Clinical Manifestations, Diagnosis, and Staging of Exocrine Pancreatic Cancer

12/4/2015
Clinicalmanifestations,diagnosis,andstagingofexocrinepancreaticcancer
OfficialreprintfromUpToDate
www.uptodate.com2015UpToDate
Author
CarlosFernandezdelCastillo,MD
SectionEditors
DeputyEditors
KennethKTanabe,MD
DianeMFSavarese,MD
DouglasAHowell,MD,FASGE,FACG
AnneCTravis,MD,MSc,FACG,AGAF
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Mar2015.|Thistopiclastupdated:Mar14,2014.
INTRODUCTIONCanceroftheexocrinepancreasisahighlylethalmalignancy.Itisthefourthleadingcause
ofcancerrelateddeathintheUnitedStatesandsecondonlytocolorectalcancerasacauseofdigestivecancer
relateddeath.(See"Epidemiologyandriskfactorsforexocrinepancreaticcancer",sectionon'Epidemiology'.)
Surgicalresectionistheonlypotentiallycurativetreatment.Unfortunately,becauseofthelatepresentation,only
15to20percentofpatientsarecandidatesforpancreatectomy.Furthermore,prognosisispoor,evenaftera
completeresection.Fiveyearsurvivalafterpancreaticoduodenectomyisabout25to30percentfornodenegative
and10percentfornodepositivedisease.(See"Overviewofsurgeryinthetreatmentofexocrinepancreaticcancer
andprognosis".)
Theclinicalpresentation,diagnosticevaluation,andstagingworkupforpancreaticexocrinecancerwillbe
reviewedhere.Epidemiologyandriskfactors,pathology,surgicalmanagement,adjuvantandneoadjuvanttherapy,
andtreatmentofadvancedpancreaticexocrinecancer,includingpalliativelocalmanagement,arediscussed
elsewhere.
(See"Epidemiologyandriskfactorsforexocrinepancreaticcancer".)
(See"Pathologyofexocrinepancreaticneoplasms".)
(See"Overviewofsurgeryinthetreatmentofexocrinepancreaticcancerandprognosis".)
(See"Adjuvanttherapyforresectedexocrinepancreaticcancer".)
(See"Initialchemotherapyandradiationfornonmetastaticlocallyadvancedunresectable,borderline
resectable,andpotentiallyresectableexocrinepancreaticcancer".)
(See"Supportivecareofthepatientwithadvancedexocrinepancreaticcancer".)
(See"Chemotherapyforadvancedexocrinepancreaticcancer".)
PATHOLOGYThecommonlyusedterm"pancreaticcancer"usuallyreferstoaductaladenocarcinomaofthe
pancreas(includingitssubtypes),whichrepresentsabout85percentofallpancreaticneoplasms.Oftheseveral
subtypesofductaladenocarcinoma,mostshareasimilarpoorlongtermprognosis,withtheexceptionofcolloid
carcinomas,whichhaveasomewhatbetterprognosis.Themoreinclusiveterm"exocrinepancreaticneoplasms"
includesalltumorsthatarerelatedtothepancreaticductalandacinarcellsandtheirstemcells(including
pancreatoblastoma),andispreferred.(See"Pathologyofexocrinepancreaticneoplasms".)
Morethan95percentofmalignantneoplasmsofthepancreasarisefromtheexocrineelements.Neoplasms
arisingfromtheendocrinepancreas(ie,pancreaticneuroendocrine[isletcell]tumors)comprisenomorethan5
percentofpancreaticneoplasmstheirclinicalmanifestations,diagnosis,andstagingisaddressedelsewhere.
(See"Classification,epidemiology,clinicalpresentation,localization,andstagingofpancreaticneuroendocrine
tumors(isletcelltumors)".)
CLINICALPRESENTATIONThemostcommonpresentingsymptomsinpatientswithexocrinepancreatic
cancerarepain,jaundice,andweightloss.Inamultiinstitutionalseriesof185patientswithexocrinepancreatic
cancerdiagnosedoverathreeyearperiod(62percentinvolvingtheheadofthegland,10percentbody,6percent
tail,andtheremaindernotdetermined),themostfrequentsymptomsatdiagnosiswere[1]:
Asthenia86percent
http://www.uptodate.com/contents/clinicalmanifestationsdiagnosisandstagingofexocrinepancreaticcancer?topicKey=GAST%2F2501&elapsedTimeMs=
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Weightloss85percent
Anorexia83percent
Abdominalpain79percent
Epigastricpain71percent
Darkurine59percent
Jaundice56percent
Nausea51percent
Backpain49percent
Diarrhea44percent
Vomiting33percent
Steatorrhea25percent
Thrombophlebitis3percent
Themostfrequentsignswere:
Jaundice55percent
Hepatomegaly39percent
Rightupperquadrantmass15percent
Cachexia13percent
Courvoisierssign(nontenderbutpalpabledistendedgallbladderattherightcostalmargin)13percent
Epigastricmass9percent
Ascites5percent
Theinitialpresentationofpancreaticcancervariesaccordingtotumorlocation.Approximately60to70percentof
exocrinepancreaticcancersarelocalizedtotheheadofthepancreas,while20to25percentareinthebody/tail
andtheremainderinvolvethewholeorgan[2].Comparedtotumorsinthebodyandtailofthegland,pancreatic
headtumorsmoreoftenpresentwithjaundice,steatorrhea,andweightloss[1,3,4].Asanexample,intheabove
notedseries,jaundicewaspresentin73percentofthe114patientswithatumorlocatedintheheadofthe
pancreas,comparedto11percentof19bodylesions,andnoneofthe11taillesions[1].Steatorrheawaspresent
in28percentofthepatientswithpancreaticheadlesionsversus11percentofthosewithbody,andnoneofthose
withtaillesions.Steatorrheaisattributabletolossofthepancreasabilitytosecretefatdigestingenzymesorto
blockageofthemainpancreaticduct.
Painisoneofthemostfrequentlyreportedsymptoms,evenwithsmall(<2cm)pancreaticcancers[5,6].Thepain
associatedwithpancreaticcancerisusuallyinsidiousinonset,andhasbeenpresentforonetotwomonthsatthe
timeofpresentation.Ithasatypicalgnawingvisceralquality,andisgenerallyepigastric,radiatingtothesides
and/orstraightthroughtotheback.Itmaybeintermittentandmadeworsebyeatingorlyingsupine.Itis
frequentlyworseatnight.Lyinginacurledorfetalpositionmayimprovethepain.Severebackpainshouldraise
suspicionforatumorarisinginthebodyandtailofthepancreas.Rarely,paindevelopsveryacutely,asaresultof
anepisodeofacutepancreatitisduetotumoralocclusionofthemainpancreaticduct[7].(See"Etiologyofacute
pancreatitis".)
Jaundice,whichisusuallyprogressive,ismostoftenduetoobstructionofthecommonbileductbyamassinthe
headofthepancreas,causinghyperbilirubinemia.Jaundicemaybeaccompaniedbypruritus,darkeningofthe
urine,andpalestools.Hyperbilirubinemiaischaracteristicallyofthecholestatictype,withapredominantincrease
intheconjugatedfractionofbilirubin.(See"Diagnosticapproachtotheadultwithjaundiceorasymptomatic
hyperbilirubinemia"and"Classificationandcausesofjaundiceorasymptomatichyperbilirubinemia".)
Jaundiceisarelativelyearlysignintumorsarisingfromthepancreatichead,andpancreatictumorsthatpresent
withpainlessjaundicehavebeenascribedarelativelymorefavorableprognosiscomparedtothosethatpresent
withpainandobstructivejaundice[3,8].Jaundicesecondarytoatumorinthebodyortailtypicallyoccurslaterin
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thecourseofthedisease,andmaybesecondarytolivermetastases.
Arecentonsetofatypicaldiabetesmellitus[911]maybenoted.Severalstudieshaveaddressedwhetherearlier
detectionofnonspecificsignsofanevolvingpancreaticneoplasm(particularlyinadultswithnewonsetdiabetes
mellitus)mightimproveresectabilityandoveralloutcomes,buttheresultsareinconclusive.Screeningfor
pancreaticcancerinadultswithnewonsetdiabetesmellitusisdiscussedelsewhere.(See"Epidemiologyandrisk
factorsforexocrinepancreaticcancer",sectionon'Diabetesmellitus,glucosemetabolism,andinsulin
resistance'.)
Unexplainedsuperficialthrombophlebitis,whichmaybemigratory(classicTrousseaussyndrome)[12],is
sometimespresentandreflectsthehypercoagulablestatethatfrequentlyaccompaniespancreaticcancer.Thereis
aparticularlyhighincidenceofthromboembolicevents(bothvenousandarterial),particularlyinthesettingof
advanceddisease,andcliniciansshouldmaintainahighindexofsuspicion.Multiplearterialemboliresultingfrom
nonbacterialthromboticendocarditismayoccasionallybethepresentingsignofapancreaticcancer[13].
Thromboemboliccomplicationsoccurmorecommonlyinpatientswithtumorsarisinginthetailorbodyofthe
pancreas[14].(See"Riskandpreventionofvenousthromboembolisminadultswithcancer"and"Nonbacterial
thromboticendocarditis".)
Skinmanifestationsoccurasparaneoplasticphenomenainsomepatients.Asanexample,bothcicatricialand
bullouspemphigoidaredescribed,evenasafirstsignofdisease[15].(See"Cutaneousmanifestationsofinternal
malignancy",sectionon'Paraneoplasticpemphigus'.)
Rarely,erythematoussubcutaneousareasofnodularfatnecrosis,typicallylocatedonthelegs(pancreatic
panniculitis),maybeevident,particularlyinpatientswiththeacinarcellvariantofpancreaticcancer(figure1).Itis
hypothesizedthattheconditionisinitiatedbyautodigestionofsubcutaneousfatsecondarytosystemicspillageof
excessdigestivepancreaticenzymes.Thepresenceofthisconditionisnotpathognomonicforanexocrine
pancreaticcancer,asithasbeendescribedwithpancreaticneuroendocrinetumors,intraductalpapillarymucinous
neoplasms,andinchronicpancreatitis.(See"Cutaneousmanifestationsofinternalmalignancy",sectionunder
constructionand"Pathologyofexocrinepancreaticneoplasms",sectionon'Acinarcellcarcinoma'and
"Panniculitis:Recognitionanddiagnosis".)
Signsofmetastaticdiseasemaybepresentatpresentation.Metastaticdiseasemostcommonlyaffectstheliver,
peritoneum,lungs,andlessfrequently,bone.Signsofadvanced,incurablediseaseinclude:
Anabdominalmass
Ascites(image1)
Leftsupraclavicularlymphadenopathy(Virchow'snode)(image2)
Apalpableperiumbilicalmass(SisterMaryJosephsnode)(image3)orapalpablerectalshelfarepresentin
somepatientswithwidespreaddisease.Pancreaticcanceristheoriginofacutaneousmetastasistothe
umbilicusin7to9percentofcases[16].
Routinelaboratorytestsareoftenabnormal,butarenotspecificforpancreaticcancer.Commonabnormalities
includeanelevatedserumbilirubinandalkalinephosphataselevels,andthepresenceofmildanemia.
IncidentalfindingAsolidpancreaticlesionisuncommonlyfoundasanincidentalfindingonCTscansdone
foranotherreason.Inonereport,24ofthe321patientswithasolidpancreaticmasswhowereidentifiedoveran
eightyearperiodhaditincidentallydiscovered(7percent)onehalfofthesewereadenocarcinomas,whilethe
remainderwerepancreaticneuroendocrinetumors[17].Themajorityofpancreaticlesionsdiscoveredon
radiographicstudiesperformedforanotherreasonarecystic,andmanyoftheserepresentintraductalpapillary
mucinousneoplasms,whichrepresentaprecursorlesiontoexocrinepancreaticcancer.(See"Pathophysiology
andclinicalmanifestationsofintraductalpapillarymucinousneoplasmofthepancreas",sectionon'Clinical
presentation'and"Pathophysiologyandclinicalmanifestationsofintraductalpapillarymucinousneoplasmofthe
pancreas",sectionon'Progressiontopancreaticcancer'.)
