J. Coloproctol. (Rio J.) vol.35 número2

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w w w . j c o l . o r g . b r

Journal

of

Coloproctology

Original

Article

Preoperative

staging

of

rectal

cancer

with

MRI:

correlation

with

pathologic

staging

Soraia

Filipa

Macado

Abreu

a,b

,

Sandra

Fátima

Fernandes

Martins

a,b,c,∗ a_Life_and_Health_Sciences_Research_Institute_(ICVS),_School_of_Health_Sciences,_University_of_Minho,_Braga,_Portugal

b_ICVS/3B’s,_PT_Government_Associate_Laboratory,_{Braga/Guimarães,}_Portugal

c_Surgery_Department,_Hospitalar_Center_of_{Trás-os-Montes}_e_Alto_Douro,_Distrito_de_Vila_Real,_Portugal

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Articlehistory:

Received20December2014 Accepted20February2015 Availableonline20April2015

Keywords: Rectalcancer

Pelvicmagneticresonance Accuracy

Sensibility Specificity

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Introduction:Anaccuratepreoperativerectalcancerstagingiscrucialtothecorrect man-agement of the disease. Despitegreat controversy around this issue, pelvic magnetic resonance(RM)issaidtobetheimagiologicstandardmodality.Thisworkaimedto evalu-atemagneticresonanceaccuracyinpreoperativerectalcancerstagingcomparingwiththe anatomopathologicalresults.

Methods:Wecalculatedsensibility,specificity,positive(VPpositive)andnegative(VP neg-ative) predictivevalues foreachTandN.We evaluatedtheconcordancebetweenboth methodsofstagingusingtheCohenweightedK(Kw),andthroughROCcurves,weevaluated

magneticresonanceaccuracyinrectalcancerstaging.

Results:41patientsmettheinclusioncriteria.Weachievedanefficacyof43.9%forTand61% forNstaging.Therespectivesensibility,specificity,positiveandnegativepredictivevalues are33.3%,94.7%,33.3%and94.7%forT1;62.5%,32%,37.0%and57.1%forT2;31.8%,79%, 63.6%and50%forT3and27.8%,87%,62.5%and60.6%forN.Weobtainedapoorconcordance forTandNstagingandtheanatomopathologicalresults.TheROCcurvesindicatedthat magneticresonanceisineffectiveinrectalcancerstaging.

Conclusion: Magneticresonancehasamoderateefficacyinrectalcancerstagingandthe majordifficultyisindifferentiatingT2andT3.

Estadiamento

pré-operatório

do

câncer

do

reto

por

ressonância

magnética:

correlac¸ão

com

estadiamento

anatomopatológico

Palavras-chave: Câncerdoreto

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Introduc¸ão: Umestadiamentopré-operatóriodoCâncerdoReto(CR)éessencialnagestãoda doenc¸a.Apesardegrandecontrovérsia,aressonânciamagnéticapélvica(RM)éapontada

∗ _{Corresponding}_author.

E-mail:[email protected](S.F.F.Martins). http://dx.doi.org/10.1016/j.jcol.2015.02.005

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Ressonânciamagnéticapélvica Acuidade

Sensibilidade Especificidade

comomodalidadeimagiológicastandard.Comestetrabalhopretendeu-seavaliaraacuidade daRMnoestadiamentodoCR,comparandocomosresultadosanatomopatológicosdapec¸a cirúrgica.

Materiaisemétodos: Calculou-seasensibilidade,especificidade,valorpreditivopositivo(VP positivo)enegativo(VPnegativo)paraTeN.Avaliou-seaconcordânciaentreambasas formasdeestadiamentoatravésdovalordeKdeCohenponderado(Kw)e,atravésdecurvas ROC,avaliou-seaprecisãodoestadiamentoporRM.

