w w w . j c o l . o r g . b r
Journal
of
Coloproctology
Review
Article
Crohn’s
disease:
risk
factor
for
colorectal
cancer
Sandra
Cristina
Dias
dos
Santos
a,∗,
Laura
Elisabete
Ribeiro
Barbosa
a,baUniversidadedoPorto,FaculdadedeMedicina,Porto,Portugal bHospitaldeSãoJoão,Servic¸odeCirurgiaGeral,Porto,Portugal
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received19June2016 Accepted29June2016
Availableonline9September2016
Keywords:
Crohndisease Colorectalneoplasms Inflammation Riskfactors
a
b
s
t
r
a
c
t
Background:Crohn’sdiseaseis aninflammatorydiseasethatcanreach any partofthe gastrointestinaltract.Thisdiseasehasbeenassociatedwithanincreasedneoplasticrisk, includingcolorectalcarcinoma.
Objective:Theobjectiveofthisworkistodescribethemechanismspresentintwodiseases, andthatareresponsiblefortheincreasedriskinCrohn’sdisease.
Methods:AbibliographicresearchwasconductedinPubMeddatabase.Inadditiontothe articlesobtainedwithaninsertedqueryinPubmed,otherreferencesrelevanttothetopic inquestionwereincluded.
Results:Colorectalcancerriskvariesaccordingtothepresenceofcertainfactors,andan exampleofthisisCrohn’sdisease.Chronicinflammationseemstobeanimportant con-tributiontocarcinogenesis,sinceitcreatesamicroenvironmentsuitablefortheonsetand progressionofthedisease.Therearemolecularchangesthatarecommontotwoconditions, thusjustifyingthefactofCrohn’sdiseasebeingariskfactorforcolorectalcarcinoma.The diseasecontrolwithanappropriatetherapyandwithsurveillancearetwowaystocontrol thisrisk.
Conclusions: AproinflammatorystateisthecornerstoneintheassociationbetweenCrohn’s diseaseandcolorectalcarcinoma.Theimplementationofsurveillancestrategiesalloweda decreaseinmorbidityandmortalityassociatedwiththiscancer.
PublishedbyElsevierEditoraLtda.onbehalfofSociedadeBrasileiradeColoproctologia. ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.
org/licenses/by-nc-nd/4.0/).
Doenc¸a
de
Crohn:
fator
de
risco
para
o
carcinoma
colorretal
Palavras-chave:
Doenc¸adecrohn Carcinomacolorretal Inflamac¸ão
Fatoresderisco
r
e
s
u
m
o
Introduc¸ão: Adoenc¸adeCrohnéumadoenc¸ainflamatóriaquepodeatingirtodootrato gastrointestinal. Esta patologia temsido associada a um risco neoplásico aumentado, nomeadamentedecarcinomacolorretal.
Objetivo:Oobjetivodestetrabalhoédescreverosmecanismosresponsáveispeloaumento doriscodecarcinomacolorretalnadoenc¸adeCrohn.
∗ Correspondingauthor.
E-mail:scristinasantos@hotmail.com(S.C.Santos).
http://dx.doi.org/10.1016/j.jcol.2016.06.005
Métodos: ApesquisabibliográficafoirealizadanabasededadosPubmed.Paraalémdos artigosobtidoscomaqueryinseridanaPubmed,foramtambémincluídasoutrasreferências comrelevânciaparaotemaemquestão.
Resultados: Oriscodecarcinomacolorretalaumentanapresenc¸adedeterminadosfatores, entreselesadoenc¸adeCrohn.Ainflamac¸ãocrónicapresentepareceserumimportante contributoparaacarcinogénese,porquepermiteacriac¸ãodeummicroambienteadequado aoaparecimentoeprogressãodadoenc¸a.Existemalterac¸õesmolecularescomunsàsduas patologiasjustificando-seofatodestadoenc¸ainflamatóriaserfatorderiscoparao carci-nomacolorretal.Ocontrolodadoenc¸acomterapêuticaadequadaeestratégiasdevigilâncias sãoduasformasdecontrolarorisco.
