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PHDTHESIS DANISHMEDICALJOURNAL

DANISH MEDICAL JOURNAL 1

ThisreviewhasbeenacceptedasathesistogetherwithfourpreviouslypublishedpapersbyUniversityofCopenhagen7thofAugust2015anddefendedon28thofAugustTutor(s):LarsNannestadJorgensen,HenrikHarling&PeerAndersWille-JørgensenOfficialopponents:IsmailGögenur,NielsQvist&PerJ.NilssonCorrespondence:DigestiveDiseaseCenter,BispebjergHospital,BispebjergBakke23,2400CopenhagenNV,Denmark E-mail:[email protected];63(1):B5190

THEFOURORIGINALPAPERSARE1. Nordholm-CarstensenA,Wille-JorgensenPA,JorgensenLN,

HarlingH.Indeterminatepulmonarynodulesatcolorectalcancerstaging:asystematicreviewofpredictiveparametersformalignancy.AnnalsofSurgicalOncology.2013;20(12):4022-4030[1].

2. Nordholm-CarstensenA,KrarupPM,JorgensenLN,Wille-JorgensenPA,HarlingH;onbehalfoftheDanishColorectalCancerGroup.Occurrenceandsurvivalofsynchronouspul-monarymetastasesincolorectalcancer:anationwidecohortstudy.EuropeanJournalofCancer.2014;50(2):447-456[2].

3. Nordholm-CarstensenA,JorgensenLN,Wille-JorgensenPA,HansenH,HarlingH.Indeterminatepulmonarynodulesincolorectal-cancer:doradiologistsagree?AnnalsofSurgicalOncology.2015;22(2):543-549[3].

4. Mismatchrepairandsynchronousmetastasesincolorectalcancer:anationwidecohortstudy.Nordholm-CarstensenA,KrarupPM,MortonD,andHarlingH,onbehalfoftheDanishColorectalCancerGroup.InternationalJournalofCancer.2015.doi:10.1002/ijc.29585.[4]

BACKGROUND

StagingCancerstagingistheshortdescriptionofacanceratapointinitsnaturalhistorythathassignificanceinguidingtreatment,inprog-nosis,andincomparisonofendresults[5].

This40-yearolddefinitionisstillvalidtodayandstagingre-mainsfundamentalintheassessmentofprognosis,intheplan-ningoftreatment,inthecommunicationbetweentreatinghealth

personnelandincomparisonofstudiesonpatientswithcancer.Cancerstaginghasbeencalled“thelanguageofcancer”[6].In1928thefirstknownattempttograderectalcancerwasmadebasedontheproportionofdifferentiatedcellsinthetumour[7].Morewell-knownis,however,theworkbyC.E.Dukes,whoin1932proposedDukes’classificationforrectalcancer[8].Thisclassificationwastheresultofobserveddifferencesinlengthofsurvivaldependingontheextentoftherectalcancerinvadingthroughthebowelwallandthepresenceoflymphaticmetasta-ses.AdecadelaterPierreDenoixbeganthedevelopmentofthetumour-nodemetastasis(TNM)systemthatcouldbeappliedtoallcancersites[6,9]resultinginthe1steditionoftheTNMclassifica-tionhandbook,“LivredePoche”,in1968[10].Todaythe7theditionoftheTNM(Table1and2)isinuseandstagingisbasedonthefurtherdevelopmentontheinitialTNMsystemwithin-formationonthetumour,regionalnodesandmetastases.Thedescriptionoftheanatomicextendofthediseaseisstillcentralindefiningcancerprognosis.Thisdescriptionprovidesthesolidfoundationforevaluationofthenumerousnewnon-anatomicalindependentprognosticfactorsofrecurrenceandoverallsurvivalunderstudyandisinadditiontohistologicalsubtypeandtopo-graphicsiteoneofthethreemainaxesoftumourclassification[6,11].Finally,aspointedoutbyComptonandGreene[12],afurtheradvantageoftheTNMsystemisitscontinuousimprove-mentbasedonon-goingexpertreviewsofexistingdata;ithasexhaustivedefinitionsensuringastringentuse;andisrelevanttoallmodernstagingevaluationtechniques[12,13].

Table1Classificationofcolorectalcancersaccordingtoextentoftheprimarytumour(Tstage),lymphnodeinvolvement(Nstage)anddistantmetastases(Mstage)T–Primarytumour Definition

Tis Tumourrestrictedtomucosa,noinfiltrationoflaminamuscularismucosae

T1 Infiltrationthroughlaminamus-cularismucosaeintosubmucosa,noinfiltrationoflaminamuscularispropria

T2 Infiltrationinto,butnotbeyond,laminamuscularispropria

T3 Infiltrationintosubserosaornon-peritonealisedpericolicorperirectaltissue,orboth.Noinfiltrationofserosaorneighbouringorgans

T4a InfiltrationoftheserosaT4b Infiltrationofneighbouring

organs

PulmonaryNodulesandMetastasesinColorectalCancer

AndreasNordholm-Carstensen


N–Regionallymphnodes N0 NolymphnodeinvolvementN1a Cancercellsdetectablein1

regionallymphnodeN1b Cancercellsdetectablein2-3

regionallymphnodesN1c Tumoursatellitesinsubserosaor

pericolicorperirectalfattissue,regionallymphnodesnotinvolved

N2a Cancercellsdetectablein4-6regionallymphnodes

N2b Cancercellsdetectablein7ormoreregionallymphnodes

M–Distantmetastasis M0 NodistantmetastasesdetectableM1a Metastasisconfinedto1distant

organordistantlymphnodesM1b Metastasistomorethan1dis-

tantorganorperitonealmetasta-sis

Tablebasedon7thed.oftheUnionforInternationalCancerControlTumourNodeMetastasisclassification[18].

Table2UICCTNMStageGroupingofColorectalCancers7thed.

Stage T N M

5-yearsurvival(%)

I T1/T2 N0 M0 92.5II T3/T4 N0 M0 IIA T3 N0 M0 83.6IIB T4a N0 M0 76.3IIC T4b N0 M0 58.8III AnyT N+ M0 IIIA T1/T2

T1N1N2a

M0M0 83.1

IIIB T3/T4aT2/T3T1/T2

N1N2aN2b

M0M0M0

63.8

IIIC T4aT3/T4aT4b

N2aN2b

N1/N2

M0M0M0

35.2

IV AnyT AnyN M+ 10.4IVA AnyT AnyN M1a IVB AnyT AnyN M1b UICC,UnionforInternationalCancerControl;TNM,TumourNodeMetastasisSurvivaldatafromtheSurveillance,EpidemiologyandEndResults(SEER)programdatabaseaspublishedbyGaoetal.2013[17].“M”Bearingthefundamentalideaofstaginginmind,theintroductionofthe“M”totheclassificationofcancersisessential.Ahallmarkofcancer,towhichtheonesofcolorectaloriginarenoexception,isthecapabilityofinvasionandmetastasis[14].About20%ofpatientsnewlydiagnosedwithcolorectalcancer(CRC)willhavesynchronouscolorectalcancermetastases(SCCM),i.e.metastaticdiseaseatthetimeofdiagnosis[15,16].

Despiteaconsiderableimprovementofadjuvanttreatmentoverthepastfivedecades,themanagementofmetastaticspreadcontinuestobeasignificantchallenge,andthechangefromlocalizedtodistant,systemicdiseasehasgreatimplicationsfortheprognosis.The5-yearrelativesurvivalinpatientswithSCCMis10-13%,whichisconsiderablylowerthanforpatientswith

localizeddisease(Table2)[16,17].Thetreatmentofpatientswithdisseminateddiseaseisamultidisciplinarytaskandmostcasesarenotcandidatesforpotentialcurativeresection.However,itisofgreatimportancetoidentifythosepatientswhoaresuitableformetastasectomyandthoseinwhomthemetastasescouldbecomeresectableafterresponsetocombinationchemotherapy[19].PulmonarymetastasesThemajorityofsynchronousmetastasesarehepatic,[15]where-asthelungsremainthemostcommonextraabdominalmetastaticlocation[20].TheprevalenceofsynchronouspulmonaryCRCmetastases(SPCM)rangesfrom2%to18%[20-25]andinprevi-ousstudiestheyaremostoftenaccompaniedbyhepaticmetasta-ses[20,22].

Noteworthy,theriskofpulmonaryinvolvementdiffersac-cordingtothelocationoftheindextumourandhasbeenreport-edto10-18%forrectalcancersand2-6%forcoloniccancers[20-25].Theriskofpulmonary(andhepatic)metastasesincolonicandrectalcancershasbeenattributedtothedirectvascularandlymphaticcommunicationwiththeintestinaltract.Furthermore,thedensecapillarysysteminthelungsandliveractingasafilterforcirculatingtumourcellsincombinationwithanespeciallysuitablemicroenvironmentforimplantationandgrowthhavebeensuggestedasunderlyingmechanismsforthehepaticandpulmonarypredilection[26,27].

DespitebeingthesecondmostcommonmetastaticsiteinCRC,theepidemiologyandoptimaltreatmentofpulmonarymetastaseshavenotbeenasintensivelystudiedasforhepaticmetastases.Pulmonarymetastasectomyhasbeenacceptedasapotentiallycurativeoptioninthemultimodalmanagementofpulmonarymetastasesdespitethelackofresultsfromprospec-tiverandomizedclinicaltrials[28,29].Essentialforcurativeresec-tionistheearlydetectionofthesemetastasesandselectionofpatientswithlimitednumberofmetastases,as“completeresec-tionbasedintheanatomiclocationandextentofdiseasewithmaintenanceofadequatefunctionisrequired”[28,30,31].Uncertaintyconcerningthe“M”–indeterminatelesionsGiventheriskofmetastaticspreadtothelungsandthesubse-quentprognosticimpact,apreoperativestagingofthechestwithcomputedtomography(CT)isrecommendedinguidelinesonthemanagementofpatientswithCRC[30-33].Thoughtheoptimalstagingprocedureofthelungscanbediscussed,thehighsensitiv-ityforpulmonarymetastasesyieldedbyachestCTisundisputed[34].AconcernregardingthechestCT,however,isasomewhatlowerspecificityandindeterminatepulmonarynodules(IPNs)areafrequentfinding;insomestudiesdetectedinmorethan1/3ofpatientsintheCRCsetting[34,35].Alungnoduleisalesionbe-tween1and30mmsurroundedbynormallungparenchymaandnotassociatedwithadenopathyoratelectasis[36]Suchlesionsmayrepresentmetastaticdisease,[23,25,37-40]buttheneedforimmediatetreatmentoftheindextumourdoesnotallowforaprospectivesurveillanceforpotentialgrowthoftheselesionsonrepeatedCTscans.Theidealtestdistinguishinglesionsofbenignoriginfromthemalignantoneshasyettobediscovered;positronemissiontomography(PET)isoflimitedvalueinthesmallestofthelesions[34,41]andinvasiveproceduresarenotviableoptionsduetothevastnumberofpatientswithIPNandtechnicaldifficul-ties[35,42].Untilnowmanagementhasbeenbasedonguidelinesonmanagementoflesionsdetectedinlungcancerscreening[43].

