LungCancer66(2009)191-197
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AccuracyofpathologicaldiagnosisofmesotheliomacasesinJapan:Accuracyofpathologicaldiagnosisofmesotheliomacasesinapan：Clinicopathologicalanalysisof382cases
YukioTakeshimaa'*,Koukilnaia,VishwaJeetAmatyaa,KenichiGembab,I<eisukeAoec,NobukazuFUjimotob,KatsuyaKatod,TakumiKishimotob
･DeIxIrtmentqfRItholo"CmduqteSdlooIQfBiomedimlStiences.Himshim(IUnivelsiq', 7-2-3kbsu"Minqmi-kll,Hirosllimq734-8557,JnpqIIbDePqrtmentqfOCCUP(IIionqIPulmomlyDiSeqse,0kqyqmqROS(IiHoSPiml,JIIPdncDepqrtmemqfMedi"IOncolOg)jNHO"mqguchiUbeMedimlα"陀脇Jﾛp"dDepqrtmentqfRddiolo"Okqy(ImqUnivelsityGmduqteSdioolqfMedicme,Jdpdn
ARTICLE INFO ABSTRACT
Arliclehistoly:
Receivedl8july2008
Receivedinl･evisedibrm6january2009
Acceptedl9january2009
Incidencesofmesotheliomaareontheriseinjapan.Howevel;theaccuratefi･equencyofmesothelioma
occul･renceisstillunknown.Theaimofthisstudyistoclarifytheaccul･aCyofpathologicaldiagnosisofmesothelioma・Amongthe2742mesotheliomadeathcasesextractedh℃mthedocumentOiVitalStatis-
ticsofjapan''fbr2003-2005,pathologicalmateriaIswereobtainedfb1･382cases.Afterthesematerials
werereviewedandimmunohistochemicalanalyseswereconducted,mesotheliomawasdiagnosedby
discussionsbasedonclinicalandradiological infbrmation.SixW-6vecases(17b0%)werecategorizedas
I'definitelynot/unlikely''mesotheliomas,and273cases(71.5%)werecategorizedas"probable/dennite"
mesotheliomas.Thepercentageof"probable/de6nite''pleuralandperitonealmesotheliomacasesin
maleswas74.3%and87b5%,respectively,andthatofpleuralcasesinfemaleswas59.2%;howeveI;the
percentageof"probable/de6nite''peritonealcasesinfemaleswasonly22.2%.TheseresultssuggestthatthediagnosticaccuracyofmesotheliomaisrelativelylowinfemalesandincaSeSofperitonealandsarco-
matoidsubWpemesotheliomas; fill･thermore,approximatelyl5%ofcasesofdeathsduetomesothelioma
injapanarediagnosticallySuspiciouS.
◎2009EIsevierll･elandLtd・Allrightsresewed.
keywolds:
MesotheIioma
Pathologicaldiagnosis
ImmunohistochemistlyPleura
Peritoneum
CalretiI1in
D2-40
1． 1，征oduction widemesotheliomaregistrysystemshavebeenestablishedinJapanthuSfar.
CurlEntly, it is recommendedthatde6nitemesothelioma
diagnosisbepossiblebyhistologicalorcytologicalanalysesby
immunohistochemistlyusingthecurrentlyavailableantibodies{7,81.HoweveI;thuSfal;theseprocedureshavenotbeencarriedoutappropriatelyeithermjapanorothercountries.InJapan,duringtheperiod2003-2005,atotalof2742deathsduetomesotheliomawere
reportedinthedocument"VitalStatisticsofJapan,"whichhasbeenpublishedbytheMinistryofHealth,LaborandWelfare.Howevel;
preciseclinicopathologicalanalyseswithregardtotheaccuracyof
thediagnosisinthesecaseshavenotyetbeenconducted.
Theaimofthisstudyistoreviewpastdeathcasesdiagnosed
with"mesothelioma''andclarifytheaccuracyoftheirpathologi-caldiagnosis. Inaddition,toimprovediagnosticaccuracyicriticalpathologicaldiagnosticproblemshavebeenanalyzed.
Mesothelioma isamalignant tumororiginating fromthemesothelialcellsofthepleura,peritoneum,pericardium,andtes-ticulartunicavaginalis.Theoccurrenceofthistumorisassociated
withoccupationalandenvironmentalasbestosexposure[1-51.ThefrequencyofmesotheliomaoccurrenceisontheriseinJapan.Thedataobtainedfromthe"VitalStatisticsofjapan" indicatedthattherewere500casesofdeathduetomesotheliomainl995,710
casesin2000,and911casesin2005.Manyofthedeathswereduetopastusageofasbestos,especiallyafterthel950s[3,41.Anepi-demiologicalstudyestimatedthattherewouldbeapproximately100,000deathsinJapanduetopleuralmesotheliomainthenext
40years,andthepeakincidenceofmesotheliomawouldoccurduF
ingtheperiod2030-2034[6].Therefbl･e, thereisanurgentneedfbracculatediagnosisandtreatmentofpatientssufferingfrommeSothelioma・Howevel;theaccuratefrequencyofmesotheliomaoccurrenceisstillunknownbecausedifferentdiagnosticmethodsandcriteriaareusedindifferentmedicalinstitutes,andnonation-
2.Materialsandnlethods
2.1. 1℃tiemSelec"on
Fromthe.0VitalStatisticsofjapan"documentfbrtheperiod2003-2005,weextracted2742deaths thatoccurreddue to
*Correspondingauthof1℃I.:+81822575151: faX:+81822575154
Emdildddirss:[email protected](M･Iakeshima).