Conclusões: Oestadopró-inflamatórioéumapec¸achavenaassociac¸ãoentredoenc¸ade Crohnecarcinomacolorretal.Aimplementac¸ãode estratégiasde vigilânciapermitiua diminuic¸ãodamorbi-mortalidadeassociadaaestaneoplasia.
PublicadoporElsevierEditoraLtda.emnomedeSociedadeBrasileirade Coloproctologia.Este ´eumartigoOpenAccesssobumalicenc¸aCCBY-NC-ND(http://
creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Inflammatoryboweldiseases,ofwhichCrohn’sdisease(CD), familialadenomatouspolyposis,andthenon-polypoid hered-itaryformareexamples,arethreediseasesthatconferahigh riskofcolorectalcarcinoma(CRC).1
CDisachronic,progressivediseasecharacterizedbya pro-inflammatorystate. Thequality oflifeofthese patients is affectedsubstantially,althoughbenefitshaveoccurredwith theappearanceofvarioustherapies.2,3
The multifactorial etiology of this disease is not fully known,butsomepathophysiologicalmechanismsunderlying ithavebeendescribed.4
CDischaracterizedbychronicdiarrhea(thesymptommost oftenpresent),weightloss,bloodlossandabdominalpain.All thegastrointestinaltractcanbeaffected,anddistalileumand colonarethepartsmostoftenaffected.3–6
Fortheprogressionofthisdisease,geneticand environ-mentalfactorsanddysbiosisarecontributingfactors.2,3,7
About2millionAmericansandEuropeanssufferfromCD, anditsdiagnosisisestablishedmainlyinthe2ndor3rddecade oflife.7
CD may have intestinal and extra-intestinal manifesta-tions, and the disease shows two predominant patterns. AccordingtotheMontrealclassification,patientsare catego-rizedaccordingtotheirageatdiagnosis,anddiseaselocation andbehavior.Withregardtoageatdiagnosis,thecategories are ≤16 years, between 17 and 40 years, and ≥40 years.
Thedisease canbefoundinthe ileum,colon,ileum-colon, oruppergastrointestinaltract,showinga non-stenotic/non-penetrating behavior, a stenotic behavior,or a penetrating behavior.8
CRCarisesduetoadysplasiaofintestinalmucosaandis morecommoninthesepatientsversusthegeneral popula-tion.Thus,thisinflammatorydiseaseisariskfactorforCRC occurrence.5,9,10
CRCcancausedeathinthesepatients,andthediagnosis israrelyestablishedbefore7yearsofdiseaseprogression.7,11 Thereisnoconsensusastothequantificationofrisksince thisisinfluencedbyseveralfactors.12
Theprognosis ofCD varies from patientto patient, but there are some factors which lead to a worse outcome, includingtheperianaldiseaseandthepresenceofupper gas-trointestinaltractlesions,aswellasanextensivelyaffected colon.
Material
and
methods
OnJuly6,2015,aliteraturesearchinPubMeddatabasewas performedwiththefollowingquery((“crohn’sdisease”[MeSH Terms]OR(“crohn”[AllFields]AND“disease”[AllFields])OR “crohn’sdisease”[AllFields])AND(“neoplasms”[MeSHTerms] OR“neoplasms”[Allfields]OR“cancer”[AllFields])).The inclu-sioncriteriawere:studiespublishedinthelast10yearsand articleswritteninPortuguese,EnglishorSpanish.Thetitles andabstractswereread,and75articleswereselected.
OnDecember22,2015,anewsearchwasconductedwith the aimof updatingthe bibliography;the same query and thesameinclusioncriteriausedintheprevioussurveywere employed,and48articleswereobtained.
Additionalstudiesrelevanttotheissueinquestionwere alsoincluded,throughacross-searchwiththearticlesalready included,andabookrelevanttothesubjectmatter.
Atotalof50referenceswereobtained.
