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OfficialreprintfromUpToDate
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Pathologyofbreastcancer
Author
IraJBleiweiss,MD

SectionEditor
DeputyEditor
AneesBChagpar,MD,MSc,MA,MPH,MBA,FACS,FRCS(C)
DonSDizon,MD,FACP

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Apr2015.|Thistopiclastupdated:Dec19,2013.
INTRODUCTIONMostbreastmalignanciesarisefromepithelialelementsandarecategorizedascarcinomas.
Breastcarcinomasareadiversegroupoflesionsthatdifferinmicroscopicappearanceandbiologicbehavior,
althoughthesedisordersareoftendiscussedasasingledisease.
Theinsitucarcinomasofthebreastareeitherductal(alsoknownasintraductalcarcinoma)orlobular.This
distinctionisprimarilybaseduponthegrowthpatternandcytologicfeaturesofthelesions,ratherthantheir
anatomiclocationwithinthemammaryductallobularsystem.
Theinvasivebreastcarcinomasconsistofseveralhistologicsubtypestheestimatedpercentagesarefroma
contemporarypopulationbasedseriesof135,157womenwithbreastcancerreportedtotheSurveillance
EpidemiologyandEndResults(SEER)databaseoftheNationalCancerInstitutebetween1992and2001[1]:
Infiltratingductal76percent

Invasivelobular8percent
Ductal/lobular7percent
Mucinous(colloid)2.4percent
Tubular1.5percent
Medullary1.2percent
Papillary1percent