TheclinicalsignificanceandoptimaldiagnosticapproachintheCRCsettingremainstoberesolved.Furtherdiagnostic


workupmaydelaythetimetoresectionoftheindexcancer,andisassociatedwithincreasedradiationexposure,morbidity,costs,uncertaintyamongdoctorsandpatientanxiety.

HYPOTHESES

ThisthesiswassettoevaluatetheoverallhypothesisthattheinitialstagingchestCTinCRCpatientsdetectspulmonarylesionsinasubstantialnumberofthepatients.Lesionsclassifiedasdefi-nitepulmonarymetastaseshaveahighimpactonsurvivalprog-nosis,whereas“indeterminate”findingsmostoftenarebenignandcanbeignoredintheinitialdecision-makingontherapyfortheindextumourandothermetastaticsites.• Increasingnumbersofpulmonarynodulesaredetectedwith

theimplementationofcomputedtomographyinstagingofpatientswithcolorectalcancer.Manyofthesenodulescan-notreadilybeclassifiedasbeingbenignormalignant

• Pulmonarymetastasectomyand/oradjuvant/palliativechemotherapyimprovesurvivalinpatientswithpulmonarymetastases

• Clinicopathologicalfactorsandradiologicalcharacteristicsareusefulforevaluationofindeterminatepulmonarylesions

• Thecharacterizationofpulmonarylesionsdependsontheevaluatingradiologist

• Analysisofbiomarkershasimplicationsinthediagnosticstrategybyidentificationofpatientsinparticularriskofpul-monarymetastases

AIMSTheoverallobjectiveofthisthesiswastoinvestigatethepreva-lence,characteristicsandclinicalsignificanceofpulmonaryle-sionsdetectedattheinitialstagingofnewlydiagnosedCRCpa-tients.Lesionsofinterestcompriseddefinite,synchronouspulmonarymetastasesandindeterminatepulmonarynodules.Specifically,thethesisaddressed• existingevidenceontheprevalenceofIPNandspecificradio-

logicaland/orclinicopathologicalfactorsassociatedwithma-lignancyofIPN

• occurrenceofandriskfactorsforsynchronouspulmonarymetastases,howtheyaremanagedonanationalbasisandtheirimpactonsurvival

• variabilityinradiologists’assessmentofthestagingchestCT• potentialapplicabilityofmismatchrepair(MMR)status

analysisoftheindexcolorectaladenocarcinomainanevalu-ationoftheriskofsynchronouspulmonarymetastases

PRESENTATIONOFSTUDIES

STUDYIIndeterminatepulmonarynodulesatcolorectalcancerstaging:asystematicreviewofpredictiveparametersformalignancy

AimTheobjectivesofthisstudyweretoevaluatetheexistingevi-denceregarding

1. theprevalenceofindeterminatepulmonarynodulesattheprimarystagingCTscaninpatientswithcolorectalcancer

2. potentialclinicopathologicalfactorsandradiologicalcharac-teristicsassociatedwithamalignantnatureoftheIPN

3. clinicalimplicationsofIPN4. theoptimalfollow-upregimenofIPNMethodsThiswasasystematicreviewoforiginalstudiespublishedinEM-BASE,theCochraneLibraryandScienceCitationIndex,PubMeddatabases,GoogleScholar,relevantconferenceproceedings(UnitedEuropeanGastroenterologyWeek,AmericanSocietyofClinicalOncology,DigestiveDiseaseWeek,EuropeanSocietyofColoproctology,TheEuropeanCancerConference),trialregistries(clinicaltrials.gov,EUClinicalTrialsRegister,theWorldHealthOrganizationinternationalclinicaltrialsregistryplatform)andreferencelistsofrelevantretrievedarticles.Thereviewwascon-ductedinaccordancewiththePreferredReportingItemsforSystematicReviewsandMeta-analyses(PRISMA)guidelines[44].TheliteraturesearchwasperformedincooperationwiththetrialssearchcoordinatorfromtheCochraneColorectalCancerGrouptoensureathorough,objectiveandreproduciblesearchoftheavailablesources.InaccordancewiththeguidelinesoftheCochraneHandbook,[45]thesearchstrategywassettohavethreesetsoftermsdefining:1. Participants:Patientswithcolonicorrectalcancersubjected

tostaging2. Intervention:Primarystagingcomputedtomographyinclud-

ingthethoraciccavityandafollow-upintervention(notfur-therspecified)oftheprimarystagingfindings

3. Comparisonsandoutcomes:Definition,prevalence,charac-teristicsandoutcomeofindeterminatepulmonarynodulesdetectedatstaging

Incaseofmultiplepublicationsonthesamepatientpopulation,themostrecentorcompletestudywasselected.Recordswerethenscreenedbytitleandhereafterbyabstract.Finally,relevantarticleswereretrievedinfull-textforfurtherassessmentofeligi-bility.Studieshadtoreporttheoutcomeofpatientsdiagnosedwithindeterminatepulmonarynodulestobeincluded.

AllstudiesincludedforanalysisinthereviewwereassessedaccordingtotherecommendationsoftheOxfordCentreforEvidence-basedMedicine46andthemethodologychecklistsdevelopedbytheScottishIntercollegiateGuidelinesNetwork[47].Forsomeoftheincludedstudiesallassessmentpointsofthemethodologychecklistcouldnotbedirectlyapplied.

Weightedmeanofratios(WMR)takingthenumberofstudyparticipantsintoaccountwereusedfordataanalysis.Thenatureofthepublishedstudiesdidnotallowforastrictdiagnostictestaccuracymeta-analysis.

ResultsIntotal,3,485titleswerescreenedofwhich12studiesencom-passing6,222patientswereincluded.Thestudydesign,aimofstudy,levelofevidence,definitionofIPNandtypeofCTscannervariedamongthestudies.AssessmentofpulmonarystagingCTfindingswasreportedfor5,873(94.4%)patientsofwhom732(WMR=9.0%)hadoneormoreIPNs.

TheriskofIPNbeingmalignantincreasedwithseverityofUICCstage.Ameta-analyticalassessmentofclinicopathologicalfactorsassociationwithmalignancyofIPNwasdeemedimpossi-bleduetothelargeheterogeneityofthestudies.


Intotal,10.8%ofIPNsprovedtorepresentCRCmetastases,whereas0.5%wereprimarylungcancers.Thevastmajoritywasconsideredtobebenignlesionsorremainedunclarified.

ConsistentfindingsofriskfactorsforIPNmalignancybetweenthestudieswerefewandlimitedtolymphnodemetastasis(n=5)[38,39,42,48,49],increasingnumberofIPN(n=3)[48-50]andirregularsize(n=2)[50,51],whereascalcificationindicatedbe-nignIPN(n=2)[50,51].

Finally,characteristicssuchassizeoftheIPN[51],intra-pulmonarylocation[50],locationoftheindextumour[50]andpresenceofextra-pulmonarymetastaticdisease[48]wereonlyreportedtobesignificantlyassociatedwithmalignancyoftheIPNinsinglestudies.

ConclusionInconclusion,9%ofpatientswithCRCsubjectedtoprimarystag-ingchestCThadIPN,butonlyonein100ofallchestCTstagedpatientshaveIPNultimatelyprovingmalignant.Mostpulmonarynoduleswereofbenignoriginorremainedunresolved.Noradio-logicalfeaturesforIPNcouldbeconcludedpathognomonicformalignancy.Mostcommonlyapositivenodalstatuswasassociat-edwithIPNrepresentingpulmonarymetastases.Basedonthesefindings,noadditionalwork-uptoIPNwasrecommendedinadditiontoroutinefollow-upregimens.

LimitationsDespitebeingasystematicandextensivereviewoftheavailableliterature,thisstudyhassomelimitations.Despitearestrictivesearchstrategy,thegreatheterogeneityoftheincludedstudiesisacentralchallenge.Thisheterogeneitywasduetodifferentdefi-nitionsofIPN(ifany),varyingdiagnosticmethods(typeofCTscanner,expertiseandnumberofevaluatingradiologists)andnostandardizedfollow-upregimenortimetofollow-up.Further-more,radiologicalandclinicopathologicalfactorsassociatedwithmalignancyofIPNwereinconsistentlyreported.Datafromthe12includedstudieswereunfortunatelysodisparateandinhomoge-neousthatthesolidityoftheconclusionisweakened.

Finally,amethodologicalcriticismcanbeexpressedregardingtheprocedureofdataextractionforthisstudy.Theextractionofstudyresultswasperformedsolelybythefirstauthor.Twootherauthorsverifiedtheaccuracyoftheextracteddata,buttheywerenotblindedtothefindingsofthefirstauthor.Optimally,allau-thorshadextractedthedataindependentlyallowingforacalcula-tionofthelevelofagreementinthedataextraction.

STUDYIIOccurrenceandsurvivalofsynchronouspulmonarymetastasesincolorectalcancer:anationwidecohortstudy

AimThisstudyaimedtoinvestigate1. theoccurrenceofsynchronouscolorectalcancermetastases

confinedtothelungsinanationwidecohortofDanishpa-tientswithCRC

2. toidentifyriskfactorsforthesepulmonarymetastases3. toanalysetheirprognosticimpactintermsofsurvivalin

relationtodifferenttherapeuticprocedures

MethodsAllpatientswithafirsttimediagnosisofcolonicorrectalcancerregisteredintheDanishColorectalCancerGroup(DCCG)data-

basebetween2001and2011wereassessedforinclusion.DatafromtheDCCGdatabaseweremergedwithdatafromtwootherpopulation-basedregistries,theNationalPatientRegistry(NPR)andtheDanishPathologyRegistry(DPR).Inadditiontodemo-graphicandclinicopathologicaldataonthepatients,dataonradiologicalexaminationsofthechestperformedfrom30daysbeforeCRCdiagnosisuntilendoffollow-upwereextractedfromtheNPR.

RiskfactorsforpulmonarymetastaseswereanalysedwithChi-squareandMann-Whitney-Wilcoxontests.Multivariablelogisticregressionwasusedtoadjustforpotentialconfounding.OverallsurvivalwasassessedbyKaplan-Meierplotsandstratifiedlog-rankanalysis.Furthermore,theimpactoftreatmentmeasuresandclinicopathologicalvariablesonsurvivalwasassessedinanextendedCoxregressionanalysistoallowfortime-varyingeffectsofthevariables[52].Atwo-tailedp-valueof0.01wasusedaslevelofsignificanceduetothelargestudycohort.