Resultados: 41doentescumpriramoscritériosdeinclusão.Obteve-seumaeficáciade43.9% paraTe61%paraN.Verificou-seumasensibilidade,especificidade,VPpositivoenegativo, respectivamente,de33.3%,94.7%,33.3%e94.7%paraT1,62.5%,32%,37.0%e57.1%paraT2, 31.8%,79%,63.6%e50%paraT3,27.8%,87%,62.5%e60.6%paraN.Aconcordânciacalculada foipobreparaTeN.AscurvasROCindicaramqueoestadiamentodoCRporRMfoiineficaz. Conclusão: ARMapresentaacuidademoderadanoestadiamentodoCR,ondeamaior difi-culdadeestánadistinc¸ãoentreT2-T3.

Introduction

The incidence and mortality of oncological diseases have increased at an alarming rate worldwide, and according toWorld Health Organization, the incidenceofcancer will increaseto22million/yearinthenexttwodecades.1

In Portugal, colorectal cancer (CRC) is the second most frequentcancerinbothmenandwomen,withanoverall inci-denceof14.5%and15.7%mortality.In2012,thisdiseasewas appointedasthesecondleadingcauseofcancerdeathinboth genders.2_Rectal_cancer_(RC),_in_particular,_exhibited_in north-ernregionofthiscountryin2008anincidenceof24.6/1,00,000 inhabitants;aprogressiveincreaseinthisvaluesince1999was found.InthedistrictofBraga,itsincidenceinthisyearwas 16.8/1,00,000inhabitants.3

RCprognosishasimprovedgreatlyinrecentdecadesand this was mainly due to advances in preoperative staging, whichwas reflectedinthe therapeuticapproach,4 _where_a changewasobserved,fromapurelysurgicaltreatmenttoa multidisciplinaryapproach,5,6_lowering_the_lower_local recur-rencerateto11%andimprovingthesurvivalrateat5yearsto 58%,7_compared_to_previous_values₍₂₇_and_48%,_{respectively).}5 PreoperativestagingofRCisdividedintolocalandremote staging.8–10 _The_information_(both_clinical_and_{pathological)} gatheredfrom thestagingisgroupedaccording to “Tumor-Node-Metastasis”(TNM)classificationoftheAmericanJoint Committee on Cancer in different prognostic groups or anatomicalstages.11,12 _T_and_N_stages_are_the_best determi-nantsofprognosis,beingcriticalcomponentsofpreoperative staging.13_Thus,_in_addition_to_the_use_of_a_reliable_imaging modalityand withhigh accuracyinpreoperativestagingof CRbeacrucialprognosisfactor,14 _this_procedure_also_helps in choosing the best therapeutic strategy, enabling a bal-ance between oncologicalsafety and quality of life ofthe patient.10,12

Nowadays,thereareseveralimagingmodalitiesfor preop-erativestagingofRC,includingcomputedtomography(CT), pelvicmagneticresonance imaging(MRI),endorectal ultra-sound(EUS),andpositronemissiontomography(PET).10

EUS and MRI are the main instruments ofpreoperative staging.15 _However, _there _is _no _consensus _about _the _best method.5,16_Several_studies_suggest_MRI_as_being_superior_to EUS,9,17–20_and_therefore_MRI_is_the_routine_imaging_modality forpreoperativestagingofRC.5,21_As_to_T_staging,_MRI_shows anacuitybetween55and86%;astoNstaging,theaccuracy variesfrom39to95%.5

InRCstaging,themainroleofMRIliesintheevaluation oftumorsinadvancedandocclusivestages.15,22_With_respect tostagesT3andT4,sensitivityandspecificityof74and76% (forT3)and82and96%(forT4)wereobserved,respectively.22 ForT1andT2stages,MRIislesssensitiveversusEUS,withno differencerelativetoT3andT4stages.16

Detection of N isthe biggest challenge of any imaging examination,with66%sensitivityofMRIinitsevaluationand 76%specificity.5

ThisstudyaimstoevaluatetheaccuracyofMRinthe pre-operativestagingofRC,comparedtotheanatomopathological resultofthesurgicalspecimen.

