Rev. Bras. Hematol. Hemoter. vol.37 número2

revbrashematolhemoter.2015;37(2):132–135

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

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

Case

Report

Hairy

cell

leukemia

variant:

the

importance

of

differential

diagnosis

Renata

Cristina

Messores

Rudolf-Oliveira,

Mayara

Marin

Pirolli,

Fernanda

Santos

de

Souza,

Juliana

Michels,

Maria

Cláudia

Santos-Silva

UniversidadeFederaldeSantaCatarina(UFSC),Florianópolis,SC,Brazil

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Articlehistory:

Received25August2014 Accepted4October2014 Availableonline11February2015

Introduction

Hairycellleukemiaisararediseasecomprisingabout2%of lymphoidneoplasms.1_{Thisneoplasmcanbeconfusedwith} otherhematologicdiseases.Therefore,adifferentialdiagnosis mustbeperformedbetweenclassichairycellleukemia,hairy cellleukemiavariant,andsplenicmarginalzonelymphoma (SMZL).2_{AccordingtotheWorldHealthOrganization(2008),} hairy cell leukemia variant was classified as a provisional entitybecauseithasclinicalandpathologicalfeaturesthat dif-ferfromclassichairycellleukemia.3_{Amongtheseaspectsare} morphologicalandimmunophenotypicvariationsand resis-tancetoconventionaltreatment.1_{Furthermore,patientswith} hairycellleukemiaare treatedwithnucleosideanalogsbut thesedrugshaveareducedresponseinhairycellleukemia variantandareevenineffectiveinsomecases.3,4_An alterna-tiveforthesepatientsistheassociationofnucleosideanalogs withthemonoclonalantibodyrituximab(anti-CD20).5_Thus, duetodifferential treatment, the aimofthis study was to reportacaseofhairycellleukemiavariantandcoversome aspectsrelatedtothedifferentialdiagnosisbetweenthe clas-sicandvariantformsofthediseaseandSMZL.Thisstudywas

∗ _{Correspondingauthorat:DivisãodeAnálisesClínicas,HospitalUniversitárioProfessorPolydoroErnanideSãoThiago,Universidade} FederaldeSantaCatarina(UFSC),CampusUniversitário,s/n◦_{,Trindade,88036-800Florianópolis,SC,Brazil.}

E-mailaddress:[email protected](M.C.Santos-Silva).

approvedbytheResearchEthicsCommitteeofthe Universi-dadeFederaldeSantaCatarina(#913/2010).

Case

report

The case of a 74-year-old male patient is reported. The presence of splenomegaly was observed since 2011, with areas of infarction in the splenic periphery evidenced by cholangiography and computed tomography. In 2012, due tothepersistenceofsplenomegaly,acompletebloodcount andimmunophenotypingbyflowcytometrywererequested. At this time, there was no lymphadenopathy. The blood count showed alterations in red blood cells (poikilocyto-sis, acanthocytes and squizocytes), anemia (hemoglobin 10.1g/dL),thrombocytopenia(100×103/mL),andmild leuko-cytosis (11.03×103/mL). A white blood cell differential revealed the following: 2.86×103neutrophils/mL (25.9%), 4.67×103lymphocytes/mL (42.3%), 1.16×103monocytes/mL (10.5%), 1.73×103eosinophils/mL (15.7%), 0.07×103 basophils/mL (0.6%) and 0.55×103lymphocytes/mL (5.0%) withcytoplasmicprojections(Figure1).Immunophenotyping ofperipheralblood(Figure2)showed23.2%ofBlymphocytes

http://dx.doi.org/10.1016/j.bjhh.2015.01.003

revbrashematolhemoter.2015;37(2):132–135

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Figure1–Small/intermediate-sizedcellswithmoderatepale-graycytoplasm,round/ovalnucleiwithsmoothnuclear

borders,stippledchromatin,occasionalnucleoli,cellshavecircumferentialhair-likeandshort,bluntcytoplasmic

projections.

(CD19+_{),monoclonal(sIg Kappa+), CD103}+_{, CD11c}+_{, CD20}++_, CD22+_,IgM+/++_FMC7++_,CD79b++_,BCL2+_{andnoexpressionof} sIgLambda,CD3, CD4,CD5, CD8,CD10,CD23,CD24,CD25, CD27,CD38,CD43,andCD123.AssessmentofsIgD,sIgG,and sIgA expression on the pathological lymphocytes was not performed.Thebonemarrowwasnotevaluatedandstaging wasnotperformedduringdiagnosis.Thetreatmentwasfour intravenousdosesofrituximab600mg.Afterthefirstdose, thepatientwasdischargedandtheresponsewasmonitored in the outpatient clinic. At the end of the treatment, the patient returned to the hospital and underwent a bone marrowaspirationforimmunophenotyping,myelogram,and immunohistochemistry. Immunophenotyping showed 1.1% ofBlymphoid cellswithasimilarphenotypetothatfound

atdiagnosis (Figure2).Themyelogram showed hypercellu-larity for the age, normal myeloid:erythroid ratio, as well asnormalityforallothermyelogramparameters. Immuno-histochemistry revealed aggregates of small lymphocytes CD20+ _{and DBA44}−/+ _{and the result ofTRAP staining was}

indeterminate.Currently,thepatientisbeingtreatedinthe outpatientclinicand undergoesperiodiclaboratoryteststo monitorthedisease.

