Paola Aghajanian, MD
ESSENTIALS OF DIAGNOSIS
Uterine bleeding in first trimester
Absence of fetal heart tones and fetal structures
Rapid enlargement of the uterus or uterine size greater than anticipated by dates
Human chorionic gonadotropin titers greater than expected for gestational age
Vaginal expulsion of vesicles
Hyperemesis gravidarum
Theca lutein cysts
Onset of preeclampsia in the first trimester
Pathogenesis
The spectrum of gestational trophoblastic disease includes hydatidiform moles (complete and partial) and gestational trophoblastic neoplasia comprising invasive moles, choriocarcinomas, and placental-site trophoblastic tumors (PSTT). These tumors are unique in that they develop from an aberrant fertilization event and hence arise from fetal tissue within the maternal host. They are composed of both syncytiotrophoblastic and cytotrophoblastic cells, with the exception of PSTT, which is derived from intermediate trophoblastic cells. In addition to being the first and only disseminated solid tumors that have proved to be highly curable by chemotherapy, they elaborate a unique and characteristic tumor marker, human chorionic gonadotropin (hCG).
A. Hydatidiform Mole
Hydatidiform mole is the most common form of gestational trophoblastic disease and is benign in nature. Its incidence varies worldwide from 1 in 125 deliveries in Mexico and Taiwan to 1 in 1500 deliveries in the United States. The incidence is higher in women younger than 20 and older than 40 years of age, in nulliparous women, in patients of low socioeconomic status, and in women whose diets are deficient in protein, folic acid, and carotene. Blood group A women impregnated by group O men have an almost 10-fold greater risk of subsequently developing gestational trophoblastic neoplasia than group A women impregnated by group A partners. Furthermore, women with blood group AB tend to have a relatively worse prognosis.
Two distinct forms of hydatidiform mole exist: complete and partial moles. Table 51–1 outlines the clinical, pathologic, and genetic characteristics of both. Cytogenetic studies demonstrate that complete moles are usually euploid, paternal in origin, and sex chromatin-positive—46 XX or 46 XY. They arise when an empty ovum (with an absent or inactivated nucleus) is fertilized by a haploid sperm that duplicates its chromosomes or by two haploid sperm. A partial mole, on the other hand, is triploid—69 XXY (70%), 69 XXX (27%), or 69 XYY (3%)—arising when an ovum with an active nucleus is fertilized by a duplicated sperm or two haploid sperm. Both of these processes result in a homozygous conceptus with a propensity for altered growth.
Table 51–1. Comparison of complete and partial hydatidiform moles.
Hydatidiform mole is thought to arise from extraembryonic trophoblasts. Histologic similarities between molar vesicles and chorionic villi support the view that one is derived from the other. Detailed morphologic studies of hysterectomy specimens containing intact molar pregnancies suggest that transformation of the embryonic inner cell mass at a stage just prior to the laying down of endoderm gives rise to hydatidiform moles. At this stage in embryogenesis, the inner cell mass has the potential to develop into trophoblasts, ectoderm, or endoderm. If normal development is interrupted, such that the inner cell mass loses its capacity to differentiate into embryonic ectoderm and endoderm, a divergent development pathway is created. This pathway may then result in production of extraembryonic mesoderm and molar vesicles with loose primitive mesoderm in their villous core.
Grossly, a hydatidiform mole is characterized by multiple grapelike vesicles filling and distending the uterus, usually in the absence of an intact fetus (Fig. 51–1). Most hydatidiform moles are recognizable on gross examination, but some are small and may seem to be ordinary abortuses. Microscopically, moles may be identified by three classic findings: edema of the villous stroma, avascular villi, and nests of proliferating trophoblastic elements surrounding villi (Figs. 51–2 and 51–3). The likelihood of malignant sequelae is higher in patients whose trophoblastic cells show increased proliferation and anaplasia. Although histologic studies of the trophoblast provide some basis for predicting a benign or malignant course for the mole, the correlation is not absolute.
Figure 51–1. Hysterectomy specimen of a complete mole with anterior wall incised, displaying typical clear, “grapelike” vesicles filling the uterine cavity. Hysterectomy was performed as primary treatment for molar gestation. (Reproduced, with permission, from Emiliano Chavira, MD.)
