ABSTRACT

Conclusion:

NEOCs usually have a good prognosis because they are detected at an early stage. FSS may be indicated for women of reproductive age with early-stage NEOCs.

Results:

NEOCs involved germ cell tumors (GCTs) in 46 (46%) patients and sex cordstromal tumors (SCSTs) in 54 (54%) patients. Thirty patients with GCTs and thirty-four patients with SCSTs possessed histological subtypes with malignant features. Most patients with GCTs (37%) and SCSTs (55.6%) had FIGO Stage 1 disease at the time of initial diagnosis. Overall, 76.6% of patients in the GCT group (n=23) underwent fertility-sparing surgery (FSS), while 76.5% of the patients in the SCST group (n=26) were treated with non-fertility-sparing surgical procedures. All patients who underwent FSS and had a recurrence in their follow-up (n=4) was stage 3 patients. Seven out of 10 patients (2 patients at stage 3 and 5 patients at stage 1) who desired pregnancy delivered between 38 and 40 gestational weeks without any congenital anomaly. The prognosis was excellent in both groups, with 5-year overall survival (OS) rates of 93.5% in GCTs and 96.3% in SCST groups. The 5-year disease-free survival was 89.1% in GCTs and 94.4% in SCSTs. FSS was not associated with worse oncologic outcomes.

Materials and Methods:

A total of 100 patients with clinicopathological diagnosis of NEOC who were treated at our tertiary care center between 1996 and 2022 were included in this retrospective cohort analysis study. Data on demographic, clinical and obstetric characteristics of patients at the time of initial diagnosis as well as tumor clinicopathologic features, treatment modalities, and oncological and reproductive outcomes were recorded.

Objective:

This study aimed to present our single-center clinical experience regarding tumor clinicopathologic features, treatment modalities, and reproductive and oncologic outcomes in patients with non-epithelial ovarian cancer (NEOC) over 25 years.

Keywords:

Disease-free survival, fertility, non-epithelial ovarian tumor, prognosis

PRECIS: We aimed to report a single-center experience in non-epithelial malignant ovarian tumors by presenting different clinical and pathological characteristics, management, and reproductive and oncologic outcomes.

Introduction

Ovarian cancer is considered the gynecologic cancer with the highest associated mortality because most patients are already at an advanced disease stage at diagnosis⁽¹⁾. Epithelial ovarian cancers are the most common type, while non-epithelial primary tumors are very rare entities accounting for 10% of all ovarian malignancies (0.25/100.000)^(2,3). Non-epithelial ovarian cancers (NEOCs) include germ cell tumors (GCTs), sex cord-stromal tumors (SCSTs), sarcomas, and small cell carcinoma of hypercalcemic type⁽⁴⁾. Malignant GCTs represent 5% of all ovarian cancers and SCST account for approximately 3-5% of ovarian malignancies with endocrine manifestations⁽⁵⁾. Both GCTs and SCSTs include a wide variety of sub-histological types along with similarities in their presentation, evaluation, management, and prognosis⁽⁶⁾. For GCTs, dysgerminomas and immature teratomas are the most common histological subtypes (70%), while the rarer subtypes include yolk sac tumor, embryonal carcinomas, non-gestational choriocarcinomas, and mixed germ cell tumors⁽⁴⁾. For SCSTs, subtypes include granulosa cell tumors (juvenile and adult type), Sertoli cell tumors and Sertoli Leydig cell tumors, fibromas, and thecomas⁽⁴⁾. Although each histological subtype has its own characteristics, they may resemble each other in terms of initial clinical presentation, radiological findings, and tumor markers.

While SCSTs are a heterogeneous group presenting over various ages, GCTs are primarily diagnosed in adolescents and younger women⁽⁵⁾. Given that these tumors occur mostly in young women, maintenance of fertility is an important consideration and each patient should be evaluated individually.

