Pathology of Breast Cancer

5/16/2015 Pathologyofbreastcancer

http://www.uptodate.com/contents/pathologyofbreastcancer?topicKey=ONC%2F783&elapsedTimeMs=1&source=search_result&searchTerm=cancer+de 1/22

OfficialreprintfromUpToDate www.uptodate.com2015UpToDate

AuthorIraJBleiweiss,MD

SectionEditorAneesBChagpar,MD,MSc,MA,MPH,MBA,FACS,FRCS(C)

DeputyEditorDonSDizon,MD,FACP

Pathologyofbreastcancer

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.Literaturereviewcurrentthrough:Apr2015.|Thistopiclastupdated:Dec19,2013.

INTRODUCTIONMostbreastmalignanciesarisefromepithelialelementsandarecategorizedascarcinomas.Breastcarcinomasareadiversegroupoflesionsthatdifferinmicroscopicappearanceandbiologicbehavior,althoughthesedisordersareoftendiscussedasasingledisease.

Theinsitucarcinomasofthebreastareeitherductal(alsoknownasintraductalcarcinoma)orlobular.Thisdistinctionisprimarilybaseduponthegrowthpatternandcytologicfeaturesofthelesions,ratherthantheiranatomiclocationwithinthemammaryductallobularsystem.

Theinvasivebreastcarcinomasconsistofseveralhistologicsubtypestheestimatedpercentagesarefromacontemporarypopulationbasedseriesof135,157womenwithbreastcancerreportedtotheSurveillanceEpidemiologyandEndResults(SEER)databaseoftheNationalCancerInstitutebetween1992and2001[1]:

Infiltratingductal76percent

Othersubtypes,includingmetaplasticbreastcancerandinvasivemicropapillarybreastcancer,allaccountforfewerthan5percentofcases[2].

Thistopicwillreviewthehistologyofductalcarcinomainsituandinvasivebreastcarcinoma.Thepathologiesofatypicalhyperplasia,lobularcarcinomainsitu,andothersubtypesofbreastcancerarediscussedseparately.

DUCTALCARCINOMAINSITUThetermductalcarcinomainsitu(DCIS)encompassesaheterogeneousgroupoflesionsthatdifferintheirclinicalpresentation,histologicappearance,andbiologicalpotential.DCISischaracterizedbyproliferationofpresumablymalignantepithelialcellswithinthemammaryductalsystem,withnoevidenceofinvasionintothesurroundingstromaonroutinelightmicroscopicexamination[3].Ductalcarcinomainsitudiffersfromlobularcarcinomainsituwithregardtoradiologicfeatures,morphology,biologicbehavior,andanatomicdistributioninthebreast(table1).Lobularcarcinomainsituisdiscussedindetailelsewhere.(See"Atypiaandlobularcarcinomainsitu:Highrisklesionsofthebreast".)

ClassificationschemesthatdivideDCIShistologicallyintoavarietyofsubtypesemphasizearchitecturalfeaturesorgrowthpatternoftheneoplasticcells,cytologicfeatures,andcellnecrosis,bothsinglyandincombination.ThetraditionalmethodforclassifyingDCISlesionsisprimarilybaseduponthegrowthpattern(architecturalfeatures)of

Invasivelobular8percentDuctal/lobular7percentMucinous(colloid)2.4percentTubular1.5percentMedullary1.2percentPapillary1percent

(See"Atypiaandlobularcarcinomainsitu:Highrisklesionsofthebreast".)(See"Breastsarcoma:Epidemiology,riskfactors,clinicalpresentation,diagnosis,andstaging".)(See"Pagetdiseaseofthebreast".)

(See"Breastlymphoma".)(See"Prognosticandpredictivefactorsinearly,nonmetastaticbreastcancer".)



thetumorandrecognizesfivemajortypes[47]:

LesscommonvariantsofDCISincludethe"clinging"carcinoma[4],intraductalsignetringcellcarcinoma[12],andcystichypersecretoryductcarcinoma[13,14].Similartothecomedotype,thesevariantsmayshowcalcificationsthatcanbedetectedmammographically.However,themammographicappearanceofthesemicrocalcificationsislessdistinctivethanthepatternseenincomedolesionsandcanresembleanumberofbenignprocesses.

