CytologyCytology of of PleuralPleural FluidFluid as a as a

DiagnosticDiagnostic ChallengeChallenge

Paavo Paavo PääkköPääkkö, MD, , MD, PhDPhD

ChiefChief PhysicianPhysician and and HeadHead of the of the DepartmentDepartment

DepartmentDepartment of of PathologyPathology,,

Oulu Oulu UniversityUniversity HospitalHospital, Finland, Finland

Oulu University Hospital

General General overviewoverview of of cytologycytology of of

pleuralpleural effusionseffusions

!! ExfoliativeExfoliative cytologicalcytological examinationexamination of of pleuralpleural effusionseffusionscommon common methodmethod for for determiningdetermining whetherwhether effusioneffusion is isbenignbenign oror malignantmalignant

!! EffusionsEffusions subdividedsubdivided into into transudatestransudates and and exudatesexudatesdependingdepending on the on the proteinprotein contentcontent

!! TransudatesTransudates resultresult fromfrom alterationsalterations in in hydrostatichydrostatic ororoncoticoncotic pressurepressure, , oftenoften duedue to to systemicsystemic factorsfactors, , e.ge.g..congestivecongestive heartheart failurefailure

!! ExudatesExudates resultresult fromfrom pathologicalpathological processesprocesses localizedlocalizedto the to the serosalserosal membranesmembranes => => higherhigher proteinprotein contentcontentand and cellularitycellularity increasedincreased comparedcompared to to transudatestransudates, , e.ge.g..infectionsinfections

UtilityUtility and and limitationslimitations of of cytologycytology of of

pleuralpleural effusionseffusions

!! CellsCells exfoliatedexfoliated into into effusioneffusion fluidfluid cancan bebe examinedexamined as as

cytologycytology smearssmears, , liquid-basedliquid-based preparationspreparations, , cytospincytospin

preparationspreparations, , oror cellcell blocksblocks

!! MostMost of the of the exudatesexudates benignbenign

!! The The absenceabsence of of malignantmalignant cellscells doesdoes notnot rulerule out out

malignancymalignancy

!! OnlyOnly 30-40 % of 30-40 % of malignantmalignant mesotheliomasmesotheliomas, and 60-70, and 60-70

% of % of cancerscancers metastaticmetastatic to the to the pleurapleura diagnoseddiagnosed byby

exfoliativeexfoliative cytologycytology

CytologyCytology vs. vs. histologyhistology

!! ExfoliativeExfoliative cytologycytology hashas of of limitedlimited usefulnessusefulness in indiagnosingdiagnosing malignantmalignant mesotheliomamesothelioma

!! BenignBenign reactivereactive mesothelialmesothelial cellscells maymay havehave featuresfeatures thatthatmimicmimic malignancymalignancy, and , and malignantmalignant mesotheliomasmesotheliomas maymaybebe cytologicallycytologically blandbland

!! WithoutWithout evidenceevidence of of invasioninvasion of of underlyingunderlying tissuestissues,,diagnosisdiagnosis of of mesotheliomamesothelioma on on cytologiccytologic groundsgrounds maybemaybedifficultdifficult

!! SarcomatousSarcomatous mesotheliomasmesotheliomas typicallytypically dodo notnot shedshed cellscellsinto into effusioneffusion

CytologicalCytological featuresfeatures of of malignancymalignancy

!! CancerCancer cellscells as as individualindividual cellscells, , sheetssheets of of cohesivecohesive cellscells,,

and and three-dimensionalthree-dimensional sphericalspherical clustersclusters, , calledcalled morulaemorulae

!! PapillaryPapillary oror acinaracinar structuresstructures

!! UsuallyUsually the the numbernumber of of malignantmalignant cellscells highhigh, , rarelyrarely a a fewfew

!! PresencePresence of of psammomapsammoma bodiesbodies

!! EnlargedEnlarged cellscells withwith enlargedenlarged nucleinuclei, , coarsecoarse chromatinchromatin,,

prominentprominent nucleolinucleoli

!! MitosesMitoses, , atypicalatypical mitosesmitoses, and , and necroticnecrotic debrisdebris

