Endometriumkarzinom Endometriumkarzinom - Diagnose und - Diagnose und

TherapieTherapie

C TempferC Tempfer

AllgemeinesAllgemeines Häufigstes Malignom - GenitaltraktHäufigstes Malignom - Genitaltrakt

31 000 neue Fälle/5400 Todesfälle pro Jahr31 000 neue Fälle/5400 Todesfälle pro Jahr hohe Prävalenzhohe Prävalenz – westl. Industriestaaten – westl. Industriestaaten geringe Prävalenzgeringe Prävalenz - Entwicklungsländer, - Entwicklungsländer,

Südasien, IndienSüdasien, Indien Östrogen-abhängigÖstrogen-abhängig

– ERT, BMI, Ernährung, anovulatorische ZyklenERT, BMI, Ernährung, anovulatorische Zyklen– Alter/Postmenopause, ger. Parität, hoher Alter/Postmenopause, ger. Parität, hoher

SozialstatusSozialstatus

PAP TestPAP Test Kein Screening-Test für Kein Screening-Test für

EndometriumkarzinomEndometriumkarzinom Sensitivität 50% (rp/k)Sensitivität 50% (rp/k)

– 50% aller Frauen mit EK zeigen 50% aller Frauen mit EK zeigen abnormale Endometriumzellen im abnormale Endometriumzellen im AbstrichAbstrich

Spezifität 25% (rp/pt)Spezifität 25% (rp/pt)– 75% falsch positiv75% falsch positiv

TVS – N. endometriiTVS – N. endometrii n=5013; TVS-Dopplern=5013; TVS-Doppler

N. endometrii stage I: 6 N. endometrii stage I: 6 (Kurjak 1994)(Kurjak 1994)• n=1000; TVSn=1000; TVS

• 4mm cut-off; N. endometrii stage I: 1 4mm cut-off; N. endometrii stage I: 1 (Karlsson (Karlsson 1996)1996)

• n=1074; TVS+Dopplern=1074; TVS+Doppler 4mm cut-off/PI; N. endometrii stage I: 3 4mm cut-off/PI; N. endometrii stage I: 3

(Vuento 1999)(Vuento 1999) n=2025; TVSn=2025; TVS

N. endometrii: 3 N. endometrii: 3 (Ciatto 1995)(Ciatto 1995)Summe: 9112/13; NNS 701Summe: 9112/13; NNS 701

ScreeningScreening

Kein etabliertes MassenscreeningKein etabliertes Massenscreening– Kein adäquater Bluttest, kein TumormarkerKein adäquater Bluttest, kein Tumormarker– Keine ideale sampling-MethodeKeine ideale sampling-Methode

HochrisikopopulationenHochrisikopopulationen– TamoxifenTamoxifen– Lynch II/HNPCCLynch II/HNPCC

TVS und TAMTVS und TAM

Gerber 2000; n=247; 10mm cut-off; 5a; Gerber 2000; n=247; 10mm cut-off; 5a; 1 asymptomatic cancer; 52 D&Cs; 4 1 asymptomatic cancer; 52 D&Cs; 4 perfor.perfor.

Love 1999; n=487; 5mm cut-off; 0 Love 1999; n=487; 5mm cut-off; 0 cancers; 134 D&Cscancers; 134 D&Cs

Fung 2003; 9mm cut-off; 304 D&Cs - 6 Fung 2003; 9mm cut-off; 304 D&Cs - 6 cancers-all with bleedingcancers-all with bleeding

1/525 D&C1/525 D&C

TVSTVS – 2 Studien 2 Studien (Rijcken 2003; Dove 2002)(Rijcken 2003; Dove 2002)

n=41; 5 yrs; 17/179 TVS positive: 3 atyp. n=41; 5 yrs; 17/179 TVS positive: 3 atyp. Hyperpl.; 1 Ca nicht entdecktHyperpl.; 1 Ca nicht entdeckt

n=269; 3 yrs; 2 Endometrium-Ca; 0/2 durch TVS n=269; 3 yrs; 2 Endometrium-Ca; 0/2 durch TVS TVS + CA 125TVS + CA 125 - - keine Daten keine Daten TVS + endometrial samplingTVS + endometrial sampling

– 1 Studie 1 Studie (Renkonen 2006)(Renkonen 2006) n=175; 5 yrs; 11/14 entdeckt (8 durch Biopsie) + n=175; 5 yrs; 11/14 entdeckt (8 durch Biopsie) +

14 atypische Hyperplasien; 0/4 N. ovarii entdeckt14 atypische Hyperplasien; 0/4 N. ovarii entdeckt

HNPCCHNPCC

EmpfehlungEmpfehlung Empfehlung American Cancer Empfehlung American Cancer

Society, US Preventive Task ForceSociety, US Preventive Task Force

– ‚…‚…annual screening with endometrial biopsy annual screening with endometrial biopsy beginning at age 35‘beginning at age 35‘

