Alimentary tract and pancreas

Alimentarni trakt i pankreas

1Miodrag @ivi}, 2Vuka Kati},

1Dragoljub Popovi},

3Aleksandar Nagorni,

4Slobodan Trenki},

4Neboj{a \or|evi},

2Vesna @ivkovi} , 2Katarina Kati},

5Sa{a Grgov, 6Marica Ota{evi}.

Clinic for Otorhinolaryngology,

Clinical Center Niš,

2 Institute of Pathology, Medical Faculty of Niš,

3 Clinic for Gastroenterology and Hepatology,

Clinical Center Niš,

4 Surgical Clinic, Clinical Center Niš,

5 Department of Gastroenterology, Health Centre of

Leskovac,

6 Institute of Microbiology, Medical Faculty of Niš.

.

ARCH GASTROENTEROHEPATOL 2003; 22 (No 1 - 2): 12 – 17

Histological, histochemical

and clinical features of

Barrett's oesophagus

Histolo{ke, histohemijske i klini~ke odlike

Barrett-ovog jednjaka

(accepted April 4th 2003 )

Key Words:

Barrett's oesophagus,

histopathology,

epithelial mucins,

genetic..

Abstract

Barrett's oesophagus refers to an acquired change charcterised by replacement of the normal epithelium

of the lower oesophagus by a columnar epithelium and ccuring in subjects with gastroesophageal reflux

disease. The mucosa represents a complex mixture of cell types and architectural patterns found in the

stomach and small intestine.Gastric metaplasia (also termed cardiac type) comprises surface and foveolar

epithelium lined by a columnar mucous cells and cardiac or pyloric-type mucous glands.Chief and

parietal cells may be present but are rarely conspicuous. Intestinal metaplasia is typically incomplete,

comprising intestinal goblet cells and gastric foveolar type columnar mucous cells. The association of

Barrett's metaplasia and oesophageal adenocarcinoma has long been recognized and cancer surveillance

by regular endoscopic examination has been advocated by many investigators. Progression of Barrett's

epithelium to dysplasia and malignancy is usually accompanied by downregulation of secretory mucins

MUC2, MUC5AC and MUC6, similar to cancer of stomach and colon. Membrane bound mucins

MUC1 and MUC4 may show upregulation, whereas the membrane bound mucin MUC3 is downregulated.

Early premalignant clones produce biological and genetic heterogeneity as seen by multiple p53

mutations, p16 mutations, aneuploidy, and abnormal methylation resulting in stepwise changes in differentiation,

proliferation and apoptosis, allowing disease progression under selective pressure.

Exploitation of these molecular events may lead to a more appropriate diagnosis and understanding of

these lesions in the future.

Sa`etak

Barrett-ov jednjak je ste~ena promena koju odlikuje zamena normalnog epitela donjeg dela jednjaka cilindri}

nim epitelom i koja se karakteristi~no javlja u osoba sa gastroezofagusnim refluksom. Sluzoko`a

prestavlja slo`enu me{avinu }elijskih tipova i gradje prisutne u `eludcu u tankom crevu. Gastri~na metaplazija

(takodje nazvana kardijalinim tipom) ~ini pokrovni i foveolarni epitel oblo`en cilindri~nim mukusnim

}elijama i kardijalnim ili pilori~nim tipom `lezda. Glavne i parijetalne }elije mogu da budu prisutne,

ali su retko upadljive. Intestinalna metapolazija je karakteristi~no inkompletna i gradjena je od intestinalnh

peharastih }elija, mukusnih i gastri~nih }elija foveolarnog tipa. Udru`enost metaplazije i adenokarcinoma

jednjaka je odavno propoznata, a otkrivanje karcinoma tokom redovnih endoskopskih kontrola zastupaju

mnogi istra`iva~i. Progresija Barrett-ovog epitela u displaziju i malignitet je obi~no pra}ena smanjenim

lu~enjem sekretornih mucina tipa MUC2, MUC5AC i MUC6, sli~no karcinomu `eludca i kolona. Mucini

koji su vezani za membranu tipa MUC1 i MUC4 mogu da poka`u hipersekreciju dok su membranski mucini

tipa MUC3 u hiposkreciji. Rani premaligni klonvi stvaraju biolo{ku i genetsku heterogenost multiplih

p53 mutacija, p16 mutacija, aneuploidiju i abnormalnu metilaciju dovode}i do stepeni~astih promena diferencijacije,

proliferacije i apoptoze, i dozvoljavaju}i napredovanje bolesti pod selektivnim pritiskom.