Figure 51–2. A complete mole characterized by enlarged, avascular chorionic villi with exuberant cytotrophoblastic and syncytiotrophoblastic proliferation. Magnified 100x. (Reproduced, with permission, from Wenxue Xing, MD.)
Figure 51–3. A partial mole showing a biphasic population of small, normal appearing, and enlarged villi with irregular contours. The large villi exhibit mild to moderate syncytiotrophoblastic proliferation. Fetal red blood cells can be appreciated in the villous capillaries. Magnified 100x. (Reproduced, with permission, from Wenxue Xing, MD.)
Today, with earlier detection, the classic pathologic presentation of molar pregnancies is less common. Therefore, it can be more difficult to differentiate histologically between a complete mole, a partial mole, and a nonmolar hydropic abortion. Use of flow cytometry can determine ploidy (eg, diploid versus triploid). Additionally, p57 immunohistochemistry staining can be used to stain for PHLDA2, a paternally imprinted, maternally expressed gene product that is absent in complete moles but present in partial moles and hydropic abortuses.
B. Invasive Mole
Invasive mole is reported in 10–15% of patients who have had a hydatidiform mole. Although considered a benign neoplasm, invasive mole, as its name implies, is locally invasive and invades the myometrium and adjacent structures. Additionally, it has the potential to completely penetrate the myometrium and cause subsequent uterine rupture and hemoperitoneum. However, it also has the ability to spontaneously regress. The microscopic findings are similar to that of a hydatidiform mole. Because adequate myometrium is rarely obtained at curettage and fewer hysterectomies are being performed in patients with trophoblastic disease, the diagnosis is less often made by histologic analysis.
C. Choriocarcinoma
Choriocarcinoma is reported in 2–5% of all cases of gestational trophoblastic neoplasia. The incidence in the United States is 1 in 40,000 pregnancies, but it is higher in Asia. It may accompany or follow any type of pregnancy. In about half of choriocarcinoma cases, the antecedent gestational event is a hydatidiform mole. Another 25% follow a term pregnancy, and the remaining 25% occur after an abortion.
Choriocarcinoma is a pure epithelial tumor composed of syncytiotrophoblastic and cytotrophoblastic cells. It usually presents as late vaginal bleeding in the postpartum period. An enlarged uterus, enlarged ovaries, and vaginal lesions may be noted during the physical examination.
Histologic evaluation of the tumor discloses sheets or foci of trophoblasts on a background of hemorrhage and necrosis, but no villi (Fig. 51–4). Assessment of trophoblastic tissue following or accompanying pregnancy may prove difficult because of the histologic similarities of the trophoblastic patterns in very early pregnancy and chorio-carcinoma. Consequently, the curettage specimen must be processed in its entirety, as the specimen may contain only small, isolated areas of choriocarcinoma. A histopathologic diagnosis of choriocarcinoma in any site is an indication for prompt treatment after confirmation by gonadotropin excretion measurements.
Figure 51–4. This choriocarcinoma demonstrates the typical avillous trophoblastic proliferation that characterizes this neoplasm. Masses of markedly atypical cytotrophoblasts are intimately associated with multinucleated syncytiotrophoblasts. Mitotic figures are readily identified. Magnified 100x. (Reproduced, with permission, from Wenxue Xing, MD.)
D. Placental-Site Trophoblastic Tumor
PSTT is a rare variant of gestational trophoblastic tumor. It may arise months to years after a hydatidiform mole or, less commonly, following a normal term pregnancy. The tumor is generally confined to the uterus, but local invasion may occur into the myometrium, lymphatics, or vasculature. It metastasizes late in its course. PSTT is derived from the intermediate trophoblasts of the placental bed, with minimal or absent syncytiotrophoblastic tissue. As syncytiotrophoblastic cells are generally absent from this tumor, minimal amounts of hCG are released in relation to the tumor burden. However, human placental lactogen is secreted, and its levels can be monitored to follow response to therapy.
Prevention
The only way to prevent the occurrence of gestational trophoblastic diseases is abstinence from sexual intercourse.
