OVARIAN MALIGNANT tumors are often diagnosed

Survival and Reproductive Function After Treatment of Malignant Germ Cell Ovarian Tumors By Gerardo Zanetta, Cristina Bonazzi, Maria Grazia Cantù, Ser...
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Survival and Reproductive Function After Treatment of Malignant Germ Cell Ovarian Tumors By Gerardo Zanetta, Cristina Bonazzi, Maria Grazia Cantù, Sergio Bini,† Anna Locatelli, Giorgio Bratina, and Costantino Mangioni Purpose: Germ cell ovarian tumors are curable. The possible sequelae of chemotherapy on long-term survivors are still unknown, but these patients may expect normal lives. The aim of this study was to evaluate the outcome and reproductive function in a population of women treated since 1982. Materials and Methods: Between 1982 and 1996, 169 women with malignant germ cell ovarian tumors were seen (70 dysgerminomas, 28 endodermal sinus tumors, 24 mixed tumors, and 47 immature teratomas). Seventy-one had advanced or recurrent disease. Fertilitysparing surgery was performed in 138 (81%) women, 81 of whom received postoperative chemotherapy. Results: With a median follow-up of 67 months, the survival rate was 94% for dysgerminoma, 89% for endodermal sinus tumors, 100% for mixed types, and 98% for immature teratoma. For women who were treated conservatively, the survival rate was 98%, 90%, 100%, and 100%, respectively. Two women had adnexal recurrences, and both received salvage treat-

ment. After treatment, all but one postpubertal woman had recovery of menses within 9 months. During follow-up, 12 untreated and 20 treated patients had 55 conceptions. We recorded 40 pregnancies at term, six terminations, and nine miscarriages. Four malformations were observed: one in 14 conceptions of patients who had not received chemotherapy and three in 41 conceptions of treated patients. Conclusion: Irrespective of subtype and stage, conservative surgery should become the standard approach to treating most patients with malignant ovarian germ cell tumors. Fertility seems to be only marginally affected by treatments. Miscarriages are in the expected range for the general population. The malformation rate is slightly higher than in the general population, but no significant difference was seen between patients who did and did not receive chemotherapy. J Clin Oncol 19:1015-1020. © 2001 by American Society of Clinical Oncology.

VARIAN MALIGNANT tumors are often diagnosed in women who are in their fifth or sixth decade of 1 life. However, malignant germ cell tumors are almost exclusively diagnosed in young females.2,3 These tumors are now curable, mainly as a result of great advances in chemotherapy in the past two decades.4,5 The possible sequelae of chemotherapy on long-term survivors are still largely unknown, but based on the available evidence, these patients may expect normal lives. Preservation of their ovarian function and fertility is becoming an important, although controversial, issue in gynecologic oncology.6,7 In practical terms, preservation of fertility requires the conservation of the uterus and the contralateral adnexum (conservative surgery). The historical rationale for routine ablation of the internal genital tract of women with ovarian malignancies was the risk of microscopic involvement of a seemingly normal contralateral ovary. However, for germ cell tumors, the risk of bilateral involvement is relatively low8,9 and the availability of highly effective chemotherapy may sterilize microscopic foci of tumor without the need for removal of the contralateral ovary. Irrespective of the treatment chosen, extremely little information exists about the reproductive function and childbearing potential of young women who are treated conservatively for germ cell ovarian malignancies, particu-

larly when chemotherapy has been used.10,11 The aim of this study was to evaluate the outcome and reproductive function in a large population of young women treated for ovarian germ cell cancers in our department since 1982.

O

MATERIALS AND METHODS Between 1982 and 1996, a total of 169 women with germ cell ovarian malignancies either underwent primary surgery in our department (22 [13%]) or were referred for postoperative treatment (147 [87%]). In all instances, the microscopic slides were reviewed by our most experienced pathologist to confirm the diagnosis. In all, 70 women had pure dysgerminoma, 28 had endodermal sinus tumors (EST), 24 had mixed germ cell tumors (MGCT), and 47 had immature teratomas (IT). Ninety-eight women had stage I tumor, 14 had stage II, 46 had stage III, and five had stage IV. Six women were referred at the time of recurrence after primary treatment was performed elsewhere.

