presentazione di powerpoint - sichig · •surgery is the cornerstone of treatment: consider...
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Nicoletta ColomboNicoletta Colombo
Sex-Cord stromal tumorsSex-Cord stromal tumors
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Sex cord-stromal tumors account Sex cord-stromal tumors account for approximately 5% of all for approximately 5% of all ovarian cancers and for the ovarian cancers and for the
majority of functioning tumors majority of functioning tumors with clinical manifestationswith clinical manifestations
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Classification of sex cord Classification of sex cord stromal tumorsstromal tumors
A) Granulosa-Stromal Cell Tumors A) Granulosa-Stromal Cell Tumors 1 - Granulosa cell tumors1 - Granulosa cell tumors 2 - Tumors in the thecoma-fibroma group2 - Tumors in the thecoma-fibroma group
B) Sertoli-Leydig cell tumors B) Sertoli-Leydig cell tumors 1 - Well differentiated1 - Well differentiated
2 - Of intermediated differentiation2 - Of intermediated differentiation 3 - Poorly differentiated3 - Poorly differentiated 4 - With heterologous elements4 - With heterologous elements
C) Gynadroblastoma C) Gynadroblastoma D) Sex Cord with anular tubules D) Sex Cord with anular tubules E) UnclassifiedE) Unclassified
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EpidemiologyEpidemiology• 1.5% of all ovarian tumors1.5% of all ovarian tumors• 3-5% of all ovarian cancer 3-5% of all ovarian cancer • Any ageAny age• Peri and early post-menopausal (median age: 50-54)Peri and early post-menopausal (median age: 50-54)• 5% premenarchal5% premenarchal• 0.99 per 100,000 in USA0.99 per 100,000 in USA• 0.4-1.7 per 100,000 in developed countries0.4-1.7 per 100,000 in developed countries• 25% endometrial hyperplasia25% endometrial hyperplasia• 5-10% endometrial cancer5-10% endometrial cancer
GRANULOSA CELL TUMORS
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GCT: Adult and Juvenile typesGCT: Adult and Juvenile types
Adult 95% Juvenile 5%Adult 95% Juvenile 5%< 1% premenarchal< 1% premenarchal 50% premenarchal50% premenarchalUsual after 30 yrsUsual after 30 yrs Rare after 30 yrsRare after 30 yrs
90% Stage I90% Stage I
from Young & Scully, 1984from Young & Scully, 1984
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GRANULOSA CELL TUMORSGRANULOSA CELL TUMORS
Endocrine manifestations:Endocrine manifestations:• ChildhoodChildhood: isosexual precocious pseudopuberty: isosexual precocious pseudopuberty
• Reproductive ageReproductive age: menstrual irregularities/ : menstrual irregularities/ secondary amenorrhea, infertility, rarely virilizationsecondary amenorrhea, infertility, rarely virilization
• Post-menopausalPost-menopausal: abnormal vaginal bleeding: abnormal vaginal bleeding Endometrial hyperplasia 25%Endometrial hyperplasia 25% Endometrial adenocarcinoma 5-10%Endometrial adenocarcinoma 5-10%
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GCT TREATMENTGCT TREATMENT
Surgery as Primary TreatmentSurgery as Primary Treatment::
TAH/BSO + Surgical Staging TAH/BSO + Surgical Staging Role of Fertility-Sparing SurgeryRole of Fertility-Sparing Surgery
Adjuvant Treatment (?)Adjuvant Treatment (?)::
Chemotherapy (CT)Chemotherapy (CT) Radiotherapy (RT)Radiotherapy (RT) Hormonal Therapy (HT)Hormonal Therapy (HT)
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Staging and Restaging• Complete surgical staging in 1/5 Complete surgical staging in 1/5
women with GCT women with GCT • No nodal metastases identified in No nodal metastases identified in
those surgically stagedthose surgically staged• 15% of first recurrences appear to 15% of first recurrences appear to
involve the retroperitoneuminvolve the retroperitoneum
Abu Rustum, Gynecol Oncol, March 2006Abu Rustum, Gynecol Oncol, March 2006
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GCT- IEO cases GCT- IEO cases RESTAGINGRESTAGING
STAGE at 1ST SurgerySTAGE at 1ST Surgery After Restaging After Restaging
IA (15 pts)IA (15 pts) 14 IA (93.3%)14 IA (93.3%) 1 IIB (6.7%)1 IIB (6.7%)
IC (9 pts)IC (9 pts)
7 IC (77.8%)7 IC (77.8%)
1IIIB (11.1%)1IIIB (11.1%) 1IIIC (11.1%)1IIIC (11.1%)
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Fertility-sparing surgery
• 134 young patients ( 134 young patients ( <<50 Years) with 50 Years) with stage I stage I
• 5 and 10 Y survival of 97% and 94%5 and 10 Y survival of 97% and 94%• 71 (54%) had a fertility-sparing surgery71 (54%) had a fertility-sparing surgery• There was no difference in the outcome There was no difference in the outcome
of women who had a standard vs of women who had a standard vs conservative surgery ( 97% vs 98%)conservative surgery ( 97% vs 98%)
Zhang et al. Gynecol Oncol , 2007Zhang et al. Gynecol Oncol , 2007
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GCTGCT
Who should you Who should you treat after surgery?treat after surgery?