Othersubtypes,includingmetaplasticbreastcancerandinvasivemicropapillarybreastcancer,allaccountfor
fewerthan5percentofcases[2].
Thistopicwillreviewthehistologyofductalcarcinomainsituandinvasivebreastcarcinoma.Thepathologiesof
atypicalhyperplasia,lobularcarcinomainsitu,andothersubtypesofbreastcancerarediscussedseparately.
(See"Atypiaandlobularcarcinomainsitu:Highrisklesionsofthebreast".)
(See"Breastsarcoma:Epidemiology,riskfactors,clinicalpresentation,diagnosis,andstaging".)
(See"Pagetdiseaseofthebreast".)
(See"Breastlymphoma".)
(See"Prognosticandpredictivefactorsinearly,nonmetastaticbreastcancer".)
DUCTALCARCINOMAINSITUThetermductalcarcinomainsitu(DCIS)encompassesaheterogeneous
groupoflesionsthatdifferintheirclinicalpresentation,histologicappearance,andbiologicalpotential.DCISis
characterizedbyproliferationofpresumablymalignantepithelialcellswithinthemammaryductalsystem,withno
evidenceofinvasionintothesurroundingstromaonroutinelightmicroscopicexamination[3].Ductalcarcinomain
situdiffersfromlobularcarcinomainsituwithregardtoradiologicfeatures,morphology,biologicbehavior,and
anatomicdistributioninthebreast(table1).Lobularcarcinomainsituisdiscussedindetailelsewhere.(See
"Atypiaandlobularcarcinomainsitu:Highrisklesionsofthebreast".)
ClassificationschemesthatdivideDCIShistologicallyintoavarietyofsubtypesemphasizearchitecturalfeatures
orgrowthpatternoftheneoplasticcells,cytologicfeatures,andcellnecrosis,bothsinglyandincombination.The
traditionalmethodforclassifyingDCISlesionsisprimarilybaseduponthegrowthpattern(architecturalfeatures)of
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thetumorandrecognizesfivemajortypes[47]:
Thecomedotypeischaracterizedbyprominentnecrosisinthecenteroftheinvolvedspaces.Thenecrotic
materialfrequentlybecomescalcifiedthecalcificationsmaybedetectedmammographically,
characteristicallyaslinear,branching("casting")calcifications.Thetumorcellsarelargeandshownuclear
pleomorphismmitoticactivitymaybeprominent(picture1).Thecomedotypeismoreoftenassociatedwith
invasion[8,9],andthedegreeofcomedonecrosisinpatientswithDCISappearstobeastrongpredictorfor
theriskofipsilateralbreastrecurrenceaftertreatment[10].
Thecribriformtypeischaracterizedbytheformationofbacktobackglandswithoutinterveningstroma.The
cellscomprisingthissubtypearetypicallysmalltomediumsizedandhaverelativelyuniformhyperchromatic
nuclei.Mitosesareinfrequentandnecrosisislimitedtosinglecellsorsmallcellclusters(picture2).
Themicropapillarytypefeaturessmalltuftsofcellsthatareorientedperpendiculartothebasement
membraneoftheinvolvedspacesandprojectintothelumina.Theapicalregionofthesesmallpapillationsis
frequentlybroaderthanthebase,impartingaclubshapedappearance.Themicropapillaelackfibrovascular
cores.ThecellscomprisingthistypeofDCISareusuallysmalltomediuminsize,andthenucleishow
diffusehyperchromasiamitosesareinfrequent(picture3).
Thepapillarytypeshowsintraluminalprojectionsoftumorcellsthat,incontrasttothemicropapillaryvariant,
demonstratefibrovascularcoresandtherebyconstitutetruepapillations.AvariantofpapillaryDCIS,
intracysticpapillarycarcinoma,ischaracterizedbytumorcellsthatareprimarilyorexclusivelypresentina
singlecysticallydilatedspace[11].
Thesolidtypeisnotaswelldefinedastheothersubtypes.Itfeaturestumorcellsthatfillanddistendthe
involvedspacesandlacksignificantnecrosis,fenestrations,orpapillations.Thetumorcellsmaybelarge,
medium,orsmall.
LesscommonvariantsofDCISincludethe"clinging"carcinoma[4],intraductalsignetringcellcarcinoma[12],
andcystichypersecretoryductcarcinoma[13,14].Similartothecomedotype,thesevariantsmayshow
calcificationsthatcanbedetectedmammographically.However,themammographicappearanceofthese
microcalcificationsislessdistinctivethanthepatternseenincomedolesionsandcanresembleanumberof
benignprocesses.
AnumberofauthorshaveproposedalternativeclassificationsystemsforDCIS(table2)[1518].Althoughthey
usedifferentterminology,allareprimarilybaseduponnucleargradeand/orthepresenceorabsenceofnecrosis,
andhaveincommontherecognitionofthreemaincategoriesofDCIS(eg,high,intermediate,andlowgrade).
Highgradelesionstypicallyexhibitaneuploidy,lackestrogenandprogesteronereceptors,andhaveahigh
proliferativerate,overexpressionoftheHER2oncogene,mutationsofthep53tumorsuppressorgenewith
accumulationofitsproteinproduct,andangiogenesisinthesurroundingstroma.
Lowgradelesionsaretypicallydiploid,estrogenandprogesteronereceptorpositive,havealowproliferative
rate,andrarely(ifever)showabnormalitiesoftheHER2/neuorp53oncogenes.
Lesionscategorizedhistologicallyasintermediategradearealsointermediatebetweenthehighgradeand
lowgradelesionswithregardtothefrequencyofalterationsinthesebiologicalmarkers.
Theseclassificationsystemsappeartocorrelatewithbiologicalprognosticmarkersandpredictgroupsofpatients
whoarelikelytohavearecurrenceofcancerfollowingbreastconservationtherapy[15,1830].(See"Breastductal
carcinomainsitu:Epidemiology,clinicalmanifestations,anddiagnosis".)
In1997,aconsensusconferencewasconvenedinanattempttoreachagreementontheclassificationofDCIS
[31].Althoughthepaneldidnotendorseanysingleclassificationsystem,theyrecommendedthatcertainfeatures
beroutinelydocumentedinthepathologyreportforDCISlesions,includingnucleargrade,thepresenceof
necrosis,cellpolarization,andarchitecturalpattern(s).
