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Lung

Cancer

j o ur n a l ho me p ag e : w w w . e l s e v i e r . c o m / l o c a t e / l u n g c a n

Endobronchial

metastasis:

An

epidemiologic

and

clinicopathologic

study

of

174

consecutive

cases

Alessandro

Marchioni

a,∗

,

Anna

Lasagni

a

,

Annalisa

Busca

b

,

Alberto

Cavazza

c

,

Lorenzo

Agostini

d

,

Mario

Migaldi

e

,

Paolo

Corradini

a

,

Giulio

Rossi

e

aDepartmentofOncologyandHematology,RespiratoryDiseasesClinic,AziendaOspedaliero-UniversitariaPoliclinico,Modena,Italy

bOperativeUnitofPulmonology,Hospital“Cattinara”,Trieste,Italy

cOperativeUnitofPathologicAnatomy,AziendaOspedalieraArcispedaleS.MariaNuova-IRCCS,ReggioEmilia,Italy

dOperativeUnitofPulmonology,AziendaOspedalieraArcispedaleS.MariaNuova-IRCCS,ReggioEmilia,Italy

eDepartmentofDiagnosticLaboratories,OperativeUnitofPathologicAnatomy,AziendaOspedaliero-UniversitariaPoliclinico,Modena,Italy

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received10January2014

Receivedinrevisedform23February2014

Accepted2March2014 Keywords: Lung Metastasis Bronchus Immunohistochemistry Endobronchial Bronchoscopy

a

b

s

t

r

a

c

t

Purpose:Endobronchialmetastasesfromextrapulmonarysolidtumorsarearareeventandcurrently

availableepidemiologicalandclinico-pathologicaldatamainlyderivefromanecdotalcasereports.

Methods:Aseriesof174consecutivecasesofendobronchialmetastasesfromextrathoracicsolidtumors

werecollectedoveraperiodof18years.Immunohistochemistrywasperformedin115cases.Complete

imagingfeatureswereavailablein81patients,andanalysisofthelatencyperiodbetweenprimitive

tumordiagnosisandoccurrenceofendobronchialmetastasiswasobtained.

Results:Amongallbronchoscopicexaminationsperformedinthesameperiodformalignancy,ameanof

5.6casesperyearconsistedofendobronchialmetastases(range2–17cases),withastatistically

signifi-cantincreasewhencomparingtheperiods1992–2000(65cases,37%)and2001–2009(109cases,63%)

(p=0.05).Overall,4%ofendobronchialbiopsiesforsuspectedmalignancydisclosedanendobronchial

metastasisfromextrapulmonarytumor.Breast(52cases,30%),colorectal(42cases,24%),renal(14%),

gas-tric(6%)andprostate(4.5%)cancersandmelanoma(4.5%)werethemostcommonmetastaticneoplasms

presentingasendobronchialmass.One-hundredfifty-fourcaseswereidentifiedaftertheprimitivetumor

diagnosis(metachronouscases,89%),11casesweresimultaneouslyevidencedinextrapulmonaryand

endobronchialsites(synchronouscases,6%),while9occultmetastaticcases(5%)firstpresentedas

endo-bronchialmass(anachronouscases).Overall,meanlatencyfromextrapulmonarytumordiagnosisand

endobronchialmetastasiswas136months(range,1–300months).Themostfrequentsymptomswere

dyspnea(23%),cough(15%)andhaemoptysis(12%),while26%ofpatientsweretotallyasymptomatic.

Atradiology,53%presentedasmultiplepulmonarynodules,whileothercasespresentedashilarand

mediastinalmass,singleperipheralnodule,atelectasisorpleuraleffusion.

Conclusions:Endobronchialmetastasesfromextrapulmonarytumorsaccountforabout4%ofall

bron-choscopicbiopsiesperformedforsuspectedmalignancyandin5%ofthecasesthemetastasisisthefirst

manifestationoftheneoplasm.

©2014ElsevierIrelandLtd.Allrightsreserved.

