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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