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DIFFERENTIALDIAGNOSISThesignsandsymptomsassociatedwithpancreaticcancerareoften
nonspecific,sothedifferentialdiagnosisislarge.Threeofthemorecommonfindingsleadingtosuspicionfor
pancreaticcancerarejaundice,epigastricpain,andweightloss.
Thepositivepredictivevalue(PPV)ofthesesymptomsforthediagnosisofpancreaticcancerislow,withthe
possibleexceptionofjaundiceinanolderpatient.Thiswasshowninacasecontrolstudythatexaminedtherisk
ofpancreaticcancerbaseduponsymptomsthatwereidentifiedintheyearbeforediagnosisin21,624patients
seeninaprimarycareclinic[18].ThePPVofjaundiceforpancreaticcancerinapatientaged60orolderwas22
percentitwas<3percentforallothersinglesymptomsorpairsofnonjaundicesymptoms,eveninolder
individuals.
JaundiceThedifferentialdiagnosisofthejaundicedpatientisbroadaclassificationofjaundiceaccordingto
thetypeofbilepigmentandunderlyingmechanismofhyperbilirubinemiaispresentedinthetable(table1).
Patientswithbiliaryobstructionduetopancreaticcancerusuallypresentwithconjugatedhyperbilirubinemia,and
thedifferentialdiagnosisincludescholedocholithiasis,biliaryobstructionfromothermalignanttumorsor
adenomas,intrahepaticcholestasis,andacuteorchronichepatocellularinjury(algorithm1).
Thediagnosticevaluationofajaundicedpatientwithbiliaryobstructionisdesignedtoeliminatebenigntumorsor
gallstonesfromthedifferential,andtoestablishthelocationandextentoftumorinvasionandspreadifamalignant
bileductobstructionisdetected.(See"Diagnosticapproachtotheadultwithjaundiceorasymptomatic
hyperbilirubinemia".)
EpigastricpainThedifferentialdiagnosisofepigastricpaininadultsisbroad.Mostpatientswithpancreatic
cancerandabdominalpainhavepainthathasbeenpresentformorethanthreedays,butnotformanymonths.As
such,theygenerallyfallintothecategoryofsubacutepain,andthecausesofbothacuteandchronicpainneedto
beincludedinthedifferentialdiagnosis.(See"Diagnosticapproachtoabdominalpaininadults",sectionon'Acute
versuschronicpain'.)
Thediagnosticapproachgenerallydependsonthehistory,locationofthepain,tempo,andthegeneralsuspicion
forbenignversusmalignantdiseasebaseduponassociatedsymptomssuchasweightloss.(See"Diagnostic
approachtoabdominalpaininadults".)
WeightlossSomeofthecausesofinvoluntaryweightlossincludemalignancies,endocrinopathies,and
psychiatricdiseases.Thisisdiscussedindetailelsewhere.(See"Approachtothepatientwithweightloss",
sectionon'Involuntaryweightloss'.)
PancreaticmassseenonanimagingstudySolidpancreaticmassesmaybedetectedincidentallyon
abdominalimagingstudies.(See'Incidentalfinding'above.)
Thedifferentialdiagnosisofapancreaticmassdependsuponwhetherthemassiscysticorsolid.Cystic
pancreaticlesionsincludenonneoplasticcysts(eg,truecysts,retentioncysts)(image4AB)andpancreatic
cysticneoplasms(eg,intraductalpapillarymucinousneoplasmofthepancreas(image5andimage6),serous
cystictumors(image7andimage8),andmucinouscysticneoplasms(image9andimage7andimage10)).The
classificationandevaluationofcysticpancreaticlesionsisdiscussedindetailelsewhere.(See"Classificationof
pancreaticcysts"and"Pancreaticcysticneoplasms".)
Thedifferentialdiagnosisofasolidpancreaticmassseenonaradiographicimagingstudyincludesaprimary
exocrinepancreaticcancer,apancreaticneuroendocrinetumor,lymphoma(rare)(image11),metastaticcancer
(rare),focalchronicpancreatitis,andautoimmunepancreatitis.
Pancreaticneuroendocrinetumorsaretypicallyhighlyvascularwithenhancementintheearlyarterialphaseand
washoutintheearlyportalvenousphase.(See"Classification,epidemiology,clinicalpresentation,localization,
andstagingofpancreaticneuroendocrinetumors(isletcelltumors)",sectionon'Computedtomography'.)
Althoughrare,thediagnosisofapancreaticmetastasismaybeconsideredinapatientwhohasevidenceof
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malignantdiseaseinothersites.
Cluessuggestingthepossibilityofaprimarypancreaticlymphomaincludealackofjaundice,constitutional
symptoms(weightloss,fever,andnightsweats),anelevatedserumlactatedehydrogenase(LDH)orbeta2
microglobulinlevel,andanormalserumCA199[19,20].Primarypancreaticlymphomasaretypicallylargerthan6
cm,andsurroundinglymphadenopathyiscommonaswithanylymphomahowever,neitherofthesefeatures
wouldexcludeadenocarcinoma.
Anendoscopicultrasound(EUS)guidedbiopsymayberecommendedifadiagnosisofchronicorautoimmune
pancreatitisissuspectedonthebasisofhistory(eg,extremeyoungage,prolongedethanolabuse,historyofother
autoimmunediseases),particularlyiffurtherimagingstudies(eitherEUS,endoscopicretrograde
cholangiopancreatography,magneticresonancecholangiopancreatography)revealmultifocalbiliarystrictures
(suggestiveofautoimmunepancreatitis)ordiffusepancreaticductalchanges(suggestiveofchronicpancreatitis).
Amongpatientswhohaveamassintheheadofthepancreasoramalignantbileductobstructioninthevicinityof
thedistalcommonbileduct,differentiatingaprimaryexocrinepancreaticcarcinomafromotherlesscommon
periampullarymalignancies(arisingintheampulla,duodenum,orbileduct)canbechallenging(figure2).Although
thediagnosismaybeevidentafterradiographicandendoscopicevaluation,itmaynotbepossibletodistinguish
thetissueoriginofamalignantperiampullaryneoplasmuntilresectionandhistopathologicevaluationoftheentire
surgicalspecimeniscompleted.(See"Ampullarycarcinoma:Epidemiology,clinicalmanifestations,diagnosisand
staging",sectionon'Diagnosticevaluation'.)
DIAGNOSTICAPPROACHItisnotpossibletoreliablydiagnoseapatientwithpancreaticcancerbasedon
symptomsandsignsalone.Thelackofspecificityforthediagnosisofpancreaticcancerwhenbasedon
symptomsthatarehighlysuggestiveandsensitiveforpancreaticcancerwasshowninalandmarkstudyinwhich
57percentofsuchpatientshadotherdiagnoses,includingnonpancreaticintraabdominalcancers(13percent),
pancreatitis(12percent),andnonpancreatic,noncancerousdisordersincludingirritablebowelsyndrome(23
percent)andmiscellaneousotherconditions(10percent)[21].
Awarenessofriskfactors(geneticpredisposition,age,smoking,diabetes)mayleadtoanearlierandmore
aggressiveevaluationforpancreaticcancerinpatientswhopresentwithsymptomssuspiciousforthedisease.
(See"Epidemiologyandriskfactorsforexocrinepancreaticcancer".)
Ingeneral,thediagnosticevaluationofapatientwithsuspectedpancreaticcancerincludesserologicevaluation
andabdominalimaging.Additionaltestingisthendirectedbaseduponthefindingsoftheinitialtestingaswellas
thepatientsclinicalpresentationandriskfactors.
InitialtestingAllpatientspresentingwithjaundiceorepigastricpainshouldhaveanassayofserum
aminotransferases,alkalinephosphatase,andbilirubintodetermineifcholestasisispresent.Inaddition,patients
withepigastricpainshouldbeevaluatedforacutepancreatitiswithaserumlipase.(See"Diagnosticapproachto
theadultwithjaundiceorasymptomatichyperbilirubinemia",sectionon'Initiallaboratorytests'and"Diagnostic
approachtoabdominalpaininadults",sectionon'Epigastricpain'.)
Thenextstepinthepatientsevaluationisabdominalimaging,thoughthechoiceoftestvariesdependinguponthe
patientspresentingsymptoms.
JaundiceForpatientswithjaundice,theinitialimagingstudyistypicallyatransabdominalultrasound(US).
TransabdominalUShashighsensitivityfordetectingbiliarytractdilationandestablishingthelevelofobstruction.
Italsohashighsensitivity(>95percent)fordetectingamassinthepancreas,althoughsensitivityislowerfor
tumors<3cm.(See'Transabdominalultrasound'belowand"Diagnosticapproachtotheadultwithjaundiceor
asymptomatichyperbilirubinemia",sectionon'Suspectedbiliaryobstructionorintrahepaticcholestasis'.)
However,insomepatientsthefirsttestobtainedmaybeanendoscopicretrogradecholangiopancreatography
(ERCP)oramagneticresonancecholangiopancreatography(MRCP).Thismostoftenoccursinapatientinwhom
thereisahighsuspicionforcholedocholithiasis.However,becauseoftheincreasedcostandrisksassociated
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withtheseprocedures,transabdominalUSispreferredastheinitialimagingstudyforpatientssuspectedofhaving
pancreaticcancer.(See'ERCP'belowand"Endoscopicretrogradecholangiopancreatography:Indications,patient
preparation,andcomplications",sectionon'IndicationsforERCP'and"Magneticresonance
cholangiopancreatography",sectionon'Clinicaluse'.)
EpigastricpainandweightlossAbdominalcomputedtomography(CT)isthepreferredinitialimagingtest
inpatientspresentingwithepigastricpainandweightloss,butwithoutjaundice.(See'AbdominalCT'below.)
Inpractice,transabdominalUSiscommonlyutilizedasaninitialscreeningtechniqueforbiliarypancreaticdisease
insuchpatientsbecauseoftoitslowcostandwideavailability[22,23].However,whiletransabdominalultrasound
hashighsensitivityfordetectingtumors>3cm,itismuchlowerforsmallertumors.(See'Transabdominal
ultrasound'below.)
Furthermore,ifacutepancreatitisisinthedifferential,transabdominalUSisnotthepreferredinitialtest.Itis
associatedwithahighfrequencyofincompleteexaminationsowingtooverlyingbowelgasfromanileus,andit
cannotclearlyidentifynecrosiswithinthepancreastheseimportantfindingsarebestseenbycontrastenhanced
CTscan.
Forthesereasons,andbecauseofthegreateramountofstaginginformationthatcanbeobtained,CTispreferred
inthissetting,particularlyforpatientswhohavesymptomsotherthanepigastricpainthatraisesuspicionfor
pancreaticcancer(eg,weightloss,recentdiagnosisofatypicaldiabetesmellitus)[2428].(See'Clinical
presentation'above.)
SubsequenttestingifinitialimagingispositiveIfapancreaticmassisseenontransabdominalUS,an
abdominalCTscanistypicallyobtainedtoconfirmthepresenceofthemassandtoassessdiseaseextent.Ifthe
CTappearanceistypical,enoughinformationisprovidedtoassessresectability,andthepatientisfitforamajor
operation,additionaltesting(includingbiopsy)maybeunnecessarybeforesurgicalintervention.Ontheotherhand,
ifthediagnosisisindoubt,resectabilityisuncertain,orifatherapeuticinterventionisneeded,additional
proceduresmaybeindicated.(See'Stagingsystemandthestagingworkup'belowand'Diagnosticalgorithmand
needforpreoperativebiopsy'below.)
ERCPisindicatedifcholedocholithiasisremainsinthedifferentialdiagnosisafterinitialevaluationorifbiliary
decompressionisrequired.However,notallpatientswithbiliaryobstructionfrompancreaticcancerrequire
decompression,andstentplacementshouldbeavoidedinpatientswhohavenotyetundergoneCTbecausea
stentmaycauseartifactinthepancreaticheadthatcanmaskthelesion,andthetraumaofstentinsertionmay
induceinflammatorychangesthatmightbeindistinguishablefromtumor.(See'ERCP'belowand"Endoscopic
stentingformalignantpancreaticobiliaryobstruction"and"Surgicalresectionoflesionsoftheheadofthe
pancreas",sectionon'Preoperativebiliarydrainage'and"Overviewofsurgeryinthetreatmentofexocrine
pancreaticcancerandprognosis",sectionon'Roleofpreoperativebiliarydrainage'.)