ReactiveReactive atypiaatypia of of mesothelialmesothelial cellscells

!! BenignBenign mesothelialmesothelial cellscells exfoliateexfoliate easilyeasily and and

displaydisplay a a spectrumspectrum of of reactivereactive changeschanges fromfrom

minimalminimal reactivereactive changechange to to highlyhighly atypicalatypical

reactivereactive changechange, , mimickingmimicking malignancymalignancy

!! ReactiveReactive mesothelialmesothelial cellscells shedshed as as invidualinvidual cellscells,,

in in clustersclusters oror sheetssheets, , withwith adjacentadjacent cellscells

separatedseparated fromfrom oneone anotheranother byby spacesspaces referredreferred

to as to as ””windowswindows””

CytologicalCytological featuresfeatures of of reactivereactive

mesothelialmesothelial cellscells

!! NucleiNuclei roundround oror ovaloval withwith distictdistict nuclearnuclear membranesmembranes,,

chromatinchromatin vesicularvesicular oror finelyfinely granulargranular, and , and cytoplasmcytoplasm

adundantadundant and and darkly-staineddarkly-stained

!! PeripheralPeripheral cytoplasmcytoplasm stainsstains darkerdarker thanthan centralcentral

cytoplasmcytoplasm, and , and microvillimicrovilli aroundaround the the peripheryperiphery resultresult in in

fuzzyfuzzy rimrim oror borderborder

!! BinucleationBinucleation oror multinucleationmultinucleation frequentfrequent

!! CytoplasmicCytoplasmic vacuolesvacuoles maymay compresscompress the the nucleusnucleus,,

suggestingsuggesting the the signetsignet ringring cellscells of of adenocarcinomaadenocarcinoma

ReactiveReactive mesothelialmesothelial cellscells

CytologicalCytological featuresfeatures of of malignantmalignant

mesotheliomamesothelioma

!! MalignantMalignant mesotheliomasmesotheliomas causecause <1 % of <1 % of

malignantmalignant pleuralpleural effusionseffusions, and , and onlyonly epithelialepithelial

malignantmalignant mesotheliomasmesotheliomas likelylikely exfoliateexfoliate cellscells

into into effusioneffusion fluidsfluids

!! MalignantMalignant mesotheliomamesothelioma cellscells lacklack the the significantsignificant

degreedegree of of cytologicalcytological pleomorphismpleomorphism

!! CellsCells arrangedarranged in in sheetssheets, , clustersclusters, , morulaemorulae oror

papillarypapillary structuresstructures

HintsHints for for correctcorrect interpretationinterpretation

!! AtypicalAtypical reactivereactive mesothelialmesothelial cellscells blendblend withwith cellscells withwith lesserlesserdegreesdegrees of of reactivereactive atypiaatypia withinwithin a a benignbenign effusioneffusion, , givinggiving the theimpression of impression of oneone populationpopulation of of cellscells

!! In In casescases of of malignancymalignancy, , reactivereactive mesothelialmesothelial cellscells and and malignantmalignantcellscells oftenoften appearappear as as twotwo separateseparate and and distinctdistinct populationpopulation of of cellscells

!! ItIt is is necessarynecessary to to firstfirst determinedetermine ifif cellscells in a in a fluidfluid areare trulytrulymalignantmalignant beforebefore secondarilysecondarily determiningdetermining the the typetype of of malignancymalignancy

!! ImmunohistochemicalImmunohistochemical confirmationconfirmation thatthat atypicalatypical cellscells arearemesothelialmesothelial in in originorigin doesdoes notnot help to help to distinguishdistinguish betweenbetweenreactivereactive mesothelialmesothelial cellcell proliferationproliferation and and mesotheliomamesothelioma

