tobacco addiction: effect on human health · 2018-03-09 · 4 tobacco addiction: effect on human...

Chapter 2

Tobacco Addiction: Effect on Human Health

Premalignant and Malignant Lesions of the Oral Cavity: Tobacco as an Etiological

Factor

Aritra Laskar1; Sayantan Jana2; Anjana Mazumdar3; Snehasikta Swarnakar2*

1Department of Oral Pathology/Diagnosis/Medicine/Radiology, Burdwan Dental College and

Hospital, West Bengal, India; 2Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology,

Jadavpur, Kolkata-700032, India.3Department of Oral Pathology, Dr. R. Ahmed Dental College and Hospital, Kolkata, India

*Correspondence to: Snehasikta Swarnakar, Cancer Biology and Inflammatory Disorder Division, CSIR-

Indian Institute of Chemical Biology, 4 Raja S C Mullick Road, Jadavpur, Kolkata-700032, India.

Email: [email protected]

1. Introduction

TheprecancerouslesionwasdefinedbyWorldHealthOrganization(WHO),in1978asamorphologicallyaltered tissueassociatedwitha significantly increased riskofcancer.Precancerouslesionsoforalcavityincludeoralsubmucousfibrosis(OSMF),PlummerVin-son syndrome, erosive lichenplanus, dyskeratosis congenita, chronichyperplastic candidi-asis,Cowden’s syndrome, discoid lupus erythromatosus, dystrophic epidermolysis bullosa,andxerodermapigmentosa[1].In2005,WHOdecidedtousetheterm‘PotentiallyMalignantDisorders(PMD)’asitdescribesthatthepathologicalconditionmaytransformintocancer.

Abbreviations

WHO:WorldHealthOrganization;OSMF:OralSubmucousFibrosis;HPV:HumanPapillomaVirus;OSCC:OralSquamousCellCarcinoma;NFHS:NationalFamilyHealthSurvey;GATS:GlobalAdultTobaccoSur-vey;GYTS:GlobalYouthTobaccoSurvey;PVL:ProliferativeVerrucousLeukoplakia;TSG:TumourSup-pressorGene;UV:UltraViolet;DNA:DeoxyribonucleicAcid;HTLV:HumanT-CellLymphomaVirus;HIV:HumanImmunodeficiencyVirus;CD:ClusterOfDifferentiation;EBV:Epstein-BarrVirus;HHV8:HumanHerpesVirus8;HBV:HepatitisBVirus;P53:TumorProtein53;Rb:RetinoblastomaProtein;ICAM:Inter-cellularAdhesionMolecule;TGFR:TransformingGrowthFactorBetaReceptor;MMP:MatrixMetallopro-teinase;TIMP:TissueInhibitorOfMetalloproteinase

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TobaccoAddiction:EffectonHumanHealth

PrecancerouslesionsthatareidentifiedPMDareleukoplakia,erythroplakia,palatalchangesassociatedwithreversesmoking,orallichenplanus,OSMF,anddiscoidlupuserythromato-sus[2].CausativefactorsforPMDsincludehumanpapillomavirus(HPV),candida,tobacco,‘gutkha’,arecanut,vitamins(suchas,A,B,C,D,andE)deficiencyandminerals(suchas,iron,calcium,copper,zincandmagnesiumetc)deficiency[3].

Themajorityoforalcancersaresquamouscellcarcinomas.Thetongue,buccalmucosa,oropharyngealregionandfloorofthemoutharethecommonestsitesforoccurrenceofthedisease.Lesseraffectedregionsoftheoralcavityarethelips,gingiva,dorsaltongueandpal-atesites.Approximatelyninety-fivepercentoforalsquamouscellcarcinoma(OSCC)occursinpeopleolderthan40years,withanaverageageatdiagnosisofapproximately60years[1].Lipcarcinomaaccountsforapproximately12%ofallnon-cutaneousheadandneckcancer.Whilemostofthelipcancerinvolveslowerlip,upperlipcancerinvolvesonly2-7%oflipcancers,followedbycommissuralareas(<1%)whicharelesssusceptibletoOSCC[4].Mostcommonlipcarcinomasarebasalcellcarcinomaandsquamouscellcarcinoma.Lesscommoncarcinomasarekeratoacanthoma,minorsalivaryglandtumours,melanomaandmesenchymaltumours.Otherheadandneckcancersincludetumoursofthesalivaryglands,thyroidglands,lymphnodes,boneandsoft tissue.The incidenceoforalcancer isage-related,whichmayreflecttimefortheaccumulationofgeneticchangesanddurationofexposuretoendogenousandexogenousfactors(includingchemicalandphysicalirritants,viruses,hormonaleffects,cellularaginganddecreasedimmunologicalresponsesetc).Evidencefromlongtermfollow-upfromimmuno-suppressedpatientsaftersolidorganandhematopoieticstemcelltransplan-tationelucidatesthatimmunosuppressionincreasestheriskofdevelopmentofOSCC[5].

