OfficialreprintfromUpToDate www.uptodate.com2015UpToDate

AuthorJohnAMartin,MD

SectionEditorDouglasAHowell,MD,FASGE,FACG

DeputyEditorsAnneCTravis,MD,MSc,FACG,AGAFDianeMFSavarese,MD

Ampullarycarcinoma:Epidemiology,clinicalmanifestations,diagnosisandstaging

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.Literaturereviewcurrentthrough:Mar2015.|Thistopiclastupdated:Jan06,2015.

INTRODUCTIONPeriampullarytumorsareneoplasmsthatariseinthevicinityoftheampullaofVater.Theycanoriginatefromthepancreas,duodenum,distalcommonbileduct(CBD),orthestructuresoftheampullary(ampullaofVater)complex.TheampullaofVaterisformedbytheduodenalaspectofthesphincterofOddimuscle,whichsurroundstheconfluenceofthedistalCBDandmainpancreaticductaswellasthepapillaofVater,amucosalpapillarymoundatthedistalinsertionoftheseductsonthemedialwalloftheduodenum(figure1).Ampullarycarcinomasaredefinedasthosethatarisewithintheampullarycomplex,distaltothebifurcationofthedistalcommonbileductandthepancreaticduct(figure2).

Thepapillaisanipplelikestructureonthemedialaspectofthesecondportionoftheduodenumbestvisualizedwithasideviewingendoscope.ThedistalbileandventralpancreaticductstraversetheduodenalwallinthislocationandopenintotheduodenallumenthroughthesmallmucosalelevationofthepapillaofVater.

Theepidemiology,clinicalfeatures,diagnosis,andstagingofampullarycarcinomawillbereviewedhere.Treatmentofampullarycancersandtheapproachtothepatientwithampullaryadenomaispresentedseparately.(See"Ampullarycarcinoma:Treatmentandprognosis"and"Clinicalmanifestationsanddiagnosisofampullaryadenomas"and"Treatmentofampullaryadenomas".)

EPIDEMIOLOGYANDBIOLOGICBEHAVIORNeoplastictransformationoftheintestinalmucosaoccursmorecommonlyneartheampullathanatanyothersiteinthesmallintestine.Despitethis,primaryampullarytumorsarerare,withanincidenceofapproximatelyfourtosixcasespermillionpopulation[14].Theyaccountforonly6percentoflesionsthatariseintheperiampullaryregion[5],butareresponsiblefor20percentofalltumorrelatedobstructionsofthecommonbileduct[6].Thereissomeevidencethattheincidencehasincreasedoverthelast30years[3].

Bothbenignandmalignantampullarytumorscanoccursporadicallyorinthesettingofageneticsyndrome.Theincidenceofampullarytumorsisincreased200to300foldamongpatientswithhereditarypolyposissyndromes,suchasfamilialadenomatouspolyposis(FAP)andhereditarynonpolyposiscolorectalcancer(HNPCC)comparedwiththegeneralpopulation[79].SurveillanceendoscopyisparticularlyimportanttodetectearlyampullarylesionsinpatientswithFAPgiventhehighincidenceofcoexistingpremalignantduodenaladenomatouspolyps.Upto90percentofpatientswithFAPdevelopadenomasintheuppergastrointestinaltract[10].(See"Familialadenomatouspolyposis:Screeningandmanagementofpatientsandfamilies".)

Theaverageageatdiagnosisofsporadicampullarycarcinomasis60to70yearsold[8,1113].Incontrast,patientswhoseampullarycarcinomasariseinthesettingofaninheritedpolyposissyndromeusuallypresentatanearlierage,dueinparttoendoscopicscreeningandsurveillanceprograms.

BiologicbehaviorSeverallinesofevidencesuggestthatthebiologyofprimaryampullaryadenomasandcarcinomasismoreanalogoustointestinalratherthanpancreaticobiliaryneoplasms:

Thehistologyofprimaryampullaryneoplasmsmoreoftenresemblesthatofadenomasandadenocarcinomasofintestinaloriginratherthanpancreaticobiliaryorigin.Inonestudyof170ampullarycarcinomas,themostcommonhistologicsubtypewasintestinal(47percent),followedbypancreatobiliary(24percent),poorlydifferentiatedadenocarcinomas(13percent),intestinalmucinous(8percent),andinvasivepapillary(5