ResultsIntotal,40,425patientswereassessedforeligibilityofwhom26,200wereincluded.SCCMwerepresentin7,742(29.5%).AmongtheseSPCMwereregisteredin1970(25.4%).Mostcom-monlythediagnosisofSPCMwasbasedonradiologicalfind-ings,whereashistologicalconfirmationwasobtainedin182(9.2%).SCCMconfinedtothelungs(Pulmonary-onlysynchronousmetastases,POSM)accountedfor37%(736patients)oftheUICCstageIVpatients.TheprevalenceofPOSMincreasedduringthestudyperiod,asdidtheuseofstagingchestCTscans.Thedetec-tionrateofSPCMwas7.0%(1,160of16,508patients)inpatientsstagedwithatraditionalchestX-ray,and8.4%(810/9,692)inthosehavingachestCTstagingperformed.

RiskfactorsforPOSMwereadvancedage,rectalcancerandarecentyearofdiagnosisafteradjustmentforpotentialconfound-ersincludingamorewidespreaduseofCTscansinrectalcancerpatientsandrecentyears.

PatientswithPOSMhadanoverallsurvival(OS)ofmedian376days(IQR:95-956),andsurvivalwashighlycorrelatedtothetherapeuticproceduresperformed.InpatientsresectedfortheirPOSMmedianOSreached1470days(95%CI:600-1905days),however,apulmonarymetastasectomywasonlyperformedin28patients(3.8%).Intotal,485(66%)underwentresectionoftheindextumour,andchemotherapy(palliativeandadjuvant)wasadministeredin367patients(50%).Pulmonarymetastasectomy,resectionoftheindextumourandadjuvantchemotherapyincombinationhadonlybeenperformedin15patients(2.0%).Patientshavingtheirindextumourresected(adjustedHazardRatio(aHR)=0.50,95%CI:0.42-0.60,P<0.001)andreceivingpalliativechemotherapyhadafavourablesurvivalprognosis.AccordingtotheextendedCox-regressionmodel,theimpactofchemotherapywasmostnotablyfrom30-365daysaftertheinitialCRCdiagnosis(effectday30-365,aHR=0.58,95%CI:0.48-0.70,P<0.001),whereasthestatisticalsignificancedisappearedbeyondthefirstyearafterthediagnosis(effectyear1-2,aHR=1.20,95%CI:0.90-1.60,P=0.225).

ConclusionSPCMweredetectedin7.5%ofallnewlydiagnosedCRCpatients,whichisahigherprevalencethanpreviouslyreported,andin37%ofthecasesthemetastasesweresolelyconfinedtothelungs.Thepresenceofpulmonarymetastasessignificantlyimpairedsurvival,butbothresectionofthemetastasesandindextumourinaddi-tiontochemotherapywereassociatedwithaprolongedoverallsurvival.


LimitationsTheuniquenessofthisstudylieswithintheepidemiologicalas-sessmentofsynchronouspulmonarymetastasesonanationalbasis.However,atthesametimethestudydesignisthemainlimitation-allowingonlyassociationsratherthancausalrelation-shipstobeexplored.Inparticular,thisimpairsthestrengthofconclusionsonthepotentialeffectofdifferenttherapeuticmeasures.Additionally,theseconclusionsarealsoweakenedbythelimitedavailabledataonthebasisforsurgicalintervention,adjuvant/palliativetreatmentandnumberofpulmonarymetasta-ses.Somedegreeofselectionbiasorconfoundingbyindicationmustbeexpectedregardingtheobservedeffectsofdifferenttreatmentmodalities.

Furthermore,fewpulmonarymetastaseswerehistologicallyconfirmed.Thiscouldberegardedasascientificshortcoming,bearinginmindthepotentialdifficultiesinassessingpulmonarynodules;thecentralissueofthisthesis.Someover-diagnosingmayoccur,asasubstantialnumberofpatientswithpulmonarymetastases,whowereonlysubjectedtoresectionoftheindexcancer,werestillalive5yearsafterdiagnosis.Inthesecases,benignandinsignificantpulmonarynodulescouldhavebeenwronglyregisteredinthedatabaseasmetastases.

STUDYIIIIndeterminatepulmonarynodulesincolorectal-cancer:Doradi-ologistsagree?AimThepurposeofthisstudywastoanalyse1. thevariabilityintheradiologists’detectionandcharacteriza-

tionofindeterminatepulmonarynodulesattheprimarypulmonarystagingCTscaninpatientswithnewlydiagnosedCRC

2. thepotentialassociationsbetweencertainradiologicalchar-acteristicsasassessedbyanexperiencedthoracicradiologistandamalignantnatureofIPN

MethodsInthesamecohortofpatientsasusedforstudyII,weidentifiedallpatientsreferredtoourcentrebetween2006and2011.Bytheinitialcut-offdateofthepresentstudyperiod,theuseofCTscansincludingthechesthadbeenfullyimplementedinthestagingofnewlydiagnosedCRCpatients.AsforstudyII,datawereextract-edfromtheDCCGdatabase,theNPRandtheDPR.Patientswerescannedwitha64-slicemultidetectorCTscannerandallscanswereassessedtwice.Aprimaryassessmentwasperformedpro-spectivelyaspartofthestagingprocedureandplanningoftreat-ment.Avastnumberofradiologistsperformedthisprimaryre-view.Secondly,anexperiencedthoracicradiologist,whowasblindedtotheprimaryassessment,reviewedthescansretrospec-tivelyforthisstudy.Thethoracicradiologistassessedthescansaccordingtoapreformeddataextractionsheet,andclassifiedscansintofourcategories:1)normalscan;2)benignpulmonarylesions;3)IPNor4)SPCM.IncaseofIPNorSPCM,thelesionsweredescribedindetailsregardingsize,number,location,calcifi-cation,ground-glassopacityandconsistencyandthedatawereenteredintoadedicateddatabase.AllreportsfromtheprimaryassessmentwereretrievedintheregionalPictureArchivingandCommunicationsSystemandmanuallysearchedforthesameinformationasreportedbythethoracicradiologist.Aresearch

assistant,blindedtothefindingsofthethoracicradiologist,ex-tracteddatafromtheprimaryscanreportstoadatabase,whichwasfinallymergedwiththedatafromthethoracicradiologist’sreviewanddatafromthenationalregistriesusingeachpatient’suniqueDanishcivilregistrationnumber.Additionally,allreportsonfollow-upradiologicalexaminationsincludingthechestfollow-ingtheinitialstagingCTwerereviewedinpatientswithIPNde-tectedateithertheprimaryorthoracicradiologist’sreport.SPCMdetectedattheseexaminationsweretobelocatedinthesamelocationastheinitialIPNtoconcludethattheSPCMoriginatedfromthisIPN.

Thelevelofinter-readeragreementbetweenradiologistswastestedwithKappastatistics.Radiologistperformancewascalcu-latedassensitivityandspecificity.MultivariablelogisticregressionwasusedtotestforassociationbetweenclinicopathologicalvariablesandamalignantnatureofIPN,whereasmultivariablelinearregressionwasusedtoassesstheimpactofadetectedIPNontimetosurgeryfortheCRC.

ResultsIntotal,841patientswereincludedofwhom8.7%(n=73)provedtohavepulmonarymetastaseseitherbyradiologicalfollow-uporhistologicalverification.IPNsweredetectedin82cases(9.8%)intheprimaryCTreviewascomparedto47(5.6%)bythededicatedthoracicradiologist.Inpatientssubjectedtoradiologicand/orinvasivefollow-up,IPNswereconcludedtobemalignantin20/73(27.4%,primaryassessor)and10/42(23.8%,thoracicradiologist).

ChestCTdiagnoseswereconsistentbetweentheprimaryandthoracicradiologistsin81.8%ofthecasesandoverallkappawas0.49(95%CI0.43–0.55),correspondingwithmoderateagree-ment[53].

Kappaforthecategories“IPN”and“SPCM”were0.31(fairagreement)(95%CI0.24–0.37;P<0.001,McNemar’stest)and0.65(95%CI0.58–0.71;P<0.001)(substantialagreement),re-spectively.

Timetoindextumourresectionwas13daysinpatientswithanormalscanorbenignnodulesonlycomparedwith20daysforpatientswithIPN.DiagnosisofIPNwasassociatedwithanaver-agesurgicaldelayof14days(95%CI2–27days;P=0.029)com-paredwithpatientswithnormal/benignfindings.NoneoftheevaluatedradiologicalfeaturesoftheIPNasassessedbythethoracicradiologistweresignificantlyassociatedwithmalignancyofthenoduleatfollow-up.

ConclusionAconsiderablenumberofradiologistsassessedtheprimaryCTscansandwithsomevariabilityinfindingswhencomparedtoadedicatedthoracicradiologist’sclassification.NoradiologicalfeaturesofIPNswerefoundpathognomonicformalignancyofthenodule.Notsurprisingly,thepresenceofsynchronouslivermetastaseswasassociatedwithahigherriskofmalignantnatureoftheIPN.Finally,timetoresectionoftheprimarytumourwasprolongedinpatientswithIPNcomparedtopatientswithnon-suspiciouspulmonaryCTfindings.

LimitationsTherearesomeimportantlimitationstothisstudy,mostofwhicharesharedwithotherpulmonarynoduledetectionstudies.Firstofall,theoutcomesoftheIPNsweredeterminedbyreviewingtheresultsoffollowupradiologicalexaminations,andonlyfewpatientsweresubjectedtothe“goldenstandard”histological


verification.IPNshadtoincreaseinsizeand/ornumbertobeconcludedtobemalignantatfollow-up.

Potentially,pulmonarymetastasesinapatientsubjectedtoadjuvant/palliativetherapycouldremainstableinsize.ResultsareflawedifsuchmetastaseswereregisteredasIPNs.

Someofthedifferencebetweentheprimaryandexpertre-viewcouldbeattributedtotheimplicationoftheradiologicaldiagnosismade.Thus,theexpertreviewdiagnosisis“only”forstudypurposes,whereasthe“reallife”primaryassessmentshaveimplicationsforthepatient’streatment.

Theoretically,theprimaryradiologistmaythereforebereluc-tanttodesignatealesion“benign”or“malignant”definitively.

Furtherlimitationscanbeattributedtotheretrospectivede-signofthestudy.Notallpatientsweresubjectedtoastandard-izedfollow-upregimenortimetofollow-upradiologicalexamina-tion.Aprospectivedesigncouldhaveallowedforanassessmentoftheimpactofanindeterminatefindingandsubsequentexami-nationsonqualityoflifeandpotentiallyacostbenefitanalysisofsuchadditionalexaminations.

DuetolimitationsregardingbothradiologicalresourcesandnumberofCTscanswewerenotabletohaveanotherdedicatedthoracicradiologisttodoare-reviewoftheCTscans.Itwouldhavebeeninterestingandindeedscientificallyrelevanttocontrolforthe“expert”.Withanestimatedproportionofdisagreementbetweentwo“experts”of0.1thesamplesizeofscanstobereviewedbyasecond“expert”wouldbe1,603withasetkappaof0.8anda95%CIfrom0.75-0.85.

