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Biopsy Approach to Barrett’s EsophagusBarrett’s Esophagus
Robert D. Odze, MD, FRCPCChief, Division of GI Pathology
Professor of PathologyBrigham and Women’s Hospital
Harvard Medical SchoolBoston, MA
Barrett’s EsophagusLecture Outline
1. Definition/Diagnosis (BE vs. Carditis)
2. Dysplasia - Pathology/diagnostic difficulties
- Unusual variants
- Adjunctive tests
3. Natural History
4. Management
5. Future biomarkers
Rising Incidence of Esophageal Adenocarcinoma
Relative change in Relative change in incidence of EAincidence of EAMelanomaMelanomaProstateProstateLungLungBreastBreastColorectalColorectal
Pohl and Welch, JNCI 2005; 97: 142-46
ColorectalColorectal
Dysplasia and Cancer in Barrett’s(Multicenter Cohort)
N=1376
Diagnosis Adenocarcinoma
Prevalent Incident* Incidence(per year)(per year)
N 1376 618 -LGD detection 7.3% 16.1% 4.3%
HGD detection 3% 3.5% 0.9%
AdenoCa detection 6.6% 1.9% 0.5%
*1 618 with ≥ 1 year follow-up Sharma et al, Clin Gastroenterol Hepat 2006;4:566-72
Definition of Barrett’sNorth American (ACG)
• Endoscopically recognizable columnar mucosa in esophaguscolumnar mucosa in esophagus
• Goblet cells identified on biopsy
Normal GEJ
Photo by J. Bergman
Diagnosis• Columnar mucosa, mixed mucous/
oxyntic type
• Squamous mucosa with reactive
changeschanges
• No goblet cell identified
• No dysplasia
Is this Barrett’s?
Management?
Barrett’s Definition
• North America– endoscopy +– goblet cell +
• UK• UK– endoscopy +– columnar epithelium +
• Japan– endoscopy +– lower limit of palisade vessels– columnar epithelium +
Problems with North American Def’n of Barrett’s
• IM not defined by goblet cells
• Sampling error• Sampling error
• Non-goblet epithelium at risk for neoplasia
• Barrett’s esophagus without goblets
• Barrett’s Esophagus vs. Gastric Carditis with IM
Non-Goblet Epithelium in Barrett’s Esophagus is “Intestinalized”
Marker Goblet-CellDeficient
N=72
Goblet-CellPoorN=96
Goblet-CellRichN=112
CDX-2 6% 42% 100%*
DAS-1 39% 29% 96%*
MUC-2 11% 33% 75%*
MUC-1 11% 17% 18%
Ki-67 33% 29% 46%
*p<0.001 Hahn et al, Am J Surg Pathol 2009;33(7):1006-15
Detection of IM in BE:Need for a Minimum of 8 Biopsies
Harrison et al. Am J Gastroenterol 2007;102:1154-1161
N=125
# of biopsies % of cases with IM
1-4 35%
5-8 68%
9-12 74%
13-16 71%
>16 100%
Cardiac Rather than Intestinal-type Background in Endoscopic Resection Specimens of Minute Barrett
AdenocarcinomaTakubo et al, Hum Pathol 2008; In Press
Cancer Type of Epithelium
(< 2 cm in size) Cardiac/Fundic Intestinal(Goblet)
Cardia -Intestinal(Goblet) Intestinal
<3 cm from GEJ (N=43)
79% 16% 5%
≥ 3 cm from GEJ (N=69)
71% 20% 9%
Total (N=141) 71% 22% 7%