NEOCs have a better prognosis than epithelial ovarian tumors because approximately 60-70% of both SCSTs and GCTs are diagnosed at a localized stage⁽²⁾. Surgery for young patients with GCTs and early-stage SCSTs should consider a fertility-sparing approach (unilateral salpingo-oophorectomy with preservation of the contralateral ovary and the uterus) without compromising the oncological management⁽⁵⁾. GCTs are very sensitive to platinum-based regimens, which makes patients with GCTs to be considered as proper candidates for fertility-sparing surgery (FSS) even at the advanced stage. However, the value of adjuvant chemotherapy in the setting of SCSTs remains inconclusive due to the lack of randomized trials and definitive prognostic factors⁽²⁾. Unilateral salpingo-oophorectomy can be performed in patients with stage 1 disease-deserving of fertility. Hysterectomy and bilateral salpingo-oophorectomy should be performed in postmenopausal women and in patients with advanced-stage disease⁽⁵⁾.

Little is known about the management of women with NEOCs, possibly due to the infrequent presentation of these cancers. Some proposed treatment policies are not widely accepted⁽⁵⁾. Treatment should be performed depending on the patients age and histopathological type. For Stage Ia pure dysgerminoma, surgery is recommended because of the relatively low recurrence rate in these patients (15-25%)⁽⁷⁾. Moreover, some studies revealed that close surveillance after FSS can be used in the management of all grades of immature teratoma and all stage I dysgerminomas with reserving chemotherapy only for the relapsed cases^(7,8). All patients with stage I yolk sac tumors are treated with adjuvant treatment after surgery⁽⁹⁾, while publications suggest close and active surveillance after the surgery⁽⁸⁾. The most commonly used regimen in patients with NEOCs is the bleomycin/etoposide/cisplatin (BEP) combination⁽¹⁰⁾. Stage Ia granulosa cell tumors do not require adjuvant therapy⁽⁵⁾. Adjuvant therapy has been administered to stage 1c patients in some studies, but its benefit remains controversial⁽¹¹⁾. Debulking surgery followed by adjuvant chemotherapy is the most effective treatment for advanced-stage SCSTs⁽⁵⁾.

This study aimed to evaluate clinical characteristics, tumor clinicopathological features, treatment modalities, and oncological and reproductive outcomes in NEOC patients according to histological subtypes.

Materials and Methods

A total of 100 patients with clinicopathological diagnosis of NEOC who were treated at our tertiary care center (Department of Gynecological Oncology, Akdeniz University Faculty of Medicine, Antalya, Turkey) between 1996 and 2022 were included in this retrospective cohort analysis study.

The study was conducted in accordance with the ethical principles stated in the “Declaration of Helsinki” and approved by the institutional ethics committee (Akdeniz University Clinical Research Ethics Committee - KAEK-657; date: 09.11.2022). Informed consent was obtained from each subject or their first-degree relatives (for the deceased ones).

Demographic, clinical and obstetric characteristics of patients at the time of initial diagnosis and tumor clinicopathologic features were retrieved from paper- and electronic medical records. Data on age, body mass index (BMI), clinical manifestations at the time of diagnosis, reproductive history, presence of pregnancy at the time of diagnosis, menopausal status, tumor characteristics (histopathological subtype and stage according to the International Federation of Gynecology and Obstetrics (FIGO 2014) staging classification⁽¹²⁾, tumor size and histological grade, serum tumor markers when available, treatment characteristics regarding the primary treatment modality, type of surgical interventions, chemotherapy (regimen, setting and the number of cycles), treatment protocols in case of recurrence, oncological outcome recurrence status, overall survival (OS), disease-free survival (DFS), reproductive outcome, congenital anomaly of offspring, and secondary malignancy were recorded. Tumors were classified according to the World Health Organization (WHO 2014) classification. Information that could not be accessed through medical reports (i.e., obstetric results and menstrual pattern) was obtained by a phone call. Patients with sarcoma and small cell carcinoma of hypercalcemic type, those with insufficient data or lack of attendance to follow-up, and those with ovarian metastasis originating from non-gynecologic primary sites were excluded from the study.

