Barrett Bey 09.pdf

8/10/2019 Barrett Bey 09.pdf

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GERD, Barretts esophagus and dysplasia

Classical and some recent featuresJean-Franois Fljou

Dept of Pathology, Hpital Saint-Antoine,

Facult de Mdecine Pierre et Maris Curie, Paris, France


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Gastroesophageal reflux

disease (GERD)The Castell Iceberg

- GER (10% population) : digestive symptoms (75%) or

extra-digestive (25%)

- Reflux esophagitis (10% endoscopies) : complication of

GER : lesions are secondary to acid (and alkaline?) GER- Ulceration, stenosis, Barretts esophagus : complications

of esophagitis


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Pathology of GERD

Histological lesions on biopsies

- Non erosive esophagitis : early oesophagitis (Ismael

Beigi)

- Peptic esophagitis, erosive or ulcerated

- Barretts esophagus (French endobrachyoesophage)


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Histological features of early reflux

oesophagitis- Basal zone hyperplasia (>15%), with mitosis and nuclear

enlargement

- Elongated papillae (>75%)

- Papillary capillary ectasia and venular dilatation- Intraepithelial inflammatory cells (lymphocytes,

eosinophils)

- spongiosis, widening of intercellular spaces, balloon cells

Described on large biopsies (capsule), diagnostic significance

debated, may have a role to diagnose clinically atypical cases.

Most guidelines do not recommend to biopsy when endoscopy isnormal or shows typical features

However, recent renewal in the potential interest


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Early reflux oesophagitis

increased stromal papillae length increased basal cells thickness

increased proliferation (mitosis)

balloon cells

widening of intercellular spaces polymorphonuclear eosinophils

Some words on eosinophilic esophagitis


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Oesophagite osinophiles

- Diminution des parasitoses et

augmentation des allergies

- La plus frquente des ites

osino. du TD

- Reconnaissance rcente

- Pas dosino dans lsophage nal

- Enfant et adulte jeune, H >> F

- Pic t automne- Symptmes variables, souvent

dysphagie progressive


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Oesophagite osinophiles Endoscopie trs variable, peut tre

normale (1/3)

Risque lev de perforation lendoscopie (et en cas dedilatation)

Dg diffrentiel : Reflux

Pas de risque de cancrisation

Tt : suppression allergnes,corticodes


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Oesophagite

osinophiles Diagnostic repose sur les

biopsiesNombreuses (1 biopsie sensibilit

55%; 10 biopsies sensibilit 100%)

sophage moyen, pour distinguerde loesophagite par reflux

Critre principal : PNE > 15/champ

au x40 En surface

microabcs

Autres lsions doesophagite(hyperplasie couches basales,

allongement papilles)


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Barrett - Summary

Some words on history

Definition

Barretts carcinogenesis

Dysplasia

Carcinogenetic processAlternative markers

Novel therapeutic possibilities

importance of double muscularis mucosae

New diagnostic methods


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A short history of Barretts

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


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A short history of Barretts oesophagus Allison & Johnstone, Thorax

1953 : reflux oesophagitis, withstomach drawn up to the

mediastinum by the contracting

scar tissue in the stricture

19532002


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A short history of Barretts oesophagus

Some may be worried because I have changed my opinion

The lesion should be called the lower esophagus lined by columnarepithelium

It is probably the result of a failure of the embryonic lining of the gullet toachieve maturity.

Lord RV. Norman Barrett, Doyen of esophageal surgery. Ann Surg1999;229:428.


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Barretts oesophagus : acronyms etc.

CELLO Columnar epithelium lined lower

oesophagus

CLE Columnar lined esophagus

EBO Endobrachyoesophage

(France)

Lortat-Jacob JL 1957

BO Barretts oesophagus

LSBO Long segment Barrettsoesophagus

SSBO Short segment Barretts

oesophagus

USSBO Ultrashort segment Barretts

oesophagus


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Which kind of epithelium lines Barretts

oesophagus? 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 thediagnosis, but...

BO ti l di ti


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BO: practical diagnostic

definitions

endoscopical and histological

Classical: circumferential

columnar epithelium > 30mm 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 BO. Can also be

present as tongues

Chatelain et al

Virchows Archiv 2003

Zonal?

Mosaic?


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BO: practical diagnostic definitions

endoscopical and histological

Short segment BO: endoscopically visible columnar epithelium


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BSG guidelines for the

management of CELLO1. Biopsies diagnostic for CELLO : metaplastic mucosa + native

oesophageal glands (10-15%)

2. Biopsies corroborative of an endoscopic diagnosis of CELLO :

intestinal metaplasia (specialized)

- Pb : IM in a hiatus hernia, IM at the cardia

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

fundic type without IM

- Pb : OGJ ?

4. Biopsies without evidence of CELLO: squamous mucosa


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Wh t b t th di ?


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What about the cardiac mucosa?

A highly controversial issue! Always short, always metaplastic?

N l GOJ L t BO


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squamous

Cardiac and oxynto-

cardiac

Fundic

Fundic with gastritis

(H pylori)

Intestinal metaplasia

Gastric folds

cm

cm

Normal GOJ Long segmt BO

Short segmt BOCarditis + IM


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cytokeratins (and other markers) ? Still discussed, not used in routine practice


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CK20CK7 B tt t IM


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CK20CK7 Barrett type IM

Gastric type IMCK7 CK20


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and for the moment, the

problem is not supposed to

exist


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Carcinogenesis of Barretts mucosa

10% of patients with GERD have Barretts oesophagus

(and 1-2% of the general population).

