Table 2) are actually designed to allow the proper selection of chemotherapy rather than to plan surgery or radiation therapy. Also, there is little emphasis on the histology of metastatic lesions (metastatic molar tissue or choriocarcinoma) because their treatment is the same. Finally, these two classifications take into consideration dynamic factors in the clinical course of the patient (level of hCG, time since onset of disease, prior chemotherapy, and number as well as site of metastases). Because of this, they define the risk of a patient not responding to chemotherapy at any given time when new treatment is being started.

Because there is such a wide range of effective chemotherapeutic agents that can be used alone or in various combinations in patients with gestational trophoblastic disease, the purpose of these two systems is to allow the clinician to select treatment that is effective in a risk category but no more toxic or dangerous than is necessary. In the low-risk categories, new developments have as their goal the avoidance of toxicity, decrease of costs, or similar considerations, without a decrease in cure rates. In the high-risk category, the goal is to increase the cure rate.


Because chemotherapy is effective in treating both metastatic and nonmetastatic disease, and surgery can still be curative in disease limited to the uterus, one of the important considerations in choosing treatment is the patient’s desire to preserve her childbearing potential. This is more important in patients with nonmetastatic disease than in those with metastases. In considering treatment of patients with nonmetastatic disease, the histologic pattern of the uterine disease is important.


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