STUDYIVMismatchrepairandsynchronousmetastasesincolorectalcancer:anationwidecohortstudy

AimThisstudyaimedtoinvestigate,1. whethertheroutinelyassessedMMRstatusofthecolorectal

tumourwasassociatedwiththelocalizationofsynchronousmetastaticdiseaseasthiscouldbevaluableintheassessmentofIPNonthestagingCT

2. andtheimpactofMMRonsurvivalinpatientswithstageIVdisease

MethodsAsforstudyIIandIII,thepatientcohortwasidentifiedintheDCCGdatabase,anddatafromtheDCCGweremergedwithdatafromtheNPRandtheDPR.ThisstudyevaluatedallpatientswithafirsttimediagnosisofCRCbetween2010and2012forinclusion.Patientswithhistologicallyverifiedcolonicorrectaladenocarci-nomasinwhomMMRproteinexpression(MLH1andMSH2)analysiswasperformedbyimmunohistochemistry(IHC)wereeligible.

DataonhistopathologywereextractedfromtheDPR.TrainedpathologistsassessedallspecimensaccordingtotheTNM5thEdition.ThemismatchrepairanalysesusingIHCfollowedtheguidelinesfromtheNordicImmunohistochemicalQualityControl[54].

AssociationsbetweenvariablesandsynchronousmetastaticdiseasewereanalysedwiththeChi-squareandMann-Whitney-Wilcoxontestsforcategoricalandcontinuousvariables,respec-tively.

Multivariableandmultinomiallogistic-andCox-regressionandproportionalexcesshazardsanalyseswereusedforcon-

founderadjustmentandtoadjustforthegeneralpopulationmortality.

ResultsIntotal,6,692patientswithcompleteregistrationofMMRstatuswereincluded.AdeficientMMRoccurredin983ofthepatientsandwasmorecommoninfemales,inelderlypatients,inproximaltumoursandindistincthistologicalsubtypes.TheriskofvenousinvasionorlymphnodemetastasiswaslowerinpatientswithdeficientMMRcomparedwithaproficientstatus.

SCCMwerepresentin935patientsinthefinalstudycohort(14.0%).Liver(566/935,60.5%)andpulmonarymetastases(204/935,21.8%)werethemostcommonmetastaticlocations.Onehundredtwenty-fourpatientshadmultiplemetastases,themajorityhavinghepaticmetastasesaswell(117/124,94.4%).Metastasectomywasperformedin30(14.7%)withpulmonarymetastases.

PatientswithdMMRhadadecreasedriskofhavingSCCM,OR=0.54,95%CI:0.41-0.71,P<0.001.dMMRwasassociatedwithadecreasedriskoflivermetastasesinmultinomiallogisticregres-sion(OR=0.30,95%CI:0.18-0.49,P<0.001),butnostatisticalsignificantassociationwasfoundforeitherpulmonarymetastases(OR=0.71,95%CI:0.39-1.29,P=0.258)ormetastasesinbothliverandlung(OR=0.26,95%CI:0.26-1.77,P=0.436).

Finally,wefoundthatdMMRhadnosignificantimpactonsurvivalintheunivariableCoxregressionanalysis,HR=1.24(95%CI:0.91-1.70,P=0.166),orintheunivariableproportionalexcesshazardsanalysis,HR=1.26(95%CI:0.90-1.76,P=0.183).NordidMMRstatusinfluencesurvivalinthemultivariableanalyses.

ConclusionPatientswithdMMRhaddecreasedriskofsynchronousmetastat-icdisease,buttheassociationwaslimitedtohepaticmetastases.SurvivalinstageIVpatientswasnotinfluencedbyMMRstatus.

LimitationsDuetothemethodologicalsimilaritieswithstudyIIthepresentstudyhassomeofthesamelimitations.

Additionally,therecommendationsforMMRimmunohisto-chemistry(IHC)wererevisedduringthestudyperiodresultinginarelativelyyoungerpatientpopulationinthebeginningofthestudyperiod.Secondly,only75%ofthepatientseligibleforthestudywereMMRIHCtested.Thesetwopointsmayresultinsomedegreeofselectionbias.

DeficientMMRtumourswerepresentedasasingleentity.Thismaybeanoversimplification.

Itiswell-knownthattumourmorphologyandbehaviourde-pendontheetiologyoftheMMRdeficiencyandthesecondarymutationsresultingfrommicrosatelliteinstability[55].

ThenumberofdeficientMMRtumoursmaybeslightlyun-derestimatedduetotheIHCtestingapplied.IHCdetectsabout95%ofMMRdeficienttumours.AmissensemutationintheMLH1genecanresultinanon-functional,butIHCdetectableprotein[56].

Finally,theriskofatypeIIerrorregardingthesignificanceofMMRstatusonpulmonarymetastasisshouldbekeptinmind.Fewpatientshadconfinedpulmonarymetastasesrelativelytopatientswithhepaticmetastasesandonlyfewofthepulmonarymetastaseswerehistologicallyconfirmed.Oneshouldtakecau-tiontogivedefinitiveconclusionsontheimpactofMMRstatusonextra-hepaticmetastasis.


METHODOLOGICALCONSIDERATIONS

ThisthesisislargelybasedonprospectivelycollecteddatafromtheDCCGdatabase.Inthissectionsomeaspectsofthemethodo-logicalapproachtohandlingthesedataforthisthesiswillbediscussed.TheapproachesweresimilarinstudiesII,IIIandIV,andwillbedescribedcollectively,thoughsmalldifferencesexist-edregardingtherelevantstudyperiodanddemographytosatisfytheindividualstudyobjectives,availabilityofCTscansanddatafromotherdatabases.

DatahavebeenprospectivelycollectedintheDCCGdatabasesincethe1stofMay2001onallnewlydiagnosedcolorectalcan-cercasesinDenmarktosurveythatthequalityofCRCtreatmentadherestothedesiredclinicalstandard[57].Furthermore,asthepatientcompletenessiscurrently>98%,[58]thecollectionofuniformandstandardizeddataenablestheconductionofna-tionwide,epidemiologicalstudiesrepresentativefortheDanishpopulationwithlowriskofselectionandreferralbias[59].Previ-ousrandomcheckshavefoundahighvalidityoftheDCCGdata[60].AmonthlylinkagetotheNPRservestovalidatethecom-pletenessofdata.

AllsurgicaldepartmentsregisterdataonpatientswithnewlydiagnosedCRCprospectivelyintothedatabaseanddepartmentsarenotifiedofmissingdataandlogicalerrorsinthedatareport-ing[61].

DataonallpatientsintheDCCGdatabasewereadditionallyretrievedfromtwoothernationwidepatientregistries:theNPR(registryofallpatientsadmittedtoDanishsomatichospitals,emergencyrooms,andoutpatientclinics)andtheDPR(registryofallindividualsinDenmarkwhohavehadahistologicalexamina-tionoftissue,cell,orautopsymaterial)[61].ThelinkbetweenthreenationwidedatabasesservedasasourceforidentificationofconfoundersnotregisteredintheDCCGdatabase.Importantly,thismergealsoservedasavalidationofvariablesregisteredintheDCCGdatabase.Incaseofamismatchbetweenthedatabasesonspecifickeyvariables,amanualsearchinthepathologyandpatientregistries,patientrecordsandradiologyreports(ifavaila-ble)wasconducted.ThekeyvariablesincludedthediagnosisofCRC,dateforthe(firsttime)diagnosisofCRC,UICCstageatthetimeofdiagnosisandcourseoftreatment.Themergeofdataacrossdifferentregistriesisuncomplicatedduetotheuniqueandpersonalcivilregistrationnumber,giventoallDanishcitizensatbirth.Themergeandmanagementofdatawasconductedcen-trallybytheDCCG’sdatabasemanagertoensurecleandatasetsforstatisticalanalyses.

ThoughtheDCCGdatabasehasbeenreportedsufficientquantitativelyaswellasqualitatively,theaccuracyofthemeta-staticcodingisnotknown.Potentialunder-andover-recordingofmetastaticspreadcouldleadtobiasedestimatesofassociation.Thereforeafurthervalidationontheregistrationofsynchronousmetastaticdiseasewasdeemedessentialtofulfiltheobjectiveofthethesis.

Additionally,thisvalidationsoughttoensurethatregisteredmetastaticdiseasewasactuallysynchronousandmostlikelydidoriginatefromacolorectalcancer.

TheprimarytumourItwasofparamountimportanceforinclusion,thatpatientshadahistologicalverificationoftheircolorectalcancer.HistologicalverificationonthediagnosiswasobtainedfromtheDPR.Ifapatienthadnotbeensubjectedtosurgeryoranyotherhistologi-calexamination,thediagnosisofamalignantcolorectaltumourhadtobeverifiedbyatrainedcolorectalsurgeonforthepatient

tobeincluded.InthesecasestheCRCdiagnosisintheDCCGdatabasehadtocorrespondtoaCRCdiagnosisintheNPR.

Onlypatientswithafirst-timediagnosisofCRCfromthecommencementofCRCregistrationintheDCCGdatabasefrom2001andonwardwereincluded.ThepatientwasexcludedinthecaseofapreviousregisteredspecimenintheDPRsuggestingCRCtominimizetheriskofanalysingdataonrecurrentCRCcasesormetachronousmetastaticdisease.Furthermore,thiswasdonetoensurethatdatafromtheregistriesconcernedtheprimarystag-ing.

MetastasesSynchronousmetastaticdiseasewasdefinedasanydetectedmetastaseswithinatimeframeof30dayspriortill120daysafterthediagnosisoftheindexcancer.Thereexistsnodefiniteconsen-susregardingthedefinitionofsynchronousandmetachronousmetastases.Thefourmonths’timerangeisinlinewiththe“timeofstagingdata”accordingtotheAmericanJointCommitteeonCancer[18].Intheliterature“synchronous”representslesionsdetectedbothatthetimeofresectionoftheindexcancer,andwithin3,6,or12monthsfromthediagnosisoftheindexcancer,butthetermisoftennotpreciselydefined[62-66].Accordingtomedicaldictionaries“synchronous”referstolesionsorconditionsattimesofaneventofinterest[67].Inthegivencase,theeventofinterestistheprimarystaging.Wedefinedtheprimarystagingasanydiagnosticwork-upperformed30daysprior-till120daysafterthediagnosisoftheindexcancer.Itistheassumptionthatanydetectedmetastaticspreadwithin120daysfromthediagno-siswaspresentatthetimeoftheCRCdiagnosiseventhoughitwasnotdetectedatthispoint.

