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DentResJ(Isfahan).2013MayJun10(3):287295.

PMCID:PMC3760349

Aninsightintosalivarymarkersinoralcancer
RamnarayanBelurKrishnaPrasad, 1AkhileshSharma, 2andHarshaMysoreBabu3
1
DepartmentofOralMedicine,DiagnosisandRadiology,TheOxfordDentalCollegeandHospital,Bommanahalli,Bangalore,India
2
Pedodontics,TheOxfordDentalCollegeandHospital,Bommanahalli,Bangalore,India
3
Periodontics,DayanandaSagarCollegeofDentalSciences,ShavigeMalleswaraHills,KumaraswamyLayout,Bangalore,India
Addressforcorrespondence:Dr.B.K.Ramnarayan,DepartmentofOralMedicine,DiagnosisandRadiology,DayanandaSagarCollegeof
DentalSciences,ShavigeMalleswaraHills,KumaraswamyLayout,Bangalore560078,India.Email:ramnarayanbk@gmail.com

Received2012MarAccepted2013Feb.

Copyright:DentalResearchJournal

ThisisanopenaccessarticledistributedunderthetermsoftheCreativeCommonsAttributionNoncommercialShareAlike3.0Unported,which
permitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.

Abstract
Salivarydiagnosticshasfascinatedmanyresearcheresandhasbeentestedasavaluabletoolinthediagnosis
ofmanysystemicconditionsandfordrugmonitoring.Advancesinthefieldofmolecularbiology,salivary
genomicsandproteomicshaveledtothediscoveryofnewmolecularmarkersfororalcancerdiagnosis,
therapeuticsandprognosis.Oralcancerisapotentiallyfataldiseaseandtheoutcomeofthetreatmentand
prognosislargelydependsonearlydiagnosis.Abnormalcellularproductselucidatedfrommalignantcells
canbedetectedandmeasuredinvariousbodyfluidsincludingsalivaandconstitutetumormarkers.This
articlediscussesthevarioussalivarytumormarkersandtheirroleinoralprecancerandcancer.

Keywords:DNAmarkers,oralcancer,proteinmarkers,RNAmarkers,salivarymarkers,tumormarkers

INTRODUCTION
Oralcancerisoneofthemajorglobalpublichealthproblemsandisthesixthmostcommonhuman
malignancywithafiveyearmortalityrateofapproximately50%.[1]Thishasnotchangedsignificantlyover
thelast50years.[2]AhighprevalenceoforalcancerinIndiaandotherAsiancountrieshasbeenattributed
totheinfluenceofregionspecificepidemiologicalfactorssuchastobaccoandbetelquidchewing.[3]
Anotheralarmingscenarioistheincreasingincidenceoforalsquamouscellcarcinoma(OSCC)inyounger
peopleowingtotheheavyabuseoftobaccoandtobaccorelatedproducts.

ThehighmorbidityrateinOSCCcanbeattributedtothedelayinthediagnosisofthedisease.[4]The
diagnosisoforalcancerand/orthemalignantpotentialofanorallesionisbasedonvariousaspectssuchas
(a)etiologyassociatedwiththeuseoftobacco,presenceoffactorssuchasdetectionofHPV(b)clinical
appearanceofthelesion(leukoplakic,erythroplakic,nodular,ulcerative,verrucous)[Figures1and2](c)
locationofthelesionthehighrisksitesbeingfloorofthemouth,ventrolateralaspectofthetongueetc.,(d)
histopathologicalaspectspresenceofepithelialdysplasia[Figure3]and(e)molecularbiologicalaspectsof
thelesion.[5]Adetaileddiscussionontheclinicalandhistopathologicaldiagnosisandthebiologicalaspects
ofcancerdevelopmentarenotwithinthescopeofthisreview.

