AdnexalMass

EavKLim,DOFACOOG

PresenterDisclosure

• IhavenoConflictofInteresttodisclose

• IhavehasnoFinancialorScientificdisclosures

• IhavehasnoOff-Labeldisclosures.

LearningObjectives

• Beabletodifferentiateadnexalmasses• Determinewhicharebenignandwhicharemalignant• Understandwhichtestingmodalitytouse• Beabletodeterminebesttreatmentapproach

• Uterineadnexaconsistofovaries,fallopiantubes,anditssurroundingvascular,lymphaticandconnectivetissues• Estimatedthatbetween5-10%ofwomenintheirlifetimewillundergosurgeryforpotentialovarianneoplasm• Prevalenceofadnexallesionsinclinicallyasymptomaticwomenhasbeenapproximately2.5%to8%

ClinicalApproach

• Determinetheetiologyoftheadnexalmass• Mustmakesurethattheconditionisnotemergentorpoisestocauseserioushealthissues• Decisionshouldbeguidedby• Ageofpatient• Reproductivestatus• Locationofmass

AnatomicLocation

• Ovary• Physiologiccyst• Benignovarianneoplasm• Ovariancancerormetastatic

• Fallopiantube• Tuboovarianabscess• Ectopicpregnancy• Hydrosalpinx• Fallopiantubecancer

• Connective&surroundingtissues• Paratubalorparaovariancyst• Broadligamentleiomyoma

DifferentialDiagnosis

• Gynecologic• Non-Gynecologic

DifferentialDiagnosis

• Gynecologic• Benign

• Functionalcyst,endometrioma,maturecysticteratoma,thecaluteincyst,luteomaofpregnancy,corpuslutealcyst,hydrosalpinx,ectopic,leiomyoma,tubo-ovarianabscess,paratubalcyst

• Malignant• Epithelialovariancancer,borderlinetumors,germcelltumor,sex-stromaltumor,metastatic

• MostcommonmetastaticdiseasewouldbefrombreastorGI

DifferentialDiagnosis

• Non-Gynecologic• Benign

• Appendicealabscess,diverticularabscess,bladder/ureteraldiverticulum,pelvickidney,peritonealcyst,ovarianremnant

• Malignant• Appendicealtumor,boweltumor,metastatic(breast,lung,lymphoma),retroperitonealsarcoma

AgeGroupStratification

• Fetuses• Children• Adolescents• Premenopausal• menopausal

AgeGroupStratification

• Fetuses• Increaseinfrequencywithgestationalage• Increaseinpatientswithunderlyingdiabetesmellitus,preeclampsia,rhesusisoimmunization

• Newborn• Mostlikelyphysiologicalthatisduetocirculatingmaternalhormonesinutero

• Differentials• Genitourinary:reproductivetractanomalies,urinarytractobstruction,urachalcyst

• Gastrointestinal:mesenteric/omentalcyst,volvulus,colonicatresia,intestinalduplication,

• Others:Choledochal,splenic,orpancreaticcyst,lymphangioma

AgeGroupStratification

• Children• Physiologiccystareuncommonduetodecreaseingonadotropinovarianstimulatinghormones

• Ifpresent,mostsimplecystsareduetoenlargingcysticfollicle

• Adolescent• Developscomplexandsimplecyst• Mostsimplecystsareduetofailureofmaturingfollicletoovulateandinvolute

• Ovarianneoplasms(benign&malignant)accountsfor1%ofalltumorsinchildrenandadolescent

• Lessthan5%ofovariancanceroccursinthisagegroup

AgeGroupStratification

• Inwomen<25yearsold,ovarianmalignancywouldbethemostcommongynecologicmalignancy• Germcelltumorswouldbethemostcommon,comprisingofapproximatelyone-halftotwo-thirdsofovarianneoplasmupto18yearsoldascomparedtoadultwomenwhichwouldbeapproximatelyone-fifth• Ingirls<9yearsold,approximately80%ofovarianneoplasmsaremalignant• Epithelialovariancancersarerareintheprepubertalagegroup

AgeGroupStratification

• Premenopausalwomen• Adnexalmassesarestimulatedbyhormonesspecificinthisagegroup• Ovarianortubalmalignanciesareuncommon,however,germcelltumorswouldbethemostcommonwithpeakagebetween10and30

Premenopausal

• Functional/corpuslutealcyst• Arisewhenrupturedoesnotoccurandthefolliclecontinuestogrow• Canbecomehemorrhagic• Typicallyresolvesonitsown• Cancausecomplicationsassociatedwithtorsion,hemorrhage,orpain