0169-5002/[email protected]:10.10161j.1!'ng".n.2009.01.011
192 MTbkEshimdemL/Lu昭の阿配r66(2"P)191-197
mesothelioma.Inaddition,weexaminedthedeathcertincatenles
ofeachofthesepatientsattheMinistryofHealth,LaborandWelbre,Japan,afterobtainingpermissionfromtheMinisteribrInternalAffairSandCommunications,japan.ARerexamination,werequestedallthemedicalinstimtesinwhichmesotheliomacases
werereportedduringthisperiodmsubmitmaterialsfbrpatholog-icaldiagnosis・Thematerials,includinghistologicalandWtologicalspecimens, immunohistochemicalslides,unstainedslides,parafnnblocks,andmrmalin-6xedtumortissues,wereobtainedbr382
cases(13.9%)from297medicalinstituteswiththepermissionofthefamiliesofthedeceasedandmedicalinstitutes,Thedetailsofmate-
rialsobtainedaIeasfbllows:46Cytologicalslides(CS),21histologyslidesstainedwithhematoxylinandeosin(H&E;SHE),7CSandSHE,and308CSand/orSHEwithimmunohistochemistly6includ-
ingthe237casesthatwereanalyzedbyimmunohistochemistryinourdepartment.
Theplanningofthisstudywasapprovedbytheethicalcommit-teeatOkayamaRosaiHospital,japan.
diagnosis・Thecaseswithquestionableand/oratypicalmesothe-liomanndingswereespeciallydiscussed.Formesothelioma analysis, each casewas cate"rized
intoeitherofthe4subcategories: ,linadequate/inSufncient''(undetenninedduetoinsufncientmaterialsandinfbnnation),"dennitelynot/unlikely'' (dennitelynotmesotheliomaand/orunlikelymesothelioma), "possible" (possiblemesothelioma),"probable/dennite" (pIDbablemesothelioma and/or dennitemesothelioma).Thisconservativecategorysystemwasusedin
thisstudybecauseoftheheterogeneousnatureoftheavail-ablediagnosticmaterialsandmethods,andbecausetherewas,
incompleteinfbrmationandinsufncientorinadequatemate㎡－alsfbrpathologicaldiagnosisthatpreventednnalandcertineddiagnosis.
2.4SmtiSdmlqnqlysiS
AstatisticalanalysiswasperfbrmedbytheMann-Whitney'SULtestfbrthedetectionofdimrencesinthedistributionineach
categorybyvariousfactors・ Inthisanalysis,thecasesintheO@inad-equate/inSufnCient''categoIywereexcluded.
2.2.mthol"icnlevaluation
Afterthematerials(H&E-stainedtissueslidesorPapanicolaouorGiemsastainedcytologyslidesandH&Eandimmunohistochem-icallystainedtissueslides)werereviewed, immunohistochemical
analyseswereconductedincaseswithunstainedslides,parafnnblocks,orfbnnalin-6xedtumortissues; theanalyseswerebasedonthemorphologyandlocationofthetumonImmunohistochem-
icalstainingwasperbrmedusingtheHistonneSimpleStainMAX-PO(MULn)kit(NichiIEi,TblUo,Japan).Duetolimitationswithregardtotheunstainedslides,antibod-
iesagainsttheわⅡowingmarkerswereinitiallySeleCted:calletinin(Polyclonal,"med,SanFrancisco,CA,USA),D2-40(cloneD2-40,NichiIEiBioScience,Tbkyo,Japan),cytokeratinmarker(CAM5.2;clone2A4,Becton-Dickinson,FranklinLake,NI,USA),pancytokel､atin(CloneAE1/AE3,DAKO,GIostrup,Denmark),carcinoembryonicantigen(CEA;cloneCOIF1,Nichirei),thyroidtIanscriptionfactoF1(TTF-1;clone8G7G3/1,DAKO),anddesmin(cloneD33,DAIC)whenepithelioidorbiphasicmesotheliomawassuspectedi9-111.CalIEtinin,D2-40,CAM5.2(clone2A4,Becton-Dickinson,FIanklin
Lake,M,USA),pancytokeratin(cloneAE1/AE3,DAKO),CEA,anddeSmin,wereselectedfbrthediagnosisofsaI℃omatoidordesmo-
plaSticmesothelioma [12-151.AdditionallybWilmstumor"ne(WT1;clone6F-H2,DAKO),thromomodulin(clonelOO9,DAKO),
epithelialmembraneantigen(EMA;cloneE29,DAKO),CA19-9(cloneNS19-9,TFB,TblWo,Japan),epithelialantigen(cloneBeFEP4,DAKO),epithelial-IElatedantigen(CloneMOC~31,DAKO),myfL3(clone3A11,Novocastra,NewcastleuponTyne,UK),CD34(cloneQBEnd/10,Novocastm),CD45R(clone2B11+PD7/26,DAKO),CD3(clonePC3/188A,DAIO),CD20(cloneI26,DAKO),andestmgenreceptor(ER;clonelD5,DAKO)wereusedasappropriate・Anti-genretrievalwasperfbnnedinanaumclave.Onthebasisof
thenumberoftumorcellSobservedfbllowingimmmunohiSto-chemicalstaining, thetumoIsweIでscoIEdusingthefbllowingsemiquantitativesystem:0,noortIacestaining; scorel+,<5%tumorcells;score2+,6-50%tumorcells;score3+,>51%mmor
cells.Thedennitionofa,,positivecase"inthisstudyisacasewithascoreofmorethanl+.Additional immunohistochem-
istryofthecytological specimenswasnotconductedinthisStudy.