Follow-up visits for recurrence assessment were performed at 3-month intervals and 6-month intervals for the first 2 years and following years. Data on symptoms, tumor markers, and pelvic examination findings were recorded at each visit. Imaging modalities used in relapse detection were chest X-ray, pelvic ultrasound, and computed tomography (CT) or positron emission tomography CT (PET/CT). OS was defined as the time from initial diagnosis to death. DFS was defined as the interval between the date of remission and the date of the first recurrence detected. FSS was defined as the preservation of the uterus and at least part of one ovary.

Statistical Analysis

Statistical analysis was performed using IBM SPSS Statistics for Windows version 23.0 (IBM Corp., Armonk, NY). For descriptive statistics, the mean, standard deviation, median, minimum-maximum values, and frequencies were used, depending on the normality of the data. Data were expressed as mean ± standard deviation (SD), median and n (%) where appropriate. Survival analysis was performed via Kaplan-Meier analysis.

Results

Overall, GCTs and SCSTs were noted in 46 (46%) and 54 (54%) patients with NEOC, respectively. Baseline demographic, clinical, and obstetric characteristics and tumor clinicopathologic features of patients are shown in Tables 1 and 2.

Table 1

Table 2

The mean age at diagnosis was 31.7 years (range, 11 to 63 years) in patients with GCT, while it was 52.8 years (range, 13 to 77 years) in those with SCST. Thirty patients in the GCT group and 34 patients in the SCST group possessed histological subtypes with malignant features. The most common subtypes of GCTs were mature teratoma (32.6%) and dysgerminoma (23.9%). Among SCSTs, the most common subtype was adult granulosa cell tumor (53.7%), followed by fibroma (27.8%). Acute abdominal pain was the key clinical presentation in 65.2% of patients with GCTs and in 40.7% of patients with SCSTs. The majority of patients with GCTs were premenopausal (78.3%), while the majority of patients with SCSTs were postmenopausal (66.7%). Most patients with GCTs (37%) and SCSTs (55.6%) had FIGO Stage 1 disease at the time of initial diagnosis. None of the patients presented with FIGO Stage 4 disease. The mean value of Ca-125 was 95.6 IU/mL in GCT patients (n=37) and 57.6 IU/mL in SCST patients (n=43).

Treatment modalities and oncological outcome in patients with malignant NEOCs are demonstrated in Table 3. Overall, 76.6% of patients in the GCT group (n=23) underwent fertility-sparing tumor resection (FSS), while 76.5% of the patients in the SCST group (n=26) were treated with non-fertility-sparing surgical procedures. FSS was applied in 29 (45.3%) patients overall, including unilateral salpingo-ovariectomy in 25 (39%) patients, cystectomy in 2 (3.1%) patients, and bilateral salpingo-ovariectomy in 2 (3.1%) patients. Adjuvant therapy was indicated in 8 patients with SCST and 24 patients with GCT. Most patients in the GCT group received bleomycin, etoposide, and cisplatin (BEP) combination chemotherapy for median 2.7 cycle. Other rarely administered chemotherapeutics were paclitaxel, carboplatin, vincristine, doxorubicin and cyclophosphamide, followed by ifosfamide and etoposide, 5-FU and prednisolone.

Table 3

The median duration of follow-up was 90 months (range, 3 to 324 months) and 83.5 months (range, 8 to 252 months) for malignant GCTs and SCSTs, respectively. Overall, 11 of 64 (17.1%) patients with malignant NEOC developed recurrence, including 6 cases with GCTs and 5 cases with SCSTs. Most of the recurrences were detected in the abdomen (8 of 11 patients) and most patients underwent a second surgery followed by chemotherapy (7 of 11 patients). GCT was the diagnosis in three out of five patients with mortality. The 5-year OS rates were 93.5% and 96.3% in the GCTs and SCSTs groups, respectively (Figure 1). The 5-year DFS rate was 89.1% in patients with GCTs and 94.4% in those with SCSTs (Figure 2).

