with colon cancer do not predict better prognosis inpatients Higher cut-offs for the number of lymph nodesharvested Coloproctology Journal of

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

Journal of

Coloproctology

Original Article

Higher cut-offs for the number of lymph nodes harvested do not predict better prognosis in patients with colon cancer

Osman S. Guner

^a^,^b^,∗

, Latif V. Tumay

^b^,^c

aAcibademBodrumHospital,DepartmentofSurgery,Bodrum,Mugla,Turkey

bAcibademUniversity,VocationalSchoolofHealthSciences,Istanbul,Turkey

cAcibademBursaHospital,DepartmentofSurgery,Bursa,Turkey

a r t i c l e i n f o

Articlehistory:

Received18May2020 Accepted14June2020

Availableonline16September2020

Keywords:

Coloncancer Lymphnodeharvest Overallsurvival Prognosis

Numberoflymphnodesexamined

a bs t r a c t

Background:Currentthresholdforminimumlymphnodeharvestmaynotbeadequatefor appropriatestagingincoloncancerandnewersurgicaltechniquesmayallowmorelymph nodestobeharvested.Theaimofthisstudywastoexaminetheprognosticroleofharvesting andexamininglymphnodeshigherinnumberthantherecommendedthreshold(≥12),in patientswithcoloncancer.

Methods:Thisretrospectivestudyincluded179patientsthatunderwentopencolonresec- tionforadenocarcinomaofthecolon.AD3resectionwithhighvascularligationwasmade sothatlargenumberoflymphnodeswasremovedinmostpatients.Differencesinoverall survivalbetweenbelowandabovethreecutoffpoints(≥18,≥24,≥40)wereestimated.

Results:Duringmedian33monthsoffollow-up,45patientsdiedandmeanoverallsurvival was108.7±5.6months(95%CI,97.7–119.7).Themeannumberoflymphnodesharvested andexaminedwas44.0±25.7(median38;range,7–150).Nosigniﬁcanteffectwasfoundfor threedifferentcut-offvalues(≥18,≥24,or≥40nodes)onmeanoverallsurvival(p>0.05for allcomparisons).ThesamewastrueforthewholestudypopulationaswellasforN0(N negative)andN1-2(Npositive)patientsubgroups,whentheyareanalyzedseparately.

Conclusions: Ourﬁndingsdonotsupportthesurvivalbeneﬁtofsubstantiallyhighernumber oflymphnodesharvestedincoloncancer.

licenses/by-nc-nd/4.0/).

∗ Correspondingauthor.

E-mail:serhatguner@yahoo.com(O.S.Guner).

https://doi.org/10.1016/j.jcol.2020.06.009

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Pontosdecortemaisaltosparaonúmerodelinfonodoscoletadosnão predizemmelhorprognósticoempacientescomcâncerdecólon

Palavras-chave:

Câncerdecolo Coletadelinfonodo Sobrevivênciageral Prognóstico

Númerodelinfonodos examinados

r e s u m o

Fundamento:Olimiteatualparaacoletamínimadelinfonodospodenãoseradequadopara oestadiamentoadequadonocâncerdecólonenovastécnicascirúrgicaspodempermitir queumnúmeromaiordelinfonodossejacoletado.Oobjetivodesteestudofoiexaminar opapelprognósticodacoletaeexamedelinfonodosemnúmeromaiordoqueolimite recomendado(≥12),empacientescomcâncerdecólon.

Método: Esteestudoretrospectivoincluiu179pacientessubmetidosàressecçãoabertade cólonparaadenocarcinomadecólon.AressecçãoD3comligaduravascularaltafoirealizada paraqueumgrandenúmerodelinfonodosfosseremovidonamaioriadospacientes.As diferençasnasobrevidaglobalentreabaixoeacimadetrêspontosdecorte(≥18,≥24,≥ 40)foramestimadas.

Resultados: Duranteamedianade33mesesdeseguimento,45pacientesmorreramea sobrevidaglobalmédiafoide108,7±5,6meses(IC95%:97,7-119,7).Onúmeromédiode linfonodoscoletadoseexaminadosfoide44,0±25,7(mediana=38;variac¸ão:7-150).Ne- nhumefeitosigniﬁcativofoiencontradoparatrêsvaloresdecortediferentes(≥18,≥24ou

≥40linfonodos)nasobrevidaglobalmédia(p>0,05paratodasascomparac¸ões).Omesmo foiverdadeiroparatodaapopulac¸ãodoestudo,bemcomoparaossubgruposdepacientes N0(Nnegativos)eN1-2(Npositivos),quandoanalisadosseparadamente.