Thediagnosisofepithelialdysplasiaisbasedonastaticpicturethoughthehistologicchangesimplythe
possibilityofadynamicprocess.However,theproblemsinevaluatingthesignificanceofepithelialdysplasia
arisefromalackofobjectivityintheevaluationofestablishedcriteria,arbitrarydivisionofthegrading,and
lackofsufficientknowledgeofwhichcriteriaareimportantforthepredictionofmalignantpotential.[6]A
betterunderstandingofthebiologicalprocessoforalcancerhaveledtomanystudiesinthefieldof
molecularbiologicalmarkerswhichhelpinassessmentofcancerrisk,potentialityofalesiontowards
malignanttransformationandalsoinpredictingtheprognosis.[7]

Neoplasticprocessgives/producesseveralabnormalcellularproductswhichcanbedetectedinvariousbody
fluidsandonthesurfaceofcancercellseitherbybiochemicalmethodsorbyimmunohistochemistrysuch
productsthataredetectedandmeasuredareknownastumormarkers.[8]Thesetumormarkersaidthe
cliniciangreatlyiftheclinicopathologicalpictureisnotaccuratelysuggestiveofmalignancyand/oris
indicativeifthepicturewouldsoonchange.CirculatingtumormarkersforOSCChavebeeninvestigatedin
variousstudies[9,10,11,12,13,14]andthesehaveshownrelativelymoderatesensitivityandspecificity
values.Investigatorsovertheyearshaveusedtwoapproachesforthestudyofmarkersofmalignant
development:Epithelialdysplasiaononehandandoralcancerontheotherarecharacterizedbythe
presence/absenceorthepatternofdistributionofthemarkerinquestion.Ingeneral,themarkeris
characterizedasapromisingtoolifthereactionpatterninepithelialdysplasiasissimilartothatincarcinomas
and/oriftheaberrantreactionpatternispositivelyrelatedtothegradeofepithelialdysplasia.These
biologicalmarkersfordeterminingfuturecancerdevelopmentinoralpremalignantlesionscanbebroadly
dividedinto(a)genomicmarkers,includingDNAcontent(ploidy)chromosomeaberration,andchangesin
expressionofoncogenesandtumorsuppressorgenes(b)proliferationmarkersand(c)differentiation
markers,includingkeratinsandcarbohydrateantigenswhichwillbediscussed.

Saliva,awateryandfrothysubstanceproducedinthemouthofhumanandmostotheranimalscontains
informativecomponentsthathavebeenusedasdiagnosticmarkersforhumandisease.Anincreasingnumber
ofsystemicdiseasesandconditions,amongstthemoralcancer,havebeenshowntobereflected
diagnosticallyinsaliva.Salivaasadiagnosticfluidmeetsthedemandforaninexpensive,noninvasiveand
accessibleinthediagnosis,prognosisprediction,aswellasformonitoringthepatientsposttherapystatusin
oralcancer.[14]

MATERIALSANDMETHODS
LiteraturesearchinMedline,PubMedandScholarGooglewasperformedusingthekeywordssalivary
markers,tumormarkersinsaliva,oralcancer,salivarydiagnostics,DNAmarkers,ProteinmarkersandRNA
markers.Manualsearchfromvariousprintedarticleswasalsoperformed.

DISCUSSION

Tumormarker
Atumormarkerisasubstancepresentinorproducedbyatumorortumorshostinresponsetothetumor's
presencethatcanbeusedtodifferentiateatumorfromnormaltissueordeterminethepresenceofatumor
basedonmeasurementinbloodorsecretions.[15]Lehto,Ponten.[16]havedefinedtumormarkersas
specific,novelorstructurallyalteredcellularmacromoleculesortemporarilyspatiallyorquantitatively
alterednormalmoleculesthatareassociatedwithmalignant(andinsomecasesbenign)neoplasticcells.
Tumormarkersmaybeuniquegenesortheirproductsthatareformedonlyintumorcellsortheymaybe
genesorgeneproductsthatarefoundinnormalcellsbutareaberrantlyexpressedinuniquelocationsinthe
tumorcells.[17]Thedistinguishingbiologicalcharacteristicsoftumorcellssuchasthecapacityforinvasion,
metastasis,unlimitedproliferation,evasionofapoptosisandangiogenesisareallmediatedbycomplex
molecularpathwaysanyoneofthesecomponentsarepotentialtumormarkers.[18]

Anidealtumormarker
Abiologicalmarkershouldhavecertaincharacteristicsthatareapplicableinallsituations.Kaplanand
Pesce[19]havesuggestedthefollowingcriteriaforanidealtumormarker:
1.Beeasyandinexpensivetomeasureinreadilyavailablebodyfluids.
2.Bespecifictothetumorbeingstudiedandcommonlyassociatedwithit.
3.Haveastoichiometricrelationshipbetweenplasmalevelsofthemarkerandtheassociatedtumormass.
4.Haveanabnormalplasmalevel,urinelevelorbothinthepresenceofmicrometastases,thatis,ata
stagewhennoclinicalorpresentlyavailablediagnosticmethodsrevealtheirpresence.
5.Haveplasmalevels,urinelevelsorboth,thatarestableandnotsubjecttowildfluctuations.Ifpresent
intheplasmaofhealthyindividuals,existinamuchlowerconcentrationthanthatfoundinassociation
withallstagesofcancer.