• Polycysticovaries• Enlargedovarieswithmultiplesmallfollicularcysts• Rotterdamncriteria

• Thecaluteincysts• LuteinizedfolliclecystsasaresultofhyperstimulationfromelevatedhCGorincreasesensitivity

• Bilateral,multiseptatedinwomenwithGTD,multiplegestation,ovarianhyperstimulationorpregnancycomplicatedbyfetalhydrops

• Mostareasymptomatic,butcancausematernalvirilization,hyperemesisgravidarum,preeclampsia,orthyroiddysfunction

Premenopausal

• EctopicPregnancy• Seenasanadnexalmassonultrasound

• CorpusLuteumofpregnancy• Associatedwithearlyintrauterinepregnancy

• Luteoma• Non-neoplasticovarianmassassociatedwithpregnancy• Solidcomponent• Resolvesspontaneouslyafterdelivery• Shouldbesuspectedinthepresenceofsolidadnexalmass,maternalhirsutismorvirilization

Premenopausal

• Stimulatedbyreproductivehormones• Endometrioma

• Relatedwithendometriosis• FirstdescribedbyKarlFreiherrVonRokitansky1860• Originaltheories:Meyer,Novak,Halban,Sampson• Histopathologywithendometrialglandsandstromaalongwithhemosiderinmacrophages

• Ultrasound:“groundglass”internalechos• Leiomyoma

• Benignneoplasmofsmoothmuscleorigin• Usuallyarisesfromuterus• Canarisefrombroadligament

Premenopausal

• Infectious/Inflammatory• Tubo-ovarianabscess

• Resultsfromuppergenitaltractinfection• Fever• Abdomino-pelvicpain• Purulentcervicaldischarge• Palpablemass• Cervicalmotiontenderness

• Hydrosalpinx/pyosalpinx• UntreatedorundertreatedofPIDresultinginscarring• Collectionoftubalsecretionorpus• Contributetoinfertility

Premenopausal

• Benignneoplasm• Serousormucinouscystandeoma

• Mostcommonbenignovarianneoplasm• Thin-walled• Uniormultilocular• Rangesfrom5to20cm

• Mucinous• Lesscommon• Multiloculated• Largesize• 5%bilateral• Collectsmucinintheircytoplasm• ResemblesendocervicalorGIepithelium

• Serous• Morecommon• 20to25%bilateral• Similartofallopiantubelining

Premenopausal

• Benignneoplasm• Maturecysticteratoma

• Commonin2nd to3rd decadeoflife• Celllayersfromectoderm,endoderm,mesoderm• US:complexmass,hyperechoiccontents,fluid,areasofacousticshadowing

• Bilateralin10to15%ofpatients• Endosalpingiosis

• Non-neoplasticectopiccysticglandsoutsideofthefallopiantubethatarelinedwithfallopiantypeciliatedepithelium

• Paraovarian/paratubalcyst• Originatefromremnantsofparamesonephricormesonephricducts• Hydatidcystofmorgagniaremostcommon• Nodatatosuggestthesecystaremalignantoritsprevalence• Keytodiagnosisisnotedasimplecystlocatednexttotheovaryonultrasound

Premenopausal

• Malignantadnexalmass• Incidencerangesfrom6to11%• Mostlyderivedfromepithelialcells,butcanarisefromgermcell,sex-stromalandmixed• Canbenon-gynecologicmetastaticcancer

• Krukenbergtumor

Menopausal

• Mostadnexalcystarebenign• However,upto30%canbemalignantinpatientsovertheageof50• MalignancycanbegynecologicoriginsuchasendometriumormetastaticfrombreastorGI

• Canhavesimilaretiologiesofadnexalcystforpremenopausalwomen• Simplecystsarecommonandarefrompersistentphysiologic/functionalcyst• Characteristicforbenignversusmalignantissimilartothoseofpremenopausal,howeveronemusthavealowerthresholdforsuspicion

Menopausal

• Neoplasms• IncludesEpithelial(75%),Sex-stromal(15%),andGermcell(10%)• Epithelialcarcinomaismostcommonhistologicaltypeinthisagegroupandencompassesapproximately90%ofovarian,peritoneal,andtubalcarcinoma• Ithasbeenproposedthatoriginofhighgradeseroustumorsmayoriginatefromfallopiantubeprecursors• Averageageisapproximately60yearsold• IncludevagueGIsymptoms:dyspepsia,earlysatiety,anorexia,constipation,andbloating

Menopausal

• Epithelial• Highgradeserouscarcinoma(70-80%)• Endometrioid(10%)• Clearcell(10%)• Mucinous(3%)• Lowgradeserouscarcinoma(5%)

• Sex-stromal:oftenproducesestrogen/androgen• Granulosacell• Fibroma• Thecoma• Sertoli-Leydig

• Germcell• Dysgerminoma• Endodermalsinustumor• Immatureteratoma• Gonadoblastoma• Choriocarcinoma• Seminoma• Embryonalcarcinoma

Potentialcomplicationswithadnexalmasses?