1. Introduction

Metastatic disease to thelungs is a commonoccurrence in routineoncologicpracticeand20–50%ofprimaryextrapulmonary solid malignancies show pulmonary metastases during their

∗ Correspondingauthorat:RespiratoryDiseasesClinic,Azienda

Ospedaliero-UniversitariaPoliclinico,viadelPozzo,71,41124Modena,Italy.

Tel.:+390594225859;fax:+390594222571.

E-mailaddress:marchioni.alessandro@unimore.it(A.Marchioni).

biologiccourse[1,2].Amongallclinico-radiologicpresentations, the findingof metastatic tumors manifesting as endobronchial massesisarareandpossiblyunderestimatedevent.

Epidemiologicalstudiesshowabroadlyvariableincidenceof endobronchialmetastases rangingfrom2 to50%depending on severalfactors,includingthedifferentclinicalsettingsand/orthe lengthoftheperiod oftime considered,theethnicbackground whichissignificantlyassociatedwithdifferentincidencesoftumor types,aswellasthecriteriausedtoidentifythisunusual occur-rence[3–6].Kiryuetal.[7]proposeda4typesclassificationofthe developmentpatternofendobronchialmetastases,asfollows:type

http://dx.doi.org/10.1016/j.lungcan.2014.03.005

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I:directmetastasistothebronchus;typeII:bronchialinvasionby parenchymallesion;typeIII:bronchialinvasionbymediastinalor hilarlymphnodemetastasis;typeIV:peripherallesionextending alongtheproximalbronchus.However,thegreatmajorityof endo-bronchialmetastasesreportedintheliteratureareoftypeIdueto thedifficultytodiscriminatethese4patternswithcertainty.

Ontheclinicalground,it isnoteworthythatseveralpatients may betotally asymptomatic and radiological findings are not particularlyhelpful in hindering differential diagnosis between endobronchialprimaryandmetastatictumors[6].

Amongsolid tumors occurringasendobronchial metastases, carcinomasfrom breast,kidneyand colon-rectumarethemost commonlyencountered[4,7–30].Thetimeframebetween primi-tivetumordiagnosisandappearanceofendobronchialmetastases is quite variable although usually long, with an averageof 50 months[7–9]. Finally, endobronchialmetastases may generally follow identification of the primary site (metachronous cases) ormore rarelyprecede(anachronous)or simultaneouslyreveal (synchronous)theprimarymalignancydiscovery.Currently, our knowledge on endobronchial metastases from extrapulmonary solidtumorsderivefromcasereportsandfewstudieswithalimited seriesofcasesorconductedbyusingdifferentclinicaland radiolog-icaldatacollectionmethods,thenresultinginfragmentedand/or controversialdata.

Theaimofourstudyistodrawamorehomogeneous epidemio-logical,clinico-radiologicandpathologicscenarioofendobronchial metastasesthroughacarefulretrospectiveanalysisof174 consec-utivecasesalongaperiodof18yearscollectedfrom2different Institutions.Theresultshereinpresentedwerethencomparedwith experiencespreviouslyappearedintheliterature,inthehopeto identifyhelpfulfeaturesforsuspectingmetastaticdiseasewhen dealingwithendobronchialmasses.

2. Materialsandmethods

Aseries of174consecutivecases ofendobronchial metasta-sisfromextrapulmonarytumorswerecollectedfromtheUnitsof PathologicAnatomyandPulmonologyoftheAzienda Ospedaliero-UniversitariaPoliclinicoofModenaandtheAziendaOspedaliera St.MariaNuovaofReggioEmilia.Diagnosesweremadebetween January1992andDecember2009andallcaseswerefirst indepen-dentlydiagnosedandthenreviewedatamultiheadedmicroscope by two expert pulmonarypathologists (AC, GR). Endobronchial metastasiswasrecordedwhenabronchoscopicallyvisible, extra-pulmonary neoplasm metastasized tothe central or segmental bronchus.Lymphoproliferativemalignancieswereexcludedfrom thestudy,sincelymphomasorplasma cellneoplasmsmay fre-quentlyarise fromthemediastinumorinvolvelymph nodesof thisanatomicsitethendirectlyinvadingthebronchialstructures. All cases consisted of bronchial biopsies that were formalin-fixed and paraffin-embedded. In all cases, 4-micron sections fromtheparaffin-blockwereperformedforroutinestainingwith hematoxylin–eosin. However, in 115 cases (66%) thediagnosis requiredfurtheranalysisbymeansofimmunohistochemicalstains. Whenrequired,immunohistochemistrywasperformedusingan automatedimmunostainer(Benchmark,Ventana,Tucson,AZ).Both institutionsindependentlyperformedimmunohistochemical anal-ysis,butusingthesametypeofinstrumentsaswellasthesame antibodyclones.Thepanelofantibodiesineachsinglecasewas appropriately selected depending onthe differential diagnosis. The primary antibodies used in the study were thefollowing: Thyroid Transcription Factor-1/TTF-1 (clone 8G7G3/3, Ventana, prediluted),Thyroglobulin(clone2H11/6E1,Ventana,prediluted), CDX2 (clone EPR2764Y, Ventana, prediluted), CD10 (clone 013, Ventana, prediluted), estrogen receptors (clone SP1, Ventana;