http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/3http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/8,11-13http://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-ampullary-adenomas?source=see_linkhttp://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/10http://www.uptodate.com/contents/treatment-of-ampullary-adenomas?source=see_linkhttp://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/5http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/7-9http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/contributorshttp://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/contributorshttp://www.uptodate.com/contents/image?imageKey=GAST%2F53240&topicKey=GAST%2F655&rank=2%7E150&source=see_linkhttp://www.uptodate.com/contents/image?imageKey=GAST%2F78786&topicKey=GAST%2F655&rank=2%7E150&source=see_linkhttp://www.uptodate.com/contents/ampullary-carcinoma-treatment-and-prognosis?source=see_linkhttp://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/contributorshttp://www.uptodate.com/http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/1-4http://www.uptodate.com/contents/familial-adenomatous-polyposis-screening-and-management-of-patients-and-families?source=see_linkhttp://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/contributorshttp://www.uptodate.com/home/editorial-policyhttp://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/contributorshttp://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/contributorshttp://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/contributorshttp://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/6

SubdividingadenocarcinomasoftheampullaofVateraccordingtohistologicsubtypeandimmunohistochemicalstainingpatternintodistinctsubsetswithdifferingbiologicbehaviorhasprognosticimportance.Inaretrospectivestudyof208patientstreatedforampullaryadenocarcinomainSydney,Australia,thosewithahistomolecularpancreaticobiliaryphenotype(CDXnegative,MUC1positive)hadasignificantlyworseoutcomethandidthosewithanintestinalphenotype(CDXpositive,MUC1negative),withmediansurvivalof16versus116months[22].Whenhistomolecularphenotypewascombinedwiththelymphnodestatus,threesubsetsofampullaryadenocarcinomasemergedwithsignificantlydifferentsurvivaloutcomes:

Theresultswerecomparableintwoadditionalindependentcohortsof90patientsfromGlasgow,Scotland,and46fromVerona,Italy.

Identificationofprognosticallyrelevantsubgroupshasalsobeenachievedbyuseofgeneexpressionprofilinginconjunctionwithimmunohistochemicalstainingforcytokeratins7and20[23].However,moleculartechniquessuchasthesearenotyetreadyforclinicalapplication.(See"Overviewofgeneexpressionprofiling,proteomics,andmicroRNAprofilinginclinicaloncology".)

Whetherandhowthisinformationcouldbeusedtoindividualizetreatmentdecisions,particularlyaboutadjuvanttherapy,isunclear.Theimpactofadjuvanttherapyonoutcomesaccordingtohistomolecularphenotypecouldnotbeaddressedinthestudydescribedabovesinceonlyaminorityofpatients(64of208)inallthreecohortsreceivedadjuvantchemotherapy,anditwasnotrandomlyassigned[22].Prospectivestudyoftreatmentselectionbaseduponhistomolecularphenotypeisneededbeforeconclusionscanbedrawn.Atpresent,adjuvanttherapyrecommendationsforpatientswithampullarycancerfollowguidelinesestablishedforpancreaticcancer,rather

percent)[14].

Ampullarycarcinomasarethoughttoarisefromampullaryadenomas,apremalignantprecursorlesiondisplayingtheadenomacarcinomasequenceobservedincolorectalneoplasia.Moreover,patientswithFAPhaveasignificantlyincreasedincidenceofbothampullaryandcolorectalcancersrelativetothegeneralpopulation,suggestingthatthemechanismofampullaryandcolorectalcarcinogenesismaybesimilar[15].

Krasmutationsareanearlyeventinampullarycarcinogenesis,withanincidence(37percent)thatissimilartothatincoloncancer(upto50percent)[16].(See"Moleculargeneticsofcolorectalcancer",sectionon'Oncogenes'.)

Expressionprofilingofcyclooxygenase2(COX2)byampullarycarcinomasismoreconsistentwithaneoplasmofintestinaloriginthanpancreaticobiliaryorigin.HighCOX2expressionhasbeendetectedin78percentofampullarycarcinomas[17].Ofampullarycarcinomasclassifiedashavinganintestinalorigin,95percenthadhighCOX2expression,whereasonly50percentoflesionswithapancreaticobiliaryorigindemonstratedhighCOX2expression.

Trueampullarycancershaveabetterprognosisthanperiampullarymalignanciesofpancreatic[1820]orextrahepaticbiliary[21]origin.Resectabilityratesarehigher(over90percentinsomecontemporaryseries),andfiveyearsurvivalratesareapproximately30to50percent,eveninpatientswithlymphnodeinvolvement.Incontrast,fewerthan10percentofpatientswithcompletelyresectednodepositivepancreaticcancerarealiveattwoyears.(See"Overviewofsurgeryinthetreatmentofexocrinepancreaticcancerandprognosis"and"Ampullarycarcinoma:Treatmentandprognosis".)

Patientswithanodenegative,nonpancreaticobiliaryhistomolecularphenotypetumorhadanexcellentprognosis(fiveyearsurvival88percent).