Clinical Findings
A. Symptoms & Signs
Abnormal uterine bleeding, usually during the first trimester, is the most common presenting symptom, occurring in more than 90% of patients with molar pregnancies. Three-fourths of these patients present before the end of the first trimester. Nausea and vomiting have been reported in 14–32% of patients with hydatidiform mole and may be confused with nausea and vomiting of pregnancy or hyperemesis gravidarum. Ten percent of these patients may have nausea and vomiting severe enough to require hospitalization.
About half of patients will have a uterine size that is greater than expected for their gestational age. However, in one-third of patients, the uterus may be smaller than expected. Multiple theca lutein cysts causing enlargement of one or both ovaries are seen in 15–30% of women with molar pregnancies. In about half of these cases, both ovaries are enlarged and may be a source of pain. Involution of the cysts proceeds over several weeks and usually parallels the decline of hCG values. In studies, patients with theca lutein cysts appear to have a greater likelihood of developing malignant sequelae of gestational trophoblastic neoplasia.
Preeclampsia in the first trimester or early second trimester—an unusual finding in normal pregnancies—has been said to be pathognomonic for a molar pregnancy. Hyperthyroidism from stimulation of thyrotropin receptors by hCG can also occur in 10% of patients, although the disease is usually subclinical, and most patients remain asymptomatic. Treatment involves evacuation of the mole. An occasional patient may require brief antithyroid therapy.
Because of the earlier diagnosis of molar pregnancies, the classic presenting symptoms and signs of gestational trophoblastic disease are now less prevalent. For instance, at the New England Trophoblastic Disease Center, the incidence of excessive uterine enlargement, hyperemesis, and preeclampsia was 28%, 8%, and 1%, respectively. The incidence of hyperthyroidism and respiratory insufficiency was negligible. Although the number of cases presenting with these classic signs and symptoms has decreased, the incidence of persistent postmolar gestational trophoblastic disease has remained static.
This highlights the importance of vigilant postmolar hCG surveillance. Any woman with a recent history of molar pregnancy, abortion, or normal pregnancy who presents with vaginal bleeding or a tumor in any organ should have a thorough physical examination and at least one hCG assay to ensure that gestational trophoblastic neoplasia is not the cause. This is of utmost importance given that the cure rate of properly treated gestational trophoblastic neoplasia approaches 90%.
B. Laboratory Findings
The principal characteristic of gestational trophoblastic neoplasms is their capacity to produce hCG. This hormone may be detected in the serum or urine of virtually all patients with hydatidiform mole or malignant trophoblastic disease, and its levels correlate closely with the presence of viable tumor cells. Consequently, monitoring of hCG levels is a necessary tool for the diagnosis, treatment, and surveillance of the disease process.
The usefulness of a serum gonadotropin assay depends on the hCG titer and the sensitivity of the test. Today, sensitive and specific immunoassays are available to differentiate hCG from luteinizing hormone by measuring the β chain of hCG. Serial β-hCG levels are best monitored in the same laboratory using the same immunoassay technique.
The rate of decline in hCG titers is also important. Normal postmolar pregnancy hCG regression curves highlighting the weekly hCG levels in patients undergoing spontaneous remission have been constructed, hence providing a reference for the comparison of random or serial values. In most instances, the hCG values exhibit a progressive decline to nondetectable levels within 14 weeks after evacuation of a molar pregnancy. If the hCG titer rises or plateaus, it must be concluded that viable tumor continues to persist. If the levels of hCG are very low and not responsive to treatment, a false-positive hCG result or “phantom hCG,” caused by cross-reaction of heterophilic antibodies with the hCG test, should be considered.
C. Ultrasonographic Findings
The simplicity, safety, and reliability of ultrasonography define it as the diagnostic method of choice for patients with suspected molar pregnancy. In a complete molar pregnancy, the characteristic ultrasound pattern consists of multiple hypoechoic areas corresponding to hydropic villi, at times described as a “snowstorm” pattern (Fig. 51–5). A normal gestational sac or fetus is not present. Theca lutein cysts may be visualized. In a partial mole, focal areas of trophoblastic changes and fetal tissue may be noted. Focal cystic changes in the placenta are also a hallmark finding. On the other hand, an ultrasonogram of a choriocarcinoma may reveal an enlarged uterus with a necrotic and hemorrhagic pattern, whereas that of PSTT may show an intrauterine mass.
