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OfficialreprintfromUpToDate www.uptodate.com2015UpToDate
AuthorCarlosFernandezdelCastillo,MD
SectionEditorsKennethKTanabe,MDDouglasAHowell,MD,FASGE,FACG
DeputyEditorsDianeMFSavarese,MDAnneCTravis,MD,MSc,FACG,AGAF
Clinicalmanifestations,diagnosis,andstagingofexocrinepancreaticcancer
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.Literaturereviewcurrentthrough:Mar2015.|Thistopiclastupdated:Mar14,2014.
INTRODUCTIONCanceroftheexocrinepancreasisahighlylethalmalignancy.ItisthefourthleadingcauseofcancerrelateddeathintheUnitedStatesandsecondonlytocolorectalcancerasacauseofdigestivecancerrelateddeath.(See"Epidemiologyandriskfactorsforexocrinepancreaticcancer",sectionon'Epidemiology'.)
Surgicalresectionistheonlypotentiallycurativetreatment.Unfortunately,becauseofthelatepresentation,only15to20percentofpatientsarecandidatesforpancreatectomy.Furthermore,prognosisispoor,evenafteracompleteresection.Fiveyearsurvivalafterpancreaticoduodenectomyisabout25to30percentfornodenegativeand10percentfornodepositivedisease.(See"Overviewofsurgeryinthetreatmentofexocrinepancreaticcancerandprognosis".)
Theclinicalpresentation,diagnosticevaluation,andstagingworkupforpancreaticexocrinecancerwillbereviewedhere.Epidemiologyandriskfactors,pathology,surgicalmanagement,adjuvantandneoadjuvanttherapy,andtreatmentofadvancedpancreaticexocrinecancer,includingpalliativelocalmanagement,arediscussedelsewhere.
PATHOLOGYThecommonlyusedterm"pancreaticcancer"usuallyreferstoaductaladenocarcinomaofthepancreas(includingitssubtypes),whichrepresentsabout85percentofallpancreaticneoplasms.Oftheseveralsubtypesofductaladenocarcinoma,mostshareasimilarpoorlongtermprognosis,withtheexceptionofcolloidcarcinomas,whichhaveasomewhatbetterprognosis.Themoreinclusiveterm"exocrinepancreaticneoplasms"includesalltumorsthatarerelatedtothepancreaticductalandacinarcellsandtheirstemcells(includingpancreatoblastoma),andispreferred.(See"Pathologyofexocrinepancreaticneoplasms".)
Morethan95percentofmalignantneoplasmsofthepancreasarisefromtheexocrineelements.Neoplasmsarisingfromtheendocrinepancreas(ie,pancreaticneuroendocrine[isletcell]tumors)comprisenomorethan5percentofpancreaticneoplasmstheirclinicalmanifestations,diagnosis,andstagingisaddressedelsewhere.(See"Classification,epidemiology,clinicalpresentation,localization,andstagingofpancreaticneuroendocrinetumors(isletcelltumors)".)
CLINICALPRESENTATIONThemostcommonpresentingsymptomsinpatientswithexocrinepancreaticcancerarepain,jaundice,andweightloss.Inamultiinstitutionalseriesof185patientswithexocrinepancreaticcancerdiagnosedoverathreeyearperiod(62percentinvolvingtheheadofthegland,10percentbody,6percenttail,andtheremaindernotdetermined),themostfrequentsymptomsatdiagnosiswere[1]:
(See"Epidemiologyandriskfactorsforexocrinepancreaticcancer".)(See"Pathologyofexocrinepancreaticneoplasms".)(See"Overviewofsurgeryinthetreatmentofexocrinepancreaticcancerandprognosis".)(See"Adjuvanttherapyforresectedexocrinepancreaticcancer".)(See"Initialchemotherapyandradiationfornonmetastaticlocallyadvancedunresectable,borderlineresectable,andpotentiallyresectableexocrinepancreaticcancer".)
(See"Supportivecareofthepatientwithadvancedexocrinepancreaticcancer".)(See"Chemotherapyforadvancedexocrinepancreaticcancer".)
Asthenia86percent
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Themostfrequentsignswere:
Theinitialpresentationofpancreaticcancervariesaccordingtotumorlocation.Approximately60to70percentofexocrinepancreaticcancersarelocalizedtotheheadofthepancreas,while20to25percentareinthebody/tailandtheremainderinvolvethewholeorgan[2].Comparedtotumorsinthebodyandtailofthegland,pancreaticheadtumorsmoreoftenpresentwithjaundice,steatorrhea,andweightloss[1,3,4].Asanexample,intheabovenotedseries,jaundicewaspresentin73percentofthe114patientswithatumorlocatedintheheadofthepancreas,comparedto11percentof19bodylesions,andnoneofthe11taillesions[1].Steatorrheawaspresentin28percentofthepatientswithpancreaticheadlesionsversus11percentofthosewithbody,andnoneofthosewithtaillesions.Steatorrheaisattributabletolossofthepancreasabilitytosecretefatdigestingenzymesortoblockageofthemainpancreaticduct.
Painisoneofthemostfrequentlyreportedsymptoms,evenwithsmall(
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thecourseofthedisease,andmaybesecondarytolivermetastases.
Arecentonsetofatypicaldiabetesmellitus[911]maybenoted.Severalstudieshaveaddressedwhetherearlierdetectionofnonspecificsignsofanevolvingpancreaticneoplasm(particularlyinadultswithnewonsetdiabetesmellitus)mightimproveresectabilityandoveralloutcomes,buttheresultsareinconclusive.Screeningforpancreaticcancerinadultswithnewonsetdiabetesmellitusisdiscussedelsewhere.(See"Epidemiologyandriskfactorsforexocrinepancreaticcancer",sectionon'Diabetesmellitus,glucosemetabolism,andinsulinresistance'.)
Unexplainedsuperficialthrombophlebitis,whichmaybemigratory(classicTrousseaussyndrome)[12],issometimespresentandreflectsthehypercoagulablestatethatfrequentlyaccompaniespancreaticcancer.Thereisaparticularlyhighincidenceofthromboembolicevents(bothvenousandarterial),particularlyinthesettingofadvanceddisease,andcliniciansshouldmaintainahighindexofsuspicion.Multiplearterialemboliresultingfromnonbacterialthromboticendocarditismayoccasionallybethepresentingsignofapancreaticcancer[13].Thromboemboliccomplicationsoccurmorecommonlyinpatientswithtumorsarisinginthetailorbodyofthepancreas[14].(See"Riskandpreventionofvenousthromboembolisminadultswithcancer"and"Nonbacterialthromboticendocarditis".)
Skinmanifestationsoccurasparaneoplasticphenomenainsomepatients.Asanexample,bothcicatricialandbullouspemphigoidaredescribed,evenasafirstsignofdisease[15].(See"Cutaneousmanifestationsofinternalmalignancy",sectionon'Paraneoplasticpemphigus'.)
Rarely,erythematoussubcutaneousareasofnodularfatnecrosis,typicallylocatedonthelegs(pancreaticpanniculitis),maybeevident,particularlyinpatientswiththeacinarcellvariantofpancreaticcancer(figure1).Itishypothesizedthattheconditionisinitiatedbyautodigestionofsubcutaneousfatsecondarytosystemicspillageofexcessdigestivepancreaticenzymes.Thepresenceofthisconditionisnotpathognomonicforanexocrinepancreaticcancer,asithasbeendescribedwithpancreaticneuroendocrinetumors,intraductalpapillarymucinousneoplasms,andinchronicpancreatitis.(See"Cutaneousmanifestationsofinternalmalignancy",sectionunderconstructionand"Pathologyofexocrinepancreaticneoplasms",sectionon'Acinarcellcarcinoma'and"Panniculitis:Recognitionanddiagnosis".)
Signsofmetastaticdiseasemaybepresentatpresentation.Metastaticdiseasemostcommonlyaffectstheliver,peritoneum,lungs,andlessfrequently,bone.Signsofadvanced,incurablediseaseinclude:
Routinelaboratorytestsareoftenabnormal,butarenotspecificforpancreaticcancer.Commonabnormalitiesincludeanelevatedserumbilirubinandalkalinephosphataselevels,andthepresenceofmildanemia.
IncidentalfindingAsolidpancreaticlesionisuncommonlyfoundasanincidentalfindingonCTscansdoneforanotherreason.Inonereport,24ofthe321patientswithasolidpancreaticmasswhowereidentifiedoveraneightyearperiodhaditincidentallydiscovered(7percent)onehalfofthesewereadenocarcinomas,whiletheremainderwerepancreaticneuroendocrinetumors[17].Themajorityofpancreaticlesionsdiscoveredonradiographicstudiesperformedforanotherreasonarecystic,andmanyoftheserepresentintraductalpapillarymucinousneoplasms,whichrepresentaprecursorlesiontoexocrinepancreaticcancer.(See"Pathophysiologyandclinicalmanifestationsofintraductalpapillarymucinousneoplasmofthepancreas",sectionon'Clinicalpresentation'and"Pathophysiologyandclinicalmanifestationsofintraductalpapillarymucinousneoplasmofthepancreas",sectionon'Progressiontopancreaticcancer'.)