• Regardlessofagegroup,canalwaysbemalignant• Mightbesignsofmetastaticdisease• Mustruleoutectopicpregnancyasitcanaffectfertilityandbelife-threatening• Canrupture• Causestorsionwhichcanresultindiminishingbloodsupplytotheovary• Hemorrhagiccystcancausebleeding

Questiontoask?

• DoIneedtoremoveit?• AmIdealingwithpotentialcancer?• Isthepatientstable?• Arethereconservativealternatives?• WhattestsdoIhavetoorderthatwillassistmeinmakingmydecision?• DoIneedareferral?

• Needdiagnostictestswhichhashighersensitivityandspecificitythatwillenableustomakebetterdecisions• Whatwillguidemostofus?

• History• Physical• Imaging• Laboratorytests

• Mostcommonimagingagynecologistwilluseisanultrasound• Mostcommonlaboratorytestordertodifferentiatevarietyofbenignconditionsversusmalignantonesaretumormarkers

Ultrasound

• Goalofanultrasoundisnottodetermine100%whetherornotamassisbenignormalignant• Thepurposeoftheultrasoundistoguideourdecisionmaking• Fortunately,ultrasoundisahighlyeffective,cheap,andsafetooltouse• adsfs

Ultrasound

• Sonogramtechniques• Grayscale

• Basedonsignalintensityanddepthmeasureditlengthoftimeitrequireforwavetobereflectedback

• Doppler• Changeinfrequencythatresultsfromsoundwavebeingreflectedoffmoving

objects,i.e.bloodvessel• Combinedgrayscale&doppler

• Preferedmethod• 3-Dtechniques

• Doesnotimprovedetectionbetweenbenignandmalignantprocess• Mayassistwithdetectionofhydrosalpinx

• Spectraldoppler• Toobroadofoverlapinresistiveindexandpulsatilityindexbetweenbenignand

malignantmasses• Velocityanddiastolicnotchmeasurementsdoesnotappeartoimprovereliability

• Consulsion:staysimple,gowithgrayscaleandcolordoppler

Ultrasound

• Stepsincharacterizingamass• Isitasimplecyst?

• Anechoicfluidfilledcavity• Thinwalls• Noimpairedsoundwave

• Arethereotherphysiologicalprocessthatcanbeacauseifthecystdoesnotappearsimple?• Corpusluteum

• Thickenedwall• Circumferentialcolordopplerflow• Smallcentrallucencythatcouldbeconfusing

• Multiplesimplecyst• Misdiagnosedashavingseptation

• Hemorrhagiccyst• Canhaveseptationandmuralnodules• Usuallyhavethinlinearechos(fishnetorreticularpattern)• Linearechosdonotextendcompletelyuninterrupted

UltrasoundAretherecharacteristicsthatarespecifictoother“entities”?

• Endometrioma• Homogeneouslowtomediumechos• Canhavesolidcomponentsandbeeitherunilocularormultilocular• Canhavedopplerflowespeciallyiffociofendometrialtissue• Havesimilarfindingsofhemorrhagiccyst

• Matureteratoma• Markedlyhyperechoicnodulewithinthemass• Containfluid,Calcificationwithusuallynocolorflow

• Pedunculatedleiomyoma• Heterogeneous,hypoechoic,solidmasses

• Hydrosalpinx• Tubularstructurewithseptationornodulesinthewall

• Peritonealinclusioncyst• Canhaveseptatedfeaturesaroundtheovaryinwomenwithadhesions• Adhesionscanbeseenasbandsoftissuewithsurroundingfluid

• Malignancy• Solidcomponent,nothyperechoic,hasnodularityorpapillary• Septationsthickerthan2-3mm• Colordopplerflowinthesolidcomponent• Presencesofascites• Peritonealmasses,enlargednodesormattedbowels• Sizeofthemassdoesnotclearlydefinemalignancy

