treatment nasal nk cell lymphoma

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TreatmentoutcomeofnasalNK-celllymphoma:

A reportof12consecutively-diagnosedcasesandareview oftheliterature

MotokoYamaguchiShokoOgawaYoshihitoNomoto

KoujiOkaMasanoriTaniguchiKazunoriNakase

TohruKobayashiandHiroshiShikuSecondDepartmentofInternalMedicineandDepartmentofRadiology,MieUniversitySchoolofMedicine,Tsu,Japan;DepartmentofInternalMedicine,SuzukaKaiseiGeneralHospital,Suzuka,Japan

Weretrospectivelyreviewedtheclinicalcoursesof12consecutively-diagnosedcasesoflocalized,

nasalNK-celllymphoma.AllpatientsrevealedaphenotypeofCD2CD3(Leu4)-cytoplasmicCD3

CD5CD45CD56.NinepatientswerestageI,andthreestageII.Sevenpatientswereinitiallytreated

withananthracycline-containingregimen(Group1).Allbutonepatientfailedtoachieveacomplete

response(CR)anddiedoflymphomawithinsixmonthsofdiagnosis.AllpatientswithBsymptomsand/

oranelevatedserum LDH levelinGroup1died.Theremainingfivepatientsweretreatedfirstwith

radiotherapy(Group2).Afterradiotherapy,twopatientsweretreatedwithanthracycline-containing

regimens,andonepatientwastreatedwithcarboplatin,etoposide,ifosfamide,anddexamethasone

(DeVIC). TwopatientsweretreatedconcurrentlywithradiotherapyandDeVIC (RT-DeVIC):one

showedBsymptoms,andbothhadhighserumLDHlevels.AllfivepatientsinGroup2achievedCRand

fourpatientsarealivewithnoevidenceofrecurrence.Basedonthepresentstudyandareviewofthe

literature,radiotherapyfollowedby,orcombinedwith,chemotherapyishighlyrecommendedastheinitialtreatmentmodalityforlocalizednasalNK-celllymphoma.

Keywordsradiotherapy,chemotherapy,drugresistance

INTRODUCTION

Extranodal, natural killer (NK)/T-cell

lymphoma,formerly known as angiocentric

lymphoma,ismuchmorecommoninAsiaand

LatinAmericathanintheUnitedStatesand

Europe.InJapan,nasalNK/T-celllymphoma

accountsfor185% ofallmalignantlymphomas

andNK/T-celllymphomaofextranodalsites,

other than the nose,accounts for 075%.

ExtranodalNK/T-celllymphomaisanEpstein-

Barrvirus(EBV)-associatedneoplasm thatis

believedtoconsistofNKcellsinmostcasesand

possibly ofT cellsin others. NK/T-cell

lymphomaofextranodalsitesotherthanthenose

isreportedtobeincurableandisalmostalways

fatal,whilenasalNK/T-celllymphomahasa

morefavorableoutcome.Reported5-yearover-

allsurvivalratesofnasalNK/T-celllymphoma

haverangedfrom14to87%.Approximately

90% ofpatientswithnasalNK/T-celllymphoma

presentwithlocalizeddisease,andtheprognosis

ofpatientswithrelapseddiseaseisextremely

poor.Therefore,amoreeffectivetherapeutic

regimenforlocalizednasalNK/T-celllymphoma

isneeded.

Inmanystudies,lymphomasarisinginthe

nasalcavity and paranasalsinuseswerenot

evaluatedseparatelybecauseithasbeenbelieved

thatany differencesbetween them werenot

apparent.Moreover,trueNK-celllymphoma,

peripheral T-cell lymphoma, and B-cell

lymphoma wereoften included in onestudy

becauseofthedifficultyinimmunophenotyping.

Received:June12,2001

Revised:August9,2001

Accepted:August16,2001

J.Clin.Exp.Hematopathol

Vol.41,No.2,Oct2001


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Therefore,thespecifictherapeuticoutcomeof

nasalNK-celllymphomahasnotbeenthoroughly

examined.

NasalNK/T-celllymphomaisknowntobe

resistantto conventionalchemotherapy,andaccordingtotheliteraturemostpatientshave

been treated withradiotherapy (RT)with or

withoutchemotherapy.However,thedetails

oftreatment,especiallythetimingofRT and

chemotherapy,areuncertaininmanyreports.

