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Gestational trophoblastic disease includes hydatidiform mole (complete and partial) and gestational trophoblastic neoplasia (invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor). The epidemiology, pathology, clinical presentation, and diagnosis of each of these trophoblastic disease variants are discussed. Particular emphasis is given to management of hydatidiform mole, including evacuation, twin mole/normal fetus pregnancy, prophylactic chemotherapy, and follow-up., (Copyright © 2010 Mosby, Inc. All rights reserved.)

Objective: Our purpose was to evaluate the efficacy and toxicity of single-agent methotrexate chemotherapy and to identify factors associated with chemotherapy resistance in patients with nonmetastatic gestational trophoblastic tumors., Study Design: A total of 337 patients with nonmetastatic gestational trophoblastic tumors (choriocarcinoma and invasive mole) received treatment at the Brewer Trophoblastic Disease Center of Northwestern University Medical School from 1962 through 1990. Of the 337 patients, 253 (75.0%) were treated initially with single-agent methotrexate 0.4 mg/kg intravenously daily for 5 days per treatment course repeated every 14 days., Results: All 337 patients with nonmetastatic gestational trophoblastic tumors were cured. Of the 253 patients initially treated with methotrexate, resistance developed in 27 (10.7%), 22 (8.7%) required a second agent (actinomycin D), 3 (1.2%) required multiagent chemotherapy, and 2 (0.8%) had a hysterectomy to achieve complete remission. Factors associated with the development of resistance were pretreatment human chorionic gonadotropin level > or = 50,000 mlU/ml (36%, p < 0.001), nonmolar antecedent pregnancy (26%, p < 0.02), and clinicopathologic diagnosis of choriocarcinoma (20.5%, p = 0.02). Significant methotrexate toxicity requiring a change to a second agent occurred in only 12 patients (4.7%), the most common side effect being severe stomatitis., Conclusions: In a large series of patients with nonmetastatic gestational trophoblastic disease, single-agent methotrexate chemotherapy proved to be an extremely well-tolerated and effective treatment.

Objective: Choriocarcinoma is a highly invasive gynecologic tumor, and hematogenous metastases frequently develop. To establish a molecular basis for antiinvasion therapy of choriocarcinoma, we examined the effects of human recombinant interferons on gelatinase production and invasion by choriocarcinoma cells., Study Design: Using five choriocarcinoma cell lines, we measured gelatinase activity by gelatin zymography. The effects of recombinant interferons (rIFN-alpha, rIFN-beta, and rIFN-gamma) were then analyzed by Western blot analysis and chemoinvasion assay., Results: High levels of 72 kd gelatinase activity were detected in the highly invasive choriocarcinoma cell lines, two of which also contained an active form of 72 kd gelatinase with an apparent molecular mass of 68 kd. Gelatinase production was decreased by incubation with rIFN-beta. In the chemoinvasion assay, only rIFN-beta had an inhibitory effect on the invasiveness of tumor cells without a cytotoxic effect., Conclusion: Choriocarcinoma cells showed high 72 kd gelatinase activity, which suggested a role for the enzyme in vascular metastasis. Studies on the use of rIFN-beta to inhibit metastasis of choriocarcinoma via suppression of gelatinase production are warranted.

Objective: We attempted to evaluate the use of ifosfamide either alone or in combination in patients with refractory malignant gestational trophoblastic disease., Study Design: Our study comprised, in part, a phase II multiinstitutional trial of ifosfamide in refractory gynecologic malignancies and, in part, a review of institutional experience with ifosfamide in combination chemotherapy., Results: Single-agent ifosfamide produced a significant response in titer in one of two patients with refractory choriocarcinoma. Ifosfamide with etoposide and cisplatin (also known as VIP) resulted in significant response in human chorionic gonadotropin titers in three patients with highly refractory metastatic gestational trophoblastic disease and one cure in this group of patients., Conclusion: Ifosfamide has activity in refractory choriocarcinoma and, when combined with etoposide and cisplatin (VIP), may be curative.

All 1391 patients treated for gestational trophoblastic tumors (invasive mole and choriocarcinoma) at the John I. Brewer Trophoblastic Disease Center of Northwestern University between 1969 (when use of combination chemotherapy for initial treatment of high-risk disease came into general use) and 1988 were evaluated. Univariate and multivariate analyses were used to determine the relative importance of prognostic factors with respect to survival. The overall cure rate was 93% (363/391): 100% for 223 patients with nonmetastatic disease and 83% for 168 patients with metastatic disease. The only patients who died had a clinicopathologic diagnosis of metastatic choriocarcinoma. In addition to presence of metastasis (83% vs 100%, p less than 0.0001) and diagnosis of choriocarcinoma (67% vs 100%, p less than 0.0001), number of metastases (47% if greater than 8 vs 92% if less than or equal to 8, p less than 0.0001), metastases to sites other than the lung or vagina (52% vs 91%, p = 0.0002), and previous failed chemotherapy (46% vs 84%, p = 0.0014) demonstrated independent significant effects on survival in patients with metastatic disease. A Brewer score, based on our multivariate analysis of survival in patients with metastatic disease, provided predictability of outcome (likelihood ratio chi 2 statistic, chi 2 = 49.8) comparable to that with the World Health Organization score (chi 2 = 45.3), both of which, in turn, were better predictors than either the traditional Hammond clinical classification system (chi 2 = 34.4) or the International Federation of Gynecology and Obstetrics stage (chi 2 = 22.9).