Inadditiontotheabove,they[19]havestatedthattheidealtumormarkershouldrelatetotheclinicalsetting
andcomplywiththefollowing:

1.Theyshouldprognosticateahigherorlowerriskforeventualdevelopmentofrecurrence.
2.Theyshouldchangeasthecurrentstatusofthetumorchangesovertime.
3.Theyshouldprecedeandpredictrecurrencesbeforetheyareclinicallydetectable.

Salivaanditsdiagnosticpotential
Theabilitytousesalivatomonitorapatient'shealthanddiseasestateisahighlydesirablegoalforhealth
promotionandhealthcareresearch.Salivahaslongbeenproposedandusedasadiagnosticmedium[20]asit
iseasilyaccessible,collectionisnoninvasive,nottimeconsuming,inexpensiveandcanbeusedformass
screeningpurposes.[21]Amajordrawbacktousingsalivaasadiagnosticfluidhasbeenthenotionthat
informativeanalytesgenerallyarepresentinloweramountsthaninserum.[22]Howeverwithnew
techniquesofdetectingsmallquantitiesofsalivarycomponentsincludingproteinsandmessenger
Ribonucleicacid(mRNA),almostanythingthatcanbemeasuredinbloodcanbemeasuredinsaliva.Hence,
salivaisconsideredasthebloodstreamoforalcavity.AlterationsinthelevelsofcertainmRNA
molecules[23]andofcertainproteinshavebeendetectedinseveralcancers,[24]includingoralcancers
indicatingtheirpossibleuseincancerdetectionandfollowup.

Mechanismforthepresenceofbiomarkerinsaliva
Thoughtheexactmechanismforthepresenceofthesetumormarkersinsalivaisnotknown,theymaybe
eitherderivedfromserumorcanbeproducedlocally.[25]Figure4[25,26,27,28,29,30,31,32,33,34,35,36,37]
summarizesthepossiblemechanismthatleadstothepresenceofbiomarkersinsaliva.

Salivarybiomarkersfororalcancerdetection
Severalsalivarytumormarkersarefoundtobesignificantlyincreasedinthesalivaoforalcancerpatients.
[14,38]Molecularmarkersforthediagnosisoforalcancercanbequestedin3levels[39]changesinthe
cellularDeoxyribonucleicacid(DNA)whichresultsinalteredmRNAtranscriptsleadingtoalteredprotein
levelsintracellularly,onthecellsurfaceorextracellularly.Markopoulosetal.,[39]havesummarizedthe
molecularmarkersforthediagnosisofOSCC[Table1].

AlterationsinhostcellularDNA
DNAmarkersareuniversali.e.,thereisnotasingletumorcellwithinthelesionwhichdoesnotcontainits
geneticmaterial.Theyoriginatefromdeadcells,aredetectedintheearlystageoftumorigenesisandare
absolutelyoncospecificshowingadirectcauseandeffectrelationshipwithtumorigenesis.However,tissue
specificityofDNAmarkersisverylow.[40]ThereareseveralchangesinthehostDNAofdysplasticor
cancercellswhichincludepointmutation,deletion,translocation,amplification,methylation,cyclinD1,
epidermalgrowthfactor(EGFR),microsatelliteinstabilityandpresenceofHPV.Sudbo,etal.,[41]and
Femiano,etal.,[42]havefoundthatpremalignantlesionswithaneuploidytransformintomalignancymore
frequentlythanlesionswithnormalDNAcontentirrespectiveofthehistopathologicalgradeofdysplasia.
DNAaneuploidyappearstobeassociatedwithadvancedstagecarcinomas,perineuralinvasionandlymph
nodemetastasis.[43]Hence,DNAcontentofatumormayhelpinpredictingtheaggressivenessofthetumor.