Figure 1

Figure 2

There were thirty-one patients younger than 40 years who had a final pathology result reported as malignant. Of these 31 patients, 17 were nulliparous, 18 were married, and 13 were single. The chemotherapy regimens included BEP in 16 patients, VIP (etoposide, ifosfamide, cisplatin) in 2 patients, and a combination of cyclophosphamide, 5-FU, and prednisolone in one patient with a Sertoli-Leydig cell tumor, while 12 patients did not receive any chemotherapy as they were diagnosed at stage 1. FSS was not performed only for 2 patients in this group because they did not have a desire for pregnancy. All patients who underwent FSS and had a recurrence in their follow-up (n=4) were stage 3b or 3c, and unfortunately one of them died due to disseminated disease. Seven out of 10 patients (two patients at stage 3 and five patients at stage 1) who desired pregnancy delivered full-term babies (n=9) between 38 and 40 gestational weeks with no congenital anomalies. The pregnancy rate was 70%, and none of the pregnancies were with assisted reproductive technology (ART) (Table 4). The median interval between surgery and delivery was 24 months (range, 9 to 156 months). No recurrence occurred in these patients. None of the patients had undergone completion surgery after childbearing. Twenty patients did not try to get pregnant after fertility-preserving procedures.

Table 4

Three women were pregnant at the time of diagnosis; the histological types in these patients were Sertoli-Leydig cell tumor (stage 1a), dysgerminoma (stage 1c2), and immature teratoma (stage 1c1). Fertility-preserving surgery including unilateral salpingo-oophorectomy and complete surgical staging was performed for treating these patients.

Discussion

NEOCs are considered to be diagnosed at an early age and to have a good prognosis in relation to the excellent chemotherapy response⁽¹³⁾. NEOCs include ovarian GCTs and SCSTs, and both groups have benign and malignant forms⁽¹³⁾. In this study, clinical and treatment characteristics and oncological and reproductive outcomes of GCTs and SCSTs were assessed in our series of NEOC patients. Moreover, the oncologic outcomes were also evaluated specifically among women undergoing FSS, which has been addressed only by a few studies to date^{(14,15,16,17,18,19,20,21,22,23,24,25,26,27)}.

NEOCs are relatively rare forms of ovarian cancer that occur mostly in women of childbearing age, except for granulosa cell tumors, which have a wide age spectrum including both premenopausal and postmenopausal women. Our findings support the data from previous studies with NEOC patients indicating overall good obstetric and survival outcomes along with no recurrences in women undergoing FSS even at the advanced stage⁽²⁸⁾. Studies on fertility preservation surgery are mainly conducted in the setting of GCTs⁽¹³⁾. FSS did not adversely affect recurrence rates in all reviewed studies, and therefore, it is recommended as the gold standard surgical management of patients with early-stage GCTs⁽²⁹⁾. Johansen et al.⁽¹⁵⁾ indicated that the ability to conceive was preserved by using FSS since all conceptions were natural and all deliveries occurred at full term in their study. The pregnancy rate varies from 50% to 93%, and the live birth rate ranges from 65% to 95%^{(19,20,25,30,31,32,33,34,35)}.

The pregnancy rate (70%) in our study was similar to that in previous studies. Literature data on FSS outcomes in women with SCSTs are scarce and mainly based on case reports or short series^{(36,37,38,39,40)}. In a systematic review by Bercow et al.⁽¹⁴⁾, FSS was considered not to be associated with worse DFS or OS compared to conventional surgery. There is a scarce amount of data regarding the fertility and pregnancy outcomes of granulosa cell tumors because these tumors are very rare and their peak incidence is in the perimenopausal period. In a review of a few retrospective studies on fertility-sparing management and pregnancy in patients with granulosa cell tumor by Iavazzo et al.⁽³⁸⁾, the authors recommended FSS to be performed only in well-selected patients after their informed consent. Some authors also reported no significant difference between FSS and radical surgery in terms of survival outcome⁽⁴¹⁾. In our study, most of the women who delivered were in the GCTs group, in accordance with consideration of GCTs rather than SCSTs to be more common in the reproductive age. Notably, chemotherapy was not considered to have a negative effect on fertility in NEOC patients⁽⁴²⁾. Various combined regimens including vincristine, dactinomycin, cyclophosphamide, bleomycin, etoposide, cisplatin, doxorubicin, and vinblastine have been used after FSS, revealing satisfactory results on conception and pregnancy rates after chemotherapy exposure^{(18,35,42,43,44,45,46,47,48,49)}. Most of our patients who delivered also received chemotherapy. Meanwhile, pregnancy or even delivery after completing chemotherapy may not affect recurrence or mortality⁽³⁴⁾.

