Braz. j. . vol.81 número5

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BrazJOtorhinolaryngol.2015;81(5):554---567

www.bjorl.org

Brazilian

Journal

of

OTORHINOLARYNGOLOGY

REVIEW

ARTICLE

Prevalence

of

oral

and

oropharyngeal

human

papillomavirus

infection

in

Brazilian

population

studies:

a

systematic

review

夽

Leandro

Luongo

de

Matos

a,b,∗

,

Giuliana

Angelucci

Miranda

c

,

Claudio

Roberto

Cernea

b

a_Instituto_do_Câncer_do_Estado_de_São_Paulo_(ICESP),_São_Paulo,_SP,_Brazil

b_Department_of_Head_and_Neck_Surgery,_Faculdade_de_Medicina,_Universidade_de_São_Paulo_(USP),_São_Paulo,_SP,_Brazil c_Faculdade_de_Medicina_do_ABC,_Santo_André,_SP,_Brazil

Received30March2015;accepted22April2015 Availableonline21July2015

KEYWORDS

Human

papillomavirus; Oropharynx; Mouth; Brazil; Prevalence

Abstract

Introduction:Human papillomavirushasbeenassociated withheadandnecksquamouscell

carcinoma.However,thereisnoconclusiveevidenceontheprevalenceoforalorpharyngeal

infectionbyhumanpapillomavirusintheBrazilianpopulation.

Objective:TodeterminetherateofhumanpapillomavirusinfectionintheBrazilianpopulation. Methods:Systematic reviewof publishedarticles. Medline, The Cochrane Library, Embase,

Lilacs(LatinAmericanandCaribbeanHealthSciences)andScieloelectronicdatabases were

searched.ThesearchincludedpublishedarticlesuptoDecember2014inPortuguese,Spanish

andEnglish.Awidesearchstrategywasemployedinordertoavoidpublicationbiasesandto

assessstudiesdealingonlywithoraland/ororopharyngealhumanpapillomavirusinfectionsin

theBrazilianpopulation.

Results:The42selectedarticlesenrolled4066patients.Itwasobservedthatoralor

oropharyn-gealhumanpapillomavirusinfectionswereidentifiedin738patients(18.2%;IC9517.6---18.8),

varying between 0.0%and91.9%. Theprevalences oforal ororopharyngeal human

papillo-mavirusinfectionswererespectively6.2%,44.6%,44.4%,27.4%,38.5%and11.9%forhealthy

people,thosewithbenignorallesions,pre-malignantlesions,oralororopharyngealsquamous

cellcarcinoma, riskgroups (patients with genital human papillomaviruslesions or infected

partners)andimmunocompromisedpatients.Theriskofhumanpapillomavirusinfectionwas

estimatedfor eachsubgroupanditwasevidentthat, whencompared tothehealthy

popu-lation, the riskofhuman papillomavirus infectionwas approximately1.5---9.0 timeshigher,

夽 _Please_cite_this_article_as:_de_Matos_LL,_Miranda_GA,_Cernea_CR._Prevalence_of_oral_and_{oropharyngeal}_human_{papillomavirus}_infection_in

Brazilianpopulationstudies:asystematicreview.BrazJOtorhinolaryngol.2015;81:554---67.

∗_{Corresponding}_author_at:_Av._Dr._Enéas_de_Carvalho_Aguiar,₂₅₅_---_8th_floor_---_room_8174,_05403-000_São_Paulo,_SP,_Brazil.

E-mail:lmatos@amcham.com.br(L.L.deMatos).

http://dx.doi.org/10.1016/j.bjorl.2015.04.001

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OralHPVprevalenceinBrazilianpopulationstudies 555

especiallyinpatientswithanimmunodeficiency,orallesionsandsquamouscellcarcinoma.The

ratesofthemostwell-knownoncogenictypes(humanpapillomavirus16and/or18)alsoshow

thisincreasedrisk.

Conclusions: Globally,theBrazilianhealthypopulationhasaveryloworalhumanpapillomavirus

infectionrate.Othergroups,suchasat-riskpatientsortheirpartners,immunocompromised

patients,peoplewithorallesionsandpatientswithoralcavityororopharyngealsquamouscell

carcinomahaveahighriskofhumanpapillomavirusinfection.

ElsevierEditoraLtda.Allrightsreserved.

PALAVRAS-CHAVE

Papilomavírus humano; Orofaringe; Boca; Brasil; Prevalência

Prevalênciadeinfecc¸ãooraleorofaríngeapeloHPVemestudosnapopulac¸ão brasileira:revisãosistemática

Resumo

Introduc¸ão: O papilomavírus humano (HPV) tem sido associado ao carcinoma de células

escamosas(CCE)decabec¸aepescoc¸o.Noentanto,nãoexistemevidênciasconclusivassobrea

prevalênciadeinfecc¸ãooraloufaríngeapeloHPVnapopulac¸ãobrasileira.

Objetivo: Determinarataxadeinfecc¸ãopeloHPVnapopulac¸ãobrasileira.

Método: Revisão sistemática deartigos publicados. Foramfeitas buscas nos seguintes

ban-cosdedadoseletrônicos:Medline,TheCochraneLibrary,Embase,Lilacs(LatinAmericanand

CaribbeanHealthSciences)eScielo.Abuscaconsiderouartigospublicadosatédezembrode

2014,emportuguês,espanholeinglês.Foiutilizadaumaamplaestratégiadebuscacomo

intu-ito deevitarviésdepublicac¸ãoetambémparaquefossemavaliadosestudosquetratassem

apenasdeinfecc¸õesoraise/ouorofaríngeaspeloHPVnapopulac¸ãobrasileira.

