Chorionic tumors, or gestational trophoblastic diseases, originate from placental tissues and are among the rare human

tumors that can be cured even in the presence of widespread metastasis.1-4 Gestational trophoblastic diseases include a spectrum of interrelated tumors, including complete and partial hydatidiform mole, placental-site trophoblastic tumor, and choriocarcinoma, that vary in their propensity for local invasion and spreading. Although persistent gestational trophoblastic tumors develop most commonly after a molar pregnancy, they may follow any gestation. This article concentrates on recent advances in the understanding of the pathogenesis, natural history, and treatment of gestational trophoblastic diseases and describes our current approach to their management. Hydatidiform moles can be categorized as either complete or partial on the basis of karyotype, gross morphology, and histopathology (Table 1Table 1Features of Complete and Partial Hydatidiform Moles.).5-8 Complete moles lack identifiable embryonic or fetal tissues, the chorionic villi exhibit generalized hydropic swelling and diffuse trophoblastic hyperplasia, and the implantation-site trophoblast has diffuse and marked atypia (Figure 1AFigure 1Photographs Showing Mature Chorionic Villi from a Normal Full-Term Placenta (Panel A, 100); Diffusely Hydropic Chorionic Villi, with Diffuse Trophoblastic Hyperplasia, from a Complete Mole (Panel B, 50); and Sheets of Anaplastic Cytotrophoblast and Syncytiotrophoblast from a Choriocarcinoma (Panel C, 400)., Figure 1B, and Figure 1C).

Cytogenetic studies have demonstrated that most complete moles (90 percent) have a 46,XX karyotype, and the chromosomes are entirely of paternal origin.9 A complete mole appears to arise from an ovum that has been fertilized by a haploid (23,X) sperm, which then duplicates its own chromosomes; the nucleus of the ovum may be either absent or inactivated.10 About 10 percent of complete moles have a 46,XY chromosomal pattern.11 The chromosomes in a 46,XY complete mole also appear to be entirely of paternal origin and probably result from dispermy. Although the chromosomes of complete moles are entirely of paternal origin, mitochondrial DNA is of maternal origin.12

Partial moles usually contain identifiable embryonic or fetal tissues, and the chorionic villi vary in size, with focal swelling, cavitation, and trophoblastic hyperplasia. The chorionic villi characteristically have marked scalloping and prominent stromal trophoblastic inclusions, and the implantation-site trophoblast may exhibit focal, mild atypia. Most partial moles (90 to 93 percent) have a triploid karyotype (69 chromosomes), with the extra haploid set of chromosomes derived from the father.13,14 Thus, both complete and partial moles are characterized by an excessive number of paternal chromosomes. When a fetus is present with a partial mole, it generally has growth retardation and multiple congenital malformations.15

Epidemiology and Risk Factors

The incidence of gestational trophoblastic disease has been reported to vary dramatically in different regions of the world.16 For example, the incidence of molar pregnancy in Japan (2.0 per 1000 pregnancies) is reported to be about three times higher than the incidence in Europe or North America (about 0.6 to 1.1 per 1000 pregnancies).17 Variations in the worldwide incidence rates of molar pregnancy may result in part from discrepancies between population-based and hospital-based data. In Ireland, the incidence of complete and partial moles has been determined to be 1 per 1945 pregnancies and 1 per 695 pregnancies, respectively, on the basis of a review of pathological studies of all products of conception from first- and second-trimester abortions.18 Careful casecontrol studies have been undertaken to identify risk factors for complete and partial molar pregnancy. The high incidence of molar pregnancy in some populations has been attributed to nutritional and socioeconomic factors. Case control studies in both Italy and the United States suggest that low dietary intake of carotene and animal fat may be associated with an increased risk of a complete mole.19,20 Vitamin A deficiency causes abnormal spermatogenesis in male rhesus monkeys and spontaneous abortion in female rhesus monkeys.21 Regions with a high incidence of molar pregnancy correspond to the geographic areas with a high frequency of vitamin A deficiency.22 A maternal age over 35 years has consistently been demonstrated to be a risk factor for a complete mole. Parazzini et al. reported that, as compared with younger women, the risk of a complete mole was 2 times higher for women over the age of 35 years and 7.5 times higher for women over 40 years.23 Ova from older women may be more susceptible to abnormal fertilization. The risk of a complete or partial mole is increased in women with a previous spontaneous abortion.24 After one spontaneous abortion, the risk of a complete or partial mole is three and two times higher, respectively, than the risk in the absence of a previous spontaneous abortion. Acaia et al. reported that after two consecutive spontaneous abortions, the risk of a complete mole is increased by a factor of 32.25

Certain epidemiologic characteristics of complete and partial moles differ markedly. For example, Parazzini et al. observed that there was no association between maternal age and the risk of a partial mole.23 Furthermore, the risk of a partial mole has been reported to be associated with a history of irregular menstrual periods and the use of oral contraceptives for more than four years but not with dietary factors.26 Thus, the risk of a partial mole appears to be associated with the reproductive history rather than dietary factors.

