Rev. Bras. Hematol. Hemoter. vol.38 número1

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rev bras hematol hemoter. 2016;38(1):82–85

w w w . r b h h . o r g

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

Case

Report

A

difficult

case

of

angioimmunoblastic

T-cell

lymphoma

to

diagnose

Elisabetta

Sachsida-Colombo

∗

_,

_Livia

_Caroline

_Barbosa

_Mariano,

Fernanda

Queiróz

Bastos,

Amanda

Bruder

Rassi,

Luís

Alberto

de

Pádua

Covas

Lage,

Ariel

Barreto,

Sheila

Siqueira,

Juliana

Pereira

UniversidadedeSãoPaulo(USP),SãoPaulo,SP,Brazil

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Articlehistory:

Received6May2015 Accepted10November2015 Availableonline14December2015

Introduction

AngioimmunoblasticT-celllymphoma(AITL)isamalignancy ofmatureT-cells.Itischaracterizedasapolymorphic

lym-phonodal lymphoid infiltrate accompanied by prominent

proliferation of endothelial venules and follicular den-dritic cells. AITL was first described in 1974 by Frizzera

et al. as an angioimmunoblastic lymphadenopathy with

dysproteinemia.1_A_short_time_later,_the_name_was_changed_to

immunoblasticlymphadenopathy,andthento lymphogranu-lomatosisXin1979.2

AITLcomprises15–20%ofallperipheralT-celllymphomas and 1–2% of all non-Hodgkin lymphomas(NHL). Most fre-quently, it occurs in aged patients, with equal prevalence between males and females. Typically, AITL displays an aggressivebehavior,whichmakesthediagnosisdifficultandit mustbedifferentiatedfromothermalignant lymphoprolifera-tivediseases,drugreactionsandviralinfections.Patientswith AITL frequentlyexhibitB-symptoms (e.g.,feverand weight loss)andageneralizedenlargementofthelymphnodes.Other

∗ _{Corresponding}_author_at_:_Cancer_Institute_of_the_State_of_São_Paulo_Octavio_Frias_de_Oliveira_(ICESP),_Universidade_de_São_Paulo_(USP),

Av.Dr.Arnaldo,251CerqueiraCésar,01246-000SãoPaulo,SP,Brazil. E-mailaddress:sachsidacolombo@yahoo.com.br(E.Sachsida-Colombo).

common symptoms include hepatomegaly, splenomegaly,

polymorphicskinrashandpleuraleffusion.Advancedstage disease (AnnArborIII/IV)isobservedin80%ofcases.AITL isalsoassociatedwithautoimmunephenomena.Polyclonal

hypergammaglobulinemia occurs in approximately 50% of

AITLcases.3

HistologicalanalysesofAITLspecimensshoweffacement of the lymph node architecture, particularly in advanced stages.Malignantcells tendtodistributeintointerfollicular regions,andaretypicallypositiveforT-helpercellmarkersand T-cellreceptors(TCRs)alphaandbeta.2,4_{Immunoblasts,}_often

positiveforEpstein–Barrvirus(EBV),arefrequentlydispersed inparacortical regions.Thischaracteristiccanbeconfused withReed-Sternbergcells,whichcanleadtoamistaken diag-nosisofHodgkin’slymphoma(HL).TCRgenerearrangements arefoundin70%ofcases.Ontheotherhand,immunoglobulin generearrangementsarefoundinonly10%ofpatientswith AITL.5

There is nostandard treatment forAITL. Consequently, patients may be treated with different drugs, including steroids,immunomodulatorsorbycytotoxicchemotherapy.

http://dx.doi.org/10.1016/j.bjhh.2015.11.002

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However,themostcommonlyusedtreatmentmodalityisthe cyclophosphamide,vincristine,doxorubicin andprednisone (CHOP)regimen,associatedornotwithetoposide.This treat-mentistypicallyfollowedbyautologoushematopoieticstem celltransplantation.Furthermore,thenaturalhistoryofAITL ischaracterizedbyseveralrelapses,withafive-yearoverall survivalof30%.6,7

Inthiscasereport,weanalyzedthemainclinical charac-teristicsthatmakeAITLdiagnosisdifficult.AsAITLisarare diseasewithapoorprognosis,anearlyandcorrectdiagnosis isessentialtoimprovesurvivalandqualityoflife.