Resultados: Os42artigosselecionadosincluíram4.066pacientes.Observou-sequeinfecc¸ões

oraisouorofaríngeaspeloHPVforamidentificadasem738pacientes(18,2%;IC9517,6-18,8),

variandoentre0,0-91,9%.Asprevalênciasdeinfecc¸õesoraisouorofaríngeaspeloHPVforam,

respectivamente, 6,2%, 44,6%, 44,4%, 27,4%, 38,5% e 11,9% em pacientes saudáveis, com

lesõesoraisbenignas,comlesõespré-malignas,comCCEoralouorofaríngeo,gruposderisco

(pacientescomlesõesgenitaispeloHPVouparceirosinfectados)epacientesimunodeficientes.

Oriscode infecc¸ãopeloHPVfoiestimado paracadasubgrupo,quandoficou evidenteque,

emcomparaçãocomapopulaçãosaudável,oriscodeinfecçãoporHPVfoiaproximadamente

1,5-9,0vezesmaisalto,especialmenteempacientescomimunodeficiência,lesõesoraiseCCE.

Ospercentuaisdostiposoncogênicosmaisconhecidos(HPV16e/ou18)tambémmostramesse

aumentonorisco.

Conclusões: Apopulac¸ãobrasileirasaudávelapresentataxadeinfecc¸ãooralpeloHPVmuito

baixa.Outros grupos,porexemplo,pacientesderiscoouseusparceiros,pacientes

imunod-eficientes, indivíduos portadores de lesões orais epacientes comCCE de cavidade oral ou

orofaringeapresentammaiorriscodeinfecc¸ãopeloHPV.

ElsevierEditoraLtda.Todososdireitosreservados.

Introduction

Human papillomavirus (HPV) is one of the most common causesofsexually transmittedinfections.HPVis classified ashigh-risk(oroncogenic),whichisassociatedwith malig-nancies,orlow-risk(ornon-oncogenic),whichisrelatedto benigndiseases.1_The_relationship_between_HPV_infections, especiallytypes 16 and 18, andanogenital cancer is well established.Inthelastdecade,relationshipsbetweenHPV andheadandnecksquamouscellcarcinoma(HNSCC)have beenestablished,especiallyinyoungerpatientswithoutthe classicriskfactors(tobaccoandalcoholabuse).2

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556 deMatosLLetal.

Therefore,theaimofthepresentstudywastodetermine therateofHPVinfectionintheBrazilianpopulationbased onasystematicreviewofpublishedarticles.

Methods

Ethics

ThepresentstudywasnotsubmittedtoIRBbecauseitwas asystematicreviewexclusivelywithpublishedarticles.

Searchstrategyandinclusioncriteria

TwoauthorsperformedsearchesofMEDLINE,TheCochrane Library,Embase,LILACS,andSciELOelectronicdatabases. The search included published articles up to Decem-ber of 2014 in Portuguese, Spanish, and English. A wide search strategy was employed in order to avoid publica-tion biases and to assess studies dealing only with oral and/ororopharyngealHPVinfectionsintheBrazilian popula-tion.ThefollowingMedicalSubjectHeadingsandkeywords were used: ‘‘human papillomavirus’’ and ‘‘Brazil’’ and ‘‘mouth’’ OR ‘‘humanpapillomavirus’’ and ‘‘Brazil’’and ‘‘oropharynx’’.Referencelistsofpreviouslyobtained arti-cles were also analyzed manually so that other relevant studiescouldbeidentifiedforinclusioninthepresentstudy.

Exclusioncriteria

Articles that were not published in Portuguese, Spanish, or English, or where the full text could notbe obtained, wereexcludedfromthesearch.Articlesthathadnodataor insufficientdataregardingHPVstatuseswerealsoexcluded. Articles from the same institution by the same set of authorswerescreenedforstudytime-periodoverlaps,and if repetitive information was presented, duplicated data wereexcludedanddatafromthemostcomplete dataset wereanalyzed.Otherexclusioncriteriawere:articlesthat includedonlypatientswhotestedpositivefororalor orop-haryngeal HPV; articles based on a pediatric population, animals,orcelllines;reviewarticles,casereports,orcase seriesstudies; HPV in sites other than the mouth and/or oropharynx; articles that did not study HPV; and studies withpopulationsotherthanBraziliansormulticentric stud-iesin which it was notpossible to separate the Brazilian population’sHPVstatus.

Dataextraction

Alldatawereextracted bytwoindependentauthorsusing a data recording form developed for this purpose, which includedthe following: cityand state, population charac-teristics,dateswhenthesamplewasobtained,thetypeof materialcollected(paraffin-embedded,freshtissue,and/or brushingmucosa)andsubsite (mouthand/or oropharynx), age, smoking status, alcohol intake, gender, technology usedforHPV detection(polymerasechain reaction[PCR],

insituhybridization,and/orimmunohistochemistry[IHC]), andgeneralandspecificHPVstatus(HPV16and/orHPV18).

Anydiscrepancieswereaddressedfollowingdiscussionand consensusbetweenthetwoauthors.

Dataanalysis

Thearticleswereinitiallyorganizedinthefollowinggroups to facilitate the analysis: (1) oral or oropharyngeal HPV infectioninhealthypatients;(2)oralororopharyngealHPV infection in patientswith benign or premalignantlesions; (3)HPVinfections intheoralcavityand/or oropharyngeal squamouscell carcinoma (SCC); (4) oral or oropharyngeal HPVinfectionwherepatientsorpatients’partnershad gen-italHPVinfections;(5)oralororopharyngealHPVinfection inimmunodeficientpatients.