3． Regqllts
31.DiSmbutionqfthe382｡,cIinicqI"mesotheliomqcqsesintcthe
diagnoStiCCatmolfes
ThediStributionofcasesinthediagnosticcategories"inad-equate/insufnCienCy," ..dennitelynot/unlikelyi""probable,"and
,@pmbable/dennite"categorieswasl9(5.0%),65(17D%),26(6.8%),and272(71.2%), respectivelyLAmongthe272 inthe"pmb-able/dennite"CategoIyb 214cases (78.7%)wereconsideredasO@dennite''mesotheliomacases.
3.2.RDportionqfcnsesinedchdiagnosticcdt昭olydependillgon
plfmmymmorsitesqndgender
Byanalysisoftheprimarytumorsite,arelativelyhigherrateof"pmbably/dennite"pleuralmesotheliomacasesweIEobserved(72.0%)ascomparedtoperitonealCaSeS(64.0%).Ontheotherhand,aIElativelyhigherrateofO4dennitelynot/unlikely"peritonealmesotheliomacaseswasnoted(32.0%)compaI℃dwiththepleulalcases(14.8%).
Outof7otherprimarysitecaseS,6CaSeS(87S%), inCluding4pericardialcases, 1testiculartunicavaginaliscase,and2caseswithunknownprimarysites,belongedtothe"probably/dennite''CategoIy.
ThepIDportionofcasesineachdiagnosticcategorybasedon
theprimarytumorsite(pleuraandperitoneum)andgenderisshowninTablel.Arelativelyhighrateof"probable/de6nite''pleuIalmesotheliomawasobsewedamongthemales(74.3%)andfemales(59.2%).FurtheI;ahighIateof"probable/dennite''peri-tonealmesotheliomawasnotedamongthemales(87S%)butthereweI℃only4CaSeS (22.2%)amongthetmales. Incon-
Clusion,arelativelyhighIateofdiagnosticallysuspiciouscaseswaSnotedinthecaseoffemaleSandinthecaseofperitonealmesothelioma.
3.3. SUmmqlyqftheimmunohismchemicqIpmnlesqf"riousIeSionsinenchmtWOly
’2.3.dmicOPqthol"iCalqndlySiSdndcntZDIfZdtiorlqfeachcnSe
Aftertheindependentdiagnosisofeachcasebypathologists(Ym,K.I.,andVJ.A､)aCCordingmWHOcriteria[161andclinicalanal-ySiSby4physicians(T:K.,K.G､,K.A.,andN.E)andlradiologist(K.K､),aclinico-pathologicaldiscussionwasinitiatedtoconnrmthennal
Asummalyofthe immunohistochemical resultsobtained
withthemarkerSCalIetinin,D2-40,Cytokeratin(CAM5.2and/orAE1/AE3),CEA,andTTF-1in308casesanalyzedineachcategolyaIでprovidedinTable2.
’
MThkeshimqetO1/LungCnncer66(2009)197-197 193
Tablel
ProportionsofcaseSineachdiagnosticcategolydependingonprimarytumorsiteFandgender
PleulabCate"ry Peritoneumこ
距、瓠e
No.ofcases(%)
MaIe
No.ofcases(%)
FemaIe
No.ofcases("
Male
No.ofcases(%)
Inadequate/insuf6cienW
Dennitelynot/unlikelyPossible
Pmbable/dennitelbt訓
12(4.3）
37(13｡4)
22(8.0）205(別.3）276(100）
7(14.3）
11(22.4）2(4.1）29(59ﾑ2）
49(100）
0(0）
3(9.4）1(3.1）28(87S)
32(100）
0(0）
13(72.2）1(5.6）
4(22?2）18(100)
aExcluding4pericardialcases,1testiculartunicavaginaliscaseand2unknownprimaIysitecasesbp=0.40byMann-Whimey'sU-test(betweenmaleandfemalepleuralcases).cp<0.0001byMann-Whimey'sU-test(betweenmaleandfemaleperitonealcases).