Figure 51–5. Vaginal ultrasound of patient in Figure 51–1 demonstrating the characteristic intrauterine hypoechoic areas corresponding to hydropic villi, at times described as a “snowstorm” pattern. (Reproduced, with permission, from Emiliano Chavira, MD.)
A pelvic ultrasound should be obtained in any patient who presents with bleeding in the first half of pregnancy and/or has a uterus greater than the gestational size. Even when the uterus is appropriate for gestational age, ultrasonography can be key in differentiating between a normal pregnancy and a hydatidiform mole.
Differential Diagnosis
Gestational trophoblastic disease must be distinguished from a normal pregnancy, an aborting pregnancy, and an ectopic pregnancy. Ultrasonography is a useful tool in this respect. Quantitative hCG levels improve the accuracy of the diagnosis. Analysis of tissue obtained from a dilatation and evacuation for histology and DNA content will prove invaluable.
Complications
The maternal–fetal barrier contains leaks large enough to permit passage of cellular and tissue elements. As a result, deportations of trophoblastic tissue to the lungs are frequent. Spontaneous regression of these ectopic trophoblastic tissues can occur. Less commonly, this results in a syndrome of acute pulmonary insufficiency. Symptoms of dyspnea and cyanosis, due to massive deportation of trophoblasts to the pulmonary vasculature and subsequent formation of pulmonary emboli, can present within 4–6 hours after evacuation of a molar pregnancy. Pulmonary edema leading to high-output congestive heart failure may complicate excessive fluid administration, preeclampsia, anemia, or hyperthyroidism.
Treatment
A. Hydatidiform Mole
1. Evacuation—After the diagnosis has been confirmed, blood type, hematocrit, and thyroid, liver, and renal function tests should be obtained. A chest radiograph can rule out metastasis to the lungs. Subsequently, the molar pregnancy should be terminated. Suction curettage under general anesthesia is the method of choice once the patient is deemed stable. This can be safely accomplished even when the uterus is the size of a 28-week gestation. Local or regional anesthesia may be an option for the stable, cooperative patient with a small uterus. Intravenous oxytocin should be administered after dilation of the cervix but before the start of evacuation and may be continued, if necessary, for 24 hours post-evacuation. Tissue should be submitted for pathologic study. Blood loss usually is moderate, but precautions should be taken for the possibility of hemorrhage requiring a transfusion. When a large hydatidiform mole (>12 weeks in size) is evacuated by suction curettage, a laparotomy setup should be readily available, as hysterotomy, hysterectomy, or bilateral hypogastric artery ligation may be necessary if perforation or hemorrhage occurs. After the completion of the evacuation, all Rh-negative patients should receive Rh immune globulin.
Hysterectomy continues to remain an option for good surgical candidates not desirous of future pregnancy and for older women (who are more likely to develop malignant sequelae). If theca lutein cysts are encountered at laparotomy, the ovaries should remain intact, as regression to normal size will occur with diminishing hCG titers. Surgical treatment of these cysts is indicated only if rupture, torsion, or hemorrhage occurs or if the enlarged ovaries become infected.
It is important to note that hysterectomy does not eliminate the need for careful postsurgical surveillance with hCG testing, although the likelihood of metastatic disease following hysterectomy for gestational trophoblastic disease decreases from 20 to 3.5%. Current recommendations restrict hysterotomy to cases complicated by hemorrhage. Medical induction of labor with prostaglandins, oxytocin, or intra-amniotic instillation of prostaglandin or hypertonic solutions is no longer an acceptable method for evacuation of a molar pregnancy.
2. Prophylactic chemotherapy—Controversy surrounds the use of prophylactic chemotherapy (with methotrexate or dactinomycin) after a complete molar pregnancy. Several studies indicate that the incidence of postmolar gestational trophoblastic neoplasia may be decreased with prophylactic chemotherapy. However, further studies are required to determine whether the potential side effects warrant such treatment in noncompliant patients and in those at high risk for persistent gestational trophoblastic disease (age >35 years, history of prior molar pregnancy, trophoblastic hyperplasia).