AnumberofauthorshaveproposedalternativeclassificationsystemsforDCIS(table2)[1518].Althoughtheyusedifferentterminology,allareprimarilybaseduponnucleargradeand/orthepresenceorabsenceofnecrosis,andhaveincommontherecognitionofthreemaincategoriesofDCIS(eg,high,intermediate,andlowgrade).

Theseclassificationsystemsappeartocorrelatewithbiologicalprognosticmarkersandpredictgroupsofpatientswhoarelikelytohavearecurrenceofcancerfollowingbreastconservationtherapy[15,1830].(See"Breastductalcarcinomainsitu:Epidemiology,clinicalmanifestations,anddiagnosis".)

In1997,aconsensusconferencewasconvenedinanattempttoreachagreementontheclassificationofDCIS[31].Althoughthepaneldidnotendorseanysingleclassificationsystem,theyrecommendedthatcertainfeaturesberoutinelydocumentedinthepathologyreportforDCISlesions,includingnucleargrade,thepresenceofnecrosis,cellpolarization,andarchitecturalpattern(s).

Thecomedotypeischaracterizedbyprominentnecrosisinthecenteroftheinvolvedspaces.Thenecroticmaterialfrequentlybecomescalcifiedthecalcificationsmaybedetectedmammographically,characteristicallyaslinear,branching("casting")calcifications.Thetumorcellsarelargeandshownuclearpleomorphismmitoticactivitymaybeprominent(picture1).Thecomedotypeismoreoftenassociatedwithinvasion[8,9],andthedegreeofcomedonecrosisinpatientswithDCISappearstobeastrongpredictorfortheriskofipsilateralbreastrecurrenceaftertreatment[10].

Thecribriformtypeischaracterizedbytheformationofbacktobackglandswithoutinterveningstroma.Thecellscomprisingthissubtypearetypicallysmalltomediumsizedandhaverelativelyuniformhyperchromaticnuclei.Mitosesareinfrequentandnecrosisislimitedtosinglecellsorsmallcellclusters(picture2).

Themicropapillarytypefeaturessmalltuftsofcellsthatareorientedperpendiculartothebasementmembraneoftheinvolvedspacesandprojectintothelumina.Theapicalregionofthesesmallpapillationsisfrequentlybroaderthanthebase,impartingaclubshapedappearance.Themicropapillaelackfibrovascularcores.ThecellscomprisingthistypeofDCISareusuallysmalltomediuminsize,andthenucleishowdiffusehyperchromasiamitosesareinfrequent(picture3).

Thepapillarytypeshowsintraluminalprojectionsoftumorcellsthat,incontrasttothemicropapillaryvariant,demonstratefibrovascularcoresandtherebyconstitutetruepapillations.AvariantofpapillaryDCIS,intracysticpapillarycarcinoma,ischaracterizedbytumorcellsthatareprimarilyorexclusivelypresentinasinglecysticallydilatedspace[11].

Thesolidtypeisnotaswelldefinedastheothersubtypes.Itfeaturestumorcellsthatfillanddistendtheinvolvedspacesandlacksignificantnecrosis,fenestrations,orpapillations.Thetumorcellsmaybelarge,medium,orsmall.

Highgradelesionstypicallyexhibitaneuploidy,lackestrogenandprogesteronereceptors,andhaveahighproliferativerate,overexpressionoftheHER2oncogene,mutationsofthep53tumorsuppressorgenewithaccumulationofitsproteinproduct,andangiogenesisinthesurroundingstroma.

Lowgradelesionsaretypicallydiploid,estrogenandprogesteronereceptorpositive,havealowproliferativerate,andrarely(ifever)showabnormalitiesoftheHER2/neuorp53oncogenes.