Table2
SummalyoftheimmunohiStochemicalpl･061esofvariousiesionsineachcategoIy
Pathologicaldiagnosis Markers
Call.etmm
仰(%）
D2－40
n(%)
Cytokeratina
"(%）
CEA
I1(%）
TTF1
脚(%）
DeSm耐
籾(%）
'!De6nitelynotﾉunlikely"mesotheliomabPulmOnalyadenocarcinoma
PuimonarySar℃omatoidcarcinoma
FibmuspleuritiSSemusadenoca1℃inoma,peritoneumSaI℃oma,NOS
J0Possible"mesothelioma
EpitheliodorbiphasicSa1℃omatoid
"Pmbable/|dennite''mesotheliomaEpithelioid
BiphasicSarcomatoid
DesmOplastic
1ﾉ8(12.5）6/7(85.7）4ﾉ8(50）0/3(0)1/4(25)
0/5(0）
3ﾉ6(500）2ﾉ4(50）0ﾉ3(の2ﾉ4(50.0）
3/4(75）5/6(83.3）3ﾉ4(75）3ﾉ3(100）1ﾉ4(25）
5ﾉ8(62.5）2ﾉ3(66.7）NDc
2ﾉ5(40）Np
6/8(75.0） 〃2(50）0/1(0） 0/4(0）ND 4ﾉ4(100)ND ND
ND O/3(0)
2/4(50）3ﾉ3(100)
2/4(50D)
2ﾉ3(66.7）3ﾉ4(75.0）2/3(66.7）
0/7(0）Oﾉ3(0）
O/3(0)
011(0)
0/1(0）0I2(50)
132/137(96.4）27ﾉ30(90)33/43(76.7）4/4(100）
81ﾉ84(96.4）15/18(833）15ﾉ21(71.4）2〃(100）
48ﾉ50(96.0)22/22(100）35ﾉ35(100）4/4(100）
3/118(2,5）
0/25(0）0/13(0）0/1(0）
0/43(0）
0/10(0）0/4(0)ND
7/72(9.7）2ﾉ17(11.8）3β1(9.7）0/4(0）
alncludingCAM5.20rAE1/AE3positivitybbPredominant6naldiagnosesareindicated亡Nordone．
Inbriefieachofthe'6probable/de6nite''mesotheliomaandpul-monarysarcomatoidcarcinomasubtypesshowedahighcalretininpositiviW(morethan50%).FurthelWD2-40positivityinthe!,possi-ble"and"probable/dennite"mesotheliomacaseswasgreaterthan50%. Inaddition,thecaSesofpulmonarysarcomatoidcarcinoma,
6brouspleuritisandsarcoma,NOSwere50%positive.CEApositivityinthecaseofpulmonaryadenoca1℃inoma,pulmonalysarcomatoidcarcinomas,andserouSpapillaIyadenocarcinomasinvadingtheperitoneuminfemaleswaSrelativelyhigh(62.5%,66.7%,and40%,respectively);howeveI;only3"pl･obable/de6nite''categorycases(2.5%) testedpositive.Only6pulmonaryadenocarcinomacasestestedpositivefbrTTF-1.
3.4. Rel,q"onshjpbetwee"p(ItilologicfIIdi(IgIIosticmethodSdnd'PmPortio"Qfc(IsesineqclldiqgnoStiCC(Itegoly
Tbevaluatetheefnciencyofthevariouspathologicaldiagnosticmethodsfbrmesothelioma, theproportionofcasesineachcate-
golywerediffel･entiatedaccordingtothe4typesofpathologicalspecimens(i.e､,onlycytologyslideswithPapanicolaou(Pap)stain(CS),onlyhiStologicalslideswithH&Estain(SHE),bothCSandSHE,andCSorSHEwithimmunohistochemistry)(Table3).ThelEsultrevealedahigherpel･centageofcasesinthe{$probable/definite"cat-egolyfOrcaseswithimmunohistochemistrythanfbrthosewithoutimmunohistochemistry.
T園bIe3
Relationshipbetweenpatho1ogicaldiagnosticmethodsandproportionofcasesineachdiagnosticcategoly
Category Methods
SHEb
No､ofCaSeS(%)CSand/orSHEwithIHc･dNo.ofcases(%)
CSa
No・ofcases(%)
BothCSandSHE
No.ofcases(%)
Inadequate/insu而CienWDefinitelynot/unlikelyPossible
Probable/definite
TbtaI
6(13.0)
14(30‘4）8(1Z4)
18(392）
46(100)
2(”）3(143）
6(28.6）10(4Z6)
21（100）
1(14.3）1(14.3）1(14.3）4(5刀）
7(100)
10(3.2）
47(15.2）Ⅷ(3.6）240(78.0)
308(100）
aCS:cytologyspecimenwithPapanicolaoustain.
bSHE:histologicalslideswithH&Estain.c IH: immunohistochemistlydp<0.0001byMann-Whitney'sU-test(differenceincategoryproportionbythepresenceofimmunohistochemistly)
194 X7bkeSilimderql./LungQInce1．66(2009ﾉ791-197
Table4
CorrectdiagnoSisofcasesin"dennitelynotﾉunlikely"category
4.Discllssion
Thepresentstudyinvolvedaclinicopathologicalanalysisofcaseswheredeathoccurredduetoclinicalmesothelioma,asperthe
filesfromthe"VitaiStatisticsofjapan''fbrtheperiod2003-2005.