prediluted), progesterone receptors (clone 1E2, Ventana, predi-luted),Wilms’Tumor-1/WT-1(clone6F-H2,Ventana,prediluted), calretinin(cloneSP65,Ventana,prediluted),S100(polyclona, Ven-tana,prediluted), melan-A(cloneMART-1,Ventana,prediluted), PSA (ER PR8, Ventana, prediluted), smooth-muscle-actin (clone 1A4,Ventana,prediluted),desmin(cloneDE-R-11,Ventana, predi-luted), pan-cytokeratins (clone AE1/AE3, Ventana, prediluted), CD34(cloneQB-END/10,Ventana,prediluted),CD31(cloneJC/70A, Ventana,prediluted)(6F-H2,Ventana,preduted),p63(clone4A4, Ventana,prediluted),calcitonin(polyclonal,Ventana,prediluted), Epithelial Membrane Antigen/EMA (clone E29, Ventana, predi-luted).

Clinicaldata(sex,age,symptoms,timelapsebetweenprimary and metastatictumors,type ofprimaryextrapulmonarytumor) wereavailableinallcases,whiledetailedimagingfeatureswere obtainedin81cases.

2.1. Statisticalanalysis

Contingencytableswereusedfordescriptiveandcomparative statisticalanalysisofcollecteddata,and significancewas evalu-atedwithPearson’schi-squaredtestandFisher’stest.Allstatistical calculationswereperformedusingSPSS13.0software(Statistical PackagefortheSocialSciences,Chicago,IL).Differenceswere con-sideredstatisticallysignificantforprobability<0.05.

Thestudywasconductedinaccordancewiththepreceptsofthe HelsinkiDeclarationandallrecordeddatawerehandled anony-mously.

3. Results

Thebaselinecharacteristicsoftheentirecaseseriesare summa-rizedinTable1.

Thecasehistoriescollectedincluded174casesofendobronchial metastasis,with a slight prevalenceof male patients(54%), an averageageof67yearsandarangebetween27and89years. Diag-nosisofendobronchialmetastasiswasobtainedafteradiagnosis ofextrapulmonarytumor(metachronouscases)in154cases(89%), whilein11cases(6%)thetumorwasdetectedonanendobronchial level simultaneously to that on the extrapulmonary site (syn-chronouscases).Intheremaining9cases(5%),theendobronchial metastasiswasthefirstmanifestationofanoccultextrapulmonary tumor(anachronous cases).Distribution of theprimary tumors andtimeofendobronchialmetastasisoccurrenceissummarized inTable2.

Itshouldbenoticedthataround50%ofanachronouscaseswere secondarytorenalcarcinoma.Onaverage,intheoverall18-year period,5.6casesofendobronchialmetastasiswereobservedper year(range:2–17cases),withstatisticallysignificantdifferences fortheperiodsbetween1992–2000(65cases,37%)and2001–2009 (109cases,63%)(p=0.05).

