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BiliaryDysplasia
•Background•Classificationofdysplasticlesions•Gallbladderdysplasia
BiliaryDysplasia
•Background•Classificationofdysplasticlesions•Gallbladderdysplasia
Figure 2
The Lancet2014 383, 2168-2179DOI: (10.1016/S0140-6736(13)61903-0)
Copyright © 2014 Elsevier Ltd Terms and Conditions
Hepat Oncol 2015;2:255-73.
Epidemiologyofcholangiocarcinoma
• Theincidenceofintrahepaticcholangiocarcinomaisincreasinginmanywestern
countries.
• Age-adjustedratesofcholangiocarcinomaarereportedtobehighestinHispanic
andAsianpopulations.
• SlightmalepredominancewiththeexceptionofthefemaleHispanicpopulation.
• Unusualinchildren.
• Ampullary andintrahepatic– commonestinAsia.
• Gallbladder– SouthAmerica.
Lancet 2014;383:2168–7
Riskfactorsforbiliaryneoplasia
• WestGallstones
Primarysclerosing cholangitis
Abnormalcholedocho-pancreatic
junction
Choledochal cyst
• AsiaHepatolithiasis
Flukes
HepatitisBandC
Normalmucosa
Adenoma Invasivecarcinoma
Metaplasia-Dysplasia-Carcinoma(Biliary intra-epithelial neoplasia)
Masslesion- Carcinoma(Adenoma/ Intraductal papillaryneoplasm)
ChronicInflammation
Pyloricmetaplasia
Intestinalmetaplasia
Low gradedysplasia
Highgradedysplasia
Invasivecarcinoma
Intraductal papillaryneoplasm
PSCandCholangiocarcinoma
• Indevelopedcountriesitisthegreatestriskfactor.
• 400timesashighastheriskinthegeneralpopulation.
• Theannualriskofcholangiocarcinomais2%.
PSCandBileductdysplasia
• bileductdysplasiaisstillarelativelyfrequentfinding,seenatleastfocallyin36%ofbenignend-stagePSCexplants
• highfrequenciesofmucinousmetaplasia,pyloricmetaplasia,and
pancreaticacinarmetaplasia,whichdidnotdifferbetween
cholangiocarcinomaandnon-cholangiocarcinoma livers.
• liverswithcholangiocarcinomaweremorelikelytoharborintestinal
metaplasia,dysplasiaandalsocontainedgreaternumbersofdysplastic
ductsthannon- cholangiocarcinomacases.
AmJSurg Pathol.2010Jan;34(1):27-34.
©2010LippincottWilliams&Wilkins,Inc.PublishedbyLippincottWilliams&Wilkins,Inc. 2
AmericanJournalofSurgical
Pathology.34(1):27-34,
January2010.
FIGURE1.Bileduct
metaplasia.A,Normalbile
ductepitheliumwith
cuboidalandlowcolumnar
cells.B,Mucinous
metaplasia.C,Pyloric
metaplasia(arrows).D,
Intestinalmetaplasia(inthis
caseinvolving adysplastic
bileduct).Arrowsmark
examplesofgobletcells.
Roleofperibiliary glandsinPSC
Peribiliary glandsexpressedHedgehogpathwayandepithelial-to-
mesenchymaltransitiontraitsinprimarysclerosing cholangitis.
Journal of Hepatology 2015 vol. 63 1220–1228
Expressionofcellcycle–relatedmoleculesinbiliarypremalignantlesionsp21,p53,cyclin D1,andDpc4tobeinvolvedinbothpathways
Butforp53:
• expressionwasdramaticallyup-regulatedattheinvasivestage
ofbiliaryintraepithelialneoplasia
• expressionwasalreadyup-regulatedinLGintraductal papillary
neoplasmandreachedaplateauinHGintraductal papillary
neoplasm
HumanPathology(2008)39,1153–1161
Biliary intra-epithelial neoplasiaGrade2
Intraductal papillaryneoplasmGrade2
BiliaryDysplasia
•Background•Classificationofdysplasticlesions•Gallbladderdysplasia
Precursorlesionsofcholangiocarcinoma
• Similarlesionsariseinthepancreas
Anovelapproachtobiliarytractpathologybasedonsimilarities topancreaticcounterparts:isthebiliarytractanincompletepancreas?
