Barrett’s oesophagus : definitions and diagnosis

An update in 2011

Jean-François Fléjou

Dept of Pathology, Hôpital Saint-Antoine,

Faculté de Médecine Pierre et Marie Curie, Paris, France

Covering the literature on Barrett’s oesophagusA difficult task!

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Medline 1985-2010 « Barrett and esophagus »

Barrett - Summary

• Some words on history• Definition • Barrett’s carcinogenesis

– Dysplasia– Carcinogenetic process– Alternative markers

• Novel therapeutic possibilities– A consequence, the importance of double muscularis

mucosae

• New diagnostic methods

Some words on the history of Barrett’s oesophagus

• Lyall, Br J Surg 1937 : “ulcers occur in the oesophagus, and are

surrounded by heterotopic gastric mucosa”• Barrett NR, Br J Surg 1950 : “chronic peptic ulcer of the oesophagus

and oesophagitis”– 2 distinct lesions :

• Reflux oesophagitis• Peptic ulcer of the oesophagus, that correspond to congenital short

oesophagus with gastric ulcer in the mediastinal stomach

• Morson & Belcher, Br J Cancer 1952 : “Adenocarcinoma of the oesophagus and ectopic gastric mucosa”

• Allison & Johnstone, Thorax 1953 : reflux oesophagitis, with stomach drawn up to the mediastinum by the contracting scar tissue in the stricture

A short history of Barrett’s oesophagus

• Some may be worried because I have changed my opinion• The lesion should be called “the lower esophagus lined by columnar

epithelium”• It is probably the result of a failure of the embryonic lining of the gullet to

achieve maturity.

Lord RV. Norman Barrett, “Doyen of esophageal surgery”. Ann Surg 1999;229:428.

Barrett’s oesophagus : acronyms

CELLO Columnar epithelium lined lower oesophagus

CLE Columnar lined esophagus

EBO Endobrachyoesophage (France)

Lortat-Jacob JL 1957

BO (BE) Barrett’s oesophagus

LSBO Long segment Barrett’s oesophagus

SSBO Short segment Barrett’s oesophagus

USSBO Ultrashort segment Barrett’s oesophagus

Which kind of epithelium lines Barrett’s esophagus?

• Initial descriptions : – “ectopic gastric mucosa”. – Accurate reading : “columnar cells, mucus secreting

units, tubular glands, no oxyntic cells” (Barrett 1957)• Morson & Belcher 1952 :

– Intestinal metaplasia• Paull et al 1976

– Classical description of 3 types of metaplastic epithelium• “Modern” period :

– Intestinal metaplasia (goblet cells) is mandatory for the diagnosis

• ? “Post-modern” period : – No need for IM in all cases

BE: practical diagnostic definitions

endoscopical and histological

• “Classical”: circumferential

columnar epithelium > 30

mm above the oesophago-

gastric junction (OGJ)

– 3 types of columnar

epithelium (Paull 1976)• “Specialized” or intestinal

• Cardiac (junctionnal)

• Fundic (gastric)

– Now considered as “long

segment BE”. Can also be

present as tongues

– Endoscopic Prague C and

M systemChatelain et alVirchows Archiv 2003

Zonal?

Mosaic?

You may also have pancreatic metaplasia, Paneth cells, endocrine cells…

BE: practical diagnostic definitionsendoscopical and histological

• “Short segment” BE: endoscopically visible columnar epithelium (10 to

30 mm) above the esophago-gastric junction (EGJ), circumferential

and/or as tongues

– 1 diagnostic columnar epithelium : “specialized” or intestinal with goblet cells

• Normal appearing EGJ (or only irregular Z line) with intestinal

metaplasia

– “Ultrashort” segment BE or carditis with IM ??

General definition (AGA, SFED...) : an abnormal appearing distal

oesophageal lining (endoscopic BE) with histologic evidence of

oesophageal IM (confirmed histologic BE)

(previous) BSG guidelines for the management of CELLO

1. Biopsies diagnostic for CELLO : metaplastic mucosa + native

oesophageal glands (10-15%)

2. Biopsies corroborative of an endoscopic diagnosis of CELLO :

intestinal metaplasia (specialized)

3. Biopsies in keeping with, but not specific for CELLO : cardiac +/-

fundic type without IM

4. Biopsies without evidence of CELLO: squamous mucosa

squamous

Cardiac and oxynto-cardiac

Fundic

Fundic with gastritis (H pylori)