Clinical Presentation Complete Molar Pregnancy

The clinical presentation of a complete mole has changed considerably over the past two decades. Vaginal bleeding was the most common presenting symptom in 89 to 97 percent of patients during the 1960s and 1970s.27-29 Because bleeding was often prolonged, about half the patients presented with anemia (hemoglobin, <10 per deciliter). The uterine size was palpably larger than the gestational age in 38 to 51 percent of the patients and was usually associated with markedly elevated levels of human chorionic gonadotropin.27-29 Theca-lutein ovarian cysts were reported in 20 to 46 percent of patients, depending on whether the diagnosis was based on clinical or ultrasonographic examination.29,30 Theca-lutein cysts result from ovarian hyperstimulation by high circulating blood levels of human chorionic gonadotropin.31 Preeclampsia and hyperemesis were reported in 12 to 27 percent and 20 to 26 percent of patients, respectively, and occurred almost exclusively in those with markedly elevated human chorionic gonadotropin values and excessive uterine size.27-29 Hyperthyroidism and respiratory insufficiency were medically important but infrequent complications (occurring in 7 percent and 2 percent of patients, respectively) and were both associated with high human chorionic gonadotropin values and excessive uterine enlargement.32 Thyroid storm sometimes developed at the time of molar evacuation in patients with untreated hyperthyroidism. Respiratory insufficiency infrequently resulted from the cardiopulmonary complications of trophoblastic emboli, preeclampsia, thyroid storm, and massive fluid replacement. Respiratory distress usually resolved within 72 hours with appropriate cardiopulmonary support. In the 1960s and 1970s, a complete mole was generally diagnosed in the second trimester (mean gestational age, 16 to 17 weeks), but in recent years the diagnosis has been made earlier in gestation (mean gestational age, 12 weeks).33,34 The earlier diagnosis is due in large part to the availability of accurate and sensitive tests for measuring human chorionic gonadotropin and the widespread use of both transabdominal and transvaginal ultrasonography.

Vaginal bleeding continues to be the most common presenting symptom, occurring in 84 percent of patients with complete moles.33 However, now the diagnosis is often made before the other classic clinical signs and symptoms develop. With the earlier diagnosis, excessive uterine enlargement, hyperemesis, anemia, and preeclampsia have been observed at presentation in only 28, 8, 5, and 1 percent of patients, respectively. Between 1988 and 1993, none of our 74 patients with complete moles had hyperthyroidism or respiratory distress. However, patients have continued to present with markedly elevated human chorionic gonadotropin levels before evacuation of the mole.

Partial Hydatidiform Molar Pregnancy

Patients with partial moles usually do not present with the dramatic clinical features that were characteristic of complete moles in the past. In general, such patients present with the signs and symptoms of incomplete or missed abortion, and the diagnosis of a partial mole is usually made after a histologic review of curettage specimens.35 The main presenting sign in patients with partial moles is vaginal bleeding (occurring in 73 percent of patients).35 Excessive uterine enlargement and preeclampsia are present in only 4 to 11 percent and 1 to 4 percent of patients, respectively.35-37 Theca-lutein ovarian cysts, hyperemesis, and hyperthyroidism develop infrequently. The clinical diagnosis at presentation was an incomplete or missed abortion in more than 90 percent of our patients with partial moles.35 Pre-evacuation human chorionic gonadotropin levels, which were measured in 30 of our patients, exceeded 100,000 mIU per milliliter in only 2 of the patients (6.7 percent).

