UterineUterine SarcomaSarcoma ChapterChapter 55
FredFred UeUelland,and, MMDD
Division of Gynecologic Oncology University of Kentucky UniveUniverrsitysity ofof KentuKentucckyky AnnualAnnual NewNew CancersCancers
140 128 120
100 Uterus 84 82 Ovary 80 Cervix 60 Vulva 42 40 Other
20 13
0 UniveUniverrsitysity ofof KentuKentucckyky AnnualAnnual RecurrentRecurrent CancersCancers
20 20 17 15 15 Uterus 10 Ovary 10 Cervix Other 5
0 OveOverrviewview
33--5%5% ofof allall uterineuterine mmalignancialignancieess 22 perper 100,000100,000 wwoomemenn inin UUSSAA AriseArise frfromom endendoommetrialetrial ssttrromaoma,, glaglanndsds oror uterineuterine mmuscusclle.e. OOttherher memesencsenchymahymall tutumormorss areare rararree 2020 yearyearss afterafter pelpelvvicic radiotheraradiotherappyy BlackBlack wwomeomenn mmoorree ccoommmmonon ClassifClassifiicaticatioonn OberOber,, 19591959
HHoomologousmologous – Pure
Stromal sarcoma (endolymphatic stromal myosis)
Leiomyosarcom
Angiosarcoma
Fibrosarcoma – Mixed
Carcinosarcoma ClassifClassifiicaticatioonn OberOber,, 19591959
HeterologousHeterologous – Pure
Rhabdomyosarcom
Chondrosarcoma
Osteosarcoma
Liposarcoma – Mixed
Mixed mullerian tumor (MMT) ClassifClassifiicaticatioonn SGOSGO EndEndoorsedrsed
LeiLeiomomyoyossarcarcoommaa EndEndoomemettrialrial StrStromomalal SaSarrccomomaa MixedMixed hhoomologousmologous MullerMulleriianan SaSarrcocomamass ((cacarrcinosarccinosarcomaoma)) MixedMixed heterologousheterologous MullerMulleriianan SaSarrcocomamass (m(mixedixed mmesodeesodermrmalal sasarrccomaoma)) OtherOther uterinuterinee sasarrcocomamass LeLeiiomyosomyosaarcomarcoma MetastaticMetastatic PotePotenntialtial
Mitoses Atypia Diagnosis Metastatic
1-4 Any Myoma Very low
5-9 None Myoma with high mitotic Very low activity 5-9 Gr 1 Smooth muscle tumor of Low uncertain malignant potential 5-9 Gr 2,3 LMS Moderate
≥10 Gr 1 LMS High
≥ 10 Gr 2,3 LMS Very high UterineUterine SSaarrcocomama
Endometrial stromal sarcoma – Age 45 – Ifosfamide Leiomyosarcoma – Age 55 – Adriamycin/Ifosfamide – Gemcitabine/Taxotere (GOG #131-G) Mixed mullerian tumor – Age 65 – Ifosfamide v. Ifos/Taxol (GOG #161) – Carbo/Taxol (GOG #232-B) UterineUterine SarcomaSarcoma EndometriaEndometriall CancerCancer RiskRisk FactorsFactors Anovulation-PCO Early menarche Exogenous estrogen Late menopause Endogenous estrogen Diabetes Family history Hypertension Nulliparity Granulosa cell tumors Age History of breast of Infertility colon cancer Tamoxifen Menstrual irregularities EndometrialEndometrial CaCanncercer RelativeRelative RisRiskk
ObesityObesity (20-50 lb) 33 ObesityObesity (>50 lb) 1010 NulliparityNulliparity 22--33 LateLate mmenopauseenopause 2.42.4 DiabeteDiabetess memellitusllitus 2.82.8 TTamamoxifenoxifen 7.57.5 UnopposedUnopposed ERTERT 9.59.5 PresentationPresentation PostmenoPostmenoppausalausal BleedBleediingng
Etiologic Factor Lahey Clinic (%) Mayo Clinic (%) ERT 27 27 Atrophy 23 20 Cancer 19.5 18 EAC 13 16 Cervix 4 1 Other 2.5 1 Atrophic vaginitis 10 9 Endometrial polyps 7 23 Cervical polyps 6.5 14 EndometriaEndometriall CancerCancer withwith PMBPMB