Indeterminatehepaticand/orpulmonarylesionsdetectedatthestagingproceduresshouldnotberegisteredasmetastasesinthedatabaseaccordingtotheDCCGregistrationguidelines.Ap-plyingatimeframefordetectionof“synchronous”metastasesthereforeallowsforafollow-upCTscanforclarificationofsuchpotentialindeterminatelesionsatthreemonths,whichisclinicalpracticeinsomeDanishcolorectalcancercentres.Subsequentexaminationswereassumedtocontrolforrecurrentdiseaseinpatientsnotpreviouslyregisteredwithdisseminateddisease.TheDCCGdatabaseholdsnoinformationonrecurrent/metachronousdisease.The30-dayslimitpriortothediagnosisoftheCRCissomewhatarbitrarily,butensuredthatallrelevantdiagnosticproceduresinthestagingprocesscouldbeidentifiedintheNPR.

Noneofthepatientsinthedatabasehadmetastasesregis-teredpriortothese30days.Anepidemiologicalcriticismtothistimeframeisthediagnosisofsynchronousmetastasesinpatientswithafollow-upshorterthan120days.Potentially,somepatientsmaydiewithinthese120daysandtherebybeforethefinaldiag-nosisofsynchronousmetastaticdisease.

Avalidationofregisteredpulmonarymetastaseswasper-formedondataobtainedfromtheDCCGdatabaseastheaccura-cyofthe“pulmonarymetastases”diagnosisisofparamountimportanceforthisthesis.Asstatedabove,onlydefinitepulmo-narymetastasesonradiologicaland/orhistologicalevaluationaretoberegisteredintheDCCGdatabase–notindeterminatefind-ings.

TheDPRwasscrutinizedforanyhistologicalconfirmationofmetastaticdisease.Inmostofthecasesthis“goldenstandard”verificationcouldnotbeobtained.Thereforedataonallradiolog-icalproceduresperformedduringtheprimarystagingperiodwereextractedfromtheNPR.Patientswereexcludediftheyhadnohistologicalverificationofapulmonarylesionornorelevantradiologicalprocedure.


TheDPRwasalsoreviewedfordataonothermetastasesthanpulmonaryregisteredintheDCCGdatabase,butnoequivalentrestrictionsondiagnosisoftheseextra-pulmonarymetastasesinrelationtoradiologicalorsurgicalprocedureswereapplied.

WeusedtheDPRtodetectsynchronousmetastaticdiseaseinthecaseswherenoinformationwasavailableintheotherregis-triesregardingthecancerstageatdiagnosis.Patientswhosecancerstageremainedundeterminedwereexcludedasthestageofthediseaseisessentialtoallaspectsoftheincludedstudies.

OthercancersthanCRCPatientswithothercancersthanCRC(exceptfornon-melanomaskincancers)fiveyearspriortillfiveyearsaftertheCRCdiagnosiswereexcluded.Ithasbeenarguedthatpatientswithmultiplemalignancieswillbecomeanincreasinglyimportanttopicincan-cerepidemiologyduetoanincreasingnumberofcancersurvivors[68].Liuetal.foundthat9%ofpatientswithaninitialCRCdevel-opasubsequentmalignantdisease.

Inanepidemiologicalperspectiveitwouldhavebeeninterest-ingtohavethecovariate“Othercancer”availableforthemulti-variableanalysis.Patientswithconcomitantcancerswere,how-ever,excludedforseveralreasons.InsomecasesothercancerformshadinitiallybeeninterpretedasCRCandfaultyenteredintheDCCGdatabase,typicallynon-CRCwithinvasiontotherectumorcolonandanalcancersregisteredasrectalcancers.Inothercaseshistologicalsamplingofwhatwasthoughttobedissemina-tionoftheCRCrevealedothercancers–e.g.histologicalsamplingofpulmonarymetastasesrevealingprimarylungcancers.

AreviewofallcaseswithspecimensregisteredintheDPRwasundertakenincooperationwithanexperiencedgastrointes-tinalpathologisttodeterminewhetherthehistologicalsubtypewasconsistentwithCRCineachcase.Additionally,areviewwasdoneinallcasesregisteredwithanothercancerthanCRCintheabdomenorthoraciccavitytoidentifycaseswherepotentialdirectinvasionormetastasesfromtheCRCerroneouslyhadbeenregisteredasanothercancer.Despitetheinitialintentiontoin-cludeallpatientsintheDCCGdatabaseandpotentialepidemio-logicalconcerns,itwasdeemednecessarytoexcludepatientswithevidentothercancerthanCRCafterthesereviewstoensurethat1)patientsactuallyhadCRC,2)metastasesdidoriginatefromtheCRCand3)thatdataononcologicaltreatmentextractedfromrelevantdatabasesconcernedtheCRC.

DISCUSSION

PrincipalfindingsPulmonarylesionsarecommonattheinitialstagingofcolorectalcancers,andthefrequencyhasincreasedwiththeintroductionofcomputedtomographyscans.Fewofthelesionswerehistologi-callyconfirmed.Theaccuracyoftheradiologicalcharacterizationisthereforeofparamountimportance.Survivalprognosisfortheincreasingnumberofpatientsregisteredashavingadefinitepulmonarymetastasiswasseverelyimpaired.However,thede-tectionofthesemetastasesisimportantassomepatientscanbecuredwithmetastasectomyandothersmaybenefitfrompallia-tivechemotherapyandresectionoftheindexcancer.Themeta-staticdiseasewasconfinedtothelungsinmorethan1/3ofthepatientswithpulmonarymetastases.

Unfortunately,asubstantialnumberofthepulmonarynod-ulescannotbeclassifiedasmetastasesorinsignificantbenignlesionsatthetimeofthestaging.Thenumberandclinicalsignifi-

canceoftheseindeterminatenodulesdependontheevaluatingradiologist.Theriskofmalignancywasabout10%inasystematicreviewofpreviousstudyresultscomparedwith20%ofIPNsdetectedataCTreviewbyanexperienced,thoracicradiologistofalocalcohortofmorethan800consecutivepatientswithnewlydiagnosedCRC.TheCTstagingscanhasahighspecificityforpulmonarymetastases,butthesensitivityisimpairedduetotheindeterminatelesions.Despitemultiplestudiesnopathognomon-icradiologicalfeatureformalignancyofanindeterminatepulmo-narynoduleexists.Arectalindexcancer,liverandlymphnodemetastases,tumourdepositsandvenousinvasionarefactorsassociatedwithpulmonaryspread,however,theiruseinthemanagementofIPNsremainsuncertain.Potentially,biomarkerscouldbeofsomevalueindeterminingthetruenatureoftheseindeterminatelesions.MismatchrepairstatushadnosignificantimpactontheoccurrenceofsynchronouspulmonarymetastasesandisthereforeunlikelytohavevalueintheclinicalmanagementofIPNs.

CRCandthemetastaticprocessColorectalcancer(CRC)isasignificantcauseofmorbidityandmortalityworldwide.In2012,GlobalCancerStatisticsestimatedmorethan1.3millionincidentcasesandalmost700,000deathsfromCRC[69].AccordingtotheDanishCancerRegistrymorethan4,400patientswerediagnosedwithcolorectalcancerinDenmarkin2011[70].HenceCRCwasthethirdmostcommonlydiagnosedcancerinDanishmenandsecondinDanishwomen,andthethirdmostcommoncauseofcancerdeathinbothgenders[70].Ap-proximately90%ofalldeathsinpatientswithCRCareduetometastaticdissemination[71].Earlydetectionisofparamountimportancewithregardstothechanceofcure,however,atpresentation15-25%ofthepatientswillhavemetastaticdisease[72].Figure1depicts5-yearsurvivalforpatientswithconfinedsynchronouspulmonarymetastasesincomparisontosurvivalforpatientswithUICCstageI-IIIdiseaseatthetimeofdiagnosis.

Figure1

SurvivalaccordingtoUICCstage(basedonstudyIIdata)[2] Colorectalcancersareheterogeneous.Despitebeingthebest-examinedtumourentitylittleisknownaboutthemoleculardeterminantsformetastasis[71].Stablefrequenciesfordissemi-nationtospecifictargetorganshasbeenarguedtosuggestforamolecularbackgroundofthemetastatictropism[72].Themajori-tyofcolorectalcancersareadenocarcinomasdevelopingfrombenignprecursors,adenomas,inamulti-stepprocessofmuta-


tionsandepigeneticchangesintumoursuppressorgenesandoncogenes[73].Sincethefirstmodelofcolorectalcarcinogenesismorethan20yearsago,[73,74]ithasbecomeclearthatCRCdevelopsthroughseveralheterogeneousmolecularpathways[75-77].Awarenessofthisheterogeneityisimportant,asitmayhaveconsequencesforthemetastaticpotentialoftheCRC[78,79].

Theunderstandingofmetastasis,theshiftfromlocalizedtosystemicdisease,isessentialinCRCtherapyandisnecessarytoaddressforfutureinterventionandpreventionstrategies[6].MorethanacenturyagoPagetdescribedthemetastaticprocessinbotanicalterms,theso-calledseed-and-soiltheory,inwhichthedistributionofthemetastasesisnotsimplyamatterofchance[80].Theprimarytumouraswellasthepredilectionsiteformetastasescouldpossessspecificpropertiesthatpredisposesecondarygrowthatspecificlocations[72].Thoughtheunderly-ingmolecularabnormalitiesforCRCcarcinogenesishavebeenextensivelyinvestigated,littleisknownaboutthedeterminantsforthemetastaticformation[71].ThetraditionalperceptionofmetastasisinCRChasthereforeadheredtothecascadehypothe-sis,inwhichtheliverisaffectedfirstlyasmostofthevenousbloodfromthecolonenterstheportalveinandtherebytransferscancercellstothelivercapillaries[81-83].Subsequently,pulmo-narymetastasesarisefromlivermetastasesandfinally,arterialmetastasesdevelopfromthepulmonarymetastases[83,84].

PulmonarymetastasesBlalockisoftencreditedforperformingthefirstpulmonaryme-tastasectomyincolorectalcancerin1944[85].

Actually,thispaperreferstoapneumonectomyofalungco-incidentallyaffectedbyCRCmetastasis.Atthistimesurgeryinthetreatmentofpulmonarymetastaseswereregardedasobsoleteasthediseasehadescapedthe“first”hepaticfilterandtherebywassystemic[86].

