Crohn's disease: risk factor for colorectal cancer

(1)

Pleasecitethisarticle in pressas: SantosSC,BarbosaLE.Crohn’s disease:risk factorforcolorectalcancer. J Coloproctol(RioJ). 2016. 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,b

a_Universidade_do_Porto,_Faculdade_de_Medicina,_Porto,_Portugal b_Hospital_de_São_João,_Servic¸o_de_Cirurgia_Geral,_Porto,_Portugal

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received19June2016 Accepted29June2016 Availableonlinexxx 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.

Coloproctologia.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: Doençadecrohn Carcinomacolorretal Inflamação Fatoresderisco

r

e

s

u

m

o

Introdução: AdoençadeCrohnéumadoençainflamatóriaquepodeatingirtodootrato

gastrointestinal. Esta patologia temsido associada a um risco neoplásico aumentado,

nomeadamentedecarcinomacolorretal.

Objetivo:Oobjetivodestetrabalhoédescreverosmecanismosresponsáveispeloaumento

doriscodecarcinomacolorretalnadoenc¸adeCrohn.

∗ _{Corresponding}_author.

E-mail:[email protected](S.C.Santos).

http://dx.doi.org/10.1016/j.jcol.2016.06.005

(2)

Pleasecitethisarticle in pressas: SantosSC,BarbosaLE. Crohn’sdisease:risk factorforcolorectalcancer. J Coloproctol(RioJ). 2016.

Métodos: ApesquisabibliográﬁcafoirealizadanabasededadosPubmed.Paraalémdos

artigosobtidoscomaqueryinseridanaPubmed,foramtambémincluídasoutrasreferências

comrelevânciaparaotemaemquestão.

Resultados: Oriscodecarcinomacolorretalaumentanapresenc¸adedeterminadosfatores,

entreselesadoençadeCrohn.Ainflamaçãocrónicapresentepareceserumimportante

contributoparaacarcinogénese,porquepermiteacriac¸ãodeummicroambienteadequado

aoaparecimentoeprogressãodadoenc¸a.Existemalterac¸õesmolecularescomunsàsduas

patologiasjustificando-seofatodestadoençainflamatóriaserfatorderiscoparao

carci-nomacolorretal.Ocontrolodadoenc¸acomterapêuticaadequadaeestratégiasdevigilâncias

sãoduasformasdecontrolarorisco.

Conclusões: Oestadopró-inflamatórioéumapeçachavenaassociaçãoentredoençade

Crohnecarcinomacolorretal.Aimplementac¸ãode estratégiasde vigilânciapermitiua

diminuic¸ãodamorbi-mortalidadeassociadaaestaneoplasia.

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

In CD, the inﬂammationoccurs transmurally. Themost

commonly affected locations are the terminal ileum and

(3)

Pleasecitethisarticle in pressas: SantosSC,BarbosaLE.Crohn’s disease:risk factorforcolorectalcancer. J Coloproctol(RioJ). 2016.

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 _Perianal_lesions,

i.e.,ulcers,ﬁssuresorﬁstulas,are complicationspresent in

20%ofpatientsatdiagnosis.5_Despite_the_medical

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 _studies_report_that

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.6_Thus,_surveillance_programs_are_of

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.22_The_{recommendations}_of_the_British_Society

ofGastroenterology(BSG)aretowardanonsetofmonitoring

about10yearsafterdiagnosis.6,10,21

However,inastudyconductedinatertiaryhospital,two

casesofCRCwithaone-yearintervalafterthediagnosisofCD

wererelated;theremainingcaseswerereportedatintervals

from11to14years.12_The_prognosis_of_both_types_of_CRC_may

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.27_Some_studies_have_raised_doubts_about_the_efﬁcacy

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

adopted by AGA to deﬁne which patients should undergo

(4)

AccordingtoAGA,biopsiesatevery10cm(min:33)shall

beobtained.21,24,29_Undeﬁned_results_are _an_indication_for_a

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 _This_diagnostic _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.22,29_On_the_other_hand,_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 _helps_to _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.39_Thus,_TNF-_␣_contributes_to_{inﬂammation}_in

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.

Severalstudieshaveconcludedthatmicro-RNAs(MIR)are

involved in the pathophysiology ofCD and CRC, and may

beakeylinkintherelationofthesetwodiseases.MIRmay

constituteearlybiomarkersofcoloncancerandmayalsobe

importantinthedetectionandpreventionofbreastcancer.

TwotypesofMIRweredescribed:thosepromotingtumor

sur-vivalandgrowth(onco-micro-RNA)andthosewhichsuppress

neoplastic progression (micro-RNA tumor suppressor).The

secondtypeofMIR,abovementioned,isthatthatismostoften

relatedtotumorigenesis,andthemechanismunderlyingthis

situationistheretardationofitsactivity.MIRderegulationthat

exacerbatesexistinginﬂammationinCDmayincreasetherisk

ofCRCinpatientswhoalreadyexhibitasomaticmutation.

Fromtheabove,onecanconcludeagainthattherelationship

betweenthese disordersincludestheinteraction ofseveral

factors.OneofthemechanismsbywhichMIRexacerbatethe

(5)

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.7,14_The_gene_for_autophagy,_ATG16L1,_can

bechanged.38_During_{tumorigenesis,}_autophagy_is_negatively

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.23,27_the_result_of_these_changes_may

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.23_The_induction_of_COX-2_has_another

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 _Regulatory_T_cells_are_a_major_intervening

factorintheinﬂammatoryprocess.Aninappropriateresponse

tothemicroﬂoraplaysanimportantroleinthepathogenesis

ofCD.Inthisinﬂammatorydisease,thereisachangeinthe

balance betweenregulatoryTcells intheblood and inthe

inﬂamedsiteintheboweland,inaddition,thereisanexcess

ofpro-inﬂammatorystimuli.18,27_However,_if_on_one_hand_it_is

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

AfamilyhistoryofCRCisanimportantfactorthatdoubles

therisk.24AstudyconcludedthattheriskofCRCinpatients

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canceris3.7timeshigherversuspatientswithnosuch

fam-ilyhistory.11,14_However,_it_is_important_to_note_that_having_a

familymemberwithDCdoesnotincreasetheriskofCRC.23

itisevidentthatfamilyhistoryisanindependentriskfactor,

butisanindicationforsmallersurveillanceintervals.24

TheriskofCRCisnaturallyhigherinpatientswith

exten-sivelesionsinthecolon.1,30,31 _is_also_known _that,_in_many

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.10_PSC_is_present

in1–3%ofpatientswithCD,butthereisnocertaintyaboutthe

actualriskofCRCinpatientswithbothpathologies.1

Phenotypicpresentationintheformofstenosiscanalso

affecttheriskofdevelopingCRC.Studiesindicateanincreased

riskwhenthediseaseisstenotic.13,30

Withthemedicaltherapyusedinthetreatment,thepatient

canbekeptinremissionforlongperiodsoftime;thus,surgery

isavoided.6,16,49_The_role_of_thiopurines_in_the_risk_of_CRC_is

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 _In_these_situations,_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.

The use ofappropriatesurveillance protocols allowsan

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decreasedincidencesandmorbidityandmortalityassociated

withthisdisease.

Conﬂicts

of

interest

Theauthorsdeclarenoconﬂictsofinterest.

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