Patientswithanodepositivepancreaticobiliaryphenotypehadapoorprognosis(fiveyearsurvival20percent).

Theremainingpatients(nodepositivenonpancreaticobiliaryphenotype,nodenegativepancreaticobiliaryphenotype)hadanintermediateprognosis(fiveyearsurvival47percent).

http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/14http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/17http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/22http://www.uptodate.com/contents/ampullary-carcinoma-treatment-and-prognosis?source=see_linkhttp://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/21http://www.uptodate.com/contents/molecular-genetics-of-colorectal-cancer?source=see_link&sectionName=Oncogenes&anchor=H10#H10http://www.uptodate.com/contents/overview-of-surgery-in-the-treatment-of-exocrine-pancreatic-cancer-and-prognosis?source=see_linkhttp://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/15http://www.uptodate.com/contents/overview-of-gene-expression-profiling-proteomics-and-microrna-profiling-in-clinical-oncology?source=see_linkhttp://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/23http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/16http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/22http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/18-20

thanintestinalcancer.(See"Ampullarycarcinoma:Treatmentandprognosis",sectionon'Adjuvanttherapy'.)

CLINICALMANIFESTATIONSAswithampullaryadenomas,themostcommonpresentingsymptomofampullarycarcinomaisobstructivejaundice(80percent)causedbycompressionofthedistalbileductbythetumor[11,24].(See"Clinicalmanifestationsanddiagnosisofampullaryadenomas".)

Ampullarycancersarenotusuallysuspectedasacauseofobstructivejaundicebecauseoftheirlowerincidencerelativetootherperiampullarymalignancies.Additionalsymptomsmayincludediarrheaduetofatmalabsorption(steatorrhea),mildweightloss,andfatigue.

Uptoonethirdofpatientshavechronic,frequentlyoccultgastrointestinalbloodlosswithanassociatedmicrocyticanemiaorhemepositivestools.Patientsoccasionallypresentwithfrankbleedingduetosloughingofthetumor,aconditionexacerbatedbytheuseofantiplateletagentssuchasaspirinandclopidogrel.Inonereport,nonspecificsymptomsincludeabdominalpain(45percent),fever(45percent),mildnausea,anddyspepsia[25].Largelesionsmayproducegastricoutletobstructionassociatedwithseverenauseaandvomiting.

DIAGNOSISANDSTAGINGThediagnosisofanampullarycarcinomaisestablishedbyacombinationofendoscopic,radiologic,andhistologicfeatures.Accuratestagingisessentialforplanningsurgicaltreatment.

TNMstagingsystemThemostcommonlyusedstagingsystemisthetumornodemetastasis(TNM)systemofthecombinedAJCC(AmericanJointCommitteeonCancer)/UICC(InternationalUnionAgainstCancer)(table1)[26].

Intheabsenceofmetastases,theprognosisofanampullarycarcinomadependsprimarilyupontwofactors:thedegreeoflocaltumorinvasion,asreflectedbytheTstage,andthepresenceoflymphaticspread,asreflectedbytheNstage.

DiagnosticevaluationThediagnosticevaluationofajaundicedpatientwithasuspectedmalignantbileductobstructionisdesignedtoeliminatebenigntumorsorgallstonesfromthedifferential,andtoestablishtheextentoftumorinvasionandspread.Althoughadvancedendoscopictechniquescanhelptodifferentiateampullaryadenomasfromcarcinomas,itmaybedifficulttocompletelyexcludeacarcinomawithoutcompleteresectionofthelesion.Ampullaryadenomashavethepotentialtoundergomalignanttransformation,andanoccultfocusofcarcinomamaybepresentwithinapredominantlybenignadenoma.(See"Clinicalmanifestationsanddiagnosisofampullaryadenomas".)

Atransabdominalultrasound(US)isareasonablefirsttestinpatientspresentingwithobstructivejaundice,butitwillgenerallynotshowthetumor.Helicalcomputedtomography(CT)scanningshouldbeobtainedtovisualizethepancreasandsurroundingstructures.Althoughitsspatialresolutionisinadequatetodeterminethedegreeoflocaltumorinvasion,itisthemostusefultesttoexcludethepresenceofdistantmetastases.(See'Transabdominalultrasonography'belowand'AbdominalCT'below.)