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Postoperative TherapyPostoperative Therapy
• Due to the rarity of the disease it is still unknown whether the Due to the rarity of the disease it is still unknown whether the use of postoperative treatment in patients with high risk GCT use of postoperative treatment in patients with high risk GCT can actually confer a survival advantagecan actually confer a survival advantage
• Postoperative treatment decisions are based on:Postoperative treatment decisions are based on:– Estimated risk of relapseEstimated risk of relapse– Observation that adjuvant treatment can Observation that adjuvant treatment can improve improve
DFS DFS– Availability of agents with known activity in GCTAvailability of agents with known activity in GCT
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Recurrence Rate in GCTRecurrence Rate in GCTAUTHORSAUTHORS N°casesN°cases N°rec. N°rec. %%
SchwartzSchwartz 3737 66 16.216.2
StenwigStenwig 118118 2424 21.221.2
EvansEvans 118118 2222 18.618.6
Kim 34 3 8.6 Kim 34 3 8.6
TotalTotal 307307 5555 17.917.9
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Survival after RecurrenceSurvival after Recurrence
AUTHORSAUTHORS IntervalInterval SurvivalSurvival
SchwartzSchwartz 1-9 yrs1-9 yrs 19%19%PanckratzPanckratz 13%13%StenwigStenwig 1-22 yrs1-22 yrs 13%13%EvansEvans 1-23 yrs1-23 yrs 27%27%
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Clinical Prognostic Factors in GCTClinical Prognostic Factors in GCT
• StageStage• AgeAge• Tumor SizeTumor Size• BilateralityBilaterality• RuptureRupture
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Survival Rates by StageSurvival Rates by Stage
FIGO stage FIGO stage 5-yrs5-yrs 10-yrs10-yrsSurvival (%)Survival (%) Survival (%)Survival (%)
II 90-10090-100 84-9584-95IIII 55-7555-75 50-6550-65III-IVIII-IV 22-5022-50 17-5717-57
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Disease-Specific Survival by StageDisease-Specific Survival by Stage
Zhang M et al. Gynecol Oncol 2007Zhang M et al. Gynecol Oncol 2007
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Age and Prognosis in GCTAge and Prognosis in GCT
AuthorAuthor SurvivalSurvival < 40 yrs< 40 yrs >40 yrs>40 yrsFox H. et al.Fox H. et al. FavorableFavorableStenwig et al.Stenwig et al. FavorableFavorable
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Age and Prognosis in GCTAge and Prognosis in GCT
Zhang M et al. Gynecol Oncol 2007Zhang M et al. Gynecol Oncol 2007
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Event-Free Survival by AgeEvent-Free Survival by Age
Schneider et al, JCO vol 21, 2003Schneider et al, JCO vol 21, 2003
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Tumor Size and Prognosis in GCTTumor Size and Prognosis in GCT
AuthorAuthor SurvivalSurvival <5cm 5-15cm >15cm
FoxFox 100%100% 64%64% 61%61%StenwigStenwig 73%73% 63%63% 34%34%BjorkholmBjorkholm 100%100% 92%92%Zhang 91% 89%Zhang 91% 89%
Difference not significant after correcting for stageDifference not significant after correcting for stage
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Clinical Features in GCT: BilateralityClinical Features in GCT: BilateralityAUTHORSAUTHORS
MansellMansellNorrisNorrisNovakNovak
FoxFoxSchwartzSchwartzPankratzPankratzStenwigStenwigEvansEvans
N°casesN°cases80809797
307307929237376161
1181181111
Bilater.Bilater.4422997711556633
%%5.05.02.12.12.92.97.67.62.72.78.28.25.15.12.52.5
TOTAL TOTAL 910 37 4.1910 37 4.1
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Bilaterality and Prognosis in GCTBilaterality and Prognosis in GCT
AUTHORSAUTHORS DOD/BILATDOD/BILAT..
