Malignant transformation in chronic osteomyelitis

rev bras ortop.2017;52(2):141–147

SOCIEDADE BRASILEIRA DE ORTOPEDIA E TRAUMATOLOGIA

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Original

article

Malignant

transformation

in

chronic

osteomyelitis

夽

Diogo

Lino

Moura

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Rui

Ferreira,

António

Garruc¸o

CentroHospitalareUniversitáriodeCoimbra,Coimbra,Portugal

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Articlehistory:

Received6January2016 Accepted6April2016 Availableonline8March2017

Keywords:

Osteomyelitis Malignanttumors Squamouscellcarcinoma Neoplasiccelltransformation

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Introduction:Carcinomatousdegenerationisarareandlatecomplicationdevelopingdecades afterthediagnosisofchronicosteomyelitis.

Objectives: Topresenttheresultsfromaretrospectivestudyofsixcasesofsquamouscell carcinomaarisingfromchronicosteomyelitis.

Methods:Sixcasesofchronicosteomyelitisrelatedtocutaneoussquamouscellcarcinoma wereidentified.Thecauseandcharacteristicsoftheosteomyelitiswereanalyzed,aswellas timeuptomalignancy,thesuspicionsignsformalignancy,thelocalizationandhistological typeofthecancer,andthetypeandresultofthetreatment.

Results:Themeantimebetweenosteomyelitisonsetandthediagnosisofmalignant degen-erationwas49.17years(range:32–65).Thecarcinomaresultedfromtibiaosteomyelitisin fivecasesandfromfemurosteomyelitisinone.Thepathologicalexaminationindicated cutaneoussquamouscellcarcinomainallcases.AllthepatientswerestagedasN0M0, exceptforone,whoselomboaorticlymphnodeswereaffected.Thetreatmentconsisted ofamputationproximaltothetumorinallpatients.Nopatientpresentedsignsoflocal recurrenceandonlyonehadcarcinomametastasis.

Conclusion: Earlydiagnosisandproximalamputationareessentialforprognosisandfinal resultsincarcinomatousdegenerationsecondarytochronicosteomyelitis.

©2016SociedadeBrasileiradeOrtopediaeTraumatologia.PublishedbyElsevierEditora Ltda.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Transformac¸ão

maligna

na

osteomielite

crônica

Palavras-chave:

Osteomielite Tumoresmalignos

Carcinomadecélulasescamosas Transformac¸ãocelularneoplásica

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Introduc¸ão: Degenerac¸ãocarcinomatosaéumacomplicac¸ãoraraetardiaquesedesenvolve décadasapósodiagnósticodeosteomielitecrônica.

Objetivos:Apresentarosresultadosdeumestudoretrospectivodeseiscasosdecarcinoma espino-celularemumcontextodeosteomielitecrônica.

夽_{StudyconductedattheCentroHospitalareUniversitáriodeCoimbra,Coimbra,Portugal.} ∗ _{Correspondingauthor.}

E-mail:dflmoura@gmail.com(D.L.Moura).

http://dx.doi.org/10.1016/j.rboe.2017.03.005

2255-4971/©2016SociedadeBrasileiradeOrtopediaeTraumatologia.PublishedbyElsevierEditoraLtda.Thisisanopenaccessarticle undertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Métodos: Identificamosseiscasosdecarcinomaespino-celularrelacionadosàosteomielite crônica.Acausaeascaracterísticasdaosteomieliteforamanalisadas,bemcomootempo decorridoatétransformac¸ãomaligna,ossinaisdesuspeitademalignizac¸ão,alocalizac¸ão eotipohistológicodocâncereotipoeosresultadosdotratamento.

Resultados: Otempomédioentreacausadaosteomieliteeodiagnósticodatransformac¸ão malignafoide49,17anos(intervalo:32a65).Ocâncerteveorigememosteomielitesda tíbiaemcincocasoseemumaosteomielitedofêmuremumcaso.Aanálisehistológica demonstroucarcinomaespinocelularcutâneoemtodososcasos.Todosospacientesforam estadiadoscomoN0M0,comexcec¸ãodeum queapresentavaatingimentodosgânglios linfáticoslomboaórticos.Otratamentofoiaamputac¸ãoproximalaotumoremtodosos pacientes.Nenhumdospacientesapresentousinaisderecidivalocaleapenasum desen-volveumetastizac¸ãodocarcinomaespinocelular.

