Extensive colectomy in colorectal cancer and hereditary nonpolyposis colorectal cancer – long-term results

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

Journal

of

Coloproctology

Original

Article

Extensive

colectomy

in

colorectal

cancer

and

hereditary

nonpolyposis

colorectal

cancer

–

long-term

results

Marisa

D. Santos

a,b,c,∗

_,

_Cláudio

_Silva

a

_,

_João

_Oliveira

a

_,

_Pedro

_Brandão

a,b,c

_,

Mónica

Sampaio

a,b,c

_,

_Ana

_Cristina

_Silva

a,b,c

_,

_Anabela

_Rocha

a,b,c

_,

_Eduarda

_Matos

d

_,

Ricardo

Marcos-Pinto

c,e

a_Centro_Hospitalar_{Universitário}_do_Porto_(CHUP),_Servic¸o_de_Cirurgia,_Porto,_Portugal

b_Centro_Hospitalar_{Universitário}_do_Porto_(CHUP),_Unidade_de_Cirurgia_Colorretal,_Porto,_Portugal c_Universidade_do_Porto,_Instituto_de_Ciências_Biomédicas_Abel_Salazar,_Porto,_Portugal

d_Universidade_do_Porto,_Instituto_de_Ciências_Biomédicas_Abel_Salazar,_Departamento_de_Saúde_{Comunitária,}_Porto,_Portugal e_Centro_Hospitalar_{Universitário}_do_Porto_(CHUP),_Servic¸o_de_{Gastroenterologia,}_Porto,_Portugal

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received1December2018 Accepted21April2019 Availableonline24June2019

Keywords: Colorectalcancer HNPCC

Lynchsyndrome Instability

Mismatchrepairgenes Totalcolectomy

a

b

s

t

r

a

c

t

Background:Colorectalcancersurvivalisbetterinhereditarynonpolyposiscolorectalcancer patientsthaninsporadiccolorectalcancerpatientsandevenforhereditarynonpolyposis colorectalcancerwithcolorectalcancerisnotconsensualthatextensivecolectomyis prefer-abletopartialcolectomy.Thisstudyanalyzesandcomparesthelong-termresultsofthese twogroupsofpatientssubmittedtocurativesubtotalcolectomyortotalcolectomy. Methods:Between2002and2018,68patientswithcolorectalcancerwithoutfamilial ade-nomatouspolyposisweresubmittedtoatotalor subtotalcolectomyinasingletertiary center.Thepatientsweredividedintwogroups:hereditarynonpolyposiscolorectalcancer patients(withAmsterdamcriteria)andsporadiccolorectalcancerpatients(theothers).The presenceofAmsterdamcriteriaforhereditarynonpolyposiscolorectalcancerandgermline mutationformismatchrepairgeneswasconﬁrmedbyclinicalrecords.Resultsandsurvival wereanalyzedfollowingsurgery.

Results:Weobtainedasporadiccolorectalcancergroupwith31patientsandahereditary nonpolyposiscolorectalcancergroupwith37patients.Thetwogroupsdifferinagebutnot ingender,tumorstageorsurgicalmorbidity.Theoverallsurvivalanddisease-freesurvival weregoodinbothgroupsbutevenbetterforhereditarynonpolyposiscolorectalcancergroup withstatisticalsigniﬁcancewhencomparingthetwogroups.

Conclusion: Totalorsubtotalcolectomyforcolorectalcancerprovidesagoodsurvival.These surgicalproceduresshouldbeconsideredtheﬁrstoptionforcolorectalcancerinyoung

∗ _{Corresponding}_author.

E-mail:marisadsantos@gmail.com(M.D.Santos). https://doi.org/10.1016/j.jcol.2019.04.005

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hereditarynonpolyposiscolorectalcancerpatients.Inthosecases,theyprovidegood long-termresults,avoidingtheriskofmetachronouscolorectalcancerandthesurveillanceis restrictedonlytotheremainingneedforrectum.

