Dynamic staging and risk factor scoring for gestational trophoblastic disease.

It is proposed that a dynamic staging and risk factor scoring system is introduced for the classification of gestational trophoblastic disease as a logical development of the system presently used by the FIGO. Modern computer technology permits such change as the disease changes and particularly if it progresses. By allowing a change of both stage and risk factor score for each patient reported, a dynamic scoring system results. Moreover, such a system allows the introduction of more clinical detail than is permitted by the present FIGO system. FIGO combining its anatomic staging, first devised by Professor Song of Beijing, with the World Health Organization risk factor scoring, first devised by Professor Kenneth Bagshawe of Charing Cross Hospital, London, in 2002 was a significant progress. The most important change of the FIGO 2002 modification was that criteria were defined for the diagnosis of postmolar gestational trophoblastic neoplasia. However, hydatidiform mole still has no place in that classification. Also, the time when the staging occurs is not mandated. The present FIGO classification allows for no change in the status of the patient. A dynamic staging and risk factor scoring system would allow such changes to be recorded and, therefore, permit a more precise account of the patient's disease. A third issue is whether invasive mole should be included in the classification, as the Japanese Gynecologic Cancer Society insists is necessary. This problem may also be solved by the use of a dynamic risk factor scoring system.

The new FIGO 2000 staging and risk factor scoring system for gestational trophoblastic disease: description and critical assessment.

The classification of the International Federation of Obstetrics and Gynecology (FIGO) for Trophoblastic Disease was changed at the meeting in Washington in September 2000 by combining the basic FIGO anatomic staging with the modified World Health Organization (WHO) risk factor scoring system. This presentation outlines the new system and provides a critical evaluation of the issues that have been resolved and those that are still outstanding.

Serum levels of macrophage colony-stimulating factor in trophoblastic disease.

OBJECTIVES: The aims of this study were to measure levels of colony stimulating factor (CSF-1) in patients with trophoblastic disease, to determine whether such measurement may be useful to supplement measurement of the prognostically reliable human chorionic gonadotrophin (hCG), and to assess whether measurement of CSF-1 may be helpful in predicting requirement for chemotherapy in patients with hydatidiform mole. METHODS: Serial weekly serum samples were selected for CSF-1 assay from representative diagnostic groups of patients with trophoblastic disease: hydatidiform-mole with spontaneous resolution, low-risk post-hydatidiform-mole trophoblastic tumor, partial hydatidiform mole, high-risk metastatic gestational trophoblastic tumor, primary ovarian choriocarcinoma, and placental site trophoblastic tumor. hCG was measured by an in-house radioimmunoassay that measures all parts of the hCG molecule. CSF-1 was measured by radioimmunoassay with (125)I-labeled recombinant CSF-1. The upper level of normal CSF-1 was taken as 8 ng/ml. RESULTS: In this study of 45 patients with trophoblastic disease, some very high levels of CSF-1 were encountered. In a few patients there was dramatic correlation with hCG. Generally, however, CSF-1 and hCG did not correlate. CSF-1 was frequently not elevated when hCG was still significantly elevated and conversely CSF-1 was elevated when hCG was negative. CONCLUSION: The measurement of CSF-1 does not appear to be useful in managing trophoblastic disease as it does not correlate with the level of hCG. Occasionally, high levels of CSF-1 were found in patients with trophoblastic disease.

Measurement of CA-125 in trophoblastic disease.

