revbrashematolhemoter.2016;38(1):75–78
w w w . r b h h . o r g
Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
Case
Report
Hematological
manifestations
of
human
T
lymphotropic
virus
type
1
infection:
a
possible
association
with
autoimmune
myelofibrosis
Ana
Ciminelli
a,
Frederico
Melo
a,
Marie-Christine
Copin
b,
Anna
Bárbara
Carneiro-Proietti
c,
Suely
Meireles
Rezende
a,∗ aUniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,BrazilbUniversitédeLille,Lille,France
cFundac¸ãoHEMOMINAS,BeloHorizonte,MG,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received14August2015
Accepted30August2015
Availableonline9October2015
Introduction
Itis estimated that the humanT lymphotropic virus type
1 (HTLV-1) infects approximately 20 million people
world-wide.Associateddiseases,however,manifestonlyin5–10%
ofinfectedindividuals.1 StudieshaveshownthatHTLV-1is
endemicinSouthernJapan,the Caribbean,SouthAmerica,
Melanesianislands,PapuaNewGuinea,theMiddleEastand
CentralandSouthernAfrica.InBrazil,HTLV-1infectionis
con-sideredapublichealthconcernasthecountryfiguresamong
theendemicareasintheworldwithprevalenceratesfrom1%
to5%.1
SincethediscoveryofHTLV-1in1979,ithasbeenclearly
associatedwithhematologicdisorders,specificallywithadult
T-cell leukemia/lymphoma (ATL), an aggressive neoplasm
∗ Correspondingauthorat:UniversidadeFederaldeMinasGerais(UFMG),AvenidaAlfredoBalena,190,2◦andar,sala243,30130-100,Belo
Horizonte,MG,Brazil.
E-mailaddresses:srezende@medicina.ufmg.br,suely.rezende@uol.com.br(S.M.Rezende).
withpoorprognosis.1AlthoughATLhasclinicalformswith
different manifestations, it is generally characterized as a
clonalproliferationofCD4+Tcellscontainingrandomly
dis-tributed HTLV-1proviral integrationsites. Theonset ofthe
disease usuallyoccurs20–30years afterviral infection and
is primarily associated with vertical transmission, mainly
throughbreastfeedingbyaseropositivewoman.1
Apart from ATL, other diseases have been consistently
linked to HTLV-1 infection over the years. Tropical spastic
paraparesis/HTLV-1-associatedmyelopathy(TSP/HAM)more
frequently affects women, with onset ranging from years
to decades after infection, atan average age of40 years.1
With an insidious manifestation and chronic evolution,
HAM/TSPtakes years toprogress from the onset of
symp-toms, suchasweakness and spasticityofoneor bothlegs
andminorsensorychanges,towheelchairconfinementand
http://dx.doi.org/10.1016/j.bjhh.2015.08.006
1516-8484/©2015Associac¸ãoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.PublishedbyElsevierEditoraLtda.Allrights
76
revbrashematolhemoter.2016;38(1):75–78bowel/bladderincontinence.1Otherdiseasessuchasuveitis,
infectivedermatitis,pulmonaryandrheumaticdisorderssuch
asrheumatoidarthritisand Sjögren’ssyndrome,aswell as
otherautoimmuneconditionssuchasbronco-alveolar
pneu-monitis,autoimmunethyroiditisandendemicpolymyositis,
havealsobeenassociatedwithHTLV-1infection.1,2 In
addi-tion, in the last two decades, HTLV-1 has been reported
in association with other blood diseases, such as acute
myeloid leukemia,3 idiopathic thrombocytopenic purpura4
andmyelodysplasticsyndrome.5
Case
report
A27-year-oldwomanwasreferredforahematology
consulta-tiontoinvestigatepancytopenia.Atadmission,shehad
spas-ticparaparesis,andbowel andbladderdysfunction,clinical
signsconsistentwiththeinitialpresentationofHAM/TSP.Her
symptomsstartedasaprogressiveweaknessofthelegswhen
shewas22yearsold.Thepatientwasborninaknownendemic
areaforHTLV-1infection,locatedintheNorthernRegionof
MinasGeraisState,Brazil.Althoughtherewasnohistoryof
bloodtransfusion,shereportedthatshewasbreastfedbya
wet nurse. HTLV-1 testing was performedand the positive
enzymeimmunoassayresultswereconfirmedbywesternblot.
Noalterationswerefoundincerebrospinalfluidanalysisora
computedtomography(CT)scanofthelumbosacralspine.At
admission,shepresentedwithpancytopeniathathadbeen
investigatedinanotherhospitalin1996bybonemarrow
aspi-rateandbiopsy;atthattime,noabnormalitieswerefound.
Theseresultscouldnotbecheckedduetothelackofmaterial.