Colectomia

extensa

em

cancro

colorretal

e

cancro

colorretal

hereditário

sem

polipose

–

resultados

a

longo

prazo

Palavras-chave: Cancrocolorretal HNPCC

SíndromedeLynch Instabilidade

Genesdereparac¸ãodoADN Colectomiatotal

r

e

s

u

m

o

Introdução: Asobreviv ênciadocancrocolorretalémelhorempacientescomcancro col-orretalhereditárionãoassociadoapoliposedoqueempacientescomcancrocolorretal esporádico.Mesmoemcasosdecancrocolorretalhereditáriosempolipose,apreferência pelacolectomiatotalemrelaçãoàparcialnãoéconsensualnaliteratura.Esteestudo anal-isaecomparaosresultadosalongoprazodestesdoisgruposdepacientessubmetidosà colectomiacurativasubtotaloutotal.

Métodos: Entre2002e2018,68pacientescomcancrocolorretalsempoliposeadenomatosa familiarforamsubmetidosacolectomiatotalousubtotalemumúnicocentroterciário.Os pacientesforamdivididosemdoisgrupos:aquelescomcancrocolorretalhereditáriosem polipose(deacordocomoscritériosdeAmsterdão)eoscomcancrocolorretalesporádico (osdemais).OscritériosdeAmsterdãoparacancrocolorretalhereditáriosempoliposeea presençademutaçãogerminativaparaosgenesdereparaçãodeADNforamconfirmados porconsultadosregistrosclínicos.Osresultadoseasobrevivênciaforamanalisadosapós acirurgia.

Resultados: Nopresenteestudo,31pacientesforamincluídosnogrupodecancrocolorretal esporádicoe37nogrupodecancrocolorretalhereditáriosempolipose.Diferenças signi-ficativasforamobservadasemrelaçãoàidade,masnãoaog énero,estadiodotumorou morbilidadecirúrgica.Asobreviv ênciaglobaleasobreviv êncialivrededoençaforamboas emambososgrupos,masosresultadosforamaindamelhoresnogrupodecancrocolorretal hereditáriosempolipose,comsignificadoestatístico.

Conclusão: Acolectomiatotalouacolectomiasubtotalparaocancrocolorretal propor-cionamumaboasobreviv ênciaedevemserconsideradasaprimeiraopçãodetratamento em pacientesjovenscomcancrocolorretalhereditáriosem polipose.Nestespacientes, umacirurgiac ólicamaisextensapermiteaobtençãodebonsresultadosalongoprazo; reduzoriscodecancrocolorretalmet ácronoerestringeavigilânciaendosc ópicaaoreto remanescente.

Introduction

Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome)isageneticdiseaseofautosomaldominant inheri-tanceduetogermlinemutationsinmismatchrepair(MMR) genesMLH1, MSH2, MSH6, PMS2or epigenetic silencingof MSH2 via inherited EPCAM mutations,1,2 _which _carries _a

cumulative risk by age 70 years of 26%–80% for colorec-tal cancer (CRC).3 Mutation carriers also are at risk for several extra-colonic cancers, particularly cancers of the endometrium,ovary,urothelium,smallbowel,stomachand brain.4

Itsprevalenceinthegeneralpopulationisabout1in500, anditcausesabout2%–3%ofallcolorectalcancers.The muta-tioninoneoffourgenesoftheDNAmismatchrepairsystem

alsoconfersamarkedlyincreasedriskforothertypesof can-cer,namelyofendometrium.5,6

ThepresenceofHNPCCissuspectedwhenapatient devel-opscanceratanunusuallyyoungageorbecauseoffamilial clustering.UsuallypatientswithCCRwhomeetthe Amster-dam criteria(Table1)areHNPCCpatientsbydeﬁnition.7 _In

familiesthatmeettheAmsterdamcriteria,theprobabilityof havingamutationinMLH1,MSH2genesishigh(50%–92%).8,9

CurrentlytheAmsterdamcriteriaalsostillcoversfamilies withnoevidenceofaDNArepairdefectinatumor,inwhich the increasedtumorriskisprobablydueto geneticcauses that have not yetbeen identiﬁed.10 _The _familial _nature_of

coloncancerisalsocaused,toanunknownextent,by sim-plecoincidence.HNPCCpatientsalsoincludethosewhomeet theweakercriteriaoftheBethesdaGuidelines11₍_Table₁₎_and

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Table1–AmsterdamIICriteriaandRevisedBethesdaGuidelines.