AnabdominalmassAscites(image1)Leftsupraclavicularlymphadenopathy(Virchow'snode)(image2)Apalpableperiumbilicalmass(SisterMaryJosephsnode)(image3)orapalpablerectalshelfarepresentinsomepatientswithwidespreaddisease.Pancreaticcanceristheoriginofacutaneousmetastasistotheumbilicusin7to9percentofcases[16].
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DIFFERENTIALDIAGNOSISThesignsandsymptomsassociatedwithpancreaticcancerareoftennonspecific,sothedifferentialdiagnosisislarge.Threeofthemorecommonfindingsleadingtosuspicionforpancreaticcancerarejaundice,epigastricpain,andweightloss.
Thepositivepredictivevalue(PPV)ofthesesymptomsforthediagnosisofpancreaticcancerislow,withthepossibleexceptionofjaundiceinanolderpatient.Thiswasshowninacasecontrolstudythatexaminedtheriskofpancreaticcancerbaseduponsymptomsthatwereidentifiedintheyearbeforediagnosisin21,624patientsseeninaprimarycareclinic[18].ThePPVofjaundiceforpancreaticcancerinapatientaged60orolderwas22percentitwas
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malignantdiseaseinothersites.
Cluessuggestingthepossibilityofaprimarypancreaticlymphomaincludealackofjaundice,constitutionalsymptoms(weightloss,fever,andnightsweats),anelevatedserumlactatedehydrogenase(LDH)orbeta2microglobulinlevel,andanormalserumCA199[19,20]. Primarypancreaticlymphomasaretypicallylargerthan6cm,andsurroundinglymphadenopathyiscommonaswithanylymphomahowever,neitherofthesefeatureswouldexcludeadenocarcinoma.
Anendoscopicultrasound(EUS)guidedbiopsymayberecommendedifadiagnosisofchronicorautoimmunepancreatitisissuspectedonthebasisofhistory(eg,extremeyoungage,prolongedethanolabuse,historyofotherautoimmunediseases),particularlyiffurtherimagingstudies(eitherEUS,endoscopicretrogradecholangiopancreatography,magneticresonancecholangiopancreatography)revealmultifocalbiliarystrictures(suggestiveofautoimmunepancreatitis)ordiffusepancreaticductalchanges(suggestiveofchronicpancreatitis).
Amongpatientswhohaveamassintheheadofthepancreasoramalignantbileductobstructioninthevicinityofthedistalcommonbileduct,differentiatingaprimaryexocrinepancreaticcarcinomafromotherlesscommonperiampullarymalignancies(arisingintheampulla,duodenum,orbileduct)canbechallenging(figure2).Althoughthediagnosismaybeevidentafterradiographicandendoscopicevaluation,itmaynotbepossibletodistinguishthetissueoriginofamalignantperiampullaryneoplasmuntilresectionandhistopathologicevaluationoftheentiresurgicalspecimeniscompleted.(See"Ampullarycarcinoma:Epidemiology,clinicalmanifestations,diagnosisandstaging",sectionon'Diagnosticevaluation'.)
DIAGNOSTICAPPROACHItisnotpossibletoreliablydiagnoseapatientwithpancreaticcancerbasedonsymptomsandsignsalone.Thelackofspecificityforthediagnosisofpancreaticcancerwhenbasedonsymptomsthatarehighlysuggestiveandsensitiveforpancreaticcancerwasshowninalandmarkstudyinwhich57percentofsuchpatientshadotherdiagnoses,includingnonpancreaticintraabdominalcancers(13percent),pancreatitis(12percent),andnonpancreatic,noncancerousdisordersincludingirritablebowelsyndrome(23percent)andmiscellaneousotherconditions(10percent)[21].
Awarenessofriskfactors(geneticpredisposition,age,smoking,diabetes)mayleadtoanearlierandmoreaggressiveevaluationforpancreaticcancerinpatientswhopresentwithsymptomssuspiciousforthedisease.(See"Epidemiologyandriskfactorsforexocrinepancreaticcancer".)
Ingeneral,thediagnosticevaluationofapatientwithsuspectedpancreaticcancerincludesserologicevaluationandabdominalimaging.Additionaltestingisthendirectedbaseduponthefindingsoftheinitialtestingaswellasthepatientsclinicalpresentationandriskfactors.
InitialtestingAllpatientspresentingwithjaundiceorepigastricpainshouldhaveanassayofserumaminotransferases,alkalinephosphatase,andbilirubintodetermineifcholestasisispresent.Inaddition,patientswithepigastricpainshouldbeevaluatedforacutepancreatitiswithaserumlipase.(See"Diagnosticapproachtotheadultwithjaundiceorasymptomatichyperbilirubinemia",sectionon'Initiallaboratorytests'and"Diagnosticapproachtoabdominalpaininadults",sectionon'Epigastricpain'.)
Thenextstepinthepatientsevaluationisabdominalimaging,thoughthechoiceoftestvariesdependinguponthepatientspresentingsymptoms.
JaundiceForpatientswithjaundice,theinitialimagingstudyistypicallyatransabdominalultrasound(US).TransabdominalUShashighsensitivityfordetectingbiliarytractdilationandestablishingthelevelofobstruction.Italsohashighsensitivity(>95percent)fordetectingamassinthepancreas,althoughsensitivityislowerfortumors
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withtheseprocedures,transabdominalUSispreferredastheinitialimagingstudyforpatientssuspectedofhavingpancreaticcancer.(See'ERCP'belowand"Endoscopicretrogradecholangiopancreatography:Indications,patientpreparation,andcomplications",sectionon'IndicationsforERCP'and"Magneticresonancecholangiopancreatography",sectionon'Clinicaluse'.)
EpigastricpainandweightlossAbdominalcomputedtomography(CT)isthepreferredinitialimagingtestinpatientspresentingwithepigastricpainandweightloss,butwithoutjaundice.(See'AbdominalCT'below.)
Inpractice,transabdominalUSiscommonlyutilizedasaninitialscreeningtechniqueforbiliarypancreaticdiseaseinsuchpatientsbecauseoftoitslowcostandwideavailability[22,23].However,whiletransabdominalultrasoundhashighsensitivityfordetectingtumors>3cm,itismuchlowerforsmallertumors.(See'Transabdominalultrasound'below.)
Furthermore,ifacutepancreatitisisinthedifferential,transabdominalUSisnotthepreferredinitialtest.Itisassociatedwithahighfrequencyofincompleteexaminationsowingtooverlyingbowelgasfromanileus,anditcannotclearlyidentifynecrosiswithinthepancreastheseimportantfindingsarebestseenbycontrastenhancedCTscan.
Forthesereasons,andbecauseofthegreateramountofstaginginformationthatcanbeobtained,CTispreferredinthissetting,particularlyforpatientswhohavesymptomsotherthanepigastricpainthatraisesuspicionforpancreaticcancer(eg,weightloss,recentdiagnosisofatypicaldiabetesmellitus)[2428].(See'Clinicalpresentation'above.)
SubsequenttestingifinitialimagingispositiveIfapancreaticmassisseenontransabdominalUS,anabdominalCTscanistypicallyobtainedtoconfirmthepresenceofthemassandtoassessdiseaseextent.IftheCTappearanceistypical,enoughinformationisprovidedtoassessresectability,andthepatientisfitforamajoroperation,additionaltesting(includingbiopsy)maybeunnecessarybeforesurgicalintervention.Ontheotherhand,ifthediagnosisisindoubt,resectabilityisuncertain,orifatherapeuticinterventionisneeded,additionalproceduresmaybeindicated.(See'Stagingsystemandthestagingworkup'belowand'Diagnosticalgorithmandneedforpreoperativebiopsy'below.)
ERCPisindicatedifcholedocholithiasisremainsinthedifferentialdiagnosisafterinitialevaluationorifbiliarydecompressionisrequired.However,notallpatientswithbiliaryobstructionfrompancreaticcancerrequiredecompression,andstentplacementshouldbeavoidedinpatientswhohavenotyetundergoneCTbecauseastentmaycauseartifactinthepancreaticheadthatcanmaskthelesion,andthetraumaofstentinsertionmayinduceinflammatorychangesthatmightbeindistinguishablefromtumor.(See'ERCP'belowand"Endoscopicstentingformalignantpancreaticobiliaryobstruction"and"Surgicalresectionoflesionsoftheheadofthepancreas",sectionon'Preoperativebiliarydrainage'and"Overviewofsurgeryinthetreatmentofexocrinepancreaticcancerandprognosis",sectionon'Roleofpreoperativebiliarydrainage'.)
MRCPisanalternativeforpatientswhocannotundergoERCP(eg,thosewithagastricoutletobstruction),butitlackstherapeuticcapability.(See'MRCP'below.)
EUSguidedorpercutaneousbiopsiesofapancreaticmasscanbeobtainedifhistologicconfirmationisneeded,thoughthisisnotalwaysrequiredinpatientswhoappeartohavepotentiallyresectablediseaseandwhohavetypicalimagingfindings.EUSmayalsobeusedasanalternativetocontrastenhancedtriplephasehelicalCTforthestagingofpancreaticcancer.(See'EUS'belowand'Biopsyandestablishingthediagnosis'below.)
SubsequenttestingifinitialimagingisnegativeForpatientswhoarestronglysuspectedofhavingpancreaticcancerbutwhoseinitialimagingisnegative,furthertestingmaybeindicated.IfanabdominalCTscanhasnotyetbeendone,thatisthenextstep.