Age Total cases Total # EAC % Cancer <50 34 0 0 50-59 161 15 9.3 60-69 92 15 16.3 70-79 43 12 27.9 >80 5 3 60 AtypicalAtypical EnEnddometrialometrial CellsCells EndometriaEndometriall CellsCells onon PapPap PostPostmenomenoppauaussalal
Cells Total Hyperplasia Polyps Cancer
Normal 74 9 1 1 (1%) +
Atypical 22 0 1 5 (23%)
Malignant 31 1 0 23 (74%) *
+Ovarian cancer *2 cervical, 1 breast, 1 ovary, 19 endometrial cancers HormonesHormones aandnd EndometriaEndometriall CancerCancer HistopathologyHistopathology LeiomyosaLeiomyosarrcomacoma LeiomyosaLeiomyosarrcomacoma
Bizarre nuclei LeiomyosaLeiomyosarrcomacoma UterineUterine SarcomaSarcoma UterineUterine SarcomaSarcoma UterineUterine SarcomaSarcoma LeiomysarLeiomysarccomaoma EndometrialEndometrial CaCanncercer HistologyHistology
Histopathology Frequency Survival Endometrioid 66% 88% Adenoacanthoma 16% 91% Adenosquamous 5% 62% Papillary serous 8% 63% Clear cell 3% 43% Secretory 2% 89% SurvivalSurvival UterineUterine CaCanncercer StagingStaging anandd PrognosisPrognosis UterineUterine SSaarrcocomama FiveFive YearYear SurvivalSurvival (%)(%)
StagStagee II SStatagege IIIIII ESSESS 9898 3838 LMSLMS 5050 88 MMTMMT 5050 <10<10 UterineUterine SSaarrcocomama %% FiveFive YeYeaarr SuSurrvivavivall
Stage I Stage III
ESS 98 38 LMS 50 8 MMT 50 <10 EndometrialEndometrial CaCanncercer
% Distribution % Survival StageStage II 7733 8686 StageStage IIII 1122 6666 StageStage IIIIII 1122 4444 StageStage IIVV 33 1616
Petterson F, ed: Annual report on treatment Gyn Ca, vol 22; Stockholm, 1994, FIGO EndometrialEndometrial CaCanncercer FiveFive yearyear survival,survival, %%
86 90 80 70 66 60 Stage 1 50 44 Stage 2 40 Stage 3 30 Stage 4 16 20 10 0 EndometrialEndometrial CaCanncercer PrognosisPrognosis
StageStage ((II--IV)IV) DepthDepth ofof invasioninvasion (A,B,(A,B,CC)) HistologicHistologic didiffferentiationferentiation (grade(grade 1,2,1,2,33)) HistologicHistologic cellcell ttypeype LLyymphvasculmphvasculaarr ssppaceace invasioninvasion PelvicPelvic ccytologyytology EndometrialEndometrial CaCanncercer ClinicalClinical StaStagging,ing, FIFIGGOO 19711971
Stage I Confined to corpus IA Sounds to ≤ 8cm IB Sounds to > 8cm Stage II Cervical involvement ECC, cervical biopsy, gross involvement Stage III Beyond uterus, confined to pelvis Stage IVA Bladder or rectal mucosa Stage IVB Extrapelvic metastasis EndometrialEndometrial CaCanncercer SurgicalSurgical StagingStaging,, 19881988
TotalTotal hysthysteerectrectomomy,y, bilabilatteraerall salpingosalpingo-- oopoophhorectorectomomyy PelvicPelvic washingwashing PelvicPelvic andand parparaa--aaoorticrtic lymlymphph nodenode ssamamplingpling OmOmententeectctomyomy,, upperupper abdabdomominalinal biopsiesbiopsies andand washingswashings forfor serousserous histologyhistology SurgSurgiicalcal RReeccommendatiommendationonss GGOOGG Manual,Manual, 19971997
PrognosticPrognostic notnot therapeutictherapeutic RRememovaloval ofof allall sususspiciouspicious nodesnodes RRememovaloval ofof oneone--halfhalf ofof pelvicpelvic nnoodesdes PAPA nodesnodes frfromom inferiorinferior mmesentesenteericric aarrterteryy toto ccoommmmonon iliiliaac,c, whwheenn indicatedindicated RecRecoommmemendednded forfor >> 50%50% invasioninvasion oror gradegrade 33 lesionslesions So,So, WhenWhen DDoo II DoDo thethe NNodes?odes?