MRCPisanalternativeforpatientswhocannotundergoERCP(eg,thosewithagastricoutletobstruction),butit
lackstherapeuticcapability.(See'MRCP'below.)
EUSguidedorpercutaneousbiopsiesofapancreaticmasscanbeobtainedifhistologicconfirmationisneeded,
thoughthisisnotalwaysrequiredinpatientswhoappeartohavepotentiallyresectablediseaseandwhohave
typicalimagingfindings.EUSmayalsobeusedasanalternativetocontrastenhancedtriplephasehelicalCTfor
thestagingofpancreaticcancer.(See'EUS'belowand'Biopsyandestablishingthediagnosis'below.)
SubsequenttestingifinitialimagingisnegativeForpatientswhoarestronglysuspectedofhaving
pancreaticcancerbutwhoseinitialimagingisnegative,furthertestingmaybeindicated.IfanabdominalCTscan
hasnotyetbeendone,thatisthenextstep.
ForpatientswithcholestasiswhohaveonlyhadtransabdominalUS,ERCPisindicated.MRCPisanalternative
forpatientswhocannotundergoERCP(eg,thosewithagastricoutletobstruction).(See'Jaundice'aboveand
'MRCP'below.)
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Ifthesetestsarenegative,additionaltestingistypicallynotrequiredandanalternativecauseforthepatients
symptomsshouldbesought.However,ifthesuspicionforpancreaticcancerremainshigh(eg,inapatientwith
profoundweightlossorwhohasriskfactorsforpancreaticcancer,suchashereditarypancreatitisorchronic
pancreatitis),anEUSisareasonablenextsteptoexcludeasmallpancreaticcancer(algorithm2).(See
"Epidemiologyandriskfactorsforexocrinepancreaticcancer",sectionon'Riskfactors'.)
AnylesionsthatarevisibleonlyonEUSshouldbebiopsiedtoconfirmthediagnosispriortosurgicalexploration.
EUSguidedfineneedleaspiration(FNA)biopsyisthebestmodalityforobtainingatissuediagnosis,evenifthe
tumorispoorlyvisualizedbyotherimagingmodalities.Inaseriesof116patientssuspectedofhavingpancreatic
cancer,butwithinconclusivefindingsonCTscan,EUSwithFNAhadasensitivityandspecificityfordiagnosing
apancreaticmalignancyof87and98percent,respectively[29].IndependentriskfactorsassociatedwithEUS
detectionofpancreaticductaladenocarcinomaincludedpancreaticductaldilationonCTscan(oddsratio[OR]4.1,
95%confidenceinterval[CI]1.511)andtumorsizedetectedbyEUSof1.5cm(OR8.5,95%CI2.035).
Specifictestsusedintheinitialevaluation
TransabdominalultrasoundTheinitialstudyinpatientswhopresentwithobstructivejaundiceor
epigastricpainandweightlossisoftentransabdominalultrasound(US).TransabdominalUShashighsensitivity
fordetectingbiliarytractdilationandestablishingthelevelofobstruction.(See"Diagnosticapproachtotheadult
withjaundiceorasymptomatichyperbilirubinemia",sectionon'Suspectedbiliaryobstructionorintrahepatic
cholestasis'.)
OnUS,apancreaticcarcinomatypicallyappearsasafocalhypoechoichypovascularsolidmasswithirregular
margins.Dilatedbileductsmayalsosuggestthepresenceofapancreatictumor.
SupportfortheutilityoffirstlineabdominalUSforthediagnosisofapancreatictumorinpatientswhopresentwith
symptomsofpancreaticcancercomesfromaprospectivecohortstudyof900patientswhounderwent
transabdominalUStoworkuppainlessjaundice,anorexia,orunexplainedweightloss[30].Thesensitivityfor
detectionofalltumorsinthepancreaswas89percent(124of140),including90percentfordetectionofexocrine
pancreaticcancer(79of88patients).Amongthe779patientswhowerefollowedovertimeandestablishednotto
havedevelopedapancreatictumor,ninehadfalsepositiveUSfindings(specificity99percent).
WhilethereportedsensitivityforUSindiagnosingpancreaticcanceris95percentfortumors>3cm,itismuch
lessforsmallertumors[22,30,31].Sensitivityisalsodependentupontheexpertiseoftheultrasonographerandthe
presenceorabsenceofbileductobstruction.
AbdominalCTAmasswithinthepancreasisthemostcommonCTfindingofpancreaticcancer,although
enlargementofthewholeglandissometimesseen[26,32].SensitivityofCTforpancreaticcancerdependson
techniqueandishighest(89to97percent)withtriplephase,helicalmultidetectorrowCT[33].Asexpected,
sensitivityishigherforlargertumorsinonestudy,thesensitivitywas100percentfortumors>2cm,butonly77
percentfortumors2cminsize[34].ThispancreaticprotocoltypeofCTisoftennottheinitialstudyfora
patientwithoutaknowndiagnosisofpancreaticcancer.(See'Technique'belowand'Initialtesting'above.)
ThetypicalCTappearanceofanexocrinepancreaticcancerisanilldefinedhypoattenuatingmasswithinthe
pancreas(image12),althoughsmallerlesionsmaybeisoattenuating,makingtheiridentificationdifficult,
particularlyonnoncontrastCT[35].
Secondarysignsofapancreaticcancer(whichareseenwithmanysmallisoattenuatingcancers)includea
pancreaticductcutoff,dilatationofthepancreaticductorcommonbileduct,parenchymalatrophy,andcontour
abnormalities(image13).Dilationofboththepancreaticductandthecommonbileduct,commonlyreferredtoas
thedoubleductsignispresentinabout62to77percentofcasesofpancreaticcancer(picture1),butisnot
diagnosticforapancreaticheadmalignancy[36,37].Approximately50percentofampullarycarcinomashavea
doubleductsign[38],anditcanalsooccasionallybeseenwithbenignadenomas.
ERCPEndoscopicretrogradecholangiopancreatography(ERCP)isahighlysensitivetoolforvisualization
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ofthebiliarytreeandpancreaticducts.(See"Endoscopicmethodsforthediagnosisofpancreatobiliary
neoplasms",sectionon'Endoscopicretrogradecholangiopancreatography'.)
Anearlymetaanalysisfoundasensitivityof92percentandspecificityof96percentfordiagnosingcancerofthe
pancreasbyERCP[39].Findingssuggestiveofamalignanttumorwithintheheadofthepancreasinclude
superimposablestricturesorobstructionofthecommonbileandpancreaticducts(the"doubleduct"sign),a
pancreaticductstrictureinexcessof1cminlength,pancreaticductobstruction,andtheabsenceofchanges
suggestiveofchronicpancreatitis(picture1).
Furthermore,ERCPprovidesanopportunitytocollecttissuesamples(forcepsbiopsy,brushcytology)for
histologicdiagnosis.However,thesensitivityfordetectionofmalignancy(approximately50to60percent)islower
thanthatofendoscopicultrasound(EUS)guidedFNA(sensitivity92percent).(See"Endoscopicmethodsforthe
diagnosisofpancreatobiliaryneoplasms",sectionon'TissuesamplingduringERCP'and'EUSguidedbiopsy'
below.)
OtherlimitationsofERCParethatparenchymalabnormalitiescanonlybedetectedbyinferencetumorscanbe
missedintheuncinateprocess,accessoryduct,andtailandtheneedforintraductalcontrastadministration.
DirectvisualizationofthepancreaticductispossibleduringERCPusingpancreatoscopy.Pancreatoscopyusesa
miniatureendoscopethatispassedthroughtheduodenoscope(image14)tovisualizethepancreaticductandto
obtaintargetedbiopsiesofpancreaticductstrictures.However,theprocedureisnotwidelyavailable.(See
"Cholangioscopyandpancreatoscopy".)
ERCPissuperiortotransabdominalUSandCTforthedetectionofextrahepaticbiliaryobstruction,andisthe
procedureofchoicewhenthereissuspicionforcholedocholithiasis.However,itisalsomoreexpensivethan
ultrasoundorCT,andasaninvasiveprocedure,itisassociatedwithafiniterateofmortality(0.2percent)and
complicationssuchaspancreatitis,bleeding,andcholangitis.Asaresult,theroleofERCPinpatientswith
suspectedpancreaticcancerisevolvingintoamainlytherapeuticmodalityforpatientswhopresentwith
cholestasisduetotumorobstructionofthebiliarysystemandrequireplacementofabiliarystent.(See
"Endoscopicstentingformalignantpancreaticobiliaryobstruction"and"Diagnosticapproachtotheadultwith
jaundiceorasymptomatichyperbilirubinemia",sectionon'Suspectedbiliaryobstructionorintrahepatic
cholestasis'.)
However,preoperativestentingisnotalwaysnecessaryinapatientwithapotentiallyresectablepancreatic
cancer,eveninthepresenceofcholangitis.Furthermore,ifitisundertaken,stentingshouldnotbeperformed
beforeCTscanningtoassessresectability,asthestentmaycauseartifactinthepancreaticheadthatcanmask
thelesion,andthetraumaofstentinsertionmayinduceinflammatorychangesthatmightbeindistinguishablefrom
tumor.Theindicationsandcontroversiessurroundingtherisksandbenefitsofpreoperativestentplacementare
discussedelsewhere.(See"Endoscopicstentingformalignantpancreaticobiliaryobstruction",sectionon
'Indications'and"Surgicalresectionoflesionsoftheheadofthepancreas",sectionon'Preoperativebiliary
drainage'and"Overviewofsurgeryinthetreatmentofexocrinepancreaticcancerandprognosis",sectionon'Role
ofpreoperativebiliarydrainage'.)
MRCPAnalternativetodiagnosticERCPismagneticresonancecholangiopancreatography(MRCP).
MRCPusesMRtechnologytocreateathreedimensionalimageofthepancreaticobiliarytree,liverparenchyma,
andvascularstructures.MRCPisbetterthanCTfordefiningtheanatomyofthebiliarytreeandpancreaticduct,
hasthecapabilitytoevaluatethebileductsbothaboveandbelowastricture,andcanalsoidentifyintrahepatic
masslesions.ItisatleastassensitiveasERCPindetectingpancreaticcancers[40,41],andunlikeconventional
ERCP,itdoesnotrequirecontrastmaterialtobeadministeredintotheductalsystem.Thus,themorbidity
associatedwithendoscopicproceduresandcontrastadministrationisavoided.(See"Magneticresonance
cholangiopancreatography".)
AlthoughMRCPhasnotyetreplacedERCPinthepatientssuspectedofhavingpancreaticcancerinmost
centers(algorithm2),itmaybepreferredinspecificsettings:
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Patientswhohavegastricoutletorduodenalstenosisorwhohavehadsurgicalrearrangement(eg,BillrothII)
orductaldisruption,resultinginductswhicharedifficulttoassesssuccessfullybyERCP.
Todetectbileductobstructionoccurringinthesettingofchronicpancreatitis.(See"Complicationsofchronic
pancreatitis".)
ForpatientsinwhomattemptedERCPiseithertotallyunsuccessfulorprovidesincompleteinformation
becauseofpancreaticductobstruction[42].
RoleoftumormarkersSeveralserummarkersforpancreaticcancerhavebeenevaluated,themostuseful
ofwhichiscancerassociatedantigen199(CA199).
CA199ThereportedsensitivityandspecificityratesofCA199forpancreaticcancerrangefrom70to
92,and68to92percent,respectively[4347].However,sensitivityiscloselyrelatedtotumorsize.CA199levels
areoflimitedsensitivityforsmallcancers[43,4851].Furthermore,CA199requiresthepresenceoftheLewis
bloodgroupantigen(aglycosyltransferase)tobeexpressed.AmongindividualswithaLewisnegativephenotype
(anestimated5to10percentofthepopulation),CA199levelsarenotausefultumormarker[50,52].