Endoscopicretrogradecholangiopancreatography(ERCP)isthesinglemostusefulendoscopicstudyfordiagnosingampullarycarcinomabecauseitpermitsidentificationofthetumor,biopsy,anddecompression,ifneeded.Whileendoscopicultrasonography(EUS)isassensitiveasERCPandsuperiortoCTandtransabdominalUSfordetectingsmallampullarytumors,itistypicallynotrequiredfordiagnosis.Itmayhavearoleinpreoperativestagingbutmayresultinoverstaging.Asaresult,wedonotroutinelyemployEUSforthediagnosisandstagingofampullarycarcinoma.(See'ERCP(endoscopicretrogradecholangiopancreatography)'belowand'Endoscopicultrasonography(EUS)'below.)

Differentiatingaprimaryampullarycarcinomafromothermorecommonperiampullarymalignancies(arisinginthepancreas,duodenum,orbileduct)ischallenging.Althoughthedistinctionmaybeevidentafterradiographicandendoscopicevaluation,itmaynotbepossibletodeterminethetissueoriginofamalignantperiampullaryneoplasmuntilresectionandhistopathologicevaluationoftheentiresurgicalspecimeniscompleted[27].Thisisparticularlytrueifthelesionislargeandobstructstheduodenallumen.Fromasurgicalstandpoint,thedistinctionbetweenampullaryandperiampullarycancersisnotessentialpreoperativelysincethetreatmentisthesameforboth

http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/25http://www.uptodate.com/contents/clopidogrel-drug-information?source=see_linkhttp://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/11,24http://www.uptodate.com/contents/aspirin-drug-information?source=see_linkhttp://www.uptodate.com/contents/ampullary-carcinoma-treatment-and-prognosis?source=see_link&sectionName=ADJUVANT+THERAPY&anchor=H19#H19http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/26http://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-ampullary-adenomas?source=see_linkhttp://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-ampullary-adenomas?source=see_linkhttp://www.uptodate.com/contents/image?imageKey=GAST%2F77606&topicKey=GAST%2F655&rank=2%7E150&source=see_linkhttp://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/27

lesions.However,theoncologicimplicationsandprognosisoftheampullaryandperiampullarytumorsaresubstantiallydifferent.(See"Overviewofsurgeryinthetreatmentofexocrinepancreaticcancerandprognosis"and"Diagnosisandstagingofsmallbowelneoplasms",sectionon'Adenocarcinoma'and"Treatmentoflocalizedcholangiocarcinoma:Adjuvantandneoadjuvanttherapyandprognosis",sectionon'Distalcholangiocarcinoma'.)

TransabdominalultrasonographyTransabdominalultrasonography(US)shouldbethefirstimagingstudyorderedforpatientswithjaundice,sinceUScanidentifyintrahepaticandextrahepaticbileductdilatationandgallstones.However,overlyingbowelgasfrequentlyobscuresthedistalbileduct,ampulla,andpancreas.Inonestudy,only10of127ampullarymassesweredetectedbyultrasound[28].Theoverallaccuracywas15percent,accordingtoonestudy[29].Asaresult,abdominalCTshouldbeorderedasthenextdiagnosticprocedureifUSdoesnotdemonstrategallstonesoranobviouspancreaticheadmassinajaundicedpatient.

AbdominalCTCTismoresensitivethanUSforevaluatingtheperiampullaryregion(image1).A"pancreaticmassprotocol"CTshouldbeordered.Specifically,patientsshouldreceivewaterastheoral"contrastagent"(todistendtheduodenumandimprovevisualizationoftheduodenallumenandadjacentpancreas),andIVcontrastisinjectedasabolustopermitbotharterialandvenousphaseimaging.Imagesareacquiredat1.0to2.5mmintervalstoimprovethesensitivityofpancreaticimaging.(See"Clinicalmanifestations,diagnosis,andstagingofexocrinepancreaticcancer",sectionon'Imagingstudies'.)

AlthoughhelicalCTcandetectmassesobstructingthedistalcommonbileduct(CBD),itssensitivityusuallydoesnotpermitthevisualizationofsmallampullaryneoplasmswithintheduodenallumen[30].Inonereport,theoverallaccuracywasonly20percent[29].Furthermore,CTbyitselfisinadequateforstagingampullarycancersbecauseitlacksthespatialresolutiontodeterminethedegreeoflocaltumorinvasionintotheduodenalwall,adjacentpancreas,orthepresenceofmajorvascularinvolvement[31].Ontheotherhand,CTisgenerallythemostusefulstudytoevaluateforthepresenceofdistantmetastaticdiseasewhichmostfrequentlyinvolvestheregionallymphnodes,liver,peritoneum,lungs,andbone.