AmsterdamIICriteria(Vasenetal.7₎ Allcriteriamustbemet:

Threeormorerelativeswithhistologicallyconﬁrmedcolorectalcancerorcanceroftheendometrium,smallbowel,ureter,orrenalpelvis, oneaffectedrelativebeingaﬁrst-degreerelativeoftheothertwo;FAPshouldbeexcluded;

Twoormoresuccessivegenerationsareaffected;

Atleastonerelativewasdiagnosedbeforetheageof50years RevisedBethesdaGuidelines(Rodriguez-Bigasetal.11₎ Oneormoreofthefollowingcriteriamustbemet: Colorectalcancerbeforetheageof50years;

SynchronousormetachronouscolorectalcancerorotherHNPCC-relatedtumorsa_,_regardless_of_age; ColorectalcancerwithMSI-highmorphologyb_before_the_age_of₆₀_years;

Colorectalcancer(regardlessofage)andaﬁrst-degreerelativewithcolorectalcanceroranHNPCC-relatedtumorbeforetheageof50years; Colorectalcancer(regardlessofage)andtwoormoreﬁrst-orsecond-degreerelativesdiagnosedwithcolorectalcanceroranHNPCC-related

tumor(regardlessofage)

FAP,familialadenomatouspolyposis;HNPCC,hereditarynonpolyposiscolorectalcancer;MSI,microsatelliteinstability.

a _{HNPCC-related}_tumors_include_colorectal,_endometrial,_stomach,_ovarian,_pancreas,_ureter_and_renal_pelvis,_biliary_tract,_and_brain_(usually

glioblastomaasseeninTurcotsyndrome)tumors,sebaceousglandadenomasandkeratoacanthomasinMuir–Torresyndrome,andcarcinoma ofthesmallbowel.

b _Presence_of_{tumor-inﬁltrating}_lymphocytes,_{Crohn’s-like}_lymphocytic_reaction,_{mucinous/signet-ring}_cell_{differentiation,}_or_medullary_growth

pattern.

haveahighersensitivitybutlowerspeciﬁcitythanthe Amster-damcriteriaregardingevidenceofamutationinanMMRgene. Allpatientscarryingacancer-causinggermlinemutationin anMMRgene (almost halfofHNPCC patients)canalso be saidto haveLynchsyndrome. However,inclinical practice theterms“HNPCC”and“Lynchsyndrome”areusuallyused synonymously.12

UsuallyforLynchsyndromeconfirmation,thetumortissue isanalyzedforevidenceofdeficientmismatchrepair.Ifsuch evidenceisfound,ageneticmutationissought.The identifi-cationofapathogenicmutationbygenetictestconfirmsthe diagnosisinthepatientandenablespredictivetestingofother familymembers.13

Yet,theidentificationofMMRgenemutationisnotalways achievedandthediagnosis,thetherapeuticplanand surveil-lancearemadetakingintoaccounttheothercardinalfeatures besides the earlier average age of cancer onset, including CRCmainlyinrightcolon,acceleratedcarcinogenesis,high riskformetachronouscolorectalcancers,specificpathology featuresforHNPCCcolorectal cancers(theyare moreoften poorlydifferentiatedandhaveanexcessofmucoidandsignet cell features, a Crohn-like reaction and an excess of infil-tratinglymphocyteswithinthetumor)14_and_importantly,_an

increased survivalwhen compare with sporadic colorectal cancerpatients.