CA199levelsalsohavelowspecificity.CA199isfrequentlyelevatedinpatientswithcancersotherthan
pancreaticcancerandvariousbenignpancreaticobiliarydisorders(table2)[4850,53,54].Onestudyfoundthat
serumconcentrationsabove37U/mLrepresentedthemostaccuratecutoffvaluefordiscriminatingpancreatic
cancerfrombenignpancreaticdisease,butthesensitivityandspecificityforpancreaticcanceratthislevelwere
only77and87percent,respectively[53].Furthermore,thepositivepredictivevalue(PPV)islow,particularly
amongasymptomaticindividuals.Inalargeseriesofover70,000asymptomaticindividuals,thePPVofaserum
CA199level>37U/mLwasonly0.9percent[55].Becauseofthis,expertguidelinesrecommendagainsttheuse
ofCA199asascreeningtestforpancreaticcancer[56].Evenamongsymptomaticindividuals(epigastricpain,
weightloss,jaundice),thesensitivity,specificity,andpositivepredictivevalueofanelevatedCA199>37U/mL
levelareonlyapproximately80,85,and72percent[49,57].
ThespecificityandPPVforthediagnosisofpancreaticcancercanbeimprovedbyusinghighercutofflevels(100
oreven1000U/mL),butattheexpenseofsensitivity[49].Importantly,thereisaverybroadrangeofCA199
levelsthatcanbeseeninbenigndisease,andtherearenospecificcutoffvalues(evenbeyond10,000U/mL)that
areseenonlyinpatientswithmalignantdisease[46,53,58].
SerumlevelsofCA199dohavesomevalueasprognosticmarkersandalsoasanindicatorofdiseaseactivityin
patientswithinitiallyelevatedlevels:
ThedegreeofelevationofCA199(bothatinitialpresentationandinthepostoperativesetting)isassociated
withlongtermprognosis[5964].
Amongpatientswhoappeartohavepotentiallyresectablepancreaticcancer,themagnitudeofthe
preoperativeCA199levelcanalsohelptopredictthepresenceofradiographicallyoccultmetastatic
disease,thelikelihoodofacomplete(R0)resection,andlongtermoutcomes[59,6568].Asexamples:
Inareportof491patientsundergoingstaginglaparoscopyforaradiographicallyresectablepancreatic
adenocarcinoma,CA199valuesabove130units/mLwereasignificantpredictoroffinding
radiographicallyoccultunresectabledisease[65].Theratesofunresectablediseaseamongallpatients
withaCA199level130units/mLversus<130units/mLwere26and11percent,respectively.Among
patientswithtumorsinthebody/tailofthepancreas,morethanonethirdofthosewhohadaCA199
level130units/mLhadunresectabledisease.
Inanotherreportof1626consecutivepatientswhounderwentresectionforaprimarypancreatic
cancer,datafrom1543patientswithpreoperativedetectableserumlevelsofCA199showed
decreasedresectabilityandsurvivalrateswithhigherCA199values[69].
WhilehighlevelsofCA199levelsmayhelpsurgeonstobetterselectpatientsforstaginglaparoscopy,an
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expertpanelconvenedbytheAmericanSocietyofClinicalOncology(ASCO)recommendedagainsttheuse
ofCA199aloneasanindicatorofoperability[56].
SerialmonitoringofCA199levels(onceeveryonetothreemonths[56])isusefultofollowpatientsafter
potentiallycurativesurgeryandforthosewhoarereceivingchemotherapyforadvanceddisease.RisingCA
199levelsusuallyprecedetheradiographicappearanceofrecurrentdisease,butconfirmationofdisease
progressionshouldbepursuedwithimagingstudiesand/orbiopsy[56].(See"Chemotherapyforadvanced
exocrinepancreaticcancer",sectionon'CA199level'.)
OthermarkersAlthoughseveralmarkercandidateshaveemergedfrompreclinicalstudies(andone,
macrophageinhibitorycytokine1,appearsparticularlypromising[70]),nonehasreplacedCA199todate.
BiopsyandestablishingthediagnosisHistologicconfirmationisrequiredtoestablishadiagnosisof
pancreaticcancer.(See"Pathologyofexocrinepancreaticneoplasms".)
Followingtheinitialevaluation,somepatientsmayhaveabiopsyprovendiagnosisofpancreaticcancer,typically
becausetheypresentedwithjaundiceandunderwentanERCP.(See'ERCP'above.)
However,inmanycases,thediagnosiswillnotyetbehistologicallyconfirmed.Oncepancreaticcanceris
suspectedoninitialimagingstudies,thenextstepintheworkupisgenerallyastagingevaluationtoestablish
diseaseextentandresectabilityratherthanbiopsy.Patientswhoarefitformajorsurgeryandwhoappeartohave
potentiallyresectablepancreaticcancerafterthestagingevaluationiscompletedonotnecessarilyneeda
preoperativebiopsyconfirmingthediagnosisofapancreaticcancerbeforeproceedingdirectlytosurgery.
However,theincreasedrecognitionofchronicorautoimmunepancreatitis,whichcancloselymimicpancreatic
cancer,hasalteredthisparadigmincertainpopulations.Apreoperativebiopsymayberecommendedifa
diagnosisofchronicorautoimmunepancreatitisissuspectedonthebasisofhistory(eg,extremeyoungage,
prolongedethanolabuse,historyofotherautoimmunediseases),particularlyifimagingstudies(EUS,ERCPor
magneticresonancecholangiopancreatography)revealmultifocalbiliarystrictures(suggestiveofautoimmune
pancreatitis)ordiffusepancreaticductalchanges(suggestiveofchronicpancreatitis).Theseissuesarediscussed
inmoredetailbelow.(See'Diagnosticalgorithmandneedforpreoperativebiopsy'below.)
Whenitisindicated,biopsyofapancreaticmasscanbeaccomplishedeitherpercutaneouslyorviaEUS.
PercutaneousbiopsyPercutaneousfineneedleaspiration(FNA)biopsyofapancreaticmasscanbe
performedusingeitherultrasoundorcomputedtomographic(CT)guidance(picture2).Thesensitivityand
specificityofthisprocedureforthediagnosisofpancreaticcancerdependsupontumorsizeandoperator
expertisevaluesintherangeof80to90and98to100percent,respectively,arereported[71].
AtheoreticalconcernisthatpercutaneousFNAbiopsyofthepancreasmaydisseminatetumorcells
intraperitoneallyoralongtheneedlepathinpatientswhoarebelievedtobecandidatesforpotentiallycurative
resection.However,theriskappearstobequiteloworabsent.Inonestudyof41patientsundergoingresection
forprimarypancreaticadenocarcinoma,21of32patientswithoutpreoperativeopenbiopsieshadundergone
preoperativeCTorfluoroscopicallyguidedFNA[72].Therewasnoincreaseinpositiveperitonealwashings,
peritonealfailurerate,ormediansurvivalinthesepatients.Nevertheless,concernpersistsand,inpractice,wetry
toavoidpercutaneousFNAinpatientswithresectablemasses.
AtransduodenalEUSguidedFNAbiopsyorERCPsamplingreducestheserisks[7375].(See'ERCP'above.)
EUSguidedbiopsyEUSguidedFNAisthebestmodalityforobtainingatissuediagnosis,evenifthe
tumorispoorlyvisualizedbyotherimagingmodalities.Thisprocedureislesslikelytocauseintraperitonealspread
ofthetumorsincethebiopsyisobtainedthroughthebowelwallratherthanpercutaneously.EUSguidedFNAhas
asensitivityofapproximately90percentandspecificityof96percentforthediagnosisofapancreaticcancer.
(See"Endoscopicultrasoundinthestagingofexocrinepancreaticcancer",sectionon'AccuracyofEUSFNA'.)
Theadditionofmoleculargeneticanalysis(eg,assayforKrasorp53genemutationsbyRTPCR)tocytologic
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examinationmayimprovesensitivity,especiallyinpatientswithsmallprimarytumors.Atpresent,however,
molecularanalysisisnotaroutinecomponentofthediagnosticevaluationforpancreaticmasses.EUSguided
FNAisaddressedindetailelsewhere.(See"Endoscopicultrasoundinthestagingofexocrinepancreaticcancer",
sectionon'EUSFNA'.)
IfFNAspecimensareinadequateornondiagnostic,EUSguidedtrucut(coreneedle)biopsymaybeconsidered,
wherelocalexpertiseisavailable.Atsomeinstitutions,atrucutbiopsymaybepreferredoverFNAforthe
evaluationofsolidpancreaticmasslesionsthatareaccessiblefromthestomach,intheabsenceofa
contraindication(inaccessibletarget,presenceofinterveningstructuresprohibitingbiopsy,uncorrectable
coagulopathyorthrombocytopenia,uncooperativepatient).TheroleofEUSguidedtrucutbiopsyintheevaluation
ofpancreaticmassesisdiscussedseparately.(See"Endoscopicultrasoundguidedtrucutbiopsy".)
STAGINGSYSTEMANDTHESTAGINGWORKUPThepreferredstagingsystemforallpancreaticcancers
(exocrineandneuroendocrine)isthetumornodemetastasissystemofthecombinedAmericanJointCommittee
onCancer(AJCC)/InternationalUnionAgainstCancer(UICC)(table3)[76].Thegoalofthestagingworkupisto
delineatetheextentofdiseasespreadandidentifypatientswhoareeligibleforresectionwithcurativeintent.
ImagingstudiesImagingstudiesplayanimportantroleinthestagingandmanagementofpancreaticcancer.
AbdominalCTAbdominalCTprovidesanassessmentoflocalandregionaldiseaseextent,which
determinesresectability,andalsoevaluatesthepossibilityofdistantmetastaticspread.
TechniqueThereliabilityofCTasastagingtoolforpancreaticcancerishighlydependentupon
technique.Triplephasecontrastenhancedthinslice(multidetectorrow)helicalcomputedtomography(MDCT)
withthreedimensionalreconstructionisthepreferredmethodtodiagnoseandstagepancreaticcancer.HelicalCT
scannerswithmultiplerowsofdetectorspermitimagingoflargervolumesoftissuewhileacquiringbotharterial
andvenousphasesinshorterperiodsoftime(seebelow)[77,78].Thishasimprovedtheevaluationofthemain
pancreaticductand,thus,thedetectionofsmalltumors[79].
Forcomprehensiveimagingofasuspectedpancreascancer,thepatientisusuallyscannedinseveraldynamic
phasesofcontrastinjection(termedapancreasprotocol)[80]:
Thearterialphaseofenhancement,whichcorrespondstothefirst30secondsafterthestartofthecontrast
injection,providesexcellentopacificationoftheceliacaxis,superiormesentericartery(SMA),and
peripancreaticarteries.
Anattenuationdifferencebetweentumorandnormalpancreas,whichincreaseslesionconspicuity,isbest
achievedafterpeakenhancementoftheaortainthearterialphasebutbeforepeakenhancementoftheliver,
whichoccursintheportalvenousphase.Thisissometimestermedthepancreaticphase[81,82].
Theportalvenousphase,whichisobtainedat60to70secondsafterthestartofthecontrastinjection,
providesbetterenhancementofthesuperiormesentericvein,splenicandportalveins.Inaddition,peak
hepaticenhancement,whichoptimizesthedetectionofhepaticmetastases,alsooccursintheportalvenous
phase[83]
AssessingresectabilityCompletesurgicalresectionistheonlypotentiallycurativemodalityof
treatmentforpancreaticcancer.Aninitialassessmentofresectabilitycanusuallybemadebaseduponthe
preoperativetriplephasestagingcontrastenhancedCTscan.Localunresectabilityisusually(butnotalways)due
tovascularinvasion,particularlyofthesuperiormesentericartery(SMA).
DefinitionsofunresectableandborderlineresectablediseaseAlthoughpracticeisvariable
acrossinstitutions,manysurgeonswouldconsiderapancreaticcancertobecategoricallyunresectableifanyof
thefollowingarepresent(see"Initialchemotherapyandradiationfornonmetastaticlocallyadvancedunresectable,
borderlineresectable,andpotentiallyresectableexocrinepancreaticcancer",sectionon'Definitions'):
Extrapancreaticinvolvement,includingextensiveperipancreaticlymphaticinvolvement,nodalinvolvement
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beyondtheperipancreatictissues,and/ordistantmetastases.
