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Barretts Esophagus:Metaplasia and Dysplasia1. Metaplasia - Defn/types
- Pathogenesis- Differential Diagnosis
2. Dysplasia - Incidence/risk factors- Pathologic Features
- Adjunctive Diagnostic tests- Natural History
- Treatment
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Barretts EsophagusDefinition
Columnar metaplasia of esophageal squamous epithelium(any length)
Recognized at endoscopy Goblet cell metaplasia
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Barretts EsophagusGross Types
Long segment (>3cm) Short segment (1-3cm) Ultrashort segment (0-1cm)
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Multilayered Epithelium
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Multilayered Epithelium
1. Hybrid epithelium (squam/colum)- EM, cytokeratins
2. Biologically active3. Phenotypically similar to Barretts
Esophagus4. Highly associated with Barretts
esophagus
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Short (Ultrashort) BE vs.
Chronic Carditis Distinction Important Different clinical, etiologic,
pathologic, outcome, risk of malignancy
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Mucin Histochemistry
______________________________________________________ Stain Esoph Cardia
Goblet Non-Goblet Goblet Non-Goblet ______________________________________________________ Alcian blue + + + +(acid mucin
High Iron diamine + + + -(sulphomucin)
_____________________________________________________
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Barretts EsophagusDysplasia: Definition Neoplastic epithelium that remains
confined within the basement membrane not reactive not synonymous with atypical unlikely to spontaneously regress
Both a marker and a precursor of adenocarcinoma
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Barretts Dysplasia/CarcinomaRisk
Prevalence : 6-8%
Incidence : 0.2 3% (1/52 1/208 patient years)
Relative Risk: 30-125x
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Incidence Rate of Adenocarcinoma inBarretts Esophagus
__________________________________________________________________
Incidence Follow-upSeries Patients Cases (Patient Incidence
(No.) (No) Years) Rate __________________________________________________________________
Haammeeteman et al 50 5 260 1/52Bonelli et al 71 2 110 1/55Roberston et al 56 4 224 1/56Miros et al 81 3 289 1/96
Iftikhar et al 107 4 462 1/115Drewitz et al 170 4 834 1/208OConnor et al 136 2 570 1/285Sepchler et al 108 4 1037 1/259
Sharma et al 618 12 2546 1/212 _________________________________________________________________
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Patient Characteristics __________________________________________________________________ Variable G ERD Barretts HGD/CA(N=2170) (N=1189) (N=131)
__________________________________________________________________ Male sex 98% 99% 99%Age (yr*) 59+13 61+11 63+10White ethnicity 76% 83% 89%
Ethanol Consumption 40% 37% 42%Smoking 34% 25% 27%Hiatal hernia 24% 65% 84%Hiatal hernia size (cm*) 0.4+1.1 2.4+1.9 3.5+2.3
Barretts length (cm*) 2.6+2.1 5.0+4.4 __________________________________________________________________
Avidan et al. Am J Gastroenterol 2002;97(8) 1930-1936
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DysplasiaPathologic Features1. Gross - Flat
- Elevated (plaque, nodule, polyp)
2. Microscopic - Adenoma-like- Non-adenoma like
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Dysplasia in the GI Tract
NegativeIndefinite
Positive (low, high)Intramucosal AdenoCa
Submucosal (Invasive) AdenoCa
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Non-Recommended Terms
AtypiaAdenomatous Changes
Carcinoma in Situ
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Barretts-related DysplasiaInterobserver Agreement __________________________________________
Category % agreement __________________________________________ HGD + IMC vs. others 85-87%
Negative vs. others 71-72% Negative + Ind vs. others 75-77% Neg vs. Ind/LGD vs. HGD/IMC 58-61% __________________________________________
Reid BJ et al. Hum Pathol 1988
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Adjunctive TechniquesProliferation Markers
DNA content (aneuploidy)Telomerase
Genetic mutations (p53, p16, Kras, APC,B catenin)