Poznavanje ovih molekularnih zbivanja i njihovo kori{}enje u praksi mo`e da dovede do rane dijagnoze i

ve~eg razumevanja ovih promena u budu}nosti.

Kljucne reci:

funkcionalna dispepsija,

podgrupe,

Helicobacter pylori.

History of the Columnar-Lined Oesophagus

Barrett was not the first to describe the columnar-lined

oesophagus. In 1906, Tileston, a pathologist, reported several

patients who had ²peptic ulcer of the oesophagus² and

noted the close resemblance of the mucous membrane

about the ulcer to that normally found in the stomach (1).

In 1950, an influential British surgeon named Norman

Barrett published a report in which he defined the oesophagus

as ²that part of the foregut, distal to the cricopharingeas

sphincter, which is lined by squamous epithelium²

(2). Today, an oesophagus lined extensively by columnar

epithelium is called, ironically, Barrett's esophagus (BE)

(3). The condition is associated both with gastroesophageal

reflux disease (GERD) and oesophageal adenocarcinoma.

Barrett's oesophagus

This term refers to an acquired change characterised by

replacement of the squamous epithelium of the lower

oesophagus by columnar epithelium and occuring in subjects

with GERD. The mucosa represents a complex mixture

of cell types and architectural patterns found in the

stomach and small intestine (4).

While the various types of epithelium lining BE may

not be arranged in definitive zonal distribution as thought

originally, it is nevertheless possible to observe discrete

areas of gastric metaplasia and intestinal metaplasia.

Gastric metaplasia (also termed cardiac type)comprises

surface and foveolar epithelium lined by columnar mucous

cells and cardiac or pyloric-type mucous glands. Chief and

parietal cells may be present but are rarely conspicious.

Intestinal metaplasia is typically incomplete, comprising

intestinal goblet cells and gastric foveolar type columnar

mucous cells (also termed specialised type epithelium).

Apsorptive cells and Paneth cells are inconspicuous.

Intestinalised Barrett's epithelium is more likely to show a

villous architecture (Fig.1) and is recognised as the precursor

od dysplasia and adenocarcinoma (5). Although some

restrict the diagnosis of Barrett's oesophagus to cases with

intestinal metaplasia, gastric or cardiac metaplasia is an

abnormal finding and a marker for GERD (6).

Barrett's mucosa is recognised in HE stained sections

not only by presence of goblet cells but by distinctive architectural

changes including villosity and crypt architectural

abnormalities (loss of parallelism, tortuosity, branching and

varying degrees of atrophy) (Fig 1). Squamous islands and

ducts of submucosal oesophageal glands confirm the site of

biopsied columnar epithelium.The lamina propria may be

replaced by fibromuscular tissue and splitting of the muscular

mucosae into two layers is often obeserved in surgical

specimens. Barrett's mucosa is therefore more than a simple

epithelial change dominated by goblet cell metaplasia.

Goblet cells in gastroesophageal biopsies are not pathognomonic

for the condition. These cells may be seen in intestinal

metaplasia of the cardia associated with Helicobacter

pylori gastritis. In this situation,however, intestinal metaplasia

is likely to be complete (7).

Factors predisposing for the development of BE and

subsequent adenocarcinoma in patients with GERD include

a markedly increased oesophageal exposure time to

refluxed gastric and duodenal contents due to a defective

barrier function of the lower oesophageal sphincter and

ineffective clearance function of the tubular oesophagus.

Experimental and clinical data indicate that combined

oesophageal exposure to gastric acid and duodenal contents

(bile acids and pancreatic enzymes) appears to be more

detrimental than isolated exposure to gastric juice of duodenal

contents alone. Combined reflux is thought to

increase cancer risk by promoting cellular proliferation, and

by exposing the oesophageal epithelium to potentially

genotoxic gastric and intestinal contents, e.g. nitrosamines

(8).

Symptoms and signs

BE as the precursor of most adenocarcinomas is clinically

silent in up to 90% of cases. The symptomatology of

BE, when present, is that of gastro-oesophageal reflux. This

is the condition where the early stages of neoplasia (intraepithelial

and intramucosal neoplasia)should be sought (9).

