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Malignant ovarian germ cell tumors: A review of 37 cases
260
SOCIETY OF GYNECOLOGIC ONCOLOGISTS-ABSTRACTS
treated by radical vulvectomy and bilateral groin node dissection with a median of 21 resected nodes per patient. Depth of tumor penetration was measured from the epithelial surface. Histologic grade was defined as the percentage of tumor area with an undifferentiated pattern: Grade I, ~30%; Grade 2, 30-49%; Grade 3, ~50%. Positive groin nodes occurred in 18% of patients with ~5 mm depth of penetration, but in 45% of patients with >5 mm. No positive nodes were found at 1 mm tumor penetration, but nodes were positive in 15% of patients at 2-4 mm and 39% at 5 mm. Quantitative associations between the risk factors and groin node status were evaluated by multiple regression using the linear logistic model. The predictors of positive groin nodes were identified in order of significance as clinically palpable nodes, depth of penetration in the pathology specimen, and the undifferentiated histologic grades II and III. When the nodes were not clinically palpable, the incidence of positive nodes was 0% (18 patients) among those with 1 mm of tumor penetration and rose to 31% (13 patients) among those with 5 mm of tumor penetration and 330% undifferentiated tumor pattern. Moreover, all 7 patients with 5 mm of tumor penetration and clinically palpable nodes had positive groin nodes. Tumor location, conventional histologic grading, vascular involvement, tumor size, and exophytic growth did not correlate with positive nodes. A scoring system derived from this analysis would be helpful in evaluating the risk of node metastases in patients with superficial cancer being considered for less than radical treatment. Germ Cell Tumors of the Ovary: The M. D. Anderson Hospital Experience. 19. Nondysgerminomatous D. M. GERSHENSON, G. DELJUNCO,L. J. COPELAND,C. L. EDWARDS, J. T. WHARTON,AND F. N. RUTLEDGE,Department of Gynecology, M. D. Anderson Hospital and Tumor Institute, The University of Texas System Cancer Center, 6723 Bertner Avenue, Houston, Texas 77030.
The present study is a retrospective analysis of 141 patients with nondysgerminomatous germ cell tumors of the ovary seen at the University of Texas M.D. Anderson Hospital and Tumor Institute from 1944 to mid-1983. The purpose of this review is to determine the biologic behavior, optimal treatment, and prognosis of these patients. The study population includes 52 patients with immature teratoma, 45 patients with endodermal sinus tumor, 40 patients with mixed germ cell tumor, 2 patients with nongestational choriocarcinoma, and 1 patient each with embryonal carcinoma and polyembryoma. Clinical data including age, race, signs and symptoms, tumor markers, and association with pregnancy are analyzed. Operative findings including tumor size, site of involvement, rupture, ascites, torsion, and FIG0 stage are discussed. Of the 141 patients, 7 are currently under treatment and are excluded from treatment and survival results. Follow-up is available on all patients until time of death or July 1, 1983, whichever came first. Survival is analyzed according to postoperative treatment-surgery alone, radiotherapy, single-agent chemotherapy, or a variety of combination regimens, including VAC and VBP. Overall survival results include 33/.52 for immature teratoma, 23/43 for EST, 17/35 for mixed GCT, l/2 for choriocarcinoma, l/l for embryomal carcinoma, and l/l for polyembryoma. Optimal therapy including surgery followed by combination chemotherapy is discussed as well as pitfalls in management. In this series, 11 pregnancies have occurred following treatment to date. 20. Malignant ROMANSKY,
Ovarian
Germ Cell Tumors: A Review of 37 Cases. J. P. MICHA, M. L. BERMAN, S. M. S. FLAM, P. KUCERA, AND P. J. DISAIA, Department of Obstetrics
M. RETTENMAIER,
& Gynecology, University of California, Irvine Medical Center, Building 25, 101 City Drive South, Orange, California 92668. Advances in adjuvant and adjunctive chemotherapy in the management of ovarian germ cell tumors has improved the prognosis dramatically. Thirty-seven patients with malignant ovarian germ cell tumors were treated at University of California Irvine Medical Center between 1972 and 1982, including 16 with immature teratoma (ImT), 6 with endodermal sinus tumors (EST), 7 with dysgerminomas, and 8 with mixed germ cell tumors (MGC). The initial mean primary tumor diameter was 19 cm. Twenty-eight of the thirty-seven patients had stage IA disease and all except one are alive without disease at intervals of 6 to 156 months, with a median follow-up of 62 months. The remaining 9 patients were divided into the following stages: 3 were stage IC, 2 were stage II, and 4 were stage III. All 9 of these patients are alive without evidence of disease at intervals of 18 to 125 months, with a median follow-up of 41 months. Postoperative treatment of patients included various chemotherapy regimens excepting 3 patients with stage IA immature teratoma and 3 patients with stage IA dysgerminoma who received no adjuvant therapy. Three additional patients with more advanced stage dysgerminomas received external radiation therapy without chemotherapy. The chemotherapy regimens
