Rev. bras. ortop. vol.51 número1

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

Original

Article

Giant-cell

tumor:

analysis

on

the

importance

of

early

diagnosis

and

the

epidemiological

profile

夽

Diego

Firmino

de

Carvalho

Diniz

Ferraz

∗

_,

_César

_Augusto

_Torres

_dos

_Santos,

Victor

Hugo

Farias

Costa,

Antônio

Marcelo

Gonc¸alves

Souza,

Paulo

Rogerio

Gomes

Lima

ServiceofOrthopedicsandTraumatology,HospitalOtáviodeFreitas,Recife,PE,Brazil

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received10October2014

Accepted5March2015

Availableonline5January2016

Keywords:

Giant-celltumors/diagnosis

Giant-celltumors/epidemiology

Giant-celltumors/therapy

a

b

s

t

r

a

c

t

Objective:Thisstudyaimedtoascertaintherelationshipbetweenearlydiagnosisof

giant-celltumors(GCT)andtheirprognosis,bycorrelatingthetimeofsymptomonsetwiththe

stagingoftheinjury(throughtheCampanacciclassificationatthetimeofdiagnosis),and

withthetypeoftreatment.Thesecondaryobjectiveofthestudywastooutlinethe

epi-demiologicalprofileofpatientswithGCTintheregionwherethedataweregathered,and

tocomparethemwithdataintheliterature.

Methods:Theauthorspresentanevaluationon61patientsdiagnosedwithboneGCT,with

regardtothesiteofinvolvement,age,initialsymptoms,timeofsymptomonset,

classi-ficationandtypeoftreatment,amongpatientsattendedbetweenMay1994andAugust

2009.

Results:ThethresholdindicatedasthelimitforCampanaccistageI_tumors_to_be_the

com-monestdiagnosis,witha98.2%chancethatthetreatmentwouldbenon-aggressive,was

2monthsaftersymptomonset.Thisfindingwasstatisticallysignificant(p=0.017).Every

additionalmonthincreasedthechancethatapatientwouldbediagnosedwithan

advanced-stagetumorby10.94%,inrelationtothechancesofhavingtheothertwostages ofthe

tumor.

Conclusion:Thestudyresultnotonlysuggeststhatthealternativehypothesisthattheearlier

thediagnosisofGCTis,thelessseverethelesionwillbe,hasbeenconfirmed;butalso

espe-ciallypredictstherelationshipbetweenthetimeofsymptomappearanceandtheseverity

ofthetumor.

Ltda.Allrightsreserved.

夽

WorkperformedintheHospitaldoCâncerdePernambuco,Recife,PE,Brazil.

∗ _{Corresponding}_author_.

E-mails:diegofirminoferraz@gmail.com,dferrazz@hotmail.com(D.F.deCarvalhoDinizFerraz).

http://dx.doi.org/10.1016/j.rboe.2015.12.012

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Tumor

de

células

gigantes:

análise

sobre

importância

do

diagnóstico

precoce

e

perfil

epidemiológico

Palavras-chave:

Tumoresdecélulas

gigantes/diagnóstico

Tumoresdecélulas

gigantes/epidemiologia

Tumoresdecélulas

gigantes/terapia

r

e

s

u

m

o

Objetivo:Presumirarelac¸ãoentreodiagnósticoprecocedotumordecélulasgigantes(TCG)

eoseuprognóstico,relacionarotempodesurgimentodossintomascomoestadiamentoda

lesão,pormeiodaclassificac¸ãodeCampanaccinomomentododiagnóstico,ecomtipode

tratamento.Oobjetivosecundáriodoestudoétrac¸aroperfilepidemiológicodospacientes

comTCGdaregiãoondeforamcolhidososdadosecompará-locomdadosdaliteratura.

Métodos: Avaliac¸ãode61pacientesdiagnosticadoscomtumordecélulasgigantesósseo

quantoaolocaldeacometimento,idade,sintomatologiainicial,tempodosurgimentodos

sintomas,classificac¸ãoetipodetratamentoempacientesatendidosentremaiode1994e

agostode2009.