Primary cervical choriocarcinoma is a rare disease; since 1915 only about 60 cases have been published. The case presented here can be defined as primary cervical choriocarcinoma since it fulfills all the criteria delineated previously.

Fifty-one patients with choriocarcinoma associated with term pregnancy were treated at the John I. Brewer Trophoblastic Disease Center of Northwestern University Medical School from 1962 through 1981. An overall remission rate of 61% was achieved: 65% for 43 patients who received all of their treatment at the center and 38% for eight patients who received treatment elsewhere before referral to the center. This remission rate was significantly less (P less than 0.005) than the 87% remission rate obtained in patients with choriocarcinoma after hydatidiform mole, abortion, or ectopic pregnancy combined. Three factors were determined which significantly influenced response to treatment in these patients: (1) time from delivery to treatment greater than 4 months (41% versus 80%, P less than 0.0005); (2) presenting symptomatology other than abnormal uterine bleeding (40% versus 87%; P less than 0.001); and (3) metastases to sites other than the lung and/or vagina (22% versus 72%, P less than 0.01). There appeared to be no advantage to treating all patients with choriocarcinoma after term pregnancy with initial multiple-agent chemotherapy unless other high-risk characteristics were present.

Combination chemotherapy with methotrexate, actinomycin D. and an alkylating agent (MAC) has become widely used for patients with "high-risk" gestational choriocarcinoma. When such chemotherapy fails to obliterate this disease the prognosis has been uniformly poor. Chemotherapy failure may result from excessive toxicity or tumor resistance. Two patients are presented who failed treatment with MAC. Both have achieved sustained clinical and serum beta subunit-hCG titer remission of choriocarcinoma with the use of the drugs cis-platinum, vinblastine, and bleomycin.

Two human choriocarcinomas serially transplanted to athymic nude mice (BALB/c, nu/nu) were treated with intraperitoneal injections of methotrexate (MTX), actinomycin D (ACTD), and vinblastine (VLB) with doses per injection slightly smaller than LD10 in mice. Both ACTD and VLB significantly suppressed the growth of one tumor strain (SCH) but MTX did not. The growth of another tumor strain (CC-1) was not inhibited by either ACTD or VLB. In strain SCH, plasma HCG of tumor-bearing animals increased approximately in parallel with the growth of tumors in control and MTX-, ACTD-, and VLB-treated groups but the suppression of the hormone release was more marked in the ACTD-treated group. The results indicate that these two transplantable human tumors are useful models for the study of choriocarcinoma, particularly for therapeutic experiments.

In order to preserve the fertility of young patients with choriocarcinoma and invasive mole, chemotherapy alone was given without hysterectomy in 265 cases from 1959 through 1980. By the end of 1985, 205 patients had become pregnant after recovery, with a total of 355 pregnancies. Among these, 23 were terminated by induced abortions, 26 as miscarriages, two as ectopic gestations, two as intrauterine deaths, and three as stillbirths. Among 303 livebirths (including four sets of twins), six infants died neonatally, three of whom were found to have congenital anomalies incompatible with life, and two died during infancy. All the remaining 295 children had normal growth and development, the oldest now being 25 years of age. The rates of fetal wastage, malformations, twin pregnancies, and neonatal and infantile deaths did not deviate from the normal. Cytogenetic study of the peripheral lymphocytes of 94 of the children revealed no increase of chromosomal aberrations. The rates of recurrence of disease and of death caused by recurrence of disease in these were not increased in comparison with those in patients who underwent hysterectomy. These data indicate that treatment of malignant trophoblastic neoplasms with chemotherapy alone is compatible with the preservation of fertility in most women.

Large dosage of 5-fluorouracil given by slow intravenous infusion has proved to be very effective in the treatment of gestational trophoblastic neoplasms. From 1965 through 1975, 5-fluorouracil was used as a single chemotherapeutic agent in 173 cases of invasive mole and 139 cases of choriocarcinoma. Complete remission was achieved in 84.9% of cases of invasive mole and in 59.3% of cases of choriocarcinoma when 5-fluorouracil was used as the initial treatment. Seven recurrences with three deaths occurred during follow-up in 216 patients who had achieved complete remission, providing a recurrence rate of 3.2% and recurrence death rate of 1.4%. All of the survivors were followed up for more than 5 years and 85.6% for more than 10 years. Toxicity of 5-fluorouracil was milder and less frequent than that of 6-mercaptopurine or methotrexate. The toxic reaction specific to 5-fluorouracil was diarrhea, which can result in pseudomembranous colitis if improperly treated. One of the two toxic deaths was due to this complication.