OBJECTIVES: Physicians treating hydatidiform mole are still seeking means of identifying those patients who will require chemotherapy. The standard accepted method is to follow human chorionic gonadotropin levels but CA-125 measurement has been suggested as a supplement that may be clinically useful. This study was undertaken to validate or refute the one previous study that addresses this issue. CA-125 was measured at the time of hydatidiform mole evacuation to determine (1) whether it would predict the need for chemotherapy and (2) whether it correlated with human chorionic gonadotropin and tumor load in following patients with hydatidiform mole and metastatic gestational trophoblastic disease. PATIENTS AND METHODS: CA-125 was measured in serial weekly samples selected from diagnostic groups of patients with trophoblastic disease. Sixteen patients had hydatidiform mole with spontaneous resolution, fourteen had nonmetastatic gestational trophoblastic tumor, and four had low-risk metastatic disease. Six patients had high-risk metastatic disease. Ten patients had partial hydatidiform mole and one of these required chemotherapy. One patient had primary ovarian choriocarcinoma and three had placental site tumor. RESULTS: The mean preevacuation CA-125 among the 15 patients with complete hydatidiform mole was 40.9 U/ml: 52.5 U/ml for 5 patients who required chemotherapy and 36.2 U/ml for 10 patients who did not require chemotherapy. There was no statistical difference between these values. There was no correlation of CA-125 with hCG. Frequently CA-125 became negative when hCG was still elevated. Among six patients with high-risk disease, CA-125 was elevated in four but in all six patients hCG remained elevated when CA-125 became negative. In nine patients with partial hydatidiform mole CA-125 was elevated prior to mole evacuation and then became negative. The patient with a tetraploid conceptus who required chemotherapy had negative CA-125. With placental site tumor CA-125 was negative, but it was elevated with ovarian choriocarcinoma. CONCLUSION: CA-125 levels do not provide reliable information in the management of patients with gestational trophoblastic disease.

Workshop Report: Combining the staging system of the International Federation of Gynecology and Obstetrics with the scoring system of the World Heath Organization for Trophoblastic Neoplasia. Report of the Working Committee of the International Society for the Study of Trophoblastic Disease and the International Gynecologic Cancer Society.

During the past 5 years the International Society for the Study of Trophoblastic Disease and the International Gynecological Cancer Society have moved to modify the staging system for trophoblastic disease by combining the staging of the International Federation of Gynecology and Obstetrics (FIGO) with the scoring system of the World Health Organization (WHO). By making significant changes in both, the classification will be more acceptable worldwide leading to uniform use by physicians reporting management results in trophoblastic disease. This is the report of the Rome Workshop, which will be presented for ratification to the FIGO Staging Committee in September 2000.

Phantom metastases in trophoblastic disease.

Trophoblastic disease occasionally presents with apparent metastases that turn out to be lesions not associated with the trophoblastic tumor. In this article, we present one case of a cerebellar hemangioma, two of lung and mediastinal teratoma, and one of pulmonary granuloma masquerading as metastases from trophoblastic disease. If an apparent metastasis associated with trophoblastic tumor does not accord with the clinical diagnosis, look for an independent cause.

Nicked human chorionic gonadotropin in trophoblastic disease.

The objectives of this study were to determine: 1) whether high proportions of nicked human chorionic gonadotropin (hCG) in serum at the time of mole evacuation and during postmolar surveillance is indicative of trophoblastic malignancy and 2) to investigate whether measurement of nicked hCG provides clinically more useful information in the management of patients with trophoblastic disease than does measurement of total hCG alone. "Tumor marker" total hCG, intact hCG, and nicked hCG were measured in serial samples of serum from our serum bank of patients with representative types of trophoblastic disease. "Tumor marker" hCG has been shown to measure all aspects of the hCG molecule. At the time of presentation of all 45 patients, 83.5% of hCG was intact and 16.5% was nicked. These proportions became reversed as hCG declined either spontaneously after hydatidiform mole evacuation or with chemotherapy in patients with postmolar trophoblastic tumor or with metastatic trophoblastic disease. We conclude that the proportion of nicked hCG compared to intact hCG increases with trophoblastic disease resolution. Measurement of nicked hCG adds no useful clinical information to that provided by reliable measurement of total hCG.

Adenocarcinoma in situ of the cervix: management and outcome.

