jcoloproctol(rioj).2016;36(1):1–3
w w w . j c o l . o r g . b r
Journal
of
Coloproctology
Editorial
Confocal
laser
endomicroscopy
in
inflammatory
bowel
diseases:
future,
reality
or
dream?
Introduction
Confocal endomicroscopy(CLE) is a new endoscopic tech-niquethatallowstoobtainhigh-resolutionlayerliningofthe gastrointestinaltractimaging.Thistechniqueisbasedon illu-minationofthemucosawithalaser.Inthisprocess,thelaser isabsorbedbyafluorescentagentandthereflectedlightis captured.Thelaserisfocusedataselecteddepthinthe tis-sueofinterestandthereflectedlightisthenredirectedtoa detectionsystemforthesame lens,excludingthereflected lightfromotherpartsofthemucosa.1–3Thisincreases
signif-icantlythespatialresolutionoftheimagesobtained,and,if thecapturingisverymagnified,high-resolutionimagesare produced.Thistechniquecanbeappliedduringthe exami-nationofendoscopy,andcellularandsubcellularstructures, withextremedetail,asintheconventionalmicroscope.1–3
CurrentlypCLEsystemsisaprobe-basedsystem(Mauna KeaTechnologies,Paris,FranceCellvizio);theprobeisplaced throughthebiopsychannelofaconventionalendoscope.The depthofviewisupto250mmwiththeendoscopicsystemand about120mmwiththeprobe-basedsystem.Alimitedareacan beexamined;nomorethan700mmintheendoscopic-based systemandlesswiththe probe-basedsystem.CLEsystems areoptimizedusingacontrastagent.Themostwidelyused agentisintravenousfluorescein,whichisFDA-approvedfor ophthalmologicimagingofbloodvesselswhenusedwitha laserscanningophthalmoscope.1–4
The use of confocal laser endomicroscopy (CLE), also known as confocal fluorescent endomicroscopy and opti-calendomicroscopy, allowsinvivo microscopic imagingof cellsduringendoscopy.CLEisproposedforavarietyof pur-poses,especiallyasareal-timealternativetohistologyduring colonoscopy and for targeting areas to undergo biopsy in patientswithinflammatoryboweldisease(IBD), differentia-tionbetweenneoplasticandbenignpolyps.2,3
Oneoftheconcernsofalltheprofessionalswhofollowup thepatientswithlongstandingIBDistheemergenceofcancer
inthis specificgroup.Itisestimatedthat thepossibilityof onset ofcolorectal canceris2–5 timeshigherinthisgroup thaninthegeneralpopulationofthesameage.4
TheCLEtechniqueofferssomedisadvantagesthatmustbe considered.Amongthen,wecanenumerate:
(1) Thelearningcurveisrelativelylonganddependsonthe trainingofthespecialisttoobtaingoodperformanceand interpretationofCLE5–8;
(2) Thehighcostofprobetobeused.Therecommendation istochangetheprobeafter20exams.Alsothecostofthe equipmenttoreadtheimages5,6;
(3) Theoperatordependencywithregardthedifficultin main-taining the stability of the probe, for interpretation of morphologicfeatures,andlimiteddepthofpenetrationof thetool.9
(4) Theimpossibilityofexaminingtheentiresurfaceofthe colon using only the endomicroscopic mode. A com-bination of endomicroscopy with chromoendoscopy in patients withulcerativecolitisisnecessary. Chromoen-doscopyunmaskscircumscriptlesionsandconfocallaser endomicroscopycanbeusedtopredictintraepithelial neo-plasiaswithhighaccuracy.1–3
Wealsoenumeratesomeadvantagesandindications:
(1) pCLEwithfluoresceinsodiumallowedustoanalyzethe cellularstructure,connectivetissue,andbloodcellsofthe colonicmucosainvivo.1–3,5
(2) pCLEcouldpromoteinvivovirtualhistologyandmay lead-ingtoanoptimizedrapiddiagnosisofcoloniclesionsthat hasimportantimplicationsforclinicaltherapy(e.g., endo-scopicresectionofneoplastictissue).6–8
2
jcoloproctol(rioj).2016;36(1):1–3(4) pCLEpromotesthepossibilityofdiagnosticinvivo.This helpssignificantlyonreductionofthenumberofbiopsies tobeperformed,restrictingtotargetbiopsyandsolimiting theadversereactionsthatcouldoccurduringmultiple ran-domizedbiopsies.1,5
(5) pCLEenablestodistinguish,withhighaccuracy,the differ-entiationbetweenhyperplasticpolypsfromadenomatous polypsandgivessupportforimmediateresectionof suspi-ciouslesions.Thedifferentiationisusuallydifficultwhen weuseonlythemacroscopiccriteria.5,6
Discussion
CurrentlypCLEhasemergedasanewtoolofendoscopic imag-ingmodalityenablingreal-timeinvivohistologyofthecellular mucosal layer at a magnification of 1000-fold.It is neces-saryapplicationofanexogenousfluorescenceagent.These agentscaneitherbeappliedsystemically(fluorescein)or top-ically(acriflavinehydrochloride,cresylviolet)totheintestinal mucosa.Theuseoffluorescenceagentsenablesimagingof mucosalstructuresandemphasizestheimagingoffeatures suchasthecapillary,architectural,andcellularpatterns.