Materials

and

methods

Population

Thetargetpopulationforthisstudyconsistsof216patients withhistologicaldiagnosisofRCtreatedintheGeneralSurgery Service,HospitaldeBraga(HB)betweenJanuary1st,2007and December31,2013.

Inclusion criteria forthis study were:patientswith his-tological diagnosis ofrectaladenocarcinoma; patientswith a conclusive preoperative staging by MRI, and patients withpathology stagingresultsbasedonthe surgical speci-men.

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Table1–MRandanatomopathologicalstagingrelatedto TandN.

RMstaging Anatomopathologicalstaging Frequency(%) Frequency(%)

T0 0(0) 0(0)

T1 3(7.2) 3(7.2) T2 27(65.9) 16(39.0) T3 11(26.8) 22(53.7)

T4 0(0) 0(0)

N0 36(87.8) 23(56.1) N+ 5(12.2) 18(43.9)

Sample

A convenience sample of 41 patients who meet inclu-sion/exclusioncriteriapreviouslydefinedwasstudied.

Datacollection

Clinicalandstagingdatacollectedinclude:age,gender, onco-logicalhistory,tumorlocation,andT/Nstagingbymeansof MRI.

PathologicaldatacomprisethehistologicaltypeandTNM staging.

Follow-updataarerelatedtotheoccurrenceofrelapseand death.

ThisprojectwasapprovedbyHB’sEthicsCommitteeand alsobyEthicsSubcommitteeforLifeandHealthSciences.

Statisticalanalysis

Thecollected datawere organized inan Excel(Microsoft®

Office2010)database, andthe StatisticalPackageforSocial Sciences(SPSS)version22.0(SPSSInc.,Chicago,IL,USA)was alsoused.

A descriptive analysis of the variables under study, to providefrequencies,meansandstandarddeviations,was per-formed.

Sensitivity,specificity,positiveandnegativepredictive val-ues(PV)ofRMstaging,relatedtoTandN,werecomparedwith pathologyresults.Forthispurpose,theonlinetoolMedCalc®

availableinhttp://www.medcalc.org/calc/diagnostictest.php, was used. Efficacy was calculated by the formula (TP+TN/n)and theconfidenceinterval (CI)bytheformula: P−Z×√P(1−P)/√n;P+Z×√P(1−P)/√N.

The agreement between the staging results obtained by MRI and anatomopathological study was assessed by calculating the value of weighted Cohen’s Kappa (Kw); to this end, we used the online toolVassarStats, available in http://vassarstats.net/kappa.html.AvalueofKwbetween0.00 and 0.20 indicates poor agreement; between0.21 and 0.40 reveals a considerable agreement; between 0.41 and 0.60, pointstoamoderateagreement;between0.61and0.80 indi-catesa good agreement;and between0.81 and 1.00shows excellentagreement.23

Finally,usingSPSSprogram,weusedROCcurvesfora com-parativestudy ofMRIandanatomopathological staging,by meansofareaunderthecurve(AUC)calculation.ROCcurve withAUCassessmentisagoodpredictoroftheaccuracyof

Table2–ComparisonbetweenRMand anatomopathologicalstaging,relatedtoT.

RMstaging

T1(%) T2(%) T3(%) Total(%)

Anatomopathologicalstaging

T1 1(2.44) 2(4.88) 0(0) 3(7.32) T2 2(4.88) 10(24.4) 4(9.76) 16(39.0) T3 0(0) 15(36.6) 7(17.1) 22(53.7) Total 3(7.32) 27(65.9) 11(26.8) 41(100)

atest.TheclosertheAUCisto1,thebettertheexamination is.Values≤0.50representapoororineffectivetest;between ≥0.70and<0.80indicateantestwithaverageorreasonable

accuracy;andvalues≥0.80predictagoodorexcellenttest.24 Forall tests,it wasassumedasignificanceof0.05anda confidenceinterval(CI)of95%.

Results

Samplecharacterization

Thestudypopulationconsistsof41subjectswhomeet inclu-sionandexclusioncriteria.Ofthese,58.5%(n=24)aremale, agedbetween31and88years.

