1. Pathological Diagnosis of Barrett’s Esophagus
MEE-YON CHO, M.D.,PD.
Department of Pathology
Wonju College of Medicine,
Yonsei University

2. History of BE
Norman Barrett : congenital origin and a part of stomach (1950)
Allison and Johnstone (1953) : esophagus lined with gastric mucous membrane
Moersch : inflammtory metaplasia (1959)
Bremner : association between columnar-lined esophagus and GERD (1970)
Intestinal metaplasia is a premalignant lesion for adenocarcinoma of esophagus

3. Definition of Barrett’s Esophagus
Columnar-lined esophagus (Naef AP. J Thorac Cardiovasc Surg 1975)
3 cm of columnar lining or intestinal metaplasia (Spechler SJ. N Engl J Med 1992)
Intestinal metaplasia in the esophagus without specification of length (Sampliner RE Am J Gastroenterol 1998)
Short-segment of Barrett’s esophagus ; <3 cm in length (Johnston MH, Weston AP. Am J Gastroenterol 1996)

4. Barrett’s Esophagus Definition: 2-Fold
Endoscopically visible columnar epithelium in the esophagus which, on biopsy, has:
Metaplastic columnar epithelium, defined by acid-mucin containing goblet cells
From Sampliner RE. ACG Practice guidelines. Am J Gastroenterol 1998;93:1028

5. Questions in the Histologic DX of Barrett’s Esophagus
Is it Barrett’s esophagus or gastric cardia ?
: Endoscopic description of columnar-lined esophagus.
How much metaplastic epithelium is needed to diagnose Barrett’s?

6. Definitional Problems in Barrett’s Esophagus
Endoscopic and histologic components both required :
Three anatomic landmarks must be separately identified and biopsied
a. Gastroesophageal junction (GEJ)
b. Proximally displaced squamocolumanr
junction (SCJ) or Z-line
c. Intervening pink mucosa in tubular esophagus
of possible Barrett’s epithelium
3. Barrett’s esophagus (vs) intestinal metaplasia in gastric cardia

7. Anatomic landmarks of Distal esophagus and proximal stomach :
A. normal and H. pylori carditis
B. GERD induced columnar metaplasia
(Am J Gastroenterol 2005;100: )

8. Endoscopic picture of the longitudinal submucosal vessels characteristic for the distal esophagus

9. Oxyntic (fundic) type
Cardiac type
Oxyntocardiac type
Intestinal type

11. Epithelial types at the gastroesophageal junctional region
Am J Surg Pathol 2000 March;24(3):

12. Gastric Cardia Chandrasoma (2000) : CM is abscent in 70% of autopsy
Hayward (1961) : Cardiac mucosa (CM) lined the distal 2cm of the tubular esophagus and extended into the proximal stomach
Chandrasoma (2000) : CM is abscent in 70% of autopsy
Kilgore (2000) : CM in all pediatric autopsy (0.1~0.4cm)
Glickman (2002) : abscence of CM in 19% of symptomatic pediatric patient

13. Summary of Studies Designed to Evaluate Cardia Mucosa
Author
Type of specimen
Study population
Mucous glands
Mixed glands
Oxyntic glands
Mean Length
Glickman
Biopsy (n=74)
0.1-18yr (median 13yr)
81%
19% 0%
<1.0mm
Kilgore
Autopsy (n=30)
16days-18yr (median 6.3yr)
100%
1.8mm
Derdoy
Autopsy (n=100
1day-18yr (median 2.2yr)
1.0mm
Park
Autopsy (n=23)
Prenatal;18-34wk, postnatal; 9days-15yr
<0.4mm
Marsman
Biopsy (n=198)
21-87yr (mean 50yr)
62%
38%
Sarbia
Resection (n=36)
Adult
Entire 56%
Partial 97%
61%
Mucous gl:1-15mm, mixed gl:1-24mm
Chandrasoma
Autopsy (n=9)
Mainly adult
80%>20yr
19/72
8/18
32/72
18/18
21/72
9/18
Zhou
Autopsy (n=77)
Prenatal (15-39wk)
Postnatal (40wk-17yr) 5%
48%
55%
46% 6%
(Am J Gastroenterol 2005;100: )

14. A summary of the pH data (expressed as percent time pH<4) in 53 patients classified as three groups.
(Am J Surg Pathol 2000;24: )

15. Patient population classified according to the percentage of patients with oxyntic mucosa only, oxyntocardiac mucosa, cardiac mucosa, and intestinal metaplasia : groups 1 to 4 based on length of abnormal columnar epithelium. (American Journal of Surgical Pathology 2003; 27(7): ).

