ww w . r e u m a t o l o g i a . c o m . b r
REVISTA
BRASILEIRA
DE
REUMATOLOGIA
Original
article
Signs
and
symptoms
of
rheumatic
diseases
as
first
manifestation
of
pediatric
cancer:
diagnosis
and
prognosis
implications
Mariana
Bertoldi
Fonseca
a,
Francisco
Hugo
Rodrigues
Gomes
a,
Elvis
Terci
Valera
a,
Gecilmara
Salviato
Pileggi
a,
Paula
Braga
Gonfiantini
b,
Marcela
Braga
Gonfiantini
b,
Virgínia
Paes
Leme
Ferriani
b,
Luciana
Martins
de
Carvalho
a,∗aUniversidadedeSãoPaulo(USP),FaculdadedeMedicinadeRibeirãoPreto(FMRP),HospitaldasClínicas,RibeirãoPreto,SP,Brazil bUniversidadedeSãoPaulo(USP),FaculdadedeMedicinadeRibeirãoPreto(FMRP),RibeirãoPreto,SP,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory: Received1June2016 Accepted8November2016 Availableonline10February2017
Keywords:
Pediatricrheumaticdisease Neoplasticdiseases Juvenileidiopathicarthritis Musculoskeletalsymptoms
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b
s
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c
t
Objective:Toassesstheprevalenceanddescribetheclinical,laboratoryandradiological find-ings,treatmentandoutcomeofchildrenwithcancerinitiallyreferredtoatertiaryoutpatient pediatricrheumatologyclinic.
Methods:Retrospectiveanalysisofmedicalrecordsfrompatientsidentifiedinalistof250 newpatientsattendingthetertiaryPediatricRheumatologyClinic,RibeirãoPretoMedical Schoolhospital,UniversityofSãoPaulo,fromJuly2013toJuly2015,whosefinaldiagnosis wascancer.
Results:Of250patientsseenduringthestudyperiod,5(2%)hadacancerdiagnosis.Among them,80%hadconstitutionalsymptoms,especiallyweightlossandasthenia,and60%had arthritis.Initially,allpatientshadatleastonealterationintheirbloodcount,lactate dehy-drogenasewasincreasedin80%andabonemarrowsmearwasconclusivein60%ofpatients. Boneandintestinebiopsieswerenecessaryforthediagnosisin2patients.JIAwasthemost commoninitialdiagnosis.Thedefinitivediagnosiswasacutelymphoblasticleukemia(2 patients),M3acutemyeloidleukemia,lymphoma,andneuroblastoma(onecaseeach).Of 5patientsstudied,3(60%)areinremissionand2(40%)died,oneofthemwithprioruseof steroids.
Conclusion:Theconstitutionalandmusculoskeletalsymptomscommontorheumaticand neoplasticdiseases candelay thediagnosisandconsequently worsenthe prognosisof neoplasms.Initialbloodcountandbonemarrowsmearmaybenormalintheinitial frame-workofneoplasms.Thus,theclinicalfollow-upofthesecasesbecomesimperativeandthe treatment,mainlywithcorticosteroids,shouldbedelayeduntildiagnosticdefinition.
©2017ElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).
∗ Correspondingauthor.
E-mail:[email protected](L.M.Carvalho). http://dx.doi.org/10.1016/j.rbre.2017.01.007
rev bras reumatol.2017;57(4):330–337
331
Sinais
e
sintomas
sugestivos
de
doenc¸as
reumáticas
como
primeira
manifestac¸ão
de
doenc¸as
neoplásicas
na
infância:
implicac¸ões
no
diagnóstico
e
prognóstico
Palavras-chave:
Doenc¸asreumáticas,Pediatria Neoplasia
Artriteidiopáticajuvenil Sintomasmusculoesqueléticos
r
e
s
u
m
o
Objetivo: Avaliara prevalênciaedescreverasprincipaismanifestac¸õesclínicas,exames complementares,tratamentoeevoluc¸ãodecrianc¸ascomdoenc¸asneoplásicasatendidas inicialmenteemumservic¸oterciáriodereumatologiapediátrica.
Métodos: Analisamosretrospectivamenteoprontuáriomédicodepacientescom diagnós-ticodefinitivodeneoplasia,identificadosentre250casosnovosatendidosnoambulatório dereumatologiapediátricadoHospitaldasClínicasdaFaculdadedeMedicinadeRibeirão Preto-USP,noperíododejulhode2013ajulhode2015.