Tobaccoconsumptioninsmokelessandsmokingformisconsideredasthemajorriskfactorsforpremalignantandmalignantlesionsinoralcavity.Driedtobaccoleavesaremainlysmoked incigarettes, cigars,pipe tobaccoandflavored shisha tobacco.Theyarealsocon-sumedassnuff,chewingtobaccoanddippingtobacco.Tobaccocontainsthealkaloidnicotine,apotentpara-sympathomimeticstimulant.Italsocontainsseveralpotentcarcinogensthatin-cludenitrosamines,polycyclicaromatichydrocarbons,nitrosodicthanolamine,nitrosoproline,poloniumetc[6].Preventionandcontroloftobacco-inducedoralmucosallesionsistheprimerequisitecurrentlyandmainlyinvolvesmeasuresundertakenatprimary,secondaryandter-tiarylevels.Primarypreventionplaysapivotalroleincontrollingtobaccoinducedlesionsandmeasurescanbetakenatpolicylevel,communityaswellasindividuallevel.

2. Global scenario for Oral Cancers and Tobacco Addiction

Worldwide,oralcarcinomaisoneofthemostprevalentcancersandisoneofthe10mostcommoncausesofdeath.In2012,approximately145,400deathsand300,400newcaseswerereportedworldwidefromoralcavitycancer(includinglipcancer).Thehighestratesare

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foundinMelanesia,South-CentralAsia,andCentralandEasternEurope(Figure1),whilethelowestisinWesternAfricaandEasternAsia[7].InUSAalone,atotalof48,330incidencesofneworalcancerswerereportedin2016,amongwhich34,780weremaleand13,550werefemale.TheestimateddeathsinUSAduetooralcancerswere9,750,amongwhich6,910weremaleand2,660werefemalein2016[8].Inhigh-incomecountries,smokingcausesapproxi-mately71%ofdeathsduetooralcavitycancer(includingpharynx)whiletheburdenis37%ofdeathsforlow-to-middle-incomecountries.Alcoholisaccountableforabout33%and14%ofdeathsinhighandlowincomecountries,respectively[9].However,forlastfewdecadesoralcavitycancerincidencerateshavedecreasedsignificantlyinAsia,NorthernAmerica,andAustraliaforbothmalesandfemales,andinSouthernandWesternEuropeformalesonly.Al-though,duetotobaccoepidemic,theratesoforalcavitycancerincidenceshaveincreasedinseveralcountriesofEasternandNorthernEuropeforbothsexesandinSouthernandWesternEuropeforfemalesonly[10].

OraluseofsmokelesstobaccoiswidelyprevalentintheSouth-EastAsiaRegion;thedifferentformsincludechewing,suckingandapplyingtobaccopreparationstotheteethandgums.SmokelesstobaccoproductsandbetelquidwithorwithouttobaccoarethemajorriskfactorsfororalcavitycancerinTaiwan,India,andotherSouthAsiancountries[11].Greaterthan250millionpeopleusesmokelesstobaccoproductsintheSouth-EastAsiansubcontinent;approximately17%oftotalpopulationinSouth-EastAsiausesoraltobaccooutofwhich95%belongtoIndiaandBangladesh[12].Increasingusehasbeenreportednotonlyamongmen,but alsoamongsuchvulnerablegroupsas children, teenagers,womenof reproductiveageandbyimmigrantsofSouthAsianoriginwherevertheyhavesettled.Aglobalepidemiologi-calstudyheldamongthecohortofyoungindividualrevealedhigh(10-20%)prevalenceofuseofsmokelessformoftobaccoinadolescents(13-15year)inSouth-EastAsia.Amongthedowntroddenyouths (45%-71%)prevalenceof tobaccousehasbeenstudied inSouth-EastAsia[13].HighincidencerateshavebeenreportedindevelopingnationslikeIndia,Pakistan,Bangladesh,TaiwanandSriLanka.WhileanincreasingtrendhasbeenobservedinPakistan,TaiwanandThailand,adecreasingtrendisseeninPhilippinesandSriLanka.Themeanageofoccurrenceofcancerindifferentpartsoforalcavityisusuallybetween51-55yearsinmostcountries[14-16].