16. Reflux-Adenocarcinoma Sequence
P Chandrasoma. (Histopathology 2005;46: )

17. Problems in defining Barrett’s esophagus by intestinal metaplasia (IM) and goblet cells
Sampling effect related to patchy distribution of goblet cells
False positive diagnosis of BE :
IM of gastric cardia

18. A Critical Review of the Diagnosis and Management of Barrett’s Esophagus : The AGA Chicago Workshop
Esophageal IM (intestinal metaplasia) documented by histology is a prerequisite criterion for the diagnosis of BE
Special stains (A. blue, PAS and others) are necessary for the histologic diagnosis of BE
Markers such as cytokeratin staining distinguish IM of esophagus from IM of stomach
The working definition of BE is displacement of the SCJ proximal to the GEJ with the presence of IM
Endoscopy with multiple systemic biopsies is needed to establish the diagnosis of BE
The normal appearing and normally located SCJ should not be biopsied
A patient with columanr-lined distal esophagus without confirmed IM on biopsy requires a follow-up endoscopy
The use of flow cytometry or biomarkers (p16 and p53) is promising and merits further clinical research
(Gastroenterology 2004;127: )

19. A Critical Review of the Diagnosis and Management of Barrett’s Esophagus : (The AGA Chicago Workshop)
Esophageal IM (intestinal metaplasia) documented by histology is a prerequisite criterion for the diagnosis of BE
(evidence linking IM to esophageal carcinoma)
: IM and dysplasia both adjascent to and remote
from adenocarcinoma
: Dysplasia arising in cardiac-type or fundic type
mucosa – uncommon
: Neoplastic risk of cardiac- and fundic-type
mucosa is not known
(Subgroup support C, Group grading accept 88%)

20. A Critical Review of the Diagnosis and Management of Barrett’s Esophagus : The AGA Chicago Workshop
2. Special stains (A. blue, PAS and others) are necessary for the histologic diagnosis of BE
: not required routinely
: In select cases, to avoid overinterpretation of pseudogoblet cells
(Subgroup support D, Group grading accept 6%)

22. Pseudogoblet cells

23. A B
AB positive cells
Normal gastric mucous neck cells
Reactive surface (foveolar) cells
Columnar epithelium in duct of submucosal gland C

24. A Critical Review of the Diagnosis and Management of Barrett’s Esophagus : The AGA Chicago Workshop
3. Markers such as cytokeratin staining distinguish IM of esophagus from IM of stomach
: Superficial and deep CK 7 + and superficial CK20 + (so-called “Barrett’s CK7/20 pattern”)
: Controversial
(Subgroup support D, Group grading accept 50%)

25. A Critical Review of the Diagnosis and Management of Barrett’s Esophagus : The AGA Chicago Workshop
4. The working definition of BE is displacement of the SCJ proximal to the GEJ with the presence of IM
: Majority agreed that the proposed definition is practical. (A few : endoscopic recognition of CLE may be sufficient for the diagnosis of BE)
: Identification of endoscopic landmarks was moderately reproducible
: good consensus
(Subgroup support B, Group grading accept 89%)

26. A Critical Review of the Diagnosis and Management of Barrett’s Esophagus : The AGA Chicago Workshop
5. Endoscopy with multiple systemic biopsies is needed to establish the diagnosis of BE
: IM is not uniformly distributed
:>20% of long-segment CLE may not have IM on a single set biopsy
: 4-quadrant biopsy protocol every 2cm.
(Subgroup support A, Group grading accept 100%)

