TheThe AdnAdneexxaall MassMass andand EarlyEarly OOvarianvarian CanCanccerer

FredFred UelanUelandd,, MMDD UniversiUniversityty ofof KentucKentuckkyy GynGynecolecoloogicgic OncolOncolooggyy ““NeveNeverr givegive in.in. NNeverever givegive in.in. NeveNeverr,, neveneverr,, nnever,ever, nevernever-- inin nothinothinngg greatgreat oror smsmallall,, larglargee oror petpetttyy-- nevernever givegive in,in, exexceceptpt toto convictionsconvictions ooff hohonnoror andand goodgood sense.sense.””

Sir Winston Churchill OvarianOvarian TTuumorsmors WhoWho Cares?Cares?

 Surgical costs exceed $5,000,000,000 annually  144 million women in USA – 5-10% will undergo a surgical procedure for a suspected ovarian neoplasm during their lifetime  30 million women over age 50 – 17% develop cystic ovarian tumors – 2 million have persistent tumors RiskRisk ofof MalMaliignancygnancy

 ManagManageemmentent chalchalllengeenge isis anan accuaccurratatee riskrisk ofof malignanmalignanccyy aasssseesssmsment.ent.  RiskRisk ofof malignanmalignanccyy withinwithin anan ovarovariaiann neoplaneoplasmsm varivarieess wwithith age:age: – 10% in children – 15% in reproductive age women – 50% in postmenopausal women OvarianOvarian TTuumorsmors PremenPremenoopaupausasall WomenWomen

 NonNon--inflinflaammmmatoratoryy ovarianovarian ttumumorsors – 70% functional cysts – 20% neoplastic – 10% endometriomas  15%15% ofof oovarianvarian neoplaneoplasmsmss inin reproductivereproductive ageage wwomomeenn aarree mamalignantlignant  OtherOther – Inflammatory process, bowel OvarianOvarian TTuumorsmors PremenPremenoopaupausasall WomenWomen  FunctionalFunctional cystscysts – < 8 cm – Unilateral – Simple, unilocular on TVS – No ascites  InitialInitial reprepeeatat TTVSVS 66--88 weeksweeks  OCPsOCPs dodo notnot incrincreeasease likelihoodlikelihood ofof resolution,resolution, butbut mamayy dedeccrereaasese riskrisk ofof recurrecurrrenceence OvarianOvarian TTuumorsmors Spanos W. Am J Obstet Gynecol 1973

Type of Cyst # of Patients % Regressed under observation 205 72 Required exploratory laparotomy 81 28 Ovarian neoplasms 46 16 Benign epithelial 32 11 Benign teratoma 9 3 Malignant epithelial 4 1.4 Dysgerminoma 1 0.3 Endometriosis 28 10 Para-ovarian cyst 4 1.4 Hydrosalpinx 3 1 Functional cysts 0 0 OvarianOvarian TTuumorsmors Modesitt et al, Gyn Oncol 2003

SpontaneousSpontaneous ResoResollutioutionn 22612261 (69%)(69%) CystCyst ++ SSepteptuumm 537537 (17%)(17%) PersistentPersistent CCysystt 220220 (7%)(7%) CystCyst +Solid+Solid aarreeaa 168168 (5%)(5%) SolidSolid MasMasss 2121 (0.6%)(0.6%) RRememovedoved byby unreunrellatedated surgesurgeryry 4040 (1.2%)(1.2%) 3,2593,259 EndometriEndometrioomama MucinousMucinous CystadenomCystadenomaa MatureMature CCysystticic TeratomaTeratoma OvarianOvarian DyDyssgerminomagerminoma OvarianOvarian TTuumorsmors PostmenoPostmenoppauaussalal WomenWomen

 BenignBenign epithelialepithelial ttuumomorr  StrStromomalal ttuumormor – Granulosa cell – Fibroma – Thecoma  EpithelialEpithelial cancanccerer  MetMetaastatistaticc cancanccerer OvarianOvarian TTuumorsmors PostmenoPostmenoppauaussalal WomenWomen

 50%50% mmalignantalignant  AsAsyymptmptoommatiaticc ssiimmpleple cyscystt << 1010 ccmm wwithith nonormrmalal CCAA--125125 – serial TVS  “Any“Any ovarianovarian ttuummoror inin aa pospostmtmenopenopaausalusal wwomomanan thatthat doedoess notnot mmeeeett thethe aboveabove critercriteriiaa shouldshould bebe assassumumeded toto bebe mamalignant”lignant” – Antiquated? SerousSerous OOvvaarianrian CancerCancer WhoWho GGetsets RReeferredferred toto aa CCaancnceerr SpecSpeciialist?alist? BenefitsBenefits ofof SurgicalSurgical Staging?Staging?