Conclusões: Nossosachadosnãoapoiamobenefícionasobrevidadeumnúmerosubstan- cialmentemaiordelinfonodoscoletadosnocâncerdecólon.

´eumartigoOpenAccesssobumalicenc¸aCCBY-NC-ND(http://creativecommons.org/

licenses/by-nc-nd/4.0/).

Introduction

Detectionofmetastaticlymphnodesiscriticalfortreatment planningandpredictingsurvivalincoloncancer.Lymphnode involvementisassociatedwithpoorlongtermoutcome,¹and detectionoflymphnodeinvolvementwouldallowidentify- ingpatientsmostlikelytobeneﬁtfromadjuvanttreatment.

Improvingtheaccuracyofstaging,therebyidentifyingmore patientswhowillbeneﬁtfromadjuvanttreatmentformsthe rationaleforharvestingincreasednumberoflymphnodes.

Theoptimalnumberoflymphnodestobeharvestedfor accuratestagingisstillunclear,althoughmostguidelinesrec- ommendharvestingatleast12lymphnodes.^1,2Ontheother hand,severalstudiesfoundarelationbetweenhighernum- berofharvestedlymphnodesandbettersurvivaloutcomes incolorectalcancer.³Highercutoffpointssuchas18,24or36 lymphnodeshavebeentestesinrelativelysmallnumberof studies.^3–5Thus,currentthresholdforminimumlymphnode harvestmaynotbeadequate.

Moreover,newersurgicaltechniqueshavethepotentialto allowfarmorelymph nodestobeharvested. For example, advancedresectiontechniquessuchashighvascularligation mayallowhigherlymphnodeyield.Therefore,itseemscritical toidentifywhetheradditionaleffortstosampleandexamine highernumbersoflymphnodeswouldtranslateintobetter long-termclinicaloutcomes.

Thisstudyaimedtoexaminetheprognosticroleofharvest- ingandexaminingsubstantiallyhighnumberoflymphnodes inpatientswithcoloncancer.

Patients and methods

Patients

Thisretrospstudyntswhounderwent opencolonresection foradenocarcinomaofthecolonlocalizedbetweencecumand distalsigmoidcolon.Patientdatawereretrievedfrommedical andfollow-uprecordsofthepatientsandmostrecentsurvival statuswasfurtherconﬁrmedbyphonecontactwithpatients orrelatives.Followingpatientswereexcluded:patientsthat curative resection wasnotpossiblewho received palliative decompression,patientswithrectumcancer(localizedwithin 15cmfromtheanalverge),patientswithoutavailablesurvival data, and patients that underwent laparoscopic resection.

The study protocolwas approvedbythe institutionallocal ethics committee (Acibadem Mehmet Ali Aydinlar Univer- sityMedicalResearchEvaluationCommittee,date,December 5, 2019; no. ATADEK-2019-19/13) and the study was per- formedinaccordancewiththeethicalstandardslaiddown intheDeclarationofHelsinki.Duetotheretrospectivenon- experimentalnatureofthestudy,informedconsentwasnot required.

Surgicaltechnique

Allpatientswereoperatedbyexperiencedcolorectalnsusing open surgical technique. Dissections were done in confor- mity withembryologicalplanes. Awideresectiontargeting macroscopically10cmofuninvolvedsurgicalmarginsprox-

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imalanddistaltothetumorwasdone.AD3resectionwith highvascular ligationwas madewiththeaimofremoving a large lymphovascular pedicle (e.g. 2cm above the outlet ofinferiormesentericarteryfrom aorta,atthe siteofileo- colicarteryoutletfromsuperiormesentericartery).Enbloc resectionwasdoneinpatientswithadjacentorganinvasion.

Extendof surgical resections were deﬁned as follow:right hemicolectomy,from10cmproximaltoileocecalvalvetothe middleof transverse colon; extendedright hemicolectomy, from10cmproximaltoileocecalvalvetothesplenicﬂexure;

lefthemicolectomy,from themiddleoftransversecolon to theproximalpartofsigmoidcolon;extendedlefthemicolectomy,fromthemiddleoftransversecolontothedistalpartof sigmoidcolon;totalcolectomy,from10cmproximaltoileoce- calvalvetotheendofsigmoidcolon;anteriorresection,from theproximalpartofdescendingcolontotheendofsigmoid colon.