Directinvolvementofthesuperiormesentericartery(SMA),inferiorvenacava,aorta,celiacaxis,orhepatic
artery,asdefinedbytheabsenceofafatplanebetweenthelowdensitytumorandthesestructuresonCT
scan.
Thereislessconsensusonthedefinitionof"borderline"resectablepancreaticcancer[8486].Somereservethe
term"borderlineresectable"forcaseswherethereisfocal(lessthanonehalfofthecircumference)(image15)
tumorabutmentofthevisceralarteriesorshortsegmentocclusionofthesuperiormesentericvein(SMV)or
SMV/portalveinconfluenceorhepaticartery.(See"Initialchemotherapyandradiationfornonmetastaticlocally
advancedunresectable,borderlineresectable,andpotentiallyresectableexocrinepancreaticcancer",sectionon
'Borderlineresectable'.)
Encasement(morethanonehalfofthevesselcircumference)(image15)orocclusion/thrombusofthesuperior
mesentericvein(SMV)ortheSMVportalveinconfluenceusedtobeuniversallyconsideredanindicatorof
unresectability.However,manycentershavedemonstratedthefeasibilityofSMVreconstruction,andthisisnow
consideredbymanytoalsorepresentborderlineresectabledisease[87].Ifvenousocclusionispresent,asuitable
segmentofportalvein(above)andSMV(belowthesiteofvenousinvolvement)mustbepresenttoallowfor
venousreconstruction.However,inmostcenters,surgerywillbeprecededbysomeformofneoadjuvant
treatmentforpatientswithvenousocclusion.(See"Overviewofsurgeryinthetreatmentofexocrinepancreatic
cancerandprognosis",sectionon'Vascularresection'and"Initialchemotherapyandradiationfornonmetastatic
locallyadvancedunresectable,borderlineresectable,andpotentiallyresectableexocrinepancreaticcancer",
sectionon'Borderlineresectable'.)
TheNationalComprehensiveCancerNetwork(NCCN)considersthefollowingtorepresentcriteriaforborderline
resectabledisease:
Fortumorsoftheheadorbody:
SevereunilateralorbilateralSMVorportalinfringement
Lessthanonehalfthecircumference(180degree)tumorabutmentontheSMA
Abutmentorencasementofthehepaticartery,ifreconstructible
ShortsegmentSMVocclusion,ifthereisanadequatesegmentofveinaboveandbelowthesiteof
tumorinvolvementtoallowforvenousresectionandreconstruction
Fortumorsofthetail:
Lessthan180degreeencasementoftheSMAorceliacartery
Insomecases,patientswithborderlineresectablediseasearereferredforneoadjuvanttherapypriortosurgical
exploration.(See"Initialchemotherapyandradiationfornonmetastaticlocallyadvancedunresectable,borderline
resectable,andpotentiallyresectableexocrinepancreaticcancer".)
Theentireconceptofaborderlineresectablepancreaticcancerisproblematicforcenterstryingtoaccurately
stageandtreatpatientsaccordingtotheAJCCstagingsystem.TheAJCCusestheT4category(tumorinvolves
theceliacaxisorthesuperiormesentericartery)todesignateanunresectableprimarytumor,withT3designating
atumorthatextendsbeyondthepancreasbutwithoutinvolvementoftheceliacaxisormesentericartery.
However,asnotedabove,involvementofafocalareaofthevisceralarteriesmaybeconsideredaborderline
resectablesituation.Onestudyof257patientswithstageIIIpancreaticcancer(allT4lesionsbasedupon
infiltrationoftheceliacaxisorSMA)foundthat30percentcouldundergoasuccessfulcomplete(R0)resection
afterchemoradiationorchemotherapyalone[88].RevisionstotheAJCCstagingsystemareanticipated.(See
'Stagingsystemandthestagingworkup'above.)
AccuracyofCT
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PrimarytumorThesensitivityoftriplephasehelicalCTforpancreaticadenocarcinomaishigh,89to97
percent[33].Asexpected,sensitivityishigherforlargertumorsinonestudy,thesensitivitywas100
percentfortumors>2cm,butonly77percentfortumors2cminsize[34].However,mostsmall
isoattenuatingpancreaticcancershavesecondarysignssuchasapancreaticductcutoffordilatedmain
pancreaticduct[35].
MetastaticdiseaseContrastenhancedCTisthemodalityofchoicetodetectdistantmetastases(image
16).Thesensitivityforhepaticmetastasesishigh,particularlyusingthepancreaticprotocoltechnique.In
onestudyof43patientswithpancreaticcancer,thesensitivity,specificity,positivepredictivevalue,and
negativepredictivevalueofcontrastenhancedmultidetectorrowhelicalCTfordetectionoflivermetastases
were88,89,92and84percent,respectively[89].Lowersensitivityrates(53and69percent)arereportedby
othersandmayberelatedtothesizeofthehepaticmetastases[90,91].
Peritonealinvolvementmaybedetectedindirectlybythepresenceofascites,mesentericnodules,or
mesentericlymphnodes.However,thesensitivityofCTforperitonealdisseminationispoorandnot
sufficientlyhightoeliminatetheneedfordiagnosticlaparoscopyinequivocalcases[9294].(See'Staging
laparoscopy'below.)
Fortumorsoftheheadandneckofthepancreas,regionallymphatictumorspreadusuallyoccursaroundthe
celiacaxisandtheperipancreaticandperiportalareas.Fortumorsarisinginthetail,regionalnodalbasinsare
locatedalongthecommonhepaticartery,celiacaxis,splenicarteryandsplenichilum.
ThesensitivityandspecificityofCTfordetectinginvolvementoflymphnodesislow,leadingsometo
suggestthatinapatientwhohasapresumedpancreaticcancerthatisconsideredresectable,thefindingof
peripancreaticnodesonCTshouldnotpreventexploration[95].However,thepresenceofextensive
peripancreaticlymphaticinvolvementandnodalinvolvementbeyondtheperipancreatictissuesisgenerally
consideredtorepresentunresectabledisease.(See'Definitionsofunresectableandborderlineresectable
disease'above.)
VascularinvasionCTcriteriaforvascularinvasionincludearterialembedmentinthetumormassor
venousobliteration,tumorinvolvementexceedingonehalfthecircumferenceofthevessel,vesselwall
irregularity,vesselcaliberstenosis,orateardropsignofthesuperiormesentericvein(SMV)[96].
Themostcommonlyusedsystemforpredictingvascularinvasionbyapancreaticcancerusesafivegrade
scale,whichisbaseduponthedegreeofcontactbetweenthetumorandthebloodvessel(table4)[97].In
theinitialreportof25patients,tumorcontiguitywith>50percentormoreoftheperimeterofthevesselwas
foundtobetheoptimalthresholdforpredictingvascularinvasion,withasensitivityof84percentanda
specificityof98percent.
However,thesecriteriawereappliedequallytovenousandarterialstructures.Asnotedabove,becauseof
advancesinvenousreconstruction,manyinstitutionsdonotconsiderinvolvementofmorethanonehalfof
thecircumferenceofthesuperiormesentericvein(SMV)ortheSMVportalveinconfluencetorepresent
unresectabledisease.(See'Definitionsofunresectableandborderlineresectabledisease'above.)
Modificationsofthisgradingsystemhavebeenproposed,toincreasethesensitivityfordetectingvenous
invasionandspecificityfordetectingarterialinvasion,butnoneisinwidespreaduse[96,98100].High
sensitivityforvenousinvasionisdesirablesothatpatientswithundiagnosedvenousinvasionwillnotbe
deemedunresectableintraoperativelyifresectionisattemptedataninstitutionwherevenousreconstruction
isnotperformed.Ontheotherhand,highspecificityforarterialinvasionisdesirabletominimizetheriskof
overstagingT3disease,whichmaydenysomepatientsachanceforpotentiallycurativesurgicalresection.
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Ingeneral,helicalCThasahighpredictivevalueforunresectability(90to100percent)[98,101103],butthe
predictivevalueforresectabilityisslightlylower(range64to90percent)[97,98,104].TheaccuracyofMDCT
forassessingvascularinvasionwasaddressedinasystematicreviewandmetaanalysisof18studies
[105].Thepooledsensitivityandspecificityfordiagnosingvascularinvasionwere77and81percent,
respectively,butwhentheanalysiswaslimitedtothefivemostrecentstudiesconductedsince2004,and
presumablyusingthemostadvancedCTtechnology,sensitivityandspecificityrateswere85and82
percent,respectively.
OtherstudiesAvarietyofotherimagingmodalities,includingendoscopicultrasound(EUS),MRI,FDG
PETaswellasstaginglaparoscopy,mayberequiredtoassessresectabilityinsomecircumstances.
EUSDuetothesmalldistancebetweentheechoendoscopeandthepancreasthroughthegastricor
duodenalwall,endoscopicultrasound(EUS)providesmuchhigherresolutionthantransabdominalultrasound.
PancreaticcanceronEUSappearsasahypoechoicmass,typicallywithdilationoftheproximalpancreaticduct.
Theborderofthelesionmayhaveanirregularcontour,andtheechopatternofthemassmaybehomogenousor
inhomogeneous.(See"Endoscopicultrasound:Normalpancreaticobiliaryanatomy"and"Endoscopicultrasoundin
thestagingofexocrinepancreaticcancer".)
MultiplestudiescomparingEUSwithotherimagingmodalitiesforinitialdiagnosisandstagingofpancreaticcancer
concludedthatEUSmaybemoreaccurateforsmallertumors,forlocalTandNstaging,andforpredicting
vascularinvasion.EUSmaydetectmetastaticdiseaseintheliverormediastinallymphnodes,butisinferiorto
CTforevaluationofdistantmetastases.Inaddition,thespecificityofEUSislimited,particularlywhen
inflammatorychangesarepresent.EUSisalsooperatordependentasaresult,itsvaluevarieswithlocally
availableexpertise.ThedevelopmentofmodernmultidetectorrowCThasmarkedlyimprovedthesensitivityofCT
forthedetectionofsmallertumorsandthepresenceofvascularinvasion,reachingvaluesthatarecomparableto
thoseobtainedbyEUSbyanexperiencedendoscopist.However,headtoheadstudiescomparingthetwo
modalitiesarelacking.(See"Endoscopicultrasoundinthestagingofexocrinepancreaticcancer",sectionon
'ComparisonofEUSwithotherimagingtechniques'.)
TheroleofEUSinthepreoperativestagingofpancreaticcancerisevolving,andthereareseveralpointsinthe
diagnosticevaluationwherethismodalitymaybeofbenefit,particularlyforpatientswhoseCTevaluationdoesnot
demonstrateadefinedmasslesion(algorithm2).(See'Subsequenttestingifinitialimagingisnegative'above.)
Inaddition,EUSguidedfineneedleaspirationbiopsy(FNA)isthebestmodalityforobtainingatissuediagnosis,
evenifthetumorispoorlyvisualizedbyotherimagingmodalities.(See'EUSguidedbiopsy'above.)
MRIAlthoughpancreaticadenocarcinomasareeasilyvisualizedonMRI(image17),thereisnoevidence
thatMRIoffersasignificantdiagnosticadvantageovertriplephaseMDCTforthelocalstagingevaluation[106
110].OnepotentialbenefitofMRIisitsincreasedsensitivityforthedetectionofsmalllivermetastasescompared
withCT[90,91,111,112].CombiningCTandMRIofferslittlethatcannotbeachievedwithonealone.Thus,the
choiceofMRIorCTdependsupontheleveloflocallyavailableexpertiseandtheclinician'scomfortwithoneor
theotherradioimagingtechnique.WepreferMDCT.
ChestCTCTofthechestmaybeusedasastagingtooltodetectlungmetastases.However,most
centerstonotperformaroutinestagingchestCTforpatientssuspectedofhavingpancreaticcancerbecausein
thepresenceoflungmetastases,theprimarytumorisusuallyunresectableforanotherreason[113].
PETscanningPETscanningwiththetracer18fluorodeoxyglucose(FDG)reliesuponfunctionalactivity
todifferentiatemetabolicallyactiveproliferativelesionssuchascancers,mostofwhichareFDGavid,frombenign
masses.MostbenignlesionsdonotaccumulateFDG,withtheexceptionofinflammatorylesionssuchaschronic
pancreatitis[114].