Balance between morbidity and utility – Lymphadenectomy is not risk free Preoperative grade – Accurate in 85% of cases Intraoperative evaluation – Frozen section 90% accurate for MM invasion Ueland’s “counsel” – IA gr 1,2 and IB gr 1 insufficient nodal risk to justify additional expense and morbidity EndometrialEndometrial CaCanncercer StageStage II
StageStage II ConfConfiinedned toto uterusuterus
IIAA LLimimitedited toto endendomeometritriuumm IBIB InnerInner ½½ mmyyoommetretriuiumm ICIC OuterOuter ½½ mmyyoommeettrriuiumm FiveFive yearyear susurrvivalvival (%)(%) StageStage II
88 90 78 80 67 70 60 IA 50 IB 40 IC 30 20 10 0 DifferentiationDifferentiation andand DepDeptthh
Grade 1 Grade 2 Grade 3
IA 24 11 11 88% IB 53 45 35 88% IC 10 20 42 UterineUterine SarcomaSarcoma SurvivalSurvival
5-year survival Stage Cell Type S S+R R I MMS 52 % 48 % 29 % LMS 58 % 75 % 33 % ESS 47 % 88 % 50 % II-IV MMS 5 % 16 % 0 % LMS 0 % 13 % 0 % ESS 0 % 33 % 0 % UterineUterine SarcomaSarcoma %% SiteSite ofof RecurRecurrrenceence MMT-Ho MMT-He LMS N=165 N=134 N=57 Pelvis 9 12 7
Distant 33 46 56
None 58 42 37 LymphLymph NoNoddee MetastaMetastasseses ((%)%) EarEarllyy StageStage UterUteriinene SarcomaSarcoma Major, Cancer 1993
20 20
18 16 16
14
12
10
8
6 4 4
2
0 MMT MMT MMT MMT LMS Homo Hetero PelvicPelvic NNoodede MetastaMetastasseses ((%)%) StageStage II
18 18 16 14 12 Grade 1 9 10 Grade 2 8 Grade 3 6 3 4 2 0 FiveFive yearyear susurrvivalvival (%)(%) StageStage II
94 95
90 88
Grade 1 85 Grade 2 79 80 Grade 3
75
70 EndometrialEndometrial CaCanncercer StageStage IIII
StageStage IIII CervicalCervical involvinvolveemmentent
IIIIAA EndocervicalEndocervical glaglanndsds IIIIBB CervicalCervical strstromomaa EndometrialEndometrial CaCanncercer StageStage IIIIII
StageStage IIIIII ExtraExtra--uterineuterine didisseeaasese
IIIIIIAA Serosa,Serosa, adnexa,adnexa, ((++)) ccytologyytology IIIIIIBB VaginalVaginal memetastasttasaseess IIIIIICC LLyymphmph nodenode mmetaetasstasestases EndometrialEndometrial CaCanncercer StageStage IVIV
StageStage IIVV Regional,Regional, distantdistant memetastasttasesases
IVIVAA BowelBowel oror bladderbladder mumucosacosa IVIVBB DistantDistant memetastasttaseasess TreatmentTreatment PrimaryPrimary TrTreeatmentatment
SurgerySurgery RadiotherapyRadiotherapy – Medically inoperable – 15% survival decrement each stage HoHormrmoneone thetherrapyapy – Only for grade 1 tumors in young women – Dilatation and curettage Confined to Uterus Extra-uterine disease
Surgical staging Resection if possible (Omit LN if extrauterine ds)
Stage I,II ESS Stage I,II other Stage IIIC, IV Stage III ESS Stage IIIA,B other No further therapy
Whole pelvic XRT XRT (+ Hormone Tx for ESS) +/- Chemotherapy +/- Hormone therapy Recurrence
No prior XRT Prior XRT
Vaginal Pelvic Extra-pelvic Surgery +/- Chemotherapy +/- Hormone therapy Surgery Whole pelvic XRT
WAR XRT +/- Chemotherapy +/- Hormone therapy ChemotherChemotheraapypy NCCNNCCN Guidelines,Guidelines, 20042004
Ifosfamide for carcinosarcoma Doxorubicin for LMS Single agent cisplatin, Taxol, Taxotere, Gemzar Hormone therapy – Megace – Provera – Tamoxifen – GnRH analogs AdjuvantAdjuvant TTrreatmenteatment
