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Borderline Ovarian Tumors (BOT)

Borderline Ovarian Tumors (BOT). Prof. Dr A. Ph. MAKAR Gynaecology/Oncology ZNA Middelheim University Hospital Gent. Ovarian cancer (OC): Histologic subtypes. Borderline or Invasive. I. Epithelial tumours (90%): Serous Mucinous Endometrioid Brenner Clear-cell Mixed

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Borderline Ovarian Tumors (BOT)

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  1. Borderline Ovarian Tumors (BOT) Prof. Dr A. Ph. MAKAR Gynaecology/Oncology ZNA Middelheim University Hospital Gent

  2. Ovarian cancer (OC): Histologic subtypes Borderline or Invasive I. Epithelial tumours (90%): • Serous • Mucinous • Endometrioid • Brenner • Clear-cell • Mixed • Undifferentiated • Unclassified II. Germ cell tumours III. Sex cord tumours

  3. Differsfrominvasivecancers Borderline Tumors of the Ovary = separate entity • Etiology • Genteic profile • Epidemiology • Clinical & pathological presentation • CA 125 • Prognosis • Response to adjuvant chemotherapy • Overtreatment: surgically and pharmacologically

  4. Taylor (1929): semi malignant tumors • Epithelial tumors with histo-pathologic features and biologic behavior intermediate between clearly benign and frankly malignant • FIGO (1971): Cancer of low malignant potential • WHO (1973): Borderline tumors Borderline Tumors of the Ovary (BOT) • Hart and Norris (1973) & Scully (1979): • Epithelial cellulair proliferation: • Stratification multi-layering • mitotic activity & nuclear atypia • Without stromal invasion

  5. Etiology & Risk Factors • Increased serum gonadotrophin levels: • postmenopausal & fertility treatment ?? • Increasing parity & lactation reduces risk of BOT • Talc minerals in hygienic powders • Oral contraceptives decrease relative risk of IOC of 0.6 (Kumle 2004): • This protective effect was persistent and related to duration of use • Not in case of BOT • No correlation with positive family history • BRCA mutations don’t increase the risk of BOT

  6. Incidence • Incidence OC in western Europe 14-19/100.000 females per year: • OC in Belgium (1998): 813 patients • BOT represents (9-20%) of OC: • Norwegian Radium Hospital: 12% • Mean age: 45years vs (invasive >55y) • 27% are <40 years • Localized tumors (FIGO stadium I): 93% • Regional (stage II) or distant spread (stage III) : 7% vs 70% (invasive)

  7. Borderline tumors- Histologic TypeNorway 1970-1993

  8. Serous cystadenoma Cytogenetic of Serous BOT Mutation in BRAF or KRAS (76%) Serous Borderline tumor High grade serous carcinoma: BRCA / P53 Tubal IE carcinoma Low grade serous carcinoma

  9. I. Serous Borderline Tumors • >40% of borderline tumors • Bilaterality is frequent: (40%) • Stage I: 67% of cases: • Exophytic implants: • hidden peritoneal spread? • No impact on prognosis • Micro-invasion • Micropapillary pattern • Advanced stage: • Serosal implants • Invasive vs non invasive A. MAKAR

  10. Micro-papillairgroei • De aanwezigheid van een micro-papillaire groeipatroon van een minimum 5 mm diameter: • Gaat geassocieerd met aanwezigheid van invasieve peritoneale implanten • agressiever biologisch gedrag & slechte prognose • Bilateraliteit • Morfologische heterogeniteit van de sereuse BOT: • Uitgebreide pathologische sampling is vereist Micro-invasie • Twee patronen worden beschreven: • Voorkomen van losse cellen met eosinofiel cytoplasma in het stroma Of • De infiltratie door celgroepen, soms papillair, met inductie desmoplastisch stroma • De totale oppervlakte van micro-invasie mag <=10 mm2 en het individueel veld mag <= 3 mm doormeter hebben • Literatuuroverzicht: micro-invasie heeft geen negatief impact op overleving • 100% overleving in 94 patiënten met een wel gedocumenteerde micro-invasie na 6.7 jaren opvolging (Seidman et al)

  11. Extra Ovarian Spread of Serous BOT: Stage II-III • 35% peritoneal & omental implants • True implantation metastases ? • Multifocal in situ lesions of peritoneum ? • Non-invasive vs invasive implants • DD: Invasive implants vs endosalpingosis