Diagnosis of Complete and Partial Molar Pregnancy

Ultrasonography is a reliable and sensitive technique for the diagnosis of a complete mole. Because the chorionic villi exhibit diffuse hydropic swelling, complete moles produce a characteristic vesicular ultrasonographic pattern. However, current cases of complete moles are commonly diagnosed in the first trimester, which may be too early to identify small molar villi or distinguish an early mole from degenerating chorionic villi by ultrasonographic examination.33,38 Correlating the ultrasonographic findings with the human chorionic gonadotropin level may aid in differentiating a complete mole from a missed abortion.39 Ultrasonography may also facilitate the diagnosis of a partial mole by demonstrating focal cystic spaces in the placenta and an increase in the transverse diameter of the gestational sac.40 When both these features are present, the positive predictive value of ultrasonography in diagnosing a partial mole is 90 percent.

Treatment of Molar Pregnancy

After a molar pregnancy has been diagnosed, the patient should be evaluated carefully for the presence of associated medical complications, including preeclampsia, hyperthyroidism, electrolyte imbalance, and anemia. After the patient has been evaluated and her condition stabilized, the most appropriate method of molar evacuation must be determined. Suction curettage is the preferred method of evacuation, regardless of the uterine size, in patients who wish to remain fertile.41 When suction evacuation is thought to be complete, careful sharp curettage is performed to remove any residual molar tissue. Because trophoblastic cells express the RhD factor, patients who are RhD-negative should receive Rh immune globulin at the time of evacuation. If the patient wants to undergo surgical sterilization, a hysterectomy may be performed, with preservation of the ovaries, even if prominent theca-lutein cysts are present. Large ovarian cysts may be decompressed by aspiration. Since hysterectomy does not prevent metastasis, human chorionic gonadotropin levels must be monitored after surgery.

Follow-up after a Molar Pregnancy

After molar evacuation, human chorionic gonadotropin levels should be monitored weekly until they have been undetectable for three consecutive weeks, followed by monthly monitoring until they have been undetectable for six consecutive months. The average time to the first undetectable human chorionic gonadotropin level after evacuation of a complete or partial mole is 9 to 11 weeks.34,42 At the completion of follow-up, the patient may choose to conceive at any time. Patients are encouraged to use effective contraception during the entire interval of follow-up. An intrauterine device should not be inserted until the human chorionic gonadotropin level is undetectable because of the risk of uterine perforation if an invasive mole is present. If the patient does not desire surgical sterilization, the choice is limited to oral or systemic contraceptives or barrier methods. The incidence of postmolar persistent tumor has been reported to be increased among patients who use oral contraceptives before gonadotropin levels have returned to undetectable values.43 Data from both our center and the Gynecologic Oncology Group, however, indicate that oral contraceptives do not increase the risk of postmolar trophoblastic disease.44,45 It appears that oral contraceptives may be safely prescribed during the entire interval of hormonal follow-up after molar evacuation.

Persistent Gestational Trophoblastic Tumors

Persistent gestational trophoblastic tumors have been reported to develop after a complete molar pregnancy in 18 to 29 percent of patients in the United States.27,28,46-48 Although complete moles are now being diagnosed earlier in pregnancy, the incidence of postmolar tumors has not been affected.33,34 Most centers in the United States diagnose postmolar tumors on the basis of reelevation or persistent plateau of human chorionic gonadotropin values for at least three

consecutive weeks. However, there is a lack of uniformity in the definition of a persistent plateau. The diagnostic criteria are less stringent in the United States than in Europe, partly because of the concern that some patients may be lost to follow-up if stricter criteria are used. Several studies have reported that the risk of a postmolar tumor is increased in patients with signs of marked trophoblastic overgrowth, such as markedly elevated human chorionic gonadotropin values and excessive uterine enlargement. Patients with these signs are considered to have high-risk complete moles, because the risk of persistent tumors in such patients has been reported to be 40 to 57 percent.28,32,49 The risk of a postmolar tumor has also been observed to be increased in older patients and in those with multiple molar pregnancies. Postmolar tumors have been reported in 33 and 37 percent of patients over 40 years of age50,51 and in 56 percent of patients over 50 years.52 The risk of a postmolar tumor is three to four times higher in patients who have had repeated molar pregnancies than in those who have had only one.53,54 The use of prophylactic chemotherapy at the time of evacuation of a complete molar pregnancy is controversial.55 However, several authors have reported that chemoprophylaxis reduces the incidence of postmolar tumor.56-58 Kim et al. performed a prospective, randomized trial of prophylactic chemotherapy in patients with complete molar pregnancies.59 Prophylactic chemotherapy reduced the incidence of postmolar tumors from 47 percent to 14 percent in patients with high-risk complete moles. Similarly, we reported that chemoprophylaxis reduced the incidence of postmolar tumors from 40 percent to 11 percent in patients with high-risk complete moles.60 Chemoprophylaxis may therefore be considered in patients with high-risk complete moles, particularly if hormonal testing is unavailable or follow-up is unreliable. After a partial molar pregnancy, only about 2 to 4 percent of patients have persistent tumors.61-64 There are no pathological or clinical features that distinguish such patients from those with partial moles who do not have persistent tumors.65 After molar evacuation, a persistent gestational trophoblastic tumor may have the histologic features of either a hydatidiform mole or choriocarcinoma. After a nonmolar pregnancy, however, a persistent tumor always has the histologic pattern of choriocarcinoma, which is characterized by sheets of anaplastic cytotrophoblast and syncytiotrophoblast without chorionic villi (Figure 1A, Figure 1B, and Figure 1C). When a persistent tumor develops, tissue is often not obtained, and a precise histopathological diagnosis may therefore not be possible. The diagnosis is usually based on a rising human chorionic gonadotropin level or a plateau in the level that persists for more than three weeks, as well as radiologic and clinical findings. A persistent tumor is generally exquisitely sensitive to chemotherapy, even in the presence of metastases, and a precise pathological diagnosis infrequently alters the management of the tumor.