3. Surveillance—Despite earlier diagnosis of molar pregnancies, the incidence of persistent gestational trophoblastic disease has not decreased. Three-fourths of patients with malignant nonmetastatic trophoblastic disease and half of patients with malignant metastatic disease develop these tumors following a hydatidiform mole. In the remainder, disease arises subsequent to a term pregnancy, abortion, or ectopic pregnancy. Several clinical features of hydatidiform moles are recognized as having a high association with malignant trophoblastic neoplasia. In general, at diagnosis, the larger the uterus and the higher the hCG titer, the greater the risk for malignant gestational trophoblastic disease. The combination of theca lutein cysts and uterine size excessive for gestational age is associated with an extremely high risk of malignant sequelae. Pathologic specimens with marked nuclear atypia, necrosis, hemorrhage, or trophoblastic proliferation may also increase the risk of persistent disease.
Regardless of the method of termination (suction curettage or hysterectomy) or presence of high-risk features, close monitoring with serial hCG titers is essential for every patient, as the incidence of malignant sequelae approaches 20–30%. After evacuation of the molar pregnancy, the patient should undergo serial hCG determinations, beginning within 48 hours after evacuation and then at weekly intervals until hCG values decline to undetectable levels (<5 mIU per milliliter) on three successive assays. If titer remission occurs spontaneously within 14 weeks and without a titer plateau, the hCG titer should then be repeated monthly for at least 6 months to 1 year before the patient is released from close medical supervision. Thereafter, the patient may enter into a routine gynecologic care program.
A gynecologic examination should be done 1 week after evacuation, at which time blood may be taken for the hCG titer. Estimates of uterine size, presence of adnexal masses (theca lutein cysts) and presence of vulvar, vaginal, or cervical lesions should be noted. Unless symptoms develop, the examination may be repeated at 4-week intervals throughout the observation period. If pre-evacuation chest radiography has revealed pulmonary metastases, chest radiographs should be repeated at 4-week intervals until spontaneous remission is confirmed, then at 3-month intervals during the remainder of the surveillance period.
Effective contraceptive measures should be implemented and maintained throughout the period of surveillance. Studies have not shown an increased risk of persistent gestational trophoblastic neoplasia after a molar pregnancy with the use of oral contraceptives. Therefore, they remain the most widely used method of birth control. A patient who has entered into spontaneous remission with negative titers, examinations, and chest radiographs for 6 months to 1 year and who is desirous of becoming pregnant may terminate contraceptive practices. Successful pregnancy is the norm, and complications are similar to those of the general population.
Therapy for persistent gestational trophoblastic neoplasia after evacuation of a hydatidiform mole is usually instituted because of an abnormal hCG regression curve. The most critical period of observation is the first 4 to 6 weeks post-evacuation. Although the hCG titer usually returns to normal by 1–2 weeks after evacuation of a hydatidiform mole, it should normalize in most women by the eighth week.
Approximately 70% of patients achieve a normal hCG level within 8 weeks of evacuation. Very few patients whose hCG titers normalize during this interval will require future treatment. In the past, therapy for persistent disease was initiated for the 30% of women whose hCG titer remained elevated at or beyond 8 weeks post-termination. However, current data suggest that half of these patients will demonstrate a continuous decline in titers and ultimately achieve normal hCG levels without further treatment. The remaining half will experience a rising or plateauing titer with histologic evidence of an invasive mole or choriocarcinoma.
Delayed postevacuation bleeding is uncommon after a molar pregnancy and signifies the presence of an invasive mole or choriocarcinoma. It is invariably attended by an enlarging uterus and an abnormal hCG regression pattern. In some cases, curettage is effective in stopping the bleeding, although little intracavitary tissue will be present in most of these cases. The mainstay of treatment is chemotherapy.
B. Malignant Gestational Trophoblastic Neoplasia
According to the 2002 criteria established by the International Federation of Gynecology and Obstetrics (FIGO), malignant gestational trophoblastic neoplasia may be diagnosed in the setting of (1) a rise in hCG levels of 10% or greater for ≥3 values over 2 weeks; (2) a plateau in ≥4 hCG values over 3 successive weeks; (3) hCG levels elevated at 6 months postevacuation; or (4) a tissue diagnosis of choriocarcinoma.