  12. Extra Ovarian Spread of Serous BOT: stage II-III Serosal implants • Invasive implants: • - Worse prognosis • LN metastases • DD endosalpingosis • Non-invasive implants: • Spontaneous regression • Good prognosis • Fertility sparing surgery Desmoplastic type Epithelial type Endosalpingosis EpitheliaalMesotheel inclusies - Tubal type glandular structures

  13. Prognosis of Serous BOT 10y survival is related to FIGO stage • Stage I: 99% survival • Stage II - III: 60-80% survival, depending on type of extra –ovarian (serosal) implants: • Non-invasive implants: 93% survival • Regression after removal of primary tumor • Invasive implants: 60% survival • Progression to invasive cancer • Lymphatic metastases

  14. II. Mucinous Borderline Tumors • 50% of all borderline tumors • Intestinal subtype (90%): • Unilateral, multicystic, smooth capsule • Pseudomyxoma peritonei • Non intestinal subtype (10%): • Bilateral 20-30% • Exophytic paucilocular, implants (sero-mucinous) • FIGO stage I: 84% (67% serous tumors) • 10 years survival FIGO stage I: 97%

  15. Pseudomyxoma Peritonei • Only with mucinous tumors of intestinal type • Not related to pre or intraoperative rupture • Often with pseudomyxoma ovarii • Mucinous tumors of the appendix • Influence on survival is unclear • Primary surgical treatment: • Repeated surgery & peritoneal stripping • HIPEC

  16. Norwegian Cancer Registery (1970-1993): 2343 BOT • Age adjusted 5 years survival ( 93%) • Survival related to: • FIGO stage (localized vs EO spread) • Histologic type • Residual disease after primary surgery • Invasive peritoneal implants • Age (<44 vs older) • < 44 ys old: 5y survival of 99% • 75-89 ys old: 5y survival of 85% • 45-64 y: RR 4.7 (CI: 2.46 - 8.99) • 65-74 y: RR 11.09 (CI: 5.84 – 21.95) • 75-89 y: RR 34.16 (CI: 18.23-64.02) • DNA ploidy state

  17. Ploidy StateNorwegian Cancer Registery: (1970-1993): 2343 BOT • Kaern et al (1993): • 370 tumors >10y FU • 90% diploid • 10% aneuploid • Aneuploidy = 19X more risk of dying of disease

  18. CA 125 in Borderline tumors. Makar et al.(1992 & 1993) • Preoperative level lowerthanwithinvasiveovariancancer (IOC): • Borderline : 66 (5-272) U/ml vs • Invasivecancer: 327 (2-125000) U/ml • Grade 1: 68 U/ml • Grade II: 221 U/ml • Grade III: 490 U/ml • Serous BOT: 131 vs 391 U/ml for IOC • Mucinous BOT: 62 vs 49 U/ml for IOC • CA125 was elevated in only 15% BOT withdiseaserecurrencevs 82% with IOC

  19. BOT & Hormonal Receptor State • Almost 100% positive ER and/or PR • Invasive counterpart <10% positive hormonal receptors • What is the place of hormonal therapy?

  20. Patterns of Spread in BOTI. Transperitoneal

  21. II. Lymphatic spread ?? • Not in case of mucinous BOT (intestinal) • Serous BOT with: • Extra-ovarian spread of invasive implants • 19% (Camatte 2002) • Aneuploid tumors • True metastases? • In situ transformation ? • 2ry Mullerian epith in LN? • Endosalpingosis? • No impact on prognosis

  22. Borderline Tumors - Symptoms • Accidental: • Followingcystectomyforasymptomaticadnexalmass • Urinarysymptoms • Abdominalmass • Lessgasterointestinalsymptomscomparedwithinvasive tumors • Torsion

  23. Frozen section • DD: grade 1 vs BOT • DD: benign cystadenoma vs BOT • More difficult with mucinous than serous BOT A. MAKAR

  24. Frozen section dilemma Ovarian mass Frozen section • St. I • St II – III without invasive implants Borderline malignancy vs Gr 1 invasive cancer Young (<40 jaar) Family planning Older age Completed family planning Fertility sparing surgery even bilat cystectomy Long term follow-up Staging/debulking surgery Definitive surgery after family planning

