Resultados del seguimiento a largo plazo de pacientes con derrame pleural no diagnosticado

w w w. a r c h b r o n c o n e u m o l . o r g

Original

Article

Long-term

Outcome

of

Patients

with

Undiagnosed

Pleural

Effusion

夽

Gulsah

Gunluoglu,

_Aysun

_Olcmen,

_Mehmet

_Zeki

_Gunluoglu,

_Ibrahim

_Dincer,

_Adnan

_Sayar,

Gungor

Camsari,

_Veysel

_Yilmaz,

_Sedat

_Altin

a_{YedikuleTeachingHospitalforChestDiseasesandThoracicSurgery,ChestDiseases,Buc¸alıs¸maTürkToraksDerne˘gi17,YıllıkKongresinde3.4.2014tarihinde‘SözelSunum’olarak} sunulmus¸tur,Estambul,Turkey

b_{YedikuleTeachingHospitalforChestDiseasesandThoracicSurgery,ThoracicSurgery,Buc¸alıs¸maTürkToraksDerne˘gi17,YıllıkKongresinde3.4.2014tarihinde‘SözelSunum’olarak} sunulmus¸tur,Estambul,Turkey

c_{MedipolUniversityFacultyofMedicine,ThoracicSurgery,Buc¸alıs¸maTürkToraksDerne˘gi17,YıllıkKongresinde3.4.2014tarihinde‘SözelSunum’olaraksunulmus¸tur,Estambul,} Turkey

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t

i

c

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Articlehistory:

Received5September2014 Accepted29September2014 Availableonline21November2015 Keywords:

Exudativepleuraleffusion Nonspecificpleuritis

Video-assistedthoracoscopicsurgery Idiopathicpleuritis

a

b

s

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Introduction:Thecauseofexudativepleuraleffusioncannotbedeterminedinsomepatients.The long-termoutcomesofpatientswithundiagnosedpleuraleffusionwereanalyzed.

Methods:Patientswithexudativepleuraleffusionwhosediagnosticproceduresincludedpleuralbiopsy usingvideo-assistedthoracoscopicsurgerycarriedoutbetween2008and2012wereevaluated retrospec-tively.Patientsdiagnosedwithnonspecificpleuritiswereincluded.Fifty-threepatientswithavailable follow-updatawereincludedinthestudy.

Results:Fortymenand13women(meanage53.9±13.9years)wereincluded.Medianfollow-uptime was24months.Nodiagnosiswasgivenin27patients(51%),andaclinicaldiagnosiswasgivenin26 patients(49%)duringthefollow-upperiod.Malignantdisease(malignantmesothelioma)wasdiagnosed in2(3.7%)patients.Otherdiseaseswereparapneumoniceffusionin12,congestiveheartfailurein8,and miscellaneousin4patients.Volumeofeffusionatthetimeofinitialexaminationandre-accumulation offluidaftervideo-assistedthoracoscopicsurgerywereassociatedwithmalignantdisease(P=.004and .0001,respectively).

Conclusion:Althoughtheprobabilityislow,somepatientswithexudativepleuraleffusionundiagnosed afterpleuralbiopsyviavideo-assistedthoracoscopicsurgerymayhavemalignantdisease.Patientswith aninitiallylargevolumeofeffusionthatre-accumulatesafterexaminationshouldbecloselymonitored. ©2014SEPAR.PublishedbyElsevierEspaña,S.L.U.Allrightsreserved.

Resultados

del

seguimiento

a

largo

plazo

de

pacientes

con

derrame

pleural

no

diagnosticado

Palabrasclave:

Derramepleuralexudativo Pleuritisinespecífica

Cirugíatoracoscópicavideoasistida Pleuritisidiopática

r

e

s

u

m

e

n

Introducción:Enalgunospacientesnoesposibleestablecerlacausadelderramepleuralexudativo.Sehan analizadolosresultadosdelseguimientoalargoplazodepacientesconderramepleuralnodiagnosticado. Métodos:Seevaluóretrospectivamenteapacientesconderramepleuralexudativoalosqueseleshabía realizadounabiopsiapleuralmediantecirugíatoracoscópicavideoasistida(VATS)entre2008y2012 comopartedelosprocedimientosdiagnósticos.Enelestudioseincluyóa53pacientescondiagnóstico depleuritisinespecíficaycondatosdeseguimientodisponibles.