Supporting the previously reported series, the survival outcome in our study confirms the overall good prognosis of ovarian non-epithelial tumors. Park et al.⁽³⁰⁾ found the 5-year DFS and OS rates for GCTs to be 86% and 97%, respectively. Malignant SCSTs carry a favorable prognosis with a 5-year OS of 97.2%⁽³⁴⁾. Due to related high rates of recurrence and mortality, OS of advanced-stage disease, especially in SCSTs, is poor⁽³⁴⁾.

The type of surgery, patient age at the time of investigation, patient desire to conceive, fear of recurrence, and tumor histologic subtype are considered amongst the factors with considerable impact on fertility rates. Bilateral salpingo-oophorectomy and uterine conservation enable pregnancy by egg donation for women with gonadoblastoma. However since the oocyte donation is illegal in our country, preservation of the uterus does not increase fertility rates. Unfortunately, two patients with gonadoblastoma in our series could not have children due to this restriction, despite their desire for pregnancy.

Nonetheless, the conception rate may increase in the longer term. Some patients in our series did not try to conceive despite having FSS, possibly due to reasons such as prediction of good outcomes after fertility preservation and high chemotherapy response in case of recurrence⁽¹³⁾. Although these reasons appear to be highly acceptable for GCTs, they should be discussed in detail with patients have SCSTs.

Patients of reproductive age with NEOC should have access to professional family planning and infertility counseling to discuss fertility outcomes and treatment options⁽⁵⁰⁾. Although the exact numbers of our patients who received presurgical family planning counseling and visited a reproductive medicine specialist are unknown, obstetric outcomes may be better if adequate counseling is given to these patients⁽¹³⁾.

To reduce the risk of recurrence, completion surgery should be discussed with women who no longer intend to conceive. However, due to high curability rates, completion surgery after childbearing may not be necessary for GCTs. The use of completion surgery after childbearing remains debatable in SCSTs⁽⁵¹⁾. This decision may be personalized because there are still uncertainties regarding the long-term outcomes after this type of surgery⁽⁵⁰⁾. The patients must be fully informed about oncological and obstetrical outcomes.

Study Limitations

The major limitations of this study seem to be retrospective single center design and small sample size of the cohort in relation to the rarity of these tumors, which prevented the conduction of reliable subgroup analyses with respect to different tumor histological subtypes. Also, our results regarding the obstetric outcomes after FSS should be interpreted with caution given the likelihood of a large sample to provide more reliable results. Furthermore, reproductive potential, which is a multifactorial phenomenon with considerable interindividual differences, was not detailed in our study.

Conclusion

In conclusion, FSS seems to be a potentially favorable surgical modality in the setting of NEOC for young women who intend to conceive. It can be offered to patients even at advanced disease stages, particularly in those with GCTs, depending on tumor histopathology and prognostic factors. Recurrence is considered to be rare in general, while it develops more frequently at advanced disease stages. Adjuvant chemotherapy does not seem to affect fertility outcomes. Larger prospective studies are needed to better evaluate long-term oncologic and reproductive outcomes in women with ovarian cancer undergoing FSS.

References

Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin 2022;72:7-33.

Kempf E, Desamericq G, Vieites B, Diaz-Padilla I, Calvo E, Estevez P, et al. Clinical and pathologic features of patients with non-epithelial ovarian cancer: retrospective analysis of a single institution 15-year experience. Clin Transl Oncol 2017;19:173-9.

