Brazilian
Journal
of
OTORHINOLARYNGOLOGY
www.bjorl.org
ORIGINAL
ARTICLE
Clinical
and
otorhinolaryngological
aspects
of
extranodal
NK/T
cell
lymphoma,
nasal
type
夽
,
夽夽
Marcel
Menon
Miyake
a,∗,
Mariana
Vendramini
Castrignano
de
Oliveira
a,
Michelle
Menon
Miyake
a,
Julio
Oliva
de
Almeida
Garcia
b,
Lidio
Granato
a,baDepartmentofOtorhinolaryngology,SantaCasadeMisericórdiadeSãoPaulo,SãoPaulo,SP,Brazil bFaculdadedeCiênciasMédicas,SantaCasadeMisericórdiadeSãoPaulo,SãoPaulo,SP,Brazil
Received6August2013;accepted9March2014 Availableonline11June2014
KEYWORDS Lymphoma extranodal; NK/T-Cell; Noseneoplasms; Epstein---Barrvirus infections
Abstract
Introduction:Extranodal NK/T-Cell lymphoma, nasal type (NKTLN) isa disease that mainly affects the nasal cavity and the paranasal sinuses. Early nasal symptoms are nonspecific, simulatingsinusinfection.Withdiseaseprogression,necrosisofthenasalmucosaincreases, hin-deringhistologicaldiagnosis.Thus,multiplebiopsiesmaybenecessaryuntildefinitivediagnosis. MoststudiesonNKTLNaddressthehematologicalandimmunologicalaspectsofthedisease. Objectives: TopresentdatafromaBrazilianquaternaryhospital,withemphasisontheclinical aspectsofthedisease,andtocorrelatethefindingswiththemostrecentliteraturedata. Methods:Casestudyofsevenpatientfiles.
Results:Patientswereevaluatedontheirmedicalhistory,numberofbiopsiesnecessary, asso-ciation withEpstein---Barrvirus,treatment,andoutcome.Allpatients hadnonspecificnasal complaintsandunderwentatleastthreecyclesofantibiotictherapy.Theearlierabiopsywas performed, thefewer biopsies were required todiagnosethe disease andstart treatment. However,thisfactdidnottranslateintobetterprognosis.
Conclusion: TheotolaryngologistplaysafundamentalroleintheprognosisofNKTLNandcan shortentimebetweensymptomonsetandtreatmentofthepatient.
© 2014Associac¸ãoBrasileira de Otorrinolaringologiae CirurgiaCérvico-Facial. Publishedby ElsevierEditoraLtda.Allrightsreserved.
夽 Pleasecitethisarticleas:MiyakeMM,OliveiraMV,MiyakeMM,GarciaJO,GranatoL.Clinicaland otorhinolaryngologicalaspectsof extranodalNK/Tcelllymphoma,nasaltype.BrazJOtorhinolaryngol.2014;80:325---9.
夽夽
Institution:DepartmentofOtorhinolaryngologyofSantaCasadeMisericórdiadeSãoPaulo,SãoPaulo,SP,Brazil. ∗Correspondingauthor.
E-mail:marcelmenon@yahoo.com.br(M.M.Miyake).
http://dx.doi.org/10.1016/j.bjorl.2014.05.013
326 MiyakeMMetal.
PALAVRAS-CHAVE Linfomaextranodal decélulasT-NK; Neoplasiasnasais; Infecc¸õesporvírus Epstein---Barr
AspectosclínicoseotorrinolaringológicosdolinfomaextranodaldecélulasNK/Ttipo nasal
Resumo
Introduc¸ão:O linfoma extranodal de células NK/T tipo nasal (LNKTN) é uma doenc¸a que acometepreferencialmenteacavidadenasaleosseiosparanasais.Ossintomasnasais inici-aissãoinespecíficos,mimetizandoumquadrodeinfecc¸ãonasossinusal.Comaprogressãoda doenc¸a,aumentaanecrosedamucosanasossinusal,dificultandoodiagnóstico histológicoe podendosernecessáriasmúltiplasbiópsiasatéodiagnósticodefinitivo.Amaioriadosestudos sobreoLNKTNabordaaspectosimunológicosehematológicosdadoenc¸a.
Objetivo:Apresentaracasuísticadeumhospitalquaternáriobrasileiro,destacandoosaspectos clínicosdospacientesecorrelacionandoaosachadosmaisrecentesdaliteratura.