PathInt.2010Jun;60(6):419-29.
Proposalofanewdiseaseconcept"biliarydiseaseswithpancreaticcounterparts".Anatomicalandpathologicalbases.
Histol Histopathol 2014Jan;29(1):1-10.
Precursorlesionsofcholangiocarcinoma
• Mostinvasivecancersarisefrompreexistingprecursorlesions:
WHOPremalignantLesionsofthegallbladderandbileducts(2010)• Adenoma:tubular,papillary,tubulo-papillary
• Biliaryintra-epithelialneoplasia(BilIN)• Intraductal /intracystic papillaryneoplasm(IPN)
• Mucinouscysticneoplasm
- Biliarypapilloma
- Biliarypapillomatosis
- Papillarycholangiocarcinoma
- Mucin-producingbileductneoplasm
- Biliarycystadenoma/adenocarcinoma
(without ovarian-likestroma)
Intraductal papillaryneoplasmof
thebileduct(IPNB)
Mucinouscysticneoplasm(MCN)
oftheliver
- Biliarycystadenoma/adenocarcinoma
withovarian-likestroma
WHO Classification 2010
Mucinouscysticneoplasm(MCN)
• Perimenopausal females
• Usuallyinvolvesintrahepaticbileducts• Linedbycolumnar,biliaryepithelium
• Ovarian-likestromainthewall.
• Notconnectedtothebiliarytract• Lowriskofmalignantchange
ModernPathology (2011) 24, 1079–1089
Mucinous cystic neoplasm
SimpleBiliary
Cyst
Precursorlesions:MacroscopicPathology
• BiliaryIntra-epithelialneoplasia:Usuallycannotbeseen
• Intraductal papillaryneoplasms:
Exophytic papillarylesion
Maybesecondarycysticchange
• Adenoma
Exophytic
Biliaryintra-epithelialneoplasia
Intraductalpapillaryneoplasm
Adenoma
Biliaryintra-epithelialneoplasia:MicroscopicPathology
• Flatbutmaybemicropapillary projections
• Classicandintestinaltypes(Histopathology2011Dec;59(6):1100-100.)• Abrupttransitiontodysplasticepithelium• Maybeinvolvementofunderlyingperibiliary glandsorRokitansky-
Aschoff sinuses.
• Grading:BilIN1-3orhighgrade/lowgrade(BestPract ResClinGastroenterol.2013Apr;27(2):285-97)
BilIN withmicropapillary projections
BilIN withabruptchange
BilIN involvingRokitansky-Aschoff sinus
GradingofBilIn
J Gastroenterol (2014) 49:64–72(Modern Pathology (2007) 20, 701–709)
BilIN 1-3
J Gastroenterol (2014) 49:64–72
Biliaryintra-epithelialneoplasia:MicroscopicPathology
0.00:pooragreement;
0.00–0.20:slightagreement;0.21–0.40:fairagreement;0.41–0.60:moderateagreement;0.61–0.80:substantialagreement;
and0.81–1.00:almostperfectagreement.