Consideringallagegroupsmenaremoreaffectedthanwomen.Itistruewhenweob-servethemaleversusfemaleincidencesfororalcavitycancersindifferentpartsofAsia.Theage-standardizedratefor2012studyforincidencesper100,000peopleshowedhighestratesformaleandfemalesinMelanesia,whichare22.9and16respectively.Theincidencesoralcancerformaleandfemalesare9.9and4.7inSouthCentralAsia,4and2.5forSouth-EasternAsia;2.7and1.6forWesternAsiaand2.4and2.2forEasternAsiarespectively[7].AmongAfricancontinentstheoralcancerincidencesformaleandfemalesare6.3and2.3forSouthern


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Africa,4.5and2.8forEasternAfrica;and1.7and1.4forWesternAfricarespectively.AmongEuropeancontinents,theoralcancerincidencesformaleandfemalesare9.1and2forCentral&EastEurope,7.9and3.2forWesternEurope,5.9and3.2forNorthernEuropeand5.8and2.1forSouthernEuroperespectively.AmongAmericans,NorthernAmericahashighestinci-dencesoforalcavitycancers,7.2and3.2formaleandfemalerespectively.SouthAmericahas5.3and2.4,andCentralAmericahas2.6and1.7incidencesoforalcavitycancersformalesandfemalesrespectivelyper100,000people[7].Australiahasincidencesof8.3and3.7formalesandfemalesrespectivelyoutof100,000people.Aetiologicalfactorsfororalcarcinomainthesecountriesincludehighrateofsmokingtobacco,increasedalcoholconsumption,dietlowinfruitsandvegetables.OverallincidenceoforalcancerinAustraliaisdecreasing.Thereis a highprevalenceof oropharyngeal carcinomadue toHPV infection in these countries,whichhasabetterprognosisthanthatinducedbysmoking[17,18].

3. Tobacco consumption in India

Tobaccoaddictions,intheformsofbothsmokingandsmokeless,arethemainreasonsfortheincreasingincidenceoforalcancersinIndia.ThesocialawarenessforthehazardsoftobaccouseisveryminimalinIndia.Moreover,thelowsocio-economicstatusandlownu-tritionalvalue-diet,lackingvegetablesandfruits,contributetowardshigherrisksforcancerdevelopment.Inaddition,viralinfections,suchasHPVandpoororalhygiene,areotherim-portantriskfactors.Poororalhygienehasbeenadvocatedasariskfactorfororalcancer.Thishasbeenassessedbymeasuringtoothlossorstatusofthedentitionandperiodontaldisease.PoorgeneraloralconditionassociatedwithincreasedriskofdevelopmentofOSCCinbothgenders[19,20].However,fromcurrenttrendoftobaccosmokingamongyoungpeopleaged15yearsandoverinIndia,WHOpredictsthatthetobaccousagewillbereducedby30%in2025withrespecttothestatisticsfor2010(Table1)[16].

InsomepartsofIndia,suchasthestatesofBiharandMaharashtra,smokelesstobaccouseismorecommonthansmoking.Apartfromregionalpreferencesduetodifferentsocio-culturalnorms,thepreferenceforsmokelesstobaccoisinverselyrelatedtoeducationandin-come.IncountriesofSouthAsia,particularlyIndia,traditionalvaluesdonotfavoursmokingbytheyoungorbywomen,butthereisnosuchtabooagainstusingsmokelesstobacco.Mostwomen,whousetobaccoinIndia,useitinsmokelessforms.InIndiaithasbeenestimatedthatroughlyone-thirdofwomenandtwo-thirdsofmenusetobaccoinoneformoranother.InanepidemiologicalstudyconductedineightruralareasofIndia,smokelesstobaccousewas3–53%amongmenand3–49%amongwomen.Moreover,2-26%ofmenand0–4%ofwomenoftheseareaswereindulgedinconsumingbothsmokingandsmokelessformsoftobacco[21].AstudyconductedbyNationalFamilyHealthSurvey(NFHS)during2005–06, found thattobaccouseismoreprevalentamongmen,illiterates,poor,andvulnerablesectionofthesoci-ety[22].Anotherstudyconductedamongindividualsof15yearsofageorolderin2009–10

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byGlobalAdultTobaccoSurvey(GATS)indicatesthat47.9%adultmalesand20.3%adultfemalesare tobaccousers.About24.3%malesand2.9%femalesof theadultsusesmoke,while32.9%malesand18.4%femalesusesmokelesstobacco.GlobalYouthTobaccoSurvey(GYTS)conductedastudyamong24,000students(aged13-15years)in2009,andfoundthat14.6%studentsweretobaccousersinIndia[23].