ERCP(endoscopicretrogradecholangiopancreatography)Inajaundicedpatientwithsuspectedmalignantbileductobstruction,ERCPisthepreferredinitialendoscopicstudysinceitpermitssimultaneousendoscopicvisualizationoftheampulla,cholangiographyofthepancreaticandbileducts,biopsyfromthepapillaandampullarysegmentoftheCBDorpancreaticduct,andplacementofastentforbiliarydecompression,ifnecessaryandtechnicallyfeasible.However,ERCPcannotdeterminetheextentoflocaltumorinvasionofanampullarycarcinomaintotheadjacentduodenumorpancreaticparenchyma,informationthatisessentialforpreoperativestagingandsurgicalplanning.

Mostampullarycancersareobviousendoscopically(image2).Ifanexophyticampullarytumorisidentifiedthathastheappearanceofanadenoma,malignancyshouldbestronglysuspectedifthemassisulceratedorover3cminsize.However,becausethefalsenegativerateofendoscopicbiopsyisashighas50percent,anegativeresultisinsufficienttoexcludethepresenceofmalignancyinanampullarylesion[3237].TheoverallaccuracyofdiagnosiswithERCPinonereportwas88percent(p>0.05)[38].

Attemptstoenhancetheaccuracyofendoscopicbiopsyincludetheacquisitionoftissueatleast48hoursfollowingsphincterotomy[39,40],theperformanceofmultiplebiopsies[41],andtheuseofpolymerasechainreaction(PCR)orimmunohistochemicalstainingtodetectp53(atumorsuppressorgenethatisfrequentlylostinperiampullaryneoplasms)orKrasgenemutations[16,4246].Noneofthesemethodsareusedroutinelyincurrentclinicalpractice.

MRCPandpercutaneoustranshepaticcholangiographyAmpullaryobstructioncanalsobeevaluatedbymagneticresonancecholangiopancreatography(MRCP)orpercutaneoustranshepaticcholangiography(PTC)inpatientswithcontraindicationstoERCP(eg,thosewhohaveundergonegastricsurgery,suchasaRouxenYgastrojejunostomy,withresultantanatomythatmaymakeendoscopicaccessoftheduodenumtechnicallychallengingorimpossible,evenwithdeepenteroscopytechniques).However,neitheroftheseimagingmodalitiespermitsdirectluminalvisualizationofthepapillaryaspectoftheampulla,nordotheyprovideaccessfortissueacquisitionviadirectforcepsbiopsy.

http://www.uptodate.com/contents/diagnosis-and-staging-of-small-bowel-neoplasms?source=see_link&sectionName=Adenocarcinoma&anchor=H20#H20http://www.uptodate.com/contents/image?imageKey=ONC%2F70689&topicKey=GAST%2F655&rank=2%7E150&source=see_linkhttp://www.uptodate.com/contents/image?imageKey=GAST%2F63759&topicKey=GAST%2F655&rank=2%7E150&source=see_linkhttp://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/31http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/29http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/30http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/39,40http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/32-37http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/16,42-46http://www.uptodate.com/contents/treatment-of-localized-cholangiocarcinoma-adjuvant-and-neoadjuvant-therapy-and-prognosis?source=see_link&sectionName=Distal+cholangiocarcinoma&anchor=H8#H8http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/38http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/28http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/29http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/41http://www.uptodate.com/contents/overview-of-surgery-in-the-treatment-of-exocrine-pancreatic-cancer-and-prognosis?source=see_linkhttp://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-staging-of-exocrine-pancreatic-cancer?source=see_link&sectionName=Imaging+studies&anchor=H11#H11

MRCPisanoninvasivemethodofimagingthepancreaticobiliarytreeviamagneticresonanceimaging.SomeauthorsrecommendthisapproachinplaceofERCPinpatientswhowillnottolerateinvasiveproceduresorinwhomalargetumoroccludestheorificeofthepancreaticobiliaryducts,thuspreventingcannulationandductopacificationatthetimeofERCP.Ampullarycarcinomasappearasmasses(fillingdefects)protrudingintotheduodenallumen,withcharacteristicdelayedenhancementandhyperintensityondiffusionweightedimaging[47,48].InonereporttheoverallaccuracyofdiagnosiswithMRCPwas76percent[38].(See"Magneticresonancecholangiopancreatography".)

Incontrast,PTCisaninvasiveprocedureduringwhichthebiliarytreeisaccessedpercutaneouslyusinganeedleinsertedthroughtheparenchymaoftheliverintoanintrahepaticbileduct,thencontrastopacifiedunderfluoroscopy.PTCismostcommonlyperformedwhenthebiliarytreeisdilatedandERCPhasfailedtocannulateoradequatelydemonstratethebiliaryanatomy.PTCprovidesnotonlycholangiographybutalsotheopportunityforbrushcytology(althoughnotforcepsbiopsyforhistology)ofradiographicstrictures,althoughampullarylesionsthatdonotextendintothedistalCBDmaynotbeamenabletotissueacquisitionviathisroute.AnotherlimitationofPTCisthatitcannotdirectlyvisualizeampullarylesions,duodenaltumoringrowth,orinvolvementofthepancreaticduct.(See"Percutaneoustranshepaticcholangiography".)