Resultados: Dos250pacientesrecebidospelo ambulatórionoperíododoestudo,5(2%) tiveramdiagnósticodeneoplasia.Desses5pacientes,80%apresentavamsintomas con-stitucionais, principalmenteperda de pesoeastenia e 60%artrite. Inicialmente, todos apresentavampelomenosumasériealteradanohemograma,80%aumentoda desidroge-naselática(LDH)e60%mielogramaconfirmatório.Doispacientesnecessitaramdebiópsia, ósseaeintestino,paraodiagnósticofinal.Artriteidiopáticajuvenilfoiodiagnóstico ini-cialmaisfrequente.Osdiagnósticosdefinitivosforamleucemialinfóideaguda(2casos), leucemiamielóideaguda-M3,neuroblastomaelinfoma(1casocada).Dospacientes estu-dados3(60%)estãoemremissão.Doispacientesforamaóbito(40%),umdelescomuso préviodecorticoide.
Conclusão:Ossintomasconstitucionaisemusculoesqueléticoscomunsàsdoenc¸as reumáti-caseneoplásicaspodemretardarodiagnósticoeconsequentementeagravaroprognóstico dasneoplasias.Ohemogramainicial,assimcomoomielograma,podemestarnormaisno quadroinicialdasneoplasias.Dessaforma,oseguimentoclínicoevolutivodestescasos torna-seimperativoeotratamento,principalmentecomcorticoides,deveserretardadoaté definic¸ãodiagnóstica.
©2017ElsevierEditoraLtda.Este ´eumartigoOpenAccesssobumalicenc¸aCC BY-NC-ND(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Systemic symptoms related to rheumatic diseases, such
as fever of unknown origin, exanthema, vasculitis,
lym-phadenopathy and hepatosplenomegaly, with or without
associationwithmusculoskeletalcomplaintssuchas arthri-tis,arthralgiaandmyositis,mayalsocorrespondtothefirst symptomsofneoplasticdiseases.Thus,inmanycases, neo-plasticdiseasesareinitiallydiagnosedasarheumaticdisease, whichprolongsthetimeelapseduntiltheestablishmentof acorrect diagnosis,delays thebeginning oftreatment and compromisestheprognosis.1–3
Themusculoskeletalmanifestationsthathavebeen asso-ciatedwithneoplasiasare,mainly,diffusebonepain,arthritis, arthralgia,andmyalgia.Thecharacteristicsofthepainhelpin theestablishmentofacorrectdiagnosis.In lymphoprolifera-tivediseases,bonepainisinitiallyclassifiedasintermittent (especiallyinthe metaphyseal region), withprogression to acontinuous andpreferably nocturnal pain.4 Onthe other hand,inrheumaticdiseases,forexample,juvenileidiopathic arthritis,thepatientsuffersfromapainoflow-to-moderate intensity,whichoccursmainlyinthemorningandis accom-paniedbyacharacteristicstiffness.3
Severalneoplasticdiseasesmaybeassociatedwith muscu-loskeletalcomplaints:primarytumorofbone,cartilaginous,
fibrous,connectivetissue,ormixedorigin withdirect inva-sionofbone,jointormuscletissue;metaphysealbonetumor; malignantinfiltrationofthebonemarrow;and paraneoplas-ticsyndromesinduced bydistant tumorsviainflammatory mediators.5,6
When thesesymptomspredominateatthebeginningof
thedisease,onemustproceedwiththedifferential diagno-sisofjuvenileidiopathicarthritis(JIA),rheumaticfever(RF), systemic lupuserythematosus (SLE), and septicor reactive arthritis,amongotherdiagnosesofrheumaticdiseases.6
Theaimofthisstudywastoevaluatetheprevalenceand todescribethemainclinicalmanifestations,complementary exams,treatment,andevolutionofchildrenwithneoplastic diseasesinitiallyattendedatatertiarypediatricrheumatology unit.
Methods
ofsymptoms,timeelapsedbetweentheonsetofsymptoms andthediagnosisofmalignancy,initialsignsandsymptoms, laboratorytests,suchas:bloodcount,erythrocyte sedimenta-tionrate(ESR),C-reactiveprotein(CRP),lactatedehydrogenase (LDH), specific antibodies; and alterations found in radio-logicalexams,treatmentsperformed,andinitial(rheumatic disease)andfinal(cancer)diagnosis.
Results
Ofatotalof250patientsreferredtothepediatric rheuma-tologyoutpatientclinicin2years,infact5(2%)werecancer patients.
Thedemographic,clinical,andlaboratorycharacteristics ofeachpatientaredescribedinTable1.
Thetimeelapsedbetweentheonsetofthesignsand
symp-toms and the diagnosis ranged from 7 days to 3months.