Laterinthesame year,the patientwas hospitalizedfor
another investigation of the pancytopenia and
metrorrha-gia.Duringherhospitalization,thepatientreceived600mLof
packedredcellsanddailyplatelettransfusions.Theabsolute
neutrophil countranged from 1.310×109/Lto 2.060×109/L
(reference range [RR]=4.0×109/L to 11.0×109/L); platelet
countvariedfrom3.74×109/Lto64.00×109/L(RR=150×109/L
to450×109/L)andhemoglobinlevelswerebetween6.0g/dL
and8.4g/dL (RR=12g/dL to14g/dL). Thereticulocytecount
was3.7%(RR=0.5%to1.5%)withtheabsoluteredcellcount
of2.35×103/L.Abdominalultrasoundrevealedliverat4cm
belowtheloweredgeoftherightcostalmarginandthespleen
wasclassifiedasBoydgradeIII.
Severaltestswerecarriedouttoinvestigatethecauseof
the pancytopenia,including leishmaniasis,HIV, hepatitisB
andC,syphilisand antinuclearantibodytest,all with
neg-ativeresults.TestsforvitaminB12,folate,ironserumlevels
and other routine tests were also performed, with results
withinnormalreferenceranges.Abonemarrowaspirateand
biopsyshowedincreasedcellularity,abnormaldistributionof
erythropoiesis,atypicalmegakaryocytes,immature
granulo-cytesandevidenceofreactivemarrowfibrosis.Marrowiron
storeswerenormal.Themetrorrhagiawascontrolledwiththe
administrationofcombinedoralcontraceptives.
Throughout11years,anon-progressivepancytopeniawas
theonlypersistentsign ofahematological disorder.A
sig-nificanthepatosplenomegalywasnoticedandconfirmedby
imagingin2002. Theliver and spleenwere nolonger
pal-pablein the patient’s first consultationin our outpatients’
clinic in 2009. An abdominal CT scan, performed in 2009,
revealedmildsplenomegalywithnootherabdominal
abnor-malities.Petechiaewerepresentinherconsultation,mainly
in the oral cavity. Platelet counts were consistently below
40.0×109/L and absolute neutrophil counts varied from
1.5×109/Lto2.0×109/L,withrelativelymphocytosis(58%to
65%).Adiscretenormocyticnormochromicanemiacouldbe
observedinmostofthebloodtests,withhemoglobinvarying
from 10.5g/dLto12g/dL.Inaddition,thepatientpresented
increased lactate dehydrogenase (LDH) levels, with values
ranging from 902U/L to 1020U/L (RR:313–618U/L). Hepatic
enzymesandcalciumlevelswereunremarkable.Ahighdose
of prednisone (60mg per day) was prescribed to increase
plateletcountsbutwasstoppedasitwasnoteffective.
Thepatientwastestedandprovedtobenegativefor:(i)the
V617FmutationoftheJanuskinase2(JAK2)gene,(ii)W515L
andW515KmutationsoftheMPLgeneand(iii)theBCR-ABL
fusiongene.Furthermore,sequencingofthecodingregionof
exon12ofJAK2andexon9ofthecalreticulin(CALR)genewas
performedbycapillaryelectrophoresisbutnomutationswere
found. Shehadanormalkaryotype byGbandinganalysis.
Theantinuclearantibodytestwaspositiveforanti-cytoplasm
in1:360–1:640dilution(RR:<1:80)and2-microglobulinwas
slightly increased (3.47g/mL; RR: <2.4g/mL). Bone
mar-row aspirationandbiopsywere repeatedin2013(Figure1).
The biopsy sample was stained using hematoxylin and
eosin,periodicacid-Schiff(PAS),giemsa,silverimpregnation
(Gordon-Sweet),Masson’strichrome,andPerls.
Immunostain-ingwasperformedforCD2,CD3,CD4,CD5,CD8,CD20,CD30,
CD34,CD56andFOXP3.Thelymphocytesreactedwithvariable
intensityforCD2,CD3,CD4,CD5andCD8butwerenegative
forCD56andFOXP3.ThereactionwithCD4wasmoreintense
than with CD8. CD34 positive blasts were not identified.
ThereactionwithCD61highlightedtheintenseproliferation
of atypical/small and medium sized megakaryocytes, with
hypolobulatednucleiandrarenakednuclei(Figure1A,Band
F).Theremainingparenchymashowedintensesubversionof
architectureduetoseveregrade3fibrosis(reticulinand
colla-gen)andduetotheneovascularformationandosteosclerosis
(Figure1C–E).Therewasscantyrepresentationofthemyeloid
anderythrocyticseries.Atthepresent,thepatientistaking
2mgclonazepam,10mgBaclofen,and5mgprednisonedaily.
Discussion
HTLV-1infectionhaslongbeendescribedinassociationwith
hematological and auto-immune disorders.1,2 In this case,
ATLwasruledoutduetotheabsenceoftypicalATL‘flower
cells’ characterized by intermediate to large pleomorphic
cells,sometimeswithhyperlobulatednucleiCD4+/CD8−and
the absence of bonemarrow infiltration. Of the
myelopro-liferative neoplasms (MPN), chronic myeloid leukemia and
polycythemiaverawerealsoruledoutduetotheabsenceof
theBCR-ABLfusiongeneandtheJAK2V617Fmutation,
respec-tively, andlackofremainingclinicalandlaboratorycriteria
usedtodiagnose bothconditions,including theabsenceof
theW515LandW515KmutationsoftheMPLgene.