Endoscopicultrasonography(EUS)Endoscopicultrasonography(EUS)isassensitiveasERCPandsuperiortoCTandtransabdominalUSfordetectingsmallampullarytumors,thoughitistypicallynotrequiredfordiagnosis[29,47,4957].Itmayhavearoleinpreoperativestagingtolookfortumorextensionandtodeterminethedepthoftumorinvasion,butitmayresultinoverstaging.Asaresult,wedonotroutinelyemployEUSforthediagnosisandstagingofampullarycarcinoma.

BecausebiliaryandpancreaticsphincterotomyandstentplacementcannotbeperformedusingEUSequipment,patientswhorequiretherapeuticinterventionmustalsoundergoanERCP,whichcanoftenbeperformedconcomitantly.

RoleindiagnosisMostcancersareclearlyseenendoscopically,andampullectomywillprovidetissueforhistologicdiagnosis,soEUSisgenerallynotrequiredfordiagnosis.Inaddition,EUSwillnotbehelpfulforidentifyingfociofcarcinomawithinotherwisebenignlesions.EUSmaybeindicatedfortheoccasionalbiopsynegativeampullarylesionthathasequivocalendoscopicfeaturesofmalignancy.(See"Treatmentofampullaryadenomas",sectionon'Endoscopicampullectomy'.)

IfmalignancyissuspectedinapatientundergoingEUS,fineneedleaspiration(FNA)oftheampulla,papilla,andsurroundingdeeperstructuresincludinglocallymphnodescanbeobtainedduringtheprocedure.However,anegativeresultdoesnotexcludethepresenceofamalignantfocuswithinanadenoma.(See"Endoscopicultrasoundguidedfineneedleaspirationbiopsyinthegastrointestinaltract".)

Inonereport,theoverallaccuracyofEUSguidedfineneedleaspirationbiopsy(FNAB)forprimarymassesoftheampullaryregionwas89percent,withasensitivityof82percentandaspecificityof100percent[58].

RoleinstagingEUSisthemostaccuratemodalityavailabletoassessthetumor(T)stageofampullarytumors,whichiscriticalforplanningsurgicalintervention.MultipleseriesconsistentlydocumentprimaryTstagingaccuraciesof70to90percent[7,49,51,54,5965].However,EUSstagingmethodstendtooverestimatethedepthoftumorinvasionandresultingTstage,whichcouldleadtoinappropriatetreatment[6].Accuracymaybedecreasedinthepresenceofanendobiliarystent[53].EUSislesshelpfulfornodal(N)staging.

EUSiscapableofobtainingimagesofthedistalbiliaryandpancreaticducts,permittingassessmentoflocalintraductaltumorextension.EUSalsoaccuratelydemonstratesthedepthoftumorpenetrationintotheduodenumbydemonstratingobliterationoftheinterfacebetweenthetumorandthemuscularispropriaoftheduodenum(afeaturethatupstagesthetumortoT2).Tumorextensionintothepancreasisassessedbythedepthofinvasion(2cmorcontiguousspreadtoadjacentorganssignifyingT4disease)(image3).

EUSislessaccurateforNstagingthanitisforTstaging.Ampullarycancersdrainintotwolymphnodebasins:

http://www.uptodate.com/contents/treatment-of-ampullary-adenomas?source=see_link&sectionName=ENDOSCOPIC+AMPULLECTOMY&anchor=H11#H11http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/53http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/29,47,49-57http://www.uptodate.com/contents/percutaneous-transhepatic-cholangiography?source=see_linkhttp://www.uptodate.com/contents/image?imageKey=GAST%2F72481&topicKey=GAST%2F655&rank=2%7E150&source=see_linkhttp://www.uptodate.com/contents/magnetic-resonance-cholangiopancreatography?source=see_linkhttp://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/38http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/47,48http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/7,49,51,54,59-65http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/6http://www.uptodate.com/contents/endoscopic-ultrasound-guided-fine-needle-aspiration-biopsy-in-the-gastrointestinal-tract?source=see_linkhttp://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/58

theretroduodenopancreaticchainandthesuperiormesentericchain.Onestudyreportedasensitivityandspecificityof67and96percent,respectively,forEUSdetectionofnodalmetastaseswhenabnormalnodeswereseen(definedasthoseoveronecentimeterindiameterandlocatedintheabovetwopositions)[65].Anotherseriesfoundsensitivityandspecificityratesof69and38percent,respectively,whenallvisualizedlymphnodespresentaroundtheduodenopancreaticblockwerepresumedtobemetastatic,regardlessofsizeorposition[64].However,othershavereportedsensitivityratesaslowas21percentfordetectionofnodalmetastasesbyEUS[66].