SOCIETY
OF GYNECOLOGIC
ONCOLOGISTS-ABSTRACTS
261
employed for the remaining patients were vincristine/actinomycin D/and cytoxan (VAC) in 25, vinblastinei bleomyciniand cis-platinum (VBP) in 2, and VBP/actinomycin D/adriamycin in one patient. Two patients failed initial therapy but had complete remissions with second regimens. Only one patient with a stage IA mixed germ cell tumor has failed multiple regimens. She is alive with disease. Of the 30 patients with ImT, EST, or MGC tumors 24 have had negative second-look laparotomies. One additional patient had a negative second-look laparoscopy and four are scheduled for secondlook procedures. No patients with negative findings at laparotomy have recurred subsequently. In summary 36 of 37 patients with malignant ovarian germ cell tumors remain without evidence of disease with median follow-up of 49 months. The primary tumors were large. Multiple agent chemotherapy has dramatically improved the prognosis of these patients such that survival in this series was independent of prognostic factors including stage and grade of disease. Patients who fail primary chemotherapy can achieve complete remissions with intensive “second-line” regimens. to Trophoblast Neoplasms by the Children of Choriocarcinoma Mothers. R. A. PATTILLO, A.C.F. RUCKERT, AND R. F. MATTINGLY, The Medical College of Wisconsin, Department of Gynecology and Obstetrics, 8700 West Wisconsin Avenue, Milwaukee. Wisconsin 53226.
21. Immunity
The children of postgestational choriocarcinoma mothers have been examined for susceptibility or resistance to the malignancies of their placental cells. Historical evidence would suggest that their placental cells had been transformed to malignancy during their intrauterine life. On the basis of the foregoing premise, three questions can be asked: (I) Did their lymphocytes become sensitized to the malignancy during intrauterine gestation? (2) Did their lymphocytes retain the memory of this event? and (3) Have their lymphocytes retained cytotoxicity to the choriocarcinoma, thus affording resistance to choriocarcinoma? The results were affirmative to each question, In all instances, the mother’s choriocarcinomas had been grown in tissue culture and lymphocytes from the child were incubated to determine their recognition and cytotoxic capacity to kill these malignant cells from their own placenta as well as from other patients with malignant trophoblastic disease. Two of the mothers had died from resistant widespread disease; three were free of disease for up to I1 years. All children showed immunity to choriocarcinoma cells. 22. Plasma Methotrexate (MTX) Levels in Patients with Gestational Trophoblastic Neoplasia (GTN) Treated by Various Methotrexate Regimens. J. ROTMENSCH, N. ROSENSHEIN, R. DANEHOWER, M. AND J. VILLAR, Department of Gynecology and Obstetrics. The Johns Hopkins Hospital, Baltimore, Maryland 21205.
DILLON,
An optimal MTX regimen and mode of administration for the treatment of GTN has not been defined. In an attempt to compare two standard regimens, MTX plasma levels for GTN were measured after intravenous (iv) and intramuscular (im) administration. In Regimen I, MTX (1 mg/kg) on Days I, 3, 5, and 7 and citrovorum factor (CF) on Days 2, 4, 6, and 8 were administered. Each cycle was alternated between iv and im administration every 3 weeks, allowing each patient to be her own control. Five patients were treated with Regimen I for I6 cycles, (8 iv and 8 im). The mean MTX plasma levels were 2.94 x IOe6, 3.53 x 10mR,and 6.46 x IO-’ M after iv MTX administration and 3.87 x 10m6,3.39 x IO-‘, and 4.25 x IO-’ M after im administration at I, 24, and 48 hr, respectively. Four patients were treated with Regimen 2 for I5 cycles (8 iv and 7 im). The mean MTX plasma levels post-MTX administration were 2.04 x lOmh,4.61 x IOmR,and 1.98 x IO-’ M after iv administration and 1.75 x 10e6, 5.87 x IO-‘, and 1.55 x IO-* M after im administration at I, 12, and 24 hr, respectively. No hematological, renal, or hepatic toxicity occurred with either regimen. Only one patient on single-agent MTX had severe stomatitis. The data indicate that in the MTX-CF regimen, MTX plasma levels were statistically greater at I hr after im administration and at 48 hr after iv administration but probably were not of clinical importance. In the single-agent regimen, there were no differences in MTX by iv or im administration. The low MTX concentrations seen at 48 hr in the MTX-CF regimen support the hypothesis that reduced toxicity may be related not to the CF but to the 48-hr administration interval. Prolonged exposures to minimal concentrations of MTX of less than lOen M in the 8-day regimen may explain the reportedly increased resistance in the MTX-CF regimen.