Case

report

A 56-year-old man with generalized lymphadenomegaly

(neck,abdomen,inguinal,supraclavicularandaxillarregions) cametotheInstitutodoCâncerdoEstadodeSãoPaulofor treatment.Thediseasewasfirstnoticedthreemonths pre-viously.Theinitiallymphnodebiopsy,performedinanother

hospital,suggestednodularsclerosisHL.Itwasdescribedas alymphoidinfiltrateinabackgroundofeosinophils, promi-nentvesselsandlargecells,suggestiveofReed-Sternbergcells (CD45+_,_CD3−_CD20−_,_CD30+_,_CD15+_,_and_EBV_negative).

Atadmission,thecomplete bloodcountshowed10.2g/L hemoglobin, 12.4×109/L white blood cell count with

5.4×109/L lymphocytes and 270×109/L platelets.

Leuko-cyteimmunophenotypingbyflowcytometryshowed11%of

mCD3−_CD5+_,_CD4bright_,_CD8−_and_CD26partial_lymphoid_T-cells

(Figure1).Furthermore,abonemarrowbiopsydemonstrated absenceoflymphomainfiltration.

Thepatientwassubmittedtoafluorine-18

fluorodeoxyglu-cose positron emission tomography scan that showed

increased uptake of FDG located in superficial and deep lymphnodechains.Theexamalsoindicatedareversalofthe metabolicpatternbetweenliverandspleen.

A review of the histologicalspecimens from the previ-ous biopsy at our center revealed atypical lymphoid cells with expansion in the paracortical zone and a moderate

number of eosinophils. However, we did not repeat the

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Figure2–Sectionoflymphnodebiopsyshowing(A)immunoperoxidase(IP)CD2showinglymphoidcellsCD2+_;_(B)

polymorphicinfiltrateincludingeosinophilsandsmalllymphocytes(hematoxylin–eosin400×);(C)IPstainshowing

lymphoidcellsCD10+_;_(D)_IP_stain_for_CD21_showing_dendritic_follicular_cells;_(E)_IP_stain_for_CD31_showing_a_high_quantity_of vessels.

immunohistochemicalanalysisinthissamplebecauseitwas verysmall.Therefore, anotherbiopsy wasindicated, and a corebiopsywaschosenbecauseitcouldbedonefaster.The histologicalanalysisofthenewmaterialwascompatiblewith reactivelymphadenopathy.

Inthe next few days, the patient’s condition worsened. Inthemeantime,anotherbiopsywasperformed,thistimea surgicallymphnodebiopsy.However,theimmunochemistry analysiswasincompletewhenthepatient’sconditionbecame aggravated.Astherevisionoftheinitialbiopsywas compati-blewithHL,andduetothequickdeteriorationinthepatient’s performancestatus,ourteamoptedtostarttreatmentforHL withthedoxorubicin,bleomycin,vinblastine,anddacarbazine (ABVD)regimen.

AftertwoABVDcyclesthepatientdevelopedsevere pan-cytopenia.Thetreatmentwasinterruptedduetotoxicity.As itwasnottheexpectedclinicalresponse,thediagnosisofHL wasoncemorequestioned.Atthattime,anewbonemarrow biopsywasmade,andthehistologyshowedthatthebone mar-rowtissuewastotallysubstitutedbyfibrosis.Simultaneously, theresultsofapolymerase chainreaction(PCR) evaluation

ofthe monoclonalrearrangement oftheTCR-gamma gene

becameavailable,andtheywerepositive:thesenewdata sug-gestedamatureT-celllymphoproliferativedisease.

Afewdayslater,theimmunohistochemistryofthe exci-sionallymphnodebiopsywascompletedandthediagnosis of AITL was confirmed (Figure 2). In the meantime, the patient’sclinicalconditiondeteriorateddrastically,soanother appropriate chemotherapeutic scheme was not prescribed. Unfortunately,thepatientdiedinashortperioddueto respi-ratorycomplications.

Discussion

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example,AITLsymptomsincludeskinrash,fever,generalized lymphadenopathyandpolyclonalhypergammaglobulinemia, whicharecommon featuresofinfections andautoimmune disorders.3

ThegoldstandardforAITLdiagnosisisexcisionallymph nodebiopsy.However,tosavetimeandtoavoidexposureto invasiveprocedures,manycentersperformacorebiopsyto obtainsamplesforpathologicalanalyses.Unfortunately,the samplesobtainedbycorebiopsy canbeinsufficientto per-formacompleteimmunohistochemicalpanelandensurethe correctdiagnosis.