Case 1Case 1

!! 60-year 60-year oldold manman

!! ExposedExposed to to asbestosasbestos

!! HydrothoraxHydrothorax and and pleuralpleural plaquesplaques

!! CytologicalCytological specimenspecimen takentaken fromfrom pleuralpleural cavitycavity

Calretinin

CK 5/6

CK7

EMA

ConclusionConclusion fromfrom Case 1 Case 1

!! StrongStrong suspicionsuspicion for for malignancymalignancy, , fittingfitting ratherrather

for for malignantmalignant mesotheliomamesothelioma thanthan metastaticmetastatic

adenocarcinomaadenocarcinoma

!! The The diagnosisdiagnosis of of malignantmalignant mesotheliomamesothelioma waswas

laterlater confirmedconfirmed byby histologicalhistological samplesample

Calretinin

WT1

EMA

Case 2Case 2

!! 76-year 76-year oldold malemale

!! SuspicionSuspicion for for lunglung malignancymalignancy

!! HydrothoraxHydrothorax

!! An An aspirationaspiration fromfrom leftleft pleuralpleural cavitycavity performedperformed,,

and and cytologicalcytological analysesanalyses requestedrequested

TTF-1

CK 7

CK 5/6

EMA

E-Cadherin

Calretinin

ConclusionConclusion fromfrom Case 2 Case 2

!! StrongStrong suspicionsuspicion for a for a metastaticmetastatic carcinomacarcinoma

!! TTF-1 TTF-1 positivitypositivity suggestssuggests for for pulmonarypulmonary originorigin

of the of the carcinomacarcinoma

Case 3Case 3

!! 76-year 76-year oldold femalefemale

!! BreastBreast carcinomacarcinoma operatedoperated 6 6 yearsyears agoago

!! FluidFluid in the in the pleuralpleural cavitycavity and and bothboth lungslungs

containcontain tumourtumour infiltrationsinfiltrations

!! PleuralPleural cytologycytology requestedrequested

PAN-CK

CK 5/6 Estrogen receptor

ConnclusionConnclusion fromfrom Case 3 Case 3

!! StrongStrong suspicionsuspicion for a for a metastaticmetastatic carcinomacarcinoma

!! EstrogenEstrogen receptor-positivityreceptor-positivity suggestssuggests for a for a

metastaticmetastatic breastbreast carcinomacarcinoma

Case 4Case 4

!! 76-year 76-year oldold malemale

!! LaryngealLaryngeal squamoussquamous cellcell carcinomacarcinoma operatedoperated

19931993

!! COPDCOPD

!! Heavy Heavy smokersmoker

!! AbundantAbundant fluidfluid in the in the leftleft pleuralpleural cavitycavity

CK 7 CK 7

CK 5/6

TTF-1

Calretinin

ConclusionConclusion fromfrom Case 4 Case 4

!! MildMild suspicionsuspicion for a for a malignancymalignancy, , originorigin of of whichwhich

possiblypossibly in the in the lungslungs

!! In In additionaddition, the , the cellcell populationpopulation containedcontained

atypicalatypical mesothelialmesothelial cellcell proliferationproliferation

SummarySummary and and conclusionsconclusions

!! MostMost of the of the exudatesexudates benignbenign

!! The The absenceabsence of of malignantmalignant cellscells doesdoes notnot rulerule out outmalignancymalignancy

!! MalignantMalignant mesotheliomasmesotheliomas causecause <1 % of <1 % of malignantmalignantpleuralpleural effusionseffusions, and , and onlyonly epithelialepithelial malignantmalignantmesotheliomasmesotheliomas likelylikely exfoliateexfoliate cellscells into into effusioneffusion fluidsfluids

!! ItIt is is necessarynecessary to to firstfirst determinedetermine ifif cellscells in a in a fluidfluid arearetrulytruly malignantmalignant beforebefore secondarilysecondarily determiningdetermining the the typetypeof of malignancymalignancy

!! ImmunohistochemistryImmunohistochemistry of of histologicalhistological sectionssections fromfrom a acellcell blockblock maymay help to help to determinedetermine the the typetype of of malignancymalignancy