amp barrett casablanca mars 2011
TRANSCRIPT
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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
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Covering the literature on Barrett’s oesophagusA difficult task!
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85 88 91 94 97 2000 2003 2006 2009
n Ref
Medline 1985-2010 « Barrett and esophagus »
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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
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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
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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.
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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
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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
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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?
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You may also have pancreatic metaplasia, Paneth cells, endocrine cells…
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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)
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(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
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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
Ultrashort BOCarditis + IM
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CK20CK7 Barrett type IM
Gastric type IMCK7 CK20
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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
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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 »…
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• 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)
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What about the cardiac mucosa?
A highly controversial issue. Always short, metaplastic?
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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.
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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
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High grade dysplasia is often multifocal and hardly visible
HGD
Chatelain and Fléjou, Virchows Archiv 2003
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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
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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 »
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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
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Low grade dyspasia in Barrett has to be confirmed before decision
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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
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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
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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
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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.
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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 with the severity of histological lesions
• In the same patient, almost never in normal mucosa, very frequent (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 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)
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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 +++
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Kaye PV, et al. Novel staining pattern of p53 in Barrett’s dysplasia. The absent pattern. Histopathology 2010 ;57 :933-40.
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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
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• chromoendoscopy
• autofluorescence
• Pillcam
• Laser confocal endoscopy
• Optical coherence tomography
• Raman Spectroscopy
• …
New endoscopical and non endoscopical methods to explore Barrett’s mucosa
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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”)
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• 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)
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« 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