Smokelesstobaccouseshowedavariationofusagefrom7.2%to59.4%indifferentstatesofIndia.InasurveyfromMumbai,thesmokelesstobaccousewas57.1%amongwom-enand45.7%amongmen[12].InTrivandrumandKeralachewinghabitswereobservedby26.8%menand26.4%womenof thestudiedpopulation[24]. InJammu&Kashmir,Goa,HimachalPradesh,Haryana,Punjab,Kerala,AndhraPradesh,TamilNadu,Delhi,Karnataka,Meghalaya,RajasthanandWestBengalindividualsmainlyconsumedsmokingformsofto-baccowhereasinMaharashtra,UttarPradesh,Sikkim,MadhyaPradesh,Assam,Orissa,Bi-har,andArunachalPradeshsmokeless tobaccousepredominated. InGujarat,ManipurandMizoramareas,equalfrequencyofusageofsmokelessandsmokingtobaccowasobservedamongmenwhileamongfemaletheratiowas5:1respectively.InNorthEasternstatesofIndiafemalesarereportedtobetheextensiveusertobaccoGulthanmenandasignificantpopula-tionofAssam,Meghalaya,Nagaland,Sikkim,andMizoramareaffectedwiththetobaccoepi-demic.TobaccowaterisusedextensivelyinNorthEastIndianstates,especiallyMizoramandManipur.Frequencyofuseoftobaccowaterusewasalmostsimilaramongmaleandfemales[12,25].

Whosurveyedastudyontobaccoaddictionformorethan10yearsofspanwith35,288respondentsofKarnatakaand29,931respondentsofUtterPradesh.Accordingtothestudy,tobaccouseinsmokelessformwaspredominantamongwomenandamongmenlessthan30yearsinbothurbanandruralareas;however,smokingwasthepredominantformoftobaccouseamongmenmorethan30yearsage.Theoverallprevalenceforuseofsmokelesstobaccowasobservedtobe13.9%inKarnataka(13.4%amongmenand14.4%amongwomen)and17.5%inUttarPradesh(24.3%amongmenand6.6%amongwomen).Useofsmokelessto-baccowashigheramongfemalesascomparedtomalesintheage-groupsabove40yearsinKarnataka[25].InUttarPradesh,theproportionofmenusingsmokelesstobaccowashigherthanwomen,inallage-groupsandprevalenceofsmokelesstobaccouseincreasedwithageinbothsexes.Betel-tobaccoquidwasfoundtobeextensivelyconsumedinKarnataka,buthadlimitedpracticeinUttarPradesh.Theprevalencerateofuseofthistobaccomodalitywas14.2%(26.9%amongmalesand0.6%amongfemales)inKarnatakaand2.0%(2.3%amongmalesand1.4%amongfemales)inUttarPradesh.Overall,ahigherprevalenceamongruralareaswasobservedinallage-groupsofKarnatakaascomparedtourbanareas,butthetrendswere variable in different age-groups inUttar Pradesh.An inverse correlation of decreaseinprevalenceratesofbetel-tobaccoquid/smokelesstobaccousewithincreasingeducational

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levelswas observed in different age-groups inKarnataka, and similar patternwas noticedonlyamongfemalesinUttarPradesh.Aninverseassociationofbetel-tobaccoquidusewithincreasingfamilyincomelevelswasobservedinKarnatakabutnotinUttarPradesh[12,25].

4. Premalignant disorders of the Oral Cavity

Themechanismsfortransformationoftheoralpremalignantdisordersintomalignanciesarenotwellunderstood;amongmanyhypothesesthe‘fieldcancerizationtheory’isthemostaccepted.Fieldcancerizationinvolvestheformationofmultipleareasofpremalignantdiseasewithahigher-than-expectedrateofmultiplelocalsecondprimarytumors.Manytheorieshavebeenproposedtoexplaintheoccurrenceofcarcinomasinspecificsites.Onetheorystatesthatmultiplesquamouscelllesionsoccurirrespectiveofeachother.Thisisduetotheexposureoftheoralcavitytocarcinogensatthesametimeleadingtomultiplegeneticaberrationsintheentirearea.Anothertheorystatesthatmultiplelesionsariseduetothemigrationofdysplasticandalteredcellswithtwodifferentpatterns,(a)migrationofmalignantcellsthroughthesaliva(micrometastasis);(b)intra-epithelialmigrationoftheprogenitorcellsofinitiallytransformedmalignantcells.Themechanismisdifferentfromthemetastasis,sincemetastaticcellsareusu-allytransportedthroughlymphaticandvascularsystemfromprimarycancersites[26,27].