Resultado: Apontaomarcodedoismesesapósoiníciodasintomatologiacomodatalimite,

quandoseriamaiscomumodiagnósticodetumorestágioI_de_Campanacci_e_com_98,2%_de

chancedesertratadodemodonãoagressivo,dadoscomrelevânciaestatística(p=0,017).A

cadaaumentodeummêsachancedeumpacienteserdiagnosticadocomtumoremestágio

avanc¸adoé10,94%maiordoqueemrelac¸ãoaosoutrosdoisestágiosdotumor.

Conclusão:Oresultadodoestudosugerenãosomenteaconfirmac¸ãodahipóteseopcionalde

quequantomaisprecoceodiagnósticodeTCG,menosgraveéalesão,mas,principalmente,

predizarelac¸ãodotempodesurgimentodosintomacomagravidadedotumor.

EditoraLtda.Todososdireitosreservados.

Introduction

Bone giant-cell tumors (GCTs) are benign mesenchymal

neoplasmswith aggressivecharacteristics. Histologically,it

is known that GCTs were first described by Cooper apud

McCarthy1_and_were_considered_to_be_“fungal_medullary

exos-toses”.In1845,Lebertetal.apudMcCarthy1_described_a_group

ofbonetumorswithgiantmultinucleatedcellsthatpresented

atendencytorecur,butwhichcouldbecuredthrough

ampu-tation.HistopathologicalevaluationsonGCTsrevealthatthey

are formed by vascularized tissue consisting of stroma of

fusiformorovoidcellsandbythepresenceofnumerous

mul-tinucleatedgiantcellsthatresembleosteoclasts.Theypresent

characteristicscommontomanydifferenttumoraland

pseu-dotumorallesions,andanalysistogetherwiththeclinicaland

imagingcharacteristicsisneededinordertoconfirmthe

diag-nosis.

Accordingto aseries attheMayo Clinic,2 _these _tumors

accountfor5%ofboneneoplasmsandareslightlymore

preva-lentinfemales.Theagegroupmostaffectedisbetweenthe

secondandfourthdecadesoflife.GCTsgenerallyaffecta

sin-glebone.Thecommonestsitesaffectedarethedistalfemur,

proximaltibiaanddistalradius.

The clinical condition consists of progressive pain and

increased joint volume, which may be associated with

joint symptoms such as mechanical blocking and

synovi-tis.These symptoms are often initially related to physical

activity and the pain only rarely becomes incapacitating.

A diagnosis of GCT is suspected when, in addition to the

abovementioned clinical condition, radiographic evaluation

reveals a tumorofosteolyticappearance that destroys the

entireepiphysisand mayreachasfarasthejointcartilage

(characteristicsofaggressivenessintheradiological

evalua-tion).Thediagnosis isconfirmedthroughhistopathological

analysis.

In1990,Campanaccietal.3_presented_a_radiographic

clas-sificationforGCTsthatdescribesthreedifferentgrades:stage

1–small,quiescentandintraosseouslesions;stage2–active

oraggressivetumors,withcompromisedbonecortex,but

pre-sentingintactperiosteum;stage3–aggressive,withinvasion

ofadjacentsoftissues.

Historically,thetreatmentconsistedofsimplecurettage,

but this method was shown to give rise to a high

recur-rencerate.Currently,thetechniquesmostusedarecurettage

withadjuvanttherapy,resectionoftheaffectedsegmentwith

fusion-likereconstructionorauto/homograftreplacementor

useofendoprostheses.