Modern Pathology (2007) 20, 701–709
DifferentialdiagnosisofBilIN
• Metaplasia
• Reactivechanges• (Pagetoid spread)
DifferentialdiagnosisofBilINMetaplasia
Pyloricmetaplasia Intestinalmetaplasia
DifferentialdiagnosisofBilIN:Reactivechanges
Modern Pathology (2007) 20, 701–709
DifferentialdiagnosisofBilIN:Reactivechanges
Arch Pathol Lab Med. 2010;134:1621–1627
Intraductal PapillaryNeoplasm:MicroscopicPathology
• Intraductal papillaryneoplasmbiliaryequivalentofpancreatic
intraductal papillarymucinousneoplasm
But:
intracystic aswellasintraductal:i.e.intraluminal
mostarenotmucinous
• highgrade/lowgrade• maybesecondarycysticchange
Intraductal PapillaryNeoplasm:MicroscopicPathology
• Halfareassociatedwithinvasivecanceratthetimeofdiagnosis
• 4histologicalsubtypes:intestinal,pancreaticobiliary,gastric,oncocytic
Intestinaltype
Adenomas:MicroscopicPathology
Maybeclassifiedaccordingto:
• Architecture:tubular,papillary,tubulo-papillary• Celltype:pyloric-glandlike,intestinal,foveolar andbiliary
Pyloric
tubular
adenoma
Intracystic papillarytubularneoplasmsofthegallbladder
Intracholecystic papillary-tubular neoplasms (ICPN)ofthegallbladder(neoplasticpolyps,adenomas,and papillary neoplasms thatare≥1.0cm):clinicopathologicandimmunohistochemical analysisof123cases.
“Theyshowvariablecellularlineages,aspectrumof
dysplasia,andamixtureofpapillaryortubulargrowthpatterns,
oftenwithsignificantoverlap,warrantingtheirclassification
under1unifiedparallelcategory,intracholecysticpapillary-tubular
neoplasm.”
AmJSurg Pathol. 2012Sep;36(9):1279-301.
Intracystic papillary-tubularneoplasmsofthegallbladder
AmJSurg Pathol. 2012Sep;36(9):1279-301.
AmJSurg Pathol. 2012Sep;36(9):1279-301.
IPMN=intraductal papillarymucinousneoplasm
ITPN =intraductal tubulopapillary neoplasm
IPN =intraductal papillaryneoplasm
IAPN =intra-ampullary papillarytubularneoplasm
ICPN=intracholecystic papillary-tubularneoplasm
Whatneedstobeincludedinthereport:
• Size• Dysplasia(extentofhighgrade)• Architecture(extentofpapillaryarchitecture)• (Celltype)• Carcinoma/not
• Margin
Immunohistochemistryfordysplasia
Immunohistochemistry:forhistologicalsubtypes
CK7: markerforbiliarydifferentiation
MUC1: markerforpancreatico-biliarytumour differentiation
CDX2: markerforintestinaldifferentiation
MUC2: markerforintestinaldifferentiation
MUC5AC: markerforgastricfoveolardifferentiation
MUC6: markerforpyloricdifferentiation
Immunohistochemistry:fordiseaseprogression
• Withincreaseddysplasiaandthedevelopmentofinvasivecarcinoma:
increasedexpressionofp53
increasedexpressionofKi-67
lossofmembranousexpressionofBeta-catenin
lossofmembranousexpressionofE-cadherin
lossofCD10expression
CD15inbiliarydysplasia
• Expressedin70.0%,cholangiocarcinoma-associateddysplasia
dysplasia andin100%ofdysplasiainintraductal biopsies
• Expressedin9%ofbenignbileduct• CD15isasensitiveandspecificmarkerforintraepithelial (andinvasive
neoplasias)ofthebile
HistopathologyDOI:10.1111/his.13041
BiliaryDysplasia
•Background•Classificationofdysplasticlesions•Gallbladderdysplasia
Incidentalnon-benigngallbladderhistopathologyaftercholecystectomyinanUnitedKingdompopulation:Needforroutinehistologicalanalysis?
4027patients:
“Dysplasia,rangingfromlowtomultifocalhigh-gradewasdemonstratedin55(1.37%).“
WorldJGastrointest Surg.2016Oct27;8(10):685-692.
Rokitansky-Aschoff SinusesMimickingAdenocarcinomaoftheGallbladder
AmJSurg Pathol 2013;37:1269–1274
“Submittingtheentiregallbladderincasesofdysplasiaisnotjustified”.
Whendysplasiaisidentifiedinagallbladder,manyexpertsrecommendsubmissionoftheentiregallbladderforhistologicexamination.
Wereviewed16,611gallbladderresections:
• 9HGD
• 16LGD
• 81atypia
NoneoftheHGDorLGDdysplasiawereidentifiedongrossexamination,butallwereidentifiedasatypicalontheinitialslidesubmittedandcorrectlygradedwiththesubmissionof4additionalslides.