OBJECTIVE: The aim of this study was to review the management and outcome of patients with adenocarcinoma in situ of the cervix and to evaluate the significance of endocervical cone margin status in these patients. METHODS: A retrospective review of records between January 1988 and December 1996 identified 40 patients with adenocarcinoma in situ on cone biopsy for whom complete information was available. The median follow-up was 38 months. RESULTS: The mean age was 37 years, and the mean parity was 1.3. Fifty-three percent of the patients had prior abnormal cervical cytology. The initial Pap smear that led to the patient's referral was abnormal in 39 (98%). Initial cervical biopsies showed adenocarcinoma in situ and/or glandular dysplasia in 28 (70%), squamous dysplasia in 2 (5%), chronic inflammation in 2 (5%), and no pathologic changes in 2 (5%) patients. Initially no biopsies were performed in 3 (7.5%) patients and the results of 3 (7.5%) biopsies were unknown. Subsequently, all patients had cone biopsies. The endocervical margins were positive for glandular abnormalities in 24% of cold knife cones (CKC), 75% of LEEPs, and 57% of laser cones. The ectocervical margins were positive for squamous and/or glandular abnormalities in 8% of CKCs, 13% of LEEPs, and 57% of laser cones. ECCs above the cone were obtained in 28 patients, and only 1 (3%) was positive. The definitive treatment was hysterectomy in 27, repeat cone in 5, and no additional therapy in 8 patients. The pathology showed residual disease in 44% of treated patients. From 16 cone biopsies with negative margins who had subsequent treatment, there was residual disease in 5 (31%) specimens (1 adenocarcinoma in situ, 1 mild glandular dysplasia, 3 glandular atypia). From 16 cones with positive margins who had subsequent treatment, there was residual disease in 9 (56%) specimens. The patients with negative ECCs above the cone regardless of margin status had residual disease in 58% of treated specimens. CONCLUSION: Women with adenocarcinoma in situ of the uterine cervix had residual disease in 31% of cases with negative margins in cone biopsies and/or with negative ECCs and in 56% of cases with positive endocervical margins. LEEP cones had higher rate of positive endocervical margins (75%) compared to CKC (24%) and laser cone (57%). If maintaining reproductive capacity is desired, we would recommend CKC; however, this does not guarantee absence of the disease.

Oral contraceptive use and risk of gestational trophoblastic tumors.

BACKGROUND: Gestational trophoblastic disease refers to a spectrum of rare benign and malignant gynecologic disorders whose pathogenesis is not well understood. Recent studies from China and the United States have raised the hypothesis that long-term use of oral contraceptives before conception may increase the risk of gestational trophoblastic tumors. A multicenter case-control study of gestational trophoblastic tumors was undertaken to test this hypothesis. METHODS: Telephone interviews were conducted with 235 case patients, including 50 with gestational choriocarcinoma, and 413 control subjects matched on recentness of pregnancy, age at pregnancy, and area of residence. Relative risks (odds ratios) were computed by conditional logistic regression. Reported P values are two-sided. RESULTS: The relative risk estimate for ever having used oral contraceptives before the index pregnancy was 1.9 (95% confidence interval [CI] = 1.2-3.0), and the risk increased with duration of use (P for trend = .05). The estimate was highest for women who used oral contraceptives during the cycle in which they became pregnant (relative risk = 4.0; 95% CI=1.6-10), but there was no consistent pattern according to the time interval since last use. Separate analyses of choriocarcinoma and persistent mole yielded similar results, i.e., the relative risk estimates for oral contraceptive use were 2.2 (95% CI=0.8-6.4) and 1.8 (95% CI=1.0-3.0), respectively. Control for the number of sexual partners, which was independently associated with risk (P for trend = .05), did not materially change the results. CONCLUSIONS: This study, the largest to date, indicates that long duration of oral contraceptive use before conception increases the risk of gestational trophoblastic tumors. These findings may provide clues to the pathogenesis of this rare disease. Changes in use of oral contraceptives are not warranted, however, because the incidence attributable to oral contraceptive use is very low.