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INFILTRATINGDUCTALCARCINOMAInfiltratingductalcarcinomaisthemostcommontypeofinvasive
breastcancer,accountingfor70to80percentofinvasivelesions.Itisalsotermedinfiltratingcarcinomaofno
specialtypeorinfiltratingcarcinomanototherwisespecified(NOS).
Ongrosspathologicevaluation,theselesionsaretypicallyhard,graywhite,grittymasseswhichinvadethe
surroundingtissueinahaphazardfashiontocreatethecharacteristicirregular,stellateshape.Theyare
characterizedmicroscopicallybycordsandnestsoftumorcellswithvaryingamountsofglandformation,and
cytologicfeaturesthatrangefromblandtohighlymalignant.Themalignantcellsinduceafibrousresponseasthey
infiltratethebreastparenchyma,andthisreactionis,inlargepart,responsiblefortheclinicallyandgrossly
palpablemass,theradiologicdensity,andsolidsonographiccharacteristicsoftypicalinvasivecarcinomas.
Infiltratingductalcarcinomasaredividedintothreegradesbaseduponacombinationofarchitecturalandcytologic
features,usuallyassessedutilizingascoringsystembasedonthreeparameters[32]:
Welldifferentiated(grade1)Welldifferentiatedtumorshavecellsthatinfiltratethestromaassolidnestsof
glands.Thenucleiarerelativelyuniformwithlittleornoevidenceofmitoticactivity(picture4).
Moderatelydifferentiated(grade2)Moderatelydifferentiatedtumorshavecellsthatinfiltrateassolidnests
withsomeglandulardifferentiation.Thereissomenuclearpleomorphismandamoderatemitoticrate(picture
5).
Poorlydifferentiated(grade3)Poorlydifferentiatedtumorsarecomposedofsolidnestsofneoplasticcells
withoutevidenceofglandformation.Thereismarkednuclearatypiaandconsiderablemitoticactivity(picture
6).
Avariableamountofassociatedductalcarcinomainsitu(DCIS)ispresentinmostcasestheextentofDCISbut
notlobularcarcinomainsitu(LCIS)isanimportantprognosticfactorinpatientstreatedwithbreastconserving
therapyinwhomthesurgicalgoaliscompleteexcisionofbothintraductalandinvasivecarcinoma[33].
INFILTRATINGLOBULARCARCINOMAInfiltratinglobularcarcinomasarethesecondmostcommontypeof
invasivebreastcancer,accountingforabout5to10percentofinvasivelesions.
IncidenceratesoflobularcancerarerisingfasterthantheratesofductalcarcinomaintheUnitedStates,and
postmenopausalhormonetherapymaybemorestronglyrelatedtolobularcancerriskthantoductalcancerrisk.
(See"Menopausalhormonetherapyandtheriskofbreastcancer",sectionon'Prognosis'and"Factorsthatmodify
breastcancerriskinwomen".)
Someinfiltratinglobularcarcinomashaveamacroscopicappearanceidenticaltothatofinfiltratingductalcancers.
However,inmanycasesnomasslesionisgrosslyevident,andtheexcisedbreasttissuemayhaveanormalor
onlyslightlyfirmconsistency.Thus,themicroscopicsizeofinvasivelobularcarcinomamaybesignificantly
greaterthanthatmeasuredgrossly.SomepathologistshaveusedlackofimmunohistochemicalstainingforE
cadherintodistinguishinvasivelobularcarcinomafrominvasiveductcarcinoma.Whileitappearstobea
reasonablyaccuratetest,itisforthemostpartunnecessaryinpractice.
Thesetumorsarecharacterizedmicroscopicallybysmallcellsthatinsidiouslyinfiltratethemammarystromaand
adiposetissueindividuallyandinasinglefilepattern,oftengrowinginatargetlikeconfigurationaroundnormal
breastducts,frequentlyinducingonlyminimalfibrousreaction(picture7).Associatedlobularcarcinomainsitu
(LCIS)ispresentinapproximatelytwothirdsofcaseshowever,DCISmayalsoaccompanyinvasivelobular
carcinoma.
Inadditiontotheirdifferenthistologicappearanceandmammographiccharacteristics,therearedistinctprognostic
andbiologicdifferencesbetweeninfiltratinglobularandductalcancers:
Infiltratinglobularcarcinomashaveahigherfrequencyofbilateralityandmulticentricitythaninfiltratingductal
carcinomas[34,35].
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Infiltratinglobularcarcinomasariseinolderwomenandarelargerandbetterdifferentiatedtumors[34,36].As
arule,invasivelobularcarcinomasareERpositive,withvariantlesionsshowingoccasionalvariable
expression.
Whileolderseriesreportasimilarprognosisforinfiltratinglobularcancersandinvasiveductallesions,more
recentreportssuggestthatoutcomes(atleastintheshortterm)maybemorefavorableforlobularcancers
andimprovingovertime[37,38].However,variantsofinfiltratinglobularcarcinomaexist,someofwhich
haveapoorerprognosis[34].
Asagroup,invasivelobularcarcinomastendtometastasizelaterthaninvasiveductcarcinomasandspread
tounusuallocationssuchasperitoneum,meninges,andthegastrointestinaltract[39].
Thereisanassociationbetweenmutationsinthecadherin(CDH1)geneandinvasivelobularbreastcancers.
Lobularbreastcancershavebeenobservedtooccurin20to54percentofwomenfromfamilieswithhereditary
diffusegastriccancerwhocarrygermlinemutationsintheCDH1gene.However,germlineCDH1mutationscan
alsobecosegregatedwithinvasivelobularbreastcancerintheabsenceofdiffusegastriccancer,suggestingthat
gastriccancerisnotanobligatoryhallmarkoffamilieswithCDH1mutations.Furthermore,approximately50
percentofsporadiclobularbreastcancerscontainEcadherinmutations[40,41].(See"Hereditarydiffusegastric
cancer",sectionon'Riskofothercancers'and"BRCA1andBRCA2:Prevalenceandrisksforbreastandovarian
cancer".)
OTHERHISTOLOGICTYPESAnumberofotherhistologictypesaccountfortheremaininginvasivebreast
cancers.Theseincludetubularcarcinoma,mucinouscarcinoma,medullarycarcinoma,invasivemicropapillary
carcinoma,metaplasticcarcinoma,adenoidcysticcarcinoma,andothers.Tumorsofotherhistologiesarisingin