Once the diagnosis of malignant trophoblastic disease is suspected or established, an accurate history and physical examination are crucial. Most patients will have an enlarged uterus as well as ovarian enlargement caused by theca lutein cysts. Sites of metastasis must be sought, especially in the lower genital tract. A chest radiograph can diagnose lung metastases, although a chest computerized tomography (CT) will miss fewer pulmonary metastatic lesions. Liver metastases may be diagnosed with ultrasonography or CT scan. Brain metastases are best evaluated with a CT scan or magnetic resonance imaging (MRI). The ratio of serum hCG values to the concentration of hCG in cerebrospinal fluid (normal >60:1) may also prove helpful. Baseline hematologic counts, coagulation studies, and hepatic and renal function tests are critical in later assessing the risk of drug toxicity. After all sites of metastases have been identified and the patient’s desires for preservation of reproductive function are determined, specific therapy should be initiated.
1. Nonmetastatic malignant gestational trophoblastic disease—Trophoblastic disease confined to the uterus is the most common malignant lesion seen in gestational trophoblastic neoplasia. The diagnosis is usually made during the postmolar surveillance period. Therapy for patients with nonmetastatic malignant trophoblastic disease includes (1) single-agent chemotherapy or (2) combination chemotherapy and hysterectomy, with surgery performed on the third day of drug therapy for patients who do not wish to preserve reproductive function.
Table 51–2 summarizes the recommended chemotherapeutic regimens available for nonmetastatic gestational trophoblastic neoplasia. Single-agent chemotherapy using methotrexate or dactinomycin has demonstrated clear-cut superiority over other protocols. A randomized trial conducted by the Gynecologic Oncology Group concluded that biweekly IV dactinomycin 1.25 mg/m2 achieved a higher complete response rate as compared to weekly IM methotrexate 30 mg/m2. The methotrexate dose used in this trial, however, was lower than the weekly dose of 50 mg/m2 given typically to most low-risk patients and may have accounted for the superiority of the dactinomycin. Therefore, the regimen of choice in this group of patients has yet to be determined.
Table 51–2. Chemotherapy regimens for nonmetastatic or low-risk metastatic gestational trophoblastic disease.
Treatment failure or intolerable side effects should result in administration of the alternative agent or regimen. Each treatment cycle should be repeated as soon as normal tissues (bone marrow and gastrointestinal mucosa) have recovered, with a minimum 7-day window between the last day of one course and the first day of the next course. Overall, the complete response rate to single-agent therapy ranges from 60 to 98%, with salvage rates approaching 100%. Methotrexate is contraindicated in the presence of hepatocellular disease or when renal function is impaired.
During treatment, weekly quantitative hCG titers and complete blood counts should be obtained. Before each course of therapy, liver and renal function assessments should be assessed. At least 1 additional course of drug therapy should be given after attainment of the first normal hCG value. The number of treatment cycles necessary to induce remission is proportionate to the magnitude of the hCG concentration at the start of therapy. An average of 3 or 4 courses of single-agent therapy is usually required. After remission has been induced and treatment is completed, hCG assays should be obtained monthly for 1 year.
2. Metastatic gestational trophoblastic disease—Treatment in metastatic disease uses either single-agent chemotherapy (Table 51–2) or multiagent chemotherapy in cases in which resistance to a single agent is anticipated. Several systems have been developed to determine at onset which patients will require more aggressive therapy. The National Cancer Institute system is used in the United States to determine whether the patient will have a good or poor prognosis in response to single-agent chemotherapy (Table 51–3).
Table 51–3. Categorization of gestational trophoblastic neoplasia.
Table 51–4 highlights the World Health Organization (WHO) scoring system in which patients are categorized into low- or high-risk groups based on risk factors such as age, type of antecedent pregnancy, interval from antecedent pregnancy to initiation of chemotherapy, pretreatment hCG level, size of largest tumor, site of metastases, number of metastases, and prior chemotherapy. A total score of 0–6 is considered low risk and a total score ≥7 is categorized as high risk.
Table 51–4. Modified WHO prognostic scoring system as adapted by FIGO.
The revised 2002 FIGO staging system combines the use of both anatomic and nonanatomic factors (Table 51–5). A patient is assigned a stage based on the anatomic location of disease and given a risk factor score based on the WHO prognostic scoring system. The goal of the revised FIGO staging is to improve the assessment and clinical management of patients and to unify staging to allow for international comparisons in treatment success.