Gatta G, Capocaccia R, Botta L, Mallone S, De Angelis R, Ardanaz E, et al. Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study. Lancet Oncol 2017;18:1022-39.

Daviu C, Blaakaer J, Eriksson AGZ, Herrstedt J, Vandborg MP, Rasmussen AMO, Fuglsang K. Nonepithelial ovarian cancer - the current clinical practice in the Nordic countries. Survey from the surgical subcommittee of the Nordic society of gynecological oncology (NSGO). Acta Oncol 2022;61:939-45.

Ray-Coquard I, Morice P, Lorusso D, Prat J, Oaknin A, Pautier P. Non-epithelial ovarian cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29(Suppl 4):iv1-iv18.

Berek JS, Kehoe ST, Kumar L, Friedlander M. Cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet 2018;143 Suppl 2:59-78.

Mangili G, Sigismondi C, Lorusso D, Cormio G, Candiani M, Scarfone G, et al. The role of staging and adjuvant chemotherapy in stage I malignant ovarian germ cell tumors (MOGTs): the MITO-9 study. Ann Oncol 2017;28:333-8.

Billmire DF, Cullen JW, Rescorla FJ, Davis M, Schlatter MG, Olson TA, et al. Surveillance after initial surgery for pediatric and adolescent girls with stage I ovarian germ cell tumors: report from the Children’s Oncology Group. J Clin Oncol 2014;32:465-70.

Dark GG, Bower M, Newlands ES, Paradinas F, Rustin GJ. Surveillance policy for stage I ovarian germ cell tumors. J Clin Oncol 1997;15:620-4.

Aurilio G, Verri E, Frassoni S, Bagnardi V, Cossu Rocca M, Cullurà D, et al. Modified-BEP Chemotherapy in Patients With Germ-Cell Tumors Treated at a Comprehensive Cancer Center. Am J Clin Oncol 2020;43:381-7.

Wilson MK, Fong P, Mesnage S, Chrystal K, Shelling A, Payne K, et al. Stage I granulosa cell tumours: A management conundrum? Results of long-term follow up. Gynecol Oncol 2015;138:285-91.

Mutch DG, Prat J. 2014 FIGO staging for ovarian, fallopian tube and peritoneal cancer. Gynecol Oncol 2014;133:401-4.

Canlorbe G, Chabbert-Buffet N, Uzan C. Fertility-Sparing Surgery for Ovarian Cancer. J Clin Med 2021;10:4235.

Bercow A, Nitecki R, Brady PC, Rauh-Hain JA. Outcomes after Fertility-sparing Surgery for Women with Ovarian Cancer: A Systematic Review of the Literature. J Minim Invasive Gynecol 2021;28:527-36.e1.

Johansen G, Dahm-Kähler P, Staf C, Flöter Rådestad A, Rodriguez-Wallberg KA. Fertility-sparing surgery for treatment of non-epithelial ovarian cancer: Oncological and reproductive outcomes in a prospective nationwide population-based cohort study. Gynecol Oncol 2019;155:287-93.

Wang D, Zhu S, Jia C, Cao D, Wu M, Shen K, et al. Role of staging surgery and adjuvant chemotherapy in adult patients with apparent stage I pure immature ovarian teratoma after fertility-sparing surgery. Int J Gynecol Cancer 2020;30:664-9.

Park JY, Kim DY, Suh DS, Kim JH, Kim YM, Kim YT, Nam JH. Outcomes of Surgery Alone and Surveillance Strategy in Young Women With Stage I Malignant Ovarian Germ Cell Tumors. Int J Gynecol Cancer 2016;26:859-64.

Kang H, Kim TJ, Kim WY, Choi CH, Lee JW, Kim BG, Bae DS. Outcome and reproductive function after cumulative high-dose combination chemotherapy with bleomycin, etoposide and cisplatin (BEP) for patients with ovarian endodermal sinus tumor. Gynecol Oncol 2008;111:106-10.