thebreast(lymphomas,sarcomas,phyllodestumors)arediscussedelsewhere.(See"Breastsarcoma:
Epidemiology,riskfactors,clinicalpresentation,diagnosis,andstaging"and"Breastlymphoma".)
Specialclinicalpresentationsofbreastcarcinomas,includingPagetdiseaseandinflammatorycarcinoma,are
discussedelsewhere.(See"Pagetdiseaseofthebreast"and"Inflammatorybreastcancer:Pathologyand
molecularpathogenesis".)
TubularcarcinomaTubularcarcinomaswererelativelyinfrequentinthepremammographyera,accountingfor
2percentorlessofinvasivebreastcancers.However,insomeseriesofmammographicallyscreenedpopulations
theincidenceishigher,accountingfor10to20percentofinvasivecancers.
Tubularcarcinomaischaracterizedbythepresenceofwellformedtubularorglandularstructuresinfiltratingthe
stroma(picture8).
Thetubulestendtobeelongated,andmanyhavepointedends
Thecellscomposingthetubulesarecuboidaltocolumnarandoftenhaveapicalcytoplasmicprotrusionsor
"snouts"
Thetumorcellsarecytologicallylowgrade
AssociatedDCIS,typicallyofthelowgradetype,ispresentinaboutthreequartersofthecases
Theselesionshavearelativelyfavorableprognosiscomparedwithinfiltratingductalcarcinomasthenatural
historyisfavorable,andmetastasesarerare[1,37,4244].
Mucinous(colloid)carcinomaMucinouscarcinomasaccountforbetween1and2percentofinvasivebreast
cancersandappeartobemorecommoninolderpatients.Theselesionsusuallyhaveasoftgelatinous
appearanceongrossexamination,andtheytendtobewellcircumscribed.Mucinouscarcinomasarecharacterized
microscopicallybynestsoftumorcellsdispersedinlargepoolsofextracellularmucusthecellstendtohave
uniform,lowgradenuclei(picture9).Similartotubularcarcinomas,theselesionsalsorepresentaprognostically
favorablevariantofinvasivebreastcarcinoma[1,37,43,45].
MedullarycarcinomaMedullarycarcinomasaccountforanywherefrom1to10percentofinvasivebreast
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cancers.However,thereisconsiderableinterobservervariabilityinthediagnosisofthistypeofbreastcancer
whichis,atleastinpart,dependentupontheclassificationsystememployed[4648].
Medullarycarcinomasarewellcircumscribedonmacroscopicexaminationandareoftensoftandtanbrownwith
areasofhemorrhageornecrosis.Circumscriptionofthelesionisalsoevidentmicroscopically.Thetumorcellsare
poorlydifferentiated(highgrade),growinasyncytialpattern,andhaveanintenseassociatedlymphoplasmacytic
infiltrate(picture10),andthistumorisactuallyquiterarewhenstrictdiagnosticcriteriaarefollowed.
Medullaryandmedullarylikecarcinomasoccurmorefrequentlyinyoungerpatientsthanothertypesofbreast
cancer.TheyarealsomorefrequentinwomenwhoinheritmutationsoftheBRCA1gene(10percentofbreast
cancersaremedullaryinthispopulation,ascomparedwith<1percentofnonBRCA1relatedbreastcancers).
However,themajorityofbreastcancersinpatientswithBRCA1genemutations(90percent)arenotmedullary
[49].
Theprognosisforpuremedullarycarcinomasappearstobesomewhatmorefavorablethanthatofinfiltrating
ductalcarcinomas,despitetheiraggressivehistologicappearance[1,37,43,50,51].Forexample,inaretrospective
reviewof12,409patientswithbreastcancer,patientswithmedullarycancer(n=127)hadasignificantlyhigher
overall14yeardiseasefreesurvivalratecomparedwithpatientswithinvasiveductalcancer(n=8096)(76versus
64percent,hazardratio[HR]0.52,p=0.0005)[51].Inaddition,patientswithmedullarycanceralsohada
significantlyhigheroverallsurvivalrate(66versus57percent,HR0.75,p=0.03).
TubulolobularcarcinomaTubulolobularcarcinomaisanoftenunrecognizedbreastcancervariantthat,asthe
nameimplies,hashybridhistologiccharacteristicsoftubularandinvasivelobularcarcinomawiththesamecells
comprisingwellformedglandscontiguouswithsinglefileinfiltrationofstroma.Whileimmunohistochemicalstudies
implyaductalphenotype[52],fromaradiologicandclinicalpointofview,thetumorismoreakintoinvasive
lobularcarcinomainthatitsimagingcharacteristicsareidenticaltolobularbreastcancer,andthereisthesame
tendencytomultifocalityandmulticentricity.Intermsofstaging,however,thetumorsbehavemorelikeinvasive
moderatelydifferentiatedductalcarcinomainthattheyhavethesamelikelihoodofnodalmetastaseswhen
matchedbysize.Oftenthesetumorsaremisclassifiedasinvasivecarcinomawithmixedductalandlobular
features.
MicropapillarycarcinomaInvasivemicropapillarycarcinomaisaparticularlyaggressiveformofcancerthat
hasaproclivityforlymphnodemetastasisevenwhensmallinsize[53].
MetaplasticcarcinomaMetaplasticcarcinomaisawellcircumscribedtumorthatconsistsofvarious
combinationsofpoorlydifferentiatedductaladenocarcinoma,mesenchymal(sarcomatous),andotherepithelial
(eg,squamouscell)components[54,55].
Whetherthesetumorshaveaworseprognosisthanordinaryinvasiveductalcancersisunclear.Somestudies
suggestthattumorsinwhichthesquamouscellcomponentpredominates(morethan90percentofthemalignant
cellsareofsquamoustype)aremoreaggressiveandfrequentlytreatmentrefractorywhencomparedwithother
infiltratingductalcancers[56,57].However,becausemetaplasticbreastcancerwasnotofficiallyrecognizedasa
distinctpathologicdiagnosisuntil2000,knowledgeabouttreatmentpatternsandoutcomesislimited.
Thecharacteristicsof892metaplasticbreastcancersreportedtotheNationalCancerDatabasebetween2001
and2003werecomparedwiththoseof255,164typicalinfiltratingductalcarcinomas[55].Incontrasttopatients
withinfiltratingductalcancers,thefollowingsignificantdifferenceswerenotedinthegroupwithmetaplastic
tumors:

