1. + Giorgia Mangili MD Cristina Sigismondi MD IRCCS Ospedale San Raffaele, Milan Gynecology Oncology Department Prof. M.Candiani The presenter has no conflict of interest to declare. Fertility-sparing surgery in borderline and non epithelial ovarian tumors: State of the Art ESGO 2013 Liverpool

2. +

3. + Borderline Ovarian Tumors (BOT)

4. + Borderline Ovarian Tumors: Early Stage  Fertility-sparing treatment: INDIPENDENT PROGNOSTIC FACTOR FOR RECURRENCE  Rate of recurrence NO IMPACT ON SURVIVAL  Risk of lethal recurrence < 0.05% Unilateral Salpingo-oophorectomy + peritoneal staging 0-5% Radical Surgery 0-25% Unilateral salpingo-oophorectomy 10-42% Cystectomy Daraï et al. Hum Reprod Update. 2013 Du Bois et al. Eur J Cancer. 2013

5. + Serous Borderline Ovarian Tumors N° Median Age I stII stIII stRelapses Progression Deaths Cystectomy18 30 1305 6 (33%) 20 USO28 38 2134 2 (7%) 02 DOC Radical surgery 53 411111 (1.8%)1 7 DOC 1 DOD Total994075420 9 (9%) 310

6. + Bilaterality in Borderline Ovarian tumors BILATERAL CYSTECTOMY (experimental group, n = 15) versus SALPINGO-OOPHORECTOMY AND CYSTECTOMY (control group, n = 17)  No difference in cumulative recurrence rate  Shorter time to first recurrence and higher rate of radical treatment  Better reproductive outcomes Human Reproduction. 2010

7. +  26 patients  All patients had a borderline histology at first recurrence  11 patients relapsed at least twice  2 patients had an invasive histology at 2-3 recurrence (1 DOD) “Fertility-preserving surgery remains a valuable alternative in young patients with recurrent BOT, in the form of a non-invasive ovarian lesion, who wish to start a pregnancy.” Human Reproduction. September 25, 2013

8. + Advanced Stages BOT Fertility-sparing Treatment Series N. of conservative treatments N. Non invasive implants N. Invasive implants N. Ns implants RelapsesDeaths Zanetta, 2001251572100 Prat, 2002109131 (invasive imp.) Longacre, 200521NR 50 De Iaco, 200921NR 40 Uzan, 2010413731221 (non invasive imp.) Viganò, 201010 60 Song, 2011510 Total13269113 50 (38%)2 (1.4%)

9. + Stromal Ovarian Tumors

10. + Granulosa cell tumors

11. + Fertility-sparing Surgery in Granulosa Cell Tumors  Unilateral salpingo-oophorectomy  Peritoneal staging  Endometrial biopsy  NO contralateral biopsy  NO lymphadenectomy Conservative surgery can be offered to young women who desire to retain fertility Colombo et al. J Clin Oncol. 2007 Thrall et al. Gynecol Oncol. 2012

12. + Sertoli-Leydig Cell Tumors No difference in survival rate between conservative and radical surgery AuthorsN.Stage IConservative surgery Young and Scully 1985207202 (97.6%)143 (69%) Gui 20124040 (100%)28 (70%) Sigismondi 20122118 (86%)11 (52%) Bath 20131513 (86.7%)13 (86%) Weng 20132318 (78%)11 (47%)

13. + Malignant germ cell ovarian tumors (MOGCT)

14. + Fertility-sparing Surgery in MOGCT StudyConservativeDemolitive Total Patient n°Patient n°Survival n°(%)Patient n°Survival n°(%) Creasman et al. 19793219 (59.3%)19/19 (100%)13 (40.6%)11/13 (85%) Gershenson et al. 19832115 (71.4%)12/15 (80%)6 (28.5%)3/6 (50%) Schwartz 19841917 (89.4%)17/17 (100%)2 (10.5%)2/2 (100%) Zanetta et al. 2001169138 (81.6%)135/138 (98%)31 (18.3%)27/31 (87%) Khi et al.20024943 (93.4%)43/43 (100%)6 (13%)6/6 (100%) Chan et al. 2008535313 (58.5%)306/313 (98%)222 (41.5%)212/222 (96%) Tangjitgamol et al. 201012489 (71. 7%)83/89 (93%)35 (28.2%)32/35(91%) Mangili et al. 201112392 (74.8%)84/92 (91%)31 (25.2%)25/31 (81%) Total1072726 (68%)699 (96%)346 (32%)318 (91%) Except for Stage IA dysgerminoma and stage I immature teratoma CONSERVATIVE SURGERY + PEB

15. + Bilateral MOGCT Bilaterality 4.3% (dysgerminoma 15%) USO+CYS+staging Residual disease could be intentionally left in order to spare fertility 3 patients reported (2 OSR, 1 Vicus et al Gyn Onc 2010) If CYS is not possible? XY disgenetic gonads  bilateral gonadectomy, spare the uterus! 2 patients conceived through IVF with donor oocyte Mangili et al. Gyn ecol Oncol. 2011

16. + Fertility Outcome in MOGCT Studyn°n° getting pregnancy Pektasides et al.175/17 (29.4%) Brewer et al143/14 (21.4%) Mitchell et al.2611/26 (42%) Low et al.7416/74 (21.6%) Zanetta et al.13832/138 (23.1%) Tangir et al.6429/64 (45.3%) Boran et al.236/23 (26%) de La Motte Rouge et al.4112/41 (29.2%) Cicin et al.297/29 (24.1%) Zanagnolo et al.7515/75 (20%) Weinberg et al.2210/22 (45.4%) Mangili et al.9212/92 (13%) Total615158/615 (25.7%) Premature ovarian failure 3%  Small number of patients  Short follow-up  Young patients

17. + Reproductive function assessment after surgery plus chemotherapy for Germ Cell Ovarian Tumors: novel clues deriving from the field of fertility preservation Age Tumor characteristics StageTreatment AMH (ng/ml) 16 Mixed germ cell tumor IIIIC USO+ ovarian biopsy+ staging+ BEP 0.1 18 Mixed germ cell tumor IIB USO+ CYS+ staging+ BEP0.7 21DysgerminomaICUSO+BEP2.3 23DysgerminomaIV USO+BEP 2.7 Oocytes cryopreservation Ottolina et al. Submitted

18. + The Fertility Window Evaluation of ovarian reserve AMH Preservation of fertility Ovarian reserve NO DESIRE FOR PREGNANCY Spontaneous conception/ ART YES La Marca et al. Eur J Obstet Gynecol Reprod Biol. 2012

19. + Conclusions Fertility-sparing surgery in borderline ovarian tumors and non epithelial ovarian cancers is feasible The fertility window may be shortened by oncological treatments Reproductive function&Oncological follow-up is required

20. + ginecologia.oncologica@hsr.it mangili.giorgia@hsr.it Thank you!