Conclusão: Odiagnósticoprecoceeaamputac¸ãoproximalaotumorsãofundamentaispara oprognósticoeosresultadosfinaisnatransformac¸ãomalignasecundáriaaosteomielite crônica.

©2016SociedadeBrasileiradeOrtopediaeTraumatologia.PublicadoporElsevier EditoraLtda.Este ´eumartigoOpenAccesssobumalicenc¸aCCBY-NC-ND(http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Chronicosteomyelitis isalong-lasting andpersistent bone infection caused by complex colonies of microorganisms involved in a matrix of proteins and polysaccharides, the biofilm,which protectsthemfromthe body’simmune sys-temandtheactionofantibiotics.1,2 _{Thisconditioncanhave} anhematogenousorigin,bycontiguitytoafocusofinfection orbydirectinoculation.1_{Unlikehematogenous} osteomyeli-tis,the incidenceofosteomyelitiscontiguous toafocus of infectionoriginating fromtrauma, surgery,orimplants has increased.3

Non-treatmentofacuteosteomyelitis,ortreatmentfailure, associatedwithimportantlesionsofthesurroundingsoft tis-sues,poorbonevascularization,systemicinvolvement,and multipleandresistantmicroorganismsleadstoachronicand refractoryboneinfection,whoseconstantinflammatory activ-itycausesbonedestructionandmayfavorthedevelopment ofneoplasias.1,3 _{Theincidenceofmalignanttransformation} inthesettingofchronicosteomyelitisisverylowin devel-opedcountries; nonetheless,itremainsamajorproblemin countrieswithpoorhealthcare.1

Parasiticinfectionanditseffectonstemcellsignalingis oneoftheoldesttheoriesofcancerorigin.4,5_{Currently,itis} acceptedthattheassociationofchronicinfectionand develop-mentofmalignanciesmaybeunderestimated.5_Someauthors acknowledge that over 25% of malignant neoplasms may originatefrom chronicinflammationandinfectiousagents. Thereisaconsiderablebodyofevidenceforsomeofthese associations,suchasbetween Salmonellatyphi and hepato-biliarycarcinoma;OpisthorchisviverriniandClonorchissinensis

andcholangiocarcinoma;Schistosomahematobiumandbladder cancer;andbetweenhidradenitissuppurativaandcutaneous squamouscellcarcinoma,amongothers.5,6

The exact mechanism of malignant transformation remains unknown. It is assumed that, in a multifactorial manner, the chronicinflammatorystate behavesas a pro-moterinthecomplexprocessofcarcinogenesis.1,6_Malignant

transformation begins inthe skinor epithelium ofthe fis-tula and infiltrate the adjacent tissues, including bone.7,8 The prevalenceofmalignant transformation in the setting of chronicosteomyelitis ranges from 1.6%to 23%,and the most commonly affected bones are the tibia and femur. Themost frequentlyobserved malignant transformationis squamouscell carcinomaoftheskin.1,5,9,10 _{Theincreasein} fistulous drainage,aswellaspersistence,exophytic growth of an ulcer or mass can be warning signs for malignant transformation.1,11_{Allpatientswithulcersandfistulas} asso-ciatedwithchronicosteomyelitis shouldbefrequently and carefully followed-up, and any characteristicalterations in a chronic wound should raise the suspicion of malignant transformation.8,12 _{Diagnosisisconfirmedthroughbiopsies,} which shouldbeperformed earlyinmultiplelocations and depths, including ulcers, fistulas, and bone, in order to increasediagnosticaccuracyandreducethenumberoffalse negatives.10,12,13 _{When malignant transformation is} diag-nosed,itisessentialtostagetheneoplastic diseaseandto assessthepresenceofdistantmetastasesthroughstudiesby computerizedtomography,magneticresonanceimaging,and positronemissiontomography.12

The definitive and most frequently used surgical treat-ment inthese situations, considering that the majority of patientshaveadvanceddisease,istheproximalamputation oftheneoplasia.7,10_{Adjuvantchemoradiotherapyisindicated} in metastaticdisease and high-gradetumors.14 _{In selected} patients withoutmetastaticdisease,limb-sparingextended tumorexcisionwithlimbsalvagemaybechosen.1