Toclarifytreatmentdetailsweretrospec-

tively reviewed the clinical courses of

consecutively-diagnosedcasesoflocalizednasal

NK-celllymphoma.

Patients,MaterialsandMethods

Between1988and2000,wediagnosed 12

patientswithnasalNK-celllymphoma. Eight

patients(Cases18)wereincludedinourprevious

reportconcerningimmunophenotypes. Nasal

tissue and/or lymph node specimens were

obtainedfrom patientsafterinformedconsent.

Immunohistochemicalstainingwithfrozensec-

tionswasperformedinallcases.

Histologicaldiagnosiswascarriedouton

hematoxilin-eosin stained,10% formalin-fixed

sectionsaccordingtotheWHO classification.

Theimmunophenotypicstudyoftumorcellswas

performedusingalabeledavidin-biotinmethod

onthefrozensections,asdescribedpreviously.

NewfuchsinandnaphtholAS-BIphosphatewere

usedassubstrate-chromogenreagents.Sections

were counterstained with Gills hematoxylin.

Themonoclonalantibodiesused wereLeu5b

(CD2),Leu4(CD3),andLeu1(CD5),(BectonDick-

inson, Mountain View, CA);NKH1 (CD56)

(Coulter,Hialeah,FL);CD3,L26(CD20),and

LCA(CD45),(DAKO,Carpinteria,CA).

Sevenpatientswereinitiallytreatedbycom-

binationchemotherapy(Group1),andtheremain-

ingfivepatientswerestartedonRTassoonas

possibleafterdiagnosis(Group2).Threeofthem

receivedconsolidationchemotherapyafterRT.

Since1998,patientshavebeentreatedconcurrent-

lywithRTandchemotherapy.

AlltreatmentprotocolsinRTusedaconven-

tionalfractionscheduleof1520Gy/day,five

timesperweek.Theplannedtotaldosetotheinvolvedareawas4050Gy.Forpatientswith

stageIIdiseasethefieldswereextended to

encompasstheinvolved paranasalsinusesor

cervicallymphnodes. Threepatientsreceived

prophylacticcervicallymphnodeirradiation.

Ninepatientsreceivedchemotherapywith

anthracycline-containing regimens,and three

weretreatedwithacombinationofcarboplatin

(CBDCA),etoposide(VP16),ifosfamide(IFM),

anddexamethasone(DMX)DeVIC.

Clinicalresponsewasevaluatedafterinduc-

tiontherapy. A completeresponse(CR)wasdefinedasthedisappearanceofallclinicalevi-

denceofdiseaseandnormalizationofalllabora-

toryvaluesandimagestudies.

Durationofsurvivalwascalculatedfromthe

timeofdiagnosistothedateoflastfollow-upor

death. Overallsurvivalwasanalyzedbythe

Kaplan-Meiermethod and wascompared by

meansofthelog-ranktest.

Results

Twelvepatientswerediagnosedwithnasal

NK-celllymphoma. Allpatientsrevealed a

phenotype of CD2CD3(Leu4)-cytoplasmic

CD3CD5CD45CD56. Theclinicalfea-

turesatpresentationofthese12patientswith

nasalNK-celllymphoma are summarized in

Table1.Eightweremaleandfourwerefemale.

Themedianagewas64/65years,witharangeof

41to78.Fivepatients(Cases1,4,10,and12)had

onlyintranasaldiseaseatpresentation. Insix

patients,tumorsextendedbeyondthenasalcav-

ityandintoneighboringsites,suchasthepar-

anasalsinuses,palate,andepipharynx. Three

patients had involvementofcervicallymph

nodes. NinepatientswerestageI,andthree

stageII.FivepatientspresentedwithBsymp-

toms.Serum LDH levelwaselevatedinthree

patients,andperformancestatuswashigherthan

M.Yamaguchietal.

J.Clin.Exp.HematopatholVol.41,No.2,Oct2001


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oneintwopatients.AccordingtotheInterna-

tionalPrognosticIndex,sixpatientswereclas-

sifiedashavinglow,fivelow intermediate,and

onehigh.