From the Department of Obstetrics and Gynecology and Department of Pathology, San Gerardo Hospital of Monza, University of Milano, Bicocca, Italy. †Deceased. Submitted January 19, 2000; accepted October 25, 2000. Address reprint requests to Gerardo Zanetta, MD, Department of Obstetrics and Gynecology, Ospedale San Gerardo, Via Solferino 16, 2 Monza Italy, 2005; email: [email protected] © 2001 by American Society of Clinical Oncology. 0732-183X/01/1904-1015

Journal of Clinical Oncology, Vol 19, No 4 (February 15), 2001: pp 1015-1020

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ZANETTA ET AL Table 1.

Main Characteristics of the Study Population Patients Characteristic

Age at diagnosis, years Median Range Median age of women treated conservatively, years Median age of women treated radically, years Conservative surgery by histologic type Dysgerminoma EST MGCT IT Chemotherapy by histologic type Dysgerminoma stage I to II Dysgerminoma stage III to IV, recurrence EST, all stages MGCT, all stages IT stage I to II IT stage III to IV, recurrence

*No.

%

21 8-41 20 21 54/70 22/28 18/24 44/47

78 78 75 93

13/41 29/29 28/28 24/24 5/41 6/6

32 100 100 100 45 100

*No. of patients/total no. of patients.

Women who underwent primary surgery in our department had unilateral salpingo-oophorectomy, omentectomy, aimed or random intraperitoneal sampling, aimed or random retroperitoneal sampling, and debulking if needed. In few cases with bilateral involvement, only an excision of the tumor was performed in the least involved ovary, with preservation of the uninvolved ovarian tissue. After the specimen was analyzed by frozen-section histopathology, the decision about further surgical procedures was made. A biopsy of the contralateral ovary usually was not performed, and only suspicious lesions on the surface of the preserved ovary were excised and sent for pathologic evaluation. Such a policy was chosen as germ cell tumors are highly chemosensitive and wedge biopsy of the ovary is a recognized cause of mechanical infertility.12 Systemic pelvic and para-aortic lymphadenectomy was not performed until 1990 but became part of the standard procedure thereafter. For women who were referred after primary surgery was performed elsewhere, the final decision about preservation of fertility was based on the histopathologic report, the description of the first surgery, the adequacy of primary staging procedures, the age of the woman, and her wish to preserve the ovarian function. The main characteristics of the patients are listed in Table 1. Fertility-sparing surgery was performed in 138 (81%) women: 88 (89%) of 98 women with stage I tumor, nine (64%) of 14 with stage II, 35 (76%) of 46 with stage III, two (40%) of five with stage IV, and four (66%) of six referred for recurrence. In all, 105 women received chemotherapy. Among those women who received conservative surgery, 73 received platinum-based chemotherapy and eight received non–platinum-based chemotherapy. No chemotherapy was given to patients with stage Ia pure dysgerminoma. Platinum-based chemotherapy was given to all patients who had advanced dysgerminoma or EST and MGCT, irrespective of the stage. The treatment of IT was based on the stage and the grade of the disease. Eleven of 47 women with IT received platinum-based chemotherapy. Four different regimens were used: A. Doxorubicin (40 mg/m2, day 1) and cyclophosphamide (200 mg/m2, days 3 to 6) were administered every 4 weeks from 1982 to 1983 in women with dysgerminoma (DC regimen).

B. Cisplatin (20 mg/m2, days 1 to 5), vinblastine (0.15 mg/kg, days 1 and 2), and bleomycin (30 mg, days 1, 8, and 15) were administered in all other cases every 3 weeks from 1982 to 1987 (PVB regimen). C. Cisplatin (60 mg/m2, day 1), etoposide (75 mg/m2, days 1 and 2), and bleomycin (30 mg, day 1) were administered in all instances every week from 1989 to 1996 (wPEB regimen). D. Cisplatin (20 mg/m2, days 1 to 5), etoposide (100 mg/m2, days 1 to 5), and bleomycin (30 mg, days 1, 8, and 15) were administered in all instances every 3 weeks in 1996 (3wPEB regimen). The number of courses was chosen on the basis of the clinical setting. Regimen A was usually administered for three courses as adjuvant treatment and for six courses in patients with residual disease. Regimens B, C, and D were administered for three to four courses in cases of adjuvant treatment and for five to six courses in cases of advanced disease with residual tumor after surgery. Follow-up examinations were conducted every 3 months for the first year after surgery and every 6 months thereafter and consisted of physical and gynecologic examination, diagnostic imaging of the abdomen and the pelvis, and measurement of serum tumor markers. Chest x-rays were performed every year. The desire for fertility specifically was addressed at each follow-up examination. When couples failed to conceive 1 year after unprotected intercourse, they were referred to our section for assisted reproduction.