Results
Epidemiology
Inflammatory bowel disease, which includes CD, is more prevalent indevelopedcountries;thisleadsonetothinkof Westernization as a risk factor for this condition. Dietary habitsandlifestylecontributeinsomewaytoitsappearance. Oneofthediagnosticpeaksoccursinpatientsagedbetween 15and30years,and30%ofpatientsarediagnosedunderthe ageof20years.13,14Thesecondpeakoccursbetween60and 80years,withalowerincidenceversusthefirstpeak.15
ileocoliclocation,30%suffer from anisolatedilealdisease, and30%areaffectedonlyinthecolon.Approximately5–10% ofpatientsexhibitassociatedlesionsoftheupper gastroin-testinaltract,and20–30%showperianaldisease.2
Thecontrolofthe disease withmedicaltherapy, partic-ularly with biological agents, constitutes an advantage for thesepatients; but despitethe advancesin science and in pharmacotherapy,theriskofcomplicationsinvolvingbowel resectionremainsintherangeof80%.12,16 Perianallesions, i.e.,ulcers,fissuresorfistulas,are complicationspresent in 20%ofpatientsatdiagnosis.5Despitethemedical therapeu-ticefficacy,thepercentageofrefractorypatientsspinsaround 25–30%.Alltheseaspectscontributetoaninadequatecontrol ofthedisease.7
CRC can arise inthe context of CD, with a location in areasofchronicinflammation.Regardingthequantification ofrisk, the resultsofthe studies are mixed. Somestudies pointtoa risk2–3 timeshigher,whileother studies cite a risksixtimeshigher.Eachyear,approximately900,000new casesofCRCand500,000deathsoccurworldwide.Thiscancer accountsforabout10–15%ofdeathsinpatientswith inflam-matoryboweldiseaseandtheamountattributabletoCDhas notyetbeen determined.10,11,14,17 Other studiesreportthat 1in12deathsofpatientswithCrohn’sdiseaseiscausedby CRC.1
ThefirstcaseofCRCrelatedtoCDwasdescribedin1948, andsincethenthecauseofthisassociationisnotyetfully understood.Infact,theriskexists,butitsmagnitudehasnot yetbeendeterminedaccurately.13
TheincidenceofCRCrelatedtoCDisvariable,reaching highervaluesintertiaryhospitals,wheretheinflammatory diseaseattainsmoreseverestages.12
Studies relatedtothis association foundthat thereis a cumulativerisk of CRC development. In evaluating a pop-ulationofEastern Europe 20 yearsafter the diagnosis,the cumulative risk was estimated at 1.1% (95% CI: 0.6–1.7%). Anotherstudyfoundthattheriskwouldbe2.9%after10years, 5.6%after20years,and8.3%after30years.13,18
Theriskofcancervarieswiththelocationofthedisease. Whenthediseaseaffectsonlythecolon,therelativeriskis5.6, whileinthecaseofileocolicinvolvement,therelativeriskis 3.2;andstudiesinpatientswithextensiveinvolvementofthe colonresultedinacalculatedrelativeriskof23.8.18
Thepresenceofmetachronouslesionsisvariable,ranging fromaminimumvalueof23%andamaximumof70%.19
Basseriet al.conducted astudy inwhich patients with Crohn’sdiseasewere monitoredfor17years;theseauthors foundaCRCdevelopmentin5.6%ofthestudypopulation.18
Otherstudieshaveconcludedthattherewasadecreasein theincidenceofCRC,butthisfindingcanbeexplainedbythe onsetofmedicaltherapiesincreasinglyeffective,appropriate surgicaltreatment,andtheexistenceofsurveillanceprograms thatallowanearlydetectionofdysplasia.1
Surveillance
AnassociationbetweenanincreasedriskofCRCinaCrohn’s patientexists,althoughthemechanismsresponsiblehavenot yetbeenfullyelucidated.6Thus,surveillanceprogramsareof
greatimportanceandare aimedatreducing morbidityand mortality.20,21
Giventhatoneofthediagnosticpeaksoccursbetween15 and30years,thedevelopmentofCRCassociatedwithCDis earlierthaninthesporadicform,similartowhatoccursin patientswithLynchsyndrome.10