 PatientsPatients inin whwhomom cocompmprrehensiveehensive surgicalsurgical stagingstaging conficonfirrmsms eearlarlyy--stagestage disdiseeasasee havehave aa betterbetter prognosisprognosis tthhanan thosethose whowho wweerree thouthougghtht toto havehave eeaarlyrly ssttageage disdiseeasease bbutut werweree unstagedunstaged  AccuraAccurattee identificidentificaationtion ofof wwoomenmen wwhhoo requirerequire adjuvantadjuvant cchheemothmotheerapyrapy AppropriateAppropriate StagingStaging

 WWomomeenn withwith earearlyly stagestage ovarianovarian ccancerancer – N=291  CCoomplemplettee surgisurgiccalal staging:staging: – 97% gynecologic oncologists – 52% general obstetrician/gynecologists – 35% general surgeons

McGowan L, et al. Obstet Gynecol 1985;65:568-72.

ReferralReferral PaPattternsterns

 Utah Cancer Registry: 848 new ovarian cancers diagnosed 1992-1998  Only 39% were ever seen by a Gyn Onc  Patients with advanced disease had significant survival advantage when managed by Gyn Onc (median survival 26 mo vs. 15 mo, p < 0.01)  Age < 40, age > 70, and residence in a rural area were not seen by a gynecologic oncologist

Carney ME, et al. Gynecol Oncol 2002;84:36-42. ValueValue ofof SpSpeecialcialiistssts

 Meta-analysis (18 studies) concluded marked benefit with Gynecologic Oncologist (Giede 2005) – Complete surgical staging with early stage disease – Optimal cytoreductive surgery with advanced disease – Improved median and overall survival  Others supporting GO involvement: – NCCN guidelines – SGO, ACOG – SOGC clinical practice guidelines – NIH consensus statement – London Medical Advisory statement SuggestiveSuggestive ofof MalignancyMalignancy ACACOOG,G, SSGGOO

 ExExamaminationination – Fixed or nodular  ImImagingaging studystudy – Mostly solid tumor or distant mets – Ascites  CACA--125125 – premenopausal > 200 – postmenopausal > 35 Im et. al. Obstet Gynecol , 2005 SoSo HHooww DoDo II KnowKnow WhoWho GGetsets ReferReferrreded aanndd WhoWho DoDoeesn’sn’tt??

ExExamaminationination ImImagingaging SerSerumum PelvicPelvic ExExamaminationination PelvicPelvic ExExamaminationination InaccuraInaccuracycy

 Patient age ≥ 55 – 30%  Patient weight ≥ 200 lb – 9%  Uterine weight ≥ 200 g – 16%

Ueland et al, Gyn Oncol 2005 SoSo HHooww DoDo II KnowKnow WhoWho GGetsets ReferReferrreded aanndd WhoWho DoDoeesn’sn’tt??

ExExamaminationination ImImagingaging SerSerumum PelvicPelvic ExExamam vs.vs. UltrasoundUltrasound Pelvic Exam Ultrasound P value

Patient age 0.30 0.74 < 0.001 ≥ 55 Patient wt 0.09 0.73 < 0.001 ≥ 200 lb Uterine wt 0.16 0.80 < 0.001 ≥ 200 g

Ueland et al, Gyn Oncol 2005 UltrasoundUltrasound DifferentiatDifferentiatiingng OvarianOvarian TumorsTumors

Author Number Prevalence Sens(%) Spec (%) PPV(%) PPV (at 20%)

Kobayashi, 1976 406 15 70 73 31 39

Hermann, 1987 241 21 82 93 75 73

Finkler, 1988 102 36 62 95 88 75

Benacerraf, 1990 100 30 80 87 72 62

Granberg, 1990 180 22 82 92 74 73

Sassone, 1991 143 10 100 83 37 59

Ueland, 2003 442 12 98 81 41 56

*Definition of (+) US varied with each author SonogSonogrraphaphiicc ChChaaractracteeristristicicss OvarianOvarian TumorsTumors

Benign Malignant  Unilateral  Bilateral  Simple (MI < 5)  Complex (MI ≥ 5)  Doppler – Partly solid – PI > 1.0, RI > 0.4 – Internal papillations – Peripheral flow  Doppler  No ascites – PI < 1.0, RI < 0.4 – Central flow  Resolution  Ascites  Persistence or growth KentuckyKentucky MMorphologyorphology IInndexdex Ueland et al Gyn Oncol 2003