FewerT1tumors(30versus65percent)
Morenodenegativetumors(78versus66percent)
Morepoorlydifferentiatedorundifferentiatedtumor(68versus39percent)
Fewerestrogenreceptorpositivetumors(11versus74percent)

Treatmentoutcomeswerenotreported.Despitetheperceptionofaworseprognosis,allmetaplasticbreast
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cancersaretreatedsimilarlytootherinvasivebreastcancers[5860].
AdenoidcysticcarcinomaTherareadenoidcysticcarcinomaofthebreasthasadistinctivehistologicpattern
thatismorphologicallyidenticaltoadenoidcysticcarcinomafoundinthesalivaryglands(andothersites).(See
"Salivaryglandtumors:Epidemiology,diagnosis,evaluation,andstaging".)Thistumortendstobeassociatedwith
afavorableprognosis,evenwhentumorsizeislargethereportedincidenceofaxillarymetastasesinmostseries
islessthan5percent[61,62].
Histologicgradingbaseduponthepercentageofsolidareas(asisusedforsalivaryglandtumors)hasbeen
suggestedasbeingprognosticallyuseful[63],althoughothersdisagree[62].Atleasttwoseriesinwhich
outcomeswerenotasfavorableasinmostreportswerepredominatedbypatientswithhighergradetumors(ie,
thesolidvariant)[64,65].
SUMMARY
DCISischaracterizedbyaproliferationofabnormalcellsconfinedwithinthemammaryductalsystem.(See
'Ductalcarcinomainsitu'above.)
DCISiscommonlyclassifiedaccordingtoarchitecturalandcytologicfeaturesandcellnecrosisaslow
andintermediategrade(papillary,cribriform,andsolid)andhighgrade(comedo).
DCISrepresentsaprecursortoinvasivebreastcancer.
Theinvasivebreastcarcinomasconsistofseveralhistologicsubtypes.
Infiltratingductalcarcinomaisthemostcommontypeofinvasivebreastcancer,accountingfor70to
80percentofinvasivecancers.(See'Infiltratingductalcarcinoma'above.)
Infiltratinglobularcarcinomaisthesecondmostcommoninvasivebreastcancer,accountingfor5to10
percentofinvasivecancers.(See'Infiltratinglobularcarcinoma'above.)
Ascomparedwithinfiltratingductalcarcinomas,infiltratinglobularcarcinomastendtobemulticentric
and/orbilateral,moredifferentiated,hormonereceptorpositive,ariseinolderwomen,metastasizelater,
andspreadtounusuallocations,suchasmeninges,peritoneum,orgastrointestinaltract.(See
'Infiltratinglobularcarcinoma'above.)
Otherlesscommoninvasivebreastcarcinomahistologiesincludetubular,mucinous,andmedullary
carcinomas.(See'Otherhistologictypes'above.)
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REFERENCES
1. LiCI,UribeDJ,DalingJR.Clinicalcharacteristicsofdifferenthistologictypesofbreastcancer.BrJCancer
200593:1046.
2. DillonDA,GuidiAJ,SchnittSJ.Pathologyofinvasivebreastcancer.In:DiseasesoftheBreast,4th,Harris
JR,LippmanME,MorrowM,OsborneCK(Eds),Lippincott,WilliamsandWilkins,Philadelphia2009.p.386.
3. AllredDC.Ductalcarcinomainsitu:terminology,classification,andnaturalhistory.JNatlCancerInst
Monogr20102010:134.
4. AzzopardiJG.ProblemsinBreastPathology,WBSaunders,Philadelphia1963.p.244.
5. PageDL,AndersonTJ.DiagnosticHistopathologyoftheBreast,ChurchillLivingstone,Edinburgh1987.
p.157.
6. RosenPP,ObermanH.TumorsoftheMammaryGland,ArmedForcesInstituteofPathology,Washington,
DC1993.p.143.
7. AlfredC.Ductalcarcinomainsitu.In:DiseasesoftheBreast,4th,HarrisJR,LippmanME,MorrowM,
http://www.uptodate.com/contents/pathologyofbreastcancer?topicKey=ONC%2F783&elapsedTimeMs=1&source=search_result&searchTerm=cancer+de