Endoscopy

The endoscopic analysis of the squamocolumnar junction

aims at the detection of columnar metaplasia in the distal

oesophagus. At endoscopy, the squamocolumnar junction

(Z-line) is in the thorax, just above the narrowed passage

across the diaphragm. In the lenght of the columnar

lining in this distal oesophageal segment is more than 3cm,

it is termed a long type of Barrett metaplasia. When the

length is less than 3 cm, it is a short type. Single or multiple

finger-like (1-3 cm) protrusions of columnar mucosa are

classified as short type.In patients with short segment BE,

the risk for developing adenocarcinoma is reported to be

lower compared to those with long segment BE (10). As BE

is restricted to cases with histologically confirmed intestinal

metaplasia, adequate tissue sampling is required.

Histopathology

Barrett epithelium is characterized by two different

types of cells, i.e. goblet cells and columnar cells, and has

also been termed 'specialized', 'distinctive' or Barrett metaplasia.

The goblet cells stain positively with Alcian blue at

low pH (2.5). The metaplastic epithelium has a flat or villiform

surface, and is identical to gastric intestinal metaplasia

of the incomplete type (type II or III) (Fig.1). Rarely,

foci of complete intestinal metaplasia (type I) with absorptive

cells and Paneth cells may be found. The mucous

glands beneath the surface epithelium and pits may also

contain metaplatic epithelium. Recent studies suggest that

the columnar metaplasia originates from multipotential

cells located in intrinsic oesophageal glands (11).

Intraepithelial neoplasia in Barrett oesophagus

Macroscopy : intraepithelial neoplasia generally has no

distinctive gross features, and is detected by systematic

sampling of a flat Barrett mucosa. The area involved is

variable, and the presence of multiple dysplastic foci is

common (12). In some cases, intraepithelial neoplasia presents

as one or several nodular masses resembling sessile

adenomas. Rare dysplastic lesions have been considered

true adenomas, with an expanding but localised growth

resulting in a well demarcated interface with the surrounding

tissue.

Microscopy: abnormal proliferation and differentiation

typify epithelial dysplasia.Normal oesophageal squamous

epithelial cells divide slowly in the basal layer, proliferate

suprabasally, and mature towards the luminal surface (13).

In Barrett's mucosa, despite its partially intestinal phenotype,

proliferation and differentiation patterns resemble

gastric mucosa, with minimal proliferation in a crypt zone

beneath the mucosal surface and differentiation into deep

glands and characteristic cell populations on the mucosal

surface (in normal small intestine,stem cells in the crypts

of Lieberkuhn feed a proliferative compartment from

which differentiating enterocytes and goblet cells migrate

to the villi,while Paneth cells migrate basally) (13).

Proliferation and differentiation compartments break down

in dysplastic epithelia. ìDysplasticì cells adjacent to an

invasive carcinoma probably represent the neoplastic clone

from which the carcinoma emerged. Dysplasia alone

implies an increased cancer risk, and motivates eradication

or increased intensity of surveillance (14).

Epithelial atypia in Barrett mucosa is usually assessed

according to the system devised for atypia in ulcerative

colitis,namely: negative, positive or indefinite for intraepithelial

neoplasia.

Negative for intraepithelial neoplasia:usually, the lamina

propria of Barrett mucosa contains a mild accompanying

inflammatory infiltrate of mononuclear cells.There

may be mild reactive changes with enlarged, hyperchromatic

nuclei, prominence of nucleoli, and occasional mild

stratification in the lower portion of the glands.However,

towards the surface there is maturation of the epithelium

with few or no abnormalities.These changes meet the criteria

of atypia negative for intraepithelial neoplasia, and

can usually be separated from low-grade intraepithelial

neoplasia (15).

Atypia indefinite for intraepithelial neoplasia:one of

the major challenges for the pathologist in Barrett oesophagus

is the differentiation of intraepithelial neoplasia from

reactive or regenerative epithelial changes.This is particularly

difficult, sometimes impossible, if erosions or ulcerations

are present (16). In areas adjacent to erosions and

ulcerations, the metaplastic epithelium may display villiform

hyperplasia of the surface foveolae with cytological

atypia and architectural disturbances. These abnormalities

are usually milder than those observed in intraepithelial

neoplasia. There is a normal expansion of the basal replication

zone in regenerative epithelium versus intraepithelial

neoplasia, where the proliferation shifts to more superficial

portions of the gland. If there is doubt as to whether

reactive and regenerative changes or intraepithelial neoplasia

is present in a biopsy, the category atypia indefinite for

intraepithelial neoplasia is appropriate and a repeat biopsy

after reflux control by medical acid supression or antireflux

therapy is indicated.