StudiesinpatientswithulcerativecolitisandCDrevealed a very similar cumulativefrequency after20 years (8% vs. 7%,respectively).AccordingtotheAmericanGastroenterology Association (AGA), currently it isaccepted that the riskof developingCRCisequivalentinbothpathologies,anditwas recommendedthatsurveillanceshouldbegineightyearsafter thediagnosis.22TherecommendationsoftheBritishSociety ofGastroenterology(BSG)aretowardanonsetofmonitoring about10yearsafterdiagnosis.6,10,21
However,inastudyconductedinatertiaryhospital,two casesofCRCwithaone-yearintervalafterthediagnosisofCD wererelated;theremainingcaseswerereportedatintervals from11to14years.12TheprognosisofbothtypesofCRCmay bemorefavorablewithanappropriatesurveillance, consider-ingthattheneoplasticprogressiontomoreadvancedstages willbeavoided.10,18,23
In the case ofestablishing a diagnosis of primary scle-rosing cholangitis(PSC), the surveillance shouldbe started immediately,beingheldannuallyinaccordancewiththe rec-ommendationsoftheAGA.22,24
Theevolutionfromaninflamedtoadysplasticmucosamay occur without macroscopically visible lesions,unlike what happensinpatientswithsporadicCRC,thatinabout70–80% ofcasesfollowtheadenoma–carcinomasequence.10,17,25,26
The lesions may be polypoid or flat, multifocal or unifocal.27Somestudieshaveraiseddoubtsabouttheefficacy ofthesurveillancewithcolonoscopy,asflatlesionsarenot visibleandmaynotbetargetedsitesofrandomizedbiopsies. Thepresenceofdysplasiaisariskmarkerforcarcinoma.17,25,27 Whenthelesionsaremacroscopicallyvisible,shouldbe tar-getedforbiopsy.28
In the caseofflat lesions, biopsieswill berandomized, nottargeted;withthis,onewillcountonasampleofonly 0.03% of the mucosal surface of the colon. Therefore, if a dysplastic area exists, and this area is not targeted for a biopsy, cancer will progress and the diagnosis will be delayed.29
There is no consensus among different organizations and societies about surveillance strategies, which means that there are different recommendations. The applica-tion of surveillance strategies for all people with CD is not a consensual procedure. Studies were published argu-ing thatsurveillance shouldbecarriedout onlyforcertain subgroups. The definition of these subgroups is based on factors that confer a greater risk of CRC, i.e., the extent and duration of the disease, and also an extrapolation from studiesinpatientswithulcerativecolitis.Thus,these studies maintain that surveillance should be applied only to patients with a widely affected colon.30 Other authors defined more specific conditions for surveillance recom-mendation, namely more than 1/3 of the affected colon and development of CD≥8 years.21 These are the criteria
AccordingtoAGA,biopsiesatevery10cm(min:33)shall beobtained.21,24,29Undefinedresultsare anindicationfora repeatexaminationafter3–6months.Thepresenceof high-grade dysplasia is an indication for colectomy. Therefore, thehistologicalresultsdefine which proceduretoperform: Surveillancecolonoscopy,orsurgicaltreatment.18,28,31
AGArecommendsconductingsurveillanceatintervalsof 1–3years,andneverexceeding8yearsafterdiagnosis.3,24,32 InthecaseofapositivefamilyhistoryforCRCin1st-degree relatives, activeinflammationand anatomical changes,for example,stenosis,monitoringintervalsshouldbeshorter.22 BSGrecommendsthatthecolonoscopyshouldbecarriedout atintervalsof3or5years,takingintoaccounttheunderlying riskfactorsafter10years.3,32,33
Asalreadymentioned,metachronouslesions mayoccur inasignificant percentageofpatients. Thus,dysplasiacan bedetectedinmorethanonebiopsy,andinmorethanone location.31
Thesurveillancemustbecarriedoutinperiodsof remis-sionunlessinthecaseofalong-standinginflammation.22
Theevolutionoftechnologyhasallowedtheuseof chro-moendoscopyinsteadofrandomizedbiopsies;bythismethod, thebiopsiesaredirected,allowinggreaterefficiencyin detec-tingdysplasia.6
Thechromoendoscopy allowsthe enhancementof dys-plasticareasthroughlightfilters,orthroughagentssuchas methyleneblueandindigocarmine.29,34
