Presentazione di PowerPoint - SICHIG · •Surgery is the cornerstone of treatment: consider...

Nicoletta ColomboNicoletta Colombo

Sex-Cord stromal tumorsSex-Cord stromal tumors

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

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

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

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

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%

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)

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

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%)

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

GCTGCT

Who should you Who should you treat after surgery?treat after surgery?

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

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

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%

Clinical Prognostic Factors in GCTClinical Prognostic Factors in GCT

• StageStage• AgeAge• Tumor SizeTumor Size• BilateralityBilaterality• RuptureRupture

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

Disease-Specific Survival by StageDisease-Specific Survival by Stage

Zhang M et al. Gynecol Oncol 2007Zhang M et al. Gynecol Oncol 2007

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

Age and Prognosis in GCTAge and Prognosis in GCT


Event-Free Survival by AgeEvent-Free Survival by Age

Schneider et al, JCO vol 21, 2003Schneider et al, JCO vol 21, 2003

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

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

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

Rupture and Prognosis in GCTRupture and Prognosis in GCT

AUTHORSAUTHORS DOD/RuptureDOD/Rupture

DinnersteinDinnerstein NONOSchwartzSchwartz NONOBjorkholmBjorkholm YESYES 86% vs 60%86% vs 60%

Tumor ruptureTumor rupture


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

Disease-Specific Survival by GradeDisease-Specific Survival by Grade


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


Histologic Prognostic Factors in GCTHistologic Prognostic Factors in GCT

• Histologic PatternHistologic Pattern• Degree Of Cellular AtypiaDegree Of Cellular Atypia• Mitotic ActivityMitotic Activity

ControversialControversialControversialControversialControversialControversial

Event-Free Survival by Mitotic ActivityEvent-Free Survival by Mitotic Activity


…….. 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.

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

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

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

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

• 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).

• 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

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

Treatment of advanced, Treatment of advanced, recurrent GCTrecurrent GCT

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%

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

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.

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

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

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

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

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

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

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

GCT- IEO cases RECURRENCES

N° pts %

SURGERY + CHEMO 23 80

SURGERY 6 20

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

GCT- IEO cases Recurrences GCT- IEO cases Recurrences Follow-upFollow-up


STATUSSTATUS N°ptsN°pts %%

NEDNED 1515 5252

AWDAWD 99 3131

DODDOD 55 1717



STATUSSTATUS N°ptsN°pts %%

NEDNED 6060 7777

AWDAWD 1111 1414

DODDOD 77 99

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

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%

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

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.

• 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

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