Low-grade and high grade intraepithelial

neoplasia:intraepithelial neoplasia in Barrett metaplastic

mucosa is defined as a neoplastic process limited to the

epithelium (17). Its prevalence in Barrett mucosa is

approximately 10%, and it develops only in the intestinal

type metaplastic epithelium. Cytological abnormalities

typically extend to the surface of the mucosa. In low-grade

intraepithelial neoplasia, there is decreased mucus secretion,

nuclear pseudostratification confined to the lower half

of the glandular epithelium, occasional mitosis, mild pleomorphism,

and minimal architectural changes (Fig 2,left).

High-grade intraepithelial neoplasia shows marked pleomorphism

and decrease of mucus secretion, frequent mitosis,

nuclear stratification extending to the upper part of the

cells and glands, and marked architectural aberrations ( Fig

2, right). The most severe architectural changes consist of

a cribriform pattern that is a feature of high-grade intraepithelial

neoplasia as a long as the basement membrane of

the neoplastic glands has not been disrupted (Fig 3).The

diagnostic reproducibility of intraepithelial neoplasia is far

from perfect; significant interobserved variation exists

(18).

Mucin expression in Barret's oesophagus

Mucins are glycoproteins containing up to 85% carbohydrate.

The oligosaccharide chains contain 2 to 12 sugars.

Each chain consists of a core region, a backbone and a

peripheral blood group-type structure.Two sugars may be

added as side-groups to the chain: sialic acid and fucose.

Carbohydrate component may be studied histochemically

by meand of traditional mucin staining, lectin binding and

immunohistochemistry. Many of the techniques are complex,

involve digestion or blockade and have generally

resulted in a literature that is difficult to disentagle.

The polypeptide component consists of a central

domain made up of repeating amino acid sequences which

carry the carbohydrate chains and peripheral domains that

are less heavily glycosylated. In MUC2, for example,

which is the dominant mucin of intestinal goblet cells, the

length of each repeat is 23 amino acids and these are

repeated between 51 and 150 times (19). The colorectal

expresses MUC1 which is a structural glycoprotein with

intracytoplasmic transmembrane and extracellular

domains. It is expressed at the apical pole of epithelial

cells, particularly within the crypt base of normal colorectum.

Immunogold labelling at the EM level shows that

MUC1 is produced by goblet cells.MUC 3 and MUC4

appear to be most abundantly expressed by columnar cells

of normal colorectum.

Studies of mucin gene expression in Barrett's oesophagus

reveal the expression of gastric mucins MUC5AC (Fig

4) and MUC6 as well as intestinal mucins (MUC2,MUC3

and MUC4) by 'intestinalised' epithelium (20).This findings

confirm the incomplete nature of intestinalisation in

Barrett's oesophagus. A similar mucin pattern is observed

in incomplete intestinal metaplasia of gastric mucosa (21)

However, whereas MUC5AC appears to be restricted to

columnar cells in Barrett's oesophagus, it is expressed by

both goblet cells and columnar cells in incomplete intestinal

metaplasia of the stomach (22). As in incomplete

intestinal metaplasia of gastric mucosa, subtypes of

Barrett's epithelium secreting sulphomucin have been

associated with neoplastic progression. This finding occurs

with high frequency in Barrett's epithelium and has not

translated into a practical marker of increased risk.

It is unclear whether Barrett's mucosa develops as an

upward extension of a metaplastic gastric mucosa or represents

a transformation of stem cells within the ducts of

oesophageal mucous glands (23).The presence of MUC5B

in oesophageal glands but not in Barrett's oesophagus fits

the first hypothesis (22).The finding of cytokeratin (CK 7)

within both Barrett's epithelium and oesophageal glands

but not to the same extent in intestinal metaplasia of gastric

mucosa supports the second hypothesis. The possibility

that reflux injury in the lower oesophagus could be

caused by defective oesophageal mucin production has

been considered (24). The main secretory mucin MUC5B

is produced by the submucous oesophageal glands but

membrane bound mucins (MUC1 and MUC4) are

expressed by oesophageal squamous epithelium and may

have an important cytoprotective role.The mixed gastric

and intestinal phenotype characterising intestinalised

mucosa could represent an adaptation to cell injury mediated

by the combination of gastric acid and bile (22). A

cytoprotective role is supported by the demonstration of

expression of trefoil peptides TFF1 and TFF2 by Barrett's

epithelium.