For the statistical analysis, the HPV status data were categorized into the following groups: healthy patients, immunodeficient patients, high-risk patients (those with genital HPV infections or infected partners), patients with benignlesions, withpremalignant lesions (dysplasia, leukoplakiaorerythroplakia), andwithsquamouscell car-cinoma(oralcavityororopharyngealSCC).MicrosoftExcel (MicrosoftCorp®_---_Redmond,_WA,_United_States)_was_used_to

tabulatedataandtoperformweightedaverage,frequency, and95%confidenceinterval(95%CI)calculations.SPSS®

ver-sion17.0(SPSS® _Inc_---_Illinois,_United_States)_was_used_for

logisticregressionstoassesstheriskofHPVinfectionineach group, calculating odds ratios (OR) and 95% CIs. In all of theseanalyses,theprobabilityofmakingan␣ortypeIerror

wasconsideredaslessthan5%(p<0.05).

Results

Using the established search strategy andinclusion crite-ria,84abstractswereidentified(Fig.1).Exclusioncriteria included: studies with subsites other than the mouth or oropharynx(13),articleswithoutHPVstudies(seven), stud-iesofpediatric populations(five),casuisticstudies(four), unobtainabledata(four),non-humansamples(three),case reports or series of cases studies (three), review articles (two),andstudiesofnon-Brazilianpopulations(one).Based on the criteria, 42 articles5---46 _were _included _in _the sys-tematicreview (Table1),andit wasnotedthat thegreat majorityofthestudieswereconductedinthelastdecade, withoralsamples.

Brazil is a large country witha population of approxi-mately 200,000,000. The articles analyzed came from all overthecountry,withconcentrationsinstatecapitalsand moredevelopedregions(forexample,theSoutheastRegion, whichhad61.9%ofthestudies,especiallySãoPauloState) asshowninFig.2.

Demographicdata

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Abstracts selected: 84

First exclusion: 33 abstracts • Other subsites that not OC/OP: 13 • Not HPV study: 7

• Only children population: 5 • Not human samples: 3

• Case reports or series of cases: 3 • Literature review: 2

Second exclusion: 9 studies • Same casuistic: 4

• Impossibility to obtain data: 4 • Not a Brazilian population: 1 Abstracts selected for

complete evaluation of the manuscript: 51

Articles included for systematic review: 42

Figure1 Flowchartofarticleselection.

studiedimmunodeficientpatients(Fanconi’sanemiaandHIV patients).

Thirty-fourarticles(80.9%)includeddemographicdata, which are displayed in Table 2. It wasobserved that the weightedaverage foragewashigherintheSCCgroup(59 yearsold)thanthe others(30---36 yearsold).Tobaccouse andalcoholintakeweresimilarlyhigherinthesepatients.

Oral/oropharyngealHPVstatus

The 42 articles included 4066 enrolled patients. It was observed that oral or oropharyngeal HPV infections were identifiedin738patients(18.2%;95%CI17.6%---18.8%), vary-ingbetween0.0%and91.9%.HPVstatuswasassessedusing PCRin 90.5%ofthestudiesandbyin situhybridizationin theothers.

GeneralHPV,HPV16,HPV18,andHPV16/18prevalences aredisplayedinTable3.Itwasobservedthathigherrates ofHPVinfectionoccurredinpatientswithorallesionsand inpeoplein high-riskgroups (patientswithgenitallesions or infected partners). It wasalso noted that the healthy populationhadaverylowHPVinfectionrate(6.2%;95%CI 5.7---6.7%).

The risk of HPV infectionwas estimated for each sub-group(Table4).Itwasevidentthat,whencomparedtothe healthypopulation,therisk ofHPVinfectionwas approxi-mately1.5-to9.0-foldhigher,especiallyinpatientswithan immunodeficiency, oral lesions,and SCC. Therates of the mostwell-knownoncogenic types(HPV16and/or 18)also showthisincreasedrisk.

Discussion

Thisstudiedsummarized,forthefirsttime,theprevalence oforalandoropharyngealinfectionsintheBrazilian popu-lation.Thissystematic reviewwasconductedwithalarge seriesoforal andoropharyngeal HPVstatusesin different populations,anddatawerestratifiedintogroupsofpatients in orderto acquireclinically relevant informationtoward

the management of each specific group. However, some pointsrequirediscussion.

Oral/oropharyngealHPVinfection

TheprevalenceoforalHPVhasbeenestimatedtobeinthe range2.4---7.5%amongyoungadultsintheUnitedStates.47_A recentstudy48_investigated_the_prevalence_of_oral_HPV infec-tionsin thegeneral US population (5579men andwomen agedbetween14and69years)in2009and2010.The over-allprevalenceoforalHPVinfectionsforanyHPVtypewas 6.9%(95% CI 5.7%---8.3%), the prevalence of high-risk HPV typeswas3.7%(95%CI3.0%---4.6%),andthatofHPV16was 1.0%(95%CI0.7%---1.3%).Thepresentstudyidentifiedarate of6.2%foranyHPVinfectionand1.4%forHPV16infection among2060healthypatients,whichissimilartolargeseries aroundtheworld.

Consideringother groupsanalyzedinthepresent study, otherstudiesalsoidentifiedanincreasedprevalenceoforal HPVinfection.AstudyconductedinZagreb,Croatia, estab-lished a rate of 17.7% for HPV positivity in oral lesions, withasignificantlyhigherpresenceinbenignproliferative mucosallesions(18.6%).High-riskHPVtypeswere predom-inantlyfound inpotentially malignant oral disorders(HPV 16in4.3%)witharateforanyHPVinfectionof15.5%.49 _A meta-analysisconductedwithdysplasiaspecimensfromthe oralcavityandoropharynxidentifiedanoverallprevalence ofHPV16/18of24.5%(95%CI16.4%---36.7%).50_Another_study identifiedaprevalenceof6.9%fororalHPVinfectioninHIV patients.51_Studies_of_this_relationship_in_other immunodefi-cientpatientsarescarce.OralHPVinfectionswerefoundin almost10.2%to75%ofpatientswithgenitalHPVlesionsor infectedpartnersworldwide.52,53

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Table1 Demographicdataofpopulationsandsamplescollectedintheincludedstudies.