Intestinal metaplasia

Gastric folds

cm

cm

Normal GOJ Long segmt BO

Ultrashort BOCarditis + IM

CK20CK7 Barrett type IM

Gastric type IMCK7 CK20

Distal oesophagus Gastric cardia

GERD clinical profile + -

Irregular Z-line + -

Esophagitis (histologic) + -

Gastritis - +

H. Pylori - +

Eosinophils ++ +

Neut, plasma, lympho. + ++

Multilayered epithelium + -

HID + non goblet cells + -

MUC 1 & 6 positive + -

Barrett CK 7/20 pattern + -

Complete > incomplete IM - +

From Odze, Am J Gastro 2005

Features that help differentiate IM

and for the moment, the problem is not supposed to exist…

Riddell and Odze, 2009

…  « it is probably wise to avoid biopsying the GEJ region in patients without endoscopic evidence of BE »…

• Guidelines– USA, Germany: goblet cells – UK, Japan: no goblet cells

• Classical arguments for goblet cells– They are always present when sampling is adequate– Cancer develops from IM

• New arguments against the definition based on goblet cells– They can be absent

• Due to insufficient sampling• Really absent (children, but also adults)

– They can be difficult to diagnose (false neg, false pos)– Non goblet cells have the same genetic alterations– Small cancers often develops from non IM mucosa (Takubo)

What about the cardiac mucosa?

A highly controversial issue. Always short, metaplastic?

Carcinogenesis of Barrett’s mucosa

• 10% of patients with GERD have Barrett’s esophagus (and 1-2% of the general population).

• Almost all esophageal adenocarcinomas develop in Barrett’s esophagus.

• The frequency of esophageal adenocarcinoma is increasing (including in France).

• Adenocarcinoma is preceded by intraepithelial neoplasia (dysplasia) in all prospective surveillance studies.

• The molecular mechanisms involved in the transformation of Barrett’s mucosa are still incompletely established.

Potet F and Barge J

Ann Pathol 1991

What’s new (?) on dysplasia on BO • Terminology : syn. intraepithelial neoplasia (WHO)

• Classification : revised Vienna, new WHO

• Problems: sampling (« Seattle protocol », or > 8 biopsies), reproducibility, natural history

• Solutions?: double lecture, markers, new diagnostic methods

High grade dysplasia is often multifocal and hardly visible

HGD

Chatelain and Fléjou, Virchows Archiv 2003

Riddell and Vienna classifications

Terminology in Riddell’s and Vienna Classification

Clinical consequences in patients with Barrett’s oesophagus

Category 1 Negative for dysplasia Follow-up

Category 2 Indefinite for dysplasia Follow-up. Reinforce medical treatment

Category 3 Low grade dysplasia Endoscopic treatment or reinforced follow-up

Category 4 4.1 High grade dysplasia4.2 Non invasive carcinoma

(carcinoma in situ)4.3 Suspicion of invasive

carcinoma

Endoscopic or surgical treatment

Category 5 Invasive neoplasia5.1 Intramucosal carcinoma5.2 Submucosal carcinoma or

beyond

Surgical resection

Diagnostic algorithm of dysplasia in Barrett’s oesophagus (Montgomery et al, Hum Pathol 2001)

Four features 1- surface maturation in comparison with the underlying glands

2 - architecture of the glands3 - cytologic pattern of the proliferating cells4 - inflammation and erosions / ulcers

Reparation Transformation (dysplasia)1 present absent2 nal or mild alteration mild (LG) or marked (HG)3 nal or atypia mild or focally LG: mild diffuse, marked focal

marked (with inflammation)HG: marked diffuse4 « cases with abundant inflammation and the other features of LGD are usually best classified in the indefinite category »

Dysplasia in Barrett’s oesophagusDiagnostic reproducibility

Montgomery et al, Hum Pathol 2001

Diagnosis k 1rst set k 2nd set

Non dysplastic 0.44 0.58Indefinite0.13 0.15Low grade 0.23 0.31High grade – cancer 0.63 0.64

Low grade dyspasia in Barrett has to be confirmed before decision

But all these descriptions and studies feature « classical » dysplasia

• Adenomatous – intestinal (ressembles adenomas of the colon)

• Recent description of new forms– Polypoid (do not use the term adenoma)– Cryptic with surface maturation– Non adenomatous - foveolar– Serrated

Biomarkers in Barrett’s oesophagus

• Any biologic measurement that can predict with reliability which individuals will develop cancer and which will not*

• Practically, three types : – histopathology : dysplasia– other tests using endoscopical bioptic sampling, mainly molecular– alternative endoscopical or non endoscopical techniques, under

development

• As the current practice is histopathology, any new markers need increased reproducibility, sensitivity, and specificity as compared with histology

• Spechler SJ “please, not another marker of Barrett’s oesophagus!”