RESULTS

In the study population, 15 women had documented bilateral involvement of the ovaries (8.9%). With a median follow-up of 67 months (range, 8 to 180 months), the survival rate was 94% (66 of 70) for dysgerminoma, 89% (25 of 28) for EST, 100% (24 of 24) for MGCT, and 98% (46 of 47) for IT. The survival for the whole population is 161 (95%) of 169. With regard to women who were treated conservatively, the figures are 98% (53 of 54), 90% (20 of 22), 100% (44 of 44), and 100% (18 of 18), respectively. We observed 16 recurrences in 138 women who were treated conservatively (11.6%) and six in 31 women who were treated radically (19.3%), but only eight women (4.7%) died. Table 2 lists the characteristics and outcome of women with recurrence. Eighty-one women who were treated conservatively received chemotherapy, representing 58% of all women who were treated conservatively (81 of 138) and 77% of women who required chemotherapy (81 of 105). Twenty-four women required chemotherapy after radical surgery. Fiftyseven women did not receive chemotherapy after conservative surgery, and seven did not require chemotherapy after radical surgery. Hypergonadotropic amenorrhea during treatment was recorded in one (12.5%) of eight women who were treated with DC, in 16 (76%) of 21 women who were treated with the PVB regimen, in 40 (95%) of 42 women who were treated with the wPEB regimen, and in all six women who were treated with the 3wPEB regimen. Irrespective of the regimen, we observed that the median time to recovery of menstruation was highly correlated to

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SURVIVAL AND FUNCTION AFTER GERM CELL TUMORS Table 2.

Site of Recurrence in the Study Population

No. of Patients Primary Surgery

Total

Recurrence

Limited surgery

138

16

Radical surgery

31

6

the length of treatment. For women who were treated for 1 month or less, we recorded a median time to recovery of the menstrual function of 2 months from the end of treatment. For those who were treated for 1 to 2 months, the median time was 3 months from the end of treatment. For those who were treated for 2 to 3 months, the interval was 4 months from the end of treatment. Two patients who were treated with the 3wPEB regimen were prepubertal and had their menarche during treatment and 11 months after the end of the treatment, respectively. All but one postmenarchal patient had full recovery of their menses within 9 months from the end of the treatment, with a median of 5 months. Of the 138 women who were treated conservatively, eight (5.8%) could not be assessed with regard to their fertility. Five had radical surgery in the follow-up period (one recurrence, one benign ovarian cyst, one stage IB cervical carcinoma, and two not wanting fertility), and three died of disease before attempting any conception. Of the remaining 130 women whose fertility had been preserved, one had early ovarian failure (menopause at the age of 33 years) and one had primary amenorrhea. Both had received platinumbased chemotherapy. These two women are, at the time of this writing, the only patients with early ovarian failure, defined as cessation of the menses with elevation of the gonadotropin levels before the age of 40.13 The reproduc-

Site of Recurrence

4 3 8 1 3 1 2

distant metastases nodes pelvis ovary ⫹ peritoneum distant metastases node pelvis

Reproductive Status of 64 Untreated Women Status

No. of Patients

Infertile after surgery Potentially fertile Not attempting conception Attempting conception Failures Conceiving patients Conceptions Normal pregnancies with normal fetus Miscarriages Terminations

9 55 43 12 0 12 14 12 – 2*

*One termination for personal reasons; one termination after detection of malformation.

2 – – 1 3 1 –

tive status and the pregnancy outcome for the remaining 128 potentially fertile conservatively treated women are listed in Tables 3 and 4. During the follow-up period, 12 untreated and 20 treated women attempted conception. We recorded 14 conceptions in 12 women who had not received postoperative chemotherapy. No miscarriage was observed. Twelve normal pregnancies with delivery at term were recorded. Two women decided to terminate their pregnancies: one for personal reasons and one after sonographic detection of posterior urethral valves in a male fetus. Sixteen of 20 women who had received chemotherapy conceived, and we recorded 41 conceptions. Nine miscarriages were recorded; three of them were observed in one patient with chimerism: 46, XY[4]/46, XX[96]. There were 28 pregnancies at term (27 singletons, one with twins) and we observed one Dandy Walker syndrome (defect of cerebellar vermis, retrocerebellar cyst, and hydrocephalus) and one perineal hypospadia. Four women decided to terminate their pregnancies, one of them after diagnosis of achondrogenesis of the fetus. In all, when the three miscarriages observed in the woman with chimerism are excluded, we record a miscarriage rate of 11% (six of 52; 95% confidence interval [CI],

Table 4. Table 3.