Growth FactorsApoptosis InhibitorsCyclooxygenase 2
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Natural History _____________________________________
Dysplasia (%) n Cancer (%) _____________________________________
None 382 9 (2)Low grade 72 5 (7)High grade 170 37 (22)
_____________________________________ Sampliner. Am J Gastroenterol 2002:97(8);1888-1895
E h t f
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Esophagectomy for High-Grade Dysplasia __________________________________________
Series Unsuspected Carcinoma
__________________________________________ Edwards (1996) 8/11 (73%)
Heimiller (1996) 13/30 (43%)Cameron (1997) 2/19 (10.5%)Ferguson (1997) 8/15 (53%)
Falk (1997) 4/12 (33%)
Total 35/87 (40%)
_________________________________________
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Management Controversial Varies between institutions Dependent on surveillance
techniques
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ACG guidelines for Surveillance in Barretts esophagus:
(Sampliner et al, Am J Gastroenterol 97:1888,2002)
Chronic GERD Symptoms
Screening Endoscopy with Biopsies
Negative for dysplasia Low grade dysplasia High-grade dysplasiax2 endoscopies
Repeat endoscopy with biopsyExpert pathologist opinion
3 year surveillance Repeat x 1Focal Mucosal Multifocal
Annual surveillance irregularityUntil no dysplasia 3 months Intervention
surveillance EMR (surgical)
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Ideal Biopsy Protocol Jumbo forceps 4 quadrant Q2 cm in BE
4 quadrant Q1 cm in dysplasia All nodules/polyps/masses
Confirm with experienced GI pathologist
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Management ConsiderationsSurveillance vs. Esophagectomy
Extent of HGD NodularityPatient age
ComorbiditiesLength of BE
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Barretts Esophagus: New Surveillance Strategies
Balloon cytology
Fluorescence spectroscopy Chromoendoscopy Flow cytometry
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l l f
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Molecular Basis of Barretts Esophagus
Stepwise genetic progressionSpecific factors
aneuploidy17p deletion/p53 mutation
p16cyclin D1
G ti P i
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Genetic Progressionin Barretts Esophagus
Barretts LGD HGD AdenoCa
7p12 amplification/EGFRoverexpression
17q21 amplification/HER2overexpression
19q12 amplification/Cyclin E
overexpressionother amplifications (2p, 8q, 20q)chromosomal deletions (3p, 4p,
7q, 12q, 17q, 22q)
E and P cadherin loss
11q13 amplification/Cyclin D1overexpression
5q21 deletion/APC inactivation9p21 deletion/p16 inactivation13q14 deletion/Rb inactivation
17p13 deletion/p53 mutationp21 overexpressionp27 lossaneuploidy
telomerase overexpression
Non Dysplastic
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Non-DysplasticBarretts Esophagus
Normal BEHigh Risk
BE
Dysplasia
Cancer
11q13 amplification/Cyclin D1overexpression
Bcl2 overexpression5q21 deletion/APC inactivation
9p21 deletion/p16 inactivation13q14 deletion/Rb inactivation17p13 deletion/p53 mutation
aneuploidy
A l id
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Aneuploidy
Normal cells:
diploid (2N)tetraploid (4N; G2 phase)S phase cells
Gains or losses of entire chromosomes
Peaks of abnormal DNA contentAbnormally large tetraploid peaks
Aneuploidy Predicts Progression
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Aneuploidy Predicts Progression
in Barretts EsophagusHistology Ploidy Dysplasia/CancerProgression
Negative diploidaneuploid/4N
2/1101/10
Indefinite diploidaneuploid/4N
1/721/11
LGD diploidaneuploid/4N
0/334/11
Total diploidaneuploid/4N
3/2156/32
Reid et al, Am J Gastroenterol 95:1669;2000
Tumor Suppressor Genes
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Tumor Suppressor Genes
Cellular brakes or checkpoints
OFF signal
Inhibit cell growth
Regulate cell division
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p53 Gene Detection
17p loss of heterozygosity (LOH)p53 gene mutationSSCPsequencing
p53 gene immunostainingmutations stabilize expression
53 G M t ti i
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p53 Gene Mutations inBarretts Esophagus
Frequency:negative 5%indefinite 5%LGD 20%