Resultados: Seincluyóa40varonesy13mujeres(promediodeedad,53,9±13,9a ˜nos).Lamediana detiempodeseguimientofuede24meses.Duranteelseguimientonosellegóaundiagnósticoen

夽 Pleasecitethisarticleas:GunluogluG,OlcmenA,GunluogluMZ,DincerI,SayarA,CamsariG,etal.Resultadosdelseguimientoalargoplazodepacientesconderrame pleuralnodiagnosticado.ArchBronconeumol.2015;51:632–636.

∗ Correspondingauthor.

E-mailaddress:gunluoglu@yahoo.com(G.Gunluoglu).

27pacientes(51%)ysealcanzódiagnósticoclínicoenlos26pacientesrestantes(49%).A2pacientes(3,7%) selesdiagnosticóneoplasiamaligna(mesoteliomamaligno).Otrasenfermedadesdiagnosticadasfueron derrameparaneumónicoen12casos,insuficienciacardíacacongestivaen8casosyotrasafeccionesen 4pacientes.ElvolumendelderrameenlaexploracióninicialylareacumulacióndefluidotrasVATSse asociaronaneoplasiamaligna(p=0,004y0,0001,respectivamente).

Conclusión: Aunquelaprobabilidadesbaja,lospacientesconderramepleuralexudativoysin diagnós-ticotrasunabiopsiapleuralmedianteVATSpuedentenerneoplasiamaligna.Esnecesariocontrolar cuidadosamente a los pacientes con un volumen de derrame inicial alto que reaparece tras la exploración.

©2014SEPAR.PublicadoporElsevierEspaña,S.L.U.Todoslosderechosreservados.

Introduction

Pleural effusion is frequently identified in patients with pulmonary orpleural diseases,and it canalso occurin associ-ation with some systemic diseases, medication use and organ dysfunction.1

Thecauseof exudativepleural effusion(EPE) canusuallybe determinedthroughmicrobiological,biochemicalandcytological analysesofa fluid sample,and sometimesbyexaminationof a closedpleural biopsy.However, nounderlyingdiseaseis found in∼20%ofpatientswithEPE.2,3_{Athoracoscopicexaminationand}

evaluationofpleuralbiopsiesmaybediagnosticinover90%ofthese patients.4–7 _{Inthisstudy,weinvestigateddiseasesthatoccurred}

duringlong-termfollow-upinpatientswithoutaspecificpleural diseasediagnosisdespiteanalysesoftheirpleuralfluidsamplesand pleuralbiopsiesobtainedbyvideo-assistedthoracoscopicsurgery (VATS).Wedeterminedthelikelihoodofdiseasedpleurainthis patientgroup.Wealsoidentifiedvariablesthatindicatedthe exist-enceofdiseasedpleura.

PatientsandMethods

Weretrospectivelyevaluatedandfolloweduppatientswitha diagnosisofEPEatourclinicbetweenJanuary2008and Decem-ber2012.Patientswithlung,pleuralormediastinaltumorswere excluded.PatientswithpleuralbiopsyspecimensobtainedbyVATS wereselected toensurethat the effusionhad been adequately investigated. Those with a specific histopathological diagnosis receivedappropriate treatment.We identified 61 patientswith nospecificdiagnosis;histopathologicalfindingsfromtheir pleu-ralspecimenswereinterpretedasacuteandchronicinflammation orfibrosisofvaryingdegrees.Ofthesepatients,53withavailable follow-up datawere includedfromthe study.These 53 partic-ipants were examinedin our clinicregularly,and pleural fluid andspecimenswereobtainedandre-examinedwhennecessary. Data on the prognosis of these patients during follow-up and theirlatestdiagnoseswererecordedinpatientfilesandentered intothehospital’selectronicdatabase.Thisstudywasperformed inaccordance withtheprinciplesoftheDeclarationofHelsinki and approved by the Ethics Committee of the Yedikule Chest Diseases and Thoracic Surgery Trainingand Research Hospital. Followingethics committeeapproval, the dataobtainedduring theinitialexaminationofthesepatientsandtheirfollow-upand imagingdatawereretrieved.Variableswereanalyzed retrospec-tively.

Thevolumeofpleural effusionwascategorizedaccordingto whetherthefluidoccupiedlessormorethan50%ofthehemithorax,

asdeterminedfromchestX-raystakenduringtheinitial examina-tion.

Fluidsampleswereobtainedbydiagnosticthoracentesisfrom allpatientsandanalyzed.Biochemicalparametersincluded lac-tate dehydrogenase (LDH), protein, albumin,pHand adenosine deaminase,and cells in fluidsamples werecountedand typed. Cytological examination of fluids from all patients was per-formed. The fluid specimens of some patientswere tested for Mycobacterium tuberculosis(direct microscopy and specific cul-ture).ClosedpleuralbiopsyusinganAbram’sneedlewasperformed in 27 patients; pathology results reported “nonspecific pleuri-tis.”