These aspects have clinical implications for HNPCC patientswithCRCmanagementnamely,extensionof surgi-calresection,theneedofchemotherapyinCRCStageIIIand frequencyofscreeningcolonoscopieswhenpartialcolectomy isdonetodetrimentofatotalorsubtotalcolectomy.15_In_fact,

theconceptthatmoreextensivecolonicresectionintheCRC andinparticularintheHNPCCdoesprovidesurvival advan-tageisnotprovenandthesurgicalpolicyvariesindifferent centers.Forthisspeciﬁcreasonwecarryoutthepresentstudy whichaimstoanalyzelong-termresultsaftertotalorsubtotal colectomyincolorectalcancer,especiallyconcerningpatients withAmsterdam criteria and based on resultsachieved to

determinate the most appropriate extension of surgical resectioninthisgroupofpatients.

Methods

Databasedesign,patientpopulationandinclusioncriteria Thestudywasanopen observationalstudy withouta con-trol group. All patients were 20 years of age or older at inclusion.Age atinclusion was thepatient age whenthey weresubmittedtoelectivetotal/subtotalcolectomyor colec-tomytotalization.Weincludedallpatientswithcoloncancer without familialadenomatouspolyposis (FAP)submittedto a curative total, subtotal colectomy or colectomy totaliza-tion between December 2002 and April 2018 in a single tertiaryreferralcenter.Otherdiagnosedneoplasia,presence of rectal cancer, clinical Stage IV and R1/R2 surgery were exclusioncriteriabutnottheclinicalpatienthistoryof pre-viouscolonoscopywithpolypectomyoraprevioussurgeryfor CRC.

Thepatientsweredividedintwogroups:HNPCCpatients (patients withAmsterdam criteria) and SCRC patients (the others).Allthepatientshaveacoloncancerdiagnosis with-outotherneoplasm.Allpatientsweresubjectedtofollow-up accordingtointernationalguidelines.Thepatientswere fol-loweduntilthelastupdateofinformation,andscoredasalive withoutdisease,alivewithdiseaseanddead.

Thefollowinginformationwasusedforthisreport: gen-der, presenceof Amsterdam criteria, geneticvariant when identiﬁed,ageatsurgery,ageandstageofpreviousCRCand surgery type and date if any, surgery extension and date, surgery morbimortality cancer stage, numbers of months betweensurgeryandlastobservationordead.When calculat-ingsurvival,eachpatientwasscoredonceonly,irrespective of how many surgeries for cancer the patient might have had.

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Diagnosis

Total colonoscopy with a biopsy-proven adenocarcinoma, chest,abdominalandpelviccomputedtomographicscan,and serumcarcinoembryonicantigen(CEA)level.

Surgicalprocedures

Surgeryconsistedmainlyoftotalorsubtotalcolectomy.For patientswithpreviouspartialcolectomythesurgeryrealized wastotalizationofcolectomy.

Thetermof“subtotalcolectomy”isusedfortheauthors onlyfortheextensivecolectomyinwhichpartofthesigmoid andsigmoidarteriesweresparedinaneartotalcolectomy.

For authors the synonymous of“partial colectomy” are “segmentalcolectomy”.Thistermincludes“rightcolectomy”, “leftcolectomy”,“sigmoidectomy”or“transversecolectomy”. Regarding the selection of the operative procedure, we consideredthepresenceofCRCwithAmsterdamcriteria, syn-chronousCRC, metachronousCRC or CRC withpolyps not removablebycolonoscopy.

Resectedspecimensamples–H&Estaining;analysisfor deﬁcientofMMR

Standard pathological tumorstaging ofthe resected spec-imen was performed in accordance with the guidelines of the American Joint Committee on Cancer (http://www. cancerstaging.net).

Tumor tissuewas analyzedfor evidenceofloss of mis-matchrepairproteinexpressionbyimmunohistochemistryor bymicrosatelliteinstabilitytest.Whenpositivethepathogenic mutationbygenetictest(denaturinghighperformanceliquid chromatographyanalysisandDNAsequencing)wasrealized. Adjuvantchemotherapyprotocol