The main prognostic factor is the staging of the neo-plastic disease.8,10 _{In most cases, chronic osteomyelitis in} squamous cell carcinomas is aggressive, with high levels of local recurrence and metastasis. Metastasis is observed early(in mostcases,inthefirst 18monthsaftermalignant transformation)andismainlylocatedinthelymphnodes.15 However,ifthepatientdoesnotpresent metastaticdisease duringthe firstthree yearsand thetumorlesion hasbeen excised correctly, prognosis is favorable.15 _{Early diagnosis} andaggressivetreatmentofthemalignanttransformationof

rev bras ortop.2017;52(2):141–147

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Fig.1–PatientLMM.(A)Radiographywithsignsofchronicosteomyelitisofthetibia;(B)Malignanttransformationofulcer intosquamouscellcarcinoma.

chronicosteomyelitisare criticaltothe prognosisandfinal results.1_{Themosteffectivemethodofpreventingtheonset} ofthesemalignanciesisappropriateanddefinitivetreatment ofchronicosteomyelitis,debridement,andantibiotictherapy.

Material

and

methods

Aretrospectiveanalysisofpatientsdiagnosedwithmalignant transformationinchronicosteomyelitiswasperformed.The evaluationwasmadethroughtheclinical recordsand con-sistedofananalysisoftheetiologyofchronicosteomyelitis anditscharacteristics,timeelapseduntildiagnosisof malig-nant transformation and reasons that led toits diagnosis, cancerlocationandhistologicaltype,andsurgicaltreatment performedanditsresults.

Results

Theauthorspresentaseriesofsixpatientsdiagnosedwith malignanttransformationofchronicosteomyelitis(Table1). Allpatientsweremale.Itwasobservedthat,intwothirdsof thesample,chronicosteomyelitisoriginatedfromatrauma that had occurred at an early age, while the other third wasassociated withahematogenous cause resulting from unspecified childhood infections. All traumatic causes of osteomyelitiswereopenfracturesofthelowerlimb,withthe exceptionofonepatientwhosetraumacouldnotbe ascer-tained.Forallpatients,thelegwastheaffectedanatomical site,andthetibiawasthemostaffectedbone.Inonepatient, althoughosteomyelitis reachedthe legbones, it had origi-natedfromanopenfractureofthefemur;patientdeveloped alatechroniculcerinthelegthatlaterbecame malignant. In83.33%ofthepatients,thecauseofosteomyelitisoccurred inchildhood,whileonepatienthadtheinitialtraumaat39 yearsofage.Inallpatients,theevolutionfromosteomyelitis

tomalignancyoccurredoverdecades,withameanintervalof 49.17years(minimumof32andmaximumof65).

The persistent presenceof achronic ulcer was the red flag sign forall patientsin this series. Other signs of sus-pectedmalignanttransformationwerealsoidentified:inone patient,therewasalsoanincreaseintheintensityof puru-lentfistulousdrainage;inanother,arecentincreaseinulcer dimensions(Figs.1–4).Staphylococcusaureuswasdetectedinall microbiologicalanalyses,Pseudomonasaeruginosawaspresent intwopatients,andProteusmirabilisinonepatient. Pathologi-caltibialfracture,whichisoneofthecomplicationsofchronic osteomyelitis,wasalsoobservedintwopatients(Fig.4).

Cutaneoussquamouscellcarcinomawasthetypeof neo-plasiaobservedinall thepatientsinthesample.In83.33% ofthepatients,nosignsofmetastasisweredetected;inturn, onepatientpresentedimagingdatasuggestinglumbar-aortic lymphnodeinvolvement.Althoughtheinitialstaging corre-sponded toN0M0, alyticlesion inthe proximalportionof thecontralateralfemurwasobservedinonepatientafterfive months,andlaterwasdiagnosedasametastasisoriginating insquamouscellcarcinoma.

Thetherapeutic choiceforall patients was limb ampu-tationsurgery,notablyamputationofthedistalthirdofthe thigh.Inthepatientwithchronicosteomyelitisofthefemur andinvasionofthelumbar-aorticlymphnodes, disarticula-tion ofthehipandthe necessarylymphadenectomywould requireahemipelvectomy.However,duetotheinherentrisks ofthissurgeryandthedifficultytoachieveskincoverage,the authorsdecidedagainstit,andthusapalliativeamputation wasperformedthroughthedistalthirdofthethigh.Noneof thepatientsdevelopedlocalrecurrence.