Weightlossandastheniawerethemostobservedsystemic manifestations.Juvenile idiopathic arthritis(JIA) and acute lymphoblastic leukemia (ALL) were, respectively, the most prevalentinitialanddefinitivediagnoses.
In addition to the musculoskeletal manifestations pre-sented in Table 1, at the initialphysical examination, one
patient suffered from adenomegaly and two patients had
hepatomegalyand splenomegaly. Nocutaneous
manifesta-tionswereobserved.
Patient4wasadmittedtotheservicetakingcorticosteroids, 2mg/kg/day for30 days; this medication wasprogressively taperedfromthefirstconsultation.
Allpatientshadsomechangeintheirbloodcount:fourhad hemoglobin<12g/dL,twohadleukopenia(whitebloodcells <4000/mm3),twohadtotalleukocytes>10,000/mm3,andone patientshowedthrombocytopenia(platelets<150,000/mm3).
Serum LDH levels were increased in four cases (mean
=1349U/L). The autoantibodies initially requested, accord-ing to the initial diagnostic suspicion, were negative for theirrespectivediagnoses,i.e.–juvenileidiopathicarthritis, antiphospholipidsyndrome,andpolyarteritisnodosa.
TheimagingstudiesareshowninTable2.Onlyonepatient hadavertebrallyticlesionontheplainradiograph.Other find-ingsweremorenonspecific,forexample,signssuggestiveof osteopenia,stroke,andsynovialthickening.Inonepatient, deepvenousthrombosis(DVT)ofthefemoropoplitealveinwas diagnosedbyDopplerultrasoundofthelower limbs.Chest tomographywasperformedin2patients,revealing compres-sivevertebralfracturesandpoorlydefinednodularopacities in the left lung in each case, respectively. Magnetic reso-nancewasrequestedinonepatient;theexaminationshowed atumormasscompatiblewithmalignantneoplasmofthehip.
Bone marrow aspiration was performed in all patients
withinthe firstmonthofinvestigation.Threepatients pre-sentedmedullaryalterationscompatiblewithcytologicand
immunophenotypingdiagnoses:acutelymphocyticleukemia
intwopatients,acutemyeloidleukemiainonepatient.Butin twopatientsitwasnotpossibletoestablishadiagnosisbased onthebonemarrow,eitherbecausetherewasnoalteration, orbecausethestudyshowedinfiltrationbyneoplasticcellsof unidentifiedetiology.Subsequently,anexcisionalbiopsywas obtainedinthesepatients,atwhichtimeT-cellnon-Hodgkin’s
lymphoma(bowelbiopsy)andneuroblastoma(bonebiopsy)
wererespectivelydiagnosed.
Two patients were treated and are currently in
post-chemotherapysurveillance(patients1and5),oneisstillon chemotherapy(patient2),andtwopatientsdiedduring treat-ment(patients3and4),includingthatpatientinitiallytreated withcorticosteroids.
Discussion
Itisnotuncommonthepresenceofmusculoskeletal involve-mentasoneofthemanifestationsofneoplasms,particularly leukemia. Brix et al.,7 in a retrospective evaluationof 286 children, and Robazzi et al.,8 studying 406 children seen
in oncology outpatient clinics and diagnosed with acute
leukemia,foundfrequenciesofjointinvolvementof18.5%and 54.7%ofthecases,respectively.Rheumaticdiseases,mainly JIA,weretheinitialsuspicionin68%ofthecasesofleukemia witharthritisevaluatedbyBrixetal.7Rheumatologic symp-toms,asinitialandisolatedmanifestationsofmalignancies, butinitiallyreferredtotherheumatologist,arelessfrequent, butnolessworrying,andthesecanleadtoadiagnosticerror, withsignificantworseningofthepatient’sprognosis.Inour study,inatwo-yearperiod,2%ofthechildrenreferredtothe rheumatologyoutpatientclinicwithadiagnostichypothesis ofrheumaticdiseasewere,infact,carriersofneoplastic dis-ease. Thisprevalenceishigher thanthatobservedinother studies,asinTrapanietal.6(lessthan1%)andinGonc¸alves etal.9(0.25%).