Almost all oesophageal adenocarcinomas develop onBarretts oesophagus.

The frequency of oesophageal adenocarcinoma is

increasing (including in France).

Adenocarcinoma is preceded by intraepithelial neoplasia

(dysplasia) in all prospective surveillance studies.

The molecular mechanisms involved in the transformationof Barretts mucosa are still incompletely established.


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Potet F and Barge J

Ann Pathol 1991

Whats new (?) on dysplasia on BO

Terminology : intraepithelial neoplasia (WHO)

Classification : revised Vienna

Problems: sampling ( Seattle protocol , or > 8

biopsies), reproducibility, natural history

Solutions?: double lecture, markers, new diagnostic

methods

intestinal metaplasia Low grade IEN


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intestinal metaplasia Low grade IEN

high grade IENadenocarcinoma


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Riddells and Vienna classifications

Terminology in Riddells and

Vienna Classification

Clinical consequences in patients with

Barretts 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 dysplasia

4.2 Non invasive carcinoma

(carcinoma in situ)

4.3 Suspicion of invasive carcinoma

Endoscopic or surgical treatment

Category 5 Invasive neoplasia

5.1 Intramucosal carcinoma

5.2 Submucosal carcinoma or

beyond

Surgical resection


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Dysplasia in Barretts oesophagus

Diagnostic reproducibilityMontgomery et al, Hum Pathol 2001

Diagnosis k 1rst set k 2nd set

Non dysplastic 0.44 0.58

Indefinite 0.13 0.15

Low grade 0.23 0.31

High grade cancer 0.63 0.64


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Diagnostic algorithm of dysplasia in Barrettsoesophagus (Montgomery et al, Hum Pathol 2001)

Four features 1- surface maturation in comparison with theunderlying glands

2 - architecture of the glands

3 - cytologic pattern of the proliferating cells

4 - inflammation and erosions / ulcers

Reparation Transformation (dysplasia)

1 present absent

2 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 diffuse

4 cases with abundant inflammation and the other features of LGD are

usually best classified in the indefinite category


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intestinal metaplasia low grade dysplasia


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intestinal metaplasia low grade dysplasia

high grade dysplasiaadenocarcinoma

mechanisms?


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From Morales et al, Lancet 2002

Squamous

epithelium

Chronic

inflammation

Barretts

metaplasia

Low-grade

dysplasia

High grade

dysplasia

Barretts

carcinoma

Growth self sufficiency Cyclin D, TGF 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

-catenin

Injury :

Acid reflux...

Genetics :

Sex, race, other... aneuploidy


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Biomarkers in Barretts oesophagus

Any biologic measurement that can predict with reliability whichindividuals 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, underdevelopment

As the current practice is histopathology, any new markers needincreased reproducibility, sensitivity, and specificity as compared withhistology

Spechler SJplease, not another marker of Barretts oesophagus!

*Reid et al, Gastrointest Endoscopy Clin N Am 2003


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Biomarkers in Barretts 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, cyclinD1, 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 2009, only p53 and Ki67 can be used,with limited value +++


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p53 in Barrett

3 methods of evaluation:

LOH

gene mutation

protein expression

Numerous phase 1-2

studies show frequent

alterations, increasing withthe severity of histological

lesions

in the same patient, almost

never in normal mucosa,

almost ever (80-90%) in

cancer tissue


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

retrospective.

Progressive increase of LOH, similar to proteinoverexpression

One large scale phase 4 study

Reid et al,

Am J Gastroenterol 2001

Still not suitable in routine practice (neither p53 genemutation)


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p53 immunohistochemistry in BO

Very numerous phase 1-2 studies, limited number ofpatients, 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 (?)


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A critical review of the diagnosis and

management of Barretts 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


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chromoendoscopy

autofluorescence

Pillcam Laser confocal

endoscopy

Optical coherencetomography

Raman

Spectroscopy

New endoscopical and non endoscopicalmethods to explore Barretts mucosa

New treatments of early neoplastic


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New treatments of early neoplastic

lesions

Destructive

Laser

Photodynamic therapy

Electro-coagulation

AblativeMucosectomy

Endoscopic submucosal dissection

For all methods, think to residual glands under

reepithelialised squamous epithelium (buried glands)


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Mucosectomy

Orientate

Givethe grade (dysplasia)

the stage (adenocarcinoma)

in an international classification (Vienna, WHO, pT UICC, Kudo,

Paris)

Evaluate margins

laterally (+/-)

deep (+++)

E t i i d th


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Extension in depth

sm1 sm2

MM

Paris classification

sm1 < 500 m

sm2 > 500 m

Specific to Barrett: double muscularis


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Specific to Barrett: double muscularis

mucosa

m sm

MM1

MM2


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Double MM in BO

Constant

May be triple

External is original

Implications forcancer staging:

Between two, it is stillmucosa

External can look asmuscularis propria

Very important onmucosectomyspecimens

(Offerhaus, VirchowArchiv)


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M


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Messages

Diagnose short segment BO (oesophagealIM)

What about ultrashort BO ??

H&E is enough in most cases

Use international classifications fordysplasia and cancer staging

Be very careful with mucosectomyspecimens

Accompany the development of new

diagnostic methods

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