Thistypeofendoscopyisrecommendedbyvarious enti-tiesforthemonitoringofpatientsatincreasedriskofCRC, forexample,patients withCD.34,35 Thisdiagnostic method allowsanincreaseof7%(95%CI:3.2–11.3)inthedetection of dysplasia versus white light endoscopy; but it remains to be seen what is its degree of technical influence on patient survival.Despite this uncertainty, the SCENIC con-sensus statement (Surveillance for Colorectal Endoscopic NeoplasiaDetectionandManagementinInflammatoryBowel DiseasePatients:InternationalConsensusRecommendations) recommendschromoendoscopyasatechniqueofchoicefor monitoringdysplasticareas inpatients withCD.3 BSG also recommendschromoendoscopyasamonitoringmethodfor allpatients;butifthistechniqueisnotavailable,2–4biopsies every10cmshouldbeobtained.22,29Ontheotherhand,AGA recommendschromoendoscopyonlyinspecialcases.29
Techniques suchas flow cytometry, immunohistochem-istry,markersurveyareessentialtoconfirmthediagnosisof cancer.4
Neoplasticbiomarkerscanalsobeanotherwaytodetector confirmthepresenceofcancer;however,theyarenotpartof thesurveillancestrategies.12
Theprogressofanti-inflammatorytherapyforCDand a propermonitoringofthesepatientshaveimprovedthe diag-nosis of CRC and increased survival.17 Thus, surveillance strategiesareanimportantwaytoimprovetheprognosisof thesepatients.Earlydiagnosisensuresatumordetectionin lessadvancedstages;thus,mostfrequentlythetreatmenthas acurativeeffect.36
Thesurveillancehasprovedtobeapowerfulweaponin thefightagainstCRC,sincethepresenceofsymptomscan benonspecific,perhapsimplyingdifficultywithadiagnosis basedonlyonclinicalfindings.37
Molecularchanges
CRCdevelopmentinpatientswithCDseemstobeduetoan interactionbetweengeneticandacquiredfactors.The interac-tionbetweeninflammationandregulatorygenesofneoplastic pathwaysappearstoplayanimportantroleintumorigenesis. Some authors argue that the contribution from inflamma-tionismoresignificantthanthecontributionofthegenetic component.18,25,27 Changes can occur in oncogenes,tumor suppressorgenes(i.e.,p53),andgenesofDNArepair(MLH1, MSH2,MSH6).18
Thegeneticalterationsarepresentevenbeforethe occur-renceofhistologicalalterationsofthemucosa.27
ThefirstgeneticchangerelatedtoCDwasinNOD2/CARD15 (nucleotide-binding oligomerization domain containing 2/caspaserecruitmentdomain-containingprotein15),which ultimately increases the production of pro-inflammatory cytokines.NOD2proteinisanintracellularsensorofbacterial peptidoglycans, which will act via nuclear factor kappa B (NF-kB).14,38 Thus, this genetic change helpsto perpetuate inflammation,beingindirectlyrelatedtocarcinogenesis.14
Pro-inflammatory factors play an important role in the development and evolution ofCD, and there may also be changes in their genes. One of the altered genes can be the tumor necrosis factor ␣ (TNF-␣), which is located on chromosome 6. Polymorphisms occurring in the promoter region of this gene can alter cytokine production; thus, theycanincreasethesusceptibilitytoconditionsrelatedto inflammation.39Thus,TNF-␣contributestoinflammationin patients with CD, notonlybeing involved intumor prolif-eration, but also in the metastatic process. This factor is associatedwithanincreasedexpressionofcyclooxygenase-2 (COX-2),cellproliferation,andangiogenesis.7
Thepresenceofamutationinthetumorsuppressorgene p53indiffersinsporadiccasesandincasesassociatedwith CD.Inthefirstsituation,themutationispresentinadvanced stages;however,inthislattersituationthemutationmaybe presentinthenon-dysplasticmucosa.10,27
Mutations in E-cadherin gene are one type of genetic change presentinsomecases.These mutationshavebeen associatedwiththeoccurrenceofcancer,i.e.,gastric carci-noma;itisbelievedthatthismaybeoneofthemechanisms ofcarcinogenesisinCD.