Article Braziliancity,state Population

characteristics

Sampledate Collectedmaterial Subsite

Oral/oropharyngealHPVinfectioninhealthypatients

Sacramento(2006)6 _São_José_do_Rio_Preto,_SP ₅₀_healthy_patients ₂₀₀₆ _Fresh_tissue _Oropharynx

Esquenazi(2010)7 _Rio_de_Janeiro,_RJ ₁₀₀_healthy_university

students

2006---2007 Brushing Mouth

Horewicz(2010)8 _Campinas,_SP ₁₀₄_patients_with

gingivaldisordersand healthymucosa

2006---2009 Paraffin-embedded tissue

Mouth

Tristão(2012)9 _Araras,_SP ₁₂₅_healthy_patients _2007---2012 _Brushing _Mouth

Kreimer(2013)10 _São_Paulo,_SP ₄₉₉_healthy_men _2007---2013 _Brushing _Mouth

Cavenaghi(2013)5 _Votuporanga,_SP ₁₂₄_healthy_patients ₂₀₁₁ _Brushing _Mouth_and

oropharynx

Araujo(2014)11 _Belém,_PA ₁₆₆_healthy_patients ₂₀₁₄ _Brushing _Mouth_and

oropharynx

Machado(2014)12 _Campo_Grande,_MS ₅₁₄_healthy_men ₂₀₁₄ _Brushing _Mouth

Oral/oropharyngealHPVinfectioninpatientswithbenignorpremalignantlesions

Betiol(2012)13 _Araras,_SP ₁₆_healthy_patients_and

8casesofleukoplakia

Fonseca-Silva(2012)14 _Montes_Claros,_MG ₂₄_normal_mucosa

samplesand48oral dysplasialesions

Institutional archive

Paraffin-embedded tissue

Mouth

HPVinfectioninoralcavityand/ororopharyngealsquamouscellcarcinomapatients Comparativestudies(healthypeopleversusSCCpatients)

Cortezzi(2004)15 _São_José_do_Rio_Preto

andSãoPaulo,SP

16SCCand142healthy patients

2004 Freshtissue(SCC)

Brushing(healthy)

Mouthand oropharynx

Silva(2007)16 _São_Paulo,_SP ₅₀_SCC_and₁₀_healthy

volunteers

2007 Freshtissue Mouth

Mazon(2011)17 _Araraquara,_SP ₁₈_benign_lesions,₁₈

premalignantlesions, and19SCC

Mouth

Comparativestudies(benignlesionsversusSCCpatients)

Soares(2002)18 _Araraquara,_SP ₂₀_cases_of_benign_oral

lesionsand10SCC

Mouth

Soares(2003)19 _Araraquara,_SP ₃₀_benign_lesions_and₂₇

SCC

Mouth

Fregonesi(2003)20 _Araraquara,_SP ₁₉_benign_lesions,₁₀

premalignantlesionsand 17SCC

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Oral

HPV

prevalence

in

Brazilian

population

studies

559

Acay(2008)21 _São_Paulo,_SP ₄₀_leukoplakia_and₁₀

SCC

Mouth

Lira(2010)22 _Ribeirão_Preto-SP ₁₆_{non-malignant}_oral

lesionsand20insitu SCCand50SCC

2009 Paraffin-embedded

tissue

Mouth

Fregonezi(2012)23 _Ribeirão_Preto,_SP ₁₉_benign_oral_lesions,

16premalignantoral lesionsand17SCC

Populationalstudies

Miguel(1998)24 _São_Paulo,_SP ₂₈_SCC _1995---1996 _Fresh_tissue _Mouth_and

oropharynx

Soares(2007)25 _Natal,_RN ₇₅_SCC _2000---2003 _{Paraffin-embedded}

tissue

Mouth

Oliveira(2008)26 _Ribeirão_Preto,_SP ₈₇_SCC _{Institutional}

archive

Mouth

Spindula-Filho(2011)31 _Goiânia,_GO ₃₉_SCC_and₈_verrucous

carcinoma

2010 Paraffin-embedded

tissue

Mouth

Cordeiro-Silva(2012)32 _Vitória,_ES_and_Goiânia,

GO

45SCC 2012 Paraffinandfresh

tissue

Mouthand oropharynx

Kaminagakura(2012)33 _São_Paulo,_SP ₁₁₄_SCC _1970---2006 _{Paraffin-embedded}

tissue

Mouth

Marques-Silva(2012)34 _Montes_Claros,_MG ₄₀_SCC _1996---2007 _{Paraffin-embedded}

tissue

Mouthand oropharynx

Cantarutti(2014)35 _Brasilia,_DF ₂₆_SCC _2005---2011 _{Paraffin-embedded}

tissue

Mouthand oropharynx

Lopez(2014)36 _Goiânia,_GO;_Rio_de

Janeiro,RJ;SãoPaulo, SP;RibeirãoPreto,SP

222SCC 1998---2008 Paraffin-embedded

andfreshtissue

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Table1 (Continuación)

Article Braziliancity,state Population

characteristics

Sampledate Collectedmaterial Subsite

Oral/oropharyngealHPVinfectioninpatientswithgenitalHPVinfection Comparativestudies(healthypeopleversuspatientswithgenitalHPVinfection)