ForpatientswithcholestasiswhohaveonlyhadtransabdominalUS,ERCPisindicated.MRCPisanalternativeforpatientswhocannotundergoERCP(eg,thosewithagastricoutletobstruction).(See'Jaundice'aboveand'MRCP'below.)
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Ifthesetestsarenegative,additionaltestingistypicallynotrequiredandanalternativecauseforthepatientssymptomsshouldbesought.However,ifthesuspicionforpancreaticcancerremainshigh(eg,inapatientwithprofoundweightlossorwhohasriskfactorsforpancreaticcancer,suchashereditarypancreatitisorchronicpancreatitis),anEUSisareasonablenextsteptoexcludeasmallpancreaticcancer(algorithm2).(See"Epidemiologyandriskfactorsforexocrinepancreaticcancer",sectionon'Riskfactors'.)
AnylesionsthatarevisibleonlyonEUSshouldbebiopsiedtoconfirmthediagnosispriortosurgicalexploration.EUSguidedfineneedleaspiration(FNA)biopsyisthebestmodalityforobtainingatissuediagnosis,evenifthetumorispoorlyvisualizedbyotherimagingmodalities.Inaseriesof116patientssuspectedofhavingpancreaticcancer,butwithinconclusivefindingsonCTscan,EUSwithFNAhadasensitivityandspecificityfordiagnosingapancreaticmalignancyof87and98percent,respectively[29].IndependentriskfactorsassociatedwithEUSdetectionofpancreaticductaladenocarcinomaincludedpancreaticductaldilationonCTscan(oddsratio[OR]4.1,95%confidenceinterval[CI]1.511)andtumorsizedetectedbyEUSof1.5cm(OR8.5,95%CI2.035).
Specifictestsusedintheinitialevaluation
TransabdominalultrasoundTheinitialstudyinpatientswhopresentwithobstructivejaundiceorepigastricpainandweightlossisoftentransabdominalultrasound(US).TransabdominalUShashighsensitivityfordetectingbiliarytractdilationandestablishingthelevelofobstruction.(See"Diagnosticapproachtotheadultwithjaundiceorasymptomatichyperbilirubinemia",sectionon'Suspectedbiliaryobstructionorintrahepaticcholestasis'.)
OnUS,apancreaticcarcinomatypicallyappearsasafocalhypoechoichypovascularsolidmasswithirregularmargins.Dilatedbileductsmayalsosuggestthepresenceofapancreatictumor.
SupportfortheutilityoffirstlineabdominalUSforthediagnosisofapancreatictumorinpatientswhopresentwithsymptomsofpancreaticcancercomesfromaprospectivecohortstudyof900patientswhounderwenttransabdominalUStoworkuppainlessjaundice,anorexia,orunexplainedweightloss[30].Thesensitivityfordetectionofalltumorsinthepancreaswas89percent(124of140),including90percentfordetectionofexocrinepancreaticcancer(79of88patients).Amongthe779patientswhowerefollowedovertimeandestablishednottohavedevelopedapancreatictumor,ninehadfalsepositiveUSfindings(specificity99percent).
WhilethereportedsensitivityforUSindiagnosingpancreaticcanceris95percentfortumors>3cm,itismuchlessforsmallertumors[22,30,31].Sensitivityisalsodependentupontheexpertiseoftheultrasonographerandthepresenceorabsenceofbileductobstruction.
AbdominalCTAmasswithinthepancreasisthemostcommonCTfindingofpancreaticcancer,althoughenlargementofthewholeglandissometimesseen[26,32].SensitivityofCTforpancreaticcancerdependsontechniqueandishighest(89to97percent)withtriplephase,helicalmultidetectorrowCT[33].Asexpected,sensitivityishigherforlargertumorsinonestudy,thesensitivitywas100percentfortumors>2cm,butonly77percentfortumors2cminsize[34].ThispancreaticprotocoltypeofCTisoftennottheinitialstudyforapatientwithoutaknowndiagnosisofpancreaticcancer.(See'Technique'belowand'Initialtesting'above.)
ThetypicalCTappearanceofanexocrinepancreaticcancerisanilldefinedhypoattenuatingmasswithinthepancreas(image12),althoughsmallerlesionsmaybeisoattenuating,makingtheiridentificationdifficult,particularlyonnoncontrastCT[35].
Secondarysignsofapancreaticcancer(whichareseenwithmanysmallisoattenuatingcancers)includeapancreaticductcutoff,dilatationofthepancreaticductorcommonbileduct,parenchymalatrophy,andcontourabnormalities(image13).Dilationofboththepancreaticductandthecommonbileduct,commonlyreferredtoasthedoubleductsignispresentinabout62to77percentofcasesofpancreaticcancer(picture1),butisnotdiagnosticforapancreaticheadmalignancy[36,37].Approximately50percentofampullarycarcinomashaveadoubleductsign[38],anditcanalsooccasionallybeseenwithbenignadenomas.
ERCPEndoscopicretrogradecholangiopancreatography(ERCP)isahighlysensitivetoolforvisualization
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ofthebiliarytreeandpancreaticducts.(See"Endoscopicmethodsforthediagnosisofpancreatobiliaryneoplasms",sectionon'Endoscopicretrogradecholangiopancreatography'.)
Anearlymetaanalysisfoundasensitivityof92percentandspecificityof96percentfordiagnosingcancerofthepancreasbyERCP[39].Findingssuggestiveofamalignanttumorwithintheheadofthepancreasincludesuperimposablestricturesorobstructionofthecommonbileandpancreaticducts(the"doubleduct"sign),apancreaticductstrictureinexcessof1cminlength,pancreaticductobstruction,andtheabsenceofchangessuggestiveofchronicpancreatitis(picture1).
Furthermore,ERCPprovidesanopportunitytocollecttissuesamples(forcepsbiopsy,brushcytology)forhistologicdiagnosis.However,thesensitivityfordetectionofmalignancy(approximately50to60percent)islowerthanthatofendoscopicultrasound(EUS)guidedFNA(sensitivity92percent).(See"Endoscopicmethodsforthediagnosisofpancreatobiliaryneoplasms",sectionon'TissuesamplingduringERCP'and'EUSguidedbiopsy'below.)
OtherlimitationsofERCParethatparenchymalabnormalitiescanonlybedetectedbyinferencetumorscanbemissedintheuncinateprocess,accessoryduct,andtailandtheneedforintraductalcontrastadministration.DirectvisualizationofthepancreaticductispossibleduringERCPusingpancreatoscopy.Pancreatoscopyusesaminiatureendoscopethatispassedthroughtheduodenoscope(image14)tovisualizethepancreaticductandtoobtaintargetedbiopsiesofpancreaticductstrictures.However,theprocedureisnotwidelyavailable.(See"Cholangioscopyandpancreatoscopy".)
ERCPissuperiortotransabdominalUSandCTforthedetectionofextrahepaticbiliaryobstruction,andistheprocedureofchoicewhenthereissuspicionforcholedocholithiasis.However,itisalsomoreexpensivethanultrasoundorCT,andasaninvasiveprocedure,itisassociatedwithafiniterateofmortality(0.2percent)andcomplicationssuchaspancreatitis,bleeding,andcholangitis.Asaresult,theroleofERCPinpatientswithsuspectedpancreaticcancerisevolvingintoamainlytherapeuticmodalityforpatientswhopresentwithcholestasisduetotumorobstructionofthebiliarysystemandrequireplacementofabiliarystent.(See"Endoscopicstentingformalignantpancreaticobiliaryobstruction"and"Diagnosticapproachtotheadultwithjaundiceorasymptomatichyperbilirubinemia",sectionon'Suspectedbiliaryobstructionorintrahepaticcholestasis'.)
However,preoperativestentingisnotalwaysnecessaryinapatientwithapotentiallyresectablepancreaticcancer,eveninthepresenceofcholangitis.Furthermore,ifitisundertaken,stentingshouldnotbeperformedbeforeCTscanningtoassessresectability,asthestentmaycauseartifactinthepancreaticheadthatcanmaskthelesion,andthetraumaofstentinsertionmayinduceinflammatorychangesthatmightbeindistinguishablefromtumor.Theindicationsandcontroversiessurroundingtherisksandbenefitsofpreoperativestentplacementarediscussedelsewhere.(See"Endoscopicstentingformalignantpancreaticobiliaryobstruction",sectionon'Indications'and"Surgicalresectionoflesionsoftheheadofthepancreas",sectionon'Preoperativebiliarydrainage'and"Overviewofsurgeryinthetreatmentofexocrinepancreaticcancerandprognosis",sectionon'Roleofpreoperativebiliarydrainage'.)
MRCPAnalternativetodiagnosticERCPismagneticresonancecholangiopancreatography(MRCP).MRCPusesMRtechnologytocreateathreedimensionalimageofthepancreaticobiliarytree,liverparenchyma,andvascularstructures.MRCPisbetterthanCTfordefiningtheanatomyofthebiliarytreeandpancreaticduct,hasthecapabilitytoevaluatethebileductsbothaboveandbelowastricture,andcanalsoidentifyintrahepaticmasslesions.ItisatleastassensitiveasERCPindetectingpancreaticcancers[40,41],andunlikeconventionalERCP,itdoesnotrequirecontrastmaterialtobeadministeredintotheductalsystem.Thus,themorbidityassociatedwithendoscopicproceduresandcontrastadministrationisavoided.(See"Magneticresonancecholangiopancreatography".)