onebindingsitelocatedwithinthenon-transcribed3′ zone ofthisenzyme,thusallowingitsdirectconnectionwiththe inflammatoryprocess.37
MIR-191hasalsobeenassociatedwithCDandCRC, dis-easesinwhichitshowsanaberrantexpression.Inthecaseof CRC,MIR-191levelsmaybeincreasedordecreased.Inmost casesthelevelsare high,and thecasesdescribed withlow levelsareassociatedwithaworseprognosis.Inthecaseof CD,MIR-191mayalsobechanged,andapparentlyregulating innateandacquiredimmunity.40
Autophagyseemstobeanotherconnectinglink,actingas atumorsuppressor.7,14Thegeneforautophagy,ATG16L1,can bechanged.38Duringtumorigenesis,autophagyisnegatively regulatedbyseveralgenes.Defectsinautophagyhavebeen associatedwithseveralpathologies,includingCDandCRC.14 Oxidativestressand its underlyingdamageare changes thatarepresentinCDandperhapscontributingto tumori-genesis. In the caseof CD, anincrease of reactive oxygen and nitrogen reactive species occurs, which in turn lead toalterations inDNA,RNA, proteins,and lipids.23,41 These geneticalterationsthataffecttheimmunesystemhavebeen describedinthesetwodiseases,withaninvolvementofinnate andacquiredimmunity.23,27theresultofthesechangesmay bethelossoffunctionoftumorsuppressorgenes,againof functionofoncogenes,orlossofgeneticstability.11
Inflammation
CD is a condition in which, it is believed, non-pathogenic commensalbacteriatriggeranunregulatedimmuneresponse againstthemucosa,whosefunctionistoserveasabarrier.42
Chronicinflammationisrelatedtotissuedamageandto therecruitmentofimmunesystemcellsthatactto perpetu-ateinflammation.Thereisalsoarapidrenewalofthecolonic mucosa,whichincreasestheriskofDNAdamage.11
InflammationisaveryimportantfeatureinCD,and sev-eralstudies show thatthe increasedneoplastic riskisdue totheirpersistence,takingintoaccountthattheassociation betweencancerandinflammationhasbeenestablished.18,20 Thus, the risk is substantially larger in situations where thecontroloftheinflammatoryresponseisinappropriate.43 thepresenceofpro-inflammatorycytokinescarriesa perma-nentpro-inflammatorystatewhichincreasestheneoplastic risk.18,25
Inflammationpromotesthecreationofasuitable microen-vironmentforneoplasticformationandprogression.Several mechanismscontributetothedevelopmentofthis microen-vironment.
Theexpressionofsomegenesrelatedtoinflammationis increasedinmucosaofthesepatients,particularlyCOX-2.11 The induction of this enzyme occurs thanks to the acti-vation of toll-like receptor-4 (TLR-4) and to the increased productionofproinflammatorycytokinesbyimmunesystem cells.7,23 This signaling pathway will lead to the pro-duction of prostaglandins in epithelial cells which, along with local cytokines, inhibit apoptosis, thereby favoring carcinogenesis.23TheinductionofCOX-2hasanother impor-tant consequence–the decrease ofunesterified arachidonic acid.Theimportanceofthisfactliesinthepro-apoptotic func-tionofthisacid.Incasesinwhichtheacidisdecreased,the
apoptosisprocessalsowillbedecreased,whichpromotescell proliferation.23
Aside TLR, there are other receptors that contribute to inflammation,theNOD-likereceptors(NLRs).Thefirstgenetic changerelatedtoCDoccurredpreciselyinoneofthese recep-tors,NOD-2.ThisreceptorandNOD-1contributesignificantly toinflammationattheintestinallevel.NOD-1andNOD-2 rec-ognizemolecules,particularlybacterialpeptidoglycans,which penetrate into cells by various processes, for example by phagocytosis.ThebindingofthepeptidoglycanstoNLRs acti-vatespro-inflammatoryandanti-microbialmolecules.NLRs, incollaborationwithTLRs,allowthedetectionofbacteriaand activationofpro-inflammatorymechanisms.44
Rodentstudieshaveconcludedthatthedeficiencyof trans-forminggrowthfactorbeta(TGF-),exacerbatestheactivation of NF-kB and the secretion of proinflammatory cytokines, whichprotectcellsfromapoptosis.7,41
In patients with CD, in addition to changes in pro-inflammatory factors,alterationsin cellularimmunityalso occur.ThechangeofTcellphenotypeiscloselylinkedtothe regulationofinflammationinCDaswell astorelated can-cer;however,theresultsofpreviouslypublishedstudiesare contradictory.43,45 RegulatoryTcellsareamajorintervening factorintheinflammatoryprocess.Aninappropriateresponse tothemicrofloraplaysanimportantroleinthepathogenesis ofCD.Inthisinflammatorydisease,thereisachangeinthe balance betweenregulatoryTcells intheblood and inthe inflamedsiteintheboweland,inaddition,thereisanexcess ofpro-inflammatorystimuli.18,27However,ifononehanditis believedthattheregulatoryTcellsareimportantin control-linginflammationinCDand,therefore,haveaprotectiverole, ontheotherhand,itisknownthat,intheinitialprocessof carcinogenesis,thesecellssuppressanti-tumormechanisms, promotingneoplasticprogression.