Todaynationalandinternationalguidelinesrecommendpul-monarymetastasectomywhenpossible[30,31,87].AsurveyofthecurrentpracticeamongmembersoftheEuropeanSocietyofThoracicSurgeonsfoundthatpulmonarymetastasectomyrepre-sentsupto10%ofthesurgicalactivityandwasperformedby99.3%oftherespondersintheCRCsetting[88].Criteriaforsurgi-calinterventionadheretotheprinciplesintroducedin1965byThomfordetal.andrequirethatprimarytumourisundercontrol,noextrathoraciclesionsarepresent(exceptforresectablelivermetastases),themetastasesappeartechnicallyresectable,andthegeneralandfunctionalrisksaretolerable[89].Thepracticeofpulmonarymetastasectomyisbasedonmainlyretrospectivedataofhighlyselectedpatientseriesdespiteawidespreadconductionandguidelinerecommendationofsurgicalintervention[90].Thesestudiesreport5-yearsurvivalratesofupto40-60%[90].ThisprognosisisinlinewiththeresultsofstudyII,however,onlyasmallfractionofthepatientsweresubjectedtopulmonaryresectionandtheresultsaremostlikelyaffectedbyselectionbiasorconfoundingbyindication.Thefirstrandomizedtrial,Pulmo-naryMetastasectomyinColorectalCancer[PulMiCC]iscurrentlybeingundertaken[91].Anoptimalassessmentofthetherapeuticstrategyinthesepatientsnecessitatesfurtherclarificationoftheunderlyingepidemiologyandcontroversiesintheoptimaldiag-nosticapproach.

TrendsindetectionInconcordancewiththecascadehypothesisandpreviousfind-ings,thelungswerethesecondmostcommonlocationforsyn-chronousmetastaticspreadinCRC,onlysurpassedinnumberby

livermetastases[2,15,20].Itiswellestablishedthatthelungsarethemostcommonextra-hepaticlocationfordiseaserecur-rence,[92]butdataonsynchronouspresentationonpulmonarymetastasesaremorescarce[20,22,65].Inthisthesis,thepreva-lenceofsynchronouspulmonarymetastaseswasinvestigatedforthefirsttimeonanationwidebasis.Mitryetal.[20]investigatedtheepidemiologyandprognosisofcolorectalcancerinaFrenchregionalcohortfrom1976to2005anddiscoveredanearlythree-foldincrementintheestimatedprevalenceofSPCM.Despiteanearlierdiagnosisovertime,theoccurrenceofmetachronouspulmonarymetastases(inpatientsresectedforcureandfollowedwithayearlychestX-rayfor5years)didnotchangeduringthestudyperiod[20].ThesetrendswereattributedtoanincreasinguseofCT-scansovertimethoughdataonthestagingprocedurewerenotavailable.In2005pulmonarystagingwithCTscanswerenotfullyintegratedatallcentrestreatingCRCinDenmark.AsfoundintheFrenchstudythecontinuousimplementationofchestCTfollowingnationalguidelineswasassociatedwithanincreasednumberofregisteredSPCM.

TheuseofpreoperativestagingwithCTofthechestincreasedsignificantlyfrom9%in2001–2004to63%in2009–2011withaconcomitantincreaseinthenumberofregisteredpulmonarySCCMfrom5.0%to9.3%(Figure2).TheincreasingapplicationofCTcanonlyexplaintheincreasedregistrationofpulmonaryme-tastasesinpart.Otherpotentialdeterminantscannotbeextract-edfromouravailabledata,butanincreasedawarenessandcon-comitantregistrationofpulmonarymetastases,increasingexperienceofevaluatingradiologistandimprovingscanningtechnology(e.g.theintroductionofmulti-slicescanners)maybeofimportance.

Figure2

NumberofstagingchestCTscansandsynchronouspulmonarymetastasesintheDanishCRCcohortfrom2001-2011

StagingchestCT-proetconThenecessityofasensitivepulmonarystagingmodalityisunder-linedbytheprognosticeffectofthedetectedpulmonarymetas-tasesandthefactthat>90%ofthesemetastasesaresolelybasedonaradiologicaldiagnosis.Furthermore,ahighaccuracyofthestagingisimportanttoavoidfirstlyunnecessarysurgeryinpa-tientswithnolungmetastases,andsecondlythepotentialexclu-sionofpatientswithasurgicallycurablediseasefromapotential-lybeneficialprocedure.


TodayapreoperativestagingchestCTisrecommendedintheDCCG’sguidelines,[32]theNationalComprehensiveCancerNet-workguidelinesforbothcolonicandrectalcancer[30,31]andtheAssociationofColoproctologyofGreatBritainandIreland[33].InthepositionpaperfromtheEuropeanRegistrationofCancerCaremultidisciplinaryconsensusconferencein2012itisstatedforcoloniccancerstaging:“Chest-CTasroutinework-upisrecom-mended;althoughthereisevidencethatachestX-raymaybeusedforroutinework-up”andinthesectionforrectalcancerstaging“AbdominalCT,chestX-rayorCTaretheminimalre-quirementsforstagingofdistantmetastases.Thoracicandab-dominalCTarerecommendedaspartofthestagingprotocoltodetectdistantmetastases,especiallyforhighriskrectalcancer”[93].Despitebeingfullyintegratedinthediagnosticwork-up,thevalueofaroutinelyperformedstagingchestCThasbeensubjecttomuchdebate.ThisisalsothereasonwhychestX-rayisstillacceptedinthediagnosticwork-upaslistedabove.Itiswellestablishedthatthepick-uprateofpulmonarymetastasesishigherinCTthanconventionalchestX-ray[34].Thisisduetoahigherspatialresolutionandthelackofsuperimposition,andCTdetectssmallernodulesatanearliertime[94].

However,scepticsdoubtanybeneficialclinicalimplicationsofthehigherdetectionrate.Furthermore,concernisraisedregard-ingthepossibledelayedtreatment,prolongedanxietyandaddi-tionaldiagnosticprocedureswithaccompanyingcostandradia-tionexposureduetoavastnumberofindeterminatepulmonarylesionsonCT[24].AreviewofstudiescomparingchestCTandchestX-rayfoundlimitedevidenceforusingchestX-ray[34].TheimplicationsofthehigherdetectionratebyCTwere,however,unclear[34].Inthesettingofmetachronouspulmonarymetasta-sesearlydetectionbyCTaccompaniedbyaggressiveresectionhasbeenassociatedwithfavourablesurvivalprognosis,[95]whereasyearlychestX-rayisofquestionablevalue[96].ThesesurrogatemarkersfortheeffectsofchestCTandX-raymaynotbedirectlytranslatedtoastatementregardingtheirrelevanceinthedetectionandtreatmentofSPCM.SPCMmayimplyamoreaggressivediseasewithpoorersurvivalratesthaninpatientswithmetachronouslesions,[97]butasformetachronouslesionsearlydetectionbeforefurtherdisseminationmayimprovethechanceofcurativesurgery[90,98].SomeauthorsproposethatchestCT

shouldbereservedforhigh-riskpatients;i.e.patientswithrectalcancer,livermetastasesornodepositivedisease[21-24,99,100].Unfortunately,evenpatientswithearlystageCRCdeveloppul-monarymetastasesand37%ofpatients(asfoundinstudyII)withpulmonaryinvolvementwillhavenodetectableextra-thoracicdissemination.Tanetal.foundanincidenceof5.9%ofisolatedpulmonarymetastasesinpatientswithcoloniccancer[22].

ThetruevalueofachestCTcanonlybeassessedinapro-spectivestudywheretheinitialsurgicalintentisknownbeforefurtherinvestigationsareperformed.AvalueoftheinitialstagingCT(oftennotdiscussed)isitsuseasabaselinestudyintherou-tinefollow-upafter12and36months(accordingtoDanishguide-lines[101])fromtheradicalresectionoftheindextumour. AschestCTiscurrentlyfullyintegratedinournationalguide-linesandeverydayclinicalpracticeadiscussiononitsrelevanceinstaginginrelationtoCXRhasbecomeobsolete.Rather,futurefocusmaybeonthepotentialintroductionofPET/CTintopulmo-narystaging.Theidentificationofpatientsinhighriskforpulmo-narymetastasesmay,however,stillbeofgreatimportanceinrelationtothestagingCT;notforthepreclusionofscansinsomepatients,butforadditionalguidance,whenindeterminatelesionsareencountered.

IndeterminatePulmonaryNodulePulmonarymetastasesmaypresentinnumerouswaysonchestCT.Asimpleexhaustiveandcompletedefinitionofapulmonarymetastasesincolorectalcancerbasedonradiologicalfeaturescannotbegiven.Asmostoftheradiologicalfeaturesareunspecif-icformetastasesandnopathognomoniccharacteristicsexist,asubstantialnumberofthepulmonarynodulescannotreadilybeclassifiedaseitherbenignormalignantimpairingthespecificityoftheCT.Oftenthenodulesofmetastaticoriginareroundedlesionsofsofttissueattenuationvaryinginsize,well-circumscribedandlocatedintheperipheryandlowerpartsofthelungs[102].

Asforotheradenocarcinomas,pulmonarymetastasesofcolo-rectaloriginmaypresentassinglelesions.Thepresenceofmulti-plepulmonarynodulesinpatientswithaknownextra-thoracicmalignancytypicallyindicatespulmonarymetastasis,butradio-logicalcharacteristicsremainunspecific;especiallywhenonlysinglelesionsareencountered[102].Theradiologicalappearance

Figure3

SolitaryIndeterminatePulmonaryNodule(redarrow)detectedatstagingCTscan


ofpulmonarymetastasesmayfurthermoredependontherouteofdissemination[103].

Mostmetastaticnodulesarelessthan1cmindiameter,butincreasingsizeofpulmonarynoduleshasbeenassociatedwithelevatedriskofmalignancy[51,104].Growthcharacteristicsofmetastaticnodulesvary(eveninthesamepatient)andvolumedoublingtimehasbeenreportedfrom11to150daysforcolorec-talcancer[105].Growthisafeaturethatcanbealteredwhenchemotherapyisadministered.Thisalsoappliestocalcificationandcavitationofthenodules,whichmaybetoounspecificfind-ingstodifferentiatemalignantnodulesfrombenignones[102].Furthermore,themetastasesmayhaveatypicalradiologicalmani-festationsmakingthediagnosisevenmoredifficult[106].Thediagnosticcriteriaforevaluatingandmanagingpulmonarynod-ulesadheretotherecommendationsdevelopedinlung-cancerscreeningtrials[43,107,108].Theaprioririskofpulmonaryma-lignancyinapatientwithacolorectalcancerisnotcomparabletoaparticipantinalung-cancerscreeningstudyandtheseguide-linesmaynotbedirectlyappliedtotheCRCsetting.Interestingly,inalung-cancerscreeningtrialtheprevalenceofsmall,non-calcifiedpulmonarynodulesdetectedonCTwas51%[108].

Recentlyadditionalstudiesinthecolorectalcancersettinghavebeenpublished[3,100,109-114].Resultsstillvaryandexter-nalvalidityofthesemainlyretrospective,single-centrestudiesareimpairedbydifferentdefinitionsofIPNs,typeofimagingperformed,patientcharacteristics,presenceofextra-thoracicmetastases,varyinginclusionofmetachronousnoduleswereincludedandexclusionofsomenoduleswithspecificmorphologi-calfeatures.Furthermore,resultsareimpairedbyvaryingfollow-upregimensanddefinitionsofamalignantoutcomeofthenod-ulesandrarelyincludeahistologicalverification.