Lesionscategorizedhistologicallyasintermediategradearealsointermediatebetweenthehighgradeandlowgradelesionswithregardtothefrequencyofalterationsinthesebiologicalmarkers.



INFILTRATINGDUCTALCARCINOMAInfiltratingductalcarcinomaisthemostcommontypeofinvasivebreastcancer,accountingfor70to80percentofinvasivelesions.Itisalsotermedinfiltratingcarcinomaofnospecialtypeorinfiltratingcarcinomanototherwisespecified(NOS).

Ongrosspathologicevaluation,theselesionsaretypicallyhard,graywhite,grittymasseswhichinvadethesurroundingtissueinahaphazardfashiontocreatethecharacteristicirregular,stellateshape.Theyarecharacterizedmicroscopicallybycordsandnestsoftumorcellswithvaryingamountsofglandformation,andcytologicfeaturesthatrangefromblandtohighlymalignant.Themalignantcellsinduceafibrousresponseastheyinfiltratethebreastparenchyma,andthisreactionis,inlargepart,responsiblefortheclinicallyandgrosslypalpablemass,theradiologicdensity,andsolidsonographiccharacteristicsoftypicalinvasivecarcinomas.

Infiltratingductalcarcinomasaredividedintothreegradesbaseduponacombinationofarchitecturalandcytologicfeatures,usuallyassessedutilizingascoringsystembasedonthreeparameters[32]:

Avariableamountofassociatedductalcarcinomainsitu(DCIS)ispresentinmostcasestheextentofDCISbutnotlobularcarcinomainsitu(LCIS)isanimportantprognosticfactorinpatientstreatedwithbreastconservingtherapyinwhomthesurgicalgoaliscompleteexcisionofbothintraductalandinvasivecarcinoma[33].

INFILTRATINGLOBULARCARCINOMAInfiltratinglobularcarcinomasarethesecondmostcommontypeofinvasivebreastcancer,accountingforabout5to10percentofinvasivelesions.

IncidenceratesoflobularcancerarerisingfasterthantheratesofductalcarcinomaintheUnitedStates,andpostmenopausalhormonetherapymaybemorestronglyrelatedtolobularcancerriskthantoductalcancerrisk.(See"Menopausalhormonetherapyandtheriskofbreastcancer",sectionon'Prognosis'and"Factorsthatmodifybreastcancerriskinwomen".)

Someinfiltratinglobularcarcinomashaveamacroscopicappearanceidenticaltothatofinfiltratingductalcancers.However,inmanycasesnomasslesionisgrosslyevident,andtheexcisedbreasttissuemayhaveanormaloronlyslightlyfirmconsistency.Thus,themicroscopicsizeofinvasivelobularcarcinomamaybesignificantlygreaterthanthatmeasuredgrossly.SomepathologistshaveusedlackofimmunohistochemicalstainingforEcadherintodistinguishinvasivelobularcarcinomafrominvasiveductcarcinoma.Whileitappearstobeareasonablyaccuratetest,itisforthemostpartunnecessaryinpractice.

Thesetumorsarecharacterizedmicroscopicallybysmallcellsthatinsidiouslyinfiltratethemammarystromaandadiposetissueindividuallyandinasinglefilepattern,oftengrowinginatargetlikeconfigurationaroundnormalbreastducts,frequentlyinducingonlyminimalfibrousreaction(picture7).Associatedlobularcarcinomainsitu(LCIS)ispresentinapproximatelytwothirdsofcaseshowever,DCISmayalsoaccompanyinvasivelobularcarcinoma.

Inadditiontotheirdifferenthistologicappearanceandmammographiccharacteristics,therearedistinctprognosticandbiologicdifferencesbetweeninfiltratinglobularandductalcancers:

Welldifferentiated(grade1)Welldifferentiatedtumorshavecellsthatinfiltratethestromaassolidnestsofglands.Thenucleiarerelativelyuniformwithlittleornoevidenceofmitoticactivity(picture4).