In12.2%(n=5)ofpatients,thereisapersonalhistoryof anothercancer.

As for tumor localization,14.6% (n=6) ofthe casesare locatedinthelowerthird,68.3%(n=28)inthemiddlethirdand 17.1%(n=7)intheupperthirdoftherectum.Disease recur-rencewasobservedin22%(n=9)patients.UntilAugust2014 therewere10deathsinthestudypopulation.

Tstaging

RegardingMRtumorstaging,7.32%(n=3)ofthetumorsare classifiedasT1,65.9%(n=27)arestagedasT2and26.8%(n=11) asT3.Withregardtoanatomopathologicalstagingofsurgical specimens,7.32%(n=3)neoplasmsareclassifiedasT1,39% (n=16)arestagedasT2and53.7%(n=22)asT3(Table1).

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Table3–KwvaluesrelatedtoTandNstaging.

Kw(95%CI) p

T 0.14(0–0.38) >0.05 N 0.16(0–0.42) >0.05

ThevalueofKwforTstagingwascalculated,inorderto

determinethecorrelationbetweenMRversus anatomopatho-logical staging. There is poor agreement between the two formsofstaging:Kw=0.14(95%CI,0–0.38)p>0.05(Table3).

Theevaluation of MRI stagingaccuracy, by formulating ROCcurvesandAUCdetermination,revealsanAUCvalueof 0.26(95%CI,0.00–0.54),p=0.18forT1,0.46(95%CI0.28–0.64), p=0.63forT2and0.61(95%CI,0.43–0.78),p=0.24forT3(Fig.1).

EstadiamentoN

WithrespecttoNstagingdonebyMRandshowninTable1, 87.8% (n=36)of all tumorsare classified as N0, and 12.2% (n=5)asN+. Astoanatomopathologicalstagingofsurgical specimens,56.1% (n=23) ofthe tumorsdonothave lymph nodeinvolvement;in26.8%(n=11)thereisaN1staging,and 9.76%(n=4),receivedaN2staging.In7.32%(n=3)oftumors isnotpossibletoclassifyN,sincetheminimumof12lymph nodes were not obtained for the analysis. However, since

Table4–ComparisonbetweenRMand anatomopathologicalstaging,relatedtoN.

RMstaging

N0(%) N+(%) Total(%)

Anatomopathologicalstaging

N0 20(48.7) 13(31.7) 33(80.5) N+ 3(7.31) 5(12.2) 8(19.5) Total 23(56.1) 18(43.9) 41(100)

theanalyzedgangliaweremetastasized,forthesakeofthe statisticalanalysisthesegangliaareconsideredasbeingN+. Thus, the anatomopathologicalanalysis, shownin Table3, revealsnodalinvolvementin43.9%(n=18)ofcases,andno suchinvolvementintheremaining56.1%(n=23).

ComparingthestagingrelativetoNobtainedbyRMandby anatomopathologicalanalysis,asubstagingisnotedin31.7% (n=13)ofcases,andanoverstagingin7.32%(n=3).Table4 comparesbothformsofstaging.

Mstaging

AsforMstaging,90.2%(n=37)ofpatientsarestagedasM0and 4.88%(n=2)asM1;in4.88%(n=2)ofcasesitisnotpossibleto determinetheexistenceofdistantmetastases.

1.0

1.0 0.8

0.8 0.6

0.6 0.4

0.4 1 - specificity ROC curve for T1

Sensitivity

0.2

0.2 0.0

0.0

1.0

1.0 0.8

0.8 0.6

0.6 0.4

Sensitivity

0.2

0.2 0.0

0.0

1.0

1.0 0.8

0.8 0.6

0.6 0.4

AUC – 0.26 AUC – 0.45

AUC – 0.61 AUC – 0.55

Sensitivity

0.2

0.2 0.0

0.0

1.0

1.0 0.8

0.8 0.6

0.6 0.4

0.4 1 - specificity ROC curve for N

Sensitivity

0.2

0.2 0.0

0.0

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Discussion

AprecisepreoperativestagingofCRiscriticalfortheproper managementofthisdisease,sincethetherapeuticstrategies shouldbeindividualized.10,12,25_Moreover,_this_staging_is_also apredictorofprognosis.12,26