PIP: Recent studies in the US and China have suggested that long-term use of oral contraceptives (OCs) before conception increases the risk of gestational trophoblastic tumors. This association was investigated further in a study conducted at 8 US medical centers that specialize in the treatment of this gynecologic disorder. 235 cases, including 50 women with gestational choriocarcinoma, were matched with 413 controls on recentness of pregnancy, age at pregnancy, and area of residence. The relative risk estimate for ever-use of OCs before the index pregnancy was 1.9 (95% confidence interval [CI], 1.2-3.0) and the risk increased with duration of OC use. The relative risk was highest (4.0; 95% CI, 1.6-10.0) for women who used OCs during the cycle in which they became pregnant, but there was no consistent pattern according to the time interval since last OC use. The relative risks for choriocarcinoma and persistent mole associated with OC use were 2.2 (95% CI, 0.8-6.4) and 1.8 (95% CI, 1.0-3.0), respectively. This study, the largest to date, suggests that a long duration of OC use before conception does, indeed, increase the risk of gestational trophoblastic tumors.

Neoadjuvant chemotherapy for advanced ovarian cancer: long-term survival.

PURPOSE: The aim of this study was to compare the progression-free and overall survivals of women with advanced ovarian cancer treated with neoadjuvant chemotherapy followed by surgery with those treated conventionally with cytoreductive surgery followed by cytotoxic chemotherapy. MATERIALS AND METHODS: Fifty-nine consecutive women with advanced malignancies compatible with ovarian cancer based on (1) physical examinations, (2) computerized tomography scans, and (3) cytologic or histologic specimens and treated with platinum-based combination chemotherapy, i.e., neoadjuvant chemotherapy, were retrospectively reviewed. Forty-one subsequently underwent cytoreductive surgery. Their overall and progression-free survivals were compared to those of 206 consecutive women with Stage IIIC and IV epithelial ovarian cancers treated with conventional cytoreductive surgery followed by platinum-based combination chemotherapy during the same era. RESULTS: No statistical difference was observed in overall survival (P = 0.1578) or in progression-free survival between the group treated with neoadjuvant chemotherapy and the conventionally treated group (P = 0.5327) despite the neoadjuvant chemotherapy patients being statistically older (median age 67 years [range 44 to 85 years] vs a median age of 60 years [range 19 to 79 years] for conventionally treated patients; P < 0. 001) and having a statistically poorer performance status (P < 0. 001) than the conventionally treated group. Women undergoing cytoreductive surgery following neoadjuvant chemotherapy had a statistically improved overall survival (P < 0.0001) compared to those who did not undergo surgery. CONCLUSIONS: Neoadjuvant chemotherapy does not compromise the survival of women treated for advanced ovarian cancer. Prospective randomized trials comparing neoadjuvant chemotherapy to conventional therapy to determine quality of life experiences and cost/benefit outcomes are now appropriate for women presenting with advanced ovarian cancer.

Necrosis of myometrial choriocarcinoma with fulminating sepsis complicating chemotherapy for trophoblastic tumor.

We report a patient who developed metastatic gestational choriocarcinoma following delivery of a normal, healthy child that, however, was anemic and required blood transfusion. The patient developed secondary postpartum hemorrhage over a period of several weeks and required curettage and myometrial contractants to control the bleeding. At the time of diagnosis the patient had extensive pulmonary metastases and ultrasound showed full penetration of the myometrium by tumor. Immediately following the second course of chemotherapy with etoposide, methotrexate, and actinomycin D, alternating with cyclophosphamide and vincristine, the patient developed sepsis associated with a uteroperitoneal fistula and required hysterectomy. The sepsis was associated with disseminated intravascular coagulopathy and adult respiratory distress syndrome. However, the patient's tumor was exquisitely sensitive to chemotherapy and with good intensive care unit support and chemotherapy the survived without residual scar except for the loss of reproductive function. There are two lessons to be learned from these events: (1) The syndrome of secondary postpartum hemorrhage with a fetus that is anemic spells a diagnosis of choriocarcinoma; and (2) color Doppler flow vaginal ultrasound performed at the time of presentation of trophoblastic tumors may be useful to show full penetration of the myometrium by tumor which may be a warning of possible scar rupture in a subsequent pregnancy.