DiddleDiddle 38/5738/57NorrisNorris 1/21/2FoxFox 6/76/7StenwigStenwig 5/65/6TotalTotal 50/7250/72
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Rupture and Prognosis in GCTRupture and Prognosis in GCT
AUTHORSAUTHORS DOD/RuptureDOD/Rupture
DinnersteinDinnerstein NONOSchwartzSchwartz NONOBjorkholmBjorkholm YESYES 86% vs 60%86% vs 60%
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Tumor ruptureTumor rupture
Schneider et al, JCO vol 21, 2003Schneider et al, JCO vol 21, 2003
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Preop rupture: 3/12 received CTPreop rupture: 3/12 received CTIntraop rupture: 4/9 received CTIntraop rupture: 4/9 received CT
Tumor ruptureTumor rupture
Schneider et al, JCO vol 22,n10, 2004Schneider et al, JCO vol 22,n10, 2004
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Disease-Specific Survival by GradeDisease-Specific Survival by Grade
Zhang M et al. Gynecol Oncol 2007Zhang M et al. Gynecol Oncol 2007
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Clinical prognostis factors Clinical prognostis factors Multivariate analysisMultivariate analysis
376 patients376 patientsFactors Hazard 95% CIFactors Hazard 95% CI p-valuep-value ratio ratio
Older age 1.03Older age 1.03 1.01-1.05 p=0.001 1.01-1.05 p=0.001
Advanced stage 1.79 1.43-2.25 p<0.001Advanced stage 1.79 1.43-2.25 p<0.001at diagnosisat diagnosis
Zhang M et al. Gynecol Oncol 2007Zhang M et al. Gynecol Oncol 2007
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Histologic Prognostic Factors in GCTHistologic Prognostic Factors in GCT
• Histologic PatternHistologic Pattern• Degree Of Cellular AtypiaDegree Of Cellular Atypia• Mitotic ActivityMitotic Activity
ControversialControversialControversialControversialControversialControversial
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Event-Free Survival by Mitotic ActivityEvent-Free Survival by Mitotic Activity
Schneider et al, JCO vol 21, 2003Schneider et al, JCO vol 21, 2003
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…….. Considering our experience, we Considering our experience, we recommend that patients with stage IA andrecommend that patients with stage IA and
accidental IC tumors be followed upaccidental IC tumors be followed up at at regular interval, whereas we would regular interval, whereas we would
recommend that patients withrecommend that patients with natural stage natural stage IC tumors with preoperative rupture or IC tumors with preoperative rupture or
malignant ascitis be treated with adjuvant malignant ascitis be treated with adjuvant cisplatin-based chemotherapy,cisplatin-based chemotherapy, especially especially
patients with tumors with high mitotic patients with tumors with high mitotic activityactivity
Schneider et al.Schneider et al.