Lossofheterozygosity(LOH)isdefinedaslossofgenomicmaterialinoneofthechromosomalpair.Studies
haveshownthatLOHinregionsthatcontainaknownhumansuppressorgeneisanearlypredictorof
malignanttransformationofprecancerouslesion.[44]Thishelpsthecliniciantoidentifyhighandlowrisk
lesionsinthecontextofmanagement.Studies[45,46,47]havedemonstratedfrequentLOHinchromosome
3p,9q,13qand17pasanearlyeventinoralcarcinogenesis.Rosin,etal.,[48]intheirstudyfoundthatallelic
lossat3pand9qincreasetheriskofmalignanttransformationby3.8foldandtheriskoffurtherincreaseto
33foldwhenLOHoccursatchromosomes4q,8p,11q,13qand17pinadditiontotheformer.

MitochondrialDNAmutationshavealsobeenusefultodetectexfoliatedOSCCcellsinsaliva.[39]Such
mutationshavebeenidentifiedin46%ofheadandneckcancerandin67%ofsalivasamplesfromOSCC
patientsbydirectsequencing.[49]

p53genelocatedonchromosome17p13.1exhibitsmutationin5070%ofepithelialtumors[50,51]andLOH
ofp53allelehasbeenreportedin22%ofprecancerand20%oforalcancer.However,theprognostic
significanceofp53inoralcancerisyettobeestablishedalthoughtherearemultiplestudiescomparingthe
expressionofp53inpremalignantlesionsandmalignancies.[52,53]Boyleetal.,[51]usingplaque
hybridizationidentifiedtumorspecificp53mutationsin71%salivasamplesfrompatientswithheadand
neckcancer.Othergenessuchasp16,p27,p63,p73relatedtop53andcellcyclehavebeenfoundtobe
alteredinvaryingdegreesinoralcancer.[50]

Promotermethylation,analternateformofgenesilencing,whichdependsontheepigeneticfactorhasbeen
describedtobeinvolvedinOSCC.[50]ThemaingenestobemethylatedareCDKN2A,CDH1,MGMT,
DAPK1.[50,54]CDKN2Awhichareinvolvedintheretinoblastomapathwayofthecellcycleappeartobe
methylatedin2367%ofprimaryOSCC's.CDH1ageneresponsibleforcelladhesion,promotesmetastasis
whenmutatedandshowspromotermethylationinupto85%oftumors.[54]Rosas,etal.,[55]identified
aberrantmethylationofatleastoneofthesegenes(p16,MGMT,DAPK)inOSSCanddetectedpromoter
hypermethylationin65%ofmatchedsalivasamplesinOSCCpatients.

AmplificationandoverexpressionofcMYCINMYChasbeenobservedin2040%oforalcancers.Das,et
al.,[56]havereportedamplificationof11q13,containing1NT2,HST1andCyclinDoncogenesin3050%
ofpatientswithoralcancer.CyclinD1geneamplificationhasbeenfoundtobeassociatedwithpoor
prognosisinOSCC.[57]STAT3expressionandactivationwasfoundin82%oforalcancersrelatedto
chewingtobacco,whiletherewasnoexpressioninnormalmucosaandpremalignantlesions.[58]

LevelsofKi67markerwereincreasedwhile8oxoguanineDNAglycosylase,phosphorylatedSrcand
mammaryserineproteaseinhibitor(Maspin)werefounddecreasedinthesalivaofpatientswithOSCC.[59]

ThepresenceofHPVandEBVvirusgenomicsequencehavebeenidentifiedaspossibleDNAmarkersin
detectingOSCCandtumorprogression.[60]