Barrett’s Oesophagus: Intestinal Metaplasia is Not Essential for Cancer Risk
Kelty et al, Scan J Gastroenterol 2007;42:1271-1274*
Feature Background Epithelium
Int Met No Int MetInt Met No Int Met
# Patients (N=712) 379(55%) 309(45%)
Adenocarcinoma 17(4.5%) 11(3.6%)
*12 year follow up
Endoscopically “Visible” Columnar Metaplasia
Ultrashort segment (<1 cm)
Terminology Management (Surveillance) Risk of Malignancy
Current Proposed Current Proposed
No goblets ? BE non-goblet type
or Columnar met of esoph
or Columnar-lined esoph
None None
-need more research
Controversial
Evidence says yes
Goblets (few) BE BE, goblet-cell poor
3 years ?>3 years Yes, unknown degree
Goblets (many) BE BE, goblet-cell rich
3 years 3 years Yes, unknown degree
Short (Ultrashort) BE vs. Chronic Carditis
• Distinction important• Distinction important
• Different clinical, etiologic, pathologic, outcome, risk of malignancy
Irregular Z-Line with Intestinal Metaplasia
Esophageal Metaplasia vs Gastric CarditisPathologic Features
Feature Metaplasia Carditis
Squamous re-epithelialization + -Hybrid glands + -Esophageal glands/ducts + -Esophageal glands/ducts + -Multilayered epithelium + -Marked atrophy/disarray + -Diffuse incomplete IM + +/-Esophagitis ++ +/-Distal Gastritis +/- ++Eosinophils ++ +/-Neutrophils/lymphocytes/plasma +/- ++H.Pylori +/- ++
Fig 3. Squamous mucosa over intestinalized crypts in BE
Fig 1. BE with crypt disarray, atrophy and diffuse IM
Fig 5. Hybrid glands (arrows) were seen exclusively in BE
Fig 7. Esophageal duct (arrow) in BE
Multilayered Epithelium and GERDProspective
Feature BE GERD Control
N=27 N=12 N=14
Multilayered 33% 33% 0%
Associated Epithelium
-Goblet cells 56% 0% N/A
-Non-goblet 44% 100% N/A
Length of columnar distal to SCJ
N/A 1.4 1.1
Glickman et al, Am J Surg Pathol 2009;33(6):818-825
BE vs Carditis with IMProposed Markers
CK 7/20 CDX-2
HID HepHID Hep
Alcian/blue CD-10
MUC 1-6 DAS-1
Villin Other
Dysplasia in Barrett’s Esophagus
Unequivocal neoplasia confined Unequivocal neoplasia confined to basement membrane
Neoplasia without Dysplasia*
Esoph - Barrett’s
- Squamous dysplasia
Stomach “Atypical Int Met”Stomach “Atypical Int Met”
“Pit dysplasia”
Pyloric gland “adenoma”
Tubule neck “dysplasia”
Colon - IBD dysplasia
- Hyperplastic/serrated polyps
*Odze et al, Arch Pathol Lab Med 2009 (In Press)
Normal Colon Barrett’s Esophagus
Esophagitis MetaplasiaDysplasiaLG HG
Carcinoma
Enviro
nm
enta
lChanges
Bile acids and pH changesCell interactions
(cadherins, catenins)
MMPs and angiogenesis
Gastrin and other growth factors
Cell cycle and apoptosis changes
Inflammatory response/infiltrate
Modified from: Atherfold PA, Jankowski JA. Molecular Biology of Barrett’s Cancer. Best Pract Res Clin Gastroenterol 2006;20:813-27.