ManagementofIPN–evaluationofexistingguidelinesSomestudiesonIPNintheCRCsettinghavestrivedtodevelopguidelinesonthemanagementofIPN.Gomezetal.[111]pre-sentedastrategyformanagementofpre-operativelydetectedIPNsinpatientsevaluatedforresectionoflivermetastases.Brief-ly,patientswithresectableliverdiseasewereresectedandre-assessedwithaPET/CTafterthreemonths.Ifpatientshadbor-derlineresectablelivermetastasestheywererecommendedtohaveaPET/CTpriortopotentiallivermetastasectomy.Baeketal.[115]failedtoestablishfollow-upguidelinesinpatientswithrectalcancerandIPNduetofewpatientshavingpulmonarymetastasesatfollow-up.Theysuggestedalongerfollow-upperi-odforpatientssubjectedtoFOLFOXtherapythanthosetreatedwith5-FUaloneornochemotherapy,asthetimetodevelopmentofpulmonarymetastaseswaslongerinpatientsinFOLFOXtreat-ment.However,thistimedifferencewasnotstatisticallysignifi-cantandtherecommendationisbasedonaverylimitedpatientcohort.NorcouldKimetal.[110]definitivelyconcludethatadju-vanttherapyhadimpactonthetimetoprogressionofIPNintodefinitemalignantlesions.Inthisstudyfiveriskfactorsformalig-nantprogressionwereidentifiedbeing:metachronousIPNs,arectalindexcancer,ahighernodalstage,bilaterallunginvolve-ment,andperineuralinvasion.Thesefactorswereusedtocon-structariskpredictionmodelaccordingtowhichthefollow-upofIPNcouldbeindividualisedfromnofurtherfollow-uptorepeatCTscanswith3monthsinterval.Unfortunately,perineuralinva-sionandnodalstatusmaynotnecessarilybeknowninthepre-operativeplanning.

Littleattentioninpreviousstudiesandguidelineproposalshasbeengiventotheexperienceoftheevaluatingradiologist,thoughexactlythisexperienceiscommonlylistedasoneofsev-

eralreasonsforvaryingresultsbetweenstudiesonIPN.InstudyIIItheinter-readervariabilityinthedetectionandcharacteriza-tionofpulmonarynodulesonCTscanswasfoundtobesubstan-tial.ThisisinlinewithresultsfromothersettingthanCRC[116-118].Apulmonarynoduleinitiallycharacterizedasindeterminatemaybereclassifiedaseitherbenignormalignantinasecondradiologicalreview[35,119].Evenbetweenexpertradiologiststhedefinitionof“truth”mayvary[116].Achallengeineverydayclinicistheinadequateaccessibilityofdedicatedthoracicradiolo-gistsforassessmentsofallstagingchestCTs.Thisissuecouldbereducedifasecondreview,byagroupofexperiencedthoracicradiologists,ofthescanswithIPNwasperformed.Intotal,only10%ofthestagingscansinthestudyIIIwouldhavehadtounder-goareviewbydedicatedthoracicradiologists.Ofcourse,thefeasibilityandvalueofthisapproachneedstobevalidatedinaprospectivetrial.

ManagementofIPN–proposalofnewguidelineBecauseIPNsaremostlikelyofbenignorigin,furtherdiagnosticworkupofthenodulesshouldnotpostponethetreatmentoftheindextumour;patientsshouldbetreated“inthebenefitofdoubt”.Preferablytreatmentplanningisbasedontheassump-tionthatIPNsarenotmalignantandarefollowedwithserialimaging.Additionalpre-operativework-uphasbeenproposedinpatientswithborderlineresectablelivermetastasesasstatedabove[111].ThelackofaconsensusinthedefinitionofIPNandvaryingCTtechniquesutilizedmakeitdifficulttomakeasingleomnipotentmanagementguidelinewithgreatexternalvalidityintheCRCsetting.Pre-operativelyknownclinicopathologicalfactors(besidessynchronouslivermetastases)andradiologicalcharac-teristicstobeusedintheriskassessmentofIPNareunconvinc-ing.Ithasbeenstated,thatnodulesizeistheonlymeasurablefactoronchestCT[110].

Bearingtheseresultsinmindandthefactthatthelevelofex-perienceoftheevaluatingradiologistisadecisiveparameterintheassessmentofIPN(asfoundinstudyIII),itmayberelevanttotaketheinter-observervarianceintoaccountwhenmanagementguidelinesofIPNsaresubmitted.InFigure4amanagementstrat-egyofIPNisputforward.

Itseemsclearthatsomenodulespossessobvioussignsofma-lignancyorbenignity.Thepatientshouldbesubjectedtothemultidisciplinaryteam(MDT)conferencewithrepresentativesfromabdominalandthoracicsurgery,oncology,pathologyandradiologyifthereisevidenceofpulmonarymetastases.Nofur-therfollow-upisnecessarybesidesroutineCRCsurveillanceifthenoduleisclearlybenign.InthecasewhereanIPNisencounteredintheprimaryCTreview,thescanistobeassessedbyagroupofdedicatedthoracicradiologists.Thiswillreservethelimitedavail-abilityofthoracicradiologicalexpertiseforasubsetofthestagedpatients.Thesecondaryreviewwilldeterminethefollowingwork-up.Ifpulmonarynodulesarestilldeemed“indeterminate”atthesecondreview,thepatientissubjectedtoalow-dosefol-low-upCTat3monthsintervaloraPET-CT,dependingonthesizeandpresenceofground-glassmorphology.Aground-glassnoduleis,accordingtotheFleischnerSociety,afocalnodularareaofincreasedlungattenuationthroughwhichnormalparenchymalstructurescanbevisualized,sometimesreferredtoasa“sub-solid”nodule[120].AsuspicionofmalignancymaypersistdespiteanegativeresultinsomeofthesmallestnodulesbeingPET-CTscanned.Thesepatientsmaybesubjectedtoalow-doseCTat3monthsintervalaswelltodeterminethepotentialgrowthrateofthenodule.Anodulethatappearsstableinsizeinsimilarprojec-tionsinaCTscanisconsideredmorelikelybenign[121].Inthe


absenceofgrowthornewnodules,wesuggestthatthepatientcanbeallocatedtothestandardfollow-upregimenforthetreat-mentoftheindexcancer.

Figure4

ManagementofIndeterminatePulmonaryNodules.IPN,indeterminatepulmonarynodule;SPCM,synchronouspulmonarymetastases;GGN,ground-glassnodule;MDT,multidisciplinaryteamconference;CT,computedtomography

AccordingtotheDCCGthisincludesaCTofthechestandab-

domenat12and36monthsafteracurativeresection,[122]whichallowsfurtherassessmentofthenoduleformorethantherecommended2yearswithrespecttothetumourgrowthkineticsofadenocarcinoma[43,121,123].ThiswouldalsobesufficientforapotentialdelayintimetoprogressionofIPNinthecaseofadju-vantchemotherapy[110,115].InfewcasestheMDTcandecidetosubjectthepatienttoaCTguidedcorebiopsy.Thisisparticu-larlyusefulforperipherallesionsandhasbeenreportedtohaveamoderatespecificity,buthigh(>95%)sensitivityformalignantlesions[124].Theneedofatissuediagnosisshould,however,beweighedagainsttheriskofpneumothoraxandhemorrhage[121,124].Onceagain,itisofoutermostimportanceinanypro-posedguidelineforthemanagementofIPNdetectedatthepri-maryCRCstagingthatIPNandtherelevantdiagnosticwork-upshouldnotpersedelaythetreatmentandcaninitiallybedisre-gardedinthetreatmentofchoice.

ManagementofIPN–insearchforthefutureguidelineThemanagementstrategyasproposedaboveisrathersimpleandpragmatic.Optimally,reproducibleandobjectivepatientandnodulecharacteristicscouldaidtodeterminethefurtherwork-upandtreatmentofpatientswithIPNs[125].“PulmonaryNoduleMalignancyRiskcalculators”basedonBayesiananalysis,asde-velopedforeducationaluse,[126,127]aredesirable.ThediversityofradiologicalpresentationformsofpulmonarymetastasesandtheabsenceofradiologicalfeaturesinIPNofmalignantnaturelimittheuseofradiologicalcharacteristicsintheriskpredictionforamalignantnatureofIPN.

Notsurprisingly,characteristicsoftheCRCalreadyknowntobeassociatedwithmetastaticspreadtothelungsarealsofoundtobeassociatedwithanelevatedriskofanIPNbeingmalignantatfollow-up[38,39,42,48-50,100,109,110].Knownriskfactorssuchasrectalindexcancer,lymphnodespreadandhepaticin-volvementshouldwarrantahighdegreeofsuspicionofpulmo-

narymetastases.However,thesefactorsremainunspecificandtheirpotentialroleinthemanagementofIPNisyettobedefined.

Despitetheassociationbetweenarectalcancerandpulmo-narymetastasesinstudyIImorethan50%ofthepatientswithsynchronousmetastasesconfinedtothelungshadanindexcan-cerinthecolon.

Thedeterminantsformetastaticspreadrelatetoanatomicalfeaturesbutaremodulatedbytumour-hostinteractionsthatarecurrentlynotfullyunderstood,inlinewiththeseed-and-soiltheory.

Whethersuchtumour-hostinteractionsunderliesomeofthediscoveredassociationinstudyIIsuchasbetweenincreasingageandpulmonarymetastasisremainsspeculative.Interestingly,loweragewasassociatedwithhepaticmetastasesinbothstudyIIandIVandcontrastedthefindingsforpulmonarymetastases.Potentialmechanismscouldbeage-relatedchangesinlymphaticflow,declineinimmunologicalfunctionandalterationsinmuta-tionalstatus[128].Ageperseismostlikelynotatrueriskfactor.TheassociationbetweenageandpulmonarymetastasescouldsimplybeexplainedbyamoreadvancedtumourstageinelderlyatdiagnosisandtheassociationdisappearedinstudyIVaftertheadjustmentforrelevantpathologicalfeaturesoftheindexcancerincludingT-andN-stage.Nevertheless,pulmonarymetastasesdooccureveninearlytumourstagesoftheCRC[26].