Studiesinrodentsshowedthatinflammation,inaddition toitslocalroleatbowellevel,alsoactsatadistance,inducing thymicinvolutionandthereforeachange(i.e.,adecrease)in theproductionofTcells.Thissuppressionmeansthatthere willbelesscontrolofinflammation.43
Smokingcanalsobedetrimentaltotheprogressofthe dis-easebyalteringthegeneexpressionand bycontributingto inflammation.Thus,insmokerstheprogressionofthedisease tendstobemoresevere.12,38,46
RiskfactorsforcolorectalcarcinomainpatientswithCD
TheriskfactorsforCRCdevelopmentarefamilyhistoryofCRC, theextentoftheinjury,diseaseduration,primarysclerosing cholangitis (PSC), histologic characteristics,disease pheno-typeandageatthetimeofdiagnosis.12,23,30,47
Theriskcanbemitigatedbyanappropriatesurveillance andsurgicaltreatmentwhennecessary.12
Thegenderofthepatientisnotconsideredariskfactor, andthereisadisparitybetweentheresults.Therearestudies indicatingthatthedifferenceisnotsignificant.However,other authorsfoundresultsthatpointtoanincreasedincidencein men.6,13
canceris3.7timeshigherversuspatientswithnosuch fam-ilyhistory.11,14However,itisimportanttonotethathavinga familymemberwithDCdoesnotincreasetheriskofCRC.23 itisevidentthatfamilyhistoryisanindependentriskfactor, butisanindicationforsmallersurveillanceintervals.24
TheriskofCRCisnaturallyhigherinpatientswith exten-sivelesionsinthecolon.1,30,31 isalsoknown that,inmany cases,canceroccursalongfissuresandfistulas.30,31
Adiagnosisestablishedatanearlyageandthepresenceof activeinflammationalsorepresentriskfactors,asdiscussed above.Studieshaveconcludedthatifthediagnosisismade beforetheageof30years,therelativeriskshowsa consider-ableincrease.11,23,48
The association between CD and PSC has been known since1964.Thecoexistenceofthesediseases constitutes a summationwithrespecttoCRCrisk,withacontributionof inflammationinCD, andofthehighconcentrations ofbile acidsinthecolon,secondarytocholangitis.10PSCispresent in1–3%ofpatientswithCD,butthereisnocertaintyaboutthe actualriskofCRCinpatientswithbothpathologies.1
Phenotypicpresentationintheformofstenosiscanalso affecttheriskofdevelopingCRC.Studiesindicateanincreased riskwhenthediseaseisstenotic.13,30
Withthemedicaltherapyusedinthetreatment,thepatient canbekeptinremissionforlongperiodsoftime;thus,surgery isavoided.6,16,49TheroleofthiopurinesintheriskofCRCis controversial.Thepurposeofusingthesedrugsisthe reduc-tionofinflammation;therefore,itsuseshoulddecreasethe riskofCRC.However,oneoftheeffectsofimmunosuppressive drugsisagreaterneoplasticrisk.Infact,thiopurinesincrease the riskof somecancers, including skincancers and lym-phomas,butbecauseofitsanti-inflammatoryeffect,theuseof thisdrugseemstocontributetoadecreasedriskofcolorectal neoplasia.Inparallel,non-steroidalanti-inflammatorydrugs alsoappeartolowertherisk.6,16
CRC associatedwithCD developsmostly in young peo-pleanditappearstobeamorediffuse,extensive,multifocal and mucinous diseasewhen comparedwith sporadicCRC. This cancer usuallyappears on the right side, and this is relatedtotheknownhigherfrequencyofinflammationatthis location.12,18
Discussion
AnincreaseintheriskofCRCinpatientswithCDisafact, despitethe stillincomplete knowledgeof themechanisms involved.