Themusculoskeletalmanifestationsofneoplasmscanbe explainedbythedirectinvasionoftumorsinbonesandjoints
and also byparaneoplastic syndromes and immunological
alterations, withsymptomsatsitesdifferentfrom thoseof theprimarytumor.10,11
Primary tumors,such asosteosarcoma andEwing’s sar-coma,areprimarilyresponsibleforthedirecteffectsfound. Thelocalizationofthetumorinlongbones,withcompression ofadjacent structures,leukemicinfiltration ofsynovial tis-sues,intra-articularbleedingsecondarytothrombocytopenia, andsynovialreactionbyperiostealorcapsularinfiltrationare someofthe factorsthat justifythe musculoskeletal symp-toms. Even in benign tumors, such as the fibrous cortical defect,thereplacementofthebonebyfibroustissuecancause pain,deformity,andspontaneousfractures.8,10
Paraneoplastic rheumaticsyndromes canbeinduced by
hormones,peptides,autocrineandparacrinemediators,and bycytotoxiclymphocytes.Inflammatorymyopathiesand
vas-culitic syndromes may precede, appear concomitantly, or
followmalignanthematologicaldiseases.Malignanciesmay alsoinducetheformationofantibodies,including antiphos-pholipidantibodies,withmanifestationsverysimilartothe antiphospholipidsyndrome(APS),includingthrombosis.10,11
The musculoskeletal symptoms related to tumors may
rev bras reumatol.2017;57(4):330–337
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Table1–Clinicalcharacteristics,initialexternaldiagnosis,initialtreatment,finaldiagnosis,timeelapsedbetweenthe initialandfinaldiagnosis,andoutcomeoffiveoncologicpatientsinitiallyreferredtotherheumatologist.
Patient(gender) 1(F) 2(M) 3(M) 4(M) 5(F)
Ageofonsetofsymptoms (years)
7 7 12 4 15
Constitutionalsymptoms Astheniaand
weightloss
– Asthenia,weight
lossandfever
Asthenia,weight
lossandfever
Asthenia,weight
loss,feverand
amenorrhea.
Pain Scapula,knees,
righthallux,feet
andlumbarspine
Medialfaceof
theleftthigh
Abdominal Cervical,lumbar,
kneeandleft
elbow.
Shouldersand
knees
Arthritis Righthallux
Metacarpopha-langeals
– – Knees,ankles,
leftelbow.
Rightknee
Firsttests
Hemoglobin(g/dl) 10.5 12.2 11.1 8.2 8.7
Leukocytes(n/mm3)
anddifferential 4800(40% segmented;53% lymphocytes) 2800(12% segmented,78% lymphocytes)
6400(5%band,
86%segmented, 11% lymphocytes) 17,800(2% metamyelocytes, 53%segmented, 44% lymphocytes)
11,500(6%band;
76%segmented;
19% lymphocytes)
Platelets(p/mm3) 186,000 87,000 233,000 293,000 389,000
LDH(U/L) %increase 325 normal 490 upperlimit 1844 4× 2080 4.5× 2006 4.3×
CRP(mg/dl) 0.81 13.4 8.64 3.67 10.32
ESR 36 17 9 34 54
Autoantibodies ANAandRF
non-reactive Anticardiolipin, Lupus Anticoagulant, andAnti-2 glycoprotein negative
ANA,AntiRo,
Anti-La,IgGand
IgMANCA
non-reactive. Anti-cardiolipin
IgMpositive
(10.4)andIgG
negative
ANAandRF
non-reactive
ANA non-reactive
Initialdiagnosis Juvenile idiopathic arthritis
APS
Femoropopliteal DVT
Vasculitis(PAN) Juvenile
idiopathic arthritis
Juvenile idiopathic arthritis
Firsttreatment NSAIDs Enoxaparin Human
Immunoglobulin
Corticosteroid NSAIDs,opioids
Finaldiagnosis Acutelymphoid
leukemia Acutemyeloid leukemia, subtypeM3 T-cell non-Hodgkin’s lymphoma
Neuroblastoma Acutelymphoid
leukemia
Timetofinaldiagnosis 28days 13days 3monthsand11
days
1monthand18
days
7days
Outcome Full1st
remission
Alivein
remission
Deathdueto
illness
Deathdueto
illness
Full1st
remission
F,female;M,male;APS,antiphospholipidsyndrome;PAN,polyarteritisnodosa;NSAID,non-hormonalanti-inflammatorydrug;DVT,deepvenous
thrombosis;ANA,anti-nuclearantibodies;RF,rheumatoidfactor;ANCA,anti-neutrophilcytoplasmicantibodies;CRP,C-reactiveprotein;ESR,
erythrocytesedimentationrate;LDH,lacticdehydrogenase.Normalvaluesoflaboratorytests:hemoglobin>12;leukocytes>4000;platelets
>150,000/mm3;CRP<0.6mg/dl;ESR<10;LDH>230and<460U/L.