RNAasabiomarker
RNAhasbeenfoundtobearobustandinformativemarkerandsalivaryRNAsignatureshavebeen
identifiedfororalcancer.RNAforyearswasthoughttodegradeinsalivaduetothevariousRNAasesthatis
presentinsaliva.[61]However,cellfreeRNAispresentinsalivabothinintactandfragmentedforms.[62]It
hasbeenspeculatedthatsalivarymRNAiscontainedinapoptoticbodies[29,30]oractivelyreleasedin
exosomesormicrovesicles.[32,34,35]Researchers[63]comparedtheclinicalaccuracyofsalivawiththatof
bloodRNAbiomarkerfororalcancerdetectionandfoundfourRNAbiomarkersthathaveasensitivityand
specificityof91%and71%andacollectivereceiveroperatorcharacteristic(roc)valueof0.95.[18]
StudieshavefoundsevenmRNAmolecules(1)IL8,[63,64](2)IL1(interleukin1)[63,64]whichtakepart
insignaltransduction,proliferation,inflammationandapoptosis,(3)DUSP1[64](dualspecificity
phosphatase1)witharoleinproteinmodification,signaltransductionandoxidativestress,(4)H3F3A[64]
(H3histone,family3A)havingaDNAbindingactivity,(5)OAZ1[63,64](ornithinedecarboxylase
antizyme1)takingpartinpolyaminebiosynthesis,(6)S100P[64](S100calciumbindingproteinP)witha
roleinproteinbindingandcalciumionbindingand(7)SAT[63,64](spermidine/spermineN1
acetyltransferase)whichtakespartinenzymeandtransferaseactivity,tobesignificantlyelevatedinOSCC
patientsratherthaninhealthycontrols.

Proteinmarkers
Proteinmarkersaredifferentiationantigensofcorrespondingnormaltissueandcharacterizeacertainstageof
itsmaturation.Theyoriginatefromlivecellsandshowhightissuespecificity.However,theymaybe
detectedinotherpathologiesaswell.[40]Salivaryproteinmarkershaveshownmoderatesensitivityand
specificityasprognosticmarkers.[39]Agroupofleadingresearchers[64,65,66]usingnewandsophisticated
approaches,suchasLuminexMultianalyteProfiling(xMAP)technology,shotgunproteomics,capillary
reversedphaseliquidchromatographywithquadrupletimeofflightmassspectrometryandmatrixassisted
laserdesorption/ionizationmassspectrometry(MALDIMS)hascontributedsignificantlyinrecentyearsto
theresearchinsalivaforcancerdiagnosis.Theirstudieshaveshownthatsalivacontainsproteinsthatmay
serveasbiomarkersforOSCC,since46peptides/proteinswerefoundatsignificantlydifferentlevels
betweentheOSCCandcontrolgroups.

Carbonylation(indicativeofoxidativedamagetoproteins)hasattractedagreatdealofattentionincancer
researchbecauseofitsirreversibleandirreparablenature,whichbecomescytotoxicandisassociatedwith
cancer.[67]Itiscurrentlyreportedthatasubstantialincreaseinsalivarycarbonyls(246%)isseeninOSCC
patientsandpointstothefactthatthereisasignificantfreeradicalattacktowhichtheepithelialcellsare
exposed.[59]

MetalloproteinasessuchasMMP9,[59]MMP11,[68]MMP2[68]aresignificantlyalteredinOSCC.MMP
9areshowntodegradetypeIVcollagen,amajortypeinthebasementmembrane,othertypesofcollagen
(V,VII,X),elastinandfibronectin.[59]Studies[68,69]haveshownhighMMP9expressioninstromalcells
surroundingtheinvadingfrontofmetastasizingtumors.[69,70]MMP9polymorphismwasshowntohavea
strongassociationwithincreasedriskfordevelopingOSCC.[71]Shpitzer,etal.,[59]founda39%increase
inMMP9withasensitivityof100%andspecificityof79%inOSCCpatients.

IL6,IL8arepostinflammatorycytokinesthatplayaprominentroleinimmunehostdefenseresponsesto
infection,theyarefoundtostimulateangiogenesis,influencetissueremodelingandtakepartinregulationof
cellproliferationanddifferentiation.Theyareidentifiedasimportantmediatorsofcancerdevelopmentand
powerfulactivatorsofnotonlyapoptosisbutalsoantiapoptoticsignalingcascade[72]andhenceplayarole
inearlydetectionoforalpremalignanciesandOSCC.Rajkumar,etal.,[38]intheirstudyfound
concentrationofIL6andIl8insalivatobesignificantlyincreased.StJohn,etal.,[73]detectedhigherlevels
ofIL8insalivaofOSCCpatients.Studieshavefoundsignificantincreaseinthelevelsoftumormarkerin
patientswithOSCCcomparedtodysplasticorallesionsandcontrols,thussuggestingitsdiagnosticvalueas
amarkerofmalignanttransformationinoralpremalignantlesions.[74]ArllanoGarcia,etal.,[75]using
LuminexMAPtechnologyshowedthatbothIL8andIL1wereexpressedatsignificantlyhigherlevelsin
OSCCpatients.