6/22

5/16/2015

Pathologyofbreastcancer

OsborneCK(Eds),LippincottRaven,Philadelphia2009.p.321.
8. SchwartzGF,PatchefskyAS,FinklesteinSD,etal.Nonpalpableinsituductalcarcinomaofthebreast.
Predictorsofmulticentricityandmicroinvasionandimplicationsfortreatment.ArchSurg1989124:29.
9. SilversteinMJ,WaismanJR,GamagamiP,etal.Intraductalcarcinomaofthebreast(208cases).Clinical
factorsinfluencingtreatmentchoice.Cancer199066:102.
10. FisherER,DignamJ,TanChiuE,etal.PathologicfindingsfromtheNationalSurgicalAdjuvantBreast
Project(NSABP)eightyearupdateofProtocolB17:intraductalcarcinoma.Cancer199986:429.
11. GrabowskiJ,SalzsteinSL,SadlerGR,BlairS.Intracysticpapillarycarcinoma:areviewof917cases.
Cancer2008113:916.
12. EusebiV,FoschiniMP,CookMG,etal.Longtermfollowupofinsitucarcinomaofthebreastwithspecial
emphasisonclingingcarcinoma.SeminDiagnPathol19896:165.
13. FisherER,BrownR.Intraductalsignetringcarcinoma.Ahithertoundescribedformofintraductalcarcinoma
ofthebreast.Cancer198555:2533.
14. RosenPP,ScottM.Cystichypersecretoryductcarcinomaofthebreast.AmJSurgPathol19848:31.
15. LagiosMD,MargolinFR,WestdahlPR,RoseMR.Mammographicallydetectedductcarcinomainsitu.
Frequencyoflocalrecurrencefollowingtylectomyandprognosticeffectofnucleargradeonlocalrecurrence.
Cancer198963:618.
16. PollerDN,SilversteinMJ,GaleaM,etal.Ideasinpathology.Ductalcarcinomainsituofthebreast:a
proposalforanewsimplifiedhistologicalclassificationassociationbetweencellularproliferationandcerbB
2proteinexpression.ModPathol19947:257.
17. HollandR,PeterseJL,MillisRR,etal.Ductalcarcinomainsitu:aproposalforanewclassification.Semin
DiagnPathol199411:167.
18. PinderSE,DugganC,EllisIO,etal.AnewpathologicalsystemforgradingDCISwithimprovedprediction
oflocalrecurrence:resultsfromtheUKCCCR/ANZDCIStrial.BrJCancer2010103:94.
19. BurME,ZimarowskiMJ,SchnittSJ,etal.Estrogenreceptorimmunohistochemistryincarcinomainsituof
thebreast.Cancer199269:1174.
20. MeyerJS.Cellkineticsofhistologicvariantsofinsitubreastcarcinoma.BreastCancerResTreat1986
7:171.
21. KilleenJL,NamikiH.DNAanalysisofductalcarcinomainsituofthebreast.Acomparisonwithhistologic
features.Cancer199168:2602.
22. vandeVijverMJ,PeterseJL,MooiWJ,etal.Neuproteinoverexpressioninbreastcancer.Associationwith
comedotypeductalcarcinomainsituandlimitedprognosticvalueinstageIIbreastcancer.NEnglJMed
1988319:1239.
23. BartkovaJ,BarnesDM,MillisRR,GullickWJ.ImmunohistochemicaldemonstrationofcerbB2proteinin
mammaryductalcarcinomainsitu.HumPathol199021:1164.
24. LodatoRF,MaguireHCJr,GreeneMI,etal.ImmunohistochemicalevaluationofcerbB2oncogene
expressioninductalcarcinomainsituandatypicalductalhyperplasiaofthebreast.ModPathol19903:449.
25. PollerDN,RobertsEC,BellJA,etal.p53proteinexpressioninmammaryductalcarcinomainsitu:
relationshiptoimmunohistochemicalexpressionofestrogenreceptorandcerbB2protein.HumPathol
199324:463.
26. O'MalleyFP,VnencakJonesCL,DupontWD,etal.p53mutationsareconfinedtothecomedotypeductal
carcinomainsituofthebreast.Immunohistochemicalandsequencingdata.LabInvest199471:67.
27. GuidiAJ,FischerL,HarrisJR,SchnittSJ.Microvesseldensityanddistributioninductalcarcinomainsitu
ofthebreast.JNatlCancerInst199486:614.
28. BobrowLG,HapperfieldLC,GregoryWM,etal.Theclassificationofductalcarcinomainsituandits
associationwithbiologicalmarkers.SeminDiagnPathol199411:199.
29. ZafraniB,LeroyerA,FourquetA,etal.Mammographicallydetectedductalinsitucarcinomaofthebreast
analyzedwithanewclassification.Astudyof127cases:correlationwithestrogenandprogesterone
receptors,p53andcerbB2proteins,andproliferativeactivity.SeminDiagnPathol199411:208.
30. WrnbergF,NordgrenH,BerghJ,HolmbergL.Ductalcarcinomainsituofthebreastfromapopulation
definedcohort:anevaluationofnewhistopathologicalclassificationsystems.EurJCancer199935:714.
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5/16/2015