HGD 60%Mucosa beside positive dysplasia
17p LOH & Progression
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17p LOH & Progression
in Barretts NeoplasiaHistology Alteration Progression Relative Risk
Neg/Indef/LGD 17p intact 16/178 (9%)
17p LOH 5/19 (26%) RR 3.6
HGD 17p intact 5/24 (21%)
17p LOH 18/35 (51%) RR 3.0
Reid et al, Am J Gastroenterol 96:2839;2001
p53 Immunostain & Progression
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p53 Immunostain & Progression
in Barretts NeoplasiaStudy p53
ImmunostainProgression From
Indefinite/LGD
Younes 1997 negative
positive
0/16 (0%)
5/9 (55%)
Bani-Hani 2000 negativepositive
7/41 (17%)4/11 (36%)
Weston 2001 negativepositive
2/25 (8%)3/6 (50%)
p53 Positive Immunostaining
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p53 Positive Immunostaining
p53 Positive Immunostaining
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p53 Positive Immunostaining
p53 Positive Barretts Indefinite
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p53 Positive Barrett s Indefinite
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p16/INK4a/CDKN2A Gene
Regulation of cell cycleG1 phase
Binds Cdk4Competes with Cyclin D1
Inhibits phosphorylation of RbInduces growth arrest
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Detection of p16 Inactivationin Barretts Esophagus
9p21 deletion (LOH)
Promoter CpG island methylationp16 mutationLoss of p16 immunostaining
16 I i i
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p16 Inactivationin Barretts Esophagus
Common early eventLarge non-dysplastic fields>85% of dysplasiasPrecedes aneuploidy/17p LOHNot characterized as risk factor
C li D1 G
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Cyclin D1 Gene
Cyclin/CDK complexesRegulation of cell cycle
G1 phaseCyclin D1/Cdk4,6
Phosphorylation of RbProgression through cell cycle
Cyclin D1 and Progression
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Cyclin D1 and Progressionin Barretts Neoplasia
Bani-Hani JNCI 92:1316;2001Case-control studyCyclin D1 positive immunostain
8/12 adenocarcinoma group14/49 control group
Odds ratio 6.85
M l l S f
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Molecular Summary of Barretts Esophagus
Non-dysplastic genetic changes
Stratify progression in negative,
indefinite, and LGD
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Molecular Summary of Barretts Esophagus
Useful predictive factors:
aneuploidy/4N fraction17p deletion/p53 inactivationCyclin D1 expression
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Dysplasia in IBD
Dysplasia in Crohns ColitisDysplasia in Ulcerative Colitis
General commentsRisk factors
Treatment/surveillance DALMs in Ulcerative Colitis
Non IBD-dysplasia
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Dysplasia in Crohns Disease Risk of Colon Cancer Similar to UC
Involved (SI and colon) anduninvolved areas
Dysplasia-carcinoma sequence Dysplasia morphologically similar
to UC Endoscopic surveillance controversial
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Dysplasia in Crohns DiseaseDysplasia-Carcinoma Sequence
Dysplasia adjacent to Ca in 40-100%
More common close to tumor 2-16% of patients without carcinoma
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Dysplasia in Crohns Disease(Sigel et al, Am J Surg Pathol 23:651,1999)
30 Cases Crohns Adenocarcinoma 27% SI, 73% colon (all involved)
Dysplasia adjacent to Ca: 87% Dysplasia distant to Ca: 41%
(75% in UC)
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Dysplasia in Ulcerative Colitis Unequivocal neoplastic epithelium
Marker of malignancy risk
Present in 90% (close and distant) of carcinomas
Any portion of colon (parallels cancer)- single, multiple, diffuse
Flat or elevated (DALM)
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Risk of Neoplasia in UC1. Dysplasia
5% incidence/10 years 25% incidence/20 years
2. Carcinoma 3-43% incidence 25-35 years- 5-10% incidence/20 years- 10-20% incidence/30 years
1-2%/year after 10 years
D l i /C i Ul i C li i
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Dysplasia/Ca in Ulcerative ColitisRisk Factors
Disease duration (> 10 years) Disease extent Primary sclerosing cholangitis Disease severity Early age of onset? Family history of colon cancer? Folate deficiency?