*Reid et al, Gastrointest Endoscopy Clin N Am 2003

From Morales et al, Lancet 2002

Squamous epithelium

Chronic inflammation

Barrett’s metaplasia

Low-grade dysplasia

High grade dysplasia

Barrett’s carcinoma

• Growth self sufficiency Cyclin D, TGFa EGF

• Insensitivity to p16 LOH methyl. APC methyl.

anti-growth signals• Avoidance of apoptosis COX2 p53 LOH mutation FasL

• Limitless replicative Telomerase

potential reactivation• Sustained angiogenesis VEGF - VEGFR

• Invasion and metastasis E-cadherin

b-catenin

Injury :Acid reflux...

Genetics :Sex, race, other... aneuploidy

Biomarkers in Barrett’s mucosa

An incomplete list of recently published biomarkers :

RANK, SPARC, cdx-2, villin, Bcl-XL, c-Src, IGF1R, Kras, BRAF, HMGI(Y), HSP27, PLA2, DAF, Neuropilin-1, RXR, Telomerase, p16, p53, DNA damage, CGH array, VEGF, CK7/20, COX2, COX1, HCA, Hep-par1, MMR, polymorphisms of cytokines, CD1a, ERK, CDK1, c-Met, CDX1, CDX2, survivin, MUC2, PITX1, MTAP, CD105, Rab11a, Claudin, CD10, MUC5AC, Defensine 5, cyclin D1, TFF1, CES2, nfKb, 7q, RUNX3, HPP1, microRNAs, Slug, racemase, GATA4, GRP78, REG1a, Ski/SnoN, AKAP12, leptin, WIF-1, SS, E2F-1, HER-2…

In routine practice, in 2010, only p53 and Ki67 can be used, with still limited value +++. The diagnosis remains on H&E.

p53 in Barrett • 3 methods of

evaluation:

LOH

gene mutation

protein expression

• Numerous phase 1-2 studies show frequent alterations, increasing with the severity of histological lesions

• In the same patient, almost never in normal mucosa, very frequent (80-90%) in cancer tissue

17p LOH in BO• Numerous phase 1-2 studies, limited number of

patients, retrospective.• Progressive increase of LOH, similar to protein

overexpression• One large scale phase 4 study

Reid et al,

Am J Gastroenterol 2001

• Still not suitable in routine practice (neither p53 gene mutation)

p53 immunohistochemistry in BO

• Very numerous phase 1-2 studies, limited number of patients, retrospective, various antibodies and cut-of values

• Progressive increase of positivity : ND (0-5%), LGD (10-25%), HGD and Ca (50-90%)

• Percentage of false negative (stop mutations) and false positive (?)

• Variable criteria and scoring systems +++

Kaye PV, et al. Novel staining pattern of p53 in Barrett’s dysplasia. The absent pattern. Histopathology 2010 ;57 :933-40.

A critical review of the diagnosis and management of Barrett’s esophagus: The

AGA Chicago workshop

Statement number 28“The use of flow cytometry or biomarkers (such as p53

and p16 mutations) is promising and merits further clinical research”– Nature of evidence : II (obtained from well-designed cohort

or case-controlled studies)– Subgroup support : A (good evidence to support the

statement)– Accept completely : 72%

Sharma et al, Gastroenterology 2004

• chromoendoscopy

• autofluorescence

• Pillcam

• Laser confocal endoscopy

• Optical coherence tomography

• Raman Spectroscopy

• …

New endoscopical and non endoscopical methods to explore Barrett’s mucosa

New treatments of early neoplastic lesions

• “Destructive”– Laser– Photodynamic therapy– Electro-coagulation

• “Ablative”– Mucosectomy– Endoscopic submucosal dissection

For all methods, think to residual glands under reepithelialised squamous epithelium (“buried glands”)

• Double MM in BO

– Constant– May be triple– External is original– Implications for

cancer staging:• Between two, it is still

mucosa• External can look as

muscularis propria– Very important on

mucosectomy specimens (Offerhaus, Virchow Archiv)

« Messages »

• Diagnose short segment BE with goblet cells (changing soon?)

• What about ultrashort BE ??• H&E is enough in most cases, p53 (and

Ki67) can be of help • Use international classifications for

dysplasia and cancer staging• Be very careful with mucosectomy

specimens• Accompany the development of new

diagnostic methods