Althoughalimitedamountofinfbrmationwasavailablefbrallcases
andtherewasacertainamountofbiasdependingonthecoopela
atinginstitutesandsubmittedmaterials,weattemptedtoidentiiy
somecharacteristiCproblemsinthediagnosisofmesotheliomain
japan.Consequently,wedecidedtoconsider65casesbelongingto
"de6nitelynot/unlil<ely"category,andtherefbre,weassumedthat
approximately15%ofmesotheliomadeathswerediagnosticaily
suspicious, especiallyinfemaleswithperitonealandsarcoma-
toidsubWpemesothelioma.Allthemedicalinstimtesfromwhich
pathologicalmaterialswerecollecteddidnotprovidetheslides
stainedwiththerecentlyrecommendedimmunohistochemicalpanel,andourdepartmentcouldnotperfbrmimmunohistochem-istrywithaunifbrmantibodypanelowingtothelimitationofsubmittedmaterials.Therefbre,theerrorscore(i.e.,approximately15%)estimatedinthisstudymightbehigherthanthe@@actual"errorscore｡HoweveI;suchcomprehensivedataconcerningtheaccu-racyofmesotheliomadiagnosiShasnotbeenpreviouslyIEportedinJapan. It isideal toanalyzetheautopsymaterialstopre-ciselyanddemitelydiagnoseclinical "mesothelioma"patients.HoweveI; thereare limitationstoconductinganautopsyinall
casesandreevaluatingallmaterialssubmittedfbrpathological
diagnosisineachmedicalinstitute・Therefbre,weusedtheconseF
vativecategorysystem, i､e., "inadequate/insufficient", "definitelynot/unlikely'',"possible",and"probable/de6nite''.TherearemanydiseaseS thatmustbedifferentiatedfrom
mesothelioma・Epithelioidmesotheliomamustbedifferentiated
frompulmonaryadenocarcinoma,metastaticadenocarcinoma,
peritonealserousadenocarcinoma,ovarianadenocarcinoma,and
reactivemesothelial hyperplasia. Sarcomatoidmesothelioma
shouldbedifferentiatedfi･ompulmonarysarcomatoidcarcinoma,
truesarcomaarisinginthechestwallandparietalpleura,pul-
monaIyprimalysarcoma, andvarioustypesofintraabdominal
sarcomas.ThebiphasictypemustbedifferentiatedfrompulmonarybiphasicpulmonaIyblastoma,carcinosarcoma,synovialsarcoma,andcarcinosarcomaofthefemalegenitaltract(ovaryanduterus).
Thedesmoplastictypemustbedifferentiatedfromfibrousororga-nizingpleuritis{7,81.1tmustbeunderstoodthatmesotheliomahasclinicalandpathologicalheterogeneitiesandthatrelativelyrare
tumorsmayposediagnosticdifiiculties・Asexpected,theabove-mentioneddiseaseswereresponsiblefbrmesotheliomadeathcases,asindicatedinTable4.
CDrrectdiagnosis No.of感冒②SitE
Mqle
Pleura PuimonaIyadenocaIcinoma
PuimonaIysaItOmatoidcarcinomaNon-smailceillungcarcinoma
PuimonaIycaItinosarcoma
FibrouSpleuritisSarcoma,NOS
Metastaticrenalcellcarcinoma
ThymiCtarcinOma
Malignantlymp随而3，
Solitaly6bmustUmOr
ReactivemesothelialhyperplaSia
Adenocarcinoma
Renalcellcarcinoma
ReactivemesothelialhyperplasiaTbtal
４６１１８２１１１１１１１１０
１
４
小心口ＶＦｆ込み輯．ｆｊ４
Peritoneum
FEmqIe
Pleu虚 PulmonaIyadenocartinOma
PuimonaIysarcomamidcar℃inoma
Non-smallcelllungCardnoma
Fibrouspleuritis
MalignantlymPhoma
SolitaIy6bmustumor
ReactiVemeSothelialhyperplaSia
Serousadenocaltmbma
AdenoCal･Cindma,NOS
CarcinoSarcoma
SarcomaiNOS
RhabdomyosarcomaTb画1
３３２１１１１６２２２１５２
Peritoneum
3.5. CbrmCtdidgnoSiSOfc(IseSm"de/mitelyIIo”""kely"c(Itego'y
Pathological diagnoses of the caSes in the "de6nitelynot/unlikely"categoryaresummarizedin ･Iable4.Amongthepleural cases inmales,pulmonaIyadenocarcinoma(14cases),
pulm叩aIysarcomatoidcarcinoma(6cases),and6brouspleuritis(8cases)weredominant.Amongthepleulalcasesinfemales,therewereamajorityofpulmonaryadenocarcinomas(3cases)andpulmonalysarcomatoidcarcinomas(3cases)similartotheresultinthecaSeofthemales.Amongtheperitonealcasesinfemales,serousadenocarcinomas(6cases)fromthefemalegenital tractwereprominent.
Representativecasesplacedinthe"definitelynot/unlikely"cat-egoryareshowninFigs.1-3.
Fig.T. Pulmonaryadenocarcinomainvadingtheparietalpleula(69-yealeoldmale).(A)Atypicalepithelialcellsshowedapapillaryinvasivegrowthpattern(H&E,×200).(B)Immunohistochemically5thetumorcellswerepositivefbrCEA(immunostaining,×200).