CA 125 may not reflect disease status in patients with uterine serous carcinoma.

BACKGROUND: Although CA 125 level correlates with response to therapy in patients with serous carcinoma of the ovary, the utility of CA 125 in patients with high risk or metastatic endometrial carcinoma has not been established. METHODS: CA 125 was tested as a marker of disease status in patients with endometrial serous carcinoma (SC) undergoing adjuvant chemotherapy. All patients received monthly intravenous chemotherapy with cisplatin, cyclophosphamide, and doxorubicin at standard doses (median number of courses, 6; range, 2-8 courses). Serum CA 125 was measured at diagnosis and before each course. After the completion of chemotherapy, patients were examined every 3 months and the CA 125 level was measured. RESULTS: A total of 220 serum specimens from 15 patients with invasive SC were analyzed. All five patients who died of disease had clinical or radiographic evidence of tumor, which CA 125 elevation did not precede or predict. One patient with advanced disease at staging never had an elevated CA 125 level but died of disseminated disease 14 months after diagnosis. At last follow-up, 3 patients who were without evidence of disease > 36 months from diagnosis had significant false-positive elevations in their CA 125 level (>50 u/mL) lasting 1, 2, and 4 months, respectively, during therapy. The sensitivity for advanced disease was only 57% at presentation. CONCLUSIONS: CA 125 may reflect advanced stage disease and portend a poor prognosis, but may not add information to that gained by history and physical examination, preoperative studies, or surgery that already is mandated by this high risk histology. This circulating marker appears to have limited utility in monitoring the effects of adjuvant therapy for SC, and may not predict recurrence in the absence of other clinical findings.

Nonmetastatic gestational trophoblastic neoplasia. Role of ultrasonography and magnetic resonance imaging.

OBJECTIVE: To determine whether routine imaging using grey-scale ultrasound, pulse and color Doppler flow, endovaginal ultrasound and magnetic resonance imaging (MRI) provide information that significantly helps determine therapy in patients with nonmetastatic gestational trophoblastic disease. STUDY DESIGN: A literature search was performed to seek all publications in English and German that reported on investigations of imaging by ultrasound and MRI in patients with a diagnosis of trophoblastic tumor without evidence of metastases. Studies performed to make a diagnosis of hydatidiform mole were excluded. Included were studies that investigated the clinical usefulness and efficacy of these imaging methods in the diagnosis of invasive mole as a visual confirmation of the diagnosis based on human chorionic gonadotropin (hCG) and histology. Furthermore, the usefulness and efficiency of imaging in determining the effectiveness of chemotherapy were investigated. RESULTS: Analysis of these reports showed that lesions are detectable by imaging modalities at relatively high levels of hCG but may not be visualized at lower levels of hCG, when chemotherapy is nevertheless indicated and the diagnosis of neoplasia is fully justified. Moreover, myometrial lesions have been observed by MRI in patients who subsequently achieved spontaneous resolution of their disease without chemotherapy. At lower levels of hCG (< 700 mIU/mL), intramyometrial lesions may not be visualized by either ultrasound or MRI. Myometrial abnormalities may persist with resolution of the tumor. Thus, the sensitivity of either method is no better than 70% and the specificity is even lower. CONCLUSION: Weekly serial levels of serum hCG remain the most accurate, reliable and definitive arbiter of treatment management. Pelvic ultrasound or MRI need not be an integral part of pretreatment assessment. Imaging techniques are expensive yet not decisive in managing nonmetastatic trophoblastic disease. This finding applies to nonmetastatic disease only. With metastases, ultrasound, MRI and computed tomography do play an integral role in diagnosis, staging and management.