Radiation therapy – High risk (IIB, III) Chemotherapy – UPSC, III and IV Chemoradiation – Residual pelvic disease Sequential – Advanced, persistent Hormonal therapy EndometrialEndometrial CaCanncercer RecentRecent GGOOGG StStuudiesdies
GOGGOG #209#209 StageStage IIIII,II,IVV,, RRecuecurrrentrent – Cisplat/Adria/Taxol vs. Carbo/Taxol GOGGOG ## 232232--BB UterineUterine MMMTMT – Carbo/Taxol GOGGOG #131#131--GG UterineUterine LMSLMS – Gemcitabine/Taxotere PelvicPelvic RadiationRadiation FieldsFields
LL5/S/S1 toto inferiorinferior bboorderrder ofof obturatorobturator ffororamamenen 22 cmcm llateaterralal toto obturatorobturator fossafossa – 15 cm wide ParaPara--aorticaortic windowwindow
– T12 to L5/S1 – 10 cm wide – Salvage 37% with PA window (Morrow ’91) AdjuvantAdjuvant RRaadiotherapydiotherapy
Decreased vaginal and pelvic recurrence No change in overall survival – Morrow, Gyn Onc 1991 PORTEC European RCT (Creutzberg, Lancet 2000) – 715 patients, intermediate risk cancers – Decreased pelvic recurrence (4% v. 14%) – Overall survival same (81% vs 85%) – 80% salvage with XRT in observation arm – ↑ Complication rate for XRT (25% vs 6%) AdjuvantAdjuvant RRaadiotherapydiotherapy StraughnStraughn et.et. al.al. GGynyn Onc,Onc, 20022002
Retrospective, single center Stage I endometrial cancer (N= 613) 53% low risk (IA, IB g1) – No radiation – 2% recurrence, 6/7 pelvic 47% intermediate risk (IB g2,3, IC) – 70% no radiation – 8% recurrence (no XRT), 4% recurrence (XRT) – 56% pelvic recurrence – 8/9 recurred in pelvis, 7 salvaged RadiationRadiation MMorbidityorbidity WholeWhole PelPelvvicic
5%5% entericenteric mmorbidityorbidity 1515--25%25% entericenteric fofolllowinglowing llymymphadenectphadenectomomyy 1010 fofolldd ↑↑ ccoomplimplicacationtion raterate forfor wholewhole pelvispelvis vs.vs. cuffcuff HormoneHormone TThherapyerapy
70%70% grgr 11 ER/PRER/PR ((+)+) 55%55% grgr 22 ER/PRER/PR ((+)+) 41%41% grgr 33 ER/PRER/PR ((+)+) ResponseResponse toto progesteroneprogesterone – PR (+) = 80% – PR (-) = 5% AdjuvantAdjuvant HHoormonermone TheTherrapyapy RCTRCT datadata
NoNo survivalsurvival advantageadvantage toto adjuvantadjuvant hohorrmonemone ththeeraprapyy followingfollowing surgerysurgery – Vergote ’89 – Britain ’88 – Lewis ‘74 EndometrialEndometrial CaCanncercer ChemotheraChemotherappyy
Stage III, IV, recurrent No RCT data saying combo > single agent Cisplatin/Adriamycin RR= 50-75% Adriamycin/Taxol
GOG # 163 No survival difference Cisplatin/Adriamycin/Taxol
GOG # 177 Survival advantage, but toxic
GOG # 184 Closed ‘04, unpublished
GOG # 209 Active SurveillanceSurveillance
LowLow riskrisk ((IIAA,, IBIB gg11--2)2) – Annual evaluation InteIntermrmedediiateate riskrisk ((IBIB g3,g3, ICIC,, IIIIA)A) – 4 to 6 months HighHigh riskrisk (II(IIBB,, CC,, IIII,II, IIV)V) – 3 months – CXR – CT scan as indicated CoConnclcluusisioonsns
1. MostMost endendomometretriialal cancecancerrss prepressentent withwith bleeding,bleeding, atat eearlarlyy stagestage,, andand withwith favorablefavorable outcoutcomomee 2. SurgicalSurgical stagingstaging isis iimpormporttantant 3. TrendTrend towardtoward llessess adjuvantadjuvant radiotherapyradiotherapy forfor ssttageage II cancanccersers 4. AdvancedAdvanced stagestage,, ccllearear cellcell andand UPSCUPSC poorlypoorly rresponsiveesponsive toto therapytherapy