TheutilityofPETscansinthediagnosticandstagingevaluationofsuspectedpancreaticcancer,particularly
whetherPETprovidesinformationbeyondthatobtainedbycontrastenhancedMDCT,remainsuncertain,as
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illustratedbythefollowingdata:
ThesensitivityofintegratedPET/CT(whichhasbetterspatialresolutionascomparedtoPETalone)inthe
initialdiagnosisofpancreaticcancerrangesfrom73to94percent,whilespecificityrangesfrom60to89
percent[115120].FalsenegativePETresultscanoccurinhyperglycemicpatientsorinsubcentimeter
lesions,whilefalsepositiveresultscanbeseeninvariousinflammatorystatessuchaspancreatitis,infected
pseudocyst,orlocalinflammationcausedbyplacementofabiliarystent.Instudiesinwhichthetwo
modalitieshavebeencompared,PETdoesnotappeartoprovideadditionalinformationtothatderivedfrom
MDCTorMRI[119121].
AmajorissueisthattheCTcomponentofintegratedPET/CTimagingisperformedinmanyinstitutions
withouttheuseofIVcontrastmaterial,atechniquethatprecludestheoptimaldetectionofsmalltumorsand
metastases.Increasingly,PET/CTisbeingcarriedoutwithIVcontrast,butthispracticeisnotwidespread.
EarlyresultsarepromisingusingintegratedPETwithacontrastenhancedCT,butfurtherstudiesareneeded
toestablishclinicalvaluecomparedwithMDCTaloneinpatientswithpancreaticcancer[122124].
OnepossiblebenefitofPETisenhanceddetectionofsmallvolumemetastaticdisease,whichisoften
missedbyCT.Unfortunately,theavailabledataareconflicting,withsomestudiessuggestingthatPETis
usefulforidentifyingmetastaticdiseasethatismissedbyCT(image18)[117,119,125127]andothersnoting
thatPEToftenmissessmallvolumemetastaseswithintheperitoneumandelsewhere,includingtheliver
[114,115,128].
However,theclinicalimpactremainsuncertain,asillustratedbythefollowingreports:
OneseriescomparedintegratedFDG/PET,MDCT,andMRIin38consecutivepatientssuspectedof
havingpancreaticcancer,withfindingsconfirmedbyoperationand/orhistopathologicanalysisorfollow
up[119].Amongthe17patientswithadvancedpancreaticadenocarcinoma,FDGPET/CThadahigher
sensitivitythaneitherMDCTorMRI(88versus30and30percent,respectively),andtheclinical
managementof10patients(26percent)wasalteredbythefindingsonPET/CT.
Inanotherreport,82patientswithapancreaticmassthatwassuspiciousforcancerunderwentstaging
withintegratedPET/CTandcontrastenhancedCTofthechest,abdomen,andpelvis[117].The
sensitivityfordetectingmetastaticdiseaseforPET/CTalone,CTalone,andcombinedCTplus
integratedPET/CTwas61,57,and87percent,respectively.However,thefindingsonPET/CT
changedmanagementinonlysevenpatients(11percent),twobecauseofanoccultsupraclavicular
lymphnode,twowithoccultliverlesions,twoperitonealimplants,andoneperiesophageallymphnode.
Twoofthesepatientshadlocallyadvanceddiseaseandwouldnothavebeenconsideredforresection,
evenifaPET/CThadnotbeendone.
Takentogether,thedataareinsufficienttoconcludethatPETorintegratedPET/CTprovidesusefulinformation
abovethatprovidedbycontrastenhancedCT.Consensusbasedguidelinesforstagingofpancreaticcancerfrom
theNCCNstatethattheroleofPET/CTremainsunclear.DefinitiveassessmentoftheroleofPETasa
componentofthediagnosticand/orstagingevaluationawaitsalargeprospectivestudydesignedtoassessthe
benefitofPET(preferablyintegratedPETwithacontrastenhancedCT)inpatientswithanegativeor
indeterminateCTscan,withaprospectivelydesignedcosteffectivenessanalysis.
StaginglaparoscopyAccuratestagingdrivespropertreatmentofpatientswithpancreaticcancer,particularly
whenselectingpatientsforsurgicalresection.Becausemosthaveunresectablediseaseatpresentation,akey
goalistoavoidafutilelaparotomywheneverpossible.
Currentlyavailableimagingtechniquesarehighlyaccurateatpredictingunresectabledisease,buttheyfallshortin
predictingresectabledisease,mainlybecauseoflimitedsensitivityforsmallvolumemetastaticdisease.
Radiographicallyoccultsubcentimetermetastasesonthesurfaceoftheliverorperitoneumthatarerarelyvisible
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byCT,MRI,PET,ortransabdominalUSmaybevisualizedlaparoscopically.Studieshaveconsistentlyshown
thatuptoonethirdofpatientsthoughttoberesectablebystateoftheartimagingwillbefoundtobeunresectable
baseduponlaparoscopicfindings[92,129131].ACochranereviewconcludedthatpatientswithpancreaticand
periampullarymalignancieswhowereconsideredtohaveresectablediseaseafterdiagnosticlaparoscopyandCT
scanhada17percentprobabilitythattheircancerwouldbeunresectablecomparedtoa40percentprobabilityfor
thoseundergoingCTalone[132].Onaverage,theuseofdiagnosticlaparoscopywithbiopsyconfirmationof
suspiciouslesionwouldavoid23unnecessarylaparotomiesperevery100patientsplannedforcurativeintent
resection.
However,thevalueofstaginglaparoscopyisnotuniversallyaccepted.Whilehospitalstay,cost,andmorbidity
arereducedwhenanunnecessaryopenlaparotomyisavoidedforunresectableormetastaticdisease,thereareno
controlledstudiesdemonstratingabenefitforthisprocedureinpatientswhohaveundergoneradiographicstaging
evaluationusingmodernhighqualityimagingsuchasMDCT[133].Thisissuewasnotaddressedinthe2013
Cochranereview,andgiventhat7ofthe15trialswereundertakeninthe1980sand1990s,itisunlikelythat
modernCTtechniqueswereused.(See'Technique'above.)
Otherssuggestaselectiveapproachtostaginglaparoscopytomaximizeyieldbylimitingtheproceduretothose
withthehighestlikelihoodofoccultmetastaticdisease[134].Thisincludespatientswithatumorofthebodyor
tailofthepancreaswhoappeartohavepotentiallyresectablediseasebycomputedtomographyscan(onehalfof
whomwillhaveoccultperitonealmetastases[135,136]),large(>3cm)primarytumors,anypatientforwhomhigh
qualityimagingisinanywaysuggestiveofoccultmetastaticdisease,andthosewithahighinitialCA199level
(>100units/mL)[66].(See"Overviewofsurgeryinthetreatmentofexocrinepancreaticcancerandprognosis",
sectionon'Tumorsinthebodyortail'and'CA199'above.)
Weselectivelyusestaginglaparoscopyinpatientswithadvancedvascularinvolvement(butnotyetcomplete
encasementorocclusionofthemajorvessels)andthosewithpancreaticbodyortaillesionswhoarenot
jaundiced.OtherindicationsforastaginglaparoscopypriortoopenlaparotomyincludeahighpreoperativeCA199
level(>1000units/mL)andanypatientforwhomhighqualityimagingisinanywaysuggestiveofoccultmetastatic
disease.Atsomeinstitutions,diagnosticlaparoscopyisperformedifneoadjuvanttherapyistoberecommended.
ImportanceofperitonealcytologyPeritonealwashingsareoftenobtainedatthetimeoflaparoscopy.
Whileitwouldseemintuitivethatpatientswhohavepositiveperitonealwashingswouldbeunlikelytobenefitfrom
radicalresectionofthepancreaticprimarytumor,ithasnotbeenconclusivelydemonstratedthatpositive
peritonealcytologyasanisolatedfindingisanindependentadverseprognosticfactor[137139].Ingeneral,most
patientswhohavecytologicallypositivewashingshaveotherfindingsthatsuggestadvanceddiseaseand
unresectabilitysuchasascitesand/orthepresenceofmetastasesintheliver,pelvis,oromentum[137,140,141].
Iftheseareabsent,mostpancreaticsurgeonsdonotrelyupontheresultsofperitonealwashingsobtainedatthe
timeoflaparoscopytoguidedecisionmakingregardingresectability.However,theAJCCstagingsystem
considerspositiveperitonealwashingstorepresentdistantmetastatic(M1)disease(table3)[76].
DIAGNOSTICALGORITHMANDNEEDFORPREOPERATIVEBIOPSYOursuggesteddiagnostic
approachtothepatientwithsuspectedpancreaticcancerisoutlinedinthealgorithm(algorithm2).(See'Biopsy
andestablishingthediagnosis'above.)
Adiagnosticbiopsyofasuspectedpancreaticmalignancymaybeindicatedifthereisevidenceofsystemic
spreadofdisease,ifthereislocalevidenceofunresectabilityonstagingstudies,ifthepatientisunfitformajor
surgery,ifneoadjuvanttreatmentisbeingcontemplated(eg,foraborderlineresectablelesion),orifalternative
diagnosesneedtobeexcluded(eg,metastaticdiseasetothepancreas).(See"Initialchemotherapyandradiation
fornonmetastaticlocallyadvancedunresectable,borderlineresectable,andpotentiallyresectableexocrine
pancreaticcancer",sectionon'Roleofsurgery'.)
However,apreoperativediagnosticbiopsymaynotbeneededinafitpatientwithapotentiallyresectable
pancreaticlesionthatishighlysuspectedofmalignancy.Whileapositivebiopsycanconfirmthesuspected
diagnosis,abenignsamplewillnotexcludethepresenceofmalignancy.Inonesystematicreviewof53studies
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addressingthisissue,thenegativepredictivevalueofpercutaneousandEUSguidedbiopsieswasonly60to70
percent[142].Attemptstomakeapreoperativetissuediagnosismayinfactbedetrimentaliftumorcellsare
disseminatedduringpercutaneousbiopsy.
Thus,ifapatientisareasonablesurgicalcandidate,andiftheclinicalpresentationandimagingaretypicalfora
resectableadenocarcinomaafterthestagingevaluationhasbeencompleted,itisreasonabletoproceedtosurgery
withoutatissuediagnosis.(See'Stagingsystemandthestagingworkup'above.)
However,itmustberecognizedbyboththeclinicianandthepatientthatuncertaintyregardingthediagnosisin
theseinstancespersistsandthatsomepatientswithbenignlesionsmaybesubjectedtotheradicalresections
usedformalignantlesions.Thesecasescomprisebetween5and11percentofpatientsresectedforapresumed
cancer[143146].Thefrequencyofradicalresectionforbenigndiseasemaybereducedwhenthisapproachis
combinedwithadditionalimaging,EUSguidedtransduodenalbiopsy.(See'EUSguidedbiopsy'above.)
Focalchronicpancreatitisandautoimmunepancreatitisarethetwobenignprocessesthataremostcommonly
mistakenforpancreaticmalignancyonCTorUS.EUSguidedbiopsymayberecommendedifadiagnosisof
chronicorautoimmunepancreatitisissuspectedonthebasisofhistory(eg,extremeyoungage,prolongedethanol
abuse,historyofotherautoimmunediseases),particularlyiffurtherimagingstudies(eitherEUS,ERCPor
magneticresonancecholangiopancreatography)revealmultifocalbiliarystrictures(suggestiveofautoimmune
pancreatitis)ordiffusepancreaticductalchanges(suggestiveofchronicpancreatitis).Inaddition,serologictesting
canaidinthediagnosisofautoimmunepancreatitis.(See"Clinicalmanifestationsanddiagnosisofchronic
pancreatitisinadults"and"Autoimmunepancreatitis".)
ForjaundicedpatientswhohavenoinvolvementorminimalinvolvementofthemajorvesselsaccordingtoCTor
EUSandnoevidenceofdistantmetastasesonhelicalCTorEUS,weproceeddirectlytoanattemptatsurgical
resection.Fornonjaundicedpatients(particularlywithbodyortailtumors),orthosewithmajorbutincomplete
involvementofthevascularstructures(tumorcontiguoustolessthanonehalfofthevesselcircumference
[97,98]),weperformpreoperativelaparoscopytoexcludetinymetastasesthatmighthavebeenoverlookedbyCT.