P i S l i Ch l i i
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Primary Sclerosing CholangitisRisk of Dysplasia
(Marchesa et al, Am J Gastro 1997;92:1285)
27 pts with UC and PSC
1185 pts with UC only all had total proctocolectomy
60% vs 12% dysplasia Rt colon dysplasia/carcinoma
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Dysplasia in UC
Gross Features
Flat Raised (DALM)
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UC-Associated Dysplasia
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UC Associated DysplasiaInterobserver Variability
_______________________________________________
Author # Specimens #Pathologist K value_______________________________________________ Odze (2001) 38 4 0.4Melville (1990) 207 5 0.2-0.5Dixon (1988) 100 6 (pairs) 0.4
_______________________________________________
Risk of Malignancy in UC
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Risk of Malignancy in UCAdjunctive Methods
Histochemical .. mucin, sialosyn TN Impox ... proliferation Molecular defects . P53, Rb, APC, MI,
CIN, P27,P16,
aneuploidy Laser fluorescence dysplasia
Flat Dysplasia
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Natural History(Bernstein et al, Lancet 1994;343:71)
1. Low grade- Co-existant carcinoma: 9%
- Progression to HGD/CA: 30-54%(5 year predictive value )
2. High grade- Co-existent carcinoma: 40-67%- Progression to CA: 40-90%
(2-5 year predictive value)
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ManagementDysplasia
Low grade High grade
Unifocal Multifocal Synchronous
Surveillance Colectomy Colectomy? Colectomy
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Colectomy for Low Grade Dysplasia_______________________________________________
Author Data_______________________________________________ Connell 1994 LGD to HGD (54%, 5 years)
Taylor 1992 LGD in CA colectomy (34%)Bernstein 1994 CA in LGD colectomy (19%)Woolrich 1992 LGD to CA (18%, 6 years)_______________________________________________
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DALM1. Adenoma-like- Sporadic (Adenoma)
- IBD-associated(Polypoid dysplasia)
2 . Non Adenoma-like
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DALM Adenoma Like
Sessile/Pedunculatedwell circumscribedsmooth surfacevisible bordersnon-ulceratedno stricture or mucosaltethering
Non Adenoma-LikeUsually sessilePoorly circumscribedIrregular surfaceindistinct border ulceration/necrosis+stricture/tethering
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Summary of DALM Studies_______________________________________________
Author #Patients % DALM % DALMwith cancer
_______________________________________________
Blackstone (1981) 112 11% 58%Butt (1983) 62 29% 83%Rosenstock (1985) 248 5% 38%
Len-Jones (1990) 401 1.5% 83%Bernstein (1994) 1225 3.2% 43%(10 studies)
_______________________________________________
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Adenoma vs Polypoid Dysplasia
1. Morphology
2. Immunohistochemistry3. Molecular defects
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Polypoid Dysplasia and
Adenomas in InflammatoryBowl DiseaseTorres, Antonioli, Odze
Am J Surg Pathol 1998;22(3):275-284
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Adenoma vs Polypoid DysplasiaValue of Impox
Adenoma: catenin, Bcl-2
Polypoid Dysplasia: P53 Non sensitive and non-specific
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IBD vs Sporadic Neoplasia_______________________________________________ IBD Sporadic
GENE Neoplasia Neoplasia ________________________________________________________ Kras early, frequent early, frequentP53 (17P) early, (44%) late (20%)
LOH 17P early, (85%) Late (20-30%)LOH 9P (P16) early, (50%) RareLOH 3P (50%) early, (50%) Rare, lateAPC (5q) late (6%) early (75%)P27 early, (90%) late (30%)
________________________________________________________
Genetic Alterations in
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Chronic ulcerative colitis-
associated adenoma likeDALMS are similar to
non-colitic sporadic
adenomas
Odze et al, am J Surg Pathol 2000;24(9
Adenoma-like DALMS in UlcerativeColitis
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___________________________________________________________ __ CUC Adenoma CUC
-like DALM non-adenoma
Molecular Non-CUC within outside like DALMMarker Adenoma Colitis Colitis (LOH)
n = 23 n = 10 n = 11 n= 12
___________________________________________________________ __
3P 5% 30% 25% 50%* 1
APC 33% 29% 38% 43%
P16 4% 0% 10% 56%*2
___________________________________________________________ __ *1P=0.01 * 2P = 0.003
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Is it possible to reliablydifferentiate adenoma from
polypoid dysplasia by
morphology, impox, or molecular methods?