Progression of Barrett's epithelium to dysplasia and

malignancy is usually accompanied by downregulation of

secretory mucins MUC2, MUC5AC and MUC6, similar to

cancer of stomach and colon (25).The other authors have

reported that Barrett's metaplasia expressed MUC2 (an

intestinal mucin), but MUC1 was consistenly absent (26).

Neither MUC1 or MUC2 were expressed in the dysplastic

epithelium whether in its form or when associated with

carcinomas.The lack of MUC1 in dysplastic epithelium

and its expression in carcinoma could be utilyzed as a

marker which could differentiate dysplasia from carcinoma

in mucosal biopsies (26). Furthermore, expression of

MUC1 in advanced stage oesophageal cancers suggests an

unfavourable prognosis.

Membrane bound mucins MUC1 and MUC4 may

show upregulation, as in the other regions of the gastrointestinal

tract, whereas the membrane bound mucin MUC3

is downregulated (Table 1) (19).

Immunohistochemistry

Minichromosome maintenance (Mcm) proteins are

essential for eukaryotic DNA replication, and their expression

implies potential for cell proliferation. xpression is

dysregulated in dysplastic states, but data for oesophageal

squamous mucosa and Barrett's mucosa have not been published

(13).

Immunostaining with the Mcm2 antibody yielded predominantly

nuclear staining. The Mcm5 antibody stains

nuclei but also cell membranes in glandular mucosae and

tumours. Qualitatively, nuclear staining is similar with the

two antibodies. Ki-67 staining is purely nuclear.

In non-dysplastic squamous epithelium and Barrett's

mucosa, strong Mcm2, Mcm5, and Ki-67 staining of most

to all nuclei are present in the expected proliferative transit

compartment-that is, the suprabasal compartment of

squamous epithelium-and in the lower crypt compartments

of Barrett's mucosa. In differentiated compartments-that is,

the surface of squamous epithelium and Barrett's mucosaand

in the small differentiated deep glands of Barrett's

mucosa, expression is downregulated. In dysplastic squamous

epithelium and dysplastic Barrett's mucosa there is

persistence of Mcm2, Mcm5,and Ki-67 expression in compartment

in which they are normally absent or sparse,

especially towards the surface of squamous epithelium and

Barrett's mucosa. Downregulation of Mcm2 and Mcm5

expression in the deep(glandular) mucosal compartment of

Barrett's mucosa is also significantly reduced in high grade

dysplasia (13,14).

Genetics

In Barrett oesophagus a variety of molecular genetic

changes has been correlated with the metaplasia-dysplasiacarcinoma

sequence (27). Prospective follow-up of lesions

biopsied at endoscopy show that alterations in TP53 and

CDKN2A occur at early stages (28).

TP53: in high-grade intraepithelial neoplasia a prevalence

of TP53 mutations of approximately 60% is found,

similar to adenocarcinoma. Mutation in one allele is often

accompanied by loss of the other (17p13.1). Mutations

occur in diploid cells and precede aneuploidy. The pattern

of mutations differs significantly from that in squamous

cell carcinomas.

CDKN2A: alterations of CDKN2A, a locus on 9p21

encoding two distinct tumour suppressors, p16 and p19

include hypermethylation of the p16 promotor and, more

rarely, mutations and LOH (29).

FHIT: among other early changes in the premalignant

stages of metaplasia are alterations of the transcripts of

FHIT, a presumptive tumour supressor gene spanning the

common fragile site FRA3B (30).

LOH and gene amplification: a number of other loci are

altered relatively late during the development of adenocarcinoma,

with no obligate sequence of events. Prevalent

changes include LOH on chromosomes 4 (long arm) and 5

(several foci including APC) and amplification of ErbB2

(31).

Phenotypic changes in Barrett oesophagus includeexpansion of the Ki-67 proliferation compartment correlating

with the degree of intraepithelial neoplasia. Molecules

involved in membrane trafficking such as rabll have

reported to be specific for the loss of polarity seen in lowgrade

intraepithelial neoplasia. In invasive carcinoma,

reduced expression of cadherin/catenin complex and

increased expression of various proteases are detectable

Table 2) (31). Non-neoplastic Barrett oesophagus expresses

the MUC2 but not the MUC1 mucin gene product,

whereas neither is expressed in intraepithelial neoplasia in

Barrett oesophagus (31). Invasive lesions exhibit variable

expression of MUC1 and MUC2.