VATS was performed in the operating room under general anesthesiabythoracicsurgeonsexperiencedinVATSprocedures. Incisionpointsweredeterminedaccordingtothelocationofthe fluid and theconditionofthepleura andlungs. Parietalpleura sampleswereobtainedfromaregionthoughttobediseased.Ifno suchregionwasevident,atleasttwoparietalpleurasampleswere obtainedfromvariousregionsofthepleura,eachwithadiameter of∼3cm.

Themeanfollow-upperiodofpatientswithnospecificdiagnosis was22.91months(median24months;range6–60months).

Duringfollow-up,adiagnosisofheartfailurewasgivenwhen impairedcardiacfunctionwasidentifiedandthefluidregressed withdiuretictreatment.A diagnosisofparapneumoniceffusion wasgivenwhenpleuralinflammationwasseenduringVATSand clinical complaintsand biochemical parameters improved after appropriateantibiotictherapy.

Statistics

TheChi-squaredorFisher’sexacttestwasusedtocompare fre-quencies,andSpearman’stestwasusedtoevaluatecorrelations. P<0.05wasconsideredtoindicateasignificantdifference.

Results

Forty patients were men and 13 were women (mean age 53.9±13.9 years; range 27–77 years). Twenty-nine patients weresmokersand24 werenonsmokers.Only16patients com-plained of chestpain. The pleural fluid appearance wasserous in 34 patients, serofibrinous in 12, and serohemorrhagic in 7 patients.

Duringthefollow-upperiod,nospecificdiagnosiswasgiven in 27 (51%) of the patients. Effusion did not relapse in 24 of thesepatients.Re-accumulationofeffusionwasobservedinonly 3 patients; however, no invasive intervention was attempted becausetheirclinicalconditions werestableandthevolumeof

Table1

Finaldiagnosesafterfollow-up.

Diagnosis Number(%) Parapneumoniceffusion 12(22.6) Heartfailure 8(15.1) Tuberculosis-inducedeffusion 1(1.8) Pulmonaryembolism 1(1.8) Churg–Strausssyndrome 1(1.8) Drug-inducedeffusion 1(1.8) Malignantmesothelioma 2(3.7) Total 26(49)

re-accumulatedfluidwassmall.Adiagnosisof“idiopathic pleu-ritis”wasacceptedinpatientsinwhomnospecificdiagnosiscould bemade.

Basedonsymptomsandtheresultsoffollow-upexaminations, a possible cause of effusion was found and a specific diagno-siswasmadein 26(49%) patients.Thediagnosesareshown in

Table1.

Diagnosesofparapneumonic effusionandheart failurewere madebasedonthecriteriaspecifiedinthePatientsandMethods section.Inonepatient,adiagnosisoftuberculosis-relatedeffusion wasgivenwhenuterineandperitonealtuberculosiswerefound and pleural fluid regressed following anti-tuberculosis therapy. Patientsdiagnosedwithpulmonaryembolismshowedno pathol-ogyoncomputedtomographyangiography(whichwasrequired priortoVATS),butanembolismwasidentifiedinsubsequent exam-inations.Onepatienthad intenseeosinophilicinfiltrationinthe pleural biopsy sample, leading toa diagnosis of Churg–Strauss syndrome in view of paranasal sinus anomaly, eosinophilia in peripheralblood, anda historyofasthma. Inthis patient,there wasnorecurrenceofeffusionaftersystemiccorticosteroid ther-apy.Fluidre-accumulationafterVATSwasseeninanotherpatient, butthis wasresolvedaftervalproicacidwhichthepatient had beenusingwasdiscontinued. Thediagnosisofthis patientwas drug-inducedeffusion.

In 2 patients, diagnosis was malignant mesothelioma. After their initialVATS procedures, re-accumulation of effusion was observed. One of these patients was diagnosed on the basis of pleural fluid cytology performed 11 months after the VATS intervention;theotherpatientwasdiagnosedonthebasisof a biopsyobtainedbyVATS24monthsafterthefirstVATS interven-tion.