27. Biopsy Protocol

28. Endoscopic picture of the longitudinal submucosal vessels characteristic for the distal esophagus

29. A Critical Review of the Diagnosis and Management of Barrett’s Esophagus : The AGA Chicago Workshop
6. The normal appearing and normally located SCJ should not be biopsied
: It is unrelated to reflux symptoms
: The prevalence of cardia IM (>15%) is much higher than BE, but cardia adenocarcinoma is less common than esophageal adenocarcinoma
(Subgroup support C, Group grading accept 99%)

30. Intestinal metaplasia at the GEJ
Incidence : 11~36% (18%) IM
No IM
Significance
Reflux Sx
38%
44% NS
Endoscopic esophagitis
10%
14%
Age
61 (29-90)
51 (22-83)
P<0.01
Antral IM
24% 6%
P=0.04
H. pylori
57%
41%
Gut 1997;41: ,
Mod Pathol 2000;13:

31. Intestinal metaplasia at the EGJ
Incidence : 11.5% in 215 Korean pt. IM
No IM
Significance
Reflux Sx
37.5%
34.6% NS
Endoscopic esophagitis
45.9%
17.1%
P <0.05
Age
56.2
39.8
P<0.05
Antral IM
45.8%
17.3%
H. pylori
75.0%
65.7%
Korean J Gastroenterol 2002;40:15-22

32. Table. Prevalence of Intestinal Metaplasia at the GEJ on Histological Examination of Biopsy Material of Patients Without Endoscopically Apparent BE.

33. GERD clinical profile + - Irregular Z-line + - Esophagitis + -
Summary of Features that help Differentiate Intestinal Metaplasia (IM) in the Distal Esophagus (DE) from the Gastric Cardia (GC)
Feature IM in DE IM in GC
GERD clinical profile
Irregular Z-line
Esophagitis
Gastritis
H pylori
Eosinophils
Neut, Plasma,Lymph
Multilayered epithelium
HID stain positive
MUC 1,6 positive
BE CK7/20 pattern ±
Complete>incomplete IM
(Am J Gastroenterol 2005;100: )

34. Proposed classification of intestinal metaplasia
Terminology
Length
Adenocarcinoma risk
Surveillance recommended
LSBE
≥ 3cm
Yes
SSBE
< 3cm
Gastric cardia IM
Unclear No
(Am J Gastroenterol 1998;93:1033-6)

35. A Critical Review of the Diagnosis and Management of Barrett’s Esophagus : The AGA Chicago Workshop
7. A patient with columanr-lined distal esophagus without confirmed IM on biopsy requires a follow-up endoscopy
: due to sampling error or interim development of IM
: should consider systemic biopsies
(Subgroup support C, Group grading accept 72 %)

36. A Critical Review of the Diagnosis and Management of Barrett’s Esophagus : The AGA Chicago Workshop
8. The use of flow cytometry or biomarkers (p16 and p53) is promising and merits further clinical research
: Flow cytometry identified low- and high-risk subset with 0% and 28% 5-year cumulative incidence of cancer
: p53 mutation and LOH
: p16 methylation, mutation and LOH
(Subgroup support A, Group grading accept 88%)

37. Diagnosis of Columnar-lined esophagus (CLE) without Intestinal metaplasia
Columnar lined esophagus with cardiac mucosa = Columnar epithelium of cardiac type
Columnar lined esophagus with Oxyntocardiac mucosa = Columnar epithelium of oxyntocardiac type
Columnar lined esophagus with oxyntic (fundic) mucosa = Columnar epithelium of oxyntic (fundic) type

38. No endoscopic information (GEJ) & No intestinal metaplaisa
Columnar epithelium of cardiac type
Columnar epithelium of oxyntocardiac type
Columnar epithelium of oxyntic (fundic) type

39. Metaplastic goblet cells = Barrett’s esophagus ?
Endoscopically
CLE : “Columnar-lined esophagus with intestinal metaplasia c/w Barrett’s esophagus”
GEJ : “Carditis with intestinal metaplasia”
No information : “Goblet cell containing mucosa, either Barrett’s esophagus or carditis with intestinal metaplasia”