AlthoughMRCPhasnotyetreplacedERCPinthepatientssuspectedofhavingpancreaticcancerinmostcenters(algorithm2),itmaybepreferredinspecificsettings:
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RoleoftumormarkersSeveralserummarkersforpancreaticcancerhavebeenevaluated,themostusefulofwhichiscancerassociatedantigen199(CA199).
CA199ThereportedsensitivityandspecificityratesofCA199forpancreaticcancerrangefrom70to92,and68to92percent,respectively[4347].However,sensitivityiscloselyrelatedtotumorsize.CA199levelsareoflimitedsensitivityforsmallcancers[43,4851].Furthermore,CA199requiresthepresenceoftheLewisbloodgroupantigen(aglycosyltransferase)tobeexpressed.AmongindividualswithaLewisnegativephenotype(anestimated5to10percentofthepopulation),CA199levelsarenotausefultumormarker[50,52].
CA199levelsalsohavelowspecificity.CA199isfrequentlyelevatedinpatientswithcancersotherthanpancreaticcancerandvariousbenignpancreaticobiliarydisorders(table2)[4850,53,54].Onestudyfoundthatserumconcentrationsabove37U/mLrepresentedthemostaccuratecutoffvaluefordiscriminatingpancreaticcancerfrombenignpancreaticdisease,butthesensitivityandspecificityforpancreaticcanceratthislevelwereonly77and87percent,respectively[53].Furthermore,thepositivepredictivevalue(PPV)islow,particularlyamongasymptomaticindividuals.Inalargeseriesofover70,000asymptomaticindividuals,thePPVofaserumCA199level>37U/mLwasonly0.9percent[55].Becauseofthis,expertguidelinesrecommendagainsttheuseofCA199asascreeningtestforpancreaticcancer[56].Evenamongsymptomaticindividuals(epigastricpain,weightloss,jaundice),thesensitivity,specificity,andpositivepredictivevalueofanelevatedCA199>37U/mLlevelareonlyapproximately80,85,and72percent[49,57].
ThespecificityandPPVforthediagnosisofpancreaticcancercanbeimprovedbyusinghighercutofflevels(100oreven1000U/mL),butattheexpenseofsensitivity[49].Importantly,thereisaverybroadrangeofCA199levelsthatcanbeseeninbenigndisease,andtherearenospecificcutoffvalues(evenbeyond10,000U/mL)thatareseenonlyinpatientswithmalignantdisease[46,53,58].
SerumlevelsofCA199dohavesomevalueasprognosticmarkersandalsoasanindicatorofdiseaseactivityinpatientswithinitiallyelevatedlevels:
Patientswhohavegastricoutletorduodenalstenosisorwhohavehadsurgicalrearrangement(eg,BillrothII)orductaldisruption,resultinginductswhicharedifficulttoassesssuccessfullybyERCP.
Todetectbileductobstructionoccurringinthesettingofchronicpancreatitis.(See"Complicationsofchronicpancreatitis".)
ForpatientsinwhomattemptedERCPiseithertotallyunsuccessfulorprovidesincompleteinformationbecauseofpancreaticductobstruction[42].
ThedegreeofelevationofCA199(bothatinitialpresentationandinthepostoperativesetting)isassociatedwithlongtermprognosis[5964].
Amongpatientswhoappeartohavepotentiallyresectablepancreaticcancer,themagnitudeofthepreoperativeCA199levelcanalsohelptopredictthepresenceofradiographicallyoccultmetastaticdisease,thelikelihoodofacomplete(R0)resection,andlongtermoutcomes[59,6568].Asexamples:
Inareportof491patientsundergoingstaginglaparoscopyforaradiographicallyresectablepancreaticadenocarcinoma,CA199valuesabove130units/mLwereasignificantpredictoroffindingradiographicallyoccultunresectabledisease[65].TheratesofunresectablediseaseamongallpatientswithaCA199level130units/mLversus
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OthermarkersAlthoughseveralmarkercandidateshaveemergedfrompreclinicalstudies(andone,macrophageinhibitorycytokine1,appearsparticularlypromising[70]),nonehasreplacedCA199todate.
BiopsyandestablishingthediagnosisHistologicconfirmationisrequiredtoestablishadiagnosisofpancreaticcancer.(See"Pathologyofexocrinepancreaticneoplasms".)
Followingtheinitialevaluation,somepatientsmayhaveabiopsyprovendiagnosisofpancreaticcancer,typicallybecausetheypresentedwithjaundiceandunderwentanERCP.(See'ERCP'above.)
However,inmanycases,thediagnosiswillnotyetbehistologicallyconfirmed.Oncepancreaticcancerissuspectedoninitialimagingstudies,thenextstepintheworkupisgenerallyastagingevaluationtoestablishdiseaseextentandresectabilityratherthanbiopsy.Patientswhoarefitformajorsurgeryandwhoappeartohavepotentiallyresectablepancreaticcancerafterthestagingevaluationiscompletedonotnecessarilyneedapreoperativebiopsyconfirmingthediagnosisofapancreaticcancerbeforeproceedingdirectlytosurgery.However,theincreasedrecognitionofchronicorautoimmunepancreatitis,whichcancloselymimicpancreaticcancer,hasalteredthisparadigmincertainpopulations.Apreoperativebiopsymayberecommendedifadiagnosisofchronicorautoimmunepancreatitisissuspectedonthebasisofhistory(eg,extremeyoungage,prolongedethanolabuse,historyofotherautoimmunediseases),particularlyifimagingstudies(EUS,ERCPormagneticresonancecholangiopancreatography)revealmultifocalbiliarystrictures(suggestiveofautoimmunepancreatitis)ordiffusepancreaticductalchanges(suggestiveofchronicpancreatitis).Theseissuesarediscussedinmoredetailbelow.(See'Diagnosticalgorithmandneedforpreoperativebiopsy'below.)
Whenitisindicated,biopsyofapancreaticmasscanbeaccomplishedeitherpercutaneouslyorviaEUS.
PercutaneousbiopsyPercutaneousfineneedleaspiration(FNA)biopsyofapancreaticmasscanbeperformedusingeitherultrasoundorcomputedtomographic(CT)guidance(picture2).Thesensitivityandspecificityofthisprocedureforthediagnosisofpancreaticcancerdependsupontumorsizeandoperatorexpertisevaluesintherangeof80to90and98to100percent,respectively,arereported[71].
AtheoreticalconcernisthatpercutaneousFNAbiopsyofthepancreasmaydisseminatetumorcellsintraperitoneallyoralongtheneedlepathinpatientswhoarebelievedtobecandidatesforpotentiallycurativeresection.However,theriskappearstobequiteloworabsent.Inonestudyof41patientsundergoingresectionforprimarypancreaticadenocarcinoma,21of32patientswithoutpreoperativeopenbiopsieshadundergonepreoperativeCTorfluoroscopicallyguidedFNA[72].Therewasnoincreaseinpositiveperitonealwashings,peritonealfailurerate,ormediansurvivalinthesepatients.Nevertheless,concernpersistsand,inpractice,wetrytoavoidpercutaneousFNAinpatientswithresectablemasses.
AtransduodenalEUSguidedFNAbiopsyorERCPsamplingreducestheserisks[7375].(See'ERCP'above.)
EUSguidedbiopsyEUSguidedFNAisthebestmodalityforobtainingatissuediagnosis,evenifthetumorispoorlyvisualizedbyotherimagingmodalities.Thisprocedureislesslikelytocauseintraperitonealspreadofthetumorsincethebiopsyisobtainedthroughthebowelwallratherthanpercutaneously.EUSguidedFNAhasasensitivityofapproximately90percentandspecificityof96percentforthediagnosisofapancreaticcancer.(See"Endoscopicultrasoundinthestagingofexocrinepancreaticcancer",sectionon'AccuracyofEUSFNA'.)
Theadditionofmoleculargeneticanalysis(eg,assayforKrasorp53genemutationsbyRTPCR)tocytologic
expertpanelconvenedbytheAmericanSocietyofClinicalOncology(ASCO)recommendedagainsttheuseofCA199aloneasanindicatorofoperability[56].
SerialmonitoringofCA199levels(onceeveryonetothreemonths[56])isusefultofollowpatientsafterpotentiallycurativesurgeryandforthosewhoarereceivingchemotherapyforadvanceddisease.RisingCA199levelsusuallyprecedetheradiographicappearanceofrecurrentdisease,butconfirmationofdiseaseprogressionshouldbepursuedwithimagingstudiesand/orbiopsy[56].(See"Chemotherapyforadvancedexocrinepancreaticcancer",sectionon'CA199level'.)
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examinationmayimprovesensitivity,especiallyinpatientswithsmallprimarytumors.Atpresent,however,molecularanalysisisnotaroutinecomponentofthediagnosticevaluationforpancreaticmasses.EUSguidedFNAisaddressedindetailelsewhere.(See"Endoscopicultrasoundinthestagingofexocrinepancreaticcancer",sectionon'EUSFNA'.)