Ifthelaparoscopyisnegative,wethenembarkonaradicalsurgicalresection.(See'Staginglaparoscopy'above.)
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and
"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyond
theBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewritten
atthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortable
withsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
"patientinfo"andthekeyword(s)ofinterest.)
Basicstopics(see"Patientinformation:Pancreaticcancer(TheBasics)")
BeyondtheBasicstopics(see"Patientinformation:Pancreaticcancer(BeyondtheBasics)")
SUMMARYANDRECOMMENDATIONS
Thecommonlyusedterm"pancreaticcancer"usuallyreferstoaductaladenocarcinomaofthepancreas
(includingitssubtypes).Morethan95percentofmalignantneoplasmsofthepancreasarisefromthe
exocrineelementsandarereferredtoasexocrinepancreaticcancers.(See'Pathology'above.)
Themostcommonpresentingsymptomsinpatientswithexocrinepancreaticcancerarepain,jaundice,and
weightloss.Comparedtotumorsinthebodyandtailofthegland,pancreaticheadtumorsmoreoften
presentwithjaundice,steatorrhea,andweightloss.(See'Clinicalpresentation'above.)
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Patientswhopresentwithjaundiceorepigastricpainandweightlossoftenundergorightupperquadrant
transabdominalultrasoundinitiallytoevaluatefordilatedbileductsorapancreaticmass.(See'Initialtesting'
aboveand'Transabdominalultrasound'above.)
Inthejaundicedpatient,ultrasoundishighlysensitivefordetectingbiliarytractdilationandestablishing
thelevelofobstructionitishighlysensitiveforpancreaticmasses>3cm.(See'Jaundice'above.)
Endoscopicretrogradecholangiopancreatography(ERCP)isahighlysensitivetoolforvisualizationof
thebiliarytreeandpancreaticductsinpatientswithjaundice.However,theroleofERCPinpatients
withsuspectedpancreaticcancerisevolvingintoamainlytherapeuticratherthandiagnosticmodality
inpatientswhopresentwithcholestasisduetotumorobstructionofthebiliarysystem.(See'ERCP'
above.)
Analternativeapproachismagneticresonancecholangiopancreatography(MRCP).MRCPisgenerally
reservedforpatientswithgastricoutletorduodenalstenosis,orwhohavehadsurgicalrearrangement
(eg,BillrothII)orductaldisruption,resultinginductsthataredifficulttoassesssuccessfullybyERCP,
inthesettingofchronicpancreatitis,orforpatientsinwhomattemptedERCPiseithertotally
unsuccessfulorprovidesincompleteinformationbecauseofpancreaticductobstruction.(See'MRCP'
above.).
Forpatientswithepigastricpainandweightlosswithoutjaundice,inwhomthedifferentialdiagnosis
includespancreatitis,transabdominalultrasoundisnotthepreferredinitialtestbecauseitisassociated
withahighfrequencyofincompleteexaminationsowingtooverlyingbowelgasduetoileus,andit
cannotclearlyidentifynecrosiswithinthepancreastheseimportantfindingsarebestseenbycontrast
enhancedCTscan.(See'Epigastricpainandweightloss'above.)
Endoscopicultrasound(EUS)maybeofuseinapatientwhoissuspectedofhavingpancreaticcancer
basedupontheclinicalpresentationofjaundice,unexplainedupperabdominalpain/weightloss,oran
unexplainedepisodeofpancreatitis,butwhohasnoevidenceofamasslesiononinitialtransabdominal
ultrasoundorCT.(See'Subsequenttestingifinitialimagingisnegative'above.)
Giventhelimitedsensitivityandspecificity,theserumtumormarkerCA199shouldnotbeusedasa
diagnostictestforpancreaticcancer.(See'CA199'above.)
Histologicconfirmationisrequiredtoestablishadiagnosisofpancreaticcancer.Biopsyofapancreaticmass
canbeaccomplishedthroughpercutaneousorendoscopicapproaches.However,notallpatientsrequirea
preoperativebiopsy,andthenextstepintheworkupofapatientwithsuspectedpancreaticcancerisoftena
stagingevaluationtoestablishdiseaseextentandresectabilityratherthanbiopsy.(See'Biopsyand
establishingthediagnosis'above.)
WhenamasslesionofthepancreasisdetectedonCTorultrasound,itisreasonabletoconcludethata
neoplasm(mostlikelymalignant)ispresent,andtriplephase,contrastenhancedhelical(preferably
multidetectorrow)CTisanappropriatenextsteptoassessdiseaseextentandresectability.Local
unresectabilityisusually(butnotalways)duetovascularinvasion,particularlyofthesuperiormesenteric
artery(SMA).(See'AbdominalCT'above.)
Endoscopicultrasound(EUS)isanothereffectivemethodtoassesstumorextentandvascularinvasion,but
wegenerallypreferCTgivenitsgreaterutilityinassessingfordistantmetastases.(See'EUS'above.)
Althoughpracticeisvariable,mostsurgeonswouldconsiderapancreaticcancertobecategorically
unresectableifanyofthefollowingarepresent(see'Definitionsofunresectableandborderlineresectable
disease'above):
Extensiveperipancreaticlymphaticinvolvement,nodalinvolvementbeyondtheperipancreatictissues,
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and/ordistantmetastases.
Directinvolvementofthesuperiormesentericartery(SMA),inferiorvenacava,aorta,celiacaxis,or
hepaticartery,asdefinedbytheabsenceofafatplanebetweenthelowdensitytumorandthese
structuresonCTscan.
Encasement(morethanonehalfofthevesselcircumference)orocclusion/thrombusofthesuperior
mesentericvein(SMV)ortheSMVportalveinconfluenceusedtobeuniversallyconsideredan
indicatorofunresectability.However,manycentershavedemonstratedthefeasibilityofSMV
reconstruction,andthisisnowconsideredbymanytorepresentborderlineresectablediseasein
practice,mostofthesepatientsarereferredforneoadjuvanttherapypriortosurgery.
TheutilityofPETscans,chestCT,andMRIinthestagingworkupofsuspectedpancreaticcancer,
particularlywhetheranyoftheseimagingstudiesprovidesinformationbeyondthatobtainedbytriplephase,
contrastenhancedhelicalmultidetectorrowCTremainsuncertain,andwedonotroutinelyorderthesetests.
(See'PETscanning'aboveand'ChestCT'aboveand'MRI'above.)
AssessmentofserumlevelsofthetumormarkerCA199priortosurgeryandfollowingresection,if
elevated,isvaluabletoassistinprognostication.Inaddition,serialmonitoringofCA199levels,ifinitially
elevated,isusefultofollowpatientsafterpotentiallycurativesurgeryandforthosewhoarereceiving
chemotherapyforadvanceddisease.(See'CA199'above.)
Ourgeneraldiagnosticapproach,asdetailedinthefollowingsections,issummarizedinthealgorithm
(algorithm2).Ingeneral(see'Diagnosticalgorithmandneedforpreoperativebiopsy'above):
Tissuediagnosisismandatoryforpatientswhoareunfittoundergoamajorresection,forthosewitha
highsuspicionofmetastaticdisease,andforanypatientbeingconsideredforneoadjuvanttherapy
becauseoflocallyadvancednonmetastaticdisease.EUSguidedFNAisthebestmodalityforobtaining
atissuediagnosis,evenifthetumorispoorlyvisualizedbyotherimagingmodalities.
Ifapatientisareasonablesurgicalcandidate,andiftheclinicalpresentationandimagingaretypicalfor
aresectableadenocarcinoma,itisreasonabletoproceedtosurgerywithoutatissuediagnosis.
Forjaundicedpatientswithnoinvolvementorminimalinvolvementofthemajorvesselsandno
evidenceofdistantmetastasesonradiographicimaging,weproceeddirectlytoopenlaparotomy.(See
"Overviewofsurgeryinthetreatmentofexocrinepancreaticcancerandprognosis".)
Fornonjaundicedpatients(includingallthosewithbodyortailtumors),aswellasthosewithmajorbut
incompleteinvolvementofthevascularstructures(eg,tumorcontiguoustolessthanonehalfofthe
vesselcircumference),weperformpreoperativelaparoscopytoexcludetinymetastasesthatmight
havebeenoverlookedbyCT.Ifthelaparoscopyisnegative,wethenproceedtoopenlaparotomyto
assessresectability.Otherindicationsforastaginglaparoscopypriortoopenlaparotomyincludeahigh
preoperativeCA199level(>1000units/mL),anypatientforwhomhighqualityimagingisinanyway
suggestiveofoccultmetastaticdisease,andatsomeinstitutions,forpatientsinwhomaneoadjuvant
approachtotherapyisbeingconsidered.(See'Staginglaparoscopy'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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Topic2501Version36.0
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GRAPHICS
Pancreaticpanniculitisinapatientwithacinarcell
pancreaticcancer
Painfulsubcutaneousnodules(pancreaticpanniculitis)[A]inapatient
withamasswithinthepancreas(onCT,arrows)[B],whichon
endoscopicallyguidedultrasound(EUS)guidedbiopsy[C]provedtobe
anacinarcellcancer(histology)[D].
Graphic85874Version2.0
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CysticcarcinomaofthepancreaswithassociatedascitesonCT
scan
ACTscanoftheupperabdomeninapatientwithpancreaticcarcinoma.Thereisacystic
massinthetailofthepancreas(arrow)withamoderateamountofascites(arrowhead).
Thereisalsoanoduleonthesurfaceoftheliverrepresentingmetastasis(dashedarrow).
CT:computedtomography.
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Virchow'snodeonCTscaninapatientwithpancreaticcarcinoma
ACTscanatthelevelofthethoracicinletinapatientwithpancreaticcarcinoma
demonstratesaleftsupraclavicularlymphnodeor"Virchow'snode"(arrow).
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SisterMaryJosephsnodeonCTscan
ACTscanoftheabdomenandpelvisattheleveloftheumbilicusshowsaperiumbilical
noduleor"SisterMaryJoseph'snode"(arrow).Thereareotherperitonealmetastatic
implants(doublearrow).
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Classificationofjaundiceaccordingtotypeofbilepigmentand
mechanism
Unconjugatedhyperbilirubinemia
Increasedbilirubinproduction*
Extravascularhemolysis
Extravasationofbloodintotissues
Intravascularhemolysis
Dyserythropoiesis
Impairedhepaticbilirubinuptake
Heartfailure
Portosystemicshunts
SomepatientswithGilbert'ssyndrome
Certaindrugs rifampin,probenecid,
flavaspadicacid,bunamiodyl
Impairedbilirubinconjugation
CriglerNajjarsyndrometypesIandII
Gilbert'ssyndrome
Neonates
Hyperthyroidism
Ethinylestradiol
Liverdiseaseschronichepatitis,advanced
cirrhosis,Wilsondisease
Conjugatedhyperbilirubinemia
Extrahepaticcholestasis(biliary
obstruction)
Choledocholithiasis
Intrinsicandextrinsictumorseg,
cholangiocarcinoma
Primarysclerosingcholangitis
AIDScholangiopathy
Acuteandchronicpancreatitis
Stricturesafterinvasiveprocedures
Certainparasiticinfectionseg,Ascaris
lumbricoides,liverflukes
Intrahepaticcholestasis
Viralhepatitis
Alcoholichepatitis
Nonalcoholicsteatohepatitis
Chronichepatitis
Primarybiliarycirrhosis
Drugsandtoxinseg,alkylatedsteroids,
chlorpromazine,herbalmedications(eg,
Jamaicanbushtea),arsenic
Sepsisandhypoperfusionstates
Infiltrativediseaseseg,amyloidosis,
lymphoma,sarcoidosis,tuberculosis
Totalparenteralnutrition
Postoperativecholestasis
Followingorgantransplantation
Hepaticcrisisinsicklecelldisease
Pregnancy
Endstageliverdisease
AIDS:acquiredimmunodeficiencysyndrome.
*Serumbilirubinconcentrationusuallylessthan4mg/dL(68mmol/L)intheabsenceofunderlying
liverdisease.
Thehyperbilirubinemiainducedbydrugsusuallyresolveswithin48hoursafterthedrugis
discontinued.