EUSguidedFNAofsuspiciouslymphnodesmayfurtherincreasetheaccuracyofnodalstaging.Thistopicisdiscussedindetailelsewhere.(See"Endoscopicultrasoundguidedfineneedleaspirationbiopsyinthegastrointestinaltract",sectionon'Pancreaticmasses'.)

IntraductalultrasonographyThetechnicalevolutionofEUShasledtothedevelopmentofsmallcaliberintraductalultrasound(IDUS)miniprobes(approximately2mm),whichcanbepassedthroughstandardendoscopesdirectlyintothebileorpancreaticduct.Thesmallcaliber,flexibility,andexcellentimagequalityproducedbythesecathetersmakesthemusefulforevaluatingavarietyofbiliaryandpancreaticdisorders.IDUSaccuratelyvisualizestheanatomyofthepapillaandistheonlyprocedurethatreliablydifferentiatesthesphincterofOddimusclefromtheremainderofthepapilla.Asaresult,IDUScanbeusefulfordiagnosingandassessingthesizeandextentofpapillarytumors.Inastudyof40patientswithampullarycarcinoma,IDUSwasmoreaccuratethanEUSforTstagingandevaluatingductalinvasion[67].(See"Intraductalultrasoundofthepancreaticobiliaryductalsystem".)

MagnificationendoscopywithnarrowbandimagingNarrowbandimagingusesopticalfilterstoenhancevisualizationofmicrovesselsandmucosalsurfacearchitectureingastrointestinaldiseases.Thetechniquedemonstratesabnormalvesselsassociatedwithhighgradedysplasiaonthesurfaceofhighgradeadenomasandadenocarcinomas.Abnormalvesselshavenotbeenidentifiedonthesurfaceofbenignampullaryadenomaswithhyperplasticorinflammatoryhistology.Preliminarystudieshavesuggestedapotentialroleforevaluationofampullarylesions[68].

LiverbiochemicaltestsBloodchemistriescannotestablishthediagnosisofampullarycarcinoma,butmayreflectthepresenceofcholestasiswhenanampullaryneoplasmresultsinpartialorcompletebiliaryobstruction.Patientsgenerallyhaveacholestaticpatternofliverbiochemicaltestabnormalities,althoughaminotransferasesmayalsobeelevated[25].TheprothrombintimemaybeelevatedduetoimpairedabsorptionoffatsolublevitaminsincludingvitaminK[69].

SerumtumormarkersSerumtumormarkersarenotspecificforampullarycarcinomasandhavelimiteddiagnosticapplication.Nevertheless,someampullarycancersareassociatedwithincreasedserumlevelsofcarbohydrateantigenCA199and/orcarcinoembryonicantigen[19,70],andserialassayofthesetumormarkersmaybeusefulforposttreatmentfollowup.(See"Ampullarycarcinoma:Treatmentandprognosis",sectionon'Posttreatmentsurveillance'.)

SUMMARYANDRECOMMENDATIONSPatientswithampullarycancermostcommonlypresentwithjaundice(80percent)causedbyobstructionofthedistalbileductbytumor.Diagnosisandstagingareachievedbyacombinationofendoscopic,radiologic,andhistologicfeatures(algorithm1).Therearetwomajorconsiderations:identificationofthetumor,anddistinctionfromanampullaryadenomaortumorarisingfromoutsideoftheampulla(mainlypancreaticcarcinomaoradistalcholangiocarcinoma).

Atransabdominalultrasound(US)isareasonablefirsttestinpatientspresentingwithobstructivejaundice,butitwillgenerallynotshowthetumor.Helicalcomputedtomography(CT)scanningshouldbeobtainedtovisualizethepancreasandsurroundingstructures.Althoughitsspatialresolutionisinadequatetodeterminethedegreeoflocaltumorinvasion,itisthemostusefultesttoexcludethepresenceofdistantmetastases.(See'Transabdominalultrasonography'aboveand'AbdominalCT'above.)