Potentiallymalignantorallesionsreflectunderlyingcellularchanges,whichareeitherredorwhiteormixedredandwhiteappearance.Alongwiththeclinicalmanifestations,theas-sociatedcellularchangesaretermedasdysplasia,whichisdefinedaslossofuniformityofin-dividualcellsandtheirarchitecturalorientation.TheWHO2005classificationrecognizesfivehistopathologicalstagesintheepithelialprecursorlesions:(i)Squamoushyperplasia:Itcanbeacanthosisandbasilarhyperplasia.Thehistopathologyshowsregularstratificationwithoutcellularatypia.(ii)Milddysplasia:Thearchitecturaldisturbanceisrestrictedtothelowerthirdoftheepitheliumaccompaniedbymildcytologicalatypia.(iii)Moderatedysplasia:Thedys-plasticchangeextendstothemiddlethirdoftheepitheliumwithmoderatecytologicalatypia.(iv)Severedysplasia:Thedysplasticchangesinvolvemorethantwo-thirdsoftheepitheliumwithseverecytologicalatypia.(v)Carcinoma-in-situ:Fullthicknessarchitecturaldisturbanceintheviablecelllayersaccompaniedbypronouncedcytologicalatypia[2,28].

Oralleukoplakiaisdefinedasapredominantlywhitelesionoftheoralmucosa.Thedis-ordercanfurtherbedividedintoahomogenousandanon-homogenoustype.Thehomogenousformisclinicallycharacterizedasawhite,well-demarcatedplaquewithanidenticalclinicalappearanceallthroughouttheentirelesion(Figure2).Thesurfacetexturemayvaryfromasmooththinsurfacetoaleatheryappearancereferredtoas“crackedmud”.Anothercharacter-isticfeatureisthelackofaperipheralerythematouszoneinhomogenousleukoplakia.Ifthesurfacetextureishomogenousbutcontainspapillary(nodular)orexophyticcomponents,theleukoplakiaisalsoregardedasnonhomogenous.Thenonhomogenoustypeoforalleukopla-

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kiamayshowwhitepatchesorplaqueamidstredtissue.Duetotheconcomitantoccurrenceofwhiteandredareas,thenonhomogenousleukoplakiaisalsocallederythroleukoplakiaorspeckledleukoplakia.Theclinicalmanifestationofthewhiteareasmayvaryfromlargewhiteverrucousareastosmallnodularstructures.Bothhomogenousandnonhomogenousleukopla-kiamaybeobservedinallsitesoforalmucosa[28].Oralleukoplakiaincludeswhitecom-ponentdominatedbypapillaryorfinger-likeprojections,whicharereferredtoasverrucousorverruciformleukoplakia.Oralleukoplakiawiththisclinicalmanifestationbutwithamoreangry-lookinggrowthpatternandrecurrencerateisdesignatedasproliferativeverrucousleu-koplakia(PVL)havinghighmalignantpotential.Asthecommonsurfacepatternissimilartooralpapillomas,thePVLissuspectedtohaveaviraletiology.Oralerythroplakiahasnotbeensowellstudiedasleukoplakia.Itisdefinedasared,velvety,plaque-likelesion oftheoralmucosathatcannotbecharacterizedasanyotherdefinablelesion(Figure3)[28,29].

5. Signs & symptoms of oral malignant lesions

TheclassicalcomplaintofpatientssufferingfromOSCCisdiscomfortwhichcompelsthemtoimmediatetreatment.Dysphagia,odynophagia,otalgia,limitedmovement,oralbleed-ing,neckmassesandweightlossmayoccurwithadvancementofthedisease.Thehighrisksitesfororalcarcinomaincludethelowerlip,theanteriorfloorofthemouthandthelateralbordersofthetongue.Thepatientmaydeveloptissuechanges,whichincludeared,whiteormixedredandwhitelesionandachangeinthesurfacetextureproducingasmooth,granular,roughorcrustedlesionorulceration(Figure4).Thelesionmaybeflatorelevatedandulcer-atedornonulceratedandmaybeminimallypalpableorindurated.Lossoffunctionoftonguecanaffectspeech,swallowingandfoodintake[28,29].

Lymphaticspreadoforalcarcinomausuallyinvolvesthesubmandibularanddigastricnodes, theuppercervicalnodes,andfinallytheremainingnodesof thecervicalchain.Thenodesmost commonly involved are those that are on the same side as the primary node,althoughthecloserthetumouristothemidlineandthemoreposteriorintheoralcavityororopharynx,themorecommonaretheinvolvementofthebilateralorcontralateralnodes.Thenodesarenottenderuntilandunlesstheyareassociatedwithsecondaryinfectionoraninflam-matoryresponseispresent,whichmayoccurafterbiopsy[28].Oralmalignantmelanomasarerelativelyrarecancersandoccurcommonlyinthemaxillarygingival,morefrequentlyonthepalatewithfewerincidencesinthemandibulargingival[30].Though,theselesionsarebio-logicallyaggressive,theyareclinicallyasymptomaticintheearlystagesandusuallypresentmerelyasahyperpigmentedpatchonthegingivalsurface(Figure5).