Smith et al. ACS guidelines for the early detection of cancer, Smith et al. ACS guidelines for the early detection of cancer, 2006. 2006. CA Cancer J Clin.CA Cancer J Clin. 2006;56:11-25 2006;56:11-25

KlinikKlinik Persist. perimenopausale Blutung Persist. perimenopausale Blutung Hämatometra/Pyometra in Postm.Hämatometra/Pyometra in Postm. PMBPMB

– endometrial cancer: 15% of PMB - endometrial cancer: 15% of PMB - specificity 15%specificity 15%

– 90% of women with endometrial 90% of women with endometrial cancer - cancer - sensitivity 90% sensitivity 90% (Hacker et al. 1986) (Hacker et al. 1986)

DiagnoseDiagnose

HistologieHistologie1) Endometrium-Biopsie 1) Endometrium-Biopsie (Pipelle(Pipelle®, Kevorkian-Curette)®, Kevorkian-Curette)

2) D&C2) D&C3) advanced stage disease – 3) advanced stage disease – LAP/LSKLAP/LSK

– 65 Studien, n=26 34665 Studien, n=26 346 (Clark et al. 2002)(Clark et al. 2002)

– Sensitivität 86.4% Spezifität 99.2%Sensitivität 86.4% Spezifität 99.2%– 13.7% of cancers will be missed13.7% of cancers will be missed– post-test LR 0.15 not low enough to negate post-test LR 0.15 not low enough to negate

need for further testing need for further testing – ERSETZT NICHT ABRASIOERSETZT NICHT ABRASIO– zusätzlich zu Abrasio? - keine Datenzusätzlich zu Abrasio? - keine Daten

HysteroskopieHysteroskopie

HysteroskopieHysteroskopie Upstaging? Prognose?Upstaging? Prognose?

10/113 (9%) pos. periton. Zytologie 10/113 (9%) pos. periton. Zytologie (Obermair et al. (Obermair et al. 2000)2000) – FIGO IIIa – FIGO IIIa

n=262, Ia, Ib +/- HSKn=262, Ia, Ib +/- HSK– assoziiert mit HSK (p=0.04), nicht Stadium, assoziiert mit HSK (p=0.04), nicht Stadium,

Grading, HistologieGrading, Histologie n=123; CO2 1.4% vs. saline 14%; n=123; CO2 1.4% vs. saline 14%; p=0.0009p=0.0009 (Lo et (Lo et

al. 2002)al. 2002) 5-yr DFS, n=135+HSK; 127-HSK: 92.4% vs. 5-yr DFS, n=135+HSK; 127-HSK: 92.4% vs.

84.7% (p=0.5) 84.7% (p=0.5) (Obermair et al. 2000)(Obermair et al. 2000)

EndometriumhyperplasieEndometriumhyperplasie 2 unterschiedliche Entitäten2 unterschiedliche Entitäten

– +/- Atypien +/- Atypien (Kurman 1985)(Kurman 1985) Risiko Progression 1.6% vs. 23% Risiko Progression 1.6% vs. 23%

(Kurman 1985; n=170)(Kurman 1985; n=170) Ansprechen auf MPA 94% vs. 50% Ansprechen auf MPA 94% vs. 50%

(Ferenczy 1989; n=85)(Ferenczy 1989; n=85)1) Die meisten Frauen mit EMH ohne Atypien 1) Die meisten Frauen mit EMH ohne Atypien

sprechen auf MPA ansprechen auf MPA an2) Hysterektomie: Atypien, non-Responder MPA2) Hysterektomie: Atypien, non-Responder MPA

EndometriumhyperplasieEndometriumhyperplasie Konkomitantes KarzinomKonkomitantes Karzinom

– n=54; EMH+Atypien, HE n=54; EMH+Atypien, HE (Hunter 1994)(Hunter 1994) Karzinom 19/54 (35%)Karzinom 19/54 (35%)

– n=46; EMH+Atypien, HE n=46; EMH+Atypien, HE (Bilgin 2004)(Bilgin 2004) Karzinom 11/46 (24%)Karzinom 11/46 (24%)

– n=289; EMH+Atypien, HE n=289; EMH+Atypien, HE (Trimble 2006)(Trimble 2006) Karzinom 123/289 (43%)Karzinom 123/289 (43%)

BiologieBiologie

AusbreitungsroutenAusbreitungsrouten– Direkte Extension - häufigsteDirekte Extension - häufigste– lymphatisch - pelvin/paraaortallymphatisch - pelvin/paraaortal– hämatogen - Lungehämatogen - Lunge– Tube - HysteroskopieTube - Hysteroskopie

StagingStaging

Surgically staged diseaseSurgically staged disease (FIGO (FIGO 1988)1988)replaced clinical staging system replaced clinical staging system