Histopathologicalexamination

Followingﬁxationofurgicalsamplesin10%neutralbuffered formalin(10%NBF) foraminimumof36h, onlythe tumor wasstainedwithIndianink,whereasthemesentericregion was not stained to allow better identiﬁcation of lymph nodes. Standard sections were made from different parts ofthe tumor and sections necessary for the evaluation of the radial margin were obtained. Then, pericolic fat was strippedoffthecolonandcutinparallel5-mmthinsections.

Thewholesamplewascarefullysectionedanddissectedin anattempt toidentifyall lymph nodesusing bothinspec- tion and palpation. All identiﬁed nodes were examined histologically. Lymph node sections are cut at 4␮m and stained withhematoxylin–eosin(H-E)forroutinehistology.

The total number of nodes identiﬁed and examined were reported.

Follow-up

Patientswere followed every threemonthsduringthe ﬁrst postoperative year, every six months during the second year,andannuallythereafter.Forthepurposeofthisstudy, patientsorrelativeswerecontactedtoconﬁrmsurvivalsta- tus.

Statisticalanalysis

Forstatisticalanalysis,(StatisticalPackageforSocialSciences) SPSS version 21 (IBM Corp.; Armonk, NY, USA) was used.

Descriptivedatawere presentedasmean±standarddevia- tionornumber(frequency),whereappropriate.Meanoverall survival(OS)wasestimatedusingKaplan-Meiertest.OSwas deﬁnedasthetimeperiodbetweensurgeryanddeathand patientsaliveatthelastfollow-upwerecensored.Log-rank testwas usedtocompare patientsubgroups oftotalnum- berofretrievedlymphnodesintermsofoverallsurvival.A pvalueof<0.05wasconsideredanindicationofstatistical signiﬁcance.

Table1–Patientcharacteristics.

Characteristic n=179

Age,y(mean±SD) 65.2±14.0

Malegender 108(60.3%)

Stage

0 3(1.7%)

I 16(8.9%)

II 49(27.4%)

III 51(28.5%)

IV 60(33.5%)

Surgicaltreatment

Righthemicolectomy 80(44.7%)

Extendedrighthemicolectomy 11(6.1%)

Lefthemicolectomy 26(14.5%)

Extendedlefthemicolectomy 3(1.7%)

Totalcolectomy 4(2.2%)

Anteriorresection 55(30.7%)

Chemotherapy

Nochemotherapy 55(30.7%)

Neoadjuvantchemotherapy 14(7.8%)

Adjuvantchemotherapy 110(61.5%)

Unless otherwise stated datapresented in n (%). SD,standard deviation.

Table2–Histopathologicalﬁndings.

n=179 Grade

1 20(11.2%)

2 100(55.9%)

3 59(33.0%)

Differentiation

Poor 49(27.4%)

Moderate 109(60.9%)

Well 21(11.7%)

Perineuralinvasion 80(44.7%)

Venousinvasion 35(19.6%)

Lymphaticinvasion^a 64(36.0%)

Extranodalinvolvement^a 64(36.4%)

Unlessotherwisestateddatapresentedinn(%).^aNotallpatients haveavailabledata.

Results

Patients

Atotalof179patientswereincluded.Mostcommonsymp- tomsonadmissionwereasfollowswithdecreasingfrequency:

abdominalpain, 24.6%;rectalbleeding,18.4%;fatigue,14%;

anemia,9.5%.Frequenciesofcomorbiditieswereasfollows:

hypertension,39.1%;diabetes,21.2%;coronaryarterydisease, 17.3%;and8.4%ofpatientshadanotherconcomitanttumor.

A family history of colorectal cancer was present in 8.9%

of the patients. Table 1 shows other characteristics of the patients.Table2showsasummaryofhistopathologicalﬁnd- ings.

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Table3–Associationbetweendifferentcut-valuesfor thenumberoflymphnodesharvestedandsurvival outcomesforthewholestudypopulationandN subgroups.

