UterineUterine SarcomaSarcoma ChapterChapter 55

FredFred UeUelland,and, MMDD

Division of University of Kentucky UniveUniverrsitysity ofof KentuKentucckyky AnnualAnnual NewNew CancersCancers

140 128 120

100 84 82 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 (endolymphatic stromal myosis)

 Leiomyosarcom

 Angiosarcoma

 Fibrosarcoma – Mixed

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 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  – 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  Endogenous estrogen  Diabetes  Family history  Hypertension  Nulliparity  Granulosa cell tumors  Age  History of breast of  Infertility colon cancer   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%) *

+ *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% 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 , 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) +/- +/- 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

– 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 (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