Genetic
Changes
CDx mutations
p53 mutations
Aneuploidy
APC LOH
p16, cyclin D1,p53 mutations
Multiple aneuploidy
Barrett's Metaplasia is a Neoplasm
• Hyperproliferative– Gulizia et al. Hum Pathol 1999; 30:412–8– Gray et al. Gastroenterology 1992;
103:1769–76
• Clonal• Clonal– Maley et al. Cancer Research 2004; 64:3414–27
• Progressive: 0.2–2% per year – Sharma et al. Clin Gastroent Hepatol 2003;
4:566–72
• Does not regress without intervention• Both metaplastic and neoplastic
Vienna System and Dysplasia Morphology Study GroupClassification of Dysplasia in GI Tract
_______________________________________________________________________
Vienna DMSG_________________________________________________________________
1. Negative for neoplasia/dysplasia Negative for dysplasia2. Indefinite for neoplasia/dysplasia Indefinite for dysplasia3. Non-invasive low-grade neoplasia Low-grade dysplasia
(low-grade adenoma/dysplasia)(low-grade adenoma/dysplasia)4. Non-invasive high-grade neoplasia High-grade dysplasia
4.1 High-grade adenoma/dysplasia4.2 Non-invasive carcinoma
(carcinoma in situ)4.3 Suspicious of invasive carcinoma
5. Invasive Neoplasia Adenocarcinoma*5.1 Intramucosal Adenocarcinoma Intramucosal5.2 Submucosal carcinoma or beyond Invasive
__________________________________________________________________*not described by DMSG
Gastric Epith Barrett Eso ph Basal Crypt Dysplasia
Low -grade Dysplasia High -grade Dysplasia Intra -mucosal CALow -grade Dysplasia High -grade Dysplasia Intra -mucosal CA
Poor Agreement in the Diagnosis of Barrett’s Dysplasia in Community
Practice
Poor Agreement in the Diagnosis of Barrett’s Dysplasia in Community
Practice
Gastric metaplasiaGastric metaplasiaIM without dysplasiaIM without dysplasiaLow-grade dysplasiaLow-grade dysplasiaHigh-grade dysplasiaHigh-grade dysplasia
100100
8080
6060
Alikhan M, et al. Gastrointest Endosc 1999; 50:23Alikhan M, et al. Gastrointest Endosc 1999; 50:23
6060
4040
2020
00
%Agreement
%Agreement
Pathologists’ ReadingPathologists’ Reading
DysplasiaFactors Affecting Fate (and detection)
Endoscopic Recognition • Incident vs. Prevalent dysplasia• Visible vs. invisible• Number of biopsies• Frequency of surveillance endoscopy• Interfering factors (strictures, polyps)• Interfering factors (strictures, polyps)• Focality of dysplasia• Recurrence of dysplasia
Pathologic Interpretation• Correct interpretation (inter-observer variation)• Unusual (non-conventional) morphologic variants• Growth pattern (flat vs. elevated)• Extent
Pathologic InterpretationInterobserver Variability
Regeneration vs. DysplasiaRegeneration vs. Dysplasia
High grade vs. Carcinoma
Low Grade vs. High Grade
How much high grade dysplasia is needed to classify a biopsy as classify a biopsy as
“high grade”?
Extent of DysplasiaOutcome
Buttar et al, Gastroenterol 2001;120:1630-1639*
Feature Cancer Free Survival
N 1 year 3 years RRN 1 year 3 years RR
Diffuse HGD 67 62% 44% 3.7
Focal HGD 33 93% 86% 1.0
*retrospective Focal = ≤ 5 crypts Diffuse >5 crypts or >1 biopsy
Extent of DysplasiaOutcome
Dar et al, Gut 2003;52:486-489*
Feature N Carcinoma at resection
Buttar criteria
Diffuse HGD 21 67% 54%
Focal HGD 21 48% 72%
*retrospective Focal = HGD in 1 level Diffuse = HGD > 1 level
Extent of Dysplasia and Cancer Risk
80
100
120
0
20
40
60
80
Total Low Grade High Grade
Progressors
Non-Progressors
#
Dys Crypts/
Patient
Srivastava et al, Am J Gastroenterol 2007;102(3):483-93
Pathologic InterpretationUnusual (Non-conventional) Variants
Dysplasia with Surface Maturation Dysplasia with Surface Maturation
Non-Adenomatous
Foveolar
Serrated
Other
Basal Crypt Dysplasia