No.
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Polypectomy may be adequatetreatment for adenoma-likedysplastic lesions in chronic
ulcerative colitisEngelsqjerd, Farraye, Odze
(Gastroenterology 1999;117:1288-1294)
______ Feature CUC patients Non-CUC
Adenoma-like AdenomaAdenoma
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AdenomaDALM
__________________________________________________________________ ______
# patients 24 1049
Follow-up (mths) 42 4137
Flat dysplasia 1 (4%) 0 (0%)
NA New polyps 58% 50%
39%Adenocarcinoma 0% 0%
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Rubin et al________________________________________
No further polyps 25 (52%)Polyps in same vicinity 13 (27%)
Polyps in different location 10 (21%)Dysplasia/CA in flat mucosa 0 (0%)________________________________________
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ConclusionIf it looks like an
adenomaIt probably is!
DALM
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Adenoma-like Non-Adenoma-like(broad-base, irregular)
Outside colitis Inside colitis
Polypectomy Polypectomy Colectomy
Regular surveillance Confirm absenceof flat dysplasia? Increase
surveillance
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Molecular Basis of
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Colitis-Associated NeoplasiaStepwise genetic progressionSporadic vs colitis-associated
Specific factorsaneuploidy
17p deletion/p53 mutationp16
Genomic instability pathways
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Normal Negative/Indefinite High RiskDysplasia/
Cancer
aneuploidy17p13 deletion/p53 mutation
9p21 deletion/p16 inactivationchromosomal instability
Genetic Progression inColitis-Associated Neoplasia
Colitis-Associated
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Versus Sporadic NeoplasiaAneuploidy pre-invasionp53 mutation pre-invasion
Chromosome 3p deletionLoss of p27 expression
Less bcl-2 expression
Less beta-catenin staining
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Aneuploidy Associations in
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Colitis-Associated Neoplasia
Associated with:durationextentseveritydysplasiaother genetic alterations
neuploidy Predicts Progressionin Colitis-Associated Neoplasia
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p
Histology Ploidy Dysplasia/Cancer
ProgressionNegative diploid 0/15
aneuploid 1/1
Indefinite diploid 1/5
aneuploid 4/4
Rubin et al, Gastroenterology 103:1611;1992
neuploidy Predicts Progressionin Non-Dysplastic Colitis
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Study Ploidy Dysplasia/Cancer
ProgressionLindberg 1999 diploid 0/127
aneuploid 4/10
Holzman 2001 diploid 1/39
aneuploid 5/10
17p LOH in
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Colitis-Associated Neoplasia __________________________________________ ______
LesionFrequency
__________________________________________ ______
Carcinoma 22/26(85%)
HGD 25/4063%
p53 inNegative/
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IndefiniteMucosa
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Other Markers in
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Colitis-Associated Neoplasia
Proliferation index (Ki67)Cyclin A
E-cadherinSialosyl-Tn antigen
MetallothioneinFurther studies needed to validate
Chromosomal Instability by FISH
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ArmDeletion
ArmAmplification
ChromosomeGain
ChromosomeLoss
Centromere probeChromosome arm probe Normal
Chromosomal Instability (CIN)
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in Colitis-Associated Neoplasia
Dual color FISH chromosomes 8, 11, 17, 18Histologically negative rectal biopsiesCIN present in:
10% non-IBD control cells22% negative colitis cells (dysplasia orcancer elsewhere)
P
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Colitis-Associated Neoplasia