All patientsin the sample, but one,died. However, the causeofdeathwasrelatedtothemalignancyof osteomyeli-tisinonlyonepatient,whileinallothersdeathwascaused byotherassociateddiseases.Survivalafterdiagnosisof neo-plasiawas3.8years,withaminimumofeightmonthsanda

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Table1–Patientseries.

Patient Causeofthe osteomyelitis

Affectedbone Ageofthe patientat osteomyelitis onset(years) Timeelapsed until neoplastic diagnosis (years) Signof suspected neoplastic lesion Infectious agents Typeof neoplasia Degreeof metastasisin theinitial staging

Treatment Survivalafter thediagnosis ofneoplasia (years) Age(years)at thetimeof deathand cause JMB,♂ Openfemoral fracture Femur+Tibia, fibula 7 65 Ulcer unresponsive totreatment andincreased fistulous drainage Staphylococcus aureusand Proteus mirabilis Cutaneous squamous cell carcinoma Lymph-aortic lymphnodes (N1M0) Amputation ofthedistal thirdofthe thigh 8 80(stroke) LMM,♂ Hematogenic after unspecified infection

Tibia 6 57 Ulcer

non-responsiveto treatment Staphylococcus aureus, Pseudomonas aeruginosa Cutaneous squamous cell carcinoma No(N0M0) Amputation ofthedistal thirdofthe thigh Currently alive – JLF,♂ Hematogenic after unspecified infection

Tibia 7 62 Ulcer

non-responsiveto treatment andrecent growth Staphylococcus aureus, Pseudomonas aeruginosa Cutaneous squamous cell carcinoma No(N0M0) Amputation ofthedistal thirdofthe thigh 2 71(stroke)

AJS,♂ Openfracture andleg slough

Tibia 6 43 Ulcer

non-responsiveto treatment Staphylococcus aureus Cutaneous squamous cell carcinoma No(N0M0) Amputation ofthedistal thirdofthe thigh 7 56(acute myocardial infarction) SCL,♂ Unspecified localtrauma

Tibia 10 32 Ulcer

non-responsiveto treatment Staphylococcus aureus Cutaneous squamous cell carcinoma No(N0M0) Amputation ofthedistal thirdofthe thigh 1 43(chronic kidney disease) AVS,♂ Opentibial

fracture

Tibia 39 36 Ulcer

non-responsiveto treatment Staphylococcus aureus Cutaneous squamous cell carcinoma No(N0M0) Thepatient later developed metastasis Amputation ofthedistal thirdofthe thigh 0.5 75 (metastatic dissemina-tionof squamous cell carcinoma)

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Fig.2–PatientJLF.(A)Radiographywithsignsofchronic osteomyelitisofthetibia;(B)Malignanttransformationof ulcerintosquamouscellcarcinoma.

maximumofsixyears.Thepatientwithconcomitantchronic osteomyelitisofthefemurpresentedinfectionofthe ampu-tationstump,whichrequiredsurgicalcleaningofthefemur (Fig.5).

Discussion

StudiesintheEnglishliteratureonmalignanttransformation inthesettingofchronicosteomyelitisarescarce,consisting primarilyofisolated clinicalcases.1 _{Onlytwoarticleswere} caseseries:onewithsixandanotherwithsevenpatients.1,7,10 Therefore, this seriesisoneofthe firsttoanalyze aseries ofpatientsdiagnosedwithmalignanttransformationinthe contextofchronicosteomyelitis.

The prevalence of males is in agreement with the literature.1 _{In the present series, most cases of chronic} osteomyelitishadtraumaastheircause.Traumaremainsthe mostfrequentcause ofosteomyelitis;openfracturesofthe longbonesareassociatedwithinfectionratesof4–64%and infectionrecurrenceratesof20–30%.9,10,16,17 _{Thetibiaisthe} mostcommonlyaffectedbone,followedbythefemur,which isinlinewiththefindingsfromotherseries.1,5,9,10

Studies inthis area demonstrated that the presenceof chronic osteomyelitiswithyears ordecades ofevolutionis themostimportantfactorformalignanttransformation;the interval from osteomyelitisdiagnosis tomalignancyranges from18to72years.1,10,12_{Inallpatientsinthissample,an} inter-valofdecadeswasobservedbetweenosteomyelitisdiagnosis anddevelopmentofmalignancy.Themainsignofsuspected malignant transformationwas thepersistence ofanatonic ulcerthatdidnotrespondtotreatment,followedbyarecent enlargementoftheulcerandincreaseddrainage.Themost frequentsymptomsthatraisesuspicionofmalignant trans-formationareincreaseddrainage,lackoflesionimprovement

Fig.3–PatientAJS.(A)Radiographywithsignsofchronicosteomyelitisofthetibiaandsignsofleadremnantsfromthe bulletthatcausedtheoriginalslough;(B)Malignanttransformationofulcerintosquamouscellcarcinoma.