Basal Crypt Dysplasia
Crypt Dysplasia With Surface Maturation. A Clinical, Pathologic and Molecular Study of a Barrett’s Cohort
___________________________________________________________________
Feature Basal Crypt Barrett’s pDysplasia ControlsN=15 N=191
___________________________________________________________________
Associated full-crypt 47% 12% 0.002Associated full-crypt 47% 12% 0.002Dysplasia
Mib-1 Proliferation*1 0.46 0.27 <0.0001
P53 Positivity 60% 13% <0.02
Molecular Abnormality*2 80% 52% 0.05___________________________________________________________________*1 Similar to full crypt dysplasia Lomo et al, Am J Surg Pathol 2006;30(4):423-435*2 9pLOH, 17pLOH, ↑ 4N, Aneuploidy
Gastric Barrett’s Crypt Low Grade High GradeDysplasia Dysplasia Dysplasia
S
DNA Content in Barrett’s NeoplasiaSuperficial vs. Basal Crypts
S
B
Aneuploidy 0% 39% 50% 67% 100%Zhan et al, Lab Invst 2007;87(s1):133A
Non-Adenomatous DysplasiaDysplasia
Non-Adenomatous Dysplasia in Barrett’s
Flow Abnormality
Tetraploidy or Aneuploidy
Tetraploidy and Aneuploidy
Tetraploidy and/or Aneuploidy
Patient Group N (1 Abnormality) (2 Abnormalities) (1, 2, or Both Abnormalities)Patient Group N (1 Abnormality) (2 Abnormalities) (1, 2, or Both Abnormalities)
Non-adenomatous dysplasia 13 23% 15% 38%
Adenomatous dysplasia 17 24% 12% 35%
Low-grade 9 33% 11% 44%
High-grade 8 13% 13% 25%
Rucker-Schmidt et al. Am J Surg Pathol 2009;33(6):886-93
Non-Adenomatous Dysplasia in Barrett’s
Maximum diagnosis upon Follow-up
Dysplasia Grade
Patient Group N Metaplasia/Indefinite (%) Low (%) High (%) EA (%)
Nonadenomatous dysplasia
18 6% 0% 78% 17%
Adenomatous dysplasia
24 - 25% 54% 21%
Low-grade 13 - 46% 31% 23%
High-grade 11 - - 82% 18%
Rucker-Schmidt et al. Am J Surg Pathol 2009;33(6):886-93
Adjunctive Diagnostic TechniquesProliferation Markers
DNA content (aneuploidy)
TelomeraseTelomerase
Genetic mutations (p53, p16, Kras, APC, B catenin)
Growth Factors
Apoptosis Inhibitors
Cyclooxygenase 2
AMACR Immunostaining is Useful in Detecting Dysplastic Epithelium in BE, UC and CD__________________________________________
Dysplasia BE Sensitivity Specificity__________________________________________
Negative 0% - -Indefinite 21% - -Low Grade 38% 38% 100%High Grade 81% 81% 100%AdenoCa 72% 72% 100%__________________________________________
Dorer et al, Am J Surg Pathol 2006;30:871-877
A B C
Figure 1. AMACR expression in Barrett’s esophagus wi thout dysplasia (regeneration) (A), with high-grade dysplasia (B), and invasive adenoca rcinoma (C).
AMACR in Barrett’s
Pathology N AMACR
BE* 39 0%
LGD 19 11%
HGD 22 64%
Adeno 12 75%Lisovsky et al, Hum Pathol 2006;37:1601-6*Including “reactive atypia”
p53
Squamous
No dysplasia
Dysplasia
Natural History
of of
Barrett’s Dysplasia
Low-Grade Dysplasia Outcome
Study N Years Follow-up
Incident Cancer
Reid (2000) 43 3.9 3 (7%)
Schnell (2001) 738 7.3 10 (1.3%)
Weston (2001) 48 3.4 1 (1.0%)
Murray (2003) 171 3.7 7 (4.0%)
Dulai (2005) 134 3.2 1 (0.7%)
Sharma (2006) 156 5.0 5 (3.2%)
Vieth (2007) 67 2.3 23 (34%)
Wani et al Clin Gastroenterol and Hepat 2009;7:27-32
Progression of Low-Grade Dysplasia to Carcinoma
__________________________________________________________________________Author # Cases # Pathologists Progression
Agree to HGD1 or Cancer2
____________________________________________________________________________________________________________
Odze (2006) 77 3 31.8%2
Skacel (2000) 25 2 41.0%1,2
3 80.0%1,2
Montgomery (2001) 15 Majority 47.0%1,2
(>6/12)________________________________________________________________________