Cut-offvalues Overallsurvival^a (95%CI) P*

Wholestudypopulation(n=179)

<18(n=17) 106.4±15.0 77.1−135.7 0.960

≥18(n=162) 108.2±6.2 96.1−120.3

<24(n=31) 109.9±11.5 87.3−132.5 0.858

≥24(n=148) 100.5±6.0 88.6−112.5

<40(n=99) 107.5±6.8 94.3−120.8 0.643

≥40(n=80) 82.0±7.0 68.4−95.7

Nodenegativepatients(N0)(n=76)

<18(n=10) 121.1±15.6 90.6−151.7 0.779

≥18(n=66) 130.5±7.8 115.2−145.7

<24(n=14) 124.0±13.2 98.2−149.9 0.695

≥24(n=62) 123.3±7.2 109.1−137.4

<40(n=41) 133.9±6.8 120.7−147.2 0.385

≥40(n=35) 87.9±7.0 74.1−101.6

Nodepositivepatients(N1-2)(n=103)

<18(n=7) 70.3±21.9 27.3−113.3 0.856

≥18(n=96) 86.7±8.1 70.9−102.4

<24(n=17) 95.6±16.5 63.4−127.9 0.745

≥24(n=86) 74.5±7.5 59.8−89.2

<40(n=58) 83.5±9.5 65.0−102.1 0.337

≥40(n=45) 72.2±9.4 53.8−90.7

a Overallsurvivalinmonths±standarderror.*Log-ranktestpval- uesfordifference.CI,conﬁdenceinterval.

Effectofdifferentcut-offvaluesonoverallsurvival

During median 33 months of follow-up, 45 patients died and mean overall survival was108.7±5.6months(95% CI, 97.7–119.7).1-year,3-yearand5-yearsurvivalrateswere92%, 78%,and70%,respectively.Themeannumberoflymphnodes harvestedandexamined was44.0±25.7(median 38;range, 7–150).Nosigniﬁcanteffectwasfoundforthreedifferentcut- offvalues(≥18,≥24,or≥40nodes)onmeanoverallsurvival (Table3).Fig.1showsKaplan-Meiercurvesofoverallsurvival forthreedifferentcut-offvalues.Thesamewastrueforthe wholestudypopulationaswellasforN0(Nnegative)andN1-2 (Npositive)patientsubgroups,whentheyareanalyzedseparately.Moreover,whenallpatientswithstageIVdiseasewere excludedfromtheanalysis,noneofthecut-offvalueswere associatedwithadifferenceinoverallsurvivalinallpatients, nodenegativepatients,andnodepositivepatients.

Discussion

Thisstudyexaminedthevalueofharvesting,identifyingand examiningconsiderablyhighnumberoflymphnodesduring surgicaltreatmentinpatientswithcoloncanceratdifferent diseasestages;however,could notfindanysurvivalbenefit associatedwithhighnumbersoflymphnodesexamined.To thebestofourknowledge,thisstudyisoneofthefewstud- iestestedseveralrelevantcutoffpointsforharvestedlymph nodes forsurvival benefit,in the whole groupof operated coloncancerpatientsaswellasNsubgroups(Npositiveand Nnegativepatients).

Mostofthepreviousstudieshavefocusedonthepoten- tialsurvivalbeneﬁtofharvesting≥12lymphnodes,^6–13mostly conﬁrming the validity ofwidely recommended threshold.

Althoughitisestimatedthataminimumof12negativelymph nodesmustbeexaminedtoruleoutNpositivediseasewith a>90%accuracy,theoptimalnumberoflymphnodestobe harvestedisstilldebated.^14,15 Harvesting≥12nodescanbe consideredaqualityassurancetool.¹⁶Ontheotherhand,a study foundthat increasednumber oflymphnodes exam- inedaftercolectomydoesnotimprovecoloncancerstaging butassociatedwithaslightimprovementinoverallsurvival.¹³ Todate,severalstudies examinedthe prognosticroleof harvesting higher numbers of lymph node using different cutoff values. A very recent study examined the relation- shipbetweennumberoflymphnodesharvestedandsurvival amongpatientsthatunderwentcolectomyfornon-metastatic coloncancer.³Thatstudyusedalargedatabaseandreported ontheoutcomesofmorethanquarterofamillionpatients.

Patientswithmorethan24harvestednodeshadbettersur- vivalthanpatientswith12–23and<23harvestednodes;and thisrelationwastrueacrossallNstagesandacrossmostother subgroupanalyses.However,accordingtotheirfindings,fur- therincreasingthenumberofnodeharvestdoesnotseemto provideadditionalbenefit,whichisinlinewithourfinding regardingthecutoffvalueof≥40nodes.Tsaietal.examined the prognosticsignificanceofharvesting and examiningat least18lymphnodesinpatientswithT2-4N0non-metastatic colorectalcancerandfoundsignificantsurvivalbenefitwhen comparedtotheharvestingof<18lymphnodes⁴.Inthestudy byChandrasingheetal.,harvesting≥14lymphnodes(slightly higherthantherecommendedthreshold)wasassociatedwith bettersurvivalinstageII-IIIcolorectalcancerpatientsandthe survivalbenefitwasevidentforbothcoloncancerandrectal cancer.¹⁷InthestudybyPeeplesetal.with3534colorectalcan- cerpatients,harvesting≥24lymphnodesandharvestingupto 36lymphnodeswasassociatedwithbettersurvivalforstageII andstageIIIdisease,respectively.⁵Hashiguchietal.identified numberoflymphnodesexaminedasaprognosticfactorwith cut-offvalueof20fornode-positiveand18fornode-negative cases,intheirstudywith859operatednon-metastaticcolon cancers.¹⁸