Gonc¸alves(2006)37 _Campinas,_SP ₇₀_women_with_genital

HPVinfectionand70 healthywomen

2001---2002 Saliva Mouth

Marques(2013)38 _Brasilia,_DF ₄₃_women_with_NIC

lesionsand21partners

2011 Brushing Mouthand

oropharynx

Ribeiro(2014)39 _Recife,_PE ₃₁_married_couples:_men

withpenissquamouscell carcinomaorprecursor lesionsandtheir partners

Vidotti(2014)40 _São_Luis,_MA ₁₀₅_women_with_genital

lesionsclinically suspectedforHPV infection

Populationalstudies

Castro(2009)41 _Maceió,_AL ₃₀_women_with_genital

HPVinfection

Xavier(2009)42 _São_Paulo,_SP ₃₀_men_with_anogenital

HPVinfection

2009 Brushingandfresh

tissue

Mouth

Peixoto(2011)43 _Salvador,_BA ₁₀₀_women_with_genital

lesionsconfirmedfor HPVinfection

2011 Brushing Mouth

Zonta(2012)44 _São_Paulo,_SP ₂₇_women_from_prison

withpre-malignantor malignantlesionsofthe uterinecervix

2012 Brushing Mouth

Oral/oropharyngealHPVinfectioninimmunodeficientpatients(allcomparativestudieswithhealthypatients)

Araujo(2011)45 _Curitiba,_PR ₆₀_patients_with

Fanconi’sanemiaand severeanaplasticanemia and16healthycontrol

2011 Brushing Mouth

Lima(2014)46 _São_Paulo,_SP ₁₀₀_women_with_HIV_and

100healthywomen

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Brasília / Distrito Federal: Marques 2013, Cantarutti 2014 Goiânia / Goiás: Spindula-Filho 2011, Cordeiro-Silva 2012, Lopez 2014

Campo Grande / Mato Grosso do Sul: Machado 2014

Votuporanga / São Paulo: Cavenaghi 2013 São José do Rio Preto / São Paulo:

Cortezzi 2004, Sacramento 2006 Araçatuba / São Paulo: Simonato 2008

Araraquara / São Paulo: Miguel 1998, Soares 2002, Soares 2003, Fregonesi 2003, Mazon 2011

Curitiba / Paraná: Araújo 2011

Belém / Pará: Araújo 2014

São Luis / Maranhão: Vidotti 2014

Natal / Rio Grande do Norte: Soares 2007, Soares 2008, Oliveira 2009, Pereira 2011

Recife / Pernambuco: Ribeiro 2014

Maceió / Alagoas: Castro 2009

Salvador / Bahia: Peixoto 2011

Montes Claros / Minas Gerais: Marques-Silva 2012, Fonseca-Silva 2012

Vitória / Espirito Santo: Cordeiro-Silva 2012

Araras / São Paulo: Betiol 2012, Tristão 2012

Campinas / São Paulo: Gonçalves 2006, Horewicz 2010 São Paulo / São Paulo:

Miguel 1998, Cortezzi 2004, Silva 2007, Acay 2008, Xavier 2009, Zonta 2012, Kaminagakura 2012, Kreimer 2013, Lima 2014, Lopez 2014

Rio de Janeiro / Rio de Janeiro: Esquenazi 2010, Lopez 2014 Ribeirão Preto / São Paulo:

Oliveira 2008, Lira 2010, Fregonezi 2012, Lopez 2014

0 400 800 1200 km

Figure2 ArticledistributionaccordingtoBraziliancityandstate.

established a similar rate of 27.4% for HPV infections in patients withSCCofthe oral cavityor oropharynxandof 8.0%specificallyforHPV16infection.ForHPV18infection, a rate of 23.7% wasobserved amongSCC patients in the present review, possibly the first reportin this fieldwith alargesample.Otherseries,55 _however,_reported_an unex-pectedextremerarityofHPV18intheoropharynxthatwas confirmedinotherlargestudies,andtheauthorsdiscussed howthiswasadifficultfacttoexplain.

O’Rorke et al.57 _performed _a _{meta-analysis} _with ₄₂ articles studying the survival rate of HNSCC patients. They concluded that patients with HPV-positive HNSCC had a 54% better overall survival rate compared to HPV-negativepatients(HR0.46,95%CI0.37---0.57)andthatboth progression-freesurvivalanddisease-freesurvivalwere sig-nificantlyimprovedinHPV-positiveHNSCCs.Thiswasnotthe aimofthepresentreview,butitdemonstratesthecurrent relevanceofthestudyofthistopic.

Demographics

Demographically, patients with HPV-related HNSCCs are morelikelytobemale,white,non-smokers,non-drinkers, youngerinage,andhaveahighersocioeconomicstatus.57---60 Changes in sexual behavior, including a higher numberof lifetime sex partners, an increase in oral sex practices, same sex-contact,and earlier age of sexualactivity have allbeenimplicatedinHPV-relatedHNSCC.57,61 _Many_of_the studiesincluded in thisreviewdidnotpresent findingsby potentiallyimportantcovariates(age,gender,tobaccouse, alcohol use, etc.), as was observed in other studies.55,62 Moreover,onlyeightstudies(38.1%)employedacancer-free controlgroup,whichisdifficultandcansometimescausean

overestimation of the odds ratio of HPV risk infection betweenHNSCC groups. The same trendwasobserved by Herreroetal.62

The variations in oral HPV prevalence amongdifferent studies may be due to differences in study populations, samplingandtestingmethods,andpossiblythetimeperiods studied.47

Sampleanalysis

Intheabsenceofastandardizeddetectiontechnique, con-siderablevariationsintheprevalenceofHPVinfectionshave beenrecordedintheliterature.54 _This_was_not_observed_in thepresentreviewbecausethegreatmajorityofthestudies employedGP5+/6+orMY09/11primersinpolymerasechain reaction(PCR)orHPVtype-specificinsituhybridization.