Verrucouscarcinomaisdescribedclinicallyaspapillary,verrucoid,fungatingorcau-liflower-likeandmaydevelop fromprogressionofproliferativeverrucous leukoplakia thatprogresstocarcinoma(Figure4).Verrucouscarcinomararelyspreadsthroughlymphaticroute

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andgenerallyremainslocallydestructive.ThereareafewothervariantsofSCCotherthanverrucouscarcinoma.Basaloidcarcinomaiscomposedofsolidgrowthofbasaloidcellswithsmallcysticspaces.IthasbeensuggestedthatHPV-associatedcancersoforalcavityaremorelikelytohavebasaloidfeatures.SpindlecellcarcinomasarerarevariantsofSCC,whereepi-thelialchangesrangingfromprominentdysplasiatofrankSCCinconjunctionwithadysplas-ticspindlecellelement[28].

6. Etiopathogenesis for Oral Cancer

Carcinogenesisisageneticprocessthatleadstoachangeintissuemorphologyandcel-lularbehavior.Thedevelopmentoforalmalignancyisattributedtoapowerfulallianceoftwofactors:nicotineandcarcinogens.Nicotineisaddictiveandtoxic,butitisnotacarcinogen.Thisaddiction,however,causespeopletousetobaccoproductscontinually,andtheseprod-uctscontainmanycarcinogens.Carcinogensalterthegeneresponsesforproto-oncogenesandtumoursuppressorgenes(TSGs)thatignitethepathogenesisoforalcarcinoma.Othergeneticfactorswhichplayamajorroleinoralcancerincludechromosomalaberrationsinthetelom-ere regionof chromosome, geneticmutationsof proto-oncogenes andTSGs, or epigeneticchangeslikeDNAmethylationorhistonemodification[6].Inaddition,angiogenesis,immunefunctionandhemostaticregulationofsurroundingnormalcellsalsoplayimportantrolesindiseasepathogenesis(Figure6).

Tobaccoandalcoholaregreatriskfactorsfororalandoropharyngealcancers.Nitro-samines,polycyclicaromatichydrocarbons,nitrosodicthanolamine,nitrosoproline,andpolo-niumarethepotentcarcinogensintobacco.Carbonmonoxide,thiocyanate,hydrogencyanide,nicotineanditsmetabolitesaremajorconstituentsintobaccosmoke.Epidemiologicalstudieshavefoundthatuptoeightypercentoforalcancerpatientsareassociatedwithsmoking.Inad-ditiontotheriskofprimarycancers,theriskofsecondaryandrecurrentprimaryoralcancersisrelatedtocontinuationofsmokingaftercancertreatment.Afollowupstudyfor1yearofpri-maryoralcancerpatients(aftersurgery)foundthat18%ofthesepatientsdeveloparecurrentoralcancer,andthosewhocontinuedtosmokehada30%riskofsecondaryoralcancerdevel-opment[31].Ithasbeensuggestedthatthedeleteriouseffectofsmokingonthedevelopmentofcancerdecreases5to10yearspoststoppage.TheincidenceofOSCCvariesworldwideandmaybeexplainedpartlybydifferencesintheuseoftobaccoproducts.Benignhyperkeratosisandepithelialdysplasiahavebeenreportedfollowingshort-termuseofsmokelesstobaccoandchronicuseisassociatedwithanincreasingincidenceofmalignantlesions[32].

Geneticdamageisthesteptowardstheprocessofcarcinogenesis.Threeclassesofcar-cinogenicagentshavebeenidentified:1)chemical,2)radiantenergyand3)microbialagents.Anothercauseoforalcarcinogenesisismechanicaltrauma;forexample,sharpcuspaledgesofteethcausingtraumatothebuccalmucosaorlateralborderofthetongue.Chemicalsandradi-


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antenergyaretheprimarycausesofcancerinhumanswhereasoncogenicvirusesareinvolvedinthepathogenesisofcancerinmainlyanimalsandsomehumantumours.

Chemical carcinogens have highly reactive electrophile groups that directly damagetheDNA.Therearetwotypesofchemicalcarcinogens:directandindirectacting.Directact-ingagents(fore.g.alkylatingagentsusedforchemotherapy)arecarcinogenicfromtheini-tialstates,whereasindirectactingagents(foreg.benzopyrene,azodyes,aflatoxins)arenotcarcinogenduringinitialstatesandareconvertedintocarcinogensbyendogenousmetabolicpathways.Hence,polymorphismsofendogenousenzymesthatarecriticalformetaboliccon-versionofchemicalscompounds(suchas,cytochromeP-450),maypromotecarcinogenesis.