SOCIETY OF GYNECOLOGIC ONCOLOGISTS-ABSTRACTS
treated by radical vulvectomy and bilateral groin node dissection with a median of 21 resected nodes per patient. Depth of tumor penetration was measured from the epithelial surface. Histologic grade was defined as the percentage of tumor area with an undifferentiated pattern: Grade I, ~30%; Grade 2, 30-49%; Grade 3, ~50%. Positive groin nodes occurred in 18% of patients with ~5 mm depth of penetration, but in 45% of patients with >5 mm. No positive nodes were found at 1 mm tumor penetration, but nodes were positive in 15% of patients at 2-4 mm and 39% at 5 mm. Quantitative associations between the risk factors and groin node status were evaluated by multiple regression using the linear logistic model. The predictors of positive groin nodes were identified in order of significance as clinically palpable nodes, depth of penetration in the pathology specimen, and the undifferentiated histologic grades II and III. When the nodes were not clinically palpable, the incidence of positive nodes was 0% (18 patients) among those with 1 mm of tumor penetration and rose to 31% (13 patients) among those with 5 mm of tumor penetration and 330% undifferentiated tumor pattern. Moreover, all 7 patients with 5 mm of tumor penetration and clinically palpable nodes had positive groin nodes. Tumor location, conventional histologic grading, vascular involvement, tumor size, and exophytic growth did not correlate with positive nodes. A scoring system derived from this analysis would be helpful in evaluating the risk of node metastases in patients with superficial cancer being considered for less than radical treatment. Germ Cell Tumors of the Ovary: The M. D. Anderson Hospital Experience. 19. Nondysgerminomatous D. M. GERSHENSON, G. DELJUNCO,L. J. COPELAND,C. L. EDWARDS, J. T. WHARTON,AND F. N. RUTLEDGE,Department of Gynecology, M. D. Anderson Hospital and Tumor Institute, The University of Texas System Cancer Center, 6723 Bertner Avenue, Houston, Texas 77030.
The present study is a retrospective analysis of 141 patients with nondysgerminomatous germ cell tumors of the ovary seen at the University of Texas M.D. Anderson Hospital and Tumor Institute from 1944 to mid-1983. The purpose of this review is to determine the biologic behavior, optimal treatment, and prognosis of these patients. The study population includes 52 patients with immature teratoma, 45 patients with endodermal sinus tumor, 40 patients with mixed germ cell tumor, 2 patients with nongestational choriocarcinoma, and 1 patient each with embryonal carcinoma and polyembryoma. Clinical data including age, race, signs and symptoms, tumor markers, and association with pregnancy are analyzed. Operative findings including tumor size, site of involvement, rupture, ascites, torsion, and FIG0 stage are discussed. Of the 141 patients, 7 are currently under treatment and are excluded from treatment and survival results. Follow-up is available on all patients until time of death or July 1, 1983, whichever came first. Survival is analyzed according to postoperative treatment-surgery alone, radiotherapy, single-agent chemotherapy, or a variety of combination regimens, including VAC and VBP. Overall survival results include 33/.52 for immature teratoma, 23/43 for EST, 17/35 for mixed GCT, l/2 for choriocarcinoma, l/l for embryomal carcinoma, and l/l for polyembryoma. Optimal therapy including surgery followed by combination chemotherapy is discussed as well as pitfalls in management. In this series, 11 pregnancies have occurred following treatment to date. 20. Malignant ROMANSKY,
Ovarian
Germ Cell Tumors: A Review of 37 Cases. J. P. MICHA, M. L. BERMAN, S. M. S. FLAM, P. KUCERA, AND P. J. DISAIA, Department of Obstetrics
M. RETTENMAIER,
& Gynecology, University of California, Irvine Medical Center, Building 25, 101 City Drive South, Orange, California 92668. Advances in adjuvant and adjunctive chemotherapy in the management of ovarian germ cell tumors has improved the prognosis dramatically. Thirty-seven patients with malignant ovarian germ cell tumors were treated at University of California Irvine Medical Center between 1972 and 1982, including 16 with immature teratoma (ImT), 6 with endodermal sinus tumors (EST), 7 with dysgerminomas, and 8 with mixed germ cell tumors (MGC). The initial mean primary tumor diameter was 19 cm. Twenty-eight of the thirty-seven patients had stage IA disease and all except one are alive without disease at intervals of 6 to 156 months, with a median follow-up of 62 months. The remaining 9 patients were divided into the following stages: 3 were stage IC, 2 were stage II, and 4 were stage III. All 9 of these patients are alive without evidence of disease at intervals of 18 to 125 months, with a median follow-up of 41 months. Postoperative treatment of patients included various chemotherapy regimens excepting 3 patients with stage IA immature teratoma and 3 patients with stage IA dysgerminoma who received no adjuvant therapy. Three additional patients with more advanced stage dysgerminomas received external radiation therapy without chemotherapy. The chemotherapy regimens