A trophoblastic tumor at the placental site is an uncommon variant of choriocarcinoma that consists predominantly of intermediate trophoblast.66 Such tumors tend to remain within the uterus, disseminate late in their course, and produce low levels of human chorionic gonadotropin relative to their mass.67 In contrast to other types of gestational trophoblastic tumor, placental-site tumors are relatively insensitive to chemotherapy.

Nonmetastatic Disease
Locally invasive tumors develop in about 20 percent of patients after a complete molar pregnancy, in 2 to 4 percent after a partial molar pregnancy, and very infrequently after any other gestation.27,28,46-48,61-64 Patients with locally invasive tumors present with a persistent plateau in the human chorionic gonadotropin level or a reelevation in the level and may have irregular vaginal bleeding, uterine subinvolution, or theca-lutein ovarian cysts. If the diagnosis is delayed, the trophoblastic tumor may cause vaginal hemorrhage, intraperitoneal bleeding, or uterine sepsis.

Metastatic Disease
Metastatic tumors develop in about 4 percent of patients after a complete molar pregnancy but develop more commonly after a nonmolar pregnancy.1 Metastasis is often associated with choriocarcinoma, a tumor that disseminates widely. Trophoblastic tumors are highly vascular and prone to severe hemorrhage either spontaneously or during biopsy. The most common sites of metastasis are the lungs (in 80 percent of patients), vagina (30 percent), pelvis (20 percent), liver (10 percent), and brain (10 percent).32 Patients with pulmonary metastases may have asymptomatic lesions on chest radiographs or may present with cough, dyspnea, hemoptysis, or signs of pulmonary hypertension. The early development of respiratory failure requiring intubation is associated with a poor outcome.68,69 Hepatic or cerebral involvement is encountered almost exclusively in patients who have had a nonmolar pregnancy with a protracted delay in the diagnosis. Virtually all patients with hepatic or cerebral metastases have concurrent pulmonary or vaginal involvement, or both, and their tumors have the histopathological features of choriocarcinoma. Some patients with extensive pulmonary and other systemic involvement have minimal gynecologic symptoms or none. The diagnosis of gestational trophoblastic tumor should therefore be considered in any woman of reproductive age who has unexplained systemic symptoms.

Anatomical Staging and Prognostic Scoring Systems

An anatomical staging system for gestational trophoblastic tumor has been adopted by

the International Federation of Gynecology and Obstetrics (Table 2Table 2 Staging of Gestational Trophoblastic Tumors.). In addition to anatomical staging, it is useful to consider other variables in selecting appropriate chemotherapy.2 The World Health Organization has proposed a prognostic scoring system that reliably predicts

the potential for resistance to chemotherapy (Table 3Table 3 Scoring System for Determining Resistance to Chemotherapy.).70 Currently, however, there is a lack of uniformity in the use of these staging and scoring systems. A patient is considered to have a high risk of chemotherapy-resistant disease if the prognostic score is higher than 7. Although patients with stage I (nonmetastatic) disease infrequently have a high-risk score, those with stage IV disease (hepatic or cerebral involvement) invariably have a high-risk score. The distinction between lowand high-risk disease therefore mainly applies to patients with stage II disease (vaginal metastasis) or stage III disease (lung metastasis). A high-risk score is generally associated with a large tumor burden (large metastases, multiple metastases, and high human chorionic gonadotropin levels), a protracted delay in the diagnosis, a nonmolar antecedent pregnancy, or the failure of prior chemotherapy. Patients with high-risk scores are more likely to have tumors that are resistant to single-agent chemotherapy and should therefore be treated initially with combination chemotherapy.