Método: Estudodecasosdesetepacientes.
Resultados: Pacientesforamavaliadosquanto aaspectosdesuahistóriaclínica,númerode biópsias necessárias, associac¸ão ao EBV, tratamento e evoluc¸ão.Todos iniciaram o quadro comqueixasinespecíficas nasais eforamsubmetidos apelomenos três ciclosde antibióti-cos.Quantomaisprecocementeabiópsiafoirealizada,menosbiópsiasforamnecessáriaspara seobterodiagnósticoeiniciarotratamento.Entretanto,estasituac¸ãonãorefletiunummelhor prognósticodospacientes.
Conclusão:OotorrinolaringologistatempapelfundamentalnoprognósticodoLNKTN,podendo encurtarotempoentreoiníciodossintomaseotratamentodopaciente.
©2014Associac¸ãoBrasileira deOtorrinolaringologiaeCirurgiaCérvico-Facial.Publicadopor ElsevierEditoraLtda.Todososdireitosreservados.
Introduction
Extranodal NK/T-Cell lymphoma, nasal type (NKTLN) is a diseasethatmainlyaffectsthenasalcavityand paranasal sinuses,1 and thus, the otorhinolaryngologist is invariably thefirst specialist toevaluate thesepatients. It is arare disease, more frequent in middle-aged adult males, with highprevalenceinEastAsia,whereitrepresents3---10%of allmalignanttumors,andisthemostprevalentlymphomain AmerindiandescendantsfromSouthandCentralAmerica.1---3 Anotherfactor that playsan importantrole inthe patho-genesisofthediseaseisinfectionbytheEpstein---Barrvirus (EBV).4,5
Historically, NKTLN has had different names. Due to thedifficultyinclearlydeterminingthephysiopathological mechanism of thedisease in the past, theterms ‘‘Lethal MidlineGranuloma’’and‘‘MidfacialGranuloma’’included, inadditiontoNKTLN,otherdiseaseswithaggressive evolu-tionthatalsoaffectedthemiddleportionoftheface,such asWegener’s granulomatosis and infectious diseases such asLeishmaniasis.Theterms‘‘polymorphicreticulosis’’and ‘‘angiocentric lymphoma’’ were attempts to histopatho-logicallycharacterize NKTLN, but were alsodiscarded, as thesepatternsarenotalwayspresent.1,6,7Thecurrentname wasadoptedbytheRevisedEuropean-AmericanLymphoma Classification(REAL),proposedbytheWHOin2001and rein-forcedin2008.8
In most cases, the initial nasal symptoms are unspe-cific,suchasrhinorrhea,nasal obstruction, andepistaxis, mimickingapictureofsinonasalinfection,whichmakesit difficulttoestablishthediagnosisofNKTLN.1Withdisease progression,edema, necrosis,anddestructionofadjacent structuresoccur,whichcancausethecollapseofthelateral wallofthenasalcavityandoronasalfistula.
In patients at an advanced stage of the disease, with abundant necrosis andlittle healthy tissue,there is diffi-cultyinestablishingthehistologicaldiagnosisandmultiple biopsies may be required until a definitive diagnosis is achieved.1,9 Extra-nasal manifestations are also possible, which may be associated with nasal injury; the main affected sites are: skin, larynx, testes, gastrointestinal tract,andkidneys.1,10 Lymphadenopathy,either inflamma-tory or tumor-related,canalsobeobserved, especiallyin patientswithnasalinvolvement.10
Sincemoststudiesavailable intheliteratureonNKTLN assessed samples of Asian origin or have their primary focus on the hematological and immunological aspects, this study aimed to assess a sample from a Brazilian quaternary hospital, highlighting the clinical aspects of patientsandcorrelatingthemtothemostrecentliterature findings.
Method
The present study is a series of cases based on medical recordsofpatientstreatedattheOtorhinolaryngology Out-patientClinicofthisinstitutionbetweenJanuary2005and June2013.
The studyincluded all patients diagnosedwithNKTLN, selectedthroughtheelectronicdatabaseofthePathology Departmentofthisinstitution.
ThestudywasapprovedbytheResearchEthics Commit-tee,opinionNo.444,035ofOctober18,2013.
Results
and
otorhinolaryngological
aspects
of
extranodal
NK/T
cell
lymphoma
327
Table1 Resultsofthestudy.