SOCIETY
OF GYNECOLOGIC
ONCOLOGISTS-ABSTRACTS
261
employed for the remaining patients were vincristine/actinomycin D/and cytoxan (VAC) in 25, vinblastinei bleomyciniand cis-platinum (VBP) in 2, and VBP/actinomycin D/adriamycin in one patient. Two patients failed initial therapy but had complete remissions with second regimens. Only one patient with a stage IA mixed germ cell tumor has failed multiple regimens. She is alive with disease. Of the 30 patients with ImT, EST, or MGC tumors 24 have had negative second-look laparotomies. One additional patient had a negative second-look laparoscopy and four are scheduled for secondlook procedures. No patients with negative findings at laparotomy have recurred subsequently. In summary 36 of 37 patients with malignant ovarian germ cell tumors remain without evidence of disease with median follow-up of 49 months. The primary tumors were large. Multiple agent chemotherapy has dramatically improved the prognosis of these patients such that survival in this series was independent of prognostic factors including stage and grade of disease. Patients who fail primary chemotherapy can achieve complete remissions with intensive “second-line” regimens. to Trophoblast Neoplasms by the Children of Choriocarcinoma Mothers. R. A. PATTILLO, A.C.F. RUCKERT, AND R. F. MATTINGLY, The Medical College of Wisconsin, Department of Gynecology and Obstetrics, 8700 West Wisconsin Avenue, Milwaukee. Wisconsin 53226.
21. Immunity
The children of postgestational choriocarcinoma mothers have been examined for susceptibility or resistance to the malignancies of their placental cells. Historical evidence would suggest that their placental cells had been transformed to malignancy during their intrauterine life. On the basis of the foregoing premise, three questions can be asked: (I) Did their lymphocytes become sensitized to the malignancy during intrauterine gestation? (2) Did their lymphocytes retain the memory of this event? and (3) Have their lymphocytes retained cytotoxicity to the choriocarcinoma, thus affording resistance to choriocarcinoma? The results were affirmative to each question, In all instances, the mother’s choriocarcinomas had been grown in tissue culture and lymphocytes from the child were incubated to determine their recognition and cytotoxic capacity to kill these malignant cells from their own placenta as well as from other patients with malignant trophoblastic disease. Two of the mothers had died from resistant widespread disease; three were free of disease for up to I1 years. All children showed immunity to choriocarcinoma cells. 22. Plasma Methotrexate (MTX) Levels in Patients with Gestational Trophoblastic Neoplasia (GTN) Treated by Various Methotrexate Regimens. J. ROTMENSCH, N. ROSENSHEIN, R. DANEHOWER, M. AND J. VILLAR, Department of Gynecology and Obstetrics. The Johns Hopkins Hospital, Baltimore, Maryland 21205.
DILLON,
An optimal MTX regimen and mode of administration for the treatment of GTN has not been defined. In an attempt to compare two standard regimens, MTX plasma levels for GTN were measured after intravenous (iv) and intramuscular (im) administration. In Regimen I, MTX (1 mg/kg) on Days I, 3, 5, and 7 and citrovorum factor (CF) on Days 2, 4, 6, and 8 were administered. Each cycle was alternated between iv and im administration every 3 weeks, allowing each patient to be her own control. Five patients were treated with Regimen I for I6 cycles, (8 iv and 8 im). The mean MTX plasma levels were 2.94 x IOe6, 3.53 x 10mR,and 6.46 x IO-’ M after iv MTX administration and 3.87 x 10m6,3.39 x IO-‘, and 4.25 x IO-’ M after im administration at I, 24, and 48 hr, respectively. Four patients were treated with Regimen 2 for I5 cycles (8 iv and 7 im). The mean MTX plasma levels post-MTX administration were 2.04 x lOmh,4.61 x IOmR,and 1.98 x IO-’ M after iv administration and 1.75 x 10e6, 5.87 x IO-‘, and 1.55 x IO-* M after im administration at I, 12, and 24 hr, respectively. No hematological, renal, or hepatic toxicity occurred with either regimen. Only one patient on single-agent MTX had severe stomatitis. The data indicate that in the MTX-CF regimen, MTX plasma levels were statistically greater at I hr after im administration and at 48 hr after iv administration but probably were not of clinical importance. In the single-agent regimen, there were no differences in MTX by iv or im administration. The low MTX concentrations seen at 48 hr in the MTX-CF regimen support the hypothesis that reduced toxicity may be related not to the CF but to the 48-hr administration interval. Prolonged exposures to minimal concentrations of MTX of less than lOen M in the 8-day regimen may explain the reportedly increased resistance in the MTX-CF regimen.