Geographicdistribution

Theprevalence of HPV wasassessedin astudy with1688 healthymen(medianageof31years)intheU.S.,Mexico, andBrazil.Theprevalence ofallHPVtypeswas4.0%(95% CI3.1%---5.0%).10_The_most_prevalent_high-risk_HPV_type_was HPV 16 in all three countries; however, HPV55 wasmore commoninMexicocomparedtotheU.S.orBrazil.The geo-graphicheterogeneitymightbepartlyexplainedbyregional differencesinthedistributionofriskfactorsotherthanHPV infectioninHNSCCpatients.55

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562 deMatosLLetal.

Table2 Clinicalcharacteristicsofpatientsoftheincludedstudies(whenobtainedfromoriginalarticle).

Article Age Smokingstatus(%) Alcoholintake(%) Men/women

Oral/oropharyngealHPVinfectioninhealthypatients

Sacramento(2006)6 _Mean_of₂₅_y _14.3% _71.4% _21/29

Esquenazi(2010)7 _Mean_of₂₃_y _3.0% _3.0% _40/60

Horewicz(2010)8 _Mean_of₃₈_y _3.8% _--- _28/76

Tristão(2012)9 _{Predominantly}_between₁₈_and₂₁

y

--- --- 37/88

Kreimer(2013)10 _47%_under₃₀_y

83%under44y

40.0% 74.0% 499/0

Cavenaghi(2013)5 _Mean_of₅₁_y _75.0% _37.1% _77/47

Araujo(2014)11 _Mean_of₃₆_y _6.6% _23.5% _63/103

Machado(2014)12 _Mean_of₂₃_y _--- _--- _0/514

Weightedaverage 30years 318/1043(30.5%) 493/939(52.5%)

---Oral/oropharyngealHPVinfectioninpatientswithbenignorpremalignantlesions Fonseca-Silva(2012)14 _Means:₃₂_y_(control);₅₄_y

(dysplasia)

56.9% 61.1% 39/33

HPVinfectioninoralcavityand/ororopharyngealsquamouscellcarcinomapatients Comparativestudies(healthypeopleversusSCCpatients)

Cortezzi(2004)15 _Mean_of₆₁_y _--- _--- _106/52

Silva(2007)16 _Over₄₀_y _100.0% _---

---Comparativestudies(benignlesionsversusSCCpatients)

Lira(2010)22 _Mean_of₅₇_y _80.2% _66.3% _71/15

Populationstudies

Miguel(1998)24 _Mean_of₆₁_y _90.5% _--- _42/3

Soares(2007)25 _Mean_of₆₅_y _--- _--- _49/26

Oliveira(2008)26 _Mean_of₅₉_y _81.6% _--- _73/14

Simonato(2008)27 _79.3%_under₆₀_y _89.7% _62.1% _27/2

Soares(2008)28 _Mean_of₆₅_y _--- _---

---Oliveira(2009)29 _59%_over₆₀_y _--- _--- _57/31

Pereira(2011)30 _Mean_of₆₃_y _--- _--- _19/8

Spindula-Filho(2011)31 _55.3%_over₆₅_y _72.3% _61.7% _34/13

Cordeiro-Silva(2012)32 _44.5%_over₅₈_y _80.0% _68.9% _35/10

Kaminagakura(2012)33 _Mean_of₅₁_y _84.0% _62.0% _81/33

Marques-Silva(2012)34 _33.3%_under₄₅_y _96.0% _93.3% _34/6

Cantarutti(2014)35 _Mean_of₅₆_y _92.0% _65.0% _16/10

Lopez(2014)36 _45%_under₅₅_y _93.7% _95.6%

---Weightedaverage 59years 703/801(87.8%) 458/609(75.2%)

---Oral/oropharyngealHPVinfectioninpatientswithgenitalHPVinfection Comparativestudies(healthypeopleversuspatientswithgenitalHPVinfection)

Gonc¸alves(2006)37 _Mean_of₃₀_y _29.3% _--- _0/140

Marques(2013)38 _Mean_of₄₅_y _--- _--- _21/43

Ribeiro(2014)39 _Mean_of₃₂_y _27.4% _--- _31/31

Vidotti(2014)40 _41.9%_under₃₀_y _7.6% _33.3% _0/105

Populationstudies

Castro(2009)41 _Mean_of₂₈_y _30.0% _0.0% _0/30

Xavier(2009)42 _Mean_of₂₉_y _--- _--- _30/0

Peixoto(2011)43 _Mean_of₃₀_y _15.0% _88.1% _0/100

Zonta(2012)44 _74.1%_under₃₅_y _66.7% _--- _0/27

Weightedaverage 32years 90/437(20.6%) 123/235(52.3%)

---Oral/oropharyngealHPVinfectioninimmunodeficientpatients(allcomparativestudieswithhealthypeople)

Lima(2014)46 _Mean_of₃₆_y _31.0% _50.0% _0/200

(10)

---Oral

HPV

prevalence

in

Brazilian

population

studies

563

Table3 HPVstatusineachsubgroup.

Article Total HPV+ HPV16 HPV18 HPV16/18

Oral/oropharyngealHPVinfectioninhealthypatients

Cortezzi(2004)15 ₁₄₂ ₁₅_(10.6%) ₁₃_(9.1%) _--- ₁₃_(9.1%)

Gonc¸alves(2006)37 ₇₀ ₃_(4.3%) _--- _---

---Sacramento(2006)6 ₅₀ ₇_(14.0%) ₁_(2.0%) ₁_(2.0%) ₂_(4.0%)

Silva(2007)16 ₁₀ ₁_(10.0%) _--- _---

---Esquenazi(2010)7 ₁₀₀ ₀_(0.0%) _--- _---

---Horewicz(2010)8 ₁₀₄ ₀_(0.0%) ₀_(0.0%) _---

---Araujo(2011)45 ₁₆ ₁_(6.2%) ₀_(0.0%) ₀_(0.0%) ₀_(0.0%)

Betiol(2012)13 ₁₆ ₃_(18.8%) ₀_(0.0%) ₃_(18.8%) ₃_(18.8%)