Patient EPS MAB ACS RGS ACM PLO HRA
Gender Male Male Male Female Male Female Male
Ageatdiagnosis 34 43 47 24 35 25 60
Ethnicity Mixed-race Mixed-race White White Mixed-race White White Signsand
symptoms
Rhinorrhea/ epistaxis
Rhinorrhea/ peritonsillar bulge/cervical lymphnode enlargement
Rhinorrhea/nasal obstruction
Rhinorrhea/oronasal fistula
Rhinorrhea/nasal
obstruc-tion/palatal pain
Rhinorrhea/ epistaxis/nasal mass
Rhinorrhea/nasal alalesion
Timebetween symptomonset anddiagnosis
1Year 7Months 6Months 3Months 2Months 4Months 3Months
ATBcyclespriorto biopsy
>Five >Five >Five Betweenthree andfive
Betweenthree andfive
>Five Betweenthree andfive
NumberofBx Three Five Three One Two One One
Affectedsites Mucosanasal/soft palate
Nasalmucosa/eye cornerskin/lymph node
Nasalmucosa Nasalmucosa Nasal mucosa/hard palate/larynx
Mucosanasal Mucosa nasal/Nasalala skin
Siteofdiagnosis Nasalmucosa Eyecornerskin Nasalmucosa Palatalmucosa Palatalmucosa Nasalmucosa Nasal
mucosa/nasalala skin
EBV Positive Negative Positive Negative Positive Negative Positive EBVinbone
marrow
Negative Negative Negative Negative Negative Negative Negative
Human immunode-ficiency
virus
Negative Negative Negative Negative Negative Negative Negative
Treatment RT+CT Didnotundergo RT+CT RT+CT RT+CT Undergoing hematological assessment
RT+CT
Survival 7Years(alive) 7Months Losttofollow-up 1Yearand2 months
3Yearsand4 months(alive)
5Months(alive) 6Months(alive)
Evolution Cured;recurrence in2011.Scheduled forBMT
Invasivefungal rhinosinusitisand death
Losttofollow-up Recurrenceafter 11monthsand death.
Laryngeal recurrenceafter2 years.NewCT cycle.
Patientnewly diagnosed.
Twoepisodesof febrile
neutropenia.
Sequelae Oronasal
fistula/necrosisof nasalpyramid
Death Oronasalfistula Oronasal fistula/death
Oronasalfistula Nasalpyramid necrosis
Nasalala necrosis/hard palateinfiltrate
328 MiyakeMMetal.
Discussion
Thedifferencesandsimilaritiesinpresentation,diagnosis, treatmentandoutcomeofdocumentedclinicalcases repre-sentadiversifiedoverviewofclinical-otorhinolaryngological aspectsofNKTLN.
Ofthesevenpatients(Table1),fivewereadultmalesand fourwerebetween34and47years,resemblingthepatient profilemore often observedin the literature.1,2 However, nonehadAsianorAmerindianancestry.
Theinitialclinicalpictureincludedatleastonesinonasal symptom in all cases (rhinorrhea/nasal obstruction) and patients were treated with antibiotics for the treatment of acute rhinosinusitis. This situation delays the diagno-sisandtreatmentofpatientswithNKTLNwho,ingeneral, onlyundergobiopsyafterseveralantibiotictreatments.In thepresent series,the timebetween symptom onsetand thehistopathologicaldiagnosisofNKTLNrangedbetween2 monthsand1year.
Astheindicationforthebiopsyispostponed,the evolu-tionofNKTLNshowsanincrease intheamount ofedema, crusting,boneerosion,andnecrosisinthesinonasalmucosa, impairingthehistopathologicaldiagnosisinthepresenceof littlesignificant samplesofdisease-affectedtissue.1Thus, theearlierthebiopsyisperformed,thegreaterthechance ofobtainingarepresentativediseasesample,reducingthe numberofrequiredbiopsies9Thediagnoseswithin3months ofthe onsetof symptoms inpatients RGS, ACM, and HRA wasattainedwithoneortwobiopsies.Inthepatients,who hadsymptomsfor6monthsormore,threeormorebiopsies werenecessary.