Cap on ends of chromosomesMaintain genome stability
Loss associated with senescenceAccelerated shortening with:
rapid cell turnoveroxidative injury
Telomere Erosion in
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Colitis-Associated Neoplasia
OSullivan et al, Nature Genetics 2002Determined telomere length innon-dysplastic mucosa by FISH
Patients with and without HGD/cancer
Telomere erosion associated with:chromosomal instabilityprogression to HGD/cancer)
Fecal DNA Mutation Testing
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Cells shed into lumen
Target DNA by hybridcapture
Test specific mutationpanel
Krasp53APC
DNA integrity
Fecal DNA Mutation Testing
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High sensitivity/specificity inCRC
Adenoma validation ongoing
Testing required on colitis
Development of cost-effective kit
Molecular Summary of
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Useful predictive factors:
Aneuploidy17p deletion/p53 inactivation
Chromosomal instabilityTelomere erosion
Colitis-Associated Neoplasia
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Squamous Dysplasia
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Esophageal squamous dysplasia General comments Clinical features Pathologic features Differential diagnosis Natural history, treatment
Squamous dysplasia
l l f
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clinical features Similar risk factors as squamous cell
carcinoma (tobacco, alcohol, nutritionalfactors, hot beverages, chronic esophagitis,?HPV)
More common in high incidence areas of squamous cell carcinoma
Dysplasia frequently (up to 60%) adjacentto invasive carcinoma
Esophageal squamous dysplasia
l f
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ClassificationCurrent/WHO
Negative
Low grade
High grade
Previous
Negative
Mild Moderate
Severe Carcinoma in situ
h l f
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Pathologic features Gross: erythematous, irregular, friable;
erosions, plaques, nodules; may be normal Location: mid-distal esophagus (similar to
SCC) Lugols iodine
Baloon cytology in high risk areas
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Squamous dysplasia- differential
di i
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diagnosis Reactive squamous epithelium Giant cell esophagitis Chemoradiotherapy effect Invasive squamous cell carcinoma
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Squamous dysplasia
Natural history
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Natural history
60-708 yrs30%High grade
2-168-15 yrs15%Low grade
RR of
carcinoma
IntervalProgressDiagnosis
Increased risk for developing carcinomaMust exclude adjacent carcinoma
Squamous dysplasia- treatment
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DYSPLASIA
FLAT
HIGHGRADE
ELEVATED
RESECTION
PROBABLECARCINOMA
FOLLOW
LOWGRADE
REBIOPSY
Molecular Basis of Squamous
Dysplasia of Esophagus
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Dysplasia of Esophagus
Stepwise genetic progression
Specific factorsp53 mutation
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P53 immunostain
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Normal Dysplasia
p53 Immunostaining in
Esophageal Squamous Neoplasia
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Fagundes Dis Esophagus 2001Esophageal Squamous Neoplasia
2/2 (100%)HGD
4/11 (36%)LGD1/3 (33%)Severe esophagitis
4/18 (22%)Moderate esophagitis6/43 (14%)Mild esophagitis
12/103 (12%) Normal p53 positivityCondition
Molecular Summary of
Esophageal Squamous Neoplasia
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Esophageal Squamous NeoplasiaPredictive markers possible
p53 immunostaining
Many further studies required
(New Technologies)
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Small Intestinal Metaplasia andDysplasia
Small intestine