Patients Who Died (no.)

Reproductive Status of 105 Treated Women Status

No. of Patients

Infertile after surgery or early death Potentially fertile Not attempting conception Attempting conception Failures Conceiving patients Conceptions Term pregnancies with normal fetus Term pregnancies with fetal malformations Miscarriages Terminations

32 73 53 20 4 16 41 26 2* 9† 4‡

*One Dandy Walker syndrome; one perineal hypospadia. †Three miscarriages in one woman with chimerism. ‡One termination for fetal achondrogenesis, three for personal reasons.

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5% to 22%) among women who had received chemotherapy, which differs little from the 10% to 15% rate observed in the general population.14 Even if the three spontaneous abortions in the woman with chimerism are added, no statistical difference is observed with the general population. When malformations are taken into account, we observed four cases in the 55 conceptions (7.2%), with 1 of 14 conceptions among untreated women and one of 12 untreated women versus three of 32 conceptions in treated women and one of 20 treated women. If we exclude the nine miscarriages (for which no information on possible malformation was available), we observe an incidence of 8.7% (95% CI, 3.6% to 20%). Because of the small study population, we were unable to find a statistically significant difference in the malformation rate of treated and untreated women (P ⫽ .6 Fisher’s exact test), but the 95% CI (3.6% to 20%) is above the estimated risk of malformation of 3% expected in the general population.15 DISCUSSION

Cure without function loss should represent one of the highest goals for each physician and the ideal treatment for each patient. Although the impact of fertility is not easily objectified as a parameter for the well-being of a young woman, it is known that women who undergo evaluation and treatment for infertility often experience grief, denial, anger, high levels of anxiety and depression, lowered self-esteem, poor body image, and problems with sexual identity and functioning.16 Moreover, apart from fertility, normal gonadal function is part of the completeness of human beings, and traumatic subtraction of this aspect of life is likely to be experienced as a loss of an important part. Until the 1980s, the search for curative procedures in ovarian tumors led to the acceptance of radical, nonconservative surgery as the standard treatment for any ovarian malignancy. However, a careful analysis of the enormous amount of medical information collected in the past three decades about the natural history of different ovarian tumors allows the classification of different entities, with completely different behavior and natural history. The identification of highly chemosensitive tumors such as most germ cell tumors has opened new perspectives in gynecologic oncology. In our population, with a mean follow-up of 67 months (range, 28 to 180 months), the disease-free survival is 135 (97.8%) of 138 for women who had undergone fertilitysparing surgery and 26 (83.9%) of 31 for those who had undergone radical surgery. In addition, we recorded only two recurrences in the preserved genital tract (one in the stump of the fallopian tube and one in the preserved ovary), and both patients were salvaged by surgery. These data confirm that conservative surgical treatment should be

considered the standard approach to treating the majority of patients with malignant germ cell tumors of the ovaries. Anxiety of the patient is often cited as a reason for the request of radical surgery, but in our population only two women decided to undergo radical surgery in the absence of recurrence. This underlines the importance of discussing treatment options thoroughly with the patient. Effective chemotherapy and surgery make possible the survival of the majority of women with recurrence of germ cell tumors irrespective of conservative or radical surgery; in our population, 14 (64%) of 22 women with recurrences survived and remain free of disease. In addition, one should consider that these results were achieved without the use of taxanes. Preliminary reports suggest that the survival rate for women with germ cell tumors could be improved further by including paclitaxel in salvage regimens.17,18 In our study population, the duration of chemotherapy probably is slightly longer than that described by others. However, this reflects the development of effective chemotherapy in germ cell tumors, and in view of our choice of nonperforming, routine, second-look operations, such policy was believed to be safe for our patients. It is of note that none of our patients had life-threatening toxicity as a result of the administration of the fourth to sixth courses of chemotherapy, and recovery of gonadal function was almost universal. We recognize that reduction in treatment time, once the safety in terms of cure is confirmed, could represent one of the best ways for lessening toxicity. One interesting detail of our study is that one of five women who underwent radical surgery in the follow-up period had pathologic diagnosis of benign ovarian cysts and received an inappropriate treatment out of fear of a recurrence. This observation raises the point of a wise follow-up for these particular patients. It is widely known that women who have undergone excision of one ovary often have function cysts in the preserved ovary.19 Diagnostic imaging, particularly transvaginal ultrasound, may allow the differential diagnosis of benign and malignant masses.20,21 In addition, even in cases of suspicious findings, intraoperative frozensection pathologic analysis of the removed cyst should always be performed before embarking on radical surgery. With regard to ovarian function and fertility, in a review of his experience with combination chemotherapy for malignant ovarian germ cell tumors, Gershenson7 reported that 68% of women maintained regular menses after completion of chemotherapy and 83% of them were having regular menses at the time of follow-up. In the same study, the author reported that 11 women delivered 22 healthy infants, none of whom had a major birth defect. More recent, other authors have described the reproductive function of young women who had undergone fertility-sparing surgery for germ cell tumors. Perrin et al22 reported seven normal