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31. ConsensusConferenceontheclassificationofductalcarcinomainsitu.TheConsensusConference
Committee.Cancer199780:1798.
32. ElstonCW,EllisIO.Pathologicalprognosticfactorsinbreastcancer.I.Thevalueofhistologicalgradein
breastcancer:experiencefromalargestudywithlongtermfollowup.Histopathology200241:154.
33. AbnerAL,ConnollyJL,RechtA,etal.Therelationbetweenthepresenceandextentoflobularcarcinomain
situandtheriskoflocalrecurrenceforpatientswithinfiltratingcarcinomaofthebreasttreatedwith
conservativesurgeryandradiationtherapy.Cancer200088:1072.
34. OrvietoE,MaioranoE,BottiglieriL,etal.Clinicopathologiccharacteristicsofinvasivelobularcarcinomaof
thebreast:resultsofananalysisof530casesfromasingleinstitution.Cancer2008113:1511.
35. WinchesterDJ,ChangHR,GravesTA,etal.Acomparativeanalysisoflobularandductalcarcinomaofthe
breast:presentation,treatment,andoutcomes.JAmCollSurg1998186:416.
36. PestalozziBC,ZahriehD,MallonE,etal.Distinctclinicalandprognosticfeaturesofinfiltratinglobular
carcinomaofthebreast:combinedresultsof15InternationalBreastCancerStudyGroupclinicaltrials.J
ClinOncol200826:3006.
37. LiCI,MoeRE,DalingJR.Riskofmortalitybyhistologictypeofbreastcanceramongwomenaged50to79
years.ArchInternMed2003163:2149.
38. CristofanilliM,GonzalezAnguloA,SneigeN,etal.Invasivelobularcarcinomaclassictype:responseto
primarychemotherapyandsurvivaloutcomes.JClinOncol200523:41.
39. FerlicotS,VincentSalomonA,MdioniJ,etal.Widemetastaticspreadingininfiltratinglobularcarcinomaof
thebreast.EurJCancer200440:336.
40. BerxG,CletonJansenAM,StrumaneK,etal.Ecadherinisinactivatedinamajorityofinvasivehuman
lobularbreastcancersbytruncationmutationsthroughoutitsextracellulardomain.Oncogene199613:1919.
41. DeLeeuwWJ,BerxG,VosCB,etal.SimultaneouslossofEcadherinandcateninsininvasivelobular
breastcancerandlobularcarcinomainsitu.JPathol1997183:404.
42. LiuGF,YangQ,HafftyBG,MoranMS.Clinicalpathologicfeaturesandlongtermoutcomesoftubular
carcinomaofthebreastcomparedwithinvasiveductalcarcinomatreatedwithbreastconservationtherapy.
IntJRadiatOncolBiolPhys200975:1304.
43. ThurmanSA,SchnittSJ,ConnollyJL,etal.Outcomeafterbreastconservingtherapyforpatientswithstage
IorIImucinous,medullary,ortubularbreastcarcinoma.IntJRadiatOncolBiolPhys200459:152.
44. SullivanT,RaadRA,GoldbergS,etal.Tubularcarcinomaofthebreast:aretrospectiveanalysisandreview
oftheliterature.BreastCancerResTreat200593:199.
45. DiSaverioS,GutierrezJ,AvisarE.Aretrospectivereviewwithlongtermfollowupof11,400casesofpure
mucinousbreastcarcinoma.BreastCancerResTreat2008111:541.
46. GaffeyMJ,MillsSE,FriersonHFJr,etal.Medullarycarcinomaofthebreast:interobservervariabilityin
histopathologicdiagnosis.ModPathol19958:31.
47. RidolfiRL,RosenPP,PortA,etal.Medullarycarcinomaofthebreast:aclinicopathologicstudywith10
yearfollowup.Cancer197740:1365.
48. WargotzES,SilverbergSG.Medullarycarcinomaofthebreast:aclinicopathologicstudywithappraisalof
currentdiagnosticcriteria.HumPathol198819:1340.
49. ArmesJE,VenterDJ.Thepathologyofinheritedbreastcancer.Pathology200234:309.
50. VuNishinoH,TavassoliFA,AhrensWA,HafftyBG.Clinicopathologicfeaturesandlongtermoutcomeof
patientswithmedullarybreastcarcinomamanagedwithbreastconservingtherapy(BCT).IntJRadiatOncol
BiolPhys200562:1040.
51. HuoberJ,GelberS,GoldhirschA,etal.Prognosisofmedullarybreastcancer:analysisof13International
BreastCancerStudyGroup(IBCSG)trials.AnnOncol201223:2843.
52. EspositoNN,ChivukulaM,DabbsDJ.TheductalphenotypicexpressionoftheEcadherin/catenincomplex
intubulolobularcarcinomaofthebreast:animmunohistochemicalandclinicopathologicstudy.ModPathol
200720:130.
53. WalshMM,BleiweissIJ.Invasivemicropapillarycarcinomaofthebreast:eightycasesofan
underrecognizedentity.HumPathol200132:583.
54. TavassoliFA.Classificationofmetaplasticcarcinomasofthebreast.PatholAnnu199227Pt2:89.
http://www.uptodate.com/contents/pathologyofbreastcancer?topicKey=ONC%2F783&elapsedTimeMs=1&source=search_result&searchTerm=cancer+de

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Pathologyofbreastcancer

55. PezziCM,PatelParekhL,ColeK,etal.Characteristicsandtreatmentofmetaplasticbreastcancer:
analysisof892casesfromtheNationalCancerDataBase.AnnSurgOncol200714:166.
56. HennessyBT,KrishnamurthyS,GiordanoS,etal.Squamouscellcarcinomaofthebreast.JClinOncol
200523:7827.
57. BehranwalaKA,NasiriN,AbdullahN,etal.Squamouscellcarcinomaofthebreast:clinicopathologic
implicationsandoutcome.EurJSurgOncol200329:386.
58. DaveG,CosmatosH,DoT,etal.Metaplasticcarcinomaofthebreast:aretrospectivereview.IntJRadiat
OncolBiolPhys200664:771.
59. RaysonD,AdjeiAA,SumanVJ,etal.Metaplasticbreastcancer:prognosisandresponsetosystemic
therapy.AnnOncol199910:413.
60. ChaoTC,WangCS,ChenSC,ChenMF.Metaplasticcarcinomasofthebreast.JSurgOncol1999
71:220.
61. VranicS,BenderR,PalazzoJ,GatalicaZ.Areviewofadenoidcysticcarcinomaofthebreastwith
emphasisonitsmolecularandgeneticcharacteristics.HumPathol201344:301.
62. KleerCG,ObermanHA.Adenoidcysticcarcinomaofthebreast:valueofhistologicgradingandproliferative
activity.AmJSurgPathol199822:569.
63. RoJY,SilvaEG,GallagerHS.Adenoidcysticcarcinomaofthebreast.HumPathol198718:1276.
64. MillarBA,KerbaM,YoungsonB,etal.Thepotentialroleofbreastconservationsurgeryandadjuvantbreast
radiationforadenoidcysticcarcinomaofthebreast.BreastCancerResTreat200487:225.
65. ShinSJ,RosenPP.Solidvariantofmammaryadenoidcysticcarcinomawithbasaloidfeatures:astudyof
ninecases.AmJSurgPathol200226:413.
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GRAPHICS
Comparativefeaturesofductalcarcinomainsitu(DCIS)andlobular
carcinomainsitu(LCIS)