IfFNAspecimensareinadequateornondiagnostic,EUSguidedtrucut(coreneedle)biopsymaybeconsidered,wherelocalexpertiseisavailable.Atsomeinstitutions,atrucutbiopsymaybepreferredoverFNAfortheevaluationofsolidpancreaticmasslesionsthatareaccessiblefromthestomach,intheabsenceofacontraindication(inaccessibletarget,presenceofinterveningstructuresprohibitingbiopsy,uncorrectablecoagulopathyorthrombocytopenia,uncooperativepatient).TheroleofEUSguidedtrucutbiopsyintheevaluationofpancreaticmassesisdiscussedseparately.(See"Endoscopicultrasoundguidedtrucutbiopsy".)
STAGINGSYSTEMANDTHESTAGINGWORKUPThepreferredstagingsystemforallpancreaticcancers(exocrineandneuroendocrine)isthetumornodemetastasissystemofthecombinedAmericanJointCommitteeonCancer(AJCC)/InternationalUnionAgainstCancer(UICC)(table3)[76].Thegoalofthestagingworkupistodelineatetheextentofdiseasespreadandidentifypatientswhoareeligibleforresectionwithcurativeintent.
ImagingstudiesImagingstudiesplayanimportantroleinthestagingandmanagementofpancreaticcancer.
AbdominalCTAbdominalCTprovidesanassessmentoflocalandregionaldiseaseextent,whichdeterminesresectability,andalsoevaluatesthepossibilityofdistantmetastaticspread.
TechniqueThereliabilityofCTasastagingtoolforpancreaticcancerishighlydependentupontechnique.Triplephasecontrastenhancedthinslice(multidetectorrow)helicalcomputedtomography(MDCT)withthreedimensionalreconstructionisthepreferredmethodtodiagnoseandstagepancreaticcancer.HelicalCTscannerswithmultiplerowsofdetectorspermitimagingoflargervolumesoftissuewhileacquiringbotharterialandvenousphasesinshorterperiodsoftime(seebelow)[77,78].Thishasimprovedtheevaluationofthemainpancreaticductand,thus,thedetectionofsmalltumors[79].
Forcomprehensiveimagingofasuspectedpancreascancer,thepatientisusuallyscannedinseveraldynamicphasesofcontrastinjection(termedapancreasprotocol)[80]:
AssessingresectabilityCompletesurgicalresectionistheonlypotentiallycurativemodalityoftreatmentforpancreaticcancer.AninitialassessmentofresectabilitycanusuallybemadebaseduponthepreoperativetriplephasestagingcontrastenhancedCTscan.Localunresectabilityisusually(butnotalways)duetovascularinvasion,particularlyofthesuperiormesentericartery(SMA).
DefinitionsofunresectableandborderlineresectablediseaseAlthoughpracticeisvariableacrossinstitutions,manysurgeonswouldconsiderapancreaticcancertobecategoricallyunresectableifanyofthefollowingarepresent(see"Initialchemotherapyandradiationfornonmetastaticlocallyadvancedunresectable,borderlineresectable,andpotentiallyresectableexocrinepancreaticcancer",sectionon'Definitions'):
Thearterialphaseofenhancement,whichcorrespondstothefirst30secondsafterthestartofthecontrastinjection,providesexcellentopacificationoftheceliacaxis,superiormesentericartery(SMA),andperipancreaticarteries.
Anattenuationdifferencebetweentumorandnormalpancreas,whichincreaseslesionconspicuity,isbestachievedafterpeakenhancementoftheaortainthearterialphasebutbeforepeakenhancementoftheliver,whichoccursintheportalvenousphase.Thisissometimestermedthepancreaticphase[81,82].
Theportalvenousphase,whichisobtainedat60to70secondsafterthestartofthecontrastinjection,providesbetterenhancementofthesuperiormesentericvein,splenicandportalveins.Inaddition,peakhepaticenhancement,whichoptimizesthedetectionofhepaticmetastases,alsooccursintheportalvenousphase[83]
Extrapancreaticinvolvement,includingextensiveperipancreaticlymphaticinvolvement,nodalinvolvement
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Thereislessconsensusonthedefinitionof"borderline"resectablepancreaticcancer[8486].Somereservetheterm"borderlineresectable"forcaseswherethereisfocal(lessthanonehalfofthecircumference)(image15)tumorabutmentofthevisceralarteriesorshortsegmentocclusionofthesuperiormesentericvein(SMV)orSMV/portalveinconfluenceorhepaticartery.(See"Initialchemotherapyandradiationfornonmetastaticlocallyadvancedunresectable,borderlineresectable,andpotentiallyresectableexocrinepancreaticcancer",sectionon'Borderlineresectable'.)
Encasement(morethanonehalfofthevesselcircumference)(image15)orocclusion/thrombusofthesuperiormesentericvein(SMV)ortheSMVportalveinconfluenceusedtobeuniversallyconsideredanindicatorofunresectability.However,manycentershavedemonstratedthefeasibilityofSMVreconstruction,andthisisnowconsideredbymanytoalsorepresentborderlineresectabledisease[87].Ifvenousocclusionispresent,asuitablesegmentofportalvein(above)andSMV(belowthesiteofvenousinvolvement)mustbepresenttoallowforvenousreconstruction.However,inmostcenters,surgerywillbeprecededbysomeformofneoadjuvanttreatmentforpatientswithvenousocclusion.(See"Overviewofsurgeryinthetreatmentofexocrinepancreaticcancerandprognosis",sectionon'Vascularresection'and"Initialchemotherapyandradiationfornonmetastaticlocallyadvancedunresectable,borderlineresectable,andpotentiallyresectableexocrinepancreaticcancer",sectionon'Borderlineresectable'.)
TheNationalComprehensiveCancerNetwork(NCCN)considersthefollowingtorepresentcriteriaforborderlineresectabledisease:
Insomecases,patientswithborderlineresectablediseasearereferredforneoadjuvanttherapypriortosurgicalexploration.(See"Initialchemotherapyandradiationfornonmetastaticlocallyadvancedunresectable,borderlineresectable,andpotentiallyresectableexocrinepancreaticcancer".)
TheentireconceptofaborderlineresectablepancreaticcancerisproblematicforcenterstryingtoaccuratelystageandtreatpatientsaccordingtotheAJCCstagingsystem.TheAJCCusestheT4category(tumorinvolvestheceliacaxisorthesuperiormesentericartery)todesignateanunresectableprimarytumor,withT3designatingatumorthatextendsbeyondthepancreasbutwithoutinvolvementoftheceliacaxisormesentericartery.However,asnotedabove,involvementofafocalareaofthevisceralarteriesmaybeconsideredaborderlineresectablesituation.Onestudyof257patientswithstageIIIpancreaticcancer(allT4lesionsbaseduponinfiltrationoftheceliacaxisorSMA)foundthat30percentcouldundergoasuccessfulcomplete(R0)resectionafterchemoradiationorchemotherapyalone[88].RevisionstotheAJCCstagingsystemareanticipated.(See'Stagingsystemandthestagingworkup'above.)
AccuracyofCT
beyondtheperipancreatictissues,and/ordistantmetastases.
Directinvolvementofthesuperiormesentericartery(SMA),inferiorvenacava,aorta,celiacaxis,orhepaticartery,asdefinedbytheabsenceofafatplanebetweenthelowdensitytumorandthesestructuresonCTscan.
Fortumorsoftheheadorbody:
SevereunilateralorbilateralSMVorportalinfringement
Lessthanonehalfthecircumference(180degree)tumorabutmentontheSMA
Abutmentorencasementofthehepaticartery,ifreconstructible
ShortsegmentSMVocclusion,ifthereisanadequatesegmentofveinaboveandbelowthesiteoftumorinvolvementtoallowforvenousresectionandreconstruction
Fortumorsofthetail:
Lessthan180degreeencasementoftheSMAorceliacartery
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PrimarytumorThesensitivityoftriplephasehelicalCTforpancreaticadenocarcinomaishigh,89to97percent[33].Asexpected,sensitivityishigherforlargertumorsinonestudy,thesensitivitywas100percentfortumors>2cm,butonly77percentfortumors2cminsize[34].However,mostsmallisoattenuatingpancreaticcancershavesecondarysignssuchasapancreaticductcutoffordilatedmainpancreaticduct[35].
MetastaticdiseaseContrastenhancedCTisthemodalityofchoicetodetectdistantmetastases(image16).Thesensitivityforhepaticmetastasesishigh,particularlyusingthepancreaticprotocoltechnique.Inonestudyof43patientswithpancreaticcancer,thesensitivity,specificity,positivepredictivevalue,andnegativepredictivevalueofcontrastenhancedmultidetectorrowhelicalCTfordetectionoflivermetastaseswere88,89,92and84percent,respectively[89].Lowersensitivityrates(53and69percent)arereportedbyothersandmayberelatedtothesizeofthehepaticmetastases[90,91].
Peritonealinvolvementmaybedetectedindirectlybythepresenceofascites,mesentericnodules,ormesentericlymphnodes.However,thesensitivityofCTforperitonealdisseminationispoorandnotsufficientlyhightoeliminatetheneedfordiagnosticlaparoscopyinequivocalcases[9294].(See'Staginglaparoscopy'below.)