Nonspecific initial symptoms, lack of medical training

directedtowardprimarycareanddifficultyinaccessing

refer-ralhospitalsmakesithardertoachieveearlydiagnosisand

adequatetreatmentforGCTs.Thepresentstudyhadtheaims

ofevaluatingtherelationshipbetweenearlydiagnosisofGCT

and its prognosis and correlatingthe lengthoftime since

symptomsappearedwiththestagingofthelesion,bymeans

oftheCampanacciclassificationatthetimeofdiagnosis,and

withthetypeoftreatment.Thisstudyalsohadthe aimof

establishing time markers for early diagnosis of GCT that

would becapableofallowingthe assumptionoflow

sever-ity ofthe lesion,withthe needforless aggressivetypesof

treatment,andservingasaguideforpublicpoliciesfor

(3)

Material

and

method

In September 2014, a cross-sectional descriptive study

was conducted among patients at the Cancer Hospital of

Pernambuco.Allthemedicalfilesofpatientswhohadbeen

diagnosedwithGCTbetweenMay1994andAugust2009were

reviewed.Patientswithsoft-tissueGCT;patientshospitalized

duetotumorrecurrence;casesinwhichthetimethathad

elapsedbetweentheonset ofsymptomsand thediagnosis

recordswasnotmentioned;andrecordswithconflictingor

incompletedata,i.e.absenceofhistopathological

confirma-tion,illegibleinformation,incompleteadmissionformsand

non-explanatory surgicaldescriptions, were excluded from

thedata-gathering.

Throughexcludingthegroupscitedabovefromthe

data-gathering,61patientswereselected.Thesecaseshadmedical

filesthathadbeenfilledoutlegibly,withtheabovementioned

information complete and non-conflicting. The following

informationwassoughtinthesemedicalfiles:timeelapsed

between the onset of symptoms and the tumor diagnosis

at the referral oncological hospital; site of tumor

involve-ment;patient’sage;patient’splaceoforigin;typeoftreatment

implemented;Campanacci classificationonadmission;and

symptomspresentedduringtheattendance.Theprocessof

clinicalinvestigation,lesionclassificationandtreatmentwas

implementedbyqualifiedprofessionalswhoweremembers

oftheBrazilianSocietyofOncologicalOrthopedics.

Thesamplewasclassifiedinaccordance withthe

Cam-panaccisystemandwasdividedintotwogroupsrelatingto

thetreatment required.Thepatientswith GCTsthatcould

beresected through curettagewith adjuvant therapy were

groupedas“non-advanced”cases,whilethosewhorequired

interventionsthatweremore“aggressive”wereconsideredto

be“advanced”cases.

Thisstudywassubmittedtotheethicscommitteeofthe

healthcareinstitutionindicatedthroughtheBrazilplatform,

forauthorization.

Statistical

analysis

Theresultsfromthequantitativevariableswereexpressedas

meansand standarddeviations, whilethe resultsfromthe

qualitativevariableswereexpressedasabsoluteandrelative

frequencies.TheKruskal–Wallis testwas usedtoascertain

possibledifferencesinmeantimetakenfortreatmentandin

patientage,inrelationtotumorstage.Alogisticregression

modelwasusedtocorrelatethetimetakenfortreatmentand

thetumorstage.

Results

ThemeanageamongthepatientswithatumorinCampanacci

stageIwas38.3± 13.7years,whilethoseinstageIIpresented

ameanof29.5± _10.6_years._Patients_with_a_stage_III_tumor

pre-sentedameanof34.1± _13.9_years._It_was_seen_that_there_was

nostatisticallysignificantdifferenceinmeanageinrelation

totumorstage(p=0.311)(Table1).

Table1–Comparisonofmeanagesandlengthsof follow-upinrelationtotumorstage.

Tumorstage(mean±SD) p-value

I II III

Age(years) 38.3±13.7 29.5±10.6 34.1±13.9 0.311 Time(months) 1.5±0.5 6.4±0.8 10.4±2.1 0.017a

a _{Statistically}_significant.

ThepatientswithstageItumorspresentedameantime

takenuntilthediagnosisof1.5± 0.5months.Thosewithstage

IItumorspresentedameanof6.4± 0.8monthsandthosewith

stageIIItumors,10.4± _2.1_months._It_was_observed_that_there

weresignificantdifferencesinthetimetakenuntilthe

diag-nosis, inrelationtothetumorstage(p=0.017),i.e.patients

attheinitialstagepresentedshortertimestakentomakethe

diagnosisthanthoseatadvancedstagesofthetumor(Table1).