bone,andbonemarrow.Boneandbonemarrowimpairment
causeseverepainandirritability.12ThepatientwithNB,who
hadbeenreferredtothehospitalwithaninitialdiagnosisofJIA andwhowastakingsteroids,hadametastaticneuroblastoma. Althoughtheoccurrenceofneuroblastomatogetherwith pol-yarthritishasbeenpreviouslydescribed,thefrequencywith whichthisassociationoccursremainsunknown.9,13
Thus, the differential diagnosis of malignancies should alwaysbeincludedinthediagnosticpropaedeuticsofpatients referredtotherheumatologistwithmusculoskeletalsignsand symptoms.9
Systemicandconstitutionalsymptomsarecommonboth
intheinitialpresentationofmalignanciesandofrheumatic diseases,andthis turnsintoadifficulttaskthe differential diagnosisandresultsindelayeddiagnosis–inourstudy,up to3months.Anexampleofsuchsymptomsisfever,which maybetheonlymanifestationoftheinitialpresentationof
severalrheumaticdiseases andtumors;this symptommay
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Table2–Imaging,bonemarrowexaminationandbiopsystudiesoffiveoncologicpatientsinitiallyreferredtotherheumatologist.
Patient X-rayoflongbones X-Rayofjoints X-Rayofotherlocations US CT MRI Bonemarrow Biopsy
1 Osteopenia Fists,hands,ankles,
knees:normal
Vertebrae:Lytic
lesions
Thorax:fracture
ofvertebral
bodies
Joints:normal Spine:compressive
fractureofvertebral
bodies
ALL
2 Thorax:normal Lowerlimbs:Left
femoropoplitealDVT
AML–M3
3 Thorax:bilateral
pleuraleffusion
Abdomen:ascites,
hepatosplenomegaly
Thorax:poorlydefined
nodularopacityinthe
leftlung.Bilateral
consolidation
Normal Bowel:T-cell
non-Hodgkin lymphoma
4 Osteopenia
Irregularityin
leftfemoralhead
Elbows,kneesand
ankles:joint
effusionand
synovialthickening.
Abdomen:normal
Joints:joint
effusion/synovial
thickening,nosigns
ofactive
inflammatory process.
Hip:diffuse
alterationof
bonemarrow,
anteriorand
posterior
neoplasticlesion,
infiltrating musculature.
Leukemiccells;
immuno-phenotyping: inconclusive
Bone: Neuroblastoma
5 Withoutchanges Withoutchanges Joint:jointeffusion. ALL
rev bras reumatol.2017;57(4):330–337
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Inourstudy,80%ofthepatientspresentedconstitutional symptomsintheinitialclinical presentation,characterized byfever,weight loss,and asthenia. Inparticular, apatient with a final diagnosis of T-cell non-Hodgkin’s lymphoma, whoclinicallymaybeassociatedwithatriadofsymptoms
called B symptoms (weight loss without apparent reason,
nightsweats,andfever),15wasinitiallydiagnosedasacaseof polyarteritisnodosa(PAN)initssystemicform.Thispatient also presented a positive PCR for tuberculosis in pleural fluid,whichmadethediagnosisanevenmoredifficulttask, illustratingthesimilarinitialsymptomatologybetween neo-plasms,infections,andrheumaticdisease.16Alsoinourstudy, twopatientshadadiagnosisofALL,themostcommoncancer inchildhood,andtheoccurrenceofconstitutionalsymptoms suchasfatigue,lethargy,weightloss,andfeverattheonset oftheconditionisdescribedinupto100%ofthecases.3,8,17 Inadditiontofeverandweightloss,proptosisandperiorbital ecchymosis(thesignoftheraccoon)arealsocommon find-ingsincasesofdisseminatedNBdisease(i.e.thediagnosisof oneofthepatients).18
Inmyeloproliferativediseasesandinbonetumors,bone painismainlyreferredtothemetaphysisoflongbones, occur-ringcharacteristicallyatnight.6Forthemostpart,intheinitial phase,thepainisintermittent,withatendencytobecome intenseandpersistent,generallybeingoutofproportioninthe faceofthephysicalexaminationfindings.19IncasesofALL, bonepainispresentin34%ofpatients,arthritiscanoccurin upto1/4ofcases,andarthralgiamayalsobepresent.3,8,17The myeloproliferativediseasesobservedinthisstudywereALL,
AML,and non-Hodgkin’slymphoma. In thesepatients, the
patternofmusculoskeletalpainwasvariable,butapainout ofproportioninthefaceofthephysicalexaminationfindings wasoftennoted(3of5cases).