Fonseca-Silva(2012)14 ₂₄ ₇_(29.2%) ₅_(20.8%) ₂_(8.3%) ₇_(29.2%)

Tristão(2012)9 ₁₂₅ ₂₉_(23.2%) _--- _---

---Kreimer(2013)10 ₄₉₉ ₁₀_(2.0%) ₃_(0.6%) ₀_(0.0%) ₃_(0.6%)

Cavenaghi(2013)5 ₁₂₄ ₃_(2.4%) _--- _---

---Araujo(2014)11 ₁₆₆ ₄₀_(24.1%) ₀_(0.0%) ₅_(3.0%) ₅_(3.0%)

Lima(2014)46 ₁₀₀ ₂_(2.0%) _--- _---

---Machado(2014)12 ₅₁₄ ₇_(1.3%) ₀_(0.0%) ₀_(0.0%) ₀_(0.0%)

Total 2060 128/2060(6.2%)

(95%CI5.7%---6.7%)

22/1551(1.4%) (95%CI1.2%---1.6%)

11/1285(0.9%) (95%CI0.8%---1.0%)

33/1551(2.1%) (95%CI1.9%---2.3%)

Oral/oropharyngealHPVinfectioninpatientswithbenignlesions

Soares(2003)19 ₃₀ ₆_(20.0%) _--- _--- ₂_(6.7%)

Fregonesi(2003) 19 6(31.6%) --- --- 4(21.0%)

Lira(2010)22 ₁₆ ₁₆_(100.0%) _--- _---

---Mazon(2011)17 ₁₈ ₆_(33.0%) ₀_(0.0%) ₀_(0.0%) ₀_(0.0%)

Fregonezi(2012)23 ₁₈ ₁₁_(61.1%) ₀_(0.0%) ₇_(39.0%) ₇_(39.0%)

Total 101 45/101(44.6%)

(95%CI43.7---45.4)

0/36(0.0%) (95%CINA)

7/36(19.4%) (95%CI17.8---21.1)

13/85(15.3%) (95%CI14.7---15.9)

Oral/oropharyngealHPVinfectioninpatientswithpremalignantlesions

Soares(2002)18 ₂₀ ₂_(10.0%) _--- _---

---Fregonesi(2003)20 ₁₀ ₆_(60.0%) _--- _--- ₄_(40.0%)

Acay(2008) 40 9(22.5%) --- --- 5(12.5%)

Mazon(2011)17 ₁₈ ₄_(22.0%) ₀_(0.0%) ₄_(22.0%) ₄_(22.0%)

Betiol(2012)13 ₈ ₈_(100.0%) ₀_(0.0%) ₅_(62.5%) ₅_(62.5%)

Fonseca-Silva(2012)14 ₄₈ ₃₄_(70.8%) ₃₁_(64.6%) ₃_(6.2%) ₃₄_(70.8%)

Fregonezi(2012)23 ₁₆ ₈_(50.0%) ₀_(0.0%) ₄_(25.0%) ₄_(25.0%)

Total 160 71/160(44.4%)

(95%CI42.7%---46.1%)

31/90(34.4%) (95%CI31.2%---37.7%)

16/90(17.8%) (95%CI17.6%---38.6%)

(11)

564

de

Matos

LL

et

al.

Table3 (Continuación)

Article Total HPV+ HPV16 HPV18 HPV16/18

Oral/oropharyngealHPVinfectioninpatientswithoralororopharyngealSCC

Miguel(1998)24 ₂₈ ₄_(14.3%) _--- _---

---Soares(2002)18 ₁₀ ₀_(0.0%) _--- _---

---Soares(2003)19 ₂₇ ₁₃_(48.1%) _--- _--- ₁₀_(37.0%)

Fregonesi(2003)20 ₁₇ ₆_(35.3%) _--- _--- ₅_(29.0%)

Cortezzi(2004)15 ₁₆ ₄_(25.0%) ₄_(25.0%) _---

---Silva(2007)16 ₅₀ ₃₇_(74.0%) _--- _---

---Soares(2007)25 ₇₅ ₁₈_(24.0%) ₁_(1.3%) ₁₄_(18.7%) ₁₅_(20.0%)

Acay(2008)21 ₁₀ ₃_(30.0%) _--- _--- ₂_(20.0%)

Oliveira(2008)26 ₈₇ ₁₇_(19.5%) ₄_(4.6%) ₃_(3.4%) ₇_(8.0%)

Simonato(2008)27 ₂₉ ₅_(17.2%) _--- _---

---Soares(2008)28 ₃₃ ₁₁_(33.3%) ₂_(6.1%) ₉_(27.3%) ₁₁_(33.3%)

Oliveira(2009)29 ₈₈ ₂₆_(29.5%) ₁_(3.8%) ₂₁_(80.8%) ₂₂_(25.0%)

Lira(2010)22 ₇₀ ₆₃_(90.0%) ₁₁_(13.9%) ₁₇_(21.5%) ₂₈_(40.0%)

Mazon(2011)17 ₁₉ ₁₁_(58.0%) ₁_(5.3%) ₁₀_(53.0%) ₁₁_(58.0%)

Pereira(2011)30 ₂₇ ₉_(33.3%) ₁_(3.7%) ₉_(33.3%) ₉_(33.3%)

Spindula-Filho(2011)31 ₄₇ ₀_(0.0%) _--- _---

---Cordeiro-Silva(2012)32 ₄₅ ₃_(6.0%) _--- _---

---Fregonezi(2012)23 ₁₇ ₅_(29.4%) ₀_(0.0%) ₂_(11.8%) ₂_(11.8%)

Kaminagakura(2012)33 ₁₁₄ ₂₂_(19.2%) ₂₂_(19.2%) _--- ₂₂_(19.2%)

Marques-Silva(2012)34 ₄₀ ₃₀_(75.0%) ₁₀_(25.0%) ₂₃_(57.5%) ₃₀_(75.0%)

Cantarutti(2014)35 ₂₆ ₀_(0.0%) _--- _---

---Lopez(2014)36 ₂₂₂ ₁₄_(6.3%) ₈_(3.6%) _--- ₈_(3.6%)

Total 1097 301/1097(27.4%) (95%CI26.6%---28.3%)

65/808(8.0%) (95%CI7.6%---8.5%)

108/456(23.7%) (95%CI23.0%---24.4%)

182/846(21.5%) (95%CI20.9%---22.1%)

Oral/oropharyngealHPVinfectioninpatientswithgenitallesions,HPVinfection,orpartnersofthispopulation.