Mikuš M, Benco N, Matak L, Planinić P, Ćorić M, Lovrić H, et al. Fertility-sparing surgery for patients with malignant ovarian germ cell tumors: 10 years of clinical experience from a tertiary referral center. Arch Gynecol Obstet 2020;301:1227-33.

Ertas IE, Taskin S, Goklu R, Bilgin M, Goc G, Yildirim Y, Ortac F. Long-term oncological and reproductive outcomes of fertility-sparing cytoreductive surgery in females aged 25 years and younger with malignant ovarian germ cell tumors. J Obstet Gynaecol Res 2014;40:797-805.

Boyraz G, Durmus Y, Cicin I, Kuru O, Bostanci E, Comert GK, et al. Prognostic factors and oncological outcomes of ovarian yolk sac tumors: a retrospective multicentric analysis of 99 cases. Arch Gynecol Obstet 2019;300:175-82.

A L Husaini H, Soudy H, El Din Darwish A, Ahmed M, Eltigani A, A L Mubarak M, et al. Pure dysgerminoma of the ovary: a single institutional experience of 65 patients. Med Oncol 2012;29:2944-8.

Mangili G, Sigismondi C, Gadducci A, Cormio G, Scollo P, Tateo S, et al. Outcome and risk factors for recurrence in malignant ovarian germ cell tumors: a MITO-9 retrospective study. Int J Gynecol Cancer 2011;21:1414-21.

Bergamini A, Cormio G, Ferrandina G, Lorusso D, Giorda G, Scarfone G, et al. Conservative surgery in stage I adult type granulosa cells tumors of the ovary: Results from the MITO-9 study. Gynecol Oncol 2019;154:323-7.

Wang D, Cao D, Jia C, Huang H, Yang J, Wu M, et al. Analysis of oncologic and reproductive outcomes after fertility-sparing surgery in apparent stage I adult ovarian granulosa cell tumors. Gynecol Oncol 2018;151:275-81.

Durmuş Y, Kılıç Ç, Çakır C, Yüksel D, Boran N, Karalök A, et al. Sertoli-Leydig cell tumor of the ovary: Analysis of a single institution database and review of the literature. J Obstet Gynaecol Res 2019;45:1311-8.

Nasioudis D, Frey MK, Chapman-Davis E, Witkin SS, Holcomb K. Safety of Fertility-Sparing Surgery for Premenopausal Women With Sex Cord-Stromal Tumors Confined to the Ovary. Int J Gynecol Cancer 2017;27:1826-32.

Benshushan A, Ben-Shachar I, Lavie M, Mejia-Gomez J, Kogan L, Shushan A. Fertility in women after surgical treatment of nonepithelial ovarian tumors. Fertil Steril 2010;94:2786-8.

El Helali A, Kwok GST, Tse KY. Adjuvant and post-surgical treatment in non-epithelial ovarian cancer. Best Pract Res Clin Obstet Gynaecol 2022;78:74-85.

Park JY, Kim DY, Suh DS, Kim JH, Kim YM, Kim YT, Nam JH. Analysis of outcomes and prognostic factors after fertility-sparing surgery in malignant ovarian germ cell tumors. Gynecol Oncol 2017;145:513-8.

Jobo T, Yonaha H, Iwaya H, Kanai T, Kuramoto H. Conservative surgery for malignant ovarian tumor in women of childbearing age. Int J Clin Oncol 2000;5:41-7.

Tamauchi S, Kajiyama H, Yoshihara M, Ikeda Y, Yoshikawa N, Nishino K, et al. Reproductive outcomes of 105 malignant ovarian germ cell tumor survivors: a multicenter study. Am J Obstet Gynecol 2018;219:385.e1-385.e7.

Weinberg LE, Lurain JR, Singh DK, Schink JC. Survival and reproductive outcomes in women treated for malignant ovarian germ cell tumors. Gynecol Oncol 2011;121:285-9.

Yang B, Yu Y, Chen J, Zhang Y, Yin Y, Yu N, et al. Possibility of women treated with fertility-sparing surgery for non-epithelial ovarian tumors to safely and successfully become pregnant-a Chinese retrospective cohort study among 148 cases. Front Med 2018;12:509-17.