M7tJkeshimuetul./LungCnncer66(2009)197-197 195
Fig2.Serouspapillalyadenocarcinomainvadingtheperitoneum(55-yeaFoldfemale).(A)AtypicalepitheliaicellsshowacomplexpapilialygrowthpatternwithpsammomabodieS(H&E,×200).(B)Tumorceliste､edpositivefbrtheestrogenreceptor(immunostaining,×200).
Recently,manymesothelialandnon-mesothelialmarkershave
beendevelopedtodifferentiatemesotheliomafi･omothermalig-nanttumorsandbenignlesions[9-11,13]・Immunoshistochemicalanalysis isabsolutelyneCessaryfbrtheaccuratediagnosisofmesothelioma.Therefbre,wediscussedthedifferentialdiagnosisofmesotheliomafi･ompulmonalyadenocarcinoma,pulmonalysarco-matoidcarcinoma,6brouspleuritis,andovarianserouscarcinomas,
whicharethepredominantdisordersasmentionedinTable4,espe-ciallywithregardtotheutilityofimmunohistochemistryusingtheantibodypanel.
Inthisstudyi 17pulmonaryadenocarcinomasweremisdi-
agnosedasmesotheliomas(4.5%of382cases).Differentiationbetweenepithelioidmesotheliomaandpulmonaryadenocal=cinoma iS sometimeSdifncult・This isbecausesomepleuralmesotheliomasinvadethepulmonalyparenchymaandexhibitlepedicgrowth[71.Sometimespulmonalyadenocarcinomasmay
growalongthevisceral and/orparietalpleura,mimickingthe
growthofmalignantpleuralmeSothelioma;thisgrowthisdetected
clinicallyand/orradiologicallyandit iscalled"pseudomesothe-liomatousadenocarcinoma" [17;18].OverthelastlOyears,many
immunohistochemicalmarkersfbrdifferentiatingbetweenepithe-lioidmesotheliomaandpulmonaryadenocarcinomahavebeendeveloped[10,19-241.Ordonez[22,231statedthatcalretininandCK5/6(orWT1)werepositivemarkersandCEAandMOC-31 (orB72.3,BeI=Ep4,orBG-8)werenegativemarkers.WedemonstratedthatthecombinationofCEA,calretinin,andWT1orthrombomod-
ulinwasthebestantibodypanel fbrdifferentialdiagnosiS[101.
RecentlyiD2-40orpodoplaninwasreportedtobeusefUlfbrdis-
tinguishinglnesotheliomafrompulmonalyadenocarcinoma[251.Onthebasisofthesefacts,weselectedtheantibodypanel fi･omamongcalretinin,D2-40,CAM5.2,CEA,TTF-1,anddeSminfbrdiffEF
entialdiagnosis.Theapplicationoftheseantibodieswillcontributetoincreasethediagnosticaccuracyofepithelioidmesothelioma.DiffErentiationbetweensarcomatoidmesotheliomaandpul-
monalysarcomatoidcarcinomaisstillverydifncultifnoadequateclinical andpathological infbrmation iSavailable.ThehighernumberofpulmonarysarcomatoidcarcinomaSintheIIdefinitelynot/unlil<ely'' categorymayberenectiveofthedif6culties inthediagnosisofsarcomatoidmesothelioma(Table4).Pulmonal･ysarcomatoidcarcinomaisdescribedasapoorlydifferentiatednon-
smallcell lungcarcinomacontainingacomponentofsarcomaor
sarcoma-likedifferentiation[7].Atpresent,nosensitiveorspeci6cmarkersfOrdifferentiationofthesetumorSareavailable;thus, it
isverylmportanttoobtainpreCiSeclinicalandgroSSpathologicalfindings(i.e.,mainlocationofmmol;presenCeofintIapulmonalynodule,presenceofadenocarcinomaorsquamouscellcarcinomafbci,etc.).Howevel;theprimalysitemustbedeterminedbyexam-inationofthesurgicallyresectedtumorand/orautopsymaterials.Histologically,therefbre,thedevelopmentofnewmarkersfbrdiiLferentialdiagnosisisnecessarybl<Ushitanietal. [101indicatedthatnosignificantdifferencesexistbetweentumorsintheexpression
ofcalretinin,WT1,AE1/AE3,CAM5.2,andEMA.Recently,Hintelz
bergeretal.[141statedthatcalretininandD2-40immunostaining
inmecaseofsarcomatoidmesotheliomawillimprovethediagnos-
Fig.3.Fibrous/organizingpleuritis(73-yealzoldmaie). (A,8)Spindie-shapedcellsprolifEratingina"zonation"砲shion.Thesurfaceofthislesioniscomposedof6brinimmamrespindlecells,andcapillarieS(H&E,A:×40,B:×200).(C)Somespindlecellstestedpositivefbrdesmin(immunostaning,×200).