VATSisknowntobenon-diagnostic inpatientswith malig-nantmesothelioma.Thefalse-negativerateofVATSforpatients with EPE in this study was 3.7%. We examined factors that may have affected the diagnosis of malignancy in this patient group. A weak (r=0.29) but significant correlation was found between age and the possibility of malignancy (P=0.04). Both patientswithmalignantmesotheliomaweremen;however,sex was not associated with malignancy (r=0.1, P=0.47). The two patientswithmalignantmesotheliomadidnotinitiallyhavechest pain,sopain wasnotassociated witha diagnosisof malignant mesothelioma (r=−0.23, P=0.21). A moderate (r=0.43) and sig-nificant(P=0.004)correlationwasfoundbetweenthevolumeof pleuralfluidattheinitialexaminationandadiagnosisof malig-nancy.Smokingwasnotariskfactorfordiagnosisofmalignant mesothelioma(r=0.19,P=0.19).Therelationshipsbetweenthe ini-tial appearance of fluid and malignant mesothelioma, as well astheotherdiagnoses,areshown inTable2.Thefluid initially appearedserousinbothpatientswhowerediagnosedwith malig-nant mesothelioma. The distribution of the appearance of the initial fluid samples of patients with malignant mesothelioma and with other diagnoses was not significantly heterogeneous (P=0.56).

Table2

Appearanceoftheinitialeffusionsamplesofpatientswithmalignantmesothelioma andotherconditions.

Serous Serofibrinous Serohemorrhagic Total

Malignant mesothelioma

2 0 0 2

Others 32 12 7 51

Total 34 12 7 53

TheLDHlevelintheinitialpleural fluidsampleswasnotan indicatorofmalignantdiseaserisk(r=−0.24,P=0.14).

EffusiondidnotrecuraftertheVATSprocedurein45patients during follow-up. Effusion re-accumulation was encountered in 8 patients. The diagnoses of these patients are shown in

Table3.

A correlation analysis between the development of fluid re-accumulation and the diagnosis of malignant mesothelioma showedamoderatecorrelation(r=0.47),whichwashighly signifi-cant(P=0.0001).

Discussion

Inover90%ofpatientswithpleuraleffusion,diagnostic exami-nations,includingVATSbiopsy,allowthecauseoftheeffusiontobe identified.4–7_{However,inaminorityofpatients,nospecificpleural}

changesarefound.Inthiscase,theconclusionthateffusiondoesnot haveaspecificcausemaynotalwaysbecorrect.Somestudieshave reportedthat25–91%ofundiagnosedpatientshavenounderlying disease.7 _{However,inourstudy,aspecificdiseasecausing}

effu-sionwasidentifiedduringfollow-upinapproximatelyhalfofthe undiagnosedpatientswithpleuraleffusion(26/53patients,49%). Themajorityofdiseasesdiagnosedduringfollow-upwerebenign. Theseresultsareinlinewithpreviousreports,7–9_{inwhichbenign}

diseases,mainlyheartfailureandparapneumoniceffusion,were themostfrequentlyidentifiedcausesofpleuraleffusion.9_Although

pleuraleffusionassociatedwithheartfailureisexpectedtobe tran-sudative, thefluid maybecome exudative in patientsreceiving diuretics,sincethesecompoundsconcentrateproteinsandother componentsofpleuraltransudatesinheartfailurepatients.10_No

histologicalchangeswereobservedinthepleuraofthesepatients, sospecificdiseasefindingsinVATSpleuralbiopsysampleswould beunlikely.Aninvasivediagnosticprocedure,suchasthat per-formedinourstudy,isindicatedincaseswheremalignancycannot beexcludedclinicallyandradiologically.11_{Asinsomeothercases}

of undiagnosed effusion,the underlyingcause doesnot always leadtospecifichistopathologicalchangesinthepleuraitself.For example,onlynonspecificpleuritiscanbedetectedinthebiopsy samplesofpatientswithparapneumoniceffusion.Specificchanges inthepleuraarenotexpectedincasesofpulmonaryembolism, Churg–Strausssyndrome(althougheosinophilicinflammationin thesubpleuralandinterlobularconnectivetissueandlymphatic luminaldilationhavebeenreportedinChurg–Strausssyndrome biopsy specimens12,13_{) or drug-related effusion. In the case of}

tuberculosisperitonitis, which in this studywas foundtobe a

Table3

Diagnosesofpatientswithre-accumulationofeffusionduringfollow-up.

Diagnosis Totalnumber Effusionrecurrence,n(%)

Idiopathicpleuritis 27 2(7.4%)

Drug-inducedeffusion 1 1(100%)

Heartfailure 8 2(25%)

Parapneumoniceffusion 12 1(8.3%)

causeofeffusion,thereactionoccurringinthepleuramaycause effusionintheabsenceofgranulomatousinflammation.14_Insuch

cases,biopsysamplesobtainedbyVATSarenot expectedtobe diagnostic.Thus,thediagnosisof“nonspecificpleuritis”obtained usingVATS in thesepatientsshouldnot beconsidered a false-negative.