Toallowabetterunderstandingontheextentoftheissueand onhowthiscouldinfluencetheclinician’sactivity,wereferredto thebronchoscopyserviceoftheAziendaOspedaliero-Universitaria Policlinico inModenatoreview allthereportsof the broncho-scopicinvestigationsperformedbetween2006and2009.Inthese 4years,4208procedureswereperformed,781(18.5%)onpatients forwhomendoscopicfindingsweresuggestiveoftumorsinthe tracheobronchialtree.Ofnote,31outof 781(4%)broncoscopic examinations revealed endobronchial metastases from nontho-racicmalignancies.

Bronchoscopywasperformedforthefollowingreasons: radio-logical features (nodules, masses and hilar-mediastinal and/or peripherallymphadenomegaly),atelectasis,and symptomssuch as dyspnea, haemoptysis and persistent cough. Biopsies were

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Table1

Clinico-pathologiccharacteristicsofpatientswithendobronchialmetastasis.

Variable Frequency(%)

Sexandage

Male(meanage:69years) 94(54) Female(meanage:66years) 80(46)

Symptoms Asymptomatic 42(24) Cough 38(22) Dyspnea 30(17) Haemoptysis 20(12) Dysphonia 2(1) Notavailable 24(14) Primarytumors Breast 52(30) Colon-rectum 42(24) Kidney 24(14) Stomach 11(6) Prostate 8(4.5) Melanoma 8(4.5) Thyroid 5a(3) Endometrium 3(2) Liver 3(2) Smallbowel 2(1) Ovary 2(1) Leiomyosarcoma 3b(2) Bladder 2(1) Renalpelvis 1(0.5) Mesothelioma 1(0.5)

Solitaryfibroustumor 1(0.5)

Vagina 1(0.5)

Cervix 1(0.5)

Esophagus 1(0.5)

Liposarcomaspermaticcord 1(0.5)

Nasopharynx 1(0.5) Meningioma 1(0.5) Typeofmetastasis Metachronous 154(89) Synchronous 11(6) Anachronous 9(5)

a3papillarytype,1eachanaplasticandmedullarytype.

b 2cutaneoustypeand1uterinetype.

Table2

Distribution of metastasis primary and time of endobronchial metastasis

occurrence.

Primarytumors Metachronous Synchronous Anachronous 154(89%) 11(6%) 9(5%) Breast=52 48 2 2 Colon-rectum=42 40 2 – Kidney=24 19 1 4 Stomach=11 6 4 1 Prostate=8 7 – 1 Melanoma=8 8 – – Thyroid=5a 5 Endometrium=3 3 – – Liver=3 3 – – Smallbowel=2 2 – – Ovary=2 2 – – Leiomyosarcoma=3b 3 Bladder=2 1 1 – Renalpelvis=1 – – 1 Mesothelioma=1 1 – –

Solitaryfibroustumor=1 1 – –

Vagina=1 1 – –

Cervix=1 1 – –

Esophagus=1 – 1 –

Liposarcomaspermaticcord=1 1 – –

Nasopharynx=1 1 – –

Meningioma=1 1 – –

a3papillarytype,1eachanaplasticandmedullarytype.

b 2cutaneoustypeand1uterinetype.

performedonmacroscopicallyvisibleendobronchiallesions with-outcomplementarymethods.

On the full cohort of 174 patients, extrapulmonary tumors mostoftenresultinginendobronchialmetastasisincludedbreast carcinoma(52cases,30%),colorectalcarcinoma(42cases,24%), renalcarcinoma(24cases,14%),stomachcarcinoma(11cases,6%), prostatecarcinoma(9cases,5%),andmelanoma(8cases,4.5%).

Although endobronchial metastases from epithelial-derived tumors(carcinomas)significantlyoverriddenmesenchymal neo-plasms(5cases)andmelanomas(8cases),itisimportanttonotice that virtually alltypes of solid tumor canmetastasize intothe bronchialtree.Supportingthis,threetypesoftumorincludedinthe currentseries(liposarcomaofthespermaticcord,solitaryfibrous tumorandcutaneousleiomyosarcoma)havenotsofarreportedin theliterature(Figs.1and2).

Althoughnotstatisticallysignificant,endobronchialmetastases morefrequentlyaffectedtheright(102cases,59%)thantheleft bronchus(72cases,41%)(p=0.07).