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Classificationofjaundiceduetobothconjugated
andunconjugatedhyperbilirubinemia
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BenignpancreaticcystonCTscan
ACTscanoftheabdomenandpelvisatthelevelofthepancreasshowsabenign
appearingcystinthetailofthepancreas(arrow)likelyduetopancreatitis.
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PancreaticcystandpolycystickidneydiseaseonCTscan
ACTscanoftheabdomenandpelvisshowsapancreaticcystintheuncinateprocessof
thepancreas(arrow)inapatientwithpolycystickidneydisease.
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IntraductalpapillarymucinousneoplasmofthepancreasonCT
scan
ACTscanoftheabdomenandpelvisinapatientwithIPMNshowsamassintheheadof
thepancreas(arrowinpanelA)andadilatedpancreaticductintheuncinateprocess(arrow
inpanelB).Histopathologydemonstratedaneoplasmwithbothpapillaryandmucinous
features.
CT:computedtomographyIPMN:intraductalpapillarymucinousneoplasm.
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IntraductalpapillarymucinousneoplasmofthepancreasonERCP
AnERCPshowingthepancreaticductinapatientwithintraductalpapillarymucinous
neoplasm.Thereisafillingdefectinadilatedpancreaticduct(arrow)andthereare
strandlikefillingdefectsofmucusinthepancreaticductinthebodyofthepancreas
(arrowheads).Theendoscopistobservedlargeamountsofmucusexudingfromthe
pancreaticductorifice.Histopathologyofanassociatedpancreaticmassrevealedboth
papillaryandmucinousfeatures.
ERCP:endoscopicretrogradecholangiopancreatographyIPMN:intraductalpapillarymucinous
neoplasm.
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MucinouscystadenomaofthepancreasonCTscan,ERCP,US,and
MRI
(A)ACTscanshowsa6cmcysticmassinthetailofthepancreas(arrowhead)withan
enhancingwall(arrow).
(B)AnERCPshowsnocommunicationofthepancreaticductalsystemwiththecystseenon
theCTscan,thusexcludingthediagnosisofapancreaticpseudocyst.
(C)AnUSshowsa3cmsofttissuenodule(arrowhead)withina6cmcyst(+..+).
(D)AT2weightedMRIshowsalowintensityT2darknodule(arrow)withinthecysticmatrix
ofthemucinouscystadenoma.
CT:computedtomographyERCP:endoscopicretrogradecholangiopancreatographyUS:ultrasound
MRI:magneticresonanceimaging.
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SerouscystadenomaofthepancreasonCT
ACTscanoftheabdomenandpelvisinapatientwithserouscystadenoma.There
isamassintheheadofthepancreas(arrow),whichhasalobulatedoutlineanda
calcifiedcentralscar.
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CystadenocarcinomaofthepancreasonCTscan
ACTscanoftheabdomenandpelvisinapatientwithmucinouscystadenocarcinoma.
Thereisasimpleappearingcystwithanenhancingwallinthetailofthepancreas(dashed
arrow).Anadjacentsofttissuemassinthebodyofthepancreas(arrowhead)issuspicious
formalignanttransformation.Theneckofthepancreas(arrow)isnormal.
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CysticcarcinomaofthepancreaswithassociatedascitesonCT
scan
ACTscanoftheupperabdomeninapatientwithpancreaticcarcinoma.Thereisacystic
massinthetailofthepancreas(dashedarrow)withamoderateamountofascites(short
arrow).Metastaticdiseaseincludesanoduleonthesurfaceoftheliver(longarrow)and
omentaldisease(arrowhead).
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LymphomaofthepancreasonCTscan
ACTscanoftheabdomenandpelvisinapatientwithlymphomaofthepancreas.
Thereisabulkymassofthepancreas(arrow)associatedwithretrocruralnodes
(arrowhead)andperipancreaticnodes(dashedarrow).
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Locationsampullarytumors
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Pancreaticcancerdiagnosisalgorithm
CA199:cancerantigen199CT:computedtomographyERCP:endoscopicretrograde
cholangiopancreatographyEUS:endoscopicultrasoundFNA:fineneedleaspirationbiopsyMDCT:
multidetectorrowcomputedtomographyMets:metastasesMRCP:magneticresonance
cholangiopancreatography.
*Basedonsymptomatologyandtheappearanceofthemassorstricture.
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Typicalappearanceofpancreaticadenocarcinoma
MultidetectorenhancedCToftwodifferentpatients,inwhichill
definedhypodense,solidtumorsarepresentintheheadanduncinate
processofthepancreas(arrows).Typically,normalpancreatictissue
enhancestoagreaterextentthandopancreaticadenocarcinomas.
CourtesyofDr.RocioPerezJohnston.
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ContrastMDCTofpancreaticmass
ContrastenhancedMDCTincoronalprojectiondemonstratesasmall
mass(yellowarrow)inthebodyofthepancreas,causingpancreatic
ductalobstruction,withabruptcutoffofthemainpancreaticduct
(whitearrow).
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"Doubleduct"signinapatientwithpancreaticcancer
Endoscopicretrogradecholangiopancreatography(ERCP)inapatientwith
adenocarcinomaintheheadofthepancreas.Thecommonbileductisdilated
proximaltoastricture(arrow).Inaddition,thepancreaticductisdilated
(arrowhead)duetoobstructionbythetumor.Thedilationofboththecommon
bileductandthepancreaticductisknownasthe"doubleduct"sign,afinding
thatishighlysuggestiveofamalignancy.
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Introductionofacholangiopancreatoscopeintothe
pancreaticduct
Fluoroscopicimageshowingacholangiopancreatoscopebeingpassedthrough
atherapeuticduodenoscopeandintothepancreaticduct.
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Conditionsassociatedwithincreasedserumlevelsofthetumor
markerCA199
Malignant
Pancreaticexocrineandneuroendocrinecancers
Biliarycancer(gallbladder,cholangiocarcinoma,ampullarycancers)
Hepatocellularcancer
Gastric,ovarian,colorectalcancer(lessoften)
Lung,breast,uterinecancer(rare)
Benign
Acutecholangitis
Cirrhosisandothercholestaticdiseases(includinggallstones)
CA199:carbohydrateantigen199.
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Fineneedleaspirateofpancreaticcancer
Aclusterofmalignantcellsisseeninthisaspiratetakenfroma
patientwithapancreaticmass.
CourtesyofMichaelLSteer,MD.
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TNMstagingsystemforexocrineandendocrinetumorsofthe
pancreas
Primarytumor(T)
TX
Primarytumorcannotbeassessed
T0
Noevidenceofprimarytumor
Tis
Carcinomainsitu*
T1
Tumorlimitedtothepancreas,2cmorlessingreatestdimension
T2
Tumorlimitedtothepancreas,morethan2cmingreatestdimension
T3
Tumorextendsbeyondthepancreasbutwithoutinvolvementoftheceliacaxisorthe
superiormesentericartery
T4
Tumorinvolvestheceliacaxisorthesuperiormesentericartery(unresectableprimary
tumor)
Regionallymphnodes(N)
NX
Regionallymphnodescannotbeassessed
N0
Noregionallymphnodemetastasis
N1
Regionallymphnodemetastasis
Distantmetastasis(M)
M0
Nodistantmetastasis
M1
Distantmetastasis
Anatomicstage/prognosticgroups
Stage
0
Tis
N0
M0
Stage
IA
T1
N0
M0
Stage
IB
T2
N0
M0
Stage
IIA
T3
N0
M0
Stage
IIB
T1
N1
M0
T2
N1
M0
T3
N1
M0
Stage
III
T4
AnyN
M0
Stage
IV
AnyT
AnyN
M1
Note:cTNMistheclinicalclassification,pTNMisthepathologicclassification.
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*ThisincludeslesionsclassifiedasPanInIIIclassification.
UsedwiththepermissionoftheAmericanJointCommitteeonCancer(AJCC),Chicago,Illinois.The
originalsourceforthismaterialistheAJCCCancerStagingManual,SeventhEdition(2010)publishedby
SpringerNewYork,Inc.
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Detectingvascularencasement
ExamplesofacontrastenhancedCTangiographydemonstratingdifferent
degreesofvascularencasementbyapancreaticadenocarcinomaaxial
images.A)Adenocarcinomaoftheheadofthepancreaswith<25percentof
involvementofthesuperiormesentericvein(SMV)circumference.B)
Adenocarcinomaoftheheadpancreaswhichiscontacting50percentofthe
circumferenceoftheSMV.C)Adenocarcinomaoftheuncinateprocessofthe
pancreasinvolving>75percentofthecircumferenceoftheSMVaswellas
narrowingofitslumen.D)Adenocarcinomaofthebodyofthepancreas
extendingsuperiorlyandencasingtheceliactrunk(Vshapedstructure
containingcontrast).
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ContrastCToftumorinpancreaticneck
ContrastenhancedCTaxialimagesofapatientwithasolid,ill
definedtumorintheneckofthepancreas(arrowinA).Novascular
encasementisobserved.However,multiplesmallhypodenselesions
areseenthroughouttheliverparenchyma(arrowsinBandC),which
arehighlysuspiciousformetastaticdisease.
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Gradingsystem*forpredictingvascularinvasionbyapancreatic
cancerondualphasecontrastenhancedCT
Category
Grade0
Description
Nocontiguityoftumorwithavessel
Comment
Vascularinvasionin0
percentofcases
Grade1
Tumorcontiguouswith<25percentofthecircumference
ofavessel
Vascularinvasionin0
percentofcases
Grade2
Tumorcontiguouswith25to50percentofthe
circumferenceofavessel
Vascularinvasionin57
percentofcases
Grade3
Tumorcontiguouswith50to75percentofthe
circumferenceofavessel
Vascularinvasionin88
percentofcases
Grade4
Tumorcontiguouswith>75percentofthecircumference
ofavesseloranyvesselconstriction
Vascularinvasioninall
cases
*ProposedbyLuDSK,etal.AJRAmJRoentgenol1997168:1439.
Reproducedfrom:WongJC,RamanS.Surgicalresectabilityofpancreaticadenocarcinoma:CTA.Abdom
Imaging201035:471.Copyright2010withkindpermissionfromSpringerScience+Business
MediaB.V.
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Pancreaticadenocarcinoma
T2weighted(A)andT1weighted(B)fatsaturatedmagnetic
resonance(MR)imagesofapatientwithpancreaticadenocarcinoma.
PanelsAandBbothdemonstrateatrophyofthepancreatictail
parenchyma,withdilatationofthemainpancreaticduct(Aarrow).
ThepancreaticcancerisbestvisualizedontheT1weightedimageas
ahypointensesolidtumor(Barrow)inthebodyofthepancreas.
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PETCTofadenocarcinomaofthepancreatichead
Coronal(A)andaxial(B)imagesofanintegratedPET/CTinapatient
withalargeadenocarcinomaoftheheadofthepancreas(Aarrow).
Theaxialimagedemonstratesalesionintheliverthatishighly
suspiciousformetastaticinvolvement(Barrow).Boththeprimary
tumorandthemetastaticlesiondemonstrateincreaseduptakeofthe
tracerfluorodeoxyglucose(FDG).
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Disclosures
Disclosures:CarlosFernandezdelCastillo,MDNothingtodisclose.KennethKTanabe,MDConsultant/AdvisoryBoards:Astellas[hepatocellul
hepatocellularcarcinoma)UseofEGFRinhibitorstopreventHCC(cirrhosis,hepatocellularcarcinoma).DouglasAHowell,MD,FASGE,FACG
scopes/supplies].Consultant/AdvisoryBoards:CookEndoscopy[advancedendoscopicequipment]OlympusAmerica[colonoscopyandERCPend
devices/stents)].DianeMFSavarese,MDNothingtodisclose.AnneCTravis,MD,MSc,FACG,AGAFEquityOwnership/Stock
Options:Proctor&Gamble[Pepticulcerdisease,esophagealreflux(omeprazole)].
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthroughamultilevel
contentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy
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Clinical Manifestations, Diagnosis, and Staging of Exocrine Pancreatic Cancer

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Clinical Manifestations, Diagnosis, and Staging of Exocrine Pancreatic Cancer

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