ItwasseenthatpatientsinstageIpresentedshortertimes

tomakethediagnosisthanthoseinstagesII_and_III:p<0.0001

and<0.0001,respectively(Fig.1).

Itwasseenthatthetimetakentomakethediagnosisfor

patientswithstageIIItumorswaslongerthan thetimefor

patientswithstageII:p=0.013(Fig.1).

Through logistic regression analysis (Eq. (1)), it was

observed that forevery 1-month increase, the chancethat

apatientwouldbediagnosedwithatumorattheadvanced

stagewas10.94%greaterthanattheothertwotumorstages.

log(− _log(1− ˘₍x₎₎₎= −₁.₆₄+ ₀.₁ _tempo ₍₁₎

where˘(x)istheprobabilitythatapatientwouldbeclassified

ashavinganadvancedstageofthetumor.

Itwas seenfrom Table 2thatpatients withatimeof1

monthtakentomakethediagnosispresentedaprobability

of0.5%ofbeingclassifiedashavinganadvancestageofthe

tumor,whileifthissamepatientweretobediagnosedonly

in the fifthmonth, this probability would be13.7%. If this

samepatientweretobediagnosedonlyafter12months,this

probabilitywouldbe81.5%.

Initial 35

30

25

20

15

10

5

0

Length of follow-up (months)

Intermediate Advanced

Tumor stage

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Table2–Probabilityoftumorstageclassification,in relationtothelengthoffollow-up.

Probabilityof classification

Lengthoffollow-up(months)

1 2 5 8 10 12

Advanced 0.5 1.8 13.7 48.2 63.3 81.5 Non-advanced 99.5 98.2 86.3 51.8 36.7 18.5

Length of follow-up

Probability of diagnosing advanced tumor (%)

6 0.0 0.2 0.4 0.6 0.8 1.0

8 10 12 14 16 18

Fig.2–Probabilityoftumorclassificationinanadvanced stage,inrelationtothetimetakentomakethediagnosis.

ItwasseeninFig.2thatapproximately20%ofthepatients

wereclassifiedwaspresentinganadvancedstageofthetumor

inthe sixth month. Inthe eighth monthofthe follow-up,

approximately 50%ofthe patients presentedtumorsatan

advancestage,while80%ofthepatients wereclassified as

presentinganadvancedstageofthediseasearoundthe11th

month.

Table3presentstheprevalencesofsymptomsamongthe

patientsstudied.Itshowsthatpainalonewasthecommonest

symptomandtumorformationwasthecommonestclinical

sign.

TheincidenceofGCTsaccordingtotheirlocation inthe

skeletonispresentedinTable4,whichshowsthattheyaffect

theepiphysesoflongbones,mostcommonlyattheknee.In

Table3–Prevalenceofsymptoms.

Symptoms N %

Pain 28 46.7

Tumorformation 17 28.3

Painandtumorformation 4 6.7

Increasedvolume 4 6.7

Painandincreasedvolume 2 3.3 Pathologicalfracture 2 3.3 Painandpathologicalfracture 2 3.3

Edemaandpain 1 1.7

Table4–IncidenceofGCTaccordingtolocationin skeleton.

Siteofinvolvement No.ofpatients Percentage

Distalfemur 20 32.78%

Proximal 7 11.47%

Distaltibia 6 9.83%

Distalradius 6 9.83%

Phalanges 5 8.19%

Others 17 27.86%

additiontotheseregions,GCTshavealsobeenfoundinthe calcaneus,proximalhumerus,ulna,hopandproximalradius.