Therefore,theimagingtechniquesusedintumorstaging provedtobedecisive,anditisextremelyimportantto ascer-taintheireffectiveness.26_EUS_and_MR_are_the_main_tools_of preoperativestaging,butthereisnoconsensusonwhichis thebestmethod5,16_;_however,_several_studies_indicate_MR_to besuperiorto EUS;therefore, MRIisthe standard imaging modalityforpreoperativestagingofRCs.9,18–20

Thisstudy wasdesignedwiththeaimtodeterminethe accuracyofMRinthepreoperativestagingprocessforRC.

With regard to T staging, when comparing the staging performed byMR withthe anatomopathological staging, a substagingoccurredin4.88%(n=2)ofcasesstagedbyRMas beingT1;therewasoverstagingin4.88%(n=2)ofpatientsand substagingin36.6%(n=15)ofthosetumorsstagedbyMRIas T2andanoverstagingin9.76%(n=4)patientsstagedasT3. Giventhat, ingeneral,superficialtumors(T1andT2) with-outmetastaticlymphnodesaretreatedsolelywithsurgery, whilelocallyadvanced tumorsor thosewith nodal metas-tases are subjected to primary treatment priorto surgical recession,14 _an_{undertreatment}_occurred _in_36.6%_(n₌₁₅₎_of patients,consideringthatthesesubjectswerestagedasT2, andtheiranatomopathologicalresultsshowedthatactually thesewereT3,andthusdidnotperformprimarytherapy.

ThelargestnumberofcasesofincorrectstagingbyMRIwas observedinthedistinction betweenstagesT2andT3.This mayinpartbeexplainedbythepresenceofadesmoplastic reactioninperitumoraltissues,makingitdifficultto distin-guishbetweenspiculationofperirectalfat,causedsimplyby fibrosis,andthatthatcontainsviabletumorcells.13,16,27

Asforthe4patientswhowere overstagedbyRMasT3, whenactuallythesewereT2tumors,thesecouldhavebeen overtreated.However,thatdidnothappenforreasons unre-latedtothisstudy.

WithrespecttothecalculationoftheMRIsensitivityforT staging,valuesof33.3%forT1,62.5%forT2,and31.8%forT3 wereobserved.Thesevaluesarelowerthan thoseobserved inseveral other studies.10,14,22,28 _However, _Beaumont _et _al. obtainedevensmallervaluesinrelationtoT1andT2stages, namely:27%forT1and59%forT2.16

Thevaluesforspecificitywereof94.7%forT1,32%forT2 and79%forT3.WithrespecttoT1andT3,theresultswere consistentwiththebibliography.10,16_In_the_case_of_T2,_these valueswerelowerthanthosefoundinmostofthereferred studies.

ThepositivePVcalculatedwas33.3%forT1,37.0%forT2 and63.6%forT3.RegardingnegativeVP,thesevalueswere 94.7%forT1,57.1%forT2and50%forT3.Thesevalueswere lower than thoseobserved byUc¸aret al. andAkasuet al., exceptinthecaseofnegativeVP forT1,whichwassimilar tothatcalculatedbyIannicellietal.4,19

Thediagnosticefficacy fortumorstaginghasbeen ben-efited from improvements due to the development of MR techniques;inearlystudies,theefficiencyreachedabout60%;

currently,thisindicatorisbetween92and94%forTstageand 63%forNstage.5_Usually_the_efficiency_increases_with_T_stage andvaries,accordingtosomeauthors,between67and94% or55and86%.23–29 _Efficacy_calculated_for_T_stage_was_43.9%, particularly90.2%forT1,43.9%forT2,and53.7%forT3.The resultsforTingeneralandforT2andT3werelowerthan thosefoundbyotherauthors.4,19,23,25_The_{effectiveness}_for_T1 stagewassimilarthatinanotherstudy.4