CONCLUDING REMARCS

Although the origin of BE is a matter of conjecture, one

current theory holds that the stem cells of squamous mucosa

or associated glandular ducts undergo altered differentiation,

producing both microvilli and intercellular ridges, and express

unique glandular phenotypes distinct from adjacent mucosal

gastric stem cells.This Barrett's metaplastic lineage may give

rise to Paneth cells and neuroendocrine cells in addition to

gastric and intestinal cells and is therefore pluripotent (32).

Curent theory indicates that these cells give rise to intestinaltype

metaplasia. However, skeptics argue that gastric type,

fundic type and sebaceous gland metaplasia (33) are also

descernible and that these metaplasia may more accurately be

refered to as a mosaic, although a convincing paradigm is

lacking (24,25,31,32). The reason behind this heterogeneity of

metaplastic phenotypes is unclear but the proportion of each

has been attributed in part to the composition of the refluxate

(environment). Phenotypic heterogeneity may also be controlled

genetically because clonal divergence in chromosomes

5,8,9,12,17, and 18 in nondysplastic Barrett's cells can also be

identified (34).

The location and composition of the proliferative compartment

in the crypts of the metaplastic epithelium are not as

well defined as in columnar lined epithelium of the stomach

(32). Interestingly, the degree of which differentiation occurs

varies considerably.BE that appears in childhood differs from

the adult variety in that intestinal mucins and cytokeratins are

not present. The adult variety also has an inflammatory cell

infiltrate and may have Helicobacter-like organisms, both of

which are less common in juvenile metaplasia. Barrett's

intestinal phenotype has higher proliferative indices; this is

associated with altered expression of multiple growth factors

and inducible nitric oxide synthase and cyclooxygenase-2.

Dysplastic cells may have proliferative controls that are

relaxed or uncoupled from the appropriate regulatory clues. In

part this may be a result of altered expression of cytokines and

growth factors, although the acquisition of genomic alterations

of cell-cycle-associated genes also occurs.These cell

cycle genes include increased cyclin D1 expression(chromosome

11q13), hypermethylated or mutated p16 (chromosome

9p21), and mobilization of cells from G0 to G1, with subsequent

accumulation in the G2 phase.Identification of

increased telomerase RNA in early dysplastic lesions including

Barrett's metaplasia has been reported. P53 mutations

occur in only 1-5% of metaplastic diploid cell populations but

are present in most aneuploid cells, suggesting they are usually

not early events (35,36). Epigenetic alterations in the

expression of growth factors and their receptors, especially of

the epidermal growth factor family, are also associated with

these cell cycle changes in dysplastic Barrett's mucosa. In particular,

the authors beleive that increased expression of

TGFalfa, and its precursor preproTGFalfa, may stimulate epidermal

growth factor receptors in dysplastic cells by autocrine

and paracrine mechanisms, respectively (37).

Apoptosis may also be inhibited late in a proportion of

dysplastic cells that give rise to invasive or metastatic cells

(38). The bcl-2 gene is not overexpressed, as is recognized in

colorectal adenomas, although p53 mutations may affect the

proliferation /apoptosis ratio in the oesophagus (39). In addition,

up-regulation of immunological death factors such as

Fas ligand in the epithelium may not only protect Barrett's

dysplastic cells but also may selectively destroy cytotoxic T

cells by crosslinking Fas (40).

Figure 1. Barrett oesophagus: dysplastic intestinal lands(right).

HE x 200.

Figure 2. Low-grade intraepithelial neoplasia on the left and high

grade on the right. HEx300.

Figure 3. Pyloric type of dysplastic metaplasia. HE x 250.

Figure 4. Conspicuous expression of MUC5AC. ABC x 250.

Recent evidence has shown that Barrett metaplasia and

dysplasia may partly involve down-regulation, mutation, or

phosphorylation of cadherin / catenin the adhesion complexes,

thereby increasing free cytosolic catenin.Increased betacatenin

levels have been shown to subsequently aggregate

with transcription factors in the nucleus, facilitating epitheliomesenchymal

transition and increased c-myc expression (41).

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