Moderatelydifferentiated(grade2)Moderatelydifferentiatedtumorshavecellsthatinfiltrateassolidnestswithsomeglandulardifferentiation.Thereissomenuclearpleomorphismandamoderatemitoticrate(picture5).

Poorlydifferentiated(grade3)Poorlydifferentiatedtumorsarecomposedofsolidnestsofneoplasticcellswithoutevidenceofglandformation.Thereismarkednuclearatypiaandconsiderablemitoticactivity(picture6).

Infiltratinglobularcarcinomashaveahigherfrequencyofbilateralityandmulticentricitythaninfiltratingductalcarcinomas[34,35].



Thereisanassociationbetweenmutationsinthecadherin(CDH1)geneandinvasivelobularbreastcancers.Lobularbreastcancershavebeenobservedtooccurin20to54percentofwomenfromfamilieswithhereditarydiffusegastriccancerwhocarrygermlinemutationsintheCDH1gene.However,germlineCDH1mutationscanalsobecosegregatedwithinvasivelobularbreastcancerintheabsenceofdiffusegastriccancer,suggestingthatgastriccancerisnotanobligatoryhallmarkoffamilieswithCDH1mutations.Furthermore,approximately50percentofsporadiclobularbreastcancerscontainEcadherinmutations[40,41].(See"Hereditarydiffusegastriccancer",sectionon'Riskofothercancers'and"BRCA1andBRCA2:Prevalenceandrisksforbreastandovariancancer".)

OTHERHISTOLOGICTYPESAnumberofotherhistologictypesaccountfortheremaininginvasivebreastcancers.Theseincludetubularcarcinoma,mucinouscarcinoma,medullarycarcinoma,invasivemicropapillarycarcinoma,metaplasticcarcinoma,adenoidcysticcarcinoma,andothers.Tumorsofotherhistologiesarisinginthebreast(lymphomas,sarcomas,phyllodestumors)arediscussedelsewhere.(See"Breastsarcoma:Epidemiology,riskfactors,clinicalpresentation,diagnosis,andstaging"and"Breastlymphoma".)

Specialclinicalpresentationsofbreastcarcinomas,includingPagetdiseaseandinflammatorycarcinoma,arediscussedelsewhere.(See"Pagetdiseaseofthebreast"and"Inflammatorybreastcancer:Pathologyandmolecularpathogenesis".)

TubularcarcinomaTubularcarcinomaswererelativelyinfrequentinthepremammographyera,accountingfor2percentorlessofinvasivebreastcancers.However,insomeseriesofmammographicallyscreenedpopulationstheincidenceishigher,accountingfor10to20percentofinvasivecancers.

Tubularcarcinomaischaracterizedbythepresenceofwellformedtubularorglandularstructuresinfiltratingthestroma(picture8).

Theselesionshavearelativelyfavorableprognosiscomparedwithinfiltratingductalcarcinomasthenaturalhistoryisfavorable,andmetastasesarerare[1,37,4244].

Mucinous(colloid)carcinomaMucinouscarcinomasaccountforbetween1and2percentofinvasivebreastcancersandappeartobemorecommoninolderpatients.Theselesionsusuallyhaveasoftgelatinousappearanceongrossexamination,andtheytendtobewellcircumscribed.Mucinouscarcinomasarecharacterizedmicroscopicallybynestsoftumorcellsdispersedinlargepoolsofextracellularmucusthecellstendtohaveuniform,lowgradenuclei(picture9).Similartotubularcarcinomas,theselesionsalsorepresentaprognosticallyfavorablevariantofinvasivebreastcarcinoma[1,37,43,45].

MedullarycarcinomaMedullarycarcinomasaccountforanywherefrom1to10percentofinvasivebreast

Infiltratinglobularcarcinomasariseinolderwomenandarelargerandbetterdifferentiatedtumors[34,36].Asarule,invasivelobularcarcinomasareERpositive,withvariantlesionsshowingoccasionalvariableexpression.