Odze et al. Am J Gastro 2007;102(3):483-493Skacel et al. Am J Gastro 2000; 95 (12) 3383-3387Montgomery et al. Hum Pathol 2001; 32; 379-398
High-Grade DysplasiaOutcome
Study N Years Follow-up
Incident Cancer
Weston (2000) 15 3 4 (27%)
Reid (2000) 76 4 42 (55%)
Schnell (2001) 75 7.3 12 (16%)
Overholt (2005) 70 1.5 20 (28%)Wani et al, Clin Gastroetnerol and Hepat 2009;7:27-32
Management• Controversial
• Varies between institutions• Varies between institutions• Dependent on surveillance techniques
ACG guidelines for Surveillance in Barrett’s esophagus: (Wang et al, Am J Gastroenterol 108(3):788-797, 2008)
Chronic GERD Symptoms
Screening Endoscopy with Biopsies
Negative for dysplasia Low grade dysplasia High-grade dysplasiax2 endoscopiesx2 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)
Low-Grade DysplasiaManagement
• Confirm with experienced GI Pathologist
• Determine extent of dysplasia
• Consider advanced endoscopy• Consider advanced endoscopy- high resolution, narrow band imaging
confocal endomicroscopy
• Consider other biomarkers - aneuploidy, P16, P53
Low-Grade DysplasiaTreatment Options
• PPI/NSAIDS: ? effect• PPI/NSAIDS: ? effect
• Surveillance: 6 mth-1 year
• Ablation (RFA, Cryo)
High Grade DysplasiaTreatment Options
1. Aggressive surveillance
2. Endoscopic ablation- Radiofrequency ablation- Radiofrequency ablation- Photodynamic therapy- Laser photoablation
3. Endoscopic mucosal resection
4. Esophagectomy
Ablation* in Barrett’sMetanalysis
Diagnosis AdenocarcinomaIncidence/1,000 pt years
No Ablation AblationNo AblationN=6,847
AblationN=1,457
BE 6.0 1.6
LGD 17.0 1.6
HGD 66.0 16.8Wani et al. Am J Gastroenterol 2009;104:502-13*APC, Laser, PDT, RFA
Radiofrequency Ablation in Barrett’s with Dysplasia
N=127
Patient Group Ablation Control(Sham)
BE 77% 2.3%
LGD 91% 23%
HGD 81% 19%
Disease Progression 3.6% 16%
Cancer outcome 1.2% 9.3%
Shaheen et al, N Engl J Med 2009;360:2277-88
Endoscopic Mucosal Resection(EMR)
• Removes mucosa/superficialsubmuocsa
• Increases diagnostic accuracy• Increases diagnostic accuracy- Grading of dysplasia
- Depth of invasion
- Lymphovascular invasion
• Therapy for dysplasia/superficial carcinoma
Endoscopic Mucosal ResectionRole of Pathologist
• Dysplasia grade
• Depth of invasion• Depth of invasion
• LVI
• Margins (37-50% recurrence
if positive)
Biomarkers in BE__________________________________________________# Studies
Biomarkers Phase of trial Comment1 or 2 3 4
__________________________________________________Dysplasia grade multiple - - Poor reproductivityNeg/Indef/LGD - - 5 Poor Ca predictorHGD - 1 3 Inconsistent resultsDNA content Multiple - 3 Strong Ca predictorP53 mutation Multiple - - ?P53 immuno Multiple 4 - High false neg/posP16 multiple - - ?Proliferation multiple - 1 Not indep. predictorCyclin D multiple 1 - Strong Ca predictor__________________________________________________________
Dysplasia gradeDysplasia gradeSeattle CriteriaSeattle Criteria
4 Biopsies per 1-2 cm plusTargeted Biopsies
Pro
babi
lity
of C
ance
r
Pro
babi
lity
of C
ance
r
All 3 biomarkers abnormal2 biomarkers abnormal1 biomarker abnormalno abnormalities
p16, p53, ploidy Biomarker Panel Progression to EA
Biomarker panel Biomarker panel ((99pLOH, pLOH, 1717pLOH, abnormal ploidy)pLOH, abnormal ploidy)
43%
21%
<HGD
Time (months)
Pro
babi
lity
of C
ance
r
HGD
Time (months)
Pro
babi
lity
of C
ance
r
1 Biopsy per 2 cm
Summary
1. Diagnosis of BE controversial2. Short segment BE distinguished from carditis in
20-30% cases20-30% cases3. Recognition and grading of dysplasia has many
limitations4. Extent of dysplasia important prognostically5. Natural history and treatment of dysplasia
evolving: esophagectomy ablation