(1971) (1971) Unterschied?Unterschied?

significant understaging significant understaging (Tiitinen 1986)(Tiitinen 1986)

Staging (FIGO 1988)Staging (FIGO 1988)

I - I - corpuscorpusIa - endometrium; Ib/Ic - </>50% myometriumIa - endometrium; Ib/Ic - </>50% myometrium

II - II - cervixcervixIII -III - extrauterine spreadextrauterine spreadIIIa - serosa/adnexae/pos. washing, IIIb - vagina, IIIc -IIIa - serosa/adnexae/pos. washing, IIIb - vagina, IIIc -

nodesnodes

IV - IV - bladder or distantbladder or distant

Verteilung nach StadiumVerteilung nach Stadium

Tumor StageTumor Stage Number (n)Number (n) Percent (%)Percent (%)

II 57305730 74.874.8IIII 871 871 11.411.4IIIIII 818 818 10.710.7IVIV 227 227 2.9 2.9No StageNo Stage 17 17 0.2 0.2TotalTotal 7663 7663 100.0 100.0

Pelvine Pelvine LymphknotenmetastasenLymphknotenmetastasen

Depth of Inv.Depth of Inv. G1 (n=180)G1 (n=180) G2 (n=288)G2 (n=288) G3 (n=153) G3 (n=153)

Endometrium Endometrium 0 (0%) 0 (0%) 1 (3%) 1 (3%) 0 (0%) 0 (0%)Inner ThirdInner Third 3 (3%) 3 (3%) 7 (5%)7 (5%) 5 (9%) 5 (9%)Middle ThirdMiddle Third 0 (0%) 0 (0%) 6 (9%)6 (9%) 1 (4%) 1 (4%)Outer ThirdOuter Third 2 (11%) 2 (11%) 11 (19%) 11 (19%) 22 (34%) 22 (34%)

Creasman et al. 1987Creasman et al. 1987

Lnn-Metastasen - TumorgrösseLnn-Metastasen - Tumorgrösse

Depth of Inv.Depth of Inv. <2cm (%)<2cm (%) >2cm (%) >2cm (%) Surf. (%) Surf. (%)

NoneNone 0/17 (0) 0/17 (0) 0/8 (0) 0/8 (0) 0/0 (0) 0/0 (0)<50%<50% 0/27 (0)0/27 (0) 5/41 (12) 5/41 (12) 2/9 (22) 2/9 (22)>50%>50% 2/9 (22)2/9 (22) 6/23 (26) 6/23 (26) 4/8 (50) 4/8 (50)

Schink et al. 1987Schink et al. 1987

Paraaortale Lnn-MetastasenParaaortale Lnn-MetastasenDepth of Inv.Depth of Inv. G1 (n=180)G1 (n=180) G2 (n=288)G2 (n=288) G3 (n=153) G3 (n=153)

Endometrium Endometrium 0 (0%) 0 (0%) 1 (3%) 1 (3%) 0 (0%) 0 (0%)Inner ThirdInner Third 1 (1%) 1 (1%) 5 (4%) 5 (4%) 2 (4%) 2 (4%)Middle ThirdMiddle Third 1 (5%) 1 (5%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)Outer ThirdOuter Third 1 (6%)1 (6%) 8 (14%) 8 (14%) 15 (23%) 15 (23%)

Creasman et al. 1987Creasman et al. 1987

PrognosefaktorenPrognosefaktoren AlterAlter

– young women better prognosis (stage, grading)young women better prognosis (stage, grading) Histo Histo 52/388 (13%) (Wilson 1990) 52/388 (13%) (Wilson 1990)

adenosquamous, clear cell, USPC, adenosquamous, clear cell, USPC, undifferentiatedundifferentiated

33% vs. 92% 5-yr OS33% vs. 92% 5-yr OS Stadium, Grading, LVSIStadium, Grading, LVSI Spülzytologie+:Spülzytologie+: 10.8%-22% (7 studies, n=1541)10.8%-22% (7 studies, n=1541) ER+, PR+ER+, PR+ better prognosis (Palmer et al. 1988)better prognosis (Palmer et al. 1988) DNA-PloidieDNA-Ploidie aneuploid worse prognosis aneuploid worse prognosis

Treatment Stage I Treatment Stage I

Abdominal washingAbdominal washingTotal abdominal hysterectomy and bilateral Total abdominal hysterectomy and bilateral

oophorectomy (TAH-BSO)oophorectomy (TAH-BSO)full pelvic lymphadenectomyfull pelvic lymphadenectomy

>50% (Ic), poor histology, G3, G2>2cm, stage II >50% (Ic), poor histology, G3, G2>2cm, stage II paraaortic lymphadenectomy?paraaortic lymphadenectomy?