Whileolderseriesreportasimilarprognosisforinfiltratinglobularcancersandinvasiveductallesions,morerecentreportssuggestthatoutcomes(atleastintheshortterm)maybemorefavorableforlobularcancersandimprovingovertime[37,38].However,variantsofinfiltratinglobularcarcinomaexist,someofwhichhaveapoorerprognosis[34].

Asagroup,invasivelobularcarcinomastendtometastasizelaterthaninvasiveductcarcinomasandspreadtounusuallocationssuchasperitoneum,meninges,andthegastrointestinaltract[39].

Thetubulestendtobeelongated,andmanyhavepointedendsThecellscomposingthetubulesarecuboidaltocolumnarandoftenhaveapicalcytoplasmicprotrusionsor"snouts"

ThetumorcellsarecytologicallylowgradeAssociatedDCIS,typicallyofthelowgradetype,ispresentinaboutthreequartersofthecases



cancers.However,thereisconsiderableinterobservervariabilityinthediagnosisofthistypeofbreastcancerwhichis,atleastinpart,dependentupontheclassificationsystememployed[4648].

Medullarycarcinomasarewellcircumscribedonmacroscopicexaminationandareoftensoftandtanbrownwithareasofhemorrhageornecrosis.Circumscriptionofthelesionisalsoevidentmicroscopically.Thetumorcellsarepoorlydifferentiated(highgrade),growinasyncytialpattern,andhaveanintenseassociatedlymphoplasmacyticinfiltrate(picture10),andthistumorisactuallyquiterarewhenstrictdiagnosticcriteriaarefollowed.

Medullaryandmedullarylikecarcinomasoccurmorefrequentlyinyoungerpatientsthanothertypesofbreastcancer.TheyarealsomorefrequentinwomenwhoinheritmutationsoftheBRCA1gene(10percentofbreastcancersaremedullaryinthispopulation,ascomparedwith



cancersaretreatedsimilarlytootherinvasivebreastcancers[5860].

AdenoidcysticcarcinomaTherareadenoidcysticcarcinomaofthebreasthasadistinctivehistologicpatternthatismorphologicallyidenticaltoadenoidcysticcarcinomafoundinthesalivaryglands(andothersites).(See"Salivaryglandtumors:Epidemiology,diagnosis,evaluation,andstaging".)Thistumortendstobeassociatedwithafavorableprognosis,evenwhentumorsizeislargethereportedincidenceofaxillarymetastasesinmostseriesislessthan5percent[61,62].

Histologicgradingbaseduponthepercentageofsolidareas(asisusedforsalivaryglandtumors)hasbeensuggestedasbeingprognosticallyuseful[63],althoughothersdisagree[62].Atleasttwoseriesinwhichoutcomeswerenotasfavorableasinmostreportswerepredominatedbypatientswithhighergradetumors(ie,thesolidvariant)[64,65].

SUMMARY

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Topic783Version11.0



GRAPHICS

Comparativefeaturesofductalcarcinomainsitu(DCIS)andlobularcarcinomainsitu(LCIS)

DCIS LCIS

Presentation Incidentalfinding,mammographicabnormality,occasionallypalpable,unifocal

Incidentalfinding,oftenmultifocal

Predominantlocation Ducts Lobules

Cellsize Mediumorlarge Small

Pattern Comedo,cribriform,micropapillary,papillary,solid

Solid

Calcifications Yesorno Usuallyno

Riskofsubsequentinvasivecancer

Higher Lower

Locationofsubsequentinvasivecancer

Ipsilateral Ipsilateralorcontraleteral

Graphic72750Version1.0



Comedoductalcarcinomainsitu

Lightmicroscopicspecimenofcomedoductalcarcinomainsitushowsalargecentralareaofnecrosisthatisfocallycalcified.Thenucleiarepoorlydifferentiated(highgrade).

CourtesyofStuartSchnitt,MD.