Inflammatoryboweldiseaseisanexcellentexampleofthe applicationofpCLEinclinicalpractice.
Patients with longstanding UC are at increased risk to developmentneoplasia,butit isdifficulttodetect bywhite lightendoscopyandrandombiopsiesisnecessarytoidentified abnormalitiesinthemucosa.Ontheotherhand, panendomi-croscopyoftheentirecolonisnotpossible.Anoptionhasbeen combined pCLE with chromoendoscopy for optimized and increasesthefindingsandcareofpatientsundersurveillance forlongstandingulcerativecolitis.Inthissetting, chromoen-doscopyisusedtoincreaseapossibilitytodiscoversuspicious regionsandpCLEisusedfortheirimmediatecharacterization. Animportantfindingwasapossibilitytopredictofnormal mucosawithanaccuracyofover99%inopticalbiopsies(with conventionalhistopathologyasthegoldstandard).
Althoughuntilnowthere isnotaclosecorrespondence betweentheconventional endoscopicimagesand histolog-icalassessment, this association oftoolsremains the best waytodiagnoseaccuratelyandthentreatasearlyas possi-blemanydiseases,especiallyofthecolorectaltract,including chronicinflammatory,preneoplastic,andneoplasticdiseases. Basedon the finding that conventional colonoscopyis not always able to differentiate between neoplastic and non-neoplasticlesions,inrecentyears,severalstudieshighlighted thepotentialuseofCLE,asanewemergingtechnique,inthe screeningofpatientsforearlycolorectalcancerdetectionand prevention.5,6,9
Aprospectivestudy wasconductedinvolved42patients wereundergoingacolonoscopyandconfocallaserendoscopy. Acriflavine hydrochloride and fluorescein sodium were usedbothyieldedhigh-quality images.Whereasacriflavine hydrochloridebe stronglylabeled tothe superficial epithe-lialcells,fluoresceinsodiumoffersdeeperimagingintothe lamina propria. Subsurface analysis during confocal laser endoscopy alloweddetailed analysis of cellularstructures. Thepresenceofneoplasticchangescouldbepredictedwith
highaccuracy(sensitivity,97.4%;specificity,99.4%;accuracy, 99.2%).1
Multicenterstudywasperformedforassessingfluorescein assistedpCLE.Nomajoradverseeventsoccurredin2272 pro-cedures,andmildadverseeventswererecordedin1.4%ofthe procedures,including nausea, vomiting,transient hypoten-sion,injectionsiteerythema,rash,andepigastricpain.3
There are some alternatives ofuse which are primarily intendedtoimprovethesensitivityofcolonoscopy,asa chro-moendoscopy. However, CLE is unique in sense that it is designedtoimmediatelycharacterizethecellularstructureof lesions.4CLEcanthuspotentiallybeusedtomakeadiagnostic
ofpolyphistology,particularlyinassociationwithscreeningor surveillancecolonoscopy,whichcouldallowtoleaveinplace thesmallhyperplasticlesionsratherthanremovethemand sendforhistologicevaluation.Thiscouldreducerisks asso-ciatedwith biopsyand reducethe number ofbiopsies and histologicevaluationsandcertainlywillimprovethe detec-tionofdysplasia.Thisisanalternativetoconductingrandom biopsiesduringsurveillance.4,5,9
Recently,theuseofCLEwasreportedinthestudyofcolonic mucosainpatientswithinflammatoryboweldiseasesandin particularinpatientsaffected byulcerativecolitis.CLEhas animportantroleinstagingthepatientswithinflammatory boweldiseases.Itcanbeusedtoassessthegradingof coli-tisandtodetectmicroscopiccolitisinendoscopicallysilent segments. Moreover, CLE can be used in surveillance pro-gramsespeciallyinhighriskpatients.Finally,CLEhasbeen effectivelyusedindiagnosingabiliarydysplasia/neoplasiain patients withprimary sclerosingcholangitis,apathological condition frequentlyassociatedwithIBD,withacoexisting bileductstricture.5,6,9
Just like any other advanced and new endoscopy, CLE techniquerequirestrainingsandhandlingoftheendoscopy andtimetolearnandinterpretwithconfidencetheimages generated.6
The American Society of Gastrointestinal Endoscopy (ASGE) recommends that the endoscopies exams achieve ≥90% negative predictive value (NPV) and concordance of
≥90%sayingthattheNPVhastoexceed90%andthe
predic-tionofthesurveillanceintervalshouldbecorrectinmorethan 90%ofthecases.Thesedatashouldalwaysbeachieved.5
CLEshouldbeusedtoenhancethediagnosticarsenalin theevaluationoftheseindications,byprovidingmicroscopic informationwhichimproves thediagnostic performanceof thephysician.Inordertoactuallyimplementthistechnology intheclinicalroutine,andtoensuregoodpractice,the ini-tialstandardizationandthecontinuinginstitutionaltraining programsshouldbeestablished.5–9
Morestudiesgiveaverypromisingglanceatpossiblefuture applications,howeverisneedalargerprospective, multicen-ter trials toprovethe advantageofthis techniqueindaily practice.10,11
Conclusion
jcoloproctol(rioj).2016;36(1):1–3
3
histologyofthemucosallayerinrealtimeongoingendoscopy. Theimagesobtainedthroughthisnewtechnologyrepresent thebeginningofanewera,thatwillpermitdetailed visual-izationofthelivingcellsandthecellularstructuresthatare belowofthesurfaceofthegut.1,2,5,6,8,11,12
Wewillneedmoretimetoimplementandmake invest-mentsinthisultimateendoscopicimagingtoolhowever,this isnotadreamorfutureisnowareality.