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Fig.4–PatientAVS.(A)Radiographywithsignsofchronictibialosteomyelitis,pathologicalfracture;(B)Non-consolidation aftersixweeks;(C)Malignanttransformationofulcerintosquamouscellcarcinoma.

afterthree months of treatment, followed by increasedor exophyticlesion,erythema,hemorrhage,lymphadenopathy and,lessfrequently,hyperkalemia,weightloss,anorexia,and hyperpigmentation ofthe surrounding skin.1 _{In agreement} withotherstudies,S.aureuswasthemostfrequentlydetected microorganism.1_{Themostfrequentlyobservedmalignancyin} chronicosteomyelitisiscutaneoussquamouscellcarcinoma, whichwastheonlyneoplastichistologicaltypeidentifiedin thepresentstudy.1,5,9,10

Asmentioned in the introduction,squamous cell carci-nomas in the context of chronic osteomyelitis are usually

aggressiveandhavehighlevelsoflocalrecurrenceandearly metastasis.15_{Despitethesedata,inthepresentstudy,tumors} showed nosignalsofmetastatic diseaseatthe momentof diagnosis in83.3%(n=5)ofpatients.All sixpatientsinthe studybyAlamietal.7_{werestagedasN0M0.Incontrast,out} of the sevenpatients in the study by Altayet al.,10 _three were at the N0M0stage; two,N1M0; one, N1M1; the other diedpriortothestaging.Oneofthepatientsinthepresent study,stagedasN0M0,developedbonemetastaseswithinfive months.Thesedatapointtotheneedforvigilanceand assid-uous monitoring ofthese cases, including those staged as

Fig.5–PatientJMB.(A)X-rayatsixyearsafterthighamputation,withradiographicsignsoffemoralosteomyelitis;(B) Fistulographydemonstratingfistulainposteriorandupwarddirection,extendingforabout6.5cmincommunicationwith themedullarycanalofthefemur.

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N0M0,duetotheprecocityandrapidityofmetastatic dissem-ination.

Amputationproximaltothelesionisasurgicaltreatment thatresolvesnotonlytheneoplasticlesionbutalsothechronic osteomyelitis;itisthegoldstandardformalignant transfor-mationsofosteomyelitis.In allpatients ofthissample, an amputation wasperformed through the distalthird ofthe thigh;nocasesoflocalrecurrencewereobserved.Mean sur-vivalafterdiagnosisoftheneoplasiawasonly3.8years.This canbeexplainedbythefactthatfourofthefivepatientsdied duetootherassociateddiseases,notduetomalignancyof osteomyelitisortothesurgicalprocedureperformed(Table1). Interestingly,thepatientwiththelongestsurvival(eightyears) wastheonewhounderwentpalliativeamputationthrough thethighandwhopresentedconcomitantchronic osteomyeli-tis ofthe femuras wellas suspectedlumbar-aortic lymph nodeinvolvement.Theneedforregionallymphadenectomy remains controversial, asthe increase inlymph node size isoftenonlyreactivetoinflammation.10_{However,itisnow} thoughtthatifthesignsoflymphadenopathypersistsixto12 weeksafteramputation,theirsurgicalremovalisrequired.10,11 Intheaforementionedcase,thelumbar-aorticadenopathies wereprobablyreactive,ratherthancausedbymetastatic dis-ease,allowingthepatienttosurviveforeightyearsafterthe diagnosisofsquamouscellcarcinoma.

Conclusion

Malignanttransformationisarareandlatecomplicationof chronicosteomyelitis,whoseclinicalsignsofsuspicionmust beidentifiedearly.Earlydiagnosisbymeansofbiopsiesand aggressivetreatmentoftheselesionsarefundamentalforthe prognosisandfinalresults.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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