Presentation

DCIS

LCIS

Incidentalfinding,mammographicabnormality,

Incidentalfinding,

occasionallypalpable,unifocal

oftenmultifocal

Predominantlocation

Ducts

Lobules

Cellsize

Mediumorlarge

Small

Pattern

Comedo,cribriform,micropapillary,papillary,
solid

Solid

Calcifications

Yesorno

Usuallyno

Riskofsubsequent
invasivecancer

Higher

Lower

Locationofsubsequent

Ipsilateral

Ipsilateralor

invasivecancer

contraleteral

Graphic72750Version1.0

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Comedoductalcarcinomainsitu

Lightmicroscopicspecimenofcomedoductalcarcinomainsitushows
alargecentralareaofnecrosisthatisfocallycalcified.Thenucleiare
poorlydifferentiated(highgrade).
CourtesyofStuartSchnitt,MD.
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Cribriformductalcarcinomainsitu

Lightmicrographofalesionfromthebreastofawomanwith
cribriformductalcarcinomainsitushowsabacktobackglandular
growthpattern.Thenucleiarewelldifferentiated(lowgrade).Asmall
calcificationisnotednearthecenteroftheinvolvedspace(arrow).
CourtesyofStuartSchnitt,MD.
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Micropapillaryductalcarcinomainsitu

Lightmicrographofaspecimenfromthebreastofawomenwith
micropapillaryductalcarcinomainsitu.Thetumorcellsformtufts
whichprojectintothelumenoftheinvolvedspace.Thenucleiare
welldifferentiated(lowgrade).
CourtesyofStuartSchnitt,MD.
Graphic58302Version2.0

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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.
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GradeIinfiltratingductalcarcinomaofthebreast

(PanelA)Lowpowerviewofawelldifferentiatedinfiltratingductalcarcinomashows
tumorcellswhichinfiltratethestromaassolidnestsandglands.
(PanelB)Highpowerviewdemonstratesrelativelyuniformnucleiwithnoevidenceof
mitoticactivity.
CourtesyofStuartSchnitt,MD.
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GradeIIinfiltratingcarcinomaofthebreast

(PanelA)Lowpowerviewofamoderatelydifferentiatedbreastcarcinomashowstumor
cellsinfiltratingassolidnestswithsomeglandulardifferentiation.
(PanelB)Highpowerviewdemonstratessomenuclearpleomorphisminthetumorcells.
CourtesyofStuartSchnitt,MD.
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GradeIIIinfiltratingductalcarcinomaofthebreast

(PanelA)Lowpowerviewofapoorlydifferentiatedbreastcarcinomashowsthatthe
tumoriscomposedofsolidnestsofneoplasticcellswithoutevidenceofglandformation.
(PanelB)Thehighpowerviewdemonstratesmarkednuclearatypiainthetumorcellswith
considerablemitoticactivity.
CourtesyofStuartSchnitt,MD.
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Infiltratinglobularcarcinomaofthebreast

(PanelA)Lowpowerviewofaninfiltratinglobularbreastcarcinomashowssmalltumor
cellsthatinfiltratethestromasinglyandinasinglefilepattern.
(PanelB)Highpowerviewdemonstratesthatthetumorcellsarerelativelysmalland
uniforminappearance.
CourtesyofStuartSchnitt,MD.
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Tubularcarcinomaofthebreast

(PanelA)Lowpowerviewofatubularbreastcarcinomashowsthatthetumoriscomposed
ofwellformedglandsortubulesthatinvadethemammarystroma.
(PanelB)Highpowerviewdemonstratesthatthetubulesarecomposedofcolumnarcells
withrelativelyuniformnuclei.Manyofthecellsshow"snouts"ofeosinophiliccytoplasmat
theirlumenalends.
CourtesyofStuartSchnitt,MD.
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Mucinouscarcinomaofthebreast

(PanelA)Lowpowerviewofamucinousbreastcarcinomashowssmallnestsoftumorcells
dispersedinlargepoolsofextracellularmucous.
(PanelB)Highpowerviewdemonstratesthatthenestsarecomposedofcellswith
relativelyuniform,lowgradenuclei.
CourtesyofStuartSchnitt,MD.
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Medullarycarcinomaofthebreast

(PanelA)Lowpowerviewofamedullarybreastcarcinomashowsthatthetumorhasawell
circumscribedborder.
(PanelB)Highpowerviewdemonstratesthatthetumorcellsgrowinasyncytialpattern
andhavemarkednuclearatypia.Aprominentlymphoplasmacyticinfiltrateisalsopresent.
CourtesyofStuartSchnitt,MD.
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Disclosures
Disclosures:IraJBleiweiss,MDNothingtodisclose.AneesBChagpar,MD,MSc,MA,MPH,MBA,FACS,FRCS(C)Nothingto
disclose.DonSDizon,MD,FACPNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthrougha
multilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriatelyreferenced
contentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
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