The overall median latency period between the detection of extrapulmonarytumor and theoccurrence of endobronchial metastasis was 136 months (range, 1–300 months). Among the most frequent extrapulmonary malignancies leading to endobronchialmetastasis,a significantdifferencewasobserved between breast carcinoma (median, 86 months; range, 1–300 months)orrenalcarcinoma(median,82months;range,18–270 months) and colorectal carcinoma (median, 53 months; range, 9–168months)(p<0.001)(Fig.3).

3.1. Clinico-radiologicfeatures

Thepatternsofclinicalandradiologicalpresentation,ordered byfrequency,forthe81analyzedpatientsweresummarizedin Table3(supplementmaterial)andTable4(supplementmaterial), respectively.Ofthecollectedcasehistories,21patients(26%)were asymptomatic,whilethemostcommonsymptomsreportedwere dyspnea,coughand haemoptysis,in19 (23%), 15(19%) and 10 (12%)casesrespectively.Inonesinglecasetheonlysymptomwas dysphoniasecondarytoleftlaryngealnervecompression.For16 patients,thepresenting symptomswerenotreportedinclinical charts.

SeeTables3and4assupplementaryfiles.Supplementary mate-rialrelatedtothisarticlecanbefound,intheonlineversion,at

http://dx.doi.org/10.1016/j.lungcan.2014.03.005.

Onlystandardchestx-rayswereavailablefor7patients,while chestx-raysandCTscanswereavailablefortheremainingpatients. “Nodules” were defined as lesions with a maximum diameter equal toor less than30mm; “masses”weredefined as lesions withadiameterover30mm; “lymphadenomegaly”wasdefined as hilar-mediastinal lymph nodes with a maximum diameter over 10mm.Multiple nodules were present in 43 cases (53%), hilar-mediastinallymphadenomegalyin38cases(47%),a periph-eralmassin24cases(30%),atelectasisin23cases(28%),pleural effusionin19cases(23%)andahilar-mediastinalmassin13cases (16%).

4. Discussion

Lungs are the commonest site of metastatic deposits from extra-pulmonarymalignancies,butmetastasespresentingas endo-bronchial growth are quite unusual and epidemiologic and/or clinic-pathologicdata onlargehomogeneousseries arelacking. The present study collected the largest series to date of con-secutiveendobronchialmetastasesfromextrapulmonarytumors disclosedinroutinepracticewithoutselectionbiases(174cases), underlyingtheclinicallyrelevantoccurrenceofthisphenomenon.

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Fig.1. Endobronchialmetastasisfromspermaticcordliposarcoma.CTscan(A)showsasolitarynoduleentirelyoccupyingthemainleftbronchuswithsmoothmarginsand

yellowishappearanceatbronchoscopy(B).Histology(C)revealsahaphazardproliferationofatypicalspindled-shapedcellswithclearcytoplasm.

Amongallbronchoscopicproceduresperformedinthesuspicion of lung tumor, the overall incidence wasabout 4% per year, a figurehigherthan1%reportedbyKreisman etal. in1983[31]. However,thisresultisdifficulttocomparewithepidemiological referencesofotherstudies,duetothevariabilityofclassification criteriainconsideringendobronchialmetastasis,thelengthand

typeoftheperiodoftimeconsideredaswellasthedifferent ethni-calbackgroundofthestudyincludingmalignancieswithdifferent incidence.It couldbereasonableto assumethat theincreasing numberofdiagnosticprocedures,includingbronchoscopy exam-inations,performedinthecurrentwork-upofoncologicpatients hasleadtohigherpossibilitytodiscloseendobronchialmetastases.

Fig.2.Endobronchialmetastasisfrommalignantsolitaryfibroustumorofthepleura.CTscan(A)displaysauniqueroundednoduleofthelowerleftlobepartiallyoccluding

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Fig. 3. Distribution of the temporal latency between the occurrence of

endobronchialmetastasesandprimarytumorsamongthemostrepresented

malig-nancies.