Zhang N, Chen R, Hua K, Zhang Y. A retrospective study of reproductive outcomes after fertility-sparing surgery and postoperative adjuvant chemotherapy in malignant ovarian germ cell tumors and sex cord-stromal tumors. J Ovarian Res 2017;10:52.

Gouy S, Arfi A, Maulard A, Pautier P, Bentivegna E, Leary A, et al. Results from a Monocentric Long-Term Analysis of 23 Patients with Ovarian Sertoli-Leydig Cell Tumors. Oncologist 2019;24:702-9.

Seidler SJ, Huber A, Nef J, Huber DE. Sertoli-Leydig Cell Ovarian Tumors: Is Fertility or Endocrine-Sparing Surgery an Option upon Relapse? Case Rep Oncol 2020;13:935-40.

Iavazzo C, Gkegkes ID, Vrachnis N. Fertility sparing management and pregnancy in patients with granulosa cell tumour of the ovaries. J Obstet Gynaecol 2015;35:331-5.

Rinne N, Farthing A, Borley J. Fertility sparing surgery in advanced and recurrent granulosa cell tumours of the ovary. J Obstet Gynaecol 2018;38:143-5.

Makhija A, Patel BM, Kenkre MA, Desai AD, Patel SM, Mankad MH, Parekh CD. Retrospective Analysis of 32 Cases of Ovarian Granulosa Cell Tumours. J Obstet Gynaecol India 2020;70:50-6.

Li J, Chu R, Chen Z, Meng J, Yao S, Song K, Kong B. Progress in the management of ovarian granulosa cell tumor: A review. Acta Obstet Gynecol Scand 2021;100:1771-8.

Ceppi L, Galli F, Lamanna M, Magni S, Dell’Orto F, Verri D, et al. Ovarian function, fertility, and menopause occurrence after fertility-sparing surgery and chemotherapy for ovarian neoplasms. Gynecol Oncol 2019;152:346-52.

Rouge TLM, Pautier P, Duvillard P, Rey A, Morice P, Haie-Meder C et al. Survival and reproductive function of 52 women treated with surgery and bleomycin, etoposide, cisplatin (BEP) chemotherapy for ovarian yolk sac tumor. Ann Oncol 2008;19:1435-41.

Brewer M, Gershenson DM, Herzog CE, Mitchell MF, Silva EG, Wharton JT. Outcome and reproductive function after chemotherapy for ovarian dysgerminoma. J Clin Oncol 1999;17:2670-75.

Zanetta G, Bonazzi C, Cantù M, Binidagger S, Locatelli A, Bratina G, Mangioni C. Survival and reproductive function after treatment of malignant germ cell ovarian tumors. J Clin Oncol 2001;19:1015-20.

Perrin LC, Low J, Nicklin JL, Ward BG, Crandon AJ. Fertility and ovarian function after conservative surgery for germ cell tumours of the ovary. Aust N Z J Obstet Gynaecol 1999;39:243-5.

Low JJ, Perrin LC, Crandon AJ, Hacker NF. Conservative surgery to preserve ovarian function in patients with malignant ovarian germ cell tumors. A review of 74 cases. Cancer 2000;89:391-8.

Tangir J, Zelterman D, Ma W, Schwartz PE. Reproductive function after conservative surgery and chemotherapy for malignant germ cell tumors of the ovary. Obstet Gynecol 2003;101:251-7.

Gershenson DM. Menstrual and reproductive function after treatment with combination chemotherapy for malignant ovarian germ cell tumors. J Clin Oncol 1988;6:270-5.

Necula D, Istrate D, Mathis J. Fertility preservation in women with early ovarian cancer. Horm Mol Biol Clin Investig 2020;43:163-9.

Schumer ST, Cannistra SA. Granulosa cell tumor of the ovary. J Clin Oncol 2003;21:1180-9.

Reproductive and oncologic outcomes in women with non-epithelial ovarian cancer: Single center experience over 25 years