InstudyIVitwasinvestigatedwhethersomeofthesediffer-encescouldbeassociatedwithfindingsatthepathologicalstag-ing,especiallyfocusingonthesignificanceofMMR.Previously,biomarkershavebeenassociatedwithdistantrecurrenceatspecificsites.Suchbiomarkerscouldthereforepotentiallybeusedinabiomarkerpanelforelucidationoftheclinicalsignifi-canceofIPNasseeninlungcancerscreening[129].KRASmuta-tionhasbeenassociatedwithpulmonarybutnotliverrelapse[130]andBRAFmutanttumoursareassociatedwithhigherratesofperitonealmetastases,distantlymphnodemetastases,andlowerratesoflungmetastases[131].Furthermore,areducedriskofmetastaticdiseasehasbeenreportedinpatientswithCRCanddeficientMMR[131-134].TheinvestigationofMMRasaprognos-ticbiomarkerinthecurrentsettingandinrelationtoorgan-specificmetastaseswaschosenforobviousreasons;MMRstatushasbeenanalysedroutinelysince2010andisinadditiontoareducedoverallriskofmetastasesknowntobeassociatedwithgender,age,locationoftheindextumour,lymphnodemetasta-sis,celltypeanddegreeofdifferentiationoftheCRC[131,132,134].However,despitethelarge-scalenationwidedataused,thereducedriskofsynchronousmetastasisindMMRtu-moursonlyappliedtopatientswithhepaticmetastases,whereasnostatisticallysignificantimpactwasfoundforpulmonarymetas-tases.Therationaleforthisdistinctpatternofmetastaticspread,associatedbyMMRstatus,isobscure.Unfortunately,basedonthepresentresultsMMRstatusaddsnovalueintheassessmentofIPNs.

CONCLUSION

Pulmonarymetastaseswereconfirmedtobethemostcommonextra-hepaticmanifestationforsynchronousmetastaticdiseaseinpatientswithCRC.TheoptimalapproachtotheinitialstagingwithregardtoSPCMisdebated.AnincreasingnumberofSPCMweredetectedwiththeimplementationofchestCTinstaging,however,asubstantialandvaryingnumberofpulmonarylesionsdetectedatchestCTcouldnotreadilybeclassifiedasbeingor


malignant.InstudyIandIIIweassessedtheprevalenceofIPNandspecificradiologicaland/orclinicopathologicalfactorsassoci-atedwithmalignancyofIPNinpreviouspublishedstudiesandinalocalcohort.Inpreviouslypublishedseries,anaverageof9%ofallpatientswithCRCandstagedwithchestCThadIPN.However,thenumberofdetectedIPNsvariedgreatlybetweenthestudiesanddefinitionsofIPNdifferediftheyweregivenatall.Onein100ofallchestCTstagedpatientshadanIPNthatultimatelyprovedtobemalignant.MostpulmonarynoduleswereofbenignoriginandthefewIPNsprovingtobemalignantwerewithoutpathog-nomonicfeatures.InourlocalcohortthenumberofIPNsregis-teredintheprimarychestCTreviewwascomparabletotheaveragenumberformpreviousstudies.

However,thenumberofIPNswassignificantlyreducedwhenscanswerere-assessedbyadedicatedthoracicradiologist.Unfor-tunately,neitherinstudyIIIwefoundanyradiologicalfeaturesofIPNspathognomonicformalignancyandtimetoresectionoftheprimarytumourwasprolongedinpatientswithIPN.

SPCMweredetectedin7.5%ofallnewlydiagnosedCRCpa-tientsinstudyII,andtheirpresencesignificantlyimpairedsurviv-al.Resectionofthemetastasesandindextumourinadditiontochemotherapywasassociatedwithaprolongedoverallsurvival,thoughonlyfewpatientsweresubjectedtoallthreetreatmentmeasures.BasedontheprevalenceofSPCM,theirimpactonsurvivalandpotentialbenefitofearlydiagnosisandtreatmentwerecommendthatIPNshouldbefollowed-upinasystematicandpre-definedway.ThetotalnumberofIPNscanbereducedbyareviewofdedicatedthoracicradiologistsandtheremainingIPNsaftersuchareviewshouldbeallocatedtofurtherinvestigationsassuggested.Ofoutermostimportanceisthatthisfurtherfollow-updoesnotdelaytreatmentoftheindexcancer.Inthefuture,biomarkersforpulmonarymetastasescouldpotentiallybeim-plementedinthemanagementstrategiesofIPN.InstudyIVMMRdid,however,notprovetobeofanyvalueinevaluationoftheriskofSPCM.

PERSPECTIVESFORFUTURERESEARCH

Evenasthisthesisisbeingwrittenthetechniquesusedforstag-ing,theirapplicabilityandtheunderstandingofthemetastaticprocessarerapidlyevolving.Ithasbeenarguedthatcancertreatment,indevelopedcountries,isbecomingacultureofex-cesscharacterizedbyover-diagnosing,overtreatmentandover-promising[135].Asaresult,globaleconomicexpenditureoncancercareisincreasing[135].Theexpensesfortheimplementa-tionofnewandevolvingdiagnosticimagingmodalitiesarenoexception[136].Futureresearchandintroductionofnew(andpotentiallymoreexpensive)stagingmodalitiesneedtotakethecost-effectivenessaspectintoaccount.Inthiscontextfutureprospectivestudiesshouldseektoclarifythe“oncologicalbene-fit”fromfollowingIPNsandtheconcurrentconsequencesinclud-ingincreasedradiationandpatientanxiety.Somescepticsarguethatthepotentialharmfuleffectsoffollow-upoutweighthepotentialbenefit,whichiswhypatientswithIPNshouldnotbesubjectedtoanyfurtherdiagnosticwork-up;mostofthemprovetobebenignanywayandtheeffectivenessofpulmonarymetas-tasectomyisstilltoberesolved.However,asstatedbyMacMa-honetal.,[43]itisimpossibletoignorethemedicolegalconsid-erationswhendiscussingmanagementofIPNandthenodulescannotsimplybeignoredbecausesomeofthemdorepresentmetastaticdisease.Akeycomponentinfutureresearchshouldbe

thatreproducibleandobjectivepatientandnodulecharacteristicsdictatethefurtherwork-upandtreatment.Therebyensuringaveryselectiveuseofsurgeryalmostreservedformalignantnod-ules.FuturepredictivemodelcouldincludebiomarkerssimilartoplasmabiomarkerpanelsfordiscerningclinicalsignificanceofIPNasseeninnon-smallcelllungcancer[129].Thetranslationofbiomarkersandincreasingknowledgeondeterminantsforthemetastaticprocessintotheclinicaldecision-makingcouldberelevantforbothpatientandsocietycostbenefit.

SUMMARYPatientswithnewlydiagnosedcolorectalcancer(CRC)aresubjectedtoapreoperativethoraco-abdominalCTscantodeter-minethecancerstage.Thisstagingisofrelevancewithregardtotreatmentandprognosis.About20%ofthepatientshavedistantmetastaticspreadatthetimeofdiagnosis,i.e.synchronousmeta-stases.Mostcommonarehepaticmetastasesfollowedbypulmo-naryinvolvement. Theoptimalstagingmodalityfordetectingsynchronouspulmonarymetastasesisdebated.Ithasbeenargued,thatsynchronouspulmonarymetastases(SPCM)arerareinCRCandthattheconsequenceofdetectingSPCMisminimal. Furthermore,thecurrentstagingpracticeiscomplicatedbyahighnumberofincidentalfindingsonthethoracicCT,so-calledindeterminatepulmonarynodules(IPN).IPNcanpotentiallyre-presentSPCM. Thepurposeofthisthesiswastoestimatetheprevalence,characteristicsandclinicalsignificanceofIPNandSPCMdetectedattheprimarystaginginCRC. StudyIwasasystematicreviewofpublishedstudiesonIPNinCRCfocusingontheprevalenceandradiologicalcharacteristicsofIPNprovingtobemalignant.ThisknowledgewouldbeofvalueinmanagementstrategiesforIPN.Onaverage9%ofallpatientsstagedwithathoracicCThadIPN,however,theprevalenceva-riedsignificantlybetweenpatientsseries.Thiswasmainlyattri-butedtovarying/lackingdefinitionsonIPNandvariableradiologi-calexpertiseintheassessmentofthescans.DataweretooinconsistentlyreportedinthecaseseriesforarobuststatementtobemadeonpotentialradiologicalcharacteristicssuggestiveofmalignancyinIPN.LymphnodemetastasiswasthemostcommonclinicopathologicalfindingassociatedwithmalignancyofIPN.Inconclusion,1patientofevery100scannedpatientshadanIPNprovingtoaSPCMatfollow-up,butwefoundnoevidencethatIPNshouldresultinintensifieddiagnosticwork-upbesidesrouti-nefollow-upforCRC. StudyIIwasananalysisoftheprevalenceofandriskfactorsforSPCMinaDanishnationwidecohortofpatientswithnewlydiagnosedCRCfrom2001to2011.SPCMweredetectedin7.5%ofthepatientsandin37%ofthesecasesthemetastaticspreadwasconfinedtothelungs.TheprevalenceofSPCMincreasedwiththeimplementationofthoracicCTinCRCstaging.SPCMimpairedsurvivalsignificantlyandwasassociatedwithincreasingageandrectalcancer.Resectionoftheprimarytumour,resectionoftheSPCMandtreatmentwithchemotherapywereassociatedwithimprovedsurvival.Unfortunately,however,onlyveryfewpatientsweresubjectedtoallthreetreatmentmeasures,andtheimprovedprognosiscouldsimplybetheresultofaselectionbias. Theinter-observervariationinclassificationoffindingsatthoracicCTscanswasinvestigatedinstudyIIIandwasbasedonstagingCTscansfromalocalcohortofpatientswithnewlydiag-


nosedCRC.Basedonanexperiencedthoracicradiologist’sasses-smentofthescans,wesearchedforradiologicalcharacteristicsofIPNthatcouldpredictmalignancyofthenodule.TherewasasignificantdifferenceinthenumberofIPNsdetectedbetweentheprimaryandthethoracicradiologist’sassessment.ThethoracicradiologistclassifiedfewernodulesasIPNandevenreportedwithhigherspecificityandsensitivityforSPCM.Morethan20%ofIPNs(asclassifiedbythethoracicradiologist)provedtobeSPCM.Unfortunately,noradiologicalcharacteristicscouldbeassociatedwithamalignantoutcome.IncontinuationofthesefindingswesuggestedasecondaryreviewofscanswithIPNbeagroupofdedicatedthoracicradiologists.Thisapproachmightreducetheneedforadditionalwork-upforIPNandcallsforclarificationinfutureprospectivestudies.IdentificationofpatientsinparticularriskofSPCMcouldbeofvalueintheassessmentofpulmonarynodules.SeveralbiomarkershavebeenproposedfordifferentialmetastaticpatternsinCRC. InstudyIVweinvestigatedthesignificanceofmismatchrepairstatus(MMR)forthelocationofmetastaticspreadinanationwideDanishcohortofpatientswithnewlydiagnosedCRCbetween2010and2012.DeficientMMRwasassociatedwithareducedriskofsynchronousmetastaticdisease,however,theriskreductiononlyappliedtohepaticmetastases.MMRhadnoim-pactonSPCMandisthereforecurrentlyofnouseintheasses-smentofIPN.

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