Althoughnotfocusingonaspeciﬁccutoffvalue,astudy from Sweden reporteda positiveassociation betweentotal numberofharvestedlymphnodesandtotalnumberofposi- tivenodesdetected.¹⁹Theydetected0.17positivelymphnode for every additional lymph node retrieved,suggesting that theremaynotbeaminimumlimitforlymphnoderetrieval.

Highernumberoflymphnodeharvestedhasbeenassociated withseveralfactorssuchasmicrosatelliteinstability,proximal tumorlocation,andlowBMI.^20,21Anotherfactormaybethe effortfortheidentiﬁcationandexaminationofallretrieved lymphnodesbythepathologist.Specimenprocessingtech- niquehasbeenfoundtobeimportantforthetotalnumber ofharvestedlymphnodes.²² Inthisstudy,maximumeffort hasbeenmadebythepathologisttoidentifyandexamineas muchlymphnodesaspossiblefromthesurgicalspecimen.

Althoughourfindingsdonotsupportthesurvivalbenefitof elevatedcut-offvalues,westilladmitthatharvestinghigher numbers oflymph nodesmay havetwo potentialbenefits.

Firstly,examiningmorelymphnodeswilldecreasethechance

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1.0 0.8 0.6 0.4 0.2 0.0

0 50 100 150 200 0 50 100 150 200

Months Months

0

Cumulative survival

50

≥40

≥24

≥18

<40

<24

<18

100 150 p=0.643 p=0.858

p=0.960

C A B

200 Months

Fig.1–Kaplan-Meiercurvesofoverallsurvival.a)<18versus≥18nodesharvestedandexamined,b)<24versus≥24nodes harvestedandexamined,c)<40versus≥40nodesharvestedandexamined.Pvaluesareobtainedfromlog-ranktest.

ofmissingpositivenodes,therebyreducethechanceofunder staging.Appropriatestagingwould helpbetteridentifythe patientswhowouldmostbenefitadjuvanttreatment,which maycontributetoimprovedtreatmentoutcomes.Secondly, highernumberoflymphnodeharvestmayhaveatreatment effectthroughremovalofthemetastaticlymphnodes,thus reducingtumorburdenorenablingcompleteresection.Recent previous studies suggest that setting the ≥12 lymph node cutoffsomewhathigherwouldresultinimprovedsurvivalout- comesincolorectalcancer.Cutoffvaluesupto36nodeshave beentestedwithencouragingresults.Ontheotherhand,our datadonotsupport suchbenefitforany ofthe subgroups tested(N stageor Mstage).Firstly,this may beduetothe highnumberoflymphnodessampledinthisstudy,duetothe effortsforharvestinghighnumberofnodesduringsurgery aswellas effortsforthe identificationand examinationof asmuchnodesaspossibleduringhistopathologicalexamina- tion.Therefore,smallnumberoflymphnodeswasretrieved from onlya minority ofour patients. Only2.8%, 9.5%and 17.3%ourpatientshadlessthan12,18,and24nodessam- pled,respectively.Suchdatadistributiontogetherwithsmall samplesizemighthaveprecludedfindingsurvivaldifference betweengroupsduetolackofcontrastandinadequatepower.

Other possibleexplanations may bethe inclusion ofcolon cancersbutnotrectumcancers.

Retrospective design and single institution setting are otherimportantlimitationsofourstudy.

Conclusions

Ourﬁndingsdonotsupportthesurvivalbeneﬁtofsubstan- tially higher number of lymph nodes harvested in colon cancer.

Conﬂicts of interest

Theauthorsdeclarenoconﬂictsofinterest.

Author’s contributions

Bothauthorsfully contributedtothestudy conceptionand design, material preparation, data collection and analysis, OSGdraftedanddevelopedthemanuscriptandLVTcritically reviewedandrevisedit,ﬁnallybothauthorsreadandapproved theﬁnalmanuscript.

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