  25. Conservative Surgery • Laparoscopic staging • More cyst rupture • Incomplete • No difference in OS • Inspection & palpation • Cytologic washing • Unilateral adnexectomy – cystectomy • Omentectomy (10% relapse risk with serous tumors) • Appendectomy (mucinous tumors) • Biopsy contralateral ovary (serous tumors) ? • Biopsy pelvic peritoneum • Curettage (endometrioid tumors)

  26. Conservative surgery & Contralateral Ovary • Serous tumors: bilateral in 40% of cases • Wedge resection ? • Microscopic disease was rarely found in grossly normal ovary • Tazelaar (1985): normal pathologic findings in wedge specimen did not exclude tumor • Adhesions and mechanical sterility

  27. Restaging Procedures • Snider (1991), Hoskins (1995), Boccara (2004), Morice (2011): • No upgrading in stage I mucinous tumors • Multifocal appendicular tumor • Upgrading in 12-20% of serous tumors • In case of cystectomy • Omentectomy ( serous tumors) • Per laparoscopy • Restaging had no impact on recurrence rate

  28. Cystectomy in case of bilateral tumorsCave mucinous tumors A. MAKAR

  29. A. MAKAR

  30. Conservative surgery -Cystectomy • Even cystectomy with bilateral tumors • Recurrence rate 15% in case of: positive resection margins or multifocality • Risk invasive cancer with mucinous tumors • Meticilous pathological examination of the resection margins • Careful follow-up: survival is not affected if patients are re-operated at recurrence

  31. Conservative surgeryClose Long Term Follow-up • Papadimitriou (1999): late recurrence in 70% of cases with stage I • Makar (1993): CA 125 was elevated in only 15% at recurrence • Vaginal sonography • Removal of the remaining ADNEX following completion of family planning ?

  32. Conservative Surgery in Stage II-III • Camatte (2002 BJOG): • Conservative surgery in 17 with stage II-III • 14/17 with non invasive implants • 6 spontaneous and 2 assisted pregnancies • No deaths • 2 recurrences (one with non invasive implant) • Morice et al (2011) in literature review: • Invasive implants is associated with >40% risk of recurrence, 2% death

  33. Pregnancy following Conservative Surgery • No difference in recurrence rate (5.4% & 6.9%) • Maintenance of menstrual cycle in patients who received cisplatinum as adjuvant treatment • Assisted fertility treatment: successful • Patients who wished to procreate succeeded • No higher incidence of miscarriages or dystocia • No increased risk of foetal malformations

  34. Adjuvant TherapyBorderline tumors are overtreated Without AdjuvantTherapy • Tropé (Gynecol Oncol 1993): • 253 BOT stage I-II in 4 randomized trials • No survival benefit of adjuvant therapy • Adjuvant therapy increased morbidity and mortality

  35. BOT in Randomized chemotherapy Trials: Tropé et al. 1993

  36. Outcome of stage II - IV AdjuvantTherapy Without AdjuvantTherapy

  37. Chemotherapy in Stage (II-III) ???? • Excellent survival without adjuvant therapy • Low response rate (<15%) • Increased morbidity • Non-invasive implants: • Good prognosis = no adjuvant therapy • Conservative surgery in young patients • Invasive implants: only progonostic factor is residual disease

  38. Conclusion-IBorderline Ovarian Tumors • Mostly as stage I with excellent long term prognosis • Women in reproductive age deserve conservative surgery • Surgeryis corner stone of treatment of advanced stages and in recurrence • No place for adjuvant CT = overtreatment = mobidity/mortality • Careful and long term follow-up • CA 125is of limited value in follow up

  39. Invasieve tumoren Borderline Conclusie: BOT hebben eigen entiteit • 55 j • 2/3 stadium III-IV • Chirurgie + 6 cycli Carbo/Taxol • Slechte overleving • Sereus: >80% • Horm receptor: negatief • Lymfadenectomie • Gevoelig voor chemo • Snelle recidieven • CA 125 follow-up: betrouwbaar • Verhoogd risico op erfelijkheid • 45 & >1/3< 40 jaar • 2/3 st. I = Fertiliteitssparende chirurgie • Chirurgie Zonder CT • Zeer goede overleving • Mucineus & sereus • Horm receptor: positief • Geen • Niet gevoelig voor CT • Recidieven na 10-15j • CA 125 follow-up: onbetrouwbaar • Geen verhoogd risico op erfelijkheid

  40. Stop georganiseerde moord op christenen in het Midden-Oosten

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