Inliterature,endobronchialmetastasesgenerallywerereported assinglecasedescriptionsorverylimitedcaseseries[4,8,32,33]. Althoughthedevelopmentofpulmonarymetastasesisinfact a commonoccurrence,theirendobronchiallocation isconsidered tobearareevent.Frequencyestimatesarestillbasedonrather outdatedstudiesandprimarilyonautopsyseries[3,6],butitcan varyconsiderablydependingonthestudyand thedefinitionof endobronchialmetastasis,rangingfrom2to50%[3,4,12–16,32,33]. Therefore,theepidemiologyofthistypeofmetastasisisstillquite unclear.

In our bronchoscopy service, endobronchial metastasis was diagnosedin4%ofthebiopticproceduresperformedasaresultof suspectedmalignancy.Consideringthatbronchoscopyisnot rou-tinelyperformedonallpatientswithtumors,itmaybeimplied thatbothincidenceandfrequencyofendobronchialmetastasesare probablyunderestimated.

Thelatencyperiodbetweenprimaryextrapulmonarytumorand endobronchialmetastasismaybeverylong[36].

Forpatientspresentingwithtumorsthatmostcommonlycause endobronchialmetastasis,thesystematicuseofchestCTscansand

bronchoscopycouldbeuseful.Inparticular,breast,colonandrenal lesionsarereported intheliterature asbeingmostoften asso-ciatedwithendobronchialmetastasis[17–24,32,33].Thisfinding wasconfirmedinourstudythatreportedhowtumorsarisingin thesesitesaccountforover60%onthetotal(seeTable1).For gas-triccancer,prostatecarcinomaandmelanoma,accountingfor16% ofendobronchialmetastasesinourcaseseries,carefulmonitoring ofthetracheobronchialtractcouldalsofacilitatethedetectionof secondarylesionsinagreaternumberofcases.

Anotherinterestingaspectconcerns thecapacityof virtually allsolidtumors ofvarious celldifferentiationtoproduce endo-bronchialmetastases. Sofar,this factwasonly documentedby sporadic single case descriptions [25–30]. Regarding the clini-cal/radiologicalpresentation,collecteddatastronglyconfirmthe literaturefindings [3–6,10,11,32,33],and reassert evidence of a presentationthat isdifficult todifferentiatefrom thatof a pri-marypulmonarytumor.Among81patientsfor whichcomplete clinico-radiologic data were available, 21 (26%) were entirely asymptomatic.Previousstudies,dependingonthecasehistories included,reportedahighlyvariablepercentageofasymptomatic patients,ranging from0to52%of cases[8–10,14,32,33]. When present,dyspnea,coughandhaemoptysiswerethemostcommon symptoms. Radiologicalfindings evidenced multiplepulmonary nodulesandhilar-mediastinallymphadenomegalyasthemost fre-quentconditions, detectedin abouthalfof theexaminedcases. Aperipheralmassandatelectasiswerereportedinabout1/3of cases,whilepleural effusionandhilar-mediastinalmasseswere lesscommon.

In some cases, radiological differential analysis vs primitive tumorwasextremelydifficult,asshowedinFig.4where radio-logical appearance strikingly suggested a primary lung cancer presentingasanexcavatedpulmonarymass,butthepatienthad anunknownrenal cellcarcinoma.Inmostcases,a diagnosisof endobronchial metastasis follows the diagnosis of the primary lesion,witha largelyvariabletime intervalbetweenthem. Our dataevidenced anaverageinterval of134months,witha very

Fig.4. Unknownrenalcellcarcinomapresentingasendobronchialmetastasis.CTscan(A)evidencesanescavatedmassinvolvingthelefthilarregionprotrudingintothe

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widerangeaccountingupto300months,thisfindingappearing tobesignificantlydiscordantwhencomparedtosimilar observa-tioninpreviousstudies.Soresen,inareviewofalreadypublished cases,reportedanintervalof50months(range0–300)[9];Sebahat evidencedavalueof32.8months(range0–96)[10];Kiryureported anaverageintervalof65.3months[7];Dursunfoundavalueof47 months(range0–19yearsor0–228months)[11].Morerecently, Leeetal.[32]evidencedameanintervalof36monthsinacase seriesof43 patients,while Kimetal. [33]foundamean inter-valof14months(range,0–112months)intheirexperienceon18 patients.Alltheseintervalsarequiteshorterthanthatobservedin ourstudyandpossiblyinfluencedbymanyfactors,amongwhich thelargernumberofpatientsandthegreaterspectrumof histo-logictypespresentinourstudy.Althoughmetastasiswasdetected followingthediagnosisoftheprimarylesioninthegreatmajority ofourcases,thefindingof5%ofcasesinwhichtheprimarylesion wasunknownwhenendobronchialbiopsywasperformeddoesnot appearanegligiblefeature.Fouroftheseanachronous9caseswere renalcellcarcinomas,whiletheothersconsistedof2breastcancers, and1caseeachofcarcinomafromstomach,prostateandupper urothelialtract(renalpelvis).