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pregnancies with healthy babies among 29 women who had received chemotherapy for germ cell tumors. Ezzat et al23 described 44 women who retained their fertility after treatment for germ cell tumors, and they reported that no abnormality was observed in 16 pregnancies. Brewer et al24 observed that 71% of young women who were treated with bleomycin, etoposide, and cisplatin after fertility-sparing surgery for pure dysgerminoma maintained their normal menstrual function during and after chemotherapy. With a median follow-up of 89 months, five pregnancies were recorded in 14 patients. In our population, at the time of this writing, the fertility of treated women (20 [24.7%] of 81 conceived) is not different from that observed among those women who did not require postoperative treatments (12 [21%] of 57 conceived). When the pregnancy outcome is taken into account, we notice that in our study population, the rate of miscarriages differs little from the general population.14 In addition, we did not observe any ectopic pregnancy. This result is partially unexpected in women whose pelvis underwent surgery, and longer follow-up is required to allow definitive conclusions. Differing from other reports,7,22-24 we did record four fetuses with documented malformation (three in treated women and one in an untreated woman). Such an incidence of malformations is slightly higher than in the general population, and at least two hypotheses may be considered. The first is that some underlying genetic disorders may be associated with the onset of germ cell tumors and that such a disorder may also cause an increased number of malformations in the offspring. Nevertheless, such genetic abnormality is usually associated to the sex chromosomes. The second might call into question a possible teratogenic effect of the regimens. Secondary malig-

nancies, particularly leukemia, have been reported in survivors of testicular cancer and ovarian germ cell tumors.25 The leukemogenic potential of some antiblastic drugs is now well known, but this refers in particular to alkylating agents and etoposide, whereas less is known about such a potential for the platinum compounds bleomycin and the vinca derivatives. We must also consider that a third possible explanation for the observed slight increase of fetal malformation is simply chance occurrence. The data of our study confirm that normal gonadal function and fertility are possible after conservative surgery for ovarian germ cell malignancies, even when chemotherapy has been used. We conclude that the survival of young patients with malignant germ cell ovarian cancer is outstanding after fertility-sparing surgery and that wedge biopsy of the contralateral ovary is not needed. Young women who are treated with multidrug chemotherapy for ovarian germ cell tumors may expect recovery of ovarian function within a few months after treatment. According to the available evidence, the fertility seems to be only marginally affected by treatment. In particular, the rate of miscarriages is within the expected range for the general population. The malformation rate in offspring is slightly higher than in the general population, but we were unable to find a statistically significant difference among women who were and were not treated after surgery, and no common etiopathologic pattern is identifiable in the four cases. The documentation of such malformations, however, underlines the importance of an accurate assessment in utero of the fetus by means of ultrasound. Longer follow-up is needed to clarify the impact of chemotherapy on the malformation rate.