Ndetectionisthemostchallengingdetectionofany imag-ingexamination.5_The_criterion_“size”_for_detection_of_lymph nodemetastasesisapoorpredictor,sincenon-tumorenlarged nodescanexist,andthereverseisalsotrue.29_The_irregular contourandheterogeneoussignalintensityaremorespecific criteriaformetastazisation.4,17,29

Inthisstudytherewassubstagingin31.7%(n=13)ofcases classified as N0, and overstaging in 7.32% (n=3); in 31.7% (n=13),undertreatmentofsubstagedpatientsoccurred.

Thesensitivity,specificity,positiveVPandVPnegative rel-ative toN were 27.8%,87%, 62.5% and 60.6%, respectively. Thevalueforsensitivitywaslowerthanthosefoundin sev-eralpreviousstudies;however,thespecificityshowedvalues higher thanthose foundinthese samestudies.5,10,13,14,16,19 Positive and negative VPs were similar to those obtained inother studies.16,19 _The_{effectiveness}_of_MR_for _N_staging was 61%,afiguresimilartothat foundbyseveralauthors, varyingbetween39and95%.5,14,16,19_The_agreement_between the stagingresultsobtainedbyMRand anatomopathologi-cal results,evaluated byKw valueforTand N,were given as:Kw=0.14,p<0.05andKw=0.16,p<0.05,respectively.These figures revealedapooragreementbetweenthe twostaging forms;additionally,theydifferfrommoststudiesconsulted, whereKwvaluesbetween0.71and0.89forTandbetween0:40 to0:56toNwereobtained.4,14,19_The_study_by_Tytherleigh_MG etal.wasthatthatobtainedtheclosestvaluestoours,namely: 0:37(p<0.001)forTstagingand0.25(p<0.002)forNstaging.30 TheevaluationofMRaccuracythroughROCcurveswith AUC determinationshowedvaluesfor AUCof0.26,p=0.18 for T1,0.46, p=0.63 forT2, 0.61,p=12.24 forT3, and 0.40, p=0.40 forNstaging.Thus,RMprovedtobeanineffective orpoormethodforNstaging.Thesevalueswerediscordant withthosefoundbyotherauthors,rangingfrom0.81to0.94 forTstagingandfrom0.57to0.78forNstaging.8

This study has some limitations, suchas the relatively small number ofpatients, particularly those staged as T1. There arealsobiasesassociatedwithretrospectivestudies, suchas selectionbias,and the resultsshouldbe validated by future prospective multicenter studies. MR and anato-mopathological stagingwerenotalwaysmadebythesame radiologistandpathologist;thismaybeanerrorfactor.

In addition, RMbegan operating inRCstagingin HBin 2007.Asinanymodality,thereisalearningcurveassociated withthisimagingtechnique,andthismayhavecontributed tosomeofthereportedstagingerrors.

Finally,publicationbiasmaybeanotherreasonforthe dis-parateresultsfoundinmostoftheliterature.

Conclusion

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evaluated the accuracy of MR in the preoperative staging ofRC, comparedtoanatomopathologicalresultsofsurgical specimens.

MRshowedamoderateacuityinRCstaging,withefficacy valuesbetween43.9and90.2%forTstagingand61%forN staging.RMwasmoresensitiveforT2stageandmorespecific forT1and N+stages.Thisimagingmodality revealedlittle sensitivitytobothT1andN+(33.3and27.8%,respectively), beingmoreusefulforexclusion,thantoconfirmthesestages. MoststagingerrorsoccurredonthedistinctionbetweenT2 andT3stages,resultingincasesofundertreatment.

TheagreementbetweenvaluesobtainedbyMRand anato-mopathologicalresultswaspoorforbothTandNstages.Thus, inthisstudy,itwasanineffectiveorpoormethodforRC stag-ing.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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