Cribriformductalcarcinomainsitu

Lightmicrographofalesionfromthebreastofawomanwithcribriformductalcarcinomainsitushowsabacktobackglandulargrowthpattern.Thenucleiarewelldifferentiated(lowgrade).Asmallcalcificationisnotednearthecenteroftheinvolvedspace(arrow).





Micropapillaryductalcarcinomainsitu

Lightmicrographofaspecimenfromthebreastofawomenwithmicropapillaryductalcarcinomainsitu.Thetumorcellsformtuftswhichprojectintothelumenoftheinvolvedspace.Thenucleiarewelldifferentiated(lowgrade).





Proposedclassificationsystemsforductalcarcinomainsitu

Lagios* VanNuys European

Lowgrade Nonhighgradewithoutnecrosis Welldifferentiated

Intermediategrade Nonhighgradewithnecrosis Intermediatelydifferentiated

Highgrade Highgrade Poorlydifferentiated

*AdaptedfromLagiosMD,MargolinFR,WestdahlPR,RoseMR.Cancer198963:618.SilversteinMJ,PollerDN,WaismanJR,etal.Lancet1995345:1154.HollandR,PeterseJL,MillisRR,etal.SeminDiagnPathol199411:167.




GradeIinfiltratingductalcarcinomaofthebreast

(PanelA)Lowpowerviewofawelldifferentiatedinfiltratingductalcarcinomashowstumorcellswhichinfiltratethestromaassolidnestsandglands.(PanelB)Highpowerviewdemonstratesrelativelyuniformnucleiwithnoevidenceofmitoticactivity.





GradeIIinfiltratingcarcinomaofthebreast

(PanelA)Lowpowerviewofamoderatelydifferentiatedbreastcarcinomashowstumorcellsinfiltratingassolidnestswithsomeglandulardifferentiation.(PanelB)Highpowerviewdemonstratessomenuclearpleomorphisminthetumorcells.





GradeIIIinfiltratingductalcarcinomaofthebreast

(PanelA)Lowpowerviewofapoorlydifferentiatedbreastcarcinomashowsthatthetumoriscomposedofsolidnestsofneoplasticcellswithoutevidenceofglandformation.(PanelB)Thehighpowerviewdemonstratesmarkednuclearatypiainthetumorcellswithconsiderablemitoticactivity.





Infiltratinglobularcarcinomaofthebreast

(PanelA)Lowpowerviewofaninfiltratinglobularbreastcarcinomashowssmalltumorcellsthatinfiltratethestromasinglyandinasinglefilepattern.(PanelB)Highpowerviewdemonstratesthatthetumorcellsarerelativelysmallanduniforminappearance.





Tubularcarcinomaofthebreast

(PanelA)Lowpowerviewofatubularbreastcarcinomashowsthatthetumoriscomposedofwellformedglandsortubulesthatinvadethemammarystroma.(PanelB)Highpowerviewdemonstratesthatthetubulesarecomposedofcolumnarcellswithrelativelyuniformnuclei.Manyofthecellsshow"snouts"ofeosinophiliccytoplasmattheirlumenalends.





Mucinouscarcinomaofthebreast

(PanelA)Lowpowerviewofamucinousbreastcarcinomashowssmallnestsoftumorcellsdispersedinlargepoolsofextracellularmucous.(PanelB)Highpowerviewdemonstratesthatthenestsarecomposedofcellswithrelativelyuniform,lowgradenuclei.





Medullarycarcinomaofthebreast

(PanelA)Lowpowerviewofamedullarybreastcarcinomashowsthatthetumorhasawellcircumscribedborder.(PanelB)Highpowerviewdemonstratesthatthetumorcellsgrowinasyncytialpatternandhavemarkednuclearatypia.Aprominentlymphoplasmacyticinfiltrateisalsopresent.





Disclosures:IraJBleiweiss,MDNothingtodisclose.AneesBChagpar,MD,MSc,MA,MPH,MBA,FACS,FRCS(C)Nothingtodisclose.DonSDizon,MD,FACPNothingtodisclose.Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.Conflictofinterestpolicy

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