Fortumorsoftheheadandneckofthepancreas,regionallymphatictumorspreadusuallyoccursaroundtheceliacaxisandtheperipancreaticandperiportalareas.Fortumorsarisinginthetail,regionalnodalbasinsarelocatedalongthecommonhepaticartery,celiacaxis,splenicarteryandsplenichilum.
ThesensitivityandspecificityofCTfordetectinginvolvementoflymphnodesislow,leadingsometosuggestthatinapatientwhohasapresumedpancreaticcancerthatisconsideredresectable,thefindingofperipancreaticnodesonCTshouldnotpreventexploration[95].However,thepresenceofextensiveperipancreaticlymphaticinvolvementandnodalinvolvementbeyondtheperipancreatictissuesisgenerallyconsideredtorepresentunresectabledisease.(See'Definitionsofunresectableandborderlineresectabledisease'above.)
VascularinvasionCTcriteriaforvascularinvasionincludearterialembedmentinthetumormassorvenousobliteration,tumorinvolvementexceedingonehalfthecircumferenceofthevessel,vesselwallirregularity,vesselcaliberstenosis,orateardropsignofthesuperiormesentericvein(SMV)[96].
Themostcommonlyusedsystemforpredictingvascularinvasionbyapancreaticcancerusesafivegradescale,whichisbaseduponthedegreeofcontactbetweenthetumorandthebloodvessel(table4)[97].Intheinitialreportof25patients,tumorcontiguitywith>50percentormoreoftheperimeterofthevesselwasfoundtobetheoptimalthresholdforpredictingvascularinvasion,withasensitivityof84percentandaspecificityof98percent.
However,thesecriteriawereappliedequallytovenousandarterialstructures.Asnotedabove,becauseofadvancesinvenousreconstruction,manyinstitutionsdonotconsiderinvolvementofmorethanonehalfofthecircumferenceofthesuperiormesentericvein(SMV)ortheSMVportalveinconfluencetorepresentunresectabledisease.(See'Definitionsofunresectableandborderlineresectabledisease'above.)
Modificationsofthisgradingsystemhavebeenproposed,toincreasethesensitivityfordetectingvenousinvasionandspecificityfordetectingarterialinvasion,butnoneisinwidespreaduse[96,98100].Highsensitivityforvenousinvasionisdesirablesothatpatientswithundiagnosedvenousinvasionwillnotbedeemedunresectableintraoperativelyifresectionisattemptedataninstitutionwherevenousreconstructionisnotperformed.Ontheotherhand,highspecificityforarterialinvasionisdesirabletominimizetheriskofoverstagingT3disease,whichmaydenysomepatientsachanceforpotentiallycurativesurgicalresection.
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OtherstudiesAvarietyofotherimagingmodalities,includingendoscopicultrasound(EUS),MRI,FDGPETaswellasstaginglaparoscopy,mayberequiredtoassessresectabilityinsomecircumstances.
EUSDuetothesmalldistancebetweentheechoendoscopeandthepancreasthroughthegastricorduodenalwall,endoscopicultrasound(EUS)providesmuchhigherresolutionthantransabdominalultrasound.PancreaticcanceronEUSappearsasahypoechoicmass,typicallywithdilationoftheproximalpancreaticduct.Theborderofthelesionmayhaveanirregularcontour,andtheechopatternofthemassmaybehomogenousorinhomogeneous.(See"Endoscopicultrasound:Normalpancreaticobiliaryanatomy"and"Endoscopicultrasoundinthestagingofexocrinepancreaticcancer".)
MultiplestudiescomparingEUSwithotherimagingmodalitiesforinitialdiagnosisandstagingofpancreaticcancerconcludedthatEUSmaybemoreaccurateforsmallertumors,forlocalTandNstaging,andforpredictingvascularinvasion.EUSmaydetectmetastaticdiseaseintheliverormediastinallymphnodes,butisinferiortoCTforevaluationofdistantmetastases.Inaddition,thespecificityofEUSislimited,particularlywheninflammatorychangesarepresent.EUSisalsooperatordependentasaresult,itsvaluevarieswithlocallyavailableexpertise.ThedevelopmentofmodernmultidetectorrowCThasmarkedlyimprovedthesensitivityofCTforthedetectionofsmallertumorsandthepresenceofvascularinvasion,reachingvaluesthatarecomparabletothoseobtainedbyEUSbyanexperiencedendoscopist.However,headtoheadstudiescomparingthetwomodalitiesarelacking.(See"Endoscopicultrasoundinthestagingofexocrinepancreaticcancer",sectionon'ComparisonofEUSwithotherimagingtechniques'.)
TheroleofEUSinthepreoperativestagingofpancreaticcancerisevolving,andthereareseveralpointsinthediagnosticevaluationwherethismodalitymaybeofbenefit,particularlyforpatientswhoseCTevaluationdoesnotdemonstrateadefinedmasslesion(algorithm2).(See'Subsequenttestingifinitialimagingisnegative'above.)
Inaddition,EUSguidedfineneedleaspirationbiopsy(FNA)isthebestmodalityforobtainingatissuediagnosis,evenifthetumorispoorlyvisualizedbyotherimagingmodalities.(See'EUSguidedbiopsy'above.)
MRIAlthoughpancreaticadenocarcinomasareeasilyvisualizedonMRI(image17),thereisnoevidencethatMRIoffersasignificantdiagnosticadvantageovertriplephaseMDCTforthelocalstagingevaluation[106110].OnepotentialbenefitofMRIisitsincreasedsensitivityforthedetectionofsmalllivermetastasescomparedwithCT[90,91,111,112].CombiningCTandMRIofferslittlethatcannotbeachievedwithonealone.Thus,thechoiceofMRIorCTdependsupontheleveloflocallyavailableexpertiseandtheclinician'scomfortwithoneortheotherradioimagingtechnique.WepreferMDCT.
ChestCTCTofthechestmaybeusedasastagingtooltodetectlungmetastases.However,mostcenterstonotperformaroutinestagingchestCTforpatientssuspectedofhavingpancreaticcancerbecauseinthepresenceoflungmetastases,theprimarytumorisusuallyunresectableforanotherreason[113].
PETscanningPETscanningwiththetracer18fluorodeoxyglucose(FDG)reliesuponfunctionalactivitytodifferentiatemetabolicallyactiveproliferativelesionssuchascancers,mostofwhichareFDGavid,frombenignmasses.MostbenignlesionsdonotaccumulateFDG,withtheexceptionofinflammatorylesionssuchaschronicpancreatitis[114].
TheutilityofPETscansinthediagnosticandstagingevaluationofsuspectedpancreaticcancer,particularlywhetherPETprovidesinformationbeyondthatobtainedbycontrastenhancedMDCT,remainsuncertain,as
Ingeneral,helicalCThasahighpredictivevalueforunresectability(90to100percent)[98,101103],butthepredictivevalueforresectabilityisslightlylower(range64to90percent)[97,98,104].TheaccuracyofMDCTforassessingvascularinvasionwasaddressedinasystematicreviewandmetaanalysisof18studies[105].Thepooledsensitivityandspecificityfordiagnosingvascularinvasionwere77and81percent,respectively,butwhentheanalysiswaslimitedtothefivemostrecentstudiesconductedsince2004,andpresumablyusingthemostadvancedCTtechnology,sensitivityandspecificityrateswere85and82percent,respectively.
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illustratedbythefollowingdata:
Takentogether,thedataareinsufficienttoconcludethatPETorintegratedPET/CTprovidesusefulinformationabovethatprovidedbycontrastenhancedCT.ConsensusbasedguidelinesforstagingofpancreaticcancerfromtheNCCNstatethattheroleofPET/CTremainsunclear.DefinitiveassessmentoftheroleofPETasacomponentofthediagnosticand/orstagingevaluationawaitsalargeprospectivestudydesignedtoassessthebenefitofPET(preferablyintegratedPETwithacontrastenhancedCT)inpatientswithanegativeorindeterminateCTscan,withaprospectivelydesignedcosteffectivenessanalysis.
StaginglaparoscopyAccuratestagingdrivespropertreatmentofpatientswithpancreaticcancer,particularlywhenselectingpatientsforsurgicalresection.Becausemosthaveunresectablediseaseatpresentation,akeygoalistoavoidafutilelaparotomywheneverpossible.
Currentlyavailableimagingtechniquesarehighlyaccurateatpredictingunresectabledisease,buttheyfallshortinpredictingresectabledisease,mainlybecauseoflimitedsensitivityforsmallvolumemetastaticdisease.Radiographicallyoccultsubcentimetermetastasesonthesurfaceoftheliverorperitoneumthatarerarelyvisible
ThesensitivityofintegratedPET/CT(whichhasbetterspatialresolutionascomparedtoPETalone)intheinitialdiagnosisofpancreaticcancerrangesfrom73to94percent,whilespecificityrangesfrom60to89percent[115120].FalsenegativePETresultscanoccurinhyperglycemicpatientsorinsubcentimeterlesions,whilefalsepositiveresultscanbeseeninvariousinflammatorystatessuchaspancreatitis,infectedpseudocyst,orlocalinflammationcausedbyplacementofabiliarystent.Instudiesinwhichthetwomodalitieshavebeencompared,PETdoesnotappeartoprovideadditionalinformationtothatderivedfromMDCTorMRI[119121].