Diagnostic Evaluation
Patients with persistent tumors should undergo a thorough pretreatment assessment of the extent of disease. If the pelvic examination and chest radiograph are normal, other sites of metastasis are uncommon.71,72 Other radiologic tests that may help detect metastasis include computed tomography (CT) of the head, chest, and abdomen and pelvis.71 Measurement of human chorionic gonadotropin levels in the cerebrospinal fluid may be useful in detecting cerebral involvement, since the ratio of plasma values to cerebrospinal fluid values tends to be less than 60 in the presence of cerebral metastases.73,74 Pelvic ultrasonography may also detect extensive uterine tumors and thus help identify patients who may benefit from hysterectomy.75

Management Stage I Tumor

In stage I disease, the selection of treatment is based on whether the patient wishes to remain fertile. Hysterectomy with adjuvant single-agent chemotherapy may be performed in patients who do not wish to remain fertile. Single-agent chemotherapy is administered perioperatively because of the risk of occult micrometastases. Chest CT has revealed micrometastases in about 40 percent of patients with presumably nonmetastatic disease.76 At our center all 29 patients with stage I disease who have been treated with hysterectomy and adjuvant single-agent chemotherapy have had a remission with no further therapy. Hysterectomy is also performed in all patients with stage I placental-site trophoblastic tumors, because these tumors are resistant to chemotherapy. Because placental-site trophoblastic tumors are rare and difficult to diagnose on the basis of uterine curettage, curettage specimens should be reviewed by a pathologist with expertise in trophoblast pathology before a hysterectomy is performed. Single-agent chemotherapy is the preferred treatment in patients with stage I disease who wish to remain fertile. A complete remission was induced in 393 of 424 patients (92.7 percent) with stage I disease who received single-agent chemotherapy at our center between 1965 and 1994. The other 31 patients subsequently had a remission with either combination chemotherapy or surgical intervention (hysterectomy or local uterine resection).

Stage II or III Tumor

Patients with low- or moderate-risk stage II or III disease may be treated with primary single-agent chemotherapy. Patients with high-risk stage II or III disease require primary intensive combination chemotherapy. At our center, a complete remission was achieved in all 27 patients with stage II tumors and in 130 of 131 patients (99.2 percent) with stage III tumors. Primary single-agent chemotherapy induced a complete remission in 16 of 19 patients (84.2 percent) with low- or moderate-risk stage II disease and in 71 of 85 (83.5 percent) with low- or moderate-risk stage III disease. Similarly, other authors have reported that primary single-agent chemotherapy induces a complete remission in about 85 to 90 percent of patients with low- or moderate-risk metastatic disease.77-80 Vaginal metastases may bleed profusely, requiring local packing, wide excision, or arteriographic embolization of the hypogastric arteries. Thoracotomy may also be performed to excise a site of resistant tumor. However, fibrotic nodules may persist indefinitely on chest radiographs, even after a sustained remission has been achieved. In patients with metastatic disease, hysterectomy may be necessary to control uterine sepsis or hemorrhage. Hysterectomy may also substantially reduce the tumor burden and thereby limit the need for chemotherapy.81

Stage IV Tumor
All patients with stage IV disease receive primary intensive combination chemotherapy, with radiation therapy and surgery used selectively as required. Since 1975, 14 of 18 patients (78 percent) with stage IV disease treated at our center have had a complete remission. Patients with stage IV disease are most likely to have rapidly progressive and unresponsive tumors, despite intensive multimodal therapy. Surgery may be required to treat acute complications, such as hepatic or intracerebral bleeding. Weed and Hammond reported the use of craniotomy to control bleeding in six patients, three of whom subsequently had a complete remission.82 Occasionally, resistant sites of disease are amenable to local resection. Whole-brain irradiation is generally administered in patients with cerebral metastases. Brain irradiation may lessen the risk of cerebral hemorrhage, because it may have a hemostatic effect, as well as a tumoricidal effect.83 However, intensive combination chemotherapy alone, including high-dose intravenous and intrathecal methotrexate, induced a complete remission in 13 of 15 patients (87 percent) with cerebral metastases.84

Follow-up
Follow-up for patients with stage I, II, or III disease consists of weekly human chorionic gonadotropin measurements until the level has been undetectable for 3 weeks, followed by monthly measurements until the level has been undetectable for 12 months. For patients with stage IV disease, follow-up consists of monthly human chorionic gonadotropin measurements until the level has been undetectable for 24 months, because such patients are at greater risk for a late relapse. Patients are encouraged to use effective contraception during the entire follow-up period.