Table2showsthetherapeuticregimensand

outcomesofsevenpatientsinitiallytreatedwith

chemotherapiesonly.Allpatientsweretreated

withanthracycline-containingregimens:vincris-

tine,cyclophosphamide,prednisolone,doxor-

ubicin,andbleomycin(VEPA-B)inCases2,6,

and9;cyclophosphamide,doxorubicin,vincris-

tine,andprednisolone(CHOP)inCases3,8,and

10;methotrexate,vindesine,cyclophosphamide,

prednisolone,anddoxorubicin(M-FEPA)incase

2;epirubicin, cyclophosphamide, vincristine,

VP16,methotrexate,prednisolone,mitoxantrone,

IFM,vindesine,dacarbazine,and bleomycin

(FARM)incase5;andDeVICinCase10.

Allbutonepatient(Case5)failedtoachieve

CR. FourreceivedadditionalRT,butdiedof

lymphomawithinsixmonthsofdiagnosis.All

patientswithBsymptomsand/orelevatedserum

LDH leveldied.Onepatient(Case5)achievedCRandisalivewithnoevidenceofdisease.

Table3showsthetherapeuticoutcomesof

patientsinitiallytreatedwithRT.Threepatients

weretreatedwithRT andconsolidationchemo-

therapy. Anthracycline-containing regimens

wereused in two patients:VEPA-B and M-

FEPA incase1,cyclophosphamide,epirubicin,

vincristine,VP16,andprednisolone(CEOPplus

VP16)inCase2.Onepatient(Case7)wastreated

withDeVICafterRT.Twopatientsdiagnosed

after1998weretreated withRT and DeVIC

concurrently.AllfiveachievedCR.Onepatient

(Case1)diedofrelapsedlymphoma19months

afterdiagnosis,theothersarealivewith no

evidenceofrecurrence.

Onepatient(Case11)whoshowedBsymp-

toms(elevatedfever,nightsweats,andweight

loss:8kg/3mo)andelevatedserum LDH level

receivedRT-DeVIC therapy. Hewastreated

nasalNK-celllymphoma

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with 45Gy oflocalRT,and simultaneously

initiated with six coursesofDeVIC therapy

(CBDCA300mg/mivDay1,VP16100mg/miv

Day13,IFM 15g/mivDay13,andDMX40mg/body iv Day 13;every 21 days). His

nasopalatalandpharyngealmassesdisappeared

withinonemonthafterinitialtherapy,andclini-

calsymptomsandabnormalfindingsonlabora-

torydataimprovedrapidlyandreturnedtonor-

mal after three courses of chemotherapy.

Mucositis(Grade3)developedduringthethird

andfourthcoursesofDeVIC. Thereisnoevi-

denceofrecurrence32monthsafterdiagnosis.

AnotherpatienttreatedwithRT-DeVICther-

apy(Case12)wasanelderlyfemale.Shewas

treatedwith40GyoflocalRT,andsimultaneous-

lyinitiatedwiththreecoursesofDeVICtherapy

(75% dose).Hernasalmassdisappearedwithin

onemonth afterinitiatingtherapy. Sinusitis

(Grade 2) developed temporarily, but was

resolvedcompletelybymedication.Thereisno

evidenceofrecurrence12monthsafterherdiag-

nosis.

The5-yearoverallsurvivalratewas39%

(Fig.1).PatientswhoreceivedRTfirst(Group2)

showedasurvivalcurvesignificantlysuperiorto

thatforpatientswho received chemotherapy

(Group1)(P=.017,Fig.2).

DISCUSSION

Wereviewedthetreatmentoutcomesof12

nasal NK-cell lymphomas, and found that

patientstreatedwithchemotherapyalonehad

pooreroutcomesthanthoseinitiallytreatedby

RT.OnlyonepatientwhopresentedBsymptoms

/

/

/

/

/ /

Fig.1.Overall survival of 12 nasal NK-cell

lymphomacases.

Fig.2.OverallsurvivalforpatientsinGroup1and

Group2.

atholVol.4

M.Yamaguchietal.