Gonc¸alves,200637 ₇₀ ₂₆_(37.1%) _--- _---

---Castro,200941 ₃₀ ₀_(0.0%) _--- _---

---Xavier,200942 ₃₀ ₁_(3.3%) _--- _---

---Peixoto,201143 ₁₀₀ ₈₁_(81.0%) _--- _---

---Zonta,201244 ₂₇ ₂₃_(85.2%) ₂_(7.4%) ₁_(3.7%) ₃_(11.1%)

Marques,201338 ₆₄ ₂_(3.1%) _--- _---

---Ribeiro,201439 ₆₂ ₃₀_(48.4%) _--- _---

---Vidotti,201440 ₁₀₅ ₂₅_(23.8%) _--- _---

---Total 488 188/488(38.5%) (95%CI36.2%---40.9%)

2/23(7.4%) (95%CINA)

1/23(3.7%) (95%CINA)

3/23(11.1%) (95%CINA)

Oral/oropharyngealHPVinfectioninimmunodeficientpatients

Araujo,201145 ₆₀ ₂₀_(33.3%) ₈_(13.3%) ₂_(3.3%) ₁₀_(16.7%)

Lima,201446 ₁₀₀ ₁₁_(11.0%) _--- _---

---Total 160 31/160(19.4%) (95%CI18.4%---20.4%)

8/60(13.3%) (95%CINA)

2/60(3.3%) (95%CINA)

(12)

Table4 RiskofHPVinfectionineachsubgroup.

Group OR(95%CI) pa

AnyHPVinfection

Healthypatients Reference

---Immunodeficient patients

5.797(3.696---9.091) <0.0001

Riskgroup 3.888(3.369---4.487) <0.0001 Benignlesions 2.686(2.312---3.121) <0.0001 Premalignantlesions 2.094(1.904---2.304) <0.0001 Oralororopharyngeal

SCC

3.097(2.700---3.553) <0.0001

HPV16infection

9.400(4.021---21.977) <0.0001

Riskgroup 2.476(1.167---5.255) 0.018

Benignlesions N/C

---Premalignantlesions 2.467(2.121---2.870) <0.0001 Oralororopharyngeal

SCC

1.725(1.180---1.522) 0.005

HPV18infection

3.894(0.844---17.960) 0.081

Riskgroup 2.254(0.793---6.402) 0.127 Benignlesions 3.044(2.169---4.271) <0.0001 Premalignantlesions 2.242(1.839---2.740) <0.0001 Oralororopharyngeal

SCC

2.051(1.807---2.327) <0.0001

HPV16/18infection

7.833(3.689---16.633) <0.0001

Riskgroup 2.476(1.324---4.629) 0.005 Benignlesions 2.040(1.624---2.562) <0.0001 Premalignantlesions 2.278(2.017---2.573) <0.0001 Oralororopharyngeal

SCC

1.477(1.043---2.092) 0.028

N/C,notcalculatedbecausetherewasnovalidcaseforanalysis.

a _Logistic_regression.

These results suggest that the prevalence of HPV may vary depending on distinct population characteristics and thetimeperiodstudied,whichmightexplainthewiderange ofHPVprevalenceamongdifferentstudiesincludedinthis systematicreview.

Limitations

There are a few limitations in this study that should be noted. The most important was in the data collection; becausethisworkwasasystematicreviewofpublished arti-cles,somedatacouldnotbeobtained,especiallyregarding demographics. Additionally, as seen in Fig. 2, the whole Brazilianpopulationwasnotincluded,becauseofthelack ofstudiesinsomeregions.Anotherimportantpointisthat becauseaggregatepatientdatawereused,itispossiblethat therewasheterogeneityinthesestudiesandinconsistencies

inthedatasetsthatwereunknownduetothe summariza-tionofthedata.Moreover,themajorityofthestudieswere smalland used nonprobability samples, and it is difficult todifferentiate studiesthat enrolledconsecutivepatients fromstudiesthatusedalternativeinclusioncriteria,suchas institutionalarchives ofparaffin-embeddedtissues. Never-theless,thesenonprobabilitysamplesdidnotrepresentthe Brazilianpopulationasawhole;however,thepresentstudy isthefirstonetoconsolidatethedataoforaland oropharyn-gealHPV infection in Brazil.HPV prevalence appeared to beinverselyproportionaltothestudysamplesize,andthe poorqualityofsomeofthecancerspecimensmayalsohave affectedtheprevalenceestimates.Allofthesepointswere also mentioned as limitations in other systematic review series.55

Conclusion

In summary, the healthy Brazilian population has a very loworal/oropharyngeal HPV infectionrate. Other groups, suchasat-riskpatientsortheirpartners,immunodeficient patients,peoplewithorallesionsand,especially,patients withoralcavityororopharyngealSCC,havehighrisksofHPV infection.Becauseaggregatepatientdataresultsvaried,a large-scalestudyconsideringthewholecountry,includinga morediversepopulation,mustbeconductedtoconfirmthe findingsofthisreview.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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