metaplasia and heterotopia
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metaplasia and heterotopia Gastric mucous cell metaplasia Pyloric gland metaplasia Gastric heterotopia
Pancreatic heterotopia
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Pyloric gland metaplasia
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Marker of chronic mucosal injury in small
intestine (e.g. Crohns disease) Up to 22% of Crohns patients
Most common in ileum Usually incidental finding
May form visible mucosal nodule
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Small intestinal dysplasia
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Crohns disease-associated dysplasia
Sporadic adenomas Polyposis-associated dysplasia
FAP Peutz-Jeghers syndrome
Other polyposis syndromes
Crohns disease-associated
dysplasia
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dysplasia 5% lifetime risk of carcinoma
median disease duration 15 years Most (70%) are in colon, rectum
20-100X risk of small intestinaladenocarcinoma
Dysplasia-carcinoma sequence appearssimilar to colon
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Gastric Metaplasia and Dysplasia
Intestinal-type gastric carcinoma-
a multistep process
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Normal Chronic (active) gastritis
Chronic atrophic gastritis
Intestinal metaplasia
Dysplasia
Carcinoma
Gastric carcinoma- risk factors
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H. pylori gastritis
Autoimmne gastritis/pernicious anemia Post-gastrectomy
Gastric polyps Diet, environmental factors
(Cardia tumors: ?reflux)
Types of gastric epithelial
metaplasia
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p Intestinal
Pseudopyloric
Ciliated
(Pancreatic: actually a heterotopia?)
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Gastric dysplasia- issues
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Different grading systems
Regeneration vs true dysplasia
Significance of mild dysplasia
High grade dysplasia vs adenocarcinoma
Gastric dysplasia
Padova classification Negative for dysplasial
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Normal Reactive foveolar hyperplasia Intestinal metaplasia (IM)
Indefinite for dysplasia Foveolar hyperproliferation
Hyperproliferative IM
Non-invasive neoplasia low-grade dysplasia
high grade dysplasia
Suspicious for invasive carcinoma Invasive carcinoma
Gastric dysplasia
Japanese classificationCATEGORY DEFINITION HISTOLOGIC EQUIVALENT
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CATEGORY DEFINITION HISTOLOGIC EQUIVALENT
Group I Normal/no atypiaNormal, regenerative,hyperplastic, intestinal metaplasia
Group IIAtypia butdiagnosedas benign
Regenerative with atypia (us.Architectural) due toinflammation
Group III Borderline betweenbenign & malignantDysplasia (flat and adenoma)?low grade ?high grade
Group IV Strongly suspectedof carcinoma High grade dysplasia?
Group V Carcinoma Invasive carcinoma.High grade dysplasia?
Adapted from Rugge M AJSP 24:167 (2000)
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Gastric dysplasia-differential
diagnosisR i i h li dj l
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Reactive epithelium adjacent to ulcer
Reactive (chemical) gastropathy Treatment effect
Invasive carcinoma
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Gastric dysplasia- natural historyN Median
timeProgress
t CAPersistRegressStarting
D
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3
16
90
9
3033%67%0%Suspicious
3069%25%6%High grade
489%38%53%Low grade
---0%11%89%Indefinite
time(mos)
to CADx
Rugge et al Gut 52:1111 (2003)
Gastric Dysplasia
ManagementLOW GRADE HIGH GRADE
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LOW GRADE
SURVEILLANCE
MASSNO MASS
HIGH GRADE
REBIOPSY,CONSIDER RESECTION
REBIOPSY,CLOSE
FOLLOWUP
Gastric polypsNon-neoplastic Dysplasia?