Bleeding,coagulopathies,leukostasis,andtumorlysis
syn-drome are possible complications of AML, being frequent
causesofmortality.20Inthecasehereindescribed,thepatient
wasdiagnosed withthe M3subtype– acute promyelocytic
leukemia (APL).21 AMLM3corresponds toabout 20% ofall AMLs,anddiffersfromothersubtypesbecauseitisstrongly associatedwiththepresenceofcoagulopathyand dissemi-natedintravascularcoagulation(DIC)inupto90%ofcases.22
Due to the hemorrhagic and thrombotic events associated
withthecondition,themaindifferentialdiagnosesarewith APS,proteinCdeficiency,andproteinSdeficiency.Regarding thepatientdescribedwithDVT,despitethepresenceof throm-bocytopenia in the initial hematological examination, the investigationwasdirectedtowardacongenitalthrombophilia; later,thispatientwasreferredtothepediatricrheumatology disciplinefor APSinvestigation.Considering that APSmay alsobeassociatedwiththepresenceofthrombocytopenia,the patientwasinvestigatedforthispathology.Thebonemarrow examinationwasperformedonlyafterthepatient’s progres-siontoasevereneutropenia.
Althoughnon-specific,laboratorytestssuchastheblood countandinflammatorytests maypresent alterationsthat giverisetotheneedtoexpandthediagnosticinvestigation.A higherythrocytesedimentationrate(ESR)inthepresenceofa normalordecreasedplateletcountmaycausethephysician tosuspectofaninfiltrativeprocess.14Inthisstudy,allpatients hadelevatedESRatbaselineexaminations;fourofthemhad
normalplatelets,andonlyoneexhibitedthrombocytopenia. Inneoplasticdiseases,thefindingofearlyanemia, particu-larlynormocyticanemia,iscommon.Inrheumaticdiseases, onemayfindlessintenseanemiasasaresultofthechronic inflammatoryprocess.Inrelationtothewhiteseries,the find-ingsoflymphocytosisand/orleucopeniaand,lessfrequently, leukocytosispredominateinneoplasticpatients;inrheumatic diseases, apredominance of leukocytosisand neutrophilia
is noted. Thrombocytopenia is found quite frequently in
neoplasmswithbonemarrowinvolvement,whereas
throm-bocytosisismorecommoninrheumaticdiseases.14However, theinitialbloodcountinpatientswithbonepain,eveninthose withleukemia,maybenormal.Thus,itisextremelycritical forthediagnosisthatthesepatientsaremonitoredwithserial bloodcounts.
Jones et al. described three main predictive factors for ALL:thepresenceofleucopeniaandthrombocytopeniaanda historyofnocturnalawakeningscausedbypain.The combina-tionofanycytopeniainperipheralblood,includinganemia,in associationwithnocturnalbonepain,increasesthe diagnos-ticsensitivity;thepresenceoftwolowhematologicalvalues, togetherwithnocturnalbonepain,resultedin100% sensitiv-ityand85%specificityforneoplasticdisease.23Inourstudy, threepatientshadnocturnalbonepainattheonsetof symp-toms,andallofthesewereanemic(patients1,4and5).The final diagnosesofthesepatientswere:neuroblastomawith bonemarrowinfiltration(1case)andALL(2cases).Afourth patienthadleukopeniaandreceivedafinaldiagnosisofAML M3.
IncreasesofLDHmayaidindiagnosticdifferentiationsince thepresenceofelevationinthismarker(morethan5timesthe normalvalue)isoftenassociatedwithneoplastic disease.23 However,anormalLDHvaluedoesnotruleoutthepossibility ofmalignancy.2Inthepresentstudy,threepatientshadhigh LDH;inoneoftheremainingpatientstheresultwasnormal, andintheother,theLDHwasslightlyabovenormal.Similarly, theelevationofserumuricacidmaybeamarkerofneoplastic diseases.24Brixetal.foundincreasesinuricacidlevelsin17% ofpatientswithALLwithjointinvolvement,andin30%of patientswithoutjointinvolvement;inthesepatients,LDHwas increasedin70%ofthecases.Inourstudy,serumuricacid dosageswerenotperformed.7
Apositiveantinuclear antibodyisnotasuitablemarker to differentiatebetweenthese twogroups ofdiseases,due toitsnon-specificity,andalsobecauseitmaybepresentin non-rheumaticdiseases,amongthemmalignancies.25Inour study,nopatientwaspositiveforthisautoantibody.Theother autoantibodiesassociatedwithrheumaticdiseases arealso subject tofalse-positiveandfalse-negative results.Thus, it iscritical tocorrectly follow thediagnostic criteria ofeach disease;ontheotherhand,thesetestsmustberepeatedat reg-ularintervals(3months),inordertoconfirmthepersistenceof theantibodies,forthepurposeofdiagnosisandclassification ofthesediseases.Onepatientdescribedinthepresentstudy wasreagenttoanticardiolipin(IgM)atlowtiters;thistestwas notrepeatedbecausethefinaldiagnosisoccurredbeforethe timerequiredforanewdosage.