Discussion

Classichairycellleukemia,hairycellleukemiavariant,and SMZL share some common features, including malignant

SSC

SSC

Slg kappa

Slg kappa

CD103

CD1

1c

CD19

A

B

C

D

E

F

CD11c

CD25

CD103 Slg lambda

Slg lambda

Figure2–Representativedotplotsofperipheralbloodimmunophenotyping.(A)Pathologicalcells(red)CD19+_atdiagnosis;

(B)pathologicalcells(red)sIgKappa+_andsIgLambda−_{atdiagnosis;(C)pathologicalcells(red)CD103}+_andCD25−_at

diagnosis;(D)pathologicalcells(red)CD11c+_{atdiagnosis;(E)pathologicalcells(red)sIgKappa}+_andsIgLambda−_inminimal

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Table1–Comparisonbetweenclassichairycellleukemia,hairycellleukemiavariant,andSMZL.

Classichairycellleukemia Hairycellleukemiavariant Splenicmarginalzonelymphoma

Age Midlife Over50years Over50years

Genderprevalence Males Nodifference Nodifference

Granulocytopenia and

monocytopenia

Present Usuallyabsent Usuallyabsent

Morphology Bonemarrowandperipheral

blood:small-ormedium-sized cells;presenceofovalor bean-shapednucleus; homogeneous,lessaggregated chromatin;absentor

inconspicuousnucleoli;cytoplasm isabundant,basophilicwithout granulesorvillousprojections

Bonemarrowcells:similartothe classichairycellleukemiacells. Peripheralblood:smallcells; roundorovalnucleus;

nucleus:cytoplasmratioisgreater; evidentnucleolus;moderately basophilic,villouscytoplasm

Bonemarrowandperipheral blood:small-andmedium-sized cells;slightlybasophilic

cytoplasm;moderatelycondensed chromatinandindistinctnucleoli; polarcytoplasmicprojections (villi)mayappear

Spleen Infiltrationoftheredpulp Infiltrationoftheredpulp Infiltrationofthewhitepulp

Bonemarrow Drytap Easyaspiration Easyaspiration

TRAP Positive Negative Negative

AnnexinA1 Positive Negative Negative

Immunophenotype CD25+_,CD103+_,CD11c+_,CD19+_,

CD20+_,CD22+_,CD79a+_,FMC7+_,

sIg++_{,Kappapredominance,CD10}

variable,CD79b−_,CD5−_,CD23−

CD25−_{CD103variable,CD19}+_,

CD20+_,CD22+_,CD11c+_,IgG+_,IgA+_,

FMC7+

CD25variable,CD103,CD19+_,

CD20+_,CD22+_,CD79a+_,IgM+_,IgD+_,

CD5−_,CD10−_,CD23−_,CD43−_, cyclinD1−

lymphocytic infiltration in bone marrow and peripheral blood, splenomegaly, and B lymphocytes with a similar immunophenotype.5 _{Unlike classichairycell leukemia,the} variantformaffectsolderindividuals.1

Anemia and/or thrombocytopenia and leukocytosis are common atdiagnosis ofhairy cell leukemia variant, while pancytopenia, granulocytopenia, and monocytopenia are morecommoninclassichairycellleukemia.Thepatientin this study presented with anemia, thrombocytopenia, and mildleukocytosisduetomonocytosis,eosinophiliaandthe presenceofpathologicallymphocytes.

Immunophenotyping by flow cytometry contributes to differential diagnosis, although it must also be associated withimmunohistochemistryandclinicaldata(Table1). Clas-sic hairy cell leukemia cells are always positive for CD25 andCD103and hairycellleukemia variantcellsarealways negative for CD25 and occasionally positive for CD103. In SMZL,onthe otherhand,CD103isnegativeandCD25may be positive or negative.3,5 _{Classic hairy cell leukemia and} the variant form are also differentiated bythe expression of CD123, which is positive in the classic form and neg-ative in the variant form.6 _{Evaluation of immunoglobulin} heavy chain isotype expression is another way to possi-blydifferentiatehairy cellleukemiavariantfrom SMZL.An unusualfeatureofhairycellleukemiavariant,nottypically observedinotherB-celllymphoproliferativedisorders,isthe expressionofpre-switchedIgM/IgDandpost-switchedIgG/IgA immunoglobulinsbythesamecellsinapproximately40%of cases.Incontrast,SMZLcells characteristicallyexpressIgM withIgDandlackIgGorIgA.7_{Unfortunatelyinthiscasethe} IgG,IgAandIgDimmunoglobulinswerenotavailablefor eval-uation. Thus,the resultsofimmunophenotypicanalysisof peripheralbloodherewereconsistentwithhairycellleukemia variant.

Inimmunohistochemistry,DBA44providesstrongstaining forlymphocyteswithcytoplasmicprojectionsintissues; how-ever,itmayalsobepresentinnormalBcells.3_{Moreover,cells} from hairycellleukemiavariantpatientsrarelyshowTRAP reactivity(unliketheclassicform).1_{Inthepatientofthisstudy,} TRAPstainingremainedindeterminate;hence,itdidnothelp inthediagnosis.Themorphologyandphenotypeconfirmed thediagnosisofhairycellleukemiavariant.

When the patient returned to the hospital of the Uni-versidade Federalde Santa Catarina (HU-UFSC)at the end oftreatment, themyelogramwas hypercellularforhisage, butthisalterationhasnoclinicalrelevancetohiscondition. The presenceof1.1% ofcells with a phenotypesimilar to thatfoundatdiagnosis,asevidencedbyimmunophenotyping ofabonemarrowaspirate, indicatesthepresenceof mini-malresidualdisease(MRD).MRDispresentinmanypatients treatedforhairycellleukemia;however,thesepatientsmay havelong-termsurvival.TreatmentwithRituximabisusedto achievecompleteremission,althoughtheresponseis depend-ent on how much bone marrow is involved and on the characteristicsoftheindividual.8

Conclusion

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Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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