 UK gynecologic ultrasound database  442 women with confirmed ovarian tumor – Morphology Indexing – Color Flow Doppler – Surgery

TumorTumor StruStrucctureture ScoreScore == 00 TumorTumor StruStrucctureture ScoreScore == 33 TumorTumor StruStrucctureture ScoreScore == 55 MorphologyMorphology IndexIndex TotalTotal ScoreScore (0(0--4)4)

100 90 80 70 60 50 % Benign 40 % Cancer 30 20 10 0 0 1 2 3 4 MorphologyMorphology IndexIndex TotalTotal ScoreScore (5(5--10)10)

100 90 92 80 83 70 77 60 50 % Benign 40 % Cancer 38 30 32 20 20 10 0 5 6 7 8 9 10 KentuckyKentucky MMorphologyorphology IInndexdex

 MIMI << 55 benignbenign

 MIMI ≥≥ 55 mamalignantlignant KentuckyKentucky MMorphologyorphology IInndexdex

 SensitivitySensitivity 0.9810.981  SpecificitSpecificityy 0.8070.807  PositivePositive predictivepredictive valuevalue 0.4090.409  NegativeNegative predictipredictivvee valuvaluee 0.9970.997  AccurAccuraaccyy 0.8280.828

Disease Prevalence = 12% WhatWhat aboutabout Doppler?Doppler? DopplerDoppler

Sens Spec PPV NPV MI 0.981 0.807 0.409 0.997 PI < 1.00 0.528 0.776 0.288 0.905

RI < 0.4 0.222 0.867 0.222 0.867 No flow 0.163 0.640 0.056 0.854 f0 = transmitted US frequency v cos θ = target velocity c = velocity of surrounding medium TVSTVS probeprobe

θθ

vesselvessel

∆∆ff == 2f2f0 vv (cos(cos θθ)) // cc DopplerDoppler RReeproducibilitproducibilityy

∆∆ff == 2f2f0vv (cos(cos θθ)) // cc  IsIs thethe angleangle ofof insonationinsonation constantconstant ((θθ))?? – 2 to 3 fold change for ∆ θ (from 30°-80°)* – Optimal angle and frequency depends on depth of vessel  IsIs eeaachch DopplerDoppler mmeasureasureemmentent ofof thethe ssameame vessel?vessel? AreAre thesthesee vesselsvessels ststrraighaightt??

*J Vasc Surg 1990; 11:688-94 UltrasoundUltrasound ConclusionConclusionss

1. MIMI ≥≥ 55 40% malignant 2. MIMI << 55 0.3% malignant 3. DopplerDoppler addsadds littllittlee OtherOther IImagingmaging

 CTCT scanscan abdabdomomenen andand pelvispelvis – IV and PO contrast – CT-guided biopsy  Accuracy exceeds 90% for solid tumors  What about high risk cystic tumors?  MRIMRI  PETPET CTCT ScanScan

Omental cake

Ovarian tumor SoSo HHooww DoDo II KnowKnow WhoWho GGetsets ReferReferrreded aanndd WhoWho DoDoeesn’sn’tt??

ExExamaminationination ImImagingaging SerSerumum CACA--125125

 Antigen derived from: – coelomic epithelium (pericardium, pleura, peritoneum) – mullerian epithelium (tubal, endometrial, endocervical)  Two different assays – Assay I < 35 U/ml – Assay II < 20 U/ml  Expressed by 80% non-mucinous EOC  FDA-approved to follow the progress of cancer treatment – Neither a screening nor a diagnostic test  Normal CA-125 values (low sensitivity) – 50% of early stage ovarian cancers – 20-25% of advanced stage ovarian cancers – Mixed mullerian tumors, clear cell cancers CACA--125125 NonNon--specificspecific

 Benign ovarian cysts  Heart failure  Uterine leiomyomata  Liver failure  Pelvic inflammatory  Renal failure disease  Peritoneal tuberculosis  Endometriosis  Diverticulitis  Adenomyosis  Pancreatitis  Pregnancy  Recent abdominal or  Menstruation thoracic surgery  Ascites  Other malignancies SoSo Again,Again, WWhathat ShouldShould II Do?Do?