Funding
ManoelÁlvarodeF. LinsNetoissupportedbytheNational CouncilforScientificandTechnologicalDevelopment(CNPq), Brazil.ElianaSilvadeAlmeidaissupportedbytheNational CouncilforScientificandTechnologicalDevelopment(CNPq), Brazil.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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1. KiesslichR,BurgJ,ViethM,GnaendigerJ,EndersM,Delaney P,etal.Confocallaserendoscopyfordiagnosing
intraepithelialneoplasiasandcolorectalcancerinvivo. Gastroenterology.2004;127:706–13.
2. GoetzM,KiesslichR.Advancesofendomicroscopyfor gastrointestinalphysiologyanddiseases.AmJPhysiol GastrointestLiverPhysiol.2010;298:G797–806.
3. WallaceMB,MeiningA,CantoMI,FockensP,MiehlkeS, RoeschT,etal.Thesafetyofintravenousfluoresceinfor confocallaserendomicroscopyinthegastrointestinaltract. AlimentPharmacolTher.2010;31:548–52.
4. IacucciM,UraokaT,FortGasiaM,YahagiN.Noveldiagnostic andtherapeutictechniquesforsurveillanceofdysplasiain patientswithinflammatoryboweldisease.CanJ
GastroenterolHepatol.2014;28:361–70.
5.McGillKS,SoetiknoR,RastogiA,RouseRS,SatoT,BansalA, etal.Endoscopistscansustainhighperformanceforthe opticaldiagnosisofcolorectalpolypsfollowingstandardized andcontinuedtraining.Endoscopy.2015;47:200–6.
6.MascoloM,StaibanoS,IlardiG,SianoM,VecchioneML, EspositoD,etal.Probe-basedconfocallaserendomicroscopy evaluationofcolonpreneoplasticlesions,withparticular attentiontotheaberrantcryptfoci,andcomparative assessmentwithhistologicalfeaturesobtainedby conventionalendoscopygastroenterology.ResPract. 2012;2012:1–6.
7.KiesslichR.Opticaldiagnosisofcolorectalpolyps:canthisbe learnedbyeveryone?Endoscopy.2015;47:188–9.
8.GoetzM.Confocallaserendomicroscopy:applicationsin clinicalandtranslationalscience—acomprehensivereview. IntSchResNetwISRNPathol.2012;2012:387145.
9.WangKK,Carr-LockeLK,SinghSK,NeumannH,BertaniH, GalmicheJP,etal.Useofprobe-basedconfocallaser endomicroscopy(pCLE)ingastrointestinalapplications.A consensusreportbasedonclinicalevidence.UnitedEur GastroenterolJ.2015;3:230–54.
10.SalvatoriF,SicilianoS,MaioneF,EspositoD,MasoneS, PersicoM,etal.Confocallaserendomicroscopyinthestudy ofcolonicmucosainIBDpatients:areview.GastroenterolRes Pract.2012;2012:525098.
11.BisschopsR.Confocallaserendomicroscopy:finallyreadyto changeclinicalpractice?GastrointestEndosc.2011;74:781–3. 12.LiWB,ZuoXL,LiCQ,ZuoF,GuXM,YuT,etal.Diagnostic
valueofconfocallaserendomicroscopyforgastricsuperficial cancerouslesions.Gut.2011;60:299–306.
ManoelAlvaroLinsNetoa,b,∗,ElianaSilvadeAlmeidaa
aUniversidadeFederaldeAlagoas(UFAL),Maceió,AL,Brazil
bServiceofColoproctology,HospitalUniversitárioProf.Alberto
Antunes,UniversidadeFederaldeAlagoas(UFAL),Maceió, AL,Brazil
∗Correspondingauthor.
E-mail:mlinsneto@gmail.com(M.A.L.Neto).