Table 51–5. FIGO anatomic staging.
A. GOOD-PROGNOSIS PATIENTS—Based on the clinical classification of malignant disease, patients can be expected to respond satisfactorily to single-agent chemotherapy if (1) metastases are confined to the lungs or pelvis, (2) serum hCG levels are below 40,000 mIU/mL at the onset of treatment, and (3) therapy is started within 4 months of apparent onset of disease. The most common site of metastasis in gestational trophoblastic disease is the lungs. When a patient develops pulmonary metastasis with elevation of the hCG titer, choriocarcinoma is a more likely cause than metastatic invasive mole, although the latter can also metastasize to the lungs.
The advantage of single-agent chemotherapy over multiagent therapy lies in its more favorable toxicity profile, with fewer total side effects, and a lower likelihood that these effects would be irreversible. It is important to keep in mind that despite the “good-prognosis” designation of low-risk disease, failure of drug therapy does occur in 10% of cases. Therefore, meticulous care by a knowledgeable physician such as a gynecologic oncologist is necessary for optimal outcomes.
In good-prognosis patients, single-agent chemotherapy (Table 51–2) with methotrexate is considered the drug of choice. Ideally, the 5-day treatment course is given every other week, as the possibility of tumor regrowth increases with treatment gaps >2 weeks. Once negative titers have been achieved, an additional course is administered before beginning the period of surveillance. In cases in which resistance to methotrexate occurs, as manifested by rising or plateauing titers or by the development of new metastases, or cases in which negative titers are not achieved by the fifth course of methotrexate, the patient should be given dactinomycin. Dactinomycin should also be the agent of choice for patients who experience severe side effects with methotrexate.
B. POOR-PROGNOSIS PATIENTS—Poor-prognosis patients, based on the Clinical Classification of Malignant Disease, are those with any of the following risk factors: (1) serum hCG titers >40,000 mIU/mL at the onset of treatment, (2) diagnosis of disease more than 4 months after molar pregnancy, (3) brain or liver metastases, (4) prior unsuccessful chemotherapy, or (5) onset after term gestation. These patients respond poorly (<40% response rate) to single-agent therapy. A poor response is also seen in patients with advanced revised FIGO stages and WHO scores ≥7. These patients present a serious challenge to the clinician, as many have been previously treated with chemotherapy, have developed resistance to key agents, and/or have accumulated considerable toxicity with depleted bone marrow reserves. In fact, prior unsuccessful chemotherapy is considered to be one of the worst prognostic factors.
Generally, poor-prognosis patients are managed by a gynecologic oncologist and may require prolonged hospitalization and multiple courses of chemotherapy. They often need multispeciality care and other life-support measures, including hyperalimentation, antibiotics, and transfusions to correct the effects of marrow depression.
Central nervous system involvement, particularly brain metastases with focal neurologic signs, commonly occurs with choriocarcinoma. Because patients with brain or liver metastases are at high risk of sudden death from hemorrhagic lesions, it is standard practice to institute whole-brain or whole-liver irradiation concomitantly with combination chemotherapy. Uncertainty remains regarding whether radiation therapy exerts its beneficial effects by destroying tumor in combination with drug therapy or by preventing fatal hemorrhage and thus keeping the patient alive until remission with chemotherapy has been achieved. For acute bleeding episodes, surgical intervention or angiographic embolization should be considered.
Cerebral metastases are treated over a 2-week period with radiation given at a dosage of 3 Gy daily, 5 days a week, to a total organ dose of 30 Gy. Whole-liver irradiation is usually accomplished over 10 days to attain a 20-Gy whole-organ dose given at a rate of 2 Gy daily, 5 days a week. Other treatment options include selective hepatic artery chemotherapy infusion.
Previously, patients with poor prognosis or high-risk gestational trophoblastic neoplasia were treated with methotrexate, dactinomycin, and chlorambucil or cyclophosphamide and the modified Bagshawe protocol (cyclophosphamide, hydroxyurea, methotrexate, vincristine, cyclophosphamide, and dactinomycin). Currently, etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine (EMACO) chemotherapy (Table 51–6) repeated every 2 weeks provides the best response rate (approximately 80%) with the lowest side-effect profile. Monitoring for drug toxicity is the same as that in single-agent therapy but with higher vigilance due to the possibility of combined toxicity.
