1. The role of chemotherapy in Borderline ovarian tumors Ines Vasconcelos, MD/PhD Oncology Center Kurfurstendamm, Berlin - DE

2. Borderline Ovarian Tumors  Serous/Mucinous/Endometrioid/Clear Cell…  Mitotic Activity  Epithelial Hyperplasia  Nuclear Atypia  NO destructive stromal invasion

3. Serous BOT  Frequency: 90% of BOT  Age: 40 years old  Stage I: 65 – 70 %  Bilateral: 30 – 40%  Exophytic component: 35%  Diagnosis:  Branching papillae, nuclear atypia, NO stromal invasion Vasconcelos I, Darb-Esfahani S, Sehouli J. BJOG 2015; DOI: 10.1111/1471-0528.13840.

4. Diagnostic Problems: Small Risk Factors and Large Risk Factors  Micropapillary Pattern: 25% (Lethal Recurrence: 16%)  Microinvasion: 22% (Lethal Recurrence 10%)  BRAF mutated, Senescent cells (p16, p21, low Ki67)  Peritoneal implants:  Non-invasive – 34% (Lethal recurrence: 16%)  Invasive – 7% (Lethal recurrence: 35%) Maniar et al. Am J Surg Pathol. 2014;38(6):473-755 Zeppernick F et al. Am J Surg Pathol. 2014;38(12 :1603-1622 Vasconcelos I et al. BJOG 2015; DOI: 10.1111/1471-0528.13840.

5. Non-invasive implants  Incidence: 35%  Metastatic: clonal  Lethal Recurrence Rate: 16%  Chemotherapy: CR rates for patients with macroscopic residual disease 5 - 40%  Meta-analysis of 13 studies OR = 7.44; 95% CI: 3.39–16.32; p < 0.0005 favoring surgical treatment only  Chemotherapy WORST than surgery Vasconcelos et al. EJOGRB 2014; Sieben et al. J Pathol, 2006

6. Invasive Implants  Rare (7%)  Fatal (Lethal recurrence rate: 35 – 45% (Short follow-up times !!!)  Invasive implants represent superficial and small foci of peritoneal low grade serous carcinoma  Chemotherapy vs. Surgery Only: Meta- analysis of 6 studies: no dif. OR, p=0.086 Vasconcelos et al. The Oncologist 2015

7. Invasive implants and Chemotherapy StudyN with inv.imp. FU Surgical Tx Recurrence Rates (%) Adjuvant Tx Recurrence Rates (%) Bell et al.31 53 months 26.748.4 Gesherson et al.39 111 months “patients who received postoperative platinum-based chemotherapy had significantly worse progression-free survival than all other patients. » Leary et al.36 65 months - (N=0)36.1% Vasconcelos et al.148 (meta) 64-122 months 23.144.3

8. Clinical Case 61 year-old woman with abdominal distention, massive ascites and bilateral ovarian masses, CA125: 319 U/L Courtesy of: Dr. Antonio González Martín Bulky Omentum major, bilateral ovarian tumors, pelvic peritoneal and mesenteric implants and an infiltration of the anterior rectum of about 5 cm Final Report: ER+/PR- Inv. Impl. Peritonectomy, a total hysterectomy with anterior en-bloc rectal resection and implant removal in the diaphragm and mesenteric peritoneum, R0 Liver lesions increased in size and number, as well as new lesions in the lesser gastric curvature, splenic hilus and descending colon Follow-up only Cytoreductive surgery, R1, Bilateral AE Tamoxifen Massive ascites and tumoral findings in the pelvis Tamoxifen Anastrozol 93 months

9. Invasive implants and Chemotherapy  Because they represent foci of peritoneal low grade serous carcinoma Yes? (Low grade CA is chemoresistant!)  No data to support this  Chemotherapy was repeatedly shown to have the SAME or WORST outcome  Think outside the box? Maintenance Therapies? eg. Aromatase-ihnibitors, Tamoxifen ….