Post-surgerypatientswithpathologicalStageIIIwere admin-istered adjuvant chemotherapy protocol for 6 months performed preferably with 5-FU or a combination of 5-FU and oxaliplatin(one ofthe followedregimens:mFolFOX6– 200mg/m2_folinic_acid_(FA)_day_1,₄₀₀_mg/m2_5-FU_bolus_day_1,

continuedinfusionfor46hof2400mg/m2_5-FU_and₈₅_mg/m2

oxaliplatin,14/14daycycle;CapeOx:1000mg/m2_capecitabine

twiceaday,days1–14,130mg/m2_oxaliplatin_day_1,_21/21_day

cycle;5-FU/FA: 200mg/m2 _FA _day_1, ₄₀₀_mg/m2 _5-FU _bolus

day1,continuedinfusionfor46hof2400mg/m2_5-FU,_14/14

daymFolFOX6orCapeOXwerethepreferredregimens.When theadministrationofoxaliplatinisnotpossibleduetoside effectsofthedrugor thecomorbiditiesofthepatient, one offollowedregimenswasused:5-ﬂuorouracil/folinicacid (5-FU/FA)200mg/m2_folinic_acid₍₁_h_infusion_prior_to_5-FU)_and

400mg/m2 _5-FU _per _day _{intravenously} _once _daily_×₅_every

5weeksor1000mg/m2capecitabinetwiceaday×5every5 weeks.

Survivalanddiseaserecurrencedeﬁnitions

Disease recurrence was evaluated according to location: locoregional (LR), systemic (DR) or mixed. All surviving

patients were followed-up and their current status was conﬁrmed. None ofthe patients were lost from follow-up. Disease-free survival (DFS) was calculated from the date ofsurgerytothe dateofprogression(local ordistant), and overallsurvival(OS)wascalculatedfromthedateofsurgery tothedateofdeathorlastfollow-up.

Statisticalanalysis

TheHNPCCgroupandtheSCRCgroupwerecomparedin rela-tiontoage(Student’st-test)andinrelationtosex,stageand morbidity(Chi-squaretest).

Overallsurvivalanddisease-freesurvivalwereestimated inthe68patientsstudiedandalsointhetwogroupsusingthe Kaplan–Meiermethod.

Thedifferenceinsurvivalratesbetweenthetwogroups wastested forsigniﬁcanceusingthelog-ranktest.Survival wascomparedwiththelogranktest.

ThestatisticalanalysiswasmadewithSPSSstatistical soft-ware(version 21.0forWindows; SPSSInc., Chicago,IL).All statisticaltestswereconductedatatwo-sidedlevelof signif-icanceof0.05.

Ethicsapproval

ThisprojectwasapprovedbytheResearchEthicsHealth Com-mittee. Patientinformed consentfortheuseofclinicaland geneticinformationwasobtained.

Results

Descriptionofstudypopulationandclinicalparameters Thiscohortstudygathered72consecutivepatientswithCRC treatedwithtotal,subtotalcolectomyortotalizationof colec-tomy atonesingleUniversity Hospital.Afterthe exclusion of4patients withpStage IV, 68patients were includedin thepresentanalysis,withamedianageofyears58.7(range 30–86years).Themaletofemaleratiowas1.72:1.Patientswere dividedintwogroups–HNPCCgroup(patientswith Amster-damcriteria):37andSCRCgroup(theothers):31.Theclinical parametersaresummarizedinTable2.

Surgery

Total colectomy was performed in 42 (61.7%) patients; subtotal colectomy in 17 (25%) patients and totalization of colectomy in 9 (13.2) patients. In 26 (38.2%) patients the surgical approach was laparoscopic. The perioperative morbidity of the series was 23.5%, with 5 (7.3%) abdom-inal or pelvic abscesses, 5 (7.3%) anastomotic leaks, that included8(11.7)reoperations(duetoﬁveleakagesandthree abdominal abscesses), without re-admissions or mortality (Table3).

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Table2–Clinicalparameters.

Entiresample(n=68) HNPCCgroup(n=37) SCRCgroup(n=31) p

Age 58.7 52.3 66.5 <0.001 Male 43 25 18 0.59 PreviousCRC 9 7 2 SynchronousCRC 20 12 6 CRC+polyps 43 21 22 CRClocation Rightcolon 31 18 13 Transversecolon 13 5 8 Leftcolon 19 11 8 Sigmoidcolon 14 6 8

Timebetweendiagnosisandsurgery(days) 42 41 43

Table3–Surgicalparameters.

