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

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

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)

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

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?

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

Anatomic landmarks of Distal esophagus and proximal stomach : A. normal and H. pylori carditis B. GERD induced columnar metaplasia (Am J Gastroenterol 2005;100:1853-1867)

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

Oxyntic (fundic) type Cardiac type Oxyntocardiac type Intestinal type

Epithelial types at the gastroesophageal junctional region Am J Surg Pathol 2000 March;24(3):344-351

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

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;100:1853-1867)

A summary of the pH data (expressed as percent time pH<4) in 53 patients classified as three groups. (Am J Surg Pathol 2000;24:344-351)

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):929-936).

Reflux-Adenocarcinoma Sequence P Chandrasoma. (Histopathology 2005;46:361-373)

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

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;127:310-330)

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%)

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%)

Pseudogoblet cells

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

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%)

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%)

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%)

Biopsy Protocol

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

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%)

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;41:585-589, Mod Pathol 2000;13:614-20.

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

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

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;100:1853-1867)

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)

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 %)

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%)

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

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

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”