196 M7hkeshimqeml./Lurgmncer66(2"9)191-197
ticaCcuIacyofspindle-celllesionsinthepleura.InthiSSmdyb6of7(87.5%)pulmonalysaI℃omatoidcarcinomastestedpositivefbrcal-
retininand3of6cases(50%)testedpositivefbrD2-40・Ontheother
hand,33of43(76.7%)sa1℃omatoidmesotheliomastestedpositive
fbrCalretininandl5of21cases(71.4%),fbrD2-40・D2-40positiv-
ityinthecasesarComatoidmesotheliomatendedtobehigherthanthatinthecaseofpulmonaIysarcomatoidcarcinoma;however;adenniteconclusioncouldnotbedrawnfromthelimitednumberof
pulmonalysarcomatoidcarcinomacasesinthisstudy.
Theotherproblemisdifferentialdiagnosisbetweendesmoplas-
ticmesotheliomaand6brouspleuritis.Inthisstudy,9of65cases(13.8%)inthe"de6nitelynot/unlikely"categoIywereconside1℃dtobenbrouspleuritis・ChuIgetal・ [261pmvidedasummaIyofdistinguishingdesmoplasticmesotheliomafrom6brouspleuristy
(pleuritis)and/ororganizingpleuritisintheir1℃viewarnCle・nley
showedthatnbrouspleuritistypicallyexhibitgQzonation''with
highcelluiarityandcytologicaWpiatowardthepleuralspaceand
incIEasingnbrosiswithdecreasingcellularityandlesseratypiatowardthecheStwall・Ontheotherhand,Sa1℃omatous(desmo-
plastic)mesotheliomadoesnotexhibitthistypeofzonationandis
sometimesaccompaniedwithblandnecmsisandovertlysal℃oma-
touSfbci.1bdifferentiatebetweenthese2diseases,arelativelylargeamountoftissueand/orpleuIalwholelayertissuesisnecessalyfbrathoracoscopicbiopsybChulgdocumentedthatneedlebiopsyisgenerallyinadequate,because"small''thoracoscopicbiopsymaynotbesufncienttoevaluate"zonation''[16].
InthiSsmdy, 10cal℃inomas, i.e.,serouspapillalyadenocarci-
nomas,adenoca1℃inoma,NOS,andcaI℃inoSarComaSofthegenital
tIactorperitoneumwereincludedinthecaseofperitonealcasesin
females,andonly4caseswerecategorizedaS"pmbable/dennite"
epithelioidmesothelioma.Theratioofperitonealmesotheliomasinjapanesefemalesamongallmesotheliomacasesisreportedly
higherthanthatinWeStemcountlieS[271.1ntmales,themostdiト
ncultdiftrentialdiagnosisisthatbetweenperitonealepithelioidmesotheliomaandserouspapillaIyadenocarcinomaoftheovalyand/orperitoneuml28}・Bakeretal・I291describedthemomhologi-
caldiffrencesbetweenperitonealepithelioidmesothelioma(PEM)andsemuspapillaryadenocalrinoma(SC).Peritonealmesothe-
liomaofteninvadestheperitonealcavitywithmultiplenodulefOrmation,associatedwithascites,oroccasionallyfbrmsalocalizedabdominalmass,includingmassmnnationintheovaryl301.There-fOre,SCofovarianorperitonealorigin{281isthemostimportantanddifncultmalignantmmorfbrdiffrentiationduetotheclinical
andhistologicalsimilaritiesinthe2casesI291・ReCentlybreportsontheapplicationofimmunohistochemistryfbrdifferentialdiag-noSiShaveemerged・Attanooseta1.1311describedthatcalIEtinin
andBeFEP4areusehlldiscriminantmarkersfbrdistinguishing
PEMinwomenfromSCsandperitonealcarcinoma・OIdonez(9,321IEportedthatcombinationsofbestpositivemarkers(D2-40andcalIでtinin)andnegativemarkers(BeIsEP4,MOC-31andER)were
usenllfbrdiSCriminatingbetweenthe2tumors・Thelelativelyhighlateofmisdiagnosedcasesamongclinicallydiagnosedtmaleperi-tonealmesotheliomaclinicallyisaproblematicissue・WedescribedcalIEtininandthrombomodulinaspositivemarkersandBeFEP4,MOC-31,CA19-9,andERasnegativemarkerswithrelativelyhigh
sensitivityandspecincity[111.ChemotheraWand/orradiotheraWcansignincantlyimprovepatientsurvivalanddecleaserecurIEnce,especiallyinprimaIyandsecondarySC,ascompaIEdwithPEMI33-351.HoweveI;Sugarbakeretal.recentlyIeportedaIでmarkablepmlongationinthemediansurvivalofperitonealmesotheliomapatientstreatedwithanintensivelocal-regionaltIEatmentstlat-egythatincludedcytoreductivesurgerywithperitonectomyandhyperthermicintlaopeIadveintraperitoneal Chemothelapy; the
prolongationwasalsoreportedmrsomepatientsthatreceivedearlyposmperativeintraperitonealchemothelaWI361.nlerefbre,appmpriateantibodyselectionfbrimmunohistochemistlyandfbr
samplingaIelativelylaIgeamountofmmortissuebylapamtomy
areneCessaIyfbrearlyandprecisediagnosis[371.TheapplicationofimmunohistochemistryfbrcytoloWmate㎡als(ascites)isalsoeftctive,especiallymrtheepithelioidWpemesothelioma1381.TheIEarevariousmethodstoobtainmesotheliomacellsand