Entiresamplen=68(%) HNPCCgroupn=37(%) SCRCgroupn=31(%) p Surgery Total/colectomy 42 23 19 Subtotal/colectomy 17 7 10 Totalization/of/colectomy 9 7 2 Morbidity Postoperativeileus 16(23.5%) 9(24.3%) 7(22.5%) Abdominal/infection 6 4 2 Abscess 3 1 2 Anastomoticleak 2 1 1 Reintervention 0.87

Withtemporarystoma 5 3 2

Withabdominal/washout 3 1 2

Readmission 0 0 0

Posteriorsurgeryforstomaclosure 5 3 2

Mortality 0 0 0

p=0.87(includesmorbidity,reintervention,readmissionandposteriorsurgeryforstomaclosure),notonlyreintervention.

Table4–Pathologicandgeneticparameters.

Entiresample(n=68) HNPCCgroup(n=37) SCRCgroup(n=31) p

Tumorgrade G1 3 0 3 G2 60 33 27 G3 5 4 1 Crohn-likereaction 10 8 2 Mucinoustumor 15 9 6

“Ringsignetcells”presence 3 3 0

Tumorstage 0.70 StageI 24 12 12 StageII 23 12 11 StageIII 22 13 8 MMRgenemutation MLH1 1 1 0 MSH2 8 8 0 MSH6 3 3 0 PMS2 0 0 0 EPCAMmutation 2 2 0

Pathologyofresectedspecimensandgenetictest

StagedistributionisshowninTable4.Theaveragenumber ofdissectedlymphnodesinthesurgicalspecimenswas23 (range18–55).AllresectedspecimenswereR0.

Geneticmutationwasidentiﬁedin14patientsof37with Amsterdamcriteria.

Clinicaloutcome

Table5showslong-termclinicaloutcome,relapseofdisease andsurvival.

Themeanofpatientsfollow-upwas79.5months(range 6–190).

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Table5–Long-termresultsafterextensivecolectomyinCRC.Meanoffollow-up:months79.5(range6–190).

Entiresample(n=68) HNPCCgroup(n=37) SCRCgroup(n=31) p Bowellmovementsperday 1.7 1.7 1.8

Surgeryrelatedwithtotal/subtotalcolectomyortotalizationofcolectomy 5 3 2

OS 0.001 1year 100% 100% 100% 2year 100% 100% 100% 3year 96.3% 100% 92.6% 5year 89.9% 100% 79.5% DFS 0.013 1year 97.0% 100% 93.4% 2year 97.0% 100% 93.4% 3year 91.4% 96.2% 86.0% 5year 87.2% 96.2% 77.2%

Concerning functional results: these patients have not

dietary restriction, regular medication for stoolregulation, nighttimedefecation,useofpaddaytimeoratnight,soiling orseepageduringdaytimeornightorurgencyofdefecation.

Also,theyhavenotanysocialhandicap. The24hstoolfrequencywas1.7.

Fiveofthe68patientshadothersurgicalproceduresrelated withthetotal/subtotalcolectomyortotalizationofcolectomy. Forexample,intestinalreconstruction(HNPCC-3andSCRC-2). Forglobalsample5yearOSwas89.9%and5yearDFSwas 87.2%.

WhencomparedOSandDFSforHNPCCandSCRCgroups,

survivalwassigniﬁcantlyhigherinHNPCCgroup(p=0.001and

p=0.013).

Fromtotalsample(68patients)onlyninepatients(13.2%) developeddistant metastases(3 hepatic metastases,3

pul-monarymetastases;1hepaticandpulmonarymetastasesand

1hepaticandretroperitoneallymphnodemetastases):7died and2werealivewithpulmonarymetastases.