Thevalueofthe relativerisk variesin differentstudies sincethisvariabledependsonseveralfactors.The heterogene-ityinthemethodologyobservedinseveralstudiescomplicates thecomparisonofresults.
AdecreaseintheriskofCRChasbeendescribed;itislikely thatthisisduetoimprovedsurveillancemethods,withthe possibilityofincreasingearlydiagnoses.
Themonitoringofthesepatientsisaimednotonlyto con-troltheinflammationoftheunderlyingdisease,butalsoto avoidCRC.Obtainingdirectedbiopsiesbychromoendoscopy isthemosteffectivemethod;thisenablesahigherpercentage
ofdysplasiadetection,consideringthatmostofthelesionsare notvisiblebyconventionalcolonoscopy.
Inmoststudies,theintervalfromdiagnosisofCDtothe diagnosisofCRCwasabout10years.However,twocasesof CRC,whosediagnosiswasestablishedoneyearaftertheonset ofsymptomswererelated.ThediagnosisofCRCmayoccur evenbeforethediagnosisofCD.12,45 Inthesesituations,the CRCappearstobeanindependenteventCD.
Theincreasedriskmayalsobeexplainedbythefactthat thegeneticchangesthatleadtotheemergenceofCDcanalso contributetotheonsetofCRC.12
Thepresenceofanaffectedcolon entailsincreasedrisk becausetheunderlyinginflammationmaycontributeto car-cinogenesis.
Regardingtheinterveningfactors,somearguethattheage ofdiagnosiscannotbeconsideredasatrueriskfactor.These authorsarguethattheriskisrelatedtothedurationofthe dis-ease.Earlydiagnosesallowonetoconcludethatforthesame age,suchpatientshavealongerdurationofthedisease.23
InthecaseofaCRCdiagnosisinapatientwithCD,itis importanttodistinguishwhetherthecarcinomaissporadic, whether it isassociated withthe inflammatorydisease,or whetherit isacaseofLynchsyndrome.Thisisparticularly relevant asit willinfluencethe treatmentoffered, consist-ing intotalcolectomyincaseswherethe diagnosisofCRC isassociatedwithCDorLynchsyndrome.Thedistinctioncan beperformedbasedonthepatient’sMIRprofile.Inpatients withLynchsyndrome,thereisanincreasedexpressionofMIRs 16–2and30-a,whileinthosesufferingfromCDthereisan increasedexpressionofMIRs191,23band16.32,37
MIRsplayanimportantroleinCDandCRC,butthereisa needforfurtherstudiessothatonecanbeabletoestablishthe actualdiagnosticandprognosticvalueofsuchsubstances.
Conclusion
InflammationisakeyelementintheassociationbetweenCD andCRC,anditscontroldecreasestheriskofcarcinogenesis. Thepro-inflammatorystateandmolecularchangesthatoccur partlyexplaintheneoplasticriskunderlyingtothis inflamma-torydisease.
RegardingCD,thereareriskfactors,inparticular,the dura-tionofdisease(analreadywell-studiedvariableforulcerative colitis, and now applied to CD) and the extent of colonic involvement.
Surveillance has becomeanincreasingly important fea-ture.Insomecases,theconventionalcolonoscopydoesnot establish a diagnosis, and the appearance of chromoen-doscopy increasedthe detectionofadysplasticmucosa.In thosecasesinwhichsuchachangeisdetected,the recom-mendationistoperformacompletecolectomy.
Immunosuppression, along with the pro-inflammatory state, may explain this association although non-steroidal anti-inflammatoryagentsappeartodelaytheonsetofcancer. Theroleofimmunosuppressioniscontroversialsincestudies havebeenpublishedwithdifferentconclusions.
decreasedincidencesandmorbidityandmortalityassociated withthisdisease.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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