Sometimes, due to the prevalence of necrotictissues, andsecondary infectionin thenasal cavity, depending on themannerinwhichthelymphomaspreads,theNKTLN diag-nosismay beachieved bya biopsy ofother disease sites, such as the palate and skin, which we noted in patients MAB,RGS,andACM.Disseminationtootherorgansisatypical andmayinvolvethelungs,gastrointestinaltract,kidneys, pancreas,testes,andbrain,inadditiontotheskin.1,2Even rarerisaprimaryinitialpresentationofNKTLNoutsidethe midfacialregion;when thisoccurs, itusually involvesthe skin.1,2
Anotherproblemcausedbythepresenceofnecrosisand crustingof the nasal mucosais the predisposition to sec-ondaryinfections,especiallybyfungi.Thisconditioncanbe aconfoundingfactorintheinterpretationofthe histopatho-logical examination, leading toa misdiagnosisof isolated fungalinfectionin apatientwhoactuallyhasNKTLNwith secondary fungal infection. Additionally, secondary infec-tioncansignificantlyworsentheprognosisofpatientswith NKTLN by worsening the patient’s clinical condition, and becauseitisaconditionthatcontraindicateschemotherapy administration.1
PatientMABunderwentbiopsiesonfourdifferent occa-sions,indifferentsites,alwayswithpresenceofMucorand necrosisinthehistopathologicaldiagnosis. Asthe antifun-galtreatment had shown only partial improvement anda newlesionhadappearedatthecorneroftheeye,thissite waschosen for the fifth biopsy, which diagnosed NKTLN. However,as the patientwas alreadyweakened clinically, chemotherapycouldnotbeinitiated andthepatientdied duringhospitalization.
Thepresence ofEBVintissuebiopsyanalysiswas posi-tiveinfourofthesevenpatients.Theassociationbetween EBVandNKTLNhasbeenwellestablishedintheliterature, althoughitsmechanismofactionisstillbeingstudied.4,5,10 ItisalsobelievedthattheEBVviralloadmaybea progno-stic factor in theevolution of NKTLN.4,10 The presence of EBVwasnotdetected inbonemarrowandnopatientwas HIVpositive.
Currently, there is no standardized treatment proto-col for NKTLN, and the combination of radiotherapy and chemotherapy is routinely used.1 All our patients were treatedinthismanner,exceptMAB,whodiedbefore treat-ment, and PLO, whohad been newly diagnosed. Another therapeuticpossibilitycurrentlybeinginvestigatedisbone marrowtransplantation;patientEPShasbeenscheduledto undergothisprocedure.
The most common sequelae observed in the patients were oronasal fistulas, present in four patients. A fifth patient(HRA)hadaninfiltrativelesioninthehardpalate, with probable progression to fistula. Of the other two remainingpatients,onewasnewlydiagnosed(PLO)andthe other showedrapid diseaseprogression, leading todeath (MAB).Anotherfrequentlyobservedsequelawasnasal pyra-midinvolvement,observedinthreepatients.Twopatients had complications: MAB had invasive fungal rhinosinusitis even before the diagnosis of NKTLN, and HRA had two episodes of febrile neutropenia. Two patients had extra-nasalinvolvement:ACM,laryngeal;andMAB,eyecornerskin andcervicallymphnode.Intheliterature,theextra-nasal manifestationofNKTLNisseeninoneineverythreetofour patients.10
Asfordiseaseevolutionandbehavior,thepatients stud-iedhadvariedcharacteristics.MABhadanevolutionofonly 7monthsbetweensymptomonsetanddeath,whereasEPS remains alive 7 years after symptom onset,in spite of a late-onset diagnosis (only after 1year of symptom onset) andaftertumorrecurrenceinthenasalcavity.Inaddition to EPS, twoother patients also had recurrence:RGS had tumor recurrence in the nasal cavity and died; and ACM hadtumor recurrencein thelarynxand underwentanew chemotherapycycle.Ingeneral,NKTLNhasapooroutcome, withoverall5-yearsurvivalrangingfrom20to65%.10---12
Conclusion
Although rare, the diagnosis of NKTLN should always be consideredincasesofrepeatedrhinosinusitisrefractoryto medicaltreatment.Theotolaryngologistplaysa fundamen-talroleintheprognosisofthisdisease,andmayshortenthe timebetweensymptomonsetandstartoftreatmentthrough anappropriateclinicalhistorythatprecedesbiopsies. Fur-thermore, it is alsoimportant to performthe removal of necrotictissue in thenasal cavity, preventing opportunis-tic infections and allowing the patient to be submitted to radiation therapy and chemotherapy in good clinical condition.
Conflicts
of
interest
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