Expression of the c-myc proto-oncogene has been shown to correlate with the rate of cellular proliferation and malignant transformation in a number of cell types. JEG-3 choriocarcinoma cells demonstrate c-myc transcript levels that are greater than those of nonmalignant trophoblastic tissue at any stage of gestation. Southern blot analysis documents c-myc gene amplification in JEG-3 cells, with a gene copy number of approximately 20. The methylation pattern and genomic structure of the amplified c-myc oncogene in JEG-3 choriocarcinoma cells are identical to those of normal placenta. Treatment of JEG-3 cells with mithramycin, a ribonucleic acid synthesis inhibitor, results in a dramatic decrease in c-myc expression relative to that of the c-Ha-Ras gene. The apparent selectivity of mithramycin for c-myc expression represents the only example, to date, of the selective pharmacologic modulation of oncogene expression.

Results of therapy of 257 patients with gestational trophoblastic disease (GTN), treated at one institution and by the same group of physicians (1966 to 1978), are presented. An overall remission rate of 92% was achieved: nonmetastatic disease, 139/139 (100%); "good" prognosis metastatic GTN, 55/55 (100%), "poor" metastatic GTN, 42/63 (66%). Chemotherapy, single- or multi-agent, was the primary treatment modality but selected patients were also treated with operation and/or x-ray therapy. Surgical therapy (hysterectomy), performed coincident with the institution of systemic chemotherapy, was shown to significantly reduce the duration of hospitalization and the amount of chemotherapy used to achieve remission, regardless of whether or not metastases were present. Delayed surgical excision of chemotherapy-resistant foci of GTN was of benefit, though less effective than initial operation. Surgical intervention for other diseases or for complications of GTN or its treatment was quite useful to stabilize patients and allow successful chemotherapy to be completed. There were no problems attributable to chemotherapy when wound healing or other postoperative complications were considered.

A radioimmunoassay for urinary human chorionic gonadotropin (hCG) which used antiserum to the hCG beta carboxy-terminal peptide was employed to detect hCG production in women with gestational trophoblastic disease. The urinary hCG assay was considerably more effective in detecting increased hCG production, and, hence, persistent tumor burden, than the commonly used serum hCG beta subunit radioimmunoassay. In two women treated for choriocarcinoma, urinary hCG levels remained distinctly elevated for 2 to 6 weeks, even though the serum hCG level was undetectable; in both cases, the urinary hCG radioimmunoassay reliably predicted the eventual reappearance of hCG in the serum. In six women whose disease remitted, the urinary hCG level declined to the normal range during chemotherapy, and remained there afterward. In eight patients who had been in remission for periods of from 1 to 14 years, urinary hCG levels were in the normal range. We conclude that this highly sensitive and reliable method for the detection of hCG production improves the ability to diagnose persistent trophoblastic disease.

Two treatment regimens for nonmetastatic gestational trophoblastic disease are compared in this retrospective study. The course of 39 patients with nonmetastatic gestational trophoblastic disease treated with methotrexate alone is contrasted to that of 29 patients with nonmetastatic gestational trophoblastic disease who were treated with methotrexate alternated with folinic acid. Of those patients initially treated with methotrexate alone, 7.7% developed methotrexate-resistant disease and required a change in chemotherapy for induction of remission. In contrast, 27.5% of patients initially treated with methotrexate and folinic acid developed methotrexate-resistant disease and required a change in chemotherapy to achieve remission. Ultimately, remission was achieved in all patients. Methotrexate as single-agent chemotherapy was found to be consistently more toxic than methotrexate alternated with folinic acid. It is concluded that methotrexate with folinic acid at the dosage used in this study, while less toxic than methotrexate alone, is less effective than methotrexate alone in the induction of remission of nonmetastatic gestational trophoblastic disease.

A case of a pelvic arteriovenous fistula is described 5 years after treatment of trophoblastic disease. Hypogastric embolization, rather than an operation, was used to obliterate the fistula. Pregnancy occurred 1 year later and a healthy infant was delivered. This is the first report of a delivery after angiographic management alone.

Radioimmunoassays and bioassays based on the reactions of the native molecule of human chorionic gonadotropin (HCG) fail to differentiate HCG from pituitary luteinizing hormone (LH). An assay based on the beta-subunit of HCG which detects HCG exclusively has been used in our laboratory to monitor patients undergoing chemotherapy for gestational trophoblastic disease (GTD). We have been able to differentiate minimal, persisting tumor activity from normal levels of pituitary gonadotropins and have based therapy on these findings. Alternatively, treatment has been terminated when HCG is no longer detectable in the serum. Tumor activity has been detected in the beta-subunit assay at a time when biologic activity in the urine indicated remission.