Discussion

Theresultsfromthisstudysuggestnotonlythatithas pro-videdconfirmationoftheoptionalhypothesisthattheearlier thediagnosis ofGCTismade,thelowertheseverityofthe lesionwillbe,butalsoespecially,thatthispredictsthe rela-tionshipbetweenthetimeofsymptomonsetandtheseverity ofthetumor.Forexample,inpatientswhoarediagnosed1 monthaftersymptomsfirstappear,theirchanceofpresenting alesionthatcanbetreatedthroughcurettageplusadjuvant treatment99.5%,whichhasbenefitsbothforthepatientand forthepublichealthcaresystem,incomparisonwithsurgical proceduresthataremoreaggressive.

GCTs were found in our series of 61 patients mostly betweentheirthirdandfourthdecadesoflife,andthisfinding isinlinewiththedataintheliterature.3–5_Unlike_a_study6_in

which31%ofthepatientswerediagnosedwithpathological

fractures,wefoundinourseriesthatonly3.3%ofourpatients

hadsuchlesions.

Theobservationthat onlyonepatientinourstudy

pre-sented metastasis (1.6%)is concordantwith theworldwide

literature,2,7 _in_which_it_has_been_estimated_that_the_risk_of

metastasisfromGCTisbetween1and3%.AccordingtoRenard

etal.,8_the_explanation_for_the_metastatic_foci_lies_in_the_fact

thattumorcellsmaybefoundinperipheralvesselsofthebone

siteaffected.

ComparingtheincidenceofGCTsregardingtheirlocation

intheskeletonwithwhatwasdemonstratedbyJesus-Garcia

etal.,6_we_obtained_similar_data,_as_can_be_seen_in_Table₄_._The

kneeisthelocationofhighestincidenceandaccountsfor44%

ofthecases.

Withtheaimofestablishingtimemarkersforearly

diag-nosisincasesofGCT,the objectivethatwastaken onwas

toidentifylesionsclassifiedasCampanaccistageIorIIthat

itwouldbepossibletotreatthroughcurettageplusadjuvant

therapy,whichwere groupedasnon-advancedcasesinthe

statistical analysisofthis study.Theresultsshowed thata

timemarkerof2monthsaftertheonsetofsymptomswasthe

timelimitfortheperiodinwhichthecommonestdiagnosis

wouldbeaCampanaccistageItumor,witha98.2%chanceof

beingcapableofnon-aggressivetreatment.Thisfindingwas

statisticallysignificant(p=0.017).

In ordertoreach thetime markerdemonstrated inthis

study, improvements in public healthcare policies will be

needed.Investmentinhumanandstructuralresourceswithin

(5)

regularizationofrapidpassagebetweenprimarycareand

spe-cialistunitsforoncologicaltreatmentarewaysofmakingthe

publichealthcaresystemcapableoftimelydiagnosisforGCT

cases.

Thepresentstudy foundthattherewashighprevalence

of generic signs and symptoms, which caused difficulty

regardingclinicalsuspicionandearlydiagnosis.Thepresence

ofjointpainand/ortumorformationwasshowntobeasign

ofsuspicionforinvestigatingpossibleGCTs.

Fromanalysisontheresultobtainedregardingmeanage

inrelationtolesionseverityatthetimeofdiagnosis,itwas

concluded that there was no statistical significance.Thus,

symptoms thatare highly prevalent amongolder patients,

suchasjointpain,needtobebetterinvestigated.Likewise,in

attendingyoungerpatients,tumoretiologyneedstobenoted,

giventhatthedataobtainedinseveralstudieshave

demon-strateditsimportanceforearlydiagnosis.

Conclusion

Thisstudy demonstrated that the mark of2months after

symptomonsetwasthetimelimitfortheperiodinwhicha

diagnosisofCampanaccistageItumorswouldbemore

com-mon, with a98.2% chanceof onlyneeding non-aggressive

treatment.Thisfindingwasstatisticallysignificant(p=0.017).

Withevery1-monthincrease,thechancethatapatientwould

bediagnosedwithatumoratanadvanced stageis10.94%

greaterthaninrelationtotheother twotumorstages.The

epidemiologicalprofileofpatientswithGCTinthisregionis

concordant withthe datainthe worldwideliterature,with

regardtoage,riskofmetastasisandsiteaffected.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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