Radiations,suchasUVraysofsun,X-rays,radio-nucleotidesetc,canalsoinduceDNAbreakageandconsideredascarcinogen.Ionizingradiationscausechromosomalaberrations,translocationsandlessfrequentlypointmutations,leadingtogeneticdamageandcarcinogen-esis.UVinducestheformationofpyrimidinedimerswithinDNA,andmayleadtocarcinomaandmelanomaoftheskin[28].

Thestudyofoncogenicretrovirusesinanimalshasprovidedspectacularinsightsintothegeneticbasisofcancer.ThehumanT-celllymphomavirus-1(HTLV-1)hasbeendemon-stratedtocausecancerinhumans.HTLV-1hasbeenreportedtobeassociatedwithavariantofTcellleukemia/lymphomainhumans.SimilartotheHIV,HTLV-1hasaffinityforCD4+Tcells,andtheseTcellsarethemajorvictimsofneoplastictransformations.Theroleofviruses,suchasHTLV-1andHPVareanewparameterforthepathogenesisofhumancancers.TheHTLV-1genome,inadditiontotheusualretroviralgenome,containsauniqueregioncalledthepXwhichencodesamajorTAXprotein,whichturnsongenesforcytokinesandtheirre-ceptorsininfectedTcells.Althoughthisproliferationisinitiallypolyclonal,theproliferatingTcellsareatincreasedriskforsecondarymutationsthatleadtotheoutgrowthofamonoclonalleukemia.Byinterferingwithseveraltranscriptionfactors,suchasNF-ĸB,theTAXproteincantransactivatetheexpressionofgenesthatencodecytokines,cytokinereceptorsandco-stimulatorymolecules.Thisinappropriategeneexpressionleadstoautocrinesignalingloopsand increased activation of promitogenic signaling cascades. Furthermore,TAX can driveprogressionthroughthecellcyclebydirectlybindingtoandactivatingcyclins.Inaddition,TAXcanrepressthefunctionofseveraltumoursuppressorgenesthatcontrolthecellcycle,includingP16andP53[33,34].

Recently, severalDNAandRNAviruses, have been identified and correlated to thedevelopementofOSCC.FourDNAvirusesHPV,Epstein-Barrvirus(EBV),humanherpesvirus8(HHV8),andHepatitisBvirus(HBV)aregainingimmenseattentionincancerbiologybecausetheyarestronglyassociatedwithhumancancer.Veryrecently,theassociationofHPV,specificallyHPV-16and-18,withoralsquamouscellcarcinomaisalsogainingimportance.

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CertainEBVgeneproductscontributetooncogenesisbystimulatinganormalBcellprolifera-tionpathway[34,35].

7. Conclusion

Oralmucosa,salivaryglandandjawsarethesitesoforalcavitythatareaffectedduringpathogenesis.Neoplastic lesionsoforalcavity includefibromas, leukoplakia,erythroplakiaandOSCC.Theriskforerythroplakiatoundergomalignanttransformationishigherthanleu-koplakia.OSCCcovers90%ofcanceroforalcavityandishighlyassociatedtotobaccoandalcoholconsumption.InrecenttimesatrendinoralcancerisobservedinyoungadultsandtheriskofOSCCisbeingincreased.Amongyoungadultswithanyhabitoftobaccoconsuming,tongueandbuccalmucosaarethesitesforoccurrenceoforalcancer.Immunefactors,dietaryfactors,geneticfactorsandoralsexarethemajoretiologyofOSCCinyoungpatients.Further-more,accordingtotheOralCancerFoundation,oralcancernowaffectsonewomanforeverytwomen,ascomparedtotheearliertrendofsixmenforeverywoman.TheincidenceofHPVassociatedorallesionsisalsoincreasinginrecentyears.HPVoncoproteins,mainlyE6andE7bindtoRb(retinoblastoma)andp53thusregulatetheirfunctions.Morethan30differenttypesoftumorsmayariseinsalivaryglands,amongwhichmucoepidermoidcarcinoma,composedofmixturesofsqamousandmucouscells,isthemostcommonmalignanttumor.Mucoepider-moidcarcinomaisreportedtodisregulatetheNotchsignalingpathway.Bothpre-malignantandmalignantlesionsoforalcavityaremainlycausedbytobacco,agreatriskfactorfordiffer-entdiseases.Tobaccospecificnitrosamineshavebeendetectedinsalivaoftobaccochewers.ThesenitrosaminesarecarcinogenthatmodifyDNAandcausemutagenesis.TheunderlyingmechanismsforOSCCstillremainunknown.Severalreportsdocumentedtheinvolvementofseveralproteins,includingP53,Rb,ICAM-5,TGFR,MMP-8,andTIMP-1indevelopmentofOSCC.Moreover,OSCCdevelopsfrequentlyinimmune-suppressedindividuals,becausethediseaseaggressivenessisdirectlyassociatedwithalteredimmuneresponses.Severalapproveddrugs,targetingdiversefactorsofcancerareclearlynotenoughforthepresenttimes(Figure7).Newdrugsarebeingdevelopedtargetingeachoftheenablingsignalingmoleculesthatarecontributingincancerdevelopment,thusholdpromiseascancertherapeutics.Moreover,so-cialawarenessagainsttobaccoandself-awarenessforearlydiagnosisarerequiredworldwidefororalcancerprevention.

