iap biliary dysplasia · risk factors for biliary neoplasia • west gall stones primary sclerosing...

DysplasiaintheBiliaryTractBDIAP

2ndDecember2016

RobGoldin

[email protected]

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


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



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


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


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