Previousstudieshaveshownthattheaccuracyofa lym-phomadiagnosisbasedoncorebiopsiesvariesfrom68%to 94%.8_Inadequate_core_biopsies_are_associated_with

misdiag-nosesordelayeddiagnoses.Guptaetal.comparedlymphnode biopsiesacquiredwith eitherfine-needleaspiration or sur-gicalexcision in100patients. Theyfoundthatthe ratesof accuratediagnosesbasedonfine-needleaspirationswere77% inreactivehyperplasia,75%inNHL,and85%inmetastatic carcinoma.Arecentmeta-analysisshowedthatcorebiopsies providedadequatematerialforhistologyin95%ofcases, par-ticularlyinsalivaryglandlesions,butinadequatematerialin 39(2.6%)casesoflymphadenopathiesoftheheadandneck. Indifferentiatingbetweenmalignantlymphomaandreactive lymphnodes,corebiopsiesshowedahighfalse-negativerate andalownegativepredictivevalue(85%).9

Afullhistologicalandimmunohistochemicalanalysisof thelymphnodeisessentialforthe differentiationbetween AITL and other diseases. For example,it can differentiate betweenlargecellswithtwoormorenuclei,whichare

fre-quently observed in AITL tumor microenvironments, and

Reed-Sternbergcells.3,4 _In_the_present_case_study,_the_small

amount oftissuewasinsufficient toperforman expanded immunohistochemicalpanel,andconsequently,thediagnosis wasincorrect.

Singhet al.demonstrated that17/17 patientswithAITL in the leukemic phase harbored a distinct population of sCD3−_/CD4+_T-cells_in_the_peripheral_blood._Furthermore,_this phenotypewashighlyspecifictoAITLbecauseitwasfound in only 1/40 patients with other T-cell lymphomas in the leukemicphase.Theyshowedthatthisphenotypeprovideda positivepredictivevalueof94%foradiagnosisofAITL.Those authorsconcludedthatimmunophenotypingperipheralblood withflowcytometrymightbeausefulmethodforachieving adifferentialdiagnosisofAITL,eventhoughtheaberrant T-cellpopulationoccursataverylowfrequencyinperipheral blood.10 _Therefore, _this_assay _should _be_part _of_lymphoma

investigations,especiallyininconclusivecases,becauseitcan savetimeandimprovetheaccuracyofdiagnosis.

Inthiscasereport, wedescribeacaseofAITL thatwas erroneouslytreatedasHL.Westatethatthismistaken diag-nosis was mainly a consequence ofan insufficient biopsy sample,whichledtoanincompletehistologicalanalysis.We recommendthat inrefractorycasesacomplete revisionof

the initialbiopsy shouldbeperformedassoonaspossible. Wealsostronglyrecommendthattoobtainanaccurateand precisediagnosis forlymphoma, excisionalbiopsiesshould beperformedinsteadofcorebiopsies.Ancillarystudies,such asperipheralbloodimmunophenotypingandPCRdetection ofTCRrearrangements,areveryimportanttoolstoestablish differentialdiagnoses,andshouldbepartoftheinvestigation toimprovetheaccuracyortoconfirmthediagnosisofAITL.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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2.WHOclassificationoftumorsofhematopoieticandlymphoid tissues.4thed.Lyon:IARCPress;2008.

3.MouradN,MounierN,BrièreJ,RaffouxE,DelmerA,FellerA, etal.Clinical,biologic,andpathologicfeaturesin157patients withangioimmunoblasticT-celllymphomatreatedwithin theGroupd’EtudedesLymphomesdel’Adulte(GELA)trials. Blood.2008;111(9):4463–70.

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6.KyriakouC,CanalsC,GoldstoneA,CaballeroD,MetznerB, KobbeG,etal.High-dosetherapyandautologousstem-cell transplantationinangioimmunoblasticlymphoma:complete remissionattransplantationisthemajordeterminantof Outcome-LymphomaWorkingPartyoftheEuropeanGroup forBloodandMarrowTransplantation.JClinOncol. 2008;26(2):218–24.

7.FedericoM,RudigerT,BelleiM,NathwaniBN,LuminariS, CoiffierB,etal.Clinicopathologiccharacteristicsof angioimmunoblasticT-celllymphoma:analysisof InternationalPeripheralT-cellLymphomaProject.JClin Oncol.2013;31(2):240–6.

8.Ben-YehudaD,PolliackA,OkonE,ShermanY,FieldsS, LebenshartP,etal.Image-guidedcoreneedlebiopsyin malignantlymphoma:experiencewith100patientsthat suggeststhetechniqueisreliable.JClinOncol.

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9.NovoaE,GürtlerN,ArnouxA,KraftM.Roleofultrasound guidedcore-needlebiopsyintheassessmentofheadand necklesions:ameta-analysisandsystematicreviewof literature.HeadNeck.2012;34(10):1497–503.

10.SinghA,SchabathR,RateiR,StrouxA,KlemkeCD,NebeT, etal.PeripheralbloodsCD3(−)CD4(+)T-cells:auseful