REFERENCES 1. Russell P: Surface epithelial-stromal tumors of the ovary, in Kurman R (ed): Blaustein’s Pathology of the Female Genital Tract (ed 4). New York, NY, Springer-Verlag, 1995, pp 705-782 2. Talerman A: Germ cell tumors of the ovary, in Kurman R (ed): Blaustein’s Pathology of the Female Genital Tract (ed 4). New York, NY, Springer-Verlag, 1995, pp 849-914 3. Norris HJ, Jensen RD: Relative frequency of ovarian neoplasms in children and adolescents. Cancer 30:713-719, 1972 4. Sessa C, Bonazzi C, Landoni F, et al: Cisplatin, vinblastine and bleomycin: Combination chemotherapy in endodermal sinus tumor of the ovary. Obstet Gynecol 70:220-223, 1987 5. Williams S, Birch R, Einhorn LH, et al: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316:1435-1440, 1987 6. Pektasides D, Rustin GJS, Newlands ES, et al: Fertility after chemotherapy for ovarian germ cell tumours. Br J Obstet Gynaecol 94:477-479, 1987 7. Gershenson DM: Menstrual and reproductive function after treatment with combination chemotherapy for malignant ovarian germ cell tumors. J Clin Oncol 6:270-275, 1988

8. Norris HJ, O’Connor DM: Pathology of malignant germ cell tumors of ovary, in Monaghan JM, Morrow CP, Tattersall MHN (eds): Gynecologic Oncology (ed 2). Edinburgh, Scotland, Churchill Livingstone, 1992, pp 917-934 9. Kurman RJ, Norris HJ: Malignant mixed germ cell tumors of the ovary: A clinical and pathologic analysis of 30 cases. Obstet Gynecol 48:579-588, 1976 10. Schwartz TE, Vidone RA: Pregnancy following combination chemotherapy for a mixed germ cell tumor of the ovary. Gynecol Oncol 12:373-378, 1981 11. Javaheri G, Lifchez A, Valle J: Pregnancy following removal and long term chemotherapy for ovarian malignant teratoma. Obstet Gynecol 61:85-95, 1983 (suppl) 12. Weinstein D, Polishuk WZ: The role of wedge resection of the ovary as a cause for mechanical sterility. Surg Gynecol Obstet 141:417-418, 1975 13. Alper MM, Garner PR, Seibel MM: Premature ovarian failure: Current concepts. J Reprod Med 31:699-708, 1986 14. United Nations, Department of Social Affairs: Foetal, Infant and Early Childhood Mortality. I: The Statistics. New York, NY, United Nations, 1954

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15. Riley MM, Halliday JL, Lumley JM: Congenital malformations in Victoria, Australia, 1983-95: An overview of infant characteristics. J Paediatr Child Health 34:233-240, 1998 16. Downey J, McKinney M: The psychiatric status of women presenting for infertility evaluation. Am J Orthopsychiatr 62:196-198, 1992 17. Motzer RJ, Green GA, McCaffrey JA, et al: Paclitaxel (T), ifosfamide (I) and cisplatin (P) as first-line salvage therapy for relapsed germ cell tumors (GCT) patients with favorable prognostic features. Proc Am Soc Clin Oncol 17:322a, 1998 (abstr 1241) 18. de Wit R, Louwerens M, de Mulder PHM, et al: Dose finding study of paclitaxel (Taxol) added to fixed doses of bleomycin, etoposide, cisplatin (BEP) in patients with adverse prognosis germ cell cancer or carcinoma of unknown primary (CUP). Proc Am Soc Clin Oncol 17:322a, 1998 (abstr 1240) 19. Muram D, Gale CL, Thompson E: Functional ovarian cysts in patients cured of ovarian neoplasm. Obstet Gynecol 75:680-683, 1990

20. Ferrazzi E, Zanetta G, Dordoni D, et al: Transvaginal ultrasonographic characterization of ovarian masses: Comparison of five scoring systems in a multicenter study. Ultrasound Obstet Gynecol 10:192-197, 1997 21. Zanetta G, Trio D, Lissoni A, et al: Ultrasound in the follow-up of young patients with malignant ovarian tumors after conservative surgery. Ultrasound Obstet Gynecol 4:60-64, 1994 22. Perrin LC, Low J, Nicklin JL, et al: Fertility and ovarian function after conservative surgery for germ cell tumours of the ovary. Aust N Z J Obstet Gynaecol 39:243-245, 1999 23. Ezzat A, Raja M, Bakri Y, et al: Malignant ovarian germ cell tumours: A survival and prognostic analysis. Acta Oncol 38:455-460, 1999 24. Brewer M, Gershenson DM, Herzog CE, et al: Outcome and reproductive function after chemotherapy for ovarian dysgerminoma. J Clin Oncol 17:2670-2673, 1999 25. Kaldor JM, Day NE, Bard P, et al: Second malignancies following testicular cancer, ovarian cancer and Hodgkin’s disease: An international collaborative study among cancer registries. Int J Cancer 39:571-585, 1986

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