AmJClin Pathol. 2012Sep;138(3):374-6.
“Submittingtheentiregallbladderincasesofdysplasiaisnotjustified.”
89%HGD,38%LGD,and1%of81atypia casesweresubsequently
entirelysubmittedwithoutidentificationofanynewlesion.
Weconcludethatforcasesofdysplasiaandatypia reviewofthegross
specimenandsubmissionofupto4additionalsectionsidentifyall
significantlesions,andsubmissionoftheentiregallbladderisnot
justified.
AmJClin Pathol. 2012Sep;138(3):374-6.
“Submittingtheentiregallbladderincasesofdysplasiaisnotjustified.”:Letter1• CholecystectomyisconsideredadequatetherapyforTisorT1invasivecancers
• Inmorestraightforwardcases,wewouldrecommendthat
consultantsaddacommentsuchas“Thisfinaldiagnosisreliesonathoroughgrossexaminationofthegallbladderandtakesintoaccountthatnomucosalormuscularabnormalitieswerenotedongrossexamination.”
AmJClin Pathol.2013;139(6):830.
GallbladderCancer:expertconsensusstatement
“Patients with T1b, T2 or T3 disease that is incidentally identified in a cholecystectomy specimen should undergo re-resection unless this is contraindicated by advanced disease or poor performance status.”
HPB2015,17,681–690
“Submittingtheentiregallbladderincasesofdysplasiaisnotjustified.“:Letter2
• Pyloricmetaplasia: noadditionalsections
• Intestinalmetaplasia: 2additionalcassettes
• LGD: 2additionalcassettes
• HGD: 12cassettes
Am J Clin Pathol 2013;140:278-28
Gallbladder Cancer Mortality Females
0 100 200 300 400 500 600
CHILEHUNGRIAALEMANIA
CHECOLOVAKIAJAPON
AUSTRIAALEMANIA
SUECIAFINLANDIAHOLANDA
SUIZALUXEMBURGO
DINAMARCAYUGOSLAVIA
BELGICAITALIA
HONG-KONGISRAEL
FRANCIAMALTA
ESPAÑACANADAKUWAIT
AUSTRALIANUEVA ZELANDIA
PORTUGALNORUEGA
IRLANDA NORTEBULGARIA
ESTADOS UNIDOSESCOCIA
MAURITIUSINGLATERRA
ISLANDIAKOREA
GRECIAIRLANDA
TAILANDIASRI LANKA
Hyalinizing Cholecystitis:(PorcelainGallBladder)
Am J Surg Pathol 2011;35:1104–1113
Hyalinizing Cholecystitis(PorcelainGallBladder)
• 2%ofcholecystectomies
• carcinomaseenin15%ofthese(OR=4.6)
• only42%oftheinvasivecaseswereassociated
withcalcifications
Am J Surg Pathol 2011;35:1104–1113
Dysplasiaatresectionmargins
Dysplasiaatresectionmargins1
• BilIN wasdetectedinthemarginin53%andwasmainlylow-grade.
• PatientswithR1resectionshadasignificantlyshorteroverallsurvivalthanthosewithR0resectionsirrespectiveofthepresenceofBilIN.
• Thisdiagnosisdoesnotrequireadditionalresection.
Virchows Arch.2015Feb;466(2):133-41.
Dysplasiaatresectionmargins2
• 5patientswithhigh-gradedysplasiaatthecysticductmarginwithoutevidenceofgallbladdermalignancywereidentified.
• Radiologicimagingwasabnormalintwopatientsofwhichonehadanenlargedportacaval lymphnode.
• All5patientsunderwentexplorationandresectionofeitherthecysticductstumporthebileduct.Onepatientwasfoundtohaveanode-positiveadenocarcinomaofthecysticduct.
• Underlyingcholangiocarcinomashouldbeconsidered,especially,ifimagingrevealsanyabnormalities.
HPB2011;13:865–868.
BiliaryDysplasia
•Background•Classificationofdysplasticlesions•Gallbladderdysplasia