AmajorissueisthattheCTcomponentofintegratedPET/CTimagingisperformedinmanyinstitutionswithouttheuseofIVcontrastmaterial,atechniquethatprecludestheoptimaldetectionofsmalltumorsandmetastases.Increasingly,PET/CTisbeingcarriedoutwithIVcontrast,butthispracticeisnotwidespread.EarlyresultsarepromisingusingintegratedPETwithacontrastenhancedCT,butfurtherstudiesareneededtoestablishclinicalvaluecomparedwithMDCTaloneinpatientswithpancreaticcancer[122124].
OnepossiblebenefitofPETisenhanceddetectionofsmallvolumemetastaticdisease,whichisoftenmissedbyCT.Unfortunately,theavailabledataareconflicting,withsomestudiessuggestingthatPETisusefulforidentifyingmetastaticdiseasethatismissedbyCT(image18)[117,119,125127]andothersnotingthatPEToftenmissessmallvolumemetastaseswithintheperitoneumandelsewhere,includingtheliver[114,115,128].
However,theclinicalimpactremainsuncertain,asillustratedbythefollowingreports:
OneseriescomparedintegratedFDG/PET,MDCT,andMRIin38consecutivepatientssuspectedofhavingpancreaticcancer,withfindingsconfirmedbyoperationand/orhistopathologicanalysisorfollowup[119].Amongthe17patientswithadvancedpancreaticadenocarcinoma,FDGPET/CThadahighersensitivitythaneitherMDCTorMRI(88versus30and30percent,respectively),andtheclinicalmanagementof10patients(26percent)wasalteredbythefindingsonPET/CT.
Inanotherreport,82patientswithapancreaticmassthatwassuspiciousforcancerunderwentstagingwithintegratedPET/CTandcontrastenhancedCTofthechest,abdomen,andpelvis[117].ThesensitivityfordetectingmetastaticdiseaseforPET/CTalone,CTalone,andcombinedCTplusintegratedPET/CTwas61,57,and87percent,respectively.However,thefindingsonPET/CTchangedmanagementinonlysevenpatients(11percent),twobecauseofanoccultsupraclavicularlymphnode,twowithoccultliverlesions,twoperitonealimplants,andoneperiesophageallymphnode.Twoofthesepatientshadlocallyadvanceddiseaseandwouldnothavebeenconsideredforresection,evenifaPET/CThadnotbeendone.
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byCT,MRI,PET,ortransabdominalUSmaybevisualizedlaparoscopically.Studieshaveconsistentlyshownthatuptoonethirdofpatientsthoughttoberesectablebystateoftheartimagingwillbefoundtobeunresectablebaseduponlaparoscopicfindings[92,129131].ACochranereviewconcludedthatpatientswithpancreaticandperiampullarymalignancieswhowereconsideredtohaveresectablediseaseafterdiagnosticlaparoscopyandCTscanhada17percentprobabilitythattheircancerwouldbeunresectablecomparedtoa40percentprobabilityforthoseundergoingCTalone[132].Onaverage,theuseofdiagnosticlaparoscopywithbiopsyconfirmationofsuspiciouslesionwouldavoid23unnecessarylaparotomiesperevery100patientsplannedforcurativeintentresection.
However,thevalueofstaginglaparoscopyisnotuniversallyaccepted.Whilehospitalstay,cost,andmorbidityarereducedwhenanunnecessaryopenlaparotomyisavoidedforunresectableormetastaticdisease,therearenocontrolledstudiesdemonstratingabenefitforthisprocedureinpatientswhohaveundergoneradiographicstagingevaluationusingmodernhighqualityimagingsuchasMDCT[133].Thisissuewasnotaddressedinthe2013Cochranereview,andgiventhat7ofthe15trialswereundertakeninthe1980sand1990s,itisunlikelythatmodernCTtechniqueswereused.(See'Technique'above.)
Otherssuggestaselectiveapproachtostaginglaparoscopytomaximizeyieldbylimitingtheproceduretothosewiththehighestlikelihoodofoccultmetastaticdisease[134].Thisincludespatientswithatumorofthebodyortailofthepancreaswhoappeartohavepotentiallyresectablediseasebycomputedtomographyscan(onehalfofwhomwillhaveoccultperitonealmetastases[135,136]),large(>3cm)primarytumors,anypatientforwhomhighqualityimagingisinanywaysuggestiveofoccultmetastaticdisease,andthosewithahighinitialCA199level(>100units/mL)[66].(See"Overviewofsurgeryinthetreatmentofexocrinepancreaticcancerandprognosis",sectionon'Tumorsinthebodyortail'and'CA199'above.)
Weselectivelyusestaginglaparoscopyinpatientswithadvancedvascularinvolvement(butnotyetcompleteencasementorocclusionofthemajorvessels)andthosewithpancreaticbodyortaillesionswhoarenotjaundiced.OtherindicationsforastaginglaparoscopypriortoopenlaparotomyincludeahighpreoperativeCA199level(>1000units/mL)andanypatientforwhomhighqualityimagingisinanywaysuggestiveofoccultmetastaticdisease.Atsomeinstitutions,diagnosticlaparoscopyisperformedifneoadjuvanttherapyistoberecommended.
ImportanceofperitonealcytologyPeritonealwashingsareoftenobtainedatthetimeoflaparoscopy.Whileitwouldseemintuitivethatpatientswhohavepositiveperitonealwashingswouldbeunlikelytobenefitfromradicalresectionofthepancreaticprimarytumor,ithasnotbeenconclusivelydemonstratedthatpositiveperitonealcytologyasanisolatedfindingisanindependentadverseprognosticfactor[137139].Ingeneral,mostpatientswhohavecytologicallypositivewashingshaveotherfindingsthatsuggestadvanceddiseaseandunresectabilitysuchasascitesand/orthepresenceofmetastasesintheliver,pelvis,oromentum[137,140,141].Iftheseareabsent,mostpancreaticsurgeonsdonotrelyupontheresultsofperitonealwashingsobtainedatthetimeoflaparoscopytoguidedecisionmakingregardingresectability.However,theAJCCstagingsystemconsiderspositiveperitonealwashingstorepresentdistantmetastatic(M1)disease(table3)[76].
DIAGNOSTICALGORITHMANDNEEDFORPREOPERATIVEBIOPSYOursuggesteddiagnosticapproachtothepatientwithsuspectedpancreaticcancerisoutlinedinthealgorithm(algorithm2).(See'Biopsyandestablishingthediagnosis'above.)
Adiagnosticbiopsyofasuspectedpancreaticmalignancymaybeindicatedifthereisevidenceofsystemicspreadofdisease,ifthereislocalevidenceofunresectabilityonstagingstudies,ifthepatientisunfitformajorsurgery,ifneoadjuvanttreatmentisbeingcontemplated(eg,foraborderlineresectablelesion),orifalternativediagnosesneedtobeexcluded(eg,metastaticdiseasetothepancreas).(See"Initialchemotherapyandradiationfornonmetastaticlocallyadvancedunresectable,borderlineresectable,andpotentiallyresectableexocrinepancreaticcancer",sectionon'Roleofsurgery'.)
However,apreoperativediagnosticbiopsymaynotbeneededinafitpatientwithapotentiallyresectablepancreaticlesionthatishighlysuspectedofmalignancy.Whileapositivebiopsycanconfirmthesuspecteddiagnosis,abenignsamplewillnotexcludethepresenceofmalignancy.Inonesystematicreviewof53studies
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addressingthisissue,thenegativepredictivevalueofpercutaneousandEUSguidedbiopsieswasonly60to70percent[142].Attemptstomakeapreoperativetissuediagnosismayinfactbedetrimentaliftumorcellsaredisseminatedduringpercutaneousbiopsy.
Thus,ifapatientisareasonablesurgicalcandidate,andiftheclinicalpresentationandimagingaretypicalforaresectableadenocarcinomaafterthestagingevaluationhasbeencompleted,itisreasonabletoproceedtosurgerywithoutatissuediagnosis.(See'Stagingsystemandthestagingworkup'above.)
However,itmustberecognizedbyboththeclinicianandthepatientthatuncertaintyregardingthediagnosisintheseinstancespersistsandthatsomepatientswithbenignlesionsmaybesubjectedtotheradicalresectionsusedformalignantlesions.Thesecasescomprisebetween5and11percentofpatientsresectedforapresumedcancer[143146].Thefrequencyofradicalresectionforbenigndiseasemaybereducedwhenthisapproachiscombinedwithadditionalimaging,EUSguidedtransduodenalbiopsy.(See'EUSguidedbiopsy'above.)
FocalchronicpancreatitisandautoimmunepancreatitisarethetwobenignprocessesthataremostcommonlymistakenforpancreaticmalignancyonCTorUS.EUSguidedbiopsymayberecommendedifadiagnosisofchronicorautoimmunepancreatitisissuspectedonthebasisofhistory(eg,extremeyoungage,prolongedethanolabuse,historyofotherautoimmunediseases),particularlyiffurtherimagingstudies(eitherEUS,ERCPormagneticresonancecholangiopancreatography)revealmultifocalbiliarystrictures(suggestiveofautoimmunepancreatitis)ordiffusepancreaticductalchanges(suggestiveofchronicpancreatitis).Inaddition,serologictestingcanaidinthediagnosisofautoimmunepancreatitis.(See"Clinicalmanifestationsanddiagnosisofchronicpancreatitisinadults"and"Autoimmunepancreatitis".)