Similarly to our results, a previousstudy onendobronchial metastasessecondarytorenalcarcinomaevidencedthatin7out of17patientstheendobronchialmetastasesoccurredbeforethe diagnosisofrenalcarcinoma[23].

Consideringthehighincidenceandlongsurvival,itisnot sur-prisingthat,inagreementwithpreviousworksonendobronchial metastases, breast and colon cancers are the most commonly described extrapulmonary malignancies showing this peculiar endobronchialgrowthpattern.However,alongaperiodof18years, wefound174endobronchialmetastasesdisclosing22different his-tologictypes,includingalsotumorentitiespreviouslyunreported, suchasaspermaticcordliposarcoma,arecurrentmalignant soli-taryfibroustumor,3leiomyosarcomas(2fromtheskinand1from theuterus)andameningioma.Pathologistsshouldthenbeaware oftheoccurrenceofendobronchialmetastaseswhendealingwith aneoplasmshowinganunusualmorphologyforaprimarylung tumorandclinico-radiologicdatadiscrepantlysupportinga pul-monarymalignancy(Figs.1,2and4).

Unfortunately,theperfectpanelofimmunistainsindetecting primaryvsmetastatictumorsorindisclosingthetypeofmetastatic neoplasmsdoesnotexist.Thecorrectdiagnosisalwaysrequiresa multidisciplinaryapproachandshouldbecontextualizedineach singlecasebasedonclinicaldata,imagingstudies,careful morpho-logicexaminationandappropriateimmunohistochemicalmarkers

[34,35].In thisstudy immunomarkerswereasked in115cases (66%),butpathologists,aswellasclinicians,shouldbeawarethat noneoftheantibodieshereemployedisabsolutelydiagnosticper se.Supportingthisfact,themetastaticmeningiomawasoriginally misdiagnosedassquamouscellcarcinomabasedonimaging stud-iesrevealingasinglecentrally-locatednodule,p63expressionand lackof TTF-1 reactivity. However,theknowledge of a previous diagnosisofrecurrentcerebralmeningiomahasleadtofurther sub-typingtumorcellsfinallydisclosingprogesteronereceptorsand EMAexpression,then leadingtothecorrect diagnosisof endo-bronchialmetastasisfrommeningioma.

Recently,Dongetal.[34]introducedtheroleofFDGPET/CTas anotherhelpfuldiagnostictoolinidentifyingendobronchial metas-tases.

Inconclusion, thecurrent studyrepresentsthelargestseries of consecutive extrapulmonary tumors presenting with endo-bronchialmetastases.Summarizingthekeypointsderivedfrom thecurrentdata,itisimportanttokeepinmindthat:(1) endo-bronchial metastases may occur in about 4% of bronchoscopic examinations performed for a suspected neoplasm; (2) a not insignificantrateofendobronchialmetastases(5%inourstudy)

maybethefirstmanifestationofanextra-pulmonarytumor;(3) virtually all kind of solid tumors may occasionally metastasize into thebronchial lumen; (4) up to onethird of patientswith endobronchialmetastasismaybeasymptomaticorevenpresent witharadiologicpatternmimickingprimarylungcancer.

Whenendobronchialmetastases lead tocontroversial issues withclinicalimplicationsondiagnosticground,theclose collab-orationbetweenclinician,radiologistandpathologististhemost critical stepin achievingthecorrect diagnosis,then preventing erroneoustherapeuticapproaches.

Conflictofintereststatement

Noconflictsofinterestforallauthors.

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