Selection of Chemotherapy Single-Agent Chemotherapy

Single-agent chemotherapy with either methotrexate or dactinomycin has resulted in high and similar remission rates among patients with nonmetastatic disease and those with low- or moderate-risk metastatic disease.85,86 Several regimens of methotrexate and dactinomycin have been effective, but no study has compared all these protocols.80,87,88 Moreover, there have been no prospective, randomized studies to determine the most effective means of administering chemotherapy. Single-agent chemotherapy may be administered either at a fixed interval or on the basis of the human chorionic gonadotropin regression curve. At our center, further single-agent chemotherapy is withheld after the first treatment as long as the human chorionic gonadotropin level is falling progressively. If the tumor is resistant to the initial regimen of single-agent chemotherapy, the patient may be switched to an alternative single-agent regimen.

Combination Chemotherapy
Triple therapy (methotrexate, dactinomycin, and cyclophosphamide or chlorambucil) was the preferred combination chemotherapy in the past. However, triple therapy induces a remission in only about half the patients with high-risk metastatic disease.77-79,89-91 Treatment with etoposide was demonstrated to be highly effective in the 1980s. Etoposide used as primary therapy induced a complete remission in 56 of 60 patients (93 percent) with nonmetastatic or low-risk metastatic tumors.92 A new combination regimen was subsequently developed that included etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine. This combination is currently the preferred treatment in patients with high-risk metastatic tumors. Treatment with etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine has induced remission in 70 to 75 percent of patients with high-risk metastatic disease.9396 If the tumor is resistant to etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine, cisplatin and etoposide may be substituted for cyclophosphamide and vincristine on day 8 of the regimen. This modified regimen, either alone or in conjunction with surgery, induced a remission in 74 percent of patients who had tumors that were resistant to etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine.94 Second-line therapy with cisplatin, vinblastine, and bleomycin may also be effective. Azab et al. and DuBeshter et al. reported a complete remission with this regimen in five of eight and four of seven patients, respectively, who had drug-resistant tumors.97,98 Patients who require combination chemotherapy must be treated intensively to induce a remission. When possible, patients with high-risk metastatic disease should be referred to a regional center with specialized expertise and experience in the treatment of trophoblastic disease. Because gestational trophoblastic tumors are rare, it is difficult for clinicians outside regional referral centers to acquire extensive experience in the treatment of these tumors. Combination chemotherapy is administered as frequently as the toxic effects permit, until the patient has undetectable human chorionic gonadotropin values. Once the human chorionic gonadotropin level is undetectable, additional chemotherapy must be administered to reduce the risk of a relapse. In the past, gestational trophoblastic tumors were often fatal, but with modern chemotherapy, this disease is now curable in most cases.

Subsequent Pregnancies
A woman who has had a complete or partial molar pregnancy can anticipate a normal reproductive outcome of subsequent conceptions.54 However, about 1 percent of subsequent conceptions result in molar gestation. Similarly, a woman with a persistent tumor who has had a remission with chemotherapy should be reassured that the probability of a subsequent normal pregnancy is about the same as that for the average American woman.54 There is no increase in the risk of a spontaneous abortion, congenital anomalies, or the need for a cesarean section.

Secondary Tumors
Contrary to their previous report, investigators in England recently reported an increased risk of secondary cancers, including leukemia, colon cancer, melanoma, and breast cancer, in patients treated with chemotherapy for gestational trophoblastic tumors.99,100 The authors attributed the increased risk of secondary tumors to the inclusion of etoposide in the chemotherapeutic regimen. The increased incidence of colon cancer, melanoma, and breast cancer did not become apparent until more than 5, 10, and 25 years after treatment, respectively.

Source Information
From the New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Brigham and Women's Hospital and DanaFarber Cancer Institute, and the Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School all in Boston. Address reprint requests to Dr. Berkowitz at the Division of Gynecologic Oncology, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115.