ForjaundicedpatientswhohavenoinvolvementorminimalinvolvementofthemajorvesselsaccordingtoCTorEUSandnoevidenceofdistantmetastasesonhelicalCTorEUS,weproceeddirectlytoanattemptatsurgicalresection.Fornonjaundicedpatients(particularlywithbodyortailtumors),orthosewithmajorbutincompleteinvolvementofthevascularstructures(tumorcontiguoustolessthanonehalfofthevesselcircumference[97,98]),weperformpreoperativelaparoscopytoexcludetinymetastasesthatmighthavebeenoverlookedbyCT.Ifthelaparoscopyisnegative,wethenembarkonaradicalsurgicalresection.(See'Staginglaparoscopy'above.)
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5 to6 gradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10 to12 gradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortablewithsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon"patientinfo"andthekeyword(s)ofinterest.)
SUMMARYANDRECOMMENDATIONS
th th
th th
Basicstopics(see"Patientinformation:Pancreaticcancer(TheBasics)")
BeyondtheBasicstopics(see"Patientinformation:Pancreaticcancer(BeyondtheBasics)")
Thecommonlyusedterm"pancreaticcancer"usuallyreferstoaductaladenocarcinomaofthepancreas(includingitssubtypes).Morethan95percentofmalignantneoplasmsofthepancreasarisefromtheexocrineelementsandarereferredtoasexocrinepancreaticcancers.(See'Pathology'above.)
Themostcommonpresentingsymptomsinpatientswithexocrinepancreaticcancerarepain,jaundice,andweightloss.Comparedtotumorsinthebodyandtailofthegland,pancreaticheadtumorsmoreoftenpresentwithjaundice,steatorrhea,andweightloss.(See'Clinicalpresentation'above.)
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Patientswhopresentwithjaundiceorepigastricpainandweightlossoftenundergorightupperquadranttransabdominalultrasoundinitiallytoevaluatefordilatedbileductsorapancreaticmass.(See'Initialtesting'aboveand'Transabdominalultrasound'above.)
Inthejaundicedpatient,ultrasoundishighlysensitivefordetectingbiliarytractdilationandestablishingthelevelofobstructionitishighlysensitiveforpancreaticmasses>3cm.(See'Jaundice'above.)
Endoscopicretrogradecholangiopancreatography(ERCP)isahighlysensitivetoolforvisualizationofthebiliarytreeandpancreaticductsinpatientswithjaundice.However,theroleofERCPinpatientswithsuspectedpancreaticcancerisevolvingintoamainlytherapeuticratherthandiagnosticmodalityinpatientswhopresentwithcholestasisduetotumorobstructionofthebiliarysystem.(See'ERCP'above.)
Analternativeapproachismagneticresonancecholangiopancreatography(MRCP).MRCPisgenerallyreservedforpatientswithgastricoutletorduodenalstenosis,orwhohavehadsurgicalrearrangement(eg,BillrothII)orductaldisruption,resultinginductsthataredifficulttoassesssuccessfullybyERCP,inthesettingofchronicpancreatitis,orforpatientsinwhomattemptedERCPiseithertotallyunsuccessfulorprovidesincompleteinformationbecauseofpancreaticductobstruction.(See'MRCP'above.).
Forpatientswithepigastricpainandweightlosswithoutjaundice,inwhomthedifferentialdiagnosisincludespancreatitis,transabdominalultrasoundisnotthepreferredinitialtestbecauseitisassociatedwithahighfrequencyofincompleteexaminationsowingtooverlyingbowelgasduetoileus,anditcannotclearlyidentifynecrosiswithinthepancreastheseimportantfindingsarebestseenbycontrastenhancedCTscan.(See'Epigastricpainandweightloss'above.)
Endoscopicultrasound(EUS)maybeofuseinapatientwhoissuspectedofhavingpancreaticcancerbasedupontheclinicalpresentationofjaundice,unexplainedupperabdominalpain/weightloss,oranunexplainedepisodeofpancreatitis,butwhohasnoevidenceofamasslesiononinitialtransabdominalultrasoundorCT.(See'Subsequenttestingifinitialimagingisnegative'above.)
Giventhelimitedsensitivityandspecificity,theserumtumormarkerCA199shouldnotbeusedasadiagnostictestforpancreaticcancer.(See'CA199'above.)
Histologicconfirmationisrequiredtoestablishadiagnosisofpancreaticcancer.Biopsyofapancreaticmasscanbeaccomplishedthroughpercutaneousorendoscopicapproaches.However,notallpatientsrequireapreoperativebiopsy,andthenextstepintheworkupofapatientwithsuspectedpancreaticcancerisoftenastagingevaluationtoestablishdiseaseextentandresectabilityratherthanbiopsy.(See'Biopsyandestablishingthediagnosis'above.)
WhenamasslesionofthepancreasisdetectedonCTorultrasound,itisreasonabletoconcludethataneoplasm(mostlikelymalignant)ispresent,andtriplephase,contrastenhancedhelical(preferablymultidetectorrow)CTisanappropriatenextsteptoassessdiseaseextentandresectability.Localunresectabilityisusually(butnotalways)duetovascularinvasion,particularlyofthesuperiormesentericartery(SMA).(See'AbdominalCT'above.)
Endoscopicultrasound(EUS)isanothereffectivemethodtoassesstumorextentandvascularinvasion,butwegenerallypreferCTgivenitsgreaterutilityinassessingfordistantmetastases.(See'EUS'above.)
Althoughpracticeisvariable,mostsurgeonswouldconsiderapancreaticcancertobecategoricallyunresectableifanyofthefollowingarepresent(see'Definitionsofunresectableandborderlineresectabledisease'above):
Extensiveperipancreaticlymphaticinvolvement,nodalinvolvementbeyondtheperipancreatictissues,
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UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
REFERENCES
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and/ordistantmetastases.
Directinvolvementofthesuperiormesentericartery(SMA),inferiorvenacava,aorta,celiacaxis,orhepaticartery,asdefinedbytheabsenceofafatplanebetweenthelowdensitytumorandthesestructuresonCTscan.
Encasement(morethanonehalfofthevesselcircumference)orocclusion/thrombusofthesuperiormesentericvein(SMV)ortheSMVportalveinconfluenceusedtobeuniversallyconsideredanindicatorofunresectability.However,manycentershavedemonstratedthefeasibilityofSMVreconstruction,andthisisnowconsideredbymanytorepresentborderlineresectablediseaseinpractice,mostofthesepatientsarereferredforneoadjuvanttherapypriortosurgery.
TheutilityofPETscans,chestCT,andMRIinthestagingworkupofsuspectedpancreaticcancer,particularlywhetheranyoftheseimagingstudiesprovidesinformationbeyondthatobtainedbytriplephase,contrastenhancedhelicalmultidetectorrowCTremainsuncertain,andwedonotroutinelyorderthesetests.(See'PETscanning'aboveand'ChestCT'aboveand'MRI'above.)
AssessmentofserumlevelsofthetumormarkerCA199priortosurgeryandfollowingresection,ifelevated,isvaluabletoassistinprognostication.Inaddition,serialmonitoringofCA199levels,ifinitiallyelevated,isusefultofollowpatientsafterpotentiallycurativesurgeryandforthosewhoarereceivingchemotherapyforadvanceddisease.(See'CA199'above.)
Ourgeneraldiagnosticapproach,asdetailedinthefollowingsections,issummarizedinthealgorithm(algorithm2).Ingeneral(see'Diagnosticalgorithmandneedforpreoperativebiopsy'above):
Tissuediagnosisismandatoryforpatientswhoareunfittoundergoamajorresection,forthosewithahighsuspicionofmetastaticdisease,andforanypatientbeingconsideredforneoadjuvanttherapybecauseoflocallyadvancednonmetastaticdisease.EUSguidedFNAisthebestmodalityforobtainingatissuediagnosis,evenifthetumorispoorlyvisualizedbyotherimagingmodalities.
Ifapatientisareasonablesurgicalcandidate,andiftheclinicalpresentationandimagingaretypicalforaresectableadenocarcinoma,itisreasonabletoproceedtosurgerywithoutatissuediagnosis.
Forjaundicedpatientswithnoinvolvementorminimalinvolvementofthemajorvesselsandnoevidenceofdistantmetastasesonradiographicimaging,weproceeddirectlytoopenlaparotomy.(See"Overviewofsurgeryinthetreatmentofexocrinepancreaticcancerandprognosis".)
Fornonjaundicedpatients(includingallthosewithbodyortailtumors),aswellasthosewithmajorbutincompleteinvolvementofthevascularstructures(eg,tumorcontiguoustolessthanonehalfofthevesselcircumference),weperformpreoperativelaparoscopytoexcludetinymetastasesthatmighthavebeenoverlookedbyCT.Ifthelaparoscopyisnegative,wethenproceedtoopenlaparotomytoassessresectability.OtherindicationsforastaginglaparoscopypriortoopenlaparotomyincludeahighpreoperativeCA199level(>1000units/mL),anypatientforwhomhighqualityimagingisinanywaysuggestiveofoccultmetastaticdisease,andatsomeinstitutions,forpatientsinwhomaneoadjuvantapproachtotherapyisbeingconsidered.(See'Staginglaparoscopy'above.)
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