Ultrasound

• InternationalOvarianTumorAnalysis(IOTA)• Largestdiagnosticaccuracystudy• Ultrasoundperformancedetermineonthelevelof“riskofmalignancy”• 4848patientsfromoncologyandnon-oncologycenters• Diagnosticcriteriabasedon“Simplerules”• 23%hadlowrisk(<1%)

• Sensitivity99.7%,specificity33.7%,• PPV44.8%,NPV98.9%

• 48%hadhighrisk(>30%)• Sensitivity89%,specificity84.7%• PPV75.4%,NPV93.9%

Ultrasound

• FromIOTAstudy• Simplerules

• Benignfeatures• Unilocularcystofanysize• Solidcomponentseithernotpresentor<7mm• Presenceofacousticshadowing• Smoothmultilocularcyst<10cm• Nobloodflow

• Malignantfeatures• Irregularsolidtumor• Ascites• Atleastfourpapillarystructures• Irregularsolid-multiloculartumor,largest>10cm• Verystrongcolordopplerflow

Ultrasound

• Ifstillinconclusive,whatotheroptionsareavailable?• Repeatultrasound

• Onlyifthereissuspicionthatprocesscouldbephysiologicalprocess• Trytoobtainultrasoundinfollicularphase,aroundday7-12toreduceriskofhemorrhagiccystinthenextcycle

• Difficultiesduetoirregularcycle• MRI

• Canbegoodmodalityifsurgicaltreatmentistobeconsidered• Irrelevantfordeterminingbenignversusmalignantadnexalmassifsurgicalinterventionwouldbecarriedoutbyagynecologicsurgeonexperienceindealingwithmalignancy

• Relyonlaboratoryresults• Referraltogynecologyoncologist

SerumMarkers

• Biomarker:acharacteristicthatisobjectivelymeasuredandevaluatedasanindicatorofnormalprocesses,pathologicalprocesses,orresponsetointervention

• Tumormarker:specificbiomarkerformalignancy• Whendealingwithadnexalmassesandconcernformalignancies,Epithelialovariancancer(EOC)isthemostcommonandmostconcerning

• Therearenomarkersdevelopedforthepurposeofevaluatingbenignprocesses,thoughcertainbenignprocessescancauseelevationintumormarkersmorespecificformalignancies

• Therearenumerousmarkersfordifferenttypesofadnexalmalignancies,mostcommon,ovarian.

• CA125,CA19-9,CEA,Inhibin,AFP,betaHCG,LDH,etc.

SerumMarkers

• Evaluatemostcommonlyusedmarker:CA125• Firstdescribedin1983• Largetransmembraneglycoproteinderivedfrombothcoelomicandmullerianepithelia• Coelomic:pericardium,pleura,peritoneum• Mullerian:Fallopiantube,endometrium,endocervical

• ApprovedbyFDAtomonitorresponsetotherapyinwomenwithknownEOC• Twotypes:CA125andCA125II,differentcutoffvalues• Nocurrentdataavailabletosupportsuperiorityofoneversustheother• CA125canbeelevatedinothernon-malignantconditions• Notoverlyusefulinpremenopausalpatientsunless“significantly”elevated• Usually,acut-offof200u/mlforpremenopausalpatientsisused• CA125andCA125IIcut-offformenopausal:35u/mland20u/ml

SerumMarkers

• Humanepididymisprotein4• Antigenderivedfromhumanepididymisprotein,aproductoftheWFDC2genethatisoverexpressedinpatientswithserousorendometrioidovariancarcinoma

• FDAapprovedin2008formonitoringrecurrentorprogressivediseaseinpatientswithEOC

• HE4<150pM• UsedinconjunctionwithROMA

• Carcinoembryonicantigen• Proteinfoundinembryonicorfetaltissue(disappearafterbirth)• MucinouscancerofGItractorovary• Canbeelevatedinbreast,pancreatic,thyroid,lungcancers• Benignconditionsinclude:cigarettesmoking,mucinouscystadenomaofovaryorappendix,cholecystitis,livercirrhosis,diverticulitis,IBD,pancreatitis,pulmonaryinfections

• Canbeusedtomonitorpatientswithpseudomyxomaperitonei

SerumMarkers

• CA19-9• Mucinproteinmarker• Elevatedinmucinousovariantumors• Monitorresponsetotherapyorrecurrenceinpatientswithgastric,pancreatic,

gallbladdercancer,cholangiocarcinoma,andadenocarcinomaoftheampullaofVater

• OVA1(Questdiagnostics)• Includes5serummarkers• FDAapprovedin2009toassesslikelihoodofmalignancyinpatientundergoingsurgery

foranadnexalmass• CA125II,Beta2macroglobulin,transferrin,transthyretin,apolipoproteinA1• Premenopausal