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Other Factors and PrognosisOther Factors and PrognosisPrognosticPrognostic SignificanceSignificance
DNA ploidyDNA ploidy controversial controversialP53 overexpressionP53 overexpression controversialcontroversialKi 67Ki 67 controversialcontroversial
Immunohystochemical determination of c-myc Immunohystochemical determination of c-myc p21-ras, c-erB2 and p53 in a panel of 32 GCT was p21-ras, c-erB2 and p53 in a panel of 32 GCT was found to be of no prognostic significancefound to be of no prognostic significance
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Event-Free Survival by DNA PloidyEvent-Free Survival by DNA Ploidy
Vlllella et al., Int J Gynecol Pathol Vol. 26(2) April2007Vlllella et al., Int J Gynecol Pathol Vol. 26(2) April2007
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Extinction of FOXL2 Expression in Extinction of FOXL2 Expression in Aggressive Ovarian GCT in ChildrenAggressive Ovarian GCT in Children
FOXL2 is not expressed or is underexpressed in FOXL2 is not expressed or is underexpressed in juvenile GCT with aggressive pattern of progression. juvenile GCT with aggressive pattern of progression.
It may be a new prognostic factor for JOGCT It may be a new prognostic factor for JOGCT
Total of 26 pts with juvenile OGCT
Extinction/reductionExtinction/reduction Normal expressionNormal expression (n=14) (n=14) (n=12) (n=12)
Recurrence (%) Recurrence (%) 21.4 21.4 0 0
Kalfa et al., Fertil Steril Vol.87(4) April 2007Kalfa et al., Fertil Steril Vol.87(4) April 2007
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Mutation of FOXL2 in Granulosa-Cell Tumors of the Ovary
• Adult-type GCTs 97% (86/89)• Thecomas 21% (3/14)• Juvenile-type GCTs 10% (1/10)• No mutation in 49 SCSTs of other types and
329 unrelated ovarian or breast tumors
Mutant FOXL2 is a potential driver in the pathogenesis of adult-type GCTs
Shah, Kobel, Senz et al, N Engl J Med 2009; 360: 2719-29
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• FOXL2 is a member of the forkhead-winged-helix family of transcription factors containing a highly conserved DNA- binding forkhead domain
• It is one of the earliest markers of ovarian differentiation and its expression persists into adult-hood
• FOXL2 is required for the normal development of granulosa cells
• It has a role in activating the transcription of GNRHR in pituitary cells and repressing the transcription of STAR (encoding steroidogenic acute regulatory protein).
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• Patients with stage I granulosa cell tumor Patients with stage I granulosa cell tumor have a very low risk of recurrence (9%)have a very low risk of recurrence (9%)
• No prognostic factors clearly identified No prognostic factors clearly identified besides stage and perhaps age besides stage and perhaps age
• No data that adjuvant treatment can No data that adjuvant treatment can improve DFS or OSimprove DFS or OS
• In a retrospective series there was no In a retrospective series there was no observed benefit to adjuvant irradiationobserved benefit to adjuvant irradiation
Adjuvant Therapy in Stage I GCTAdjuvant Therapy in Stage I GCT
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Role of Adjuvant Radiotherapy in Granulosa Cell Tumors of the Ovary
103 patients31 adjuvant RT39 total local recurrenceTumor size, incidence of intraoperative rupture and
concurrent endometrial cancer are not significant risk factors for DFS
On multivariate analysis aduvant RT remained a significant prognostic factor for DFS (p=.004)
Hauspy et al. Int J Radiat Oncol Biol Phys 2010 May 14
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Treatment of advanced, Treatment of advanced, recurrent GCTrecurrent GCT
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Chemotherapy in advanced /recurrent Chemotherapy in advanced /recurrent sex-cord stromal tumorssex-cord stromal tumors
AuthorAuthor CTCT N.N. RRRR • GershersonGersherson 19871987 CAPCAP 88 63%63%• PectasidesPectasides 19921992 CAPCAP 1010 60%60%• Uygun Uygun 20032003 CAPCAP 99 44%44%• Colombo Colombo 19861986 PVBPVB 1111 82%82%• Zambetti Zambetti 19901990 PVBPVB 77 66%66%• Pecorelli Pecorelli 19991999 PVBPVB 3838 61%61%• GershersonGersherson 19961996 BEPBEP 66 83%83%• Homsley Homsley 19991999 BEPBEP 5757
Measur dis.Measur dis. 2525 40%40%Neg II lookNeg II look 3838 38%38%
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Newly DiagnosedNewly Diagnosed Taxane group BEP group p
RR 82% 82% NSRR 82% 82% NSMedian OS (months) Median OS (months) 97.2 (52+) .99497.2 (52+) .994Median PFS (months) (52+) 46.1 .213Median PFS (months) (52+) 46.1 .213 Recurrent DiseaseRecurrent DiseaseRR 37% 71% NSRR 37% 71% NSMedian PFS (months) Median PFS (months) 7.2 11.27.2 11.2 NS NS
Brown et al, Gynecol Oncol 97, March 2005Brown et al, Gynecol Oncol 97, March 2005
The activity of taxanes compared with bleomycin, etoposide, and cisplatin in the
treatment of sex cord-stromal ovarian tumors
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Advanced Tumors: RadiotherapyAdvanced Tumors: Radiotherapy• Although most reported series include patients Although most reported series include patients
treated with radiotherapy, the lack of uniformity treated with radiotherapy, the lack of uniformity in the staging and treatment program precludes in the staging and treatment program precludes any definitive conclusion.any definitive conclusion.