J.Clin.Exp.Hematop01o.2,Oct21,N 0


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obtainedCR.Twopatientswhoweretreatedby

RT-DeVIC therapy achieved CR,and none

involvedsevereadverseevents.Duetothelowincidenceofthisdisease,there

hasbeennoprospectivestudyforlocalized,nasal

NK-celllymphoma.Afterreviewingthelitera-

ture, we selected reports containing well-

documenteddetailsoftherapies,andhavelisted

theresultsinTable4.IntheseriesbyYu,etal.

,sevenpatientshadcombinationchemotherapy

followedbyRT.The5-yearoverallsurvivalrate

was14%,aresultsimilarours.In18casesof

CD56-positive localized (stage I) nasal NK

lymphoma,reported byKwong,etal.,the

5-yearoverallsurvivalratewas28%.Liang,etal.,reportedamorefavorableresult,buttheir

studyincludedbothNK/T-celllymphomaand

B-celllymphoma.Inpatientswhoreceivedonly

RT,the 5-year overallsurvivalrates were

approximately40% .Therefore,RTaloneis

notsufficienttoobtainacure.Patientswhowere

treated with RT followed by chemotherapy

seemedtoexhibitagoodprognosis,simi-

larinoutcometoours. Basedonthepresent

studyandareviewoftheliterature,RTishighly

recommendedasthefirsttherapyforlocalized

nasalNK-celllymphoma.

WehaveusedRT-DeVIC therapyasour

first-line therapy forlocalized nasalNK-cell

lymphomasince1998.RT-DeVICisaconcurrent

regimen consisting ofinvolved-field RT and

DeVIC. DeVIC wasdesigned as a salvage

chemotherapeuticregimenforaggressivenon-

Hodgkinslymphoma.

Previously,weexaminedtheexpressionof

P-glycoprotein,whichistheproductofthemulti-

drugresistance(MDR)1geneinnasalNK/

T-celllymphomacells,toclarifythemechanisms

ofdrugresistance.Wefoundfrequentexpres-

sion of P-glycoprotein on nasal NK/T-cell

lymphomacells.Therefore,wecanrecommendnot using MDR-related drugs or using P-

glycoprotein/MDR1modulatorsfornasalNK/

T-celllymphoma.ThereasonweselectedDeVIC

asachemotherapeuticregimenfornasalNK-cell

lymphomaisthatDeVICconsistsofCBDCAand

IFM, which are MDR-unrelated anticancer

agents. Indeed,DeVIC showedtemporary

efficacyinapatientwithrefractoryNK/T-cell

lymphoma.

AsinourCases8and9,highlyaggressive

casesoflocalizednasalNK-celllymphomado

exist. Infact,thereportedsurvivalcurveofnasallymphomadeclineswithinafew months

afterdiagnosis.Sincewespeculatedthat

RTandchemotherapyseparatelyareinsufficient

forsuchhighlyaggressivecases,wedesigned

RT-DeVICtherapytobeaconcurrenttreatment

withRT andchemotherapy. Concurrentther-

apiesarecommonly used in non-hematologic

malignancies,forexampleinesophagealcancer

andlungcancer.SinceCBDCA enhancesthe

efficacyofRT,itiswidelyusedwithRT.Our

twopatientstreatedwithRT-DeVICtherapydid

notshowanysevereadverseeffects.Although

theyshowedahighserum LDH leveland/orB

symptoms,theyachievedCR.

Fromtheresultsofthisstudyandareviewof

theliterature,RT ishighlyrecommendedasan

initial therapy for localized nasal NK-cell

lymphoma.TheefficacyofRT-DeVICtherapy

should beevaluated by a prospective,multi-

institutionalstudy.

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Acknowledgments

Wethank thefollowingcollaboratorsfor

providingpatientdataandspecimens:Depart-

mentofOtorhinolaryngologyandDepartmentofRadiology,MieUniversitySchoolofMedicine;

Matsusaka Chuo GeneralHospital;Yamada

RedCrossHospital;IseMunicipalGeneralHos-

pital. Thisworkwassupportedinpartbya

Grant-in-aidforDelineationofmolecularbio-

logicalprofileoftherefractorylymphoidmalig-

nancyandthedevelopmentofitstumortype-

specific management from the Ministry of

Health,LabourandWelfare,Japan.

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