Endoscopicretrogradecholangiopancreatography(ERCP)isthesinglemostusefulendoscopicstudysinceit

http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/66http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/64http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/19,70http://www.uptodate.com/contents/intraductal-ultrasound-of-the-pancreaticobiliary-ductal-system?source=see_linkhttp://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/67http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/68http://www.uptodate.com/contents/ampullary-carcinoma-treatment-and-prognosis?source=see_link&sectionName=POSTTREATMENT+SURVEILLANCE&anchor=H23#H23http://www.uptodate.com/contents/endoscopic-ultrasound-guided-fine-needle-aspiration-biopsy-in-the-gastrointestinal-tract?source=see_link&sectionName=PANCREATIC+MASSES&anchor=H109379223#H109379223http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/65http://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/25http://www.uptodate.com/contents/image?imageKey=GAST%2F51015&topicKey=GAST%2F655&rank=2%7E150&source=see_linkhttp://www.uptodate.com/contents/ampullary-carcinoma-epidemiology-clinical-manifestations-diagnosis-and-staging/abstract/69

ACKNOWLEDGMENTTheauthorsandUpToDatewouldliketothankDr.A.JamesMoser,whocontributedtoearlierversionsofthistopicreview.

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

Topic655Version11.0

permitsidentificationofthetumor,biopsy,anddecompression,ifneeded.Whileendoscopicultrasonography(EUS)isassensitiveasERCPandsuperiortoCTandtransabdominalUSfordetectingsmallampullarytumors,itistypicallynotrequiredfordiagnosis.Itmayhavearoleinpreoperativestagingbutmayresultinoverstaging.Asaresult,wedonotroutinelyemployEUSforthediagnosisandstagingofampullarycarcinoma.(See'ERCP(endoscopicretrogradecholangiopancreatography)'aboveand'Endoscopicultrasonography(EUS)'above.)

http://www.uptodate.com/contents/license

GRAPHICS

SphincterofOddiinrelationtotheampullaofVater

DiagramoftheanatomyofthesphincterofOddiandampullaofVater.ThemusclefibersofthesphincterofOddisurroundtheintraduodenalsegmentofthecommonbileductandtheampullaofVater.Acircularaggregateofmusclefibers,knownasthesphinctercholedochus(orsphincterofBoyden),keepsresistancetobileflowhigh,andtherebypermitsfillingofthegallbladderduringfastingandpreventsretrograderefluxofduodenalcontentsintothebiliarytree.Aseparatestructure,calledthesphincterpancreaticus,encirclesthedistalpancreaticduct.Themusclefibersofthesphincterpancreaticusareinterlockedwiththoseofthesphinctercholedochusinafigureeightpattern.

Graphic78786Version3.0

Locationsampullarytumors

Graphic53240Version1.0

TNMstagingforampullarycarcinoma

Primarytumor(T)

TX Primarytumorcannotbeassessed

T0 Noevidenceofprimarytumor

Tis Carcinomainsitu

T1 TumorlimitedtotheampullaofVaterorsphincterofOddi

T2 Tumorinvadesduodenalwall

T3 Tumorinvadespancreas

T4 Tumorinvadesperipancreaticsofttissuesorotheradjacentorgansorstructuresotherthanpancreas

Regionallymphnodes(N)

NX Regionallymphnodescannotbeassessed

N0 Noregionallymphnodemetastasis

N1 Regionallymphnodemetastasis

Distantmetastasis(M)

M0 Nodistantmetastasis

M1 Distantmetastasis

Anatomicstage/prognosticgroups

Stage0 Tis N0 M0

StageIA

T1 N0 M0

StageIB

T2 N0 M0

StageIIA

T3 N0 M0

StageIIB

T1 N1 M0

T2 N1 M0

T3 N1 M0

StageIII

T4 AnyN M0

StageIV

AnyT AnyN M1

Note:cTNMistheclinicalclassification,pTNMisthepathologicclassification.

UsedwiththepermissionoftheAmericanJointCommitteeonCancer(AJCC),Chicago,Illinois.TheoriginalsourceforthismaterialistheAJCCCancerStagingManual,SeventhEdition(2010)publishedbySpringerNewYork,Inc.

Graphic77606Version9.0

Ampullarycarcinoma

SpiralabdominalCTscanshowingasmallampullarymass(arrow)ina74yearoldwomanwithoccultgastrointestinalbloodloss.Notethatthepancreaticheadappearsuninvolved.

CourtesyofAJamesMoser,MD.

Graphic63759Version2.0

Ampullarycancerendoscopy

Endoscopicviewofanampullarycarcinoma.Notethenodularappearanceofthetumor.

CourtesyofDavidCarrLocke,MD.

Graphic70689Version2.0

Ampullarycarcinoma

EndoonographicimageobtainedduringEUSshowinginvasionofanampullarylesionintothepancreatichead(T3).Thetumorclearlypenetratesthemuscularispropria.

CourtesyofAJamesMoser,MD.

Graphic72481Version2.0

Ampullarycarcinomaalgorithm

Graphic51015Version1.0