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Hyperplastic rare Fundic gland polyp Sporadic -
FAP-associated + Other polyposis rare
(juvenile, Cowdens)Neoplastic Adenoma ++
Gastric hyperplastic polyps
Most common gastric polyp
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Most common gastric polyp
Prevalence 0.1% More common a/w gastritis
Gross: antrum>fundus, cardia; avergae 1.0cm
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Dysplasia in hyperplastic polyps
Intestinal metaplasia in 15-25%
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Intestinal metaplasia in 15 25%
Dysplasia in 2-19% Carcinoma in 0-17% (average 2%)
Dysplasia more common in larger (>2 cm) pedunculated polyps with intestinalizedepithelium
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Fundic gland polyps
Clinical features Hamartomatous polypS di 0 1 1% l F M iddl
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Sporadic: 0.1-1% prevalence, F>M, middleaged, 40% multiple
Association with PPI therapy
FAP: present in 50-100% of patients, >90%multiple
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Dysplasia in fundic gland polyps
Sporadic:
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Sporadic: 1%
FAP: 25%
Usually low grade Relationship to gastric carcinoma?
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Molecular Basis of
Gastric Dysplasia
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Stepwise genetic progressionSpecific factors
p53MLH1
APCFundic gland polyps
Genetic Progression
in Gastric NeoplasiaC-met/HGF amplification/
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Normal Metaplasia Dysplasia AdenoCa
poverexpression
9p21 deletion/p16 inactivation19q12 amplification/Cyclin E
overexpression18q deletion16q22 deletion/E-cadherin losschromosomal deletions (1p, 1q,
7q, 13q)
5q21 deletion/APC inactivation17p13 deletion/p53 mutationMLH1 methylation
p53 Alterations in Gastric
Metaplasia and Dysplasia
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Shiao Am J Pathol 199412 resectionsp53 immunostaining/mutationsmetaplasia 38%dysplasia 58%carcinoma 67%
i h i d f
Microsatellite Instability in
Gastric Adenocarcinoma
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Mismatch repair gene defectMicrosatellite instabilityPresent in 15-25% gastric CaRarely germline (HNPCC)Most caused by:
MLH1 methylationLoss of MLH1 expression
M L H 1
M S H 2 MS H 3
DNA mismatch
mismatch binding
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PM S 1
Modified from Fishel et alCancer Research 61:7369;2001
M S H 2 M
S H 3
M L H 1 P M S 1
M S H 2 M
S H 3
conformation change
recruit partners
Immunohistochemistry 6 X 6 micron
R i d k lid
Analysis of DNA MismatchRepair From Tumours
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B r i gh am
an d
W om en s
TN
H&E X1
Unstained 10 X 10 micron
Review and mark slide
for dissection
Overlay on H&E and scrape tissue from unstained
Extract DNA for MSI testing
B r i gh am
an d
W om en s
Mismatch Repair Gene Immunohistochemistry
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MLH1
MLH1
MSH2
MSH2
Microsatellite Instability in
Gastric Metaplasia/Dysplasia
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Leung Am J Pathol 2000
MSI in 7/75 (9%) intestinalmetaplasia
Associated with MSI cancers
MLH1 Methylation inGastric Metaplasia/Dysplasia
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Kang Canc Res 2001
MLH1 methylation in:chronic gastritis 0%intestinal metaplasia 6%
adenoma 10%carcinoma 20%
Kang Canc Res 2001
CpG Island Methylation inGastric Metaplasia/Dysplasia
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Kang Canc Res 2001
p16, THBS1, TIMP3
CpG island methylation in:chronic gastritis 0-15%intestinal metaplasia 2-36%adenoma 11-27%carcinoma 42-57%
Occur in two settings
Fundic Gland Polyps
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g
Familial Adenomatous Polyposis
Occasionally have epithelial dysplasia
SporadicRarely have dysplasia
AX
WNT
Frizzled
Dvl
APC in
WNTSignaling
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X
IN
APC-catenin
-catenin
-catenin
GSK3 P
C-Mycand othersLEF1
Genetic Predictors of Dysplasiain Fundic Gland Polyps
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APC mutation associated with dysplasiaFAP-associated FGPsrare sporadic FGPs
Beta-catenin mutation not dysplastic
most sporadic FGPs
Molecular Summary of Gastric Dysplasia
Predictive markers possible
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pPromising markers:
p53 immunostaining
MLH1/other gene methylation