tissueS,suchascytology,needlebiopsybandbiopsyundertho-racoscopyor lapamscopy.Amongthesemethods, pleural orperitonealbiopsyunderthoracoscopyorlaparoscopyisaIでliablemethodtoobtainsufncienttumortissuefiomthepleumandperi-toneumfbraccuIatepathologicaldiagnosis[39,401.Cytologyfrombodycavitynuidsisalsousefillfbrcancerdiag-
nosis;howeveI;morphologicalobservationonlybyPapanicolaou,
Giemsa,andPASstainingwouldnotbesufncient,evenfbrexpe-
riencedpathologistsI411.Inparticulal;assmallamountsoftumorCellshomsarcomatoidordesmoplasticmesotheliomaareshedinto
thebodycavitybdiagnosisbyonlycytoloWisimpossiblel71.InthiS
smdyjofthe46casesfbrwhichonlythecytologicaltestswerepeF
fbrmed,18cases(39.2%)(allofepithelioidsubtype)belongedtothe"pmbable/dennite"categoIyaccoIdingtothecytologicalandIadi-
ologicaltatures,thelevelofhyaluronaninbodynuids,andsoon.Thecytologicalcriteriafbrepithelioidmesotheliomawerebasedon
classicalmorphologicalfeaturessuchashighcellularityiunifbnn
cellpopulation, inteI℃ellulargap,centlalorpaIacentIalnucleus,
multinucleationwithatypia,villosityinuclearpleomorphiSm,and
soon. 1411.Ontheotherhand,5caseswhe1℃cytologyspecimens
werestainedbyimmunohistochemistryb includingcalretinin,D2-40,CEA,TTF-1,andsoon,wereincludedinthisstudyandamong
them3cases(60%)(allofepithelioidsubtype)belongedto"prob-
ably/dennite"categoIy.TherefOI℃,itisassumedthatcytologywithimmunohistochemistIyusinganappropriateantibodypanelmayincreasetheacculacyofmesotheliomadiagnosis,especiallyinthecaseofepithelioidWpemesotheliomal381.Lyons-Boudreauxrec-ommendedtheuseofD2-40andMOC-31,whicharesensitiveand
spedncmarkersfbrmesothelialandepithelialcells, IEspectively,toimpmvethediagnosticacculacywithbodycavityeffUsions[381.
Puetal.reportedtheutilityofWT1,p63,MOC31,andcytokelatin
(K903andCK5/6) immunostainsindifrrentiatingadenocarci-
noma,squamouscellcarcinoma,andmalignantmesotheliomainpleuraleffUsions{421.HoweveI;noeffectivemarkersareavailable
thusfarwithsensitivityandspecincityhighenoughmdiffelでntiatebetweenepithelioidmesotheliomaandbenignmesotheliallesions(reactivemesothelialandreactivehyperplasiacells),becausethediagnosisofepithelioidmesotheliomaisbasedonthe"invasiveness
ofmesothelialcells''I161.TheIでfbIE,weconsideredthatthecasesofthe"probable/dennite"cate印Ⅳamongthe"cytology-only"cat-e"Iyinthissmdyshouldbelongtothe"pmbable"mesothelioma
categolyandnottothe"dennite"categorybWesupposedthat
bodynuidcytologyisusefUlfbrmesotheliomadiagnosis;howeveI;
adequatetissuesamplingbybiopsyandimmunohistochemistly
usinganappmpriateantibodypanelaIでnecessalyfbr"dennite"mesotheliomadiagnosis.RecentlyiHanleyetal.reportedtheutilityofanti-L523Santibody(antibodymKhomologdomaincontainingpmteinoveIExpIEssedincancer(KOC))incombinationwithcalle-tininandCK5/6fbrdiffeIEntiatingreaCtivemesothelialcellsfiom
malignantmesotheliomaandmetastaticcarcinomal431・FUrther
effbrtstoevaluatenewmarkersusefUlfbrdifrlentiatingmesothe-
liomaespeciallyfrombenignmesotheliallesionsarerequired.Inconclusion, itisascertainedthatthediagnosisofmesothe-
liomaintmalesandinthecaseofperitonealandsarcomatoidsubtypecaseshasIElativelylowdiagnosticaccuIacy,andapprox-imatelyl5%of thedeathsbymesothelioma injapanarediagnosticallysuspicious・TherefbIE, pIECisepathological pro-cedul℃s, includingimmunohistochemistryusinganappropriateantibodypanelselectedbasedonhistologyandclinical infOnna-
tion,arenecessalyfbraccuratemesotheliomadiagnosis.MoreoveI;thenationwidemesotheliomaregistrationsystemmustalsobe
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M7bkeshimqemL/LungCnncer66(2009)791-197 197
establishedmrobtainingprecisedataonmesotheliomafbrepi-demiologicalsmdybTheseeffbrtSwillhelppromoteearlydetectionandtherapyofmesotheliomaandfaCilitatesignincantimprove-mentsinpatientpIDgnoses.
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Acknowled"mentS
Theauthorsthank297medicalinstimtesinjapanfbrprovidingpathologicaimaterials・ThisstudywassupportedinpartbyaglantfromtheMinistryofHealth,IaborandWelblEofjapan.
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b