Discussion

CCRisoneofthemostfrequentworldwidecancers.Inthecase ofnon-metastaticcoloncancer,segmentalcolectomy contin-uestobethetreatmentplancornerstonefollowedbyadjuvant chemotherapyfortumorStagesIII.16_Most_of_CRC_are_sporadic

cancersbutcirca3%areHNPCCwithamorefavorablesurvival. So,inthosecasestherapy,surveillanceandgeneticcounseling arenecessarilydifferent.

ThefirstproblemthatarisesistheHNPCCidentification in population withCRC. Weknow that a large number of cliniciansare stillnotsensitized forscreeningand inmost centersthesystematicdetectionofmicrosatelliteinstability inpatientswithcoloncancerandageunder70yearsisnot yetimplemented.Intheotherhand,about15%ofsporadic cancershowsmicrosatelliteinstabilityandtherearepatients withAmsterdamcriteriainwhichmicrosatelliteinstabilityis negative.Forthatreason,inourcenterthepolicyadoptedfor patientswithAmsterdamcriteriaregardlesstheidentification ornotofthegeneticmutationthathavethe firstCRCwas amoreextensivecolectomyinsteadasegmentalcolectomy. Thisexplainswhy aconsiderable number ofpatients with Amsterdamcriteriaandmicrosatelliteinstabilitynegativetest weresubmittedtoamoreextensivecolectomyinoursample.

Thesecond issue isrelatedwith theconcept thatmore extensive colonicresectioninthe CRC andinparticularin the HNPCCdoes providesurvivaladvantage.Surgical man-agement ofcoloncancerforpatientswithLynchSyndrome whocarryamismatchrepairgenemutationiscontroversial. Actually,currentrecommendationsintheUSA,suggestthat personswithLynchsyndromeundergoingsurgicalresection of acolon cancer should beoffered toextensive resection rather than asegmentalresection, eventhoughthis policy hasnotpreviouslybeenproventobesuperiortoapolicyof1–2 yearlycolonoscopicsurveillance.17_Despite_this

recommenda-tion,theextentofresectionperformedvariesbetweencenters in the USA. For example, the Cleveland Clinic performed total colectomyfor16of33 CRCpatientsfrom Amsterdam criteria-positive families compared with seven of 60 from clinics elsewhere in the USA.18 _In _Europe, _on _the _basis_of

adecisionanalysisstudy9 _and_the_documented_high_risk_of

ametachronous cancer,current guidelines recommendthe optionofextensiveresectionbediscussedwithpatients, par-ticularlythoseundertheageof50years.19_In_fact,_there_are

nocontrolledstudiesavailablethataddressthequestionof whetherradicalsurgeryisappropriate.Anydecisionon radi-calsurgery,uptoandincludingcolectomy,wouldneedtotake into accountthe risk ofsurgery,the patient’s ageand sex, long-term medicalprognosis, and thequality and capacity todoannualcolonoscopysurveillancewithpreventive ade-nomaremoval.Infact,thedecisiontoremovemoreorlessof thecoloninvolvestheconsiderationofarelativelyhighrisk ofmetachronousColorectalCancer(CRC)withtheimpactof moreextensivesurgeryqualityoflife.20 _The_relatively _high

riskofmetachronousCRC,i.e.primaryCRCdiagnosedmore than12monthsaftertheﬁrstdiagnosisofprimarycolon can-cer,(16%after10years)21_supports_a_more_aggressive_primary

surgicalapproachinvolvingtheremovalofall,oratleastmost, ofthecolonafterdiagnosis.22_The_functional_consequence_of

anincreaseinbowelfrequencyandpossiblenegativeimpact onqualityoflifemightbebalancedagainstthereductionin riskofmetachronousCRCaffordedbymoreextensivesurgery, particularlyifthepersonisagedlessthan60yearsatthetime ofsurgery.23_On_the_other_hand,_surveillance_of_the_remaining

colonandrectumwillberequiredaftermostsurgeryandthe inconvenience ofyearlycolonoscopy(withthe requirement forstandardbowelpreparationratherthanenema prepara-tion) may be offset bythe better functional outcome after segmentalsurgery.Thisclinicalequipoiseisreﬂectedinworld

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surgicalopinion4,24_and_our_opinion_is_in_favor_of_a_more

exten-sivesurgery.