• This modality may represent an alternative to This modality may represent an alternative to chemotherapy only in pts with small volume chemotherapy only in pts with small volume disease or can be used to palliate isolated pelvic disease or can be used to palliate isolated pelvic recurrences.recurrences.
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Therapy of Advanced Tumors: Therapy of Advanced Tumors: Hormonal TherapyHormonal Therapy
• Receptors for FSH demonstrated in Receptors for FSH demonstrated in granulosa cell tumorsgranulosa cell tumors
• FSH supports the growth of this FSH supports the growth of this tumor in nude micetumor in nude mice
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Therapy of Advanced Tumors: Therapy of Advanced Tumors: Hormonal TherapyHormonal Therapy
AUTHORS Pts (n°) Prior Treat HT Response AUTHORS Pts (n°) Prior Treat HT Response
Martikainem (1989)Martikainem (1989) 1 CAP 1 CAP GnRHaGnRHa PRPRFishman (1996)Fishman (1996) 4 CAP-PEB 4 CAP-PEB GnRHaGnRHa 2PR-2SD 2PR-2SDMalik and Slevin (1991)Malik and Slevin (1991) 2 P/RT-PA 2 P/RT-PA MPAMPA 1PR-1SD 1PR-1SDIsaacs (1991) Isaacs (1991) 2 Chlorambucil 2 Chlorambucil MPA/MEGMPA/MEG 1CR1PR 1CR1PR Briasoulis (1997)Briasoulis (1997) 1 P/Chlor1 P/Chlor MEGMEG PR PRHardy (2005) Hardy (2005) 1 AC 1 AC MEG/TAMMEG/TAM CR CRFreeman (2006) Freeman (2006) 2 TP2 TP AnastrozoleAnastrozole SDSD
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Molecular targeted therapyMolecular targeted therapy• The immunohistochemical expression of The immunohistochemical expression of
EGFR (Her-1), Her-2, Her-3, and Her-4 was EGFR (Her-1), Her-2, Her-3, and Her-4 was analyzed in 38 adult type and 2 juvenile GCTanalyzed in 38 adult type and 2 juvenile GCT
• 31 (77.5%) were positive for at least one 31 (77.5%) were positive for at least one receptorsreceptors
• These findings provide some evidence to These findings provide some evidence to further explore the potential use of agents further explore the potential use of agents targeting these receptorstargeting these receptors
Leibl et al. Gynecol Oncol 2006Leibl et al. Gynecol Oncol 2006
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Vorinostat in Stage IV GGCT Vorinostat in Stage IV GGCT Histone Deacetylase (HDAC) Inhibitor
Response after 11 months of treatment. Prior treatment included bleomycin with cisplatin and etoposide, doxorubicin, tamoxifen, carboplatin, leuprolide, topotecan, paclitaxel, and an experimental medication.