Table 51–6. Current treatment regimens for high-risk metastatic gestational trophoblastic disease.
Treatment of malignant trophoblastic disease must be continued with repeated courses of combination chemotherapy until hCG titers return to undetectable levels (<5 mIU/mL). Complete remission is documented only after 3 consecutive weekly normal hCG titers have been achieved. It is recommended that all high-risk patients receive at least 3 courses of multiagent chemotherapy after hCG titers have returned to normal. After remission is achieved, follow-up is the same as for hydatidiform moles and metastatic good-prognosis disease.
Salvage therapy for disease not responsive to EMACO substitutes cisplatin and etoposide for cyclophosphamide and vincristine (EP-EMA) (Table 51–6). Close monitoring of renal function is required because of nephrotoxicity secondary to cisplatin and renally excreted methotrexate. Other treatment options include paclitaxel, topotecan, and high-dose chemotherapy with autologous bone marrow transplantation. As stated previously, chemotherapy should be continued for at least 3 cycles after a negative hCG is achieved. In resistant cases, adjunctive measures along with chemotherapy may include hysterectomy, resection of metastatic tumors, or irradiation of unresectable lesions.
During and after treatment, a thorough discussion about birth control and reproductive options is of utmost importance. Oral contraceptive pills should be used if not contra-indicated. Contraceptive efforts should be continued for at least 1 year after remission.
3. Placental-Site Trophoblastic Tumor—As treatment of PSTT is generally resistant to chemotherapy, hysterectomy is the recommended route of treatment. Partial uterine resection involving the tumor is possible if the patient desires future fertility. Chemotherapy is indicated in cases of metastatic disease. EP-EMA is the preferred regimen over EMACO, with paclitaxel and topotecan used when resistance develops. The greatest adverse outcomes are associated with an interval of >2 years from the antecedent pregnancy to diagnosis.
Prognosis
The prognosis for molar pregnancies treated with evacuation is uniformly excellent, although close surveillance is needed, as outlined previously. After spontaneous normalization of hCG values after evacuation, recurrence rates are <0.5%. The prognosis for malignant nonmetastatic disease with appropriate therapy is also quite good, as almost all patients are cured. More than 90% of these patients can preserve reproductive function, but first-line therapy fails in 6.5%.
Additionally, more than 90% of patients with good-prognosis or low-risk metastatic disease respond to single-agent chemotherapy. Virtually all patients with this type of disease can be cured without the need for hysterectomy. In poor-prognosis or high-risk metastatic disease, the best results are achieved with the EMACO chemotherapy regimen and concurrent radiation. Approximately 75–85% of patients achieve remission with a 69% salvage rate. This is a similar response rate to agents used previously but with fewer side effects. Women with nonpulmonary metastases have the worst prognosis, with reports of survival ranging from 0 to 60% for hepatic involvement and 50–80% for central nervous system involvement. Survival decreases to <20% when prior chemotherapeutic agents have been administered or if brain metastasis develops while undergoing treatment. In metastatic disease that is in remission, relapse can occur in 8% of patients, usually in the first several months after termination of therapy but even as late as 3 years.
Over the years, deaths from chemotherapeutic drug toxicity have decreased considerably. However, multiagent chemotherapy, specifically a regimen containing etoposide, is associated with a 50% increased risk for secondary tumors. One retrospective study found that the relative risk for developing myeloid leukemia and colon cancer was 16.6 and 4.6, respectively. When survival exceeded 25 years, the relative risk for developing breast cancer was 5.8.
Subsequent pregnancies are not at increased risk for complications such as preterm labor, congenital anomalies, or stillbirth. These pregnancies should, however, be monitored early with ultrasonography and hCG levels as there is a 1% risk of recurrent gestational trophoblastic disease after 1 molar pregnancy and a 15% risk of recurrence after 2 molar pregnancies. After delivery, the placenta should be sent to pathology and an hCG level checked at the 6-week postpartum visit.
In cases in which pregnancy occurs before completion of standard postmolar surveillance, the pregnancy may be continued with close observation, and the risks discussed with the patient. Most of these pregnancies have a favorable outcome, but a small risk exists for delayed diagnosis of recurrent gestational trophoblastic disease.
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