Basedon theseassumptionsweanalyzedﬁrst the long-termoverallresultsofoursampleandthenthesamesample dividedintotwogroups:patientsintwogroupswith Amster-dam criteria that we named HNPCC group and the other patientswithCRCbutwithoutcriteriaofAmsterdamwhere the surgery was more extensive due to the presence of metachronousneoplasmsorthepresenceofpolypsthatcould notbeendoscopicallyeasilyremoved.

Astheﬁrstanalysisoftheoverallsamplewecanconsider asgood the resultsofpatientstreated withamore exten-sivesurgery.Themorbidityofthesurgerywastheexpected, withoutdeﬁnitivestomasandwithoutmortality.Themeanof movementsbowelnumberperdaywere1.7,withoutdietary restriction,needofmedicationforstoolregulationorsocial handicap; there were few subsequent abdominal surgeries relatedtothe total/subtotal colectomy;the overall survival anddisease-freesurvivalweregood(5year,OS:89.9%;5year, DFS:87.2%).So,inourseriesmorbidityandfunctionalquality ofamoreextensivesurgerywereacceptablewithouta nega-tiveburden.

In the other hand, the division ofthe sample into two groupsallowedustoobtaintwogroupswithdifferencesinage asexpectedbutwithoutsignificantdifferencesinsex,surgery, surgicalcomplicationsandstage,whichallowsustostatethat thesurvivalandsurvivalofthefirstgroupissignificantly bet-terthanthatofthesecondgroup.Thisisinaccordancewith thestatementthatCRCinHNPCCpatientshavebetter progno-sisandprobablyisnotfundamentaltocharacterizedpatient genemutationtoadoptamoreextensivesurgerysincepatient showsAmsterdamcriteria.

Finally, the third aspect the CRC treatment of HNPCC patient: patients with microsatellite-unstable tumors have abetterprognosisthan thosewithstabletumors(probably due to an immune response to tumor cells). This means thatthere maybeless beneﬁtfrom adjuvant therapy. Sev-eral retrospective studies have shown that patients with microsatellite-unstableStageII andIII coloncancer donot beneﬁtfrom adjuvant5-FU-basedchemotherapy.25_Ongoing

researchisinvestigatingwhether thisisalsotrue forcolon cancersinHNPCCpatients.Thisaspectwasnotconsideredin ourseries.AllthepatientswithtumorStageIIIweretreated withadjuvantchemotherapywhichdoesnotinterferewith theresultspresented.

The strength of our study includes long mean follow-up, dataand surgeryrealized inasingle center.There are somelimitations inherenttothis study:the small number of patients and a small number of patients with genetic mutationconfirmation.Thisisatechnicaldifficultythatwe faceinthelastyearsinourcenter.Weintendinthefuture revisedallFormalin-FixedParaffin-Embeddedblocksoftumor resectedspecimens(FFPEtissuesample)fromthePathology DepartmentatourHospitalandrepeated themicrosatellite instabilityanalysisbyimmunohistochemistryandbyPCR.In meantimethemissingknowofgeneticmutationstatushas notpreventedthatitmaybeconsideredagoodpolicytoadopt amoreextensivecolicsurgerywheneverthepatientpresents Amsterdamcriteria.

Thevirtueofthisstudyiswarningtheneedforlarge-scale studies to conﬁrmthe advantageof more extensive colon surgeryforpatientswithCRC,especiallyfortheﬁrstCRCin patientswithAmsterdamcriteria.

Conclusion

Total or subtotal colectomy in CRC provides a good sur-vival.Thesesurgicalproceduresshouldbeconsideredtheﬁrst optionforcolorectalcancerinyoungHNPCCpatients.Inthose cases,theyprovidegoodlong-termresults,avoidingtherisk ofmetachronousCRCandsurveillanceisrestrictedonlytothe remainingrectum.

Conﬂicts

of

interest

Theauthorsdeclarenoconﬂictsofinterest.

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