Rubin et al, Clin Cancer Res December 1, 2006Rubin et al, Clin Cancer Res December 1, 2006
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Anti-angiogenesis therapy with bevacizumab for patients with ovarian
granulosa cell tumors
Retrospective study 8 patients bevacizumab +/- chemotherapy for RD1 CR; 2 PR, 2 SD, 3 PDMedian PFS 7.2 months
VEGF overexpression and microvessel density were associated with poor outcome (sample too small to calculate statistical significance)
Tao X et al, Gynecol Oncol 2009 Sept
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New pathwaysNew pathways • PTEN expression may be a trigger for
proliferation/differentiation transition in human granulosa cells
• cFLIP is an essential pro-survival factor for granulosa cells and it prevents granulosa cell apoptosis by inhibiting procaspase-8-activation
• Inhibition of proteasoma• mTOR-HIF-1alpha-VEGF pathway
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GCT: Treatment of recurrenceGCT: Treatment of recurrence
Due to its indolent growth Due to its indolent growth repeat surgical resection is repeat surgical resection is the treatment of choice for the treatment of choice for recurrent GCT patientsrecurrent GCT patients
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GCT- IEO cases RECURRENCES
N° pts %
SURGERY + CHEMO 23 80
SURGERY 6 20
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GCT- IEO cases GCT- IEO cases Numbers of Surgeries at RelapseNumbers of Surgeries at Relapse
N° PtsN° Pts2929
1 Surgery1 Surgery 2929
2 Surgeries2 Surgeries 1616
3 Surgeries 3 Surgeries 66
4 Surgeries4 Surgeries 11
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GCT- IEO cases Recurrences GCT- IEO cases Recurrences Follow-upFollow-up
GCT- IEO cases Recurrences GCT- IEO cases Recurrences Follow-upFollow-up
STATUSSTATUS N°ptsN°pts %%
NEDNED 1515 5252
AWDAWD 99 3131
DODDOD 55 1717
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GCT- IEO cases Recurrences GCT- IEO cases Recurrences Follow-upFollow-up
GCT- IEO cases Recurrences GCT- IEO cases Recurrences Follow-upFollow-up
STATUSSTATUS N°ptsN°pts %%
NEDNED 6060 7777
AWDAWD 1111 1414
DODDOD 77 99
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Sertoli-Leydig cell tumorsSertoli-Leydig cell tumors
• 0.2% ovarian neoplasm0.2% ovarian neoplasm• Average age : about 25 yrsAverage age : about 25 yrs• 50% : hirsutism or virilization50% : hirsutism or virilization• Occasionally oestrogen-related manifestationOccasionally oestrogen-related manifestation
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SLCT:prognostic factorsSLCT:prognostic factors
•StageStage • recurrence 12.7% st.I, 100% st. II-IVrecurrence 12.7% st.I, 100% st. II-IV
•Degree of differentiationDegree of differentiation •Well diff. S= 100%, Well diff. S= 100%, •Poorly diff. S= 41% Poorly diff. S= 41%
•Presence of mesenchymal heterologous Presence of mesenchymal heterologous elements or retiform componentelements or retiform component
•Fatal cases up to 70%Fatal cases up to 70%
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Management of granulosa cell tumorsManagement of granulosa cell tumors
*stage IC with preoperative rupture or malignant stage IC with preoperative rupture or malignant ascites and high mitotic activityascites and high mitotic activity
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Management of Sertoli-Leydig tumorsManagement of Sertoli-Leydig tumors
*Stage I poorly differentiatedwith retiform component *Stage I poorly differentiatedwith retiform component and mesenchymal heterologous elements.and mesenchymal heterologous elements.
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• Surgery is the cornerstone of treatment: consider Surgery is the cornerstone of treatment: consider fertility-preserving surgery in young ptsfertility-preserving surgery in young pts
• Postoperative chemotherapy for Postoperative chemotherapy for – GCT GCT st. II-IV , recurrences, and perhaps high risk st. II-IV , recurrences, and perhaps high risk
st. IC ( preop rupture )st. IC ( preop rupture )– Sertoli-Leydig tumorSertoli-Leydig tumor st. II-IV and stage I poorly st. II-IV and stage I poorly
differentiated ,with mesenchimal differentiated ,with mesenchimal heter. elem. heter. elem. and/or retiform componentand/or retiform component
• Repeat surgical resections, whenever feasible, for Repeat surgical resections, whenever feasible, for recurrent diseasesrecurrent diseases
• Hormonal therapy and radiation in selected casesHormonal therapy and radiation in selected cases
ConclusionConclusion