G2/3 outer third invasion, grossly positive pelvic nodes G2/3 outer third invasion, grossly positive pelvic nodes or adnexae, palp. paraaortic nodes (GOG-study, Morrow or adnexae, palp. paraaortic nodes (GOG-study, Morrow 1991)1991)

Therapie ITherapie I Adjuvant irradiation does not improve OSAdjuvant irradiation does not improve OSAdjuvant irradiation improves local controlAdjuvant irradiation improves local control

vault irrad. vault irrad. recurrences: 14%-1.7% recurrences: 14%-1.7% (Lotocki 1983)(Lotocki 1983)pelvic irrad. pelvic irrad. G3, Ic, II, pN+G3, Ic, II, pN+extended field irrad. extended field irrad. G2/3+outer third, aN+, G2/3+outer third, aN+,

multiple pN+multiple pN+whole adominal irrad. whole adominal irrad. perit., oment. metast., perit., oment. metast.,

+cytology?+cytology?

PORTEC PORTEC

n=715; Stadium I (G1 Ic, G2, G3 Ib)n=715; Stadium I (G1 Ic, G2, G3 Ib)adjuvant pelvic irradiation vs. no therapyadjuvant pelvic irradiation vs. no therapy

no lymphadenectomy; 46 Grayno lymphadenectomy; 46 Gray Lokalrezidive 4 vs. 14% (p<0.001)Lokalrezidive 4 vs. 14% (p<0.001) 5-YOS: 81 vs. 85% (p=n.s.)5-YOS: 81 vs. 85% (p=n.s.) complications: 25 vs. 6%complications: 25 vs. 6%

keine adjuvante Bestrahlungkeine adjuvante BestrahlungPrädiktiver Faktor: Alter >60yrsPrädiktiver Faktor: Alter >60yrs

PORTEC PORTEC

G1 Ia,b.........................keine IrradG1 Ia,b.........................keine IrradG1 Ic, G2 Ib..................Irrad >60 yrsG1 Ic, G2 Ib..................Irrad >60 yrsG2 Ic, G3………….………..IrradG2 Ic, G3………….………..Irrad

pelvic irradiationpelvic irradiation

G1 Ia, Ib, G1 Ic <60 yrs, G2 Ib <60 yrsG1 Ia, Ib, G1 Ic <60 yrs, G2 Ib <60 yrsvaginal vault irradiationvaginal vault irradiation

Stage II: surgery, combined Stage II: surgery, combined radiation/surgery, Wertheim-procedureradiation/surgery, Wertheim-procedure

Stage III: surgical removal of all macroscopic Stage III: surgical removal of all macroscopic tumortumor

Stage IV: combinationStage IV: combinationsurgery: local control - palliation, bowel; exenteration surgery: local control - palliation, bowel; exenteration

(sole bladder or rectum involvement)(sole bladder or rectum involvement) irradiation, progestins: 10% CR, 28% PR irradiation, progestins: 10% CR, 28% PR (Thigpen 1986; (Thigpen 1986;

n=331)n=331)chemotherapy: Carbo/Taxolchemotherapy: Carbo/Taxol

Therapie II Therapie II

Prognose 5-Jahres ÜberlebenPrognose 5-Jahres ÜberlebenGradeGrade Stage (%)Stage (%)

IaIa Ib Ib Ic Ic IIa IIa IIb IIb

11 92.392.3 94.1 94.1 83.2 83.2 86.1 86.1 72.772.722 89.789.7 84.9 84.9 79.8 79.8 71.8 71.8 71.171.133 81.581.5 76.3 76.3 68.3 68.3 65.9 65.9 49.049.0

Stage III-IV: 5-Year OS rates 0%-16% Stage III-IV: 5-Year OS rates 0%-16% (Aalders 1984)(Aalders 1984)Stage III ovary/tube only: 80% 5-Year OSStage III ovary/tube only: 80% 5-Year OS (Bruckman 1980) (Bruckman 1980)

UPSC/CCC/recurrentUPSC/CCC/recurrent

UPSC/CCC/recurrentUPSC/CCC/recurrent

Serös-papillärSerös-papillär Prognosis, treatmentPrognosis, treatment

50% of all relapses caused by UPSC & CC50% of all relapses caused by UPSC & CC subsequent breast cancer: 3.2% vs. 25% subsequent breast cancer: 3.2% vs. 25% (Geisler (Geisler

et al. 2001)et al. 2001) paclitaxel - III, IV, recurrent; n=20 paclitaxel - III, IV, recurrent; n=20 (Ramondetta et (Ramondetta et

al. 2001)al. 2001)– OR rate 77%; med. time to progess. 7.3 OR rate 77%; med. time to progess. 7.3

mosmos treat equivalent to ovarian cancer treat equivalent to ovarian cancer

(Carbo/Taxol) (Carbo/Taxol)