Whenthediagnosesobtainedinthis studyduringfollow-up werereviewed,diseasesotherthanmalignantmesotheliomacould notberecognizedbyexaminingthepleuralbiopsysamples.Only malignantmesotheliomawasencounteredasacauseof histolog-icalimpairmentinthepleura.Thefalse-negativerateofVATSfor malignantmesotheliomawas3.7%.

Subsequent diagnosis of malignant diseasein patients with undiagnosedeffusionhasbeenreportedinupto25.5%ofcases.15

Incontemporarystudies,thefrequencyofmalignantdisease dur-ingfollow-upinpatientslackingaspecificdiagnosisdespiteVATS isbetween2.1%16_and5%.9

Malignant mesothelioma is the malignancy mostfrequently diagnosedduring follow-upof patientswithundiagnosed pleu-ral effusion.8,9,16,17 _{In pleural malignant mesothelioma, pleural}

involvementisuniform,buttheappearanceofthepleuravaries. Thetypicalappearance includesextensivemacronodules inthe pleura. However, in some patients, gross pleural findings may appearcompletelynormal.Extensivefibrosismaybepredominant inotherpatients. Thesefactors cancomplicatethediagnosisof malignantmesotheliomabyVATS18,19_{andmayexplainwhyVATS}

wasnotdiagnosticforpatientswithmalignantmesotheliomain ourseries.

Whenwereviewed thefactorsthat increasedthelikelihood ofunderlyingmalignantdiseaseinpatientswithpleuraleffusion whocouldnot bediagnoseddespiteundergoinginvasive inter-ventions including VATS,we foundthat the appearanceof the pleuralfluidwasnotsignificant.Malignantdiseasesofthepleura generallyresultinhemorrhagiceffusion.20_{Inourseries,the}

under-lyingdiseaseinpatientswithhemorrhagicpleuraleffusionwas heart failurein 2patientsand parapneumonic effusion in5. In contrast,fluidwithaserousappearancedoesnotruleout malig-nantdisease.Nordoesbiochemicalanalysisofthefluidindicate malignantdisease,asdemonstratedhereandinanearlierstudy.17

We found that recurrence of pleural effusion during follow-up mightbeassociatedwithmalignantdisease.Althoughpleural effu-sionmayre-accumulatefor reasonsotherthanthe presenceof malignant disease, recurrence during follow-up warrants addi-tional examination or, if necessary, furtherVATS. Another risk factorfor malignantdiseaseisthepresenceofan initiallylarge volumeofpleuralfluid.Such patientsmayrequirecloser moni-toring.

In this study,we foundno cause for effusion in abouthalf ofpatients,andnofindingsweremadethatsuggestedthe pres-ence of a specific disease in these patients during follow-up. Althoughthesepatientswereclassifiedashavingidiopathic pleu-ritis,theiractualconditionwasunknown,andthis isapossible limitationofthestudy.Idiopathicpleuritisdescribesasituation inwhichtheunderlyingdiseaseisunknown,andthiscanbedue tomanyfactors.Somepatientsmaypresentseveral difficult-to-identifycausesofeffusion,suchasconnectivetissuediseasesand viralormycoplasmainfections,21_{asweobservedinsomeofour}

cases.

Inconclusion,nospecificdiseasecouldbediagnosedina num-ber of patients despite invasive interventions including VATS. ThediagnosisinmostpatientswithEPEisbenigndisease. How-ever,malignant diseaseis also a possibility,and these patients shouldbeclosely monitored.Thecharacteristicsofpleural fluid shouldnotbeusedasa criterion todiscontinue follow-up.The

likelihoodofmalignantdiseaseincreasesinthepresenceof effu-sionthatoccupiesmorethanhalfofthehemithoraxatthetime of initial examination, and that re-accumulates during follow-up. Repetition pleural sampling should be considered in such patients.

Authors’Contributions

GGmadesubstantialcontributionstoconceptionanddesign, datacollectionanddraftingthemanuscript.

AOperformeddatacollectionandanalysis.

MZGperformeddatacollection,contributedtostudyconception anddesign,andstatisticalanalysis.

AScontributedtostudydesignandstatisticalanalysis. IDperformeddatacollectionandanalysis.

GCperformeddatacollectionandanalysis. VYperformeddatacollectionandanalysis.

SAmadesubstantialcontributionstoconceptionanddesign.

ConflictofInterest

Alltheauthorsdeclarethattheyhavenofinancialrelationship withanybiotechnological,manufacturerorpharmaceutical com-pany,oranyothercommercialentitythathasaninterestinthe subjectmatterormaterialsdiscussedinthemanuscript.

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