generalizedbonerarefaction,corticalandperiostealosteolytic lesions,radiolucentbands,andgrowtharrestlinesare com-monfindings.Osteopeniaand jointeffusions canbefound inbothrheumaticand myeloproliferativediseases.26,27 Two patientswithdiagnosesofALLand neuroblastoma, respec-tively,hadosteopeniaattheonsetofthedisease.Thepatient withneuroblastomaandoneofthepatientswithALLhadjoint effusion.Otherimagingtests(ultrasound,MRI,and tomogra-phy)mayaidinthediagnosticinvestigation.
Thefirst analyses ofthe bonemarrow may also fail to establishthediagnosis,especiallyincasesofleukemia.28All patientsinthepresentstudyhadbonemarrowexaminations. Oneofthesepatientshadinconclusiveresultsontwoserial exams.Thispatienthadbeenmedicatedwithcorticosteroids to treatthe rheumatic disease,suspected in another unit, beforetheexam.Itisknownthattheuseofthis pharmaco-logicalclassmayhinderordelaythediagnosisofmalignancy, asitalleviatesthesymptomsandmayalterthecytologyand histologyofthebonemarrow.1Thispatientinquestionwas diagnosedwithneuroblastomaonlyafterabonebiopsy.To beginatreatmentwithcorticosteroids,itisimperativetohave acorrectdiagnosis,sincetheuseofthismedicationworsens theprognosisofneoplasticdiseases,particularlyALL.6
Conclusion
Thegroupofneoplasticdiseases shouldbeincludedinthe differentialdiagnosis ofrheumaticdiseases.Severe noctur-nalbonepain,hepatosplenomegaly,lymphadenomegaly,daily fever,weightloss,andastheniaarefindingssuggestiveof neo-plasia.Laboratorytests,forexample,completeblood count
and LDH, and more specifically abone marrow evaluation
andimagingtests,arefundamentalproceduresthathelpin theearlydiagnosis.However,ifsuchprocedureshavenormal resultsinthefirstsample,theyshouldbeperformedserially, thusavoidingtheinitiationofaninadequatetreatmentand delaysinestablishingthediagnosis.Inthecaseof diagnos-ticdoubt,corticosteroidtherapyshouldbeproscribed,since, specificallyinthecaseofneoplasticdiseases,thistreatment isstronglyassociatedwithaworseprognosis.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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1. BarbosaCM,NakamuraC,TerreriMT,LeeML,PetrilliAS, HilarioMO.Musculoskeletalmanifestationsastheonsetof acuteleukemiasinchildhood.JPediatr.2002;78:481–4. 2. CamposLM,GoldsteinS,SantiagoRA,JesusAA,Cristofani
LM,OdoneFilhoV,etal.Musculoskeletalinvolvementasa firstmanifestationofneoplasmdisease.RevAssocMedBras. 2008;54:132–8.
3. TamashiroMS,AikawaNE,CamposLM,CristofaniLM, Odone-FilhoV,SilvaCA.Discriminationofacute lymphoblasticleukemiafromsystemic-onsetjuvenile idiopathicarthritisatdiseaseonset.Clinics.2011;66:1665–9.
4.CostelloPB,BrecherML,StarrJI,FreemanAI,GreenFA.A prospectiveanalysisofthefrequency,course,andpossible prognosticsignificanceofthejointmanifestationsof childhoodleukemia.JRheumatol.1983;10:753–7.
5.EhrenfeldM,GurH,ShoenfeldY.Rheumatologicfeaturesof hematologicdisorders.CurrOpinRheumatol.1999;11:62–7. 6.TrapaniS,GrisoliaF,SimoniniG,CalabriGB,FalciniF.
Incidenceofoccultcancerinchildrenpresentingwith musculoskeletalsymptoms:a10-yearsurveyinapediatric rheumatologyunit.SeminArthritisRheum.2000;29: 348–59.
7.BrixN,RosthojS,HerlinT,HasleH.Arthritisaspresenting manifestationofacutelymphoblasticleukaemiainchildren. ArchDisChild.2015;100:821–5.