• Lowprobabilityofmalignancy:<5• Highprobabilityofmalignancy:>5

• Postmenopausal• Lowprobabilityofmalignancy:<4.4• Highprobabilityofmalignancy:>4.4

• Triglyceridelevelsexceeding4.5g/Lorrheumatoidfactor>250IU/mlmayinterfere

• Riskofmalignancyalgorithm(ROMA)• FDAapprovedin2011toassesswomenforplannedsurgerytodetectriskofmalignancy• UsesCA125andHE4throughanalgorithmdependingonmenopausalstatus• Premenopausal:highrisk>13.1%• Postmenopausal:highrisk>27.7%• Availableinternationallyonwebsitesandsmartphoneapplications

• Riskofmalignancyindex(RMII-IV)• Originallydevelopedin1990• UseprimarilyinUK• CombinesCA125,pelvicultrasound(U),andmenopausalstatus(M)• RMII=UxMxCA125,ifscoreis>200,shouldrefertospecialist• Ultrasound:multi-locular,solidareas,metastasis,ascites,bilateralmasses• Size<7cmor>7cm

• ADNEXmodel• Designedforuseinwomenwithadnexalmassplanningforsurgery• Firstreportedin2014• Predictnotonlyaboutmalignancyversusbenign,butalsoborderline,stageI-IV,andsecondarymetastaticadnexaltumors

• HasnotbeenvalidatedoutsideofEuropeanresearchcollaborativegroup• Computerizedmodelthatcombinesdifferentcharacteristic

• Age• CA125• Typeofcenter• Ultrasoundfeatures:maximumdiameteroflesion,proportionofsolidtissue,>10

cystlocules,numberofpapillaryprojections,acousticshadows,ascites

• www.iotagroup.org/adnexmodel/

• Diagnosticperformance• CA125

• Alonehaslowsensitivityandspecificity,especiallyforearlystageovariancancerwithsensitivityof25%andspecificityof61%

• Meta-analysisof77studieswithvalue>35U/mLhadasensitivityandspecificityof78%,lowvaluessecondarytoothertypesofovarianmalignancythatdoesnothaveelevatedCA125,i.e.mucinous,clearcell,mixmullerianovariantumors

• Premenopausal:Sensitivity50-74%,specificity69-78%,duetobenigncausesofCA125elevation

• Postmenopausal:Sensitivity69-87%,specificity81-93%• OVA1

• Prospectiveserieswith524women,comparedOVA1withCA125IIandclinicalassessment• OVA1sensitivity93%andspecificity43%,CA125sensitivity69%andspecificity84%,

clinicalassessmentsensitivity75%andspecificity79%• Withmenopausalstatus:HighersensitivitywithOVA1100%versusCA12592%• HighersensitivityinOVA1versusCA125inStageIandIIprimaryovariancancer

• ImproveddiagnostictoolcomparedtoCA125alone

• DiagnosticPerformance• ROMA

• Prospectivemulti-institutionalstudyof531patients• Highriskpatient(Incidenceofmalignancy24%)• Postmenopausal:Sensitivity92%• Premenopausal:Sensitivity76%

• Prospectivemulti-institutionalstudyof472patients• Lowriskpatients(Incidenceofmalignancy10%)• Postmenopausal:Sensitivity92%andspecificity76%• Premenopausal:sensitivity100%andspecificity74%

• ROMAversusHE4versusCA125• ROMAwasmostsensitive(86%:80%:84%)• HE4wasmostspecific(84%:94%:78%)• Resultshoweverarenotstatisticallysignificant

• Diagnosticperformance• RMI

• SimilarsensitivityandspecificityamongRMIIthroughIV• Advantagesoverserumbiomarkersisthatitcombinesmostimportantclinicalelementsinpredictingmalignancy

• DisadvantageisthattheriskcalculatorusesabsoluteCA125levelinsteadofascoringsystem.PatientswithearlystagecancercanoftenhavelowCA125andbemisleading

• ADNEXmodel• Novalidationstudyavailableatthistime

• Conclusion:• Notalladnexalmassesaremalignant• Tumormarkersandultrasoundsaretoguideusindifferentiatingbetweenbenignandmalignantwithacertainlevelofconfidence• CA125isNOTusedasacancerscreening• OVA1&ROMAareadditionaltoolswhichareavailabletoaideindecidingbenignversusmalignant.Theyshouldbeusedinpatientsthatarealreadyundergoingplannedsurgery• Whenindoubt,askacolleague

ThankYou!