The presenceofatypical megakaryocytes,bone marrow
revbrashematolhemoter.2016;38(1):75–78
77
Figure1–Bonemarrowbiopsy.(AandB)Bonemarrowbiopsystainedusinghematoxylinandeosinshowingclustersof abnormalmegakaryocytes(arrow).(CandD)BonemarrowbiopsystainedusingGordonSweetstainshowingamarked increaseincoarsereticulinfibers(arrow).(E)PerivascularcollagenfibrosisstainedusingMasson’strichrome(arrow).(F) ImmunostainingforCD61withmegakaryocytehyperplasia(arrow).
diagnosis of myelofibrosis. Myelofibrosis, characterized by
chronic and persistent pancytopenia associated with bone
marrowfibrosisandproliferationofmegakaryocytes,isoneof
themostcommontypesofMPN.Itcanbeprimaryordevelop
asanend-stagebonemarrowfailure,secondarytootherMPN.
Myelofibrosiscan alsobepresent asareaction ofthe bone
marrowagainstotherneoplasmsorinflammatoryprocesses,
andcanemergeasanautoimmunephenomenon.6,7
Classi-calfindingsofprimarymyelofibrosisarehepatosplenomegaly,
teardroperythrocytesandleukoerythroblastosisinthe
periph-eralblood,whichwerenotpresentinthispatient.Moreover,
thebenign,non-progressivecourseofthediseasedisfavored
the diagnosis of primary myelofibrosis as the median
sur-vivalofpatientswiththisconditionisabout69months.8The
clinicalpictureandlaboratorytestssuggestthediagnosisof
autoimmunemyelofibrosis(AIMF).
AIMFisanunder-recognizedcauseofmarrowfibrosis,and
hasbeendefinedusingthefollowingcriteria:(1)Grade3or
4reticulinfibrosisofthebonemarrow; (2)lackofclustered
oratypicalmegakaryocytes;(3)lackofmyeloidorerythroid
dysplasia,eosinophilia,orbasophilia;(4)lymphocyte
infiltra-tionofthebonemarrow;(5)lackofosteosclerosis;(6)absent
ormildsplenomegaly;(7)presenceofautoantibodies;and(8)
absenceofadisorderknowntocausemyelofibrosis.6Arecent
studyreported thatmildatypiasincluding occasional
clus-tered,left-shifted,small,and hypolobatedmegakaryocytes,
canbeobservedinAIMF.7
AIMF is classified as primary or secondary, the latter
named when associated with autoimmune disorders.
Dis-easessuchassystemiclupuserythematous(SLE),scleroderma
and Sjögren’s syndrome are the main disorders described
in associationwith secondary AIMF.6,7 AIMFhasalso been
describedinassociationwithHIVinfection9butnotwithHTLV
infection. Thedifferentiation between AIMFand the
MPN-relatedmyelofibrosisisimperativeoncethesedisordershave
differentmanagementandprognoses.AIMFtendstorespond
welltosteroidsand/orotherimmunosuppressiveagentsand
hasabetterprognosis.
Anadditionalunusualaspectofthiscaseistherare
over-lapofHTLV-1-relateddiseases:HAM/TSPandahematological
disorder. ATL and HAM/TSP seem to differ in their route
of transmission (ATL being mainly via breast-feeding, and
HAM/TSPviabloodtransfusion),pathogenesisand
immuno-logical response.Afterinfection,bothcellularand humoral
immune responsesare formedagainstHTLV. The humoral
reactioncontributesasdelayedprotectionbyproducing
anti-bodiesagainstviralproteins,includingTax.However,recently,
Tax-antibodieshavebeen associatedwiththedevelopment
ofHAM/TSP, suggestinganautoimmune component tothe
disease.ThisantibodycouldalsobeassociatedwithAIMF.
Fur-thermore,HAM/TSPapparentlyrelatestopatientswithhigh
proviralloads,whichissupposedlydeterminedbyhost
fac-torssuchaspolymorphismsinthemajorhistocompatibility
complexclassI(MHC-I)moleculesanditsinfluenceonantigen
presentationtoCD8+T-cells.
Inconclusion,thisisthecaseofayoungwomanwith
HTLV-1infectionandHAM/TSP,whoevolvedwithpancytopeniaand
bonemarrowfibrosis.Toourknowledge,exceptforashort
reportbyEngels,10whodoesnotprovidedetailedinformation,
thisisthefirstreportofAIMFassociatedwithHTLV-1
infec-tion.Thiscasereportstrengthensthedescribedassociation
78
revbrashematolhemoter.2016;38(1):75–78Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgements
The authors wish to thank Laboratorio Fleury, São Paulo,
Brazil,inparticularDr.MariaCarolinaTostesPintão,for
per-forming some of the molecular tests for the diagnosis of
myeloproliferativeneoplasms.
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