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8. Table

CURRENTTOBACCOSMOKING(%)

Year

Men Women Bothsexes

Lower95%CI

Pointestimate

Upper95%CI

Lower95%CI

Pointestimate

Upper95%CI

Lower95%CI

Pointestimate

Upper95%CI

Estimatedno.ofcurrentsmokers

2000 23.7 33.8 46.9 3.7 5.7 7.8 14.0 20.2 28.0 138,505,200

2005 22.1 28.0 34.3 2.9 3.8 4.7 12.8 16.3 19.9 124,176,100

2010 19.1 23.5 28.1 1.9 2.5 3.0 10.7 13.3 15.9 111,856,400

2015 13.7 19.9 26.3 1.2 1.7 2.2 7.6 11.0 14.6 101,399,700

2020 9.5 17.0 25.3 0.7 1.1 1.7 5.6 9.3 13.8 91,913,300

2025 6.4 14.6 25.1 0.4 0.8 1.3 3.5 7.9 13.5 83,514,000

Voluntarytarget(30%relativereductionfrom2010to2025

16.5 1.8 9.3

Men-Fittedcurrenttobaccosmoking(%)Women-Fittedcurrenttobaccosmoking(%)

Table 1: Currenttrendoftobaccosmokingamongyoungpeopleaged15yearsandoverinIndia[16].

Figure 1: Countries with high incidence and mortality from oral cancer (in red). Theareascharacterizedbyhighincidenceratesfororalcancer(excludinglip)arefoundin theSouthandSoutheastAsia(e.g.SriLanka,India,PakistanandTaiwan),partsofWestern(e.g.France)andEasternEurope(e.g.Hungary,SlovakiaandSlovenia),partsofLatinAmericaandtheCaribbean(e.g.Brazil,UruguayandPuertoRico)andinPacificregions(e.g.PapuaNewGuineaandMelanesia)[15].

9.Figures

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Figure 2: (inclockwisemanner)Reticularlichenplanusintheleftbuccalmucosaofapatient;erosivelichenplanusintheupperleftpalatalaspectofanimmunocompromisedpatient;proliferativeverrucousleukoplakiainapatienthavinghabitofretaining‘gutkha’inthebuccalvestibule;speckledleukoplakiaintheleftbuccalvestibule(allpicturesweretakenintheDeptofOP&ODofBurdwanDentalCollege&Hospital).

Figure 3: Anulceratedareaontheleftlateralborderofthetongueofapatientsuggestiveoferythroplakiawithareasofleukoplakicgrowthsituatedposteriortothereddenedarea(picturestakenintheDept.ofOP&ODofBDC&H)


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Figure 4: (fromleft toright)Hyperkeratoticareasignificantofepithelialdysplasiaseenin the leftbuccalmucosa;Carcinomainsituoftheleftbuccalmucosa;SquamousCellCarcinomaoftherightbuccalmucosaandassociatedalveolus.Thelesionwasassociatedwithextensiveboneloss,(picturestakenintheDept.ofOP&ODofBDC&H)

Figure 5: Malignantmelanoma of the hard palate(left); Histological section stained with H&E showingmalignantmelanomafromsamplecollectedfromthesamepatient(right)(slidepicturetakenintheDept.ofOPofBCD&H).

Figure 6: Endogenousandexogenousagentsaffectingsomaticmutations,epigeneticalterations,telomeraseshortening and DNA damage that leads to cancer progression through chromatin modifications andtranscriptionalregulationofoncogenes.


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Figure 7: Different signaling molecules associated to cancers that are targeted for therapeutic purpose.CDK,Cyclin-DependentKinase; PARP, PolyADP-Ribose Polymerase; EGFR,EpidermalGrowth FactorReceptor;MAPK,Mitogen-ActivatedProteinKinase;TGF,TransformingGrowthFactor;HGF,HepatocyteGrowthFactor;VEGF,VascularEndothelialGrowthFactor; APC,Anaphase-PromotingComplex,PI3K,Phosphatidylinositide3Kinase.10. References

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