Cytokeratinsarecytoskeletalintermediatefilamentspresentinalmostallnormalandmalignantepithelial
cells.[76]Inmalignantepithelialcells,theactivatedproteaseincreasesdegradationofcytokeratinfree
filamentsintotheblood.IncreasedlevelsofCyfra211insalivahasbeenfoundinOSCC.[10,11,14]

Defensinsarepeptideswhichprocessantimicrobialsandcytotoxicproperties.Theyarefoundinazurophil
granulesofpolymorphonuclearleukocytes.[77,78]Mizukawa,etal.,[79]foundelevatedlevelsofsalivary
Defensin1inOSCCpatientscomparedwithhealthycontrols.Someoftheothersalivarybiomarkerswhich
aresignificantlyalteredinOSCCpatientsascomparedwithhealthycontrolsareinhibitorsofapoptosis
(IAP),[80]squamouscellcarcinomaassociatedantigen(SCCAg),[13,14]carcinoembryonicantigen
(CEA),[12,14]carcinoantigen(CA199),[13,14]CA128,[13]serumtumormarker(CA125),[14,81]tissue
polypeptidespecificantigen(PPS),[14,82]reactivenitrogenspecies(RNS),[9]lactatedehydrogenase(LDH)
[11]andimmunoglobulinG(IgG),[11]sIgA,[68]insulingrowthfactor(IGF).[68]

Usesoftumormarkers
Recenttechnologicaladvancesinmolecularbiologyhasledtodiscoveryofnewtumormarkersandthus
increaseditsscopeofuseinoralbiology.Tumormarkershavearoleinthediagnosis,prognosis,formulating
thetreatmentandinthedetectionofrecurrenceofcancer.ChanandSell.[15]havesummarizedthepotential
usesoftumormarkersasfollows:

(a)screeningingeneralpopulation(b)differentialdiagnosisinsymptomaticpatients(c)clinicalstagingof
cancer(d)estimatingtumorvolume(e)prognosticindicatorsfordiseaseprogression(f)evaluatingthe
successoftreatment(g)detectingrecurrences(h)Monitoringresponsestotherapy(i)
radioimmunolocalizationoftumormassesand(j)Determiningdirectionforimmunotherapy.

CONCLUSION
Presentdayscreeningtestsbyvisualexamination,orotherwellestablishedandtimetesteddiagnostictools
suchasvitalstainingwithtoluidineblue,brushbiopsy,chemiluminescence,tissueautofluorescenceandthe
diagnosticgoldstandardbeingtissuebiopsyfollowedbyhistopathologicalevaluationforOSCCarestill
criticalforthediagnosisofpotentiallymalignantlesionsandmalignancies.Thefieldofsalivarydiagnosticsis
abroad,complexandcrosscuttingareaofscientificresearchwithenormouspotentialtoimpactthediagnosis
ofvariousdiseasesincludingoralcancer.Thesignificantincreaseintumormarkersinsalivaisquite
encouragingassalivaoffersmanyadvantagessuchassalivaharvestingisnoninvasivethusmakingitan
effectivealternativetoserumtesting.Thoughatpresentnosingletumormarkercanvalidatethepresenceor
prognosisofdisease,apanelofbiomarkerswouldbemorehelpful.Recentadvancesandemerging
technologiessuchasnanotechnology,proteomicandgenomicsmakesalivarydiagnosticsahighlysensitive
tool.Thepresentmethodsarenotreadyforimmediatedirectuseandmuchneedstobedonetocomeupwith
afast,simple,costeffectiveclinicaldiagnosticsystem.Salivawillpossiblyoutperformothermediainthe
diagnosisofnotonlycancerbutotherdiseasesaswell.

Footnotes
SourceofSupport:Nil

ConflictofInterest:Nonedeclared

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FiguresandTables

Figure1

Potentiallymalignantlesions(a)Leukoplakiaand(b)ErosiveLichenplanus

Figure2
Variousclinicalpresentationsoforalcancer(a)Erythroleukoplakia(b)Ulcerative(c)Nodular/verruciod(d)Ulcero
proliferative

Figure3

Photomicrographshowing(a)Severedysplasia(b)ModeratelydifferentiatedOSCC

Figure4
Mechanismthatleadtothepresenceofmolecularmarkersinsaliva

Table1

Molecularmarkersfororalcancer[39]

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