Staging and assessing trophoblastic tumors. A possible solution to an intractable problem.

The present situation of staging gestational trophoblastic tumors by the system of the International Federation of Obstetrics and Gynecology (FIGO) and of scoring systems of risk factors in such tumors is examined critically. A solution for resolving staging and scoring difficulties is offered by combining the present FIGO staging with the accepted standardized World Health Organization system.

Effective treatment of stage I uterine papillary serous carcinoma with high dose-rate vaginal apex radiation (192Ir) and chemotherapy.

PURPOSE: Uterine papillary serous carcinoma (UPSC) is a morphologically distinct variant of endometrial carcinoma that is associated with a poor prognosis, high recurrence rate, frequent clinical understaging, and poor response to salvage treatment. We retrospectively analyzed local control, actuarial overall survival (OS), actuarial disease-free survival (DFS), salvage rate, and complications for patients with Federation International of Gynecology and Obstetrics (FIGO) (1988) Stage I UPSC. METHODS AND MATERIALS: This retrospective analysis describes 38 patients with FIGO Stage I UPSC who were treated with the combinations of radiation therapy, chemotherapy, total abdominal hysterectomy, and bilateral salpingo-oophorectomy (TAH/BSO), with or without a surgical staging procedure. Twenty of 38 patients were treated with a combination of low dose-rate (LDR) uterine/vaginal brachytherapy using 226Ra or 137Cs and conventional whole-abdomen radiation therapy (WART) or whole-pelvic radiation therapy (WPRT). Of 20 patients (10%) in this treatment group, 2 received cisplatin chemotherapy. Eighteen patients were treated with high dose-rate (HDR) vaginal apex brachytherapy using 192Ir with an afterloading device and cisplatin, doxorubicin, and cyclophosphamide (CAP) chemotherapy (5 of 18 patients). Only 6 of 20 UPSC patients treated with combination LDR uterine/vaginal brachytherapy and conventional external beam radiotherapy underwent complete surgical staging, consisting of TAH/BSO, pelvic/para-aortic lymph node sampling, omentectomy, and peritoneal fluid analysis, compared to 15 of 18 patients treated with HDR vaginal apex brachytherapy. RESULTS: The 5-year actuarial OS for patients with complete surgical staging and adjuvant radiation/chemotherapy treatment was 100% vs. 61% for patients without complete staging (p = 0.002). The 5-year actuarial OS for all Stage I UPSC patients treated with postoperative HDR vaginal apex brachytherapy and systemic chemotherapy was 94% (18 patients). The 5-year actuarial OS for Stage I UPSC patients treated with HDR vaginal apex brachytherapy and chemotherapy who underwent complete surgical staging was 100% (15 patients). The 5-year actuarial OS for the 20 Stage I UPSC patients treated with combinations of pre- and postoperative LDR brachytherapy and postop WART was 65%. None of the 6 surgically staged UPSC patients treated with LDR radiation and WART/WPRT developed recurrent disease. For patients with FIGO Stage IA, IB, and IC UPSC who underwent complete surgical staging, the 5-year actuarial DFS by depth of myometrial invasion was 100, 71, and 40%, respectively (p = 0.006). The overall salvage rate for local and distant recurrence was 0%. Complications following HDR vaginal apex brachytherapy included only Radiation Therapy Oncology Group (RTOG) grade 1 and 2 toxicity in 16% of patients. However, complications from patients treated with WART/WPRT, and/or LDR brachytherapy, included RTOG grade 3 and 4 toxicity in 15% of patients. CONCLUSION: Patients with UPSC should undergo complete surgical staging, and completely surgically staged FIGO Stage I UPSC patients can be effectively and safely treated with HDR vaginal apex brachytherapy and chemotherapy. Both OS and DFS of patients with UPSC are dependent on depth of myometrial invasion. The salvage rate for both local and distant UPSC recurrences is extremely poor. Complications from HDR vaginal apex brachytherapy were minimal.