 Surgical removal of ovarian tumor if symptomatic or high risk imaging  Sonographic observation if asymptomatic, low risk MI – 6 wks, 3 mo, 6 mo  CT scan abdomen/pelvis if suspect malignancy HighHigh RiskRisk IndicatorsIndicators

 UltrasoundUltrasound (Ueland et al, 2003; Sassone et al, 1991) – Internal papillary projection – Cystic and solid, solid – Ascites  CTCT ScanScan//MRIMRI (Kurtz et al 1999) – Cystic and solid, solid – Ascites  CACA--125125 (Roman et al, 1997) – Premenopausal >100 U/mL – Postmenopausal >35 U/mL LaparoscopyLaparoscopy OvarianOvarian TTuumormor LapaLaparroscooscopypy GGuiduideelilinneses

 Prepared for laparotomy – Informed consent  Surgical technique – Abdominopelvic inspection, biopsy – Washings – Tumor removal and containment with endoscopic bag – No morcellation, please – Intraoperative frozen section PrinciplesPrinciples OvarianOvarian TTuumormor LapaLaparroscooscopypy

 Be principled – Do not delay treatment to “confirm diagnosis” at laparoscopy – For high risk tumor, consider referral to specialist – Informed consent for surgery includes explanation of alternatives – “What would I do for my mother?” OvarianOvarian CCaancerncer IncidenIncidenccee andand MortaliMortalityty

Data from the American Cancer Society

200 Kentucky deaths from ovarian cancer in 2006 StageStage andand OutcomeOutcome

StageStage PercentPercent SurvivalSurvival II 2424 95%95% IIII 66 65%65% IIIIII 5555 1515--30%30% IVIV 1515 00--20%20% OverallOverall 50%50%

American Cancer Society OvarianOvarian CCaancerncer SSymptomsymptoms

 SurveySurvey distributeddistributed toto 15001500 wwoomenmen wwhoho subscribesubscribe toto COCONNVERSATIONSVERSATIONS!!,, aa newslettenewsletterr aboutabout ovarianovarian ccaarcinrcinomomaa  17251725 surveyssurveys retureturrnedned  MedianMedian ageage 5252 yyeeaarsrs  70%70% hadhad stagestage IIIIII oror IVIV disdiseeasease

Goff, B, et al. Cancer 2000;89:2068-75. OvarianOvarian CCaancerncer SSymptomsymptoms

 95%95% ofof patientspatients reportedreported havinghaving ssyymmptptoomsms priorprior toto diagnosisdiagnosis – Abdominal 77% – Gastrointestinal 70% – Pain 58% – Constitutional 50% – Urinary 34% – Pelvic 26% OvarianOvarian CCaancerncer SSymptomsymptoms

 AsAsyymptmptoommatiaticc prpriioror toto diagnosisdiagnosis – Stage I/II – 11% – Stage III/IV – 3%  WWomomeenn whowho ignoredignored theirtheir symsymptptomsoms werweree momorere likelikellyy toto bbee diagnoseddiagnosed withwith advancedadvanced stagestage diseadiseassee OvarianOvarian CCaancerncer SSymptomsymptoms

 Factors associated with delay in diagnosis – Omission of pelvic exam at first visit – Multiple symptoms – Missed diagnosis: no problem, depression, stress, IBS, or gastritis – No imaging or CA-125 – Younger age  Type of health care provider seen initially, insurance, and specific symptoms did not correlate with a delay in diagnosis CancerCancer HistoryHistory

 Ovarian cancer  Breast cancer  Endometrial cancer  Other  BRCA 1,2  HNPCC ConclusionConclusionss

 IdentifyIdentify patientspatients aatt riskrisk – Cancer history, symptoms, other  OvarianOvarian exexaamminatinatiionon isis oftenoften inaccurateinaccurate – Age, obesity, large uterus  StratifyStratify riskrisk withwith ultrasound,ultrasound, otherother iimmagingaging  InfoInforrmedmed surgisurgiccalal consentconsent  ConsiderConsider laparoslaparosccopicopic approachapproach ifif feasiblefeasible ConclusionConclusionss

 ReferralReferral forfor anan adnexaladnexal ttumumoror dependependdss onon riskrisk ofof mmalignancalignancyy assesassesssmmentent  WhenWhen aa GGynyn OnOncc perfoperforrmmss surgesurgerryy forfor earearllyy stagstagee ovariaovariann cancanccer,er, patpatiientsents araree mmoorree likelylikely toto bebe accuaccurraattelyely ssttagedaged andand rrececeeiveive properproper adjuvantadjuvant trtreeaatmtmentent "Le"Lett usus havehave faithfaith tthathat rightright mmakeakess mimight,ght, andand inin thatthat faith,faith, letlet usus,, toto thethe end,end, dadarree ttoo dodo ourour dutyduty asas wwee understandunderstand itit..""

Lincoln's's CooperCooper Institute Address February 27, 1860.