10. Mucinous BOT  Mucinous Carcinoma is very rare (3%) – usually metastatic disease from GI Tumor  Intestinal : 85%  Endocervical (Seromucinous) : 15%  Frequency: 10-15%  Age: 38 years old  Bilateral: 8%  Exophytic component: <1%  Stage 1: >99% Vasconcelos I, Darb-Esfahani S, Sehouli J. BJOG 2015; DOI: 10.1111/1471- 0528.13840.

11. Mucinous BOT – Spectrum  Benign  Borderline  Intraepithelial Carcinoma (IECA)  Microinvasive Carcinoma  Invasive Carcinoma Mucinous Tumors are heterogeneous and extensive sampling is indicated

12. Survival – the case of Pseudomixoma Peritonei  Stage I : >99%  Stage III : 50 %  Incidence: 35%  Lethal Recurrence Rate: 3%  Incidence: 19%  Lethal Recurrence Rate: 2% Survival – IECA Survival – Microinvasion Vasconcelos I, Darb-Esfahani S, Sehouli J. BJOG 2015; DOI: 10.1111/1471- 0528.13840.

13. Mucinous BOT and Chemotherapy  Virtually always Stage I  Stage III: Pseudomixoma (HIPEC)? Primary GI?  IECA/Mi have no impact on prognosis  Def. NO chemotherapy!!!!

14. Young Patients  Fertility Sparing Options  Balancing pregnancy rates with prognosis  Unilateral Disease: USO vs. Cystectomy  Bilateral Disease: BC vs. USO + CC

15. Conservative surgery for serous BOT Paloma et al. RCT Vasconcelos et al. Meta-analysis Uzan et al. Retrospective N Patients 32433119 Recurrence Rate - Pregnancy Rate Cystectomy N=043.3% - 45.4%37.6% - no data USO N=015.3% - 40.3%24.0% - no data Bilateral C 60.0% - 93.3%25.6% - insuf. data N=0 USO + CC 58.8% - 58.8%28.0% - insuf. data N=0 Palomba et al. Hum. Reprod. 2010 Aug; 25(8):1966-72 Vasconcelos et al. Eur J Cancer 2015 Mar;51(5):620-31 Uzan et al. Ann. Oncol. 2014 (Jan;25(1):166-71

16. Conservative Surgery for serous BOT – What to do?  For Bilateral disease: No doubt bilateral cystectomy  For unilateral disease: Discuss with patient:  More/less ovarian tissue remaining  Similar pregnancy rates?  Higher recurrence rates: BUT usually salvaged by surgical treatment…

17. Fertility sparing surgery in mucinous BOT Vasconcelos et al. Meta-analysis Khunamornpong Retrospective Koskas et al. Retrospective N 39417131 Recurrence – Pregnancy rate Cystectomy 29.0% - insuff. data Insuff. data49.1% - 41.8% USO 7.9% - insuff. data 5.0% - no data5.3% - 45.9% Vasconcelos et al. Eur J Cancer 2015 Mar;51(5):620-31 Khunamornpong et al. Int J Gynecol Pathol 2011 30: 218-230. Koskas M, et al. Hum Reprod 2011 26: 808-814.

18. Fertility sparing surgery in mucinous BOT  Mucinous BOT is cured by surgery in 99% of the cases  However it represents a continuum with benign, BOT and malign findings coexisting – Specimen sampling is important!  It may recur as mucinous carcinoma because of this KRAS supported progression  Cure with USO (only 5% recurrence) or risk recurrence with cystectomy (30%,), recurrence as mucinous carcinoma  Similar pregnancy rates… Worth the risk?

19. Final thoughts Histology? Serous / Mucinous Histology? Serous / Mucinous Age? Children? Age? Children?  Unilateral or Bilateral Disease? Bilateral cystectomy Unilateral SO Implants?  Invasive or non- invasive? Follow up Maintenance Therapy Mucinous: Consider GI Metastasis !!! Thank you for you time ines.mv@gmail.com