8.RobazziTC,BarretoJH,SilvaLR,SantiagoMB,MendoncaN. Osteoarticularmanifestationsasinitialpresentationofacute leukemiasinchildrenandadolescentsinBahia,Brazil.J PediatrHematolOncol.2007;29:622–6.
9.GoncalvesM,TerreriMT,BarbosaCM,LenCA,LeeL,Hilario MO.Diagnosisofmalignanciesinchildrenwith
musculoskeletalcomplaints.RevPaulMed.2005;123: 21–3.
10.WaimannCA,LuH,SuarezAlmazorME.Rheumatic manifestationsofprimaryandmetastaticbonetumorsand paraneoplasticbonedisease.RheumDisClinNorthAm. 2011;37:527–49.
11.AliasA,RodriguezEJ,BatemanHE,SterrettAG,
Valeriano-MarcetJ.Rheumatologyandoncology:anupdated reviewofrheumaticmanifestationsofmalignancyand anti-neoplastictherapy.BullHospJtDis.2012;70:109–14. 12.SalimA,MullasseryD,PizerB,McDowellHP,LostyPD.
Neuroblastoma:a20-yearexperienceinaUKregionalcentre. PediatrBloodCancer.2011;57:1254–60.
13.ThapaR,MallickD,MandalP,GhoshA.Neuroblastoma masqueradingasjuvenileidiopathicarthritis.IndianJ Pediatr.2007;74:421–2.
14.CabralDA,TuckerLB.Malignanciesinchildrenwhoinitially presentwithrheumaticcomplaints.JPediatr.1999;134: 53–7.
15.AllenCE,KellyKM,BollardCM.Pediatriclymphomasand histiocyticdisordersofchildhood.PediatrClinNorthAm. 2015;62:139–65.
16.SharmaR,CunninghamD,SmithP,RobertsonG,DentO, ClarkeSJ.Inflammatory(B)symptomsareindependent predictorsofmyelosuppressionfromchemotherapyin Non-HodgkinLymphoma(NHL)patients–analysisofdata fromaBritishNationalLymphomaInvestigationphaseIII trialcomparingCHOPtoPMitCEBO.BMCCancer.2009;9:153. 17.SinigagliaR,GiganteC,BisinellaG,VarottoS,ZanescoL,Turra
S.Musculoskeletalmanifestationsinpediatricacute leukemia.JPediatrOrthop.2008;28:20–8.
18.ParkJR,EggertA,CaronH.Neuroblastoma:biology,prognosis, andtreatment.PediatrClinNorthAm.2008;55:97–120. 19.CarsonsS.Theassociationofmalignancywithrheumaticand
connectivetissuediseases.SeminOncol.1997;24: 360–72.
20.GamisAS,AlonzoTA,PerentesisJP,MeshinchiS,Committee COGAML.Children’sOncologyGroup’s2013blueprintfor research:acutemyeloidleukemia.PediatrBloodCancer. 2013;60:964–71.
21.SchochC,SchnittgerS,KlausM,KernW,HiddemannW, HaferlachT.AMLwith11q23/MLLabnormalitiesasdefinedby theWHOclassification:incidence,partnerchromosomes,FAB subtype,agedistribution,andprognosticimpactinan unselectedseriesof1897cytogeneticallyanalyzedAMLcases. Blood.2003;102:2395–402.
22.ChoudhryA,DeLougheryTG.Bleedingandthrombosisin acutepromyelocyticleukemia.AmJHematol.
rev bras reumatol.2017;57(4):330–337
337
23.JonesOY,SpencerCH,BowyerSL,DentPB,GottliebBS, RabinovichCE.Amulticentercase–controlstudyon predictivefactorsdistinguishingchildhoodleukemiafrom juvenilerheumatoidarthritis.Pediatrics.2006;117:e840–4. 24.FinkCW,WindmillerJ,SartainP.Arthritisasthepresenting
featureofchildhoodleukemia.ArthritisRheum. 1972;15:347–9.
25.VermeerschP,BossuytX.Prevalenceandclinicalsignificance ofrareantinuclearantibodypatterns.AutoimmunRev. 2013;12:998–1003.
26.RiccioI,MarcarelliM,DelRegnoN,FuscoC,DiMartinoM, SavareseR,etal.Musculoskeletalproblemsinpediatricacute leukemia.JPediatrOrthopB.2013;22:264–9.
27.Mostoufi-MoabS,HaltonJ.Bonemorbidityinchildhood leukemia:epidemiology,mechanisms,diagnosis,and treatment.CurrOsteoporosRep.2014;12:300–12. 28.BradlowA,BartonC.Arthriticpresentationofchildhood
