1. Cardiac mucosa in the remnant
esophagus after esophagectomy is an
acquired epithelium with Barrett’s-like
features
Reginald V. N. Lord, MBBS, MD, Kumari Wickramasinghe, MD, Jan J. Johansson, MD,
Steven R. DeMeester, MD, Jan Brabender, MD, and Tom R. DeMeester, MD, Los Angeles, Calif
Background. The cervical esophagus is normally lined by squamous epithelium and is usually not
exposed to gastroesophageal reflux. The aims of this study were, first, to investigate whether cardiac
mucosa can be acquired in the remnant cervical esophagus after esophagectomy and cervical
esophagogastrostomy and, second, to characterize this mucosa if present.
Methods. The medical records of 100 patients who had undergone esophagectomy with gastric pull-up
reconstruction were studied retrospectively to identify those who had biopsies from the cervical esophagus
proximal to the gastroesophageal anastomosis during postoperative follow-up. The histopathology and
immunohistochemical stains were reviewed to assess similarity to Barrett’s mucosa (cytokeratins [CK] 7
and 20 and DAS-1), cellular proliferation (topoisomerase 2a), and the potential for dysplasia (cyclo-
oxygenase 2 [COX-2] and ornithine decarboxylase [ODC]).
Results. Supra-anastomotic biopsies were performed in 20 patients. Cardiac mucosa was present in 10 of
20 (50%) patients in whom biopsies were performed. Four patients had areas of intestinal metaplasia,
and dysplasia, and adenocarcinoma developed in 1 patient. The CK7/20 and DAS-1 staining of the
columnar mucosa showed a pattern similar to Barrett’s mucosa. Topoisomerase 2a protein expression
was present in 50% of patients with cardiac mucosa. DAS-1 protein was expressed in cervical columnar
mucosa but not in normal squamous esophagus mucosa. The cardiac mucosa stained weakly for COX-2
and ODC.
Conclusions. Cardiac mucosa can be acquired. Its expression profile is similar to cardiac mucosa and
intestinal metaplasia found in Barrett’s esophagus, and different from normal esophageal or gastric
mucosa. The development of cardiac mucosa is likely to be related to reflux of acid into the remnant
cervical esophagus as the first step in the development of Barrett’s esophagus. These findings are
applicable to the development of similar changes at the gastroesophageal junction. (Surgery
2004;136:633-40.)
From the Departments of Surgery and Pathology, University of Southern California Keck School of Medicine,
Los Angeles, Calif
CARDIAC MUCOSA IS A SIMPLE, MUCINOUS COLUMNAR
mucosa with foveolar hyperplasia and no parietal
cells. It is found in the region of the gastroesoph-
ageal junction in most adults in Western society.
When present, it is almost invariably accompanied
by an infiltrate of chronic or acute inflammatory
cells and may thus be termed ‘‘carditis.’’1
Cardiac
mucosa is distinguished from the intestinal meta-
plasia (IM) that characterizes Barrett’s esophagus
only by the absence of goblet cells.
In the past, it was believed that up to 2 cm of
cardiac mucosa was normally present in the most
proximal section of the stomach, where it separa-
tes the parietal cell-containing gastric oxyntic mu-
cosa from the esophageal squamous mucosa.2,3
This prevailing view was challenged by a study
suggesting that cardiac mucosa, rather than being a
normally occurring mucosa, might be an acquired,
Accepted for publication January 17, 2004.
Supported by grants from the American Cancer Society, the
International Society for Diseases of the Esophagus, and the
STOP Cancer Foundation (R.V.N.L.).
Presented at the Society of University Surgeons 62nd Annual
Meeting, February 8-10, 2001.
Reprint requests: Reginald V. N. Lord, MBBS, MD, HCC 514,
1510 San Pablo St., Los Angeles CA 90033.
0039-6060/$ - see front matter
Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.surg.2004.01.009
SURGERY 633

2. metaplastic epithelium that develops in response to
exposure of esophageal squamous epithelium to
gastric acid.4
According to this hypothesis, the
histology of the normal gastroesophageal junction
consists of squamous mucosa abutting the parietal
cell-containing gastric oxyntic mucosa. Subsequent
studies have confirmed that this histologic pattern,
with squamous epithelium directly abutting oxyntic,
does occur.5,6
Further observations suggest that
the development of cardiac mucosa is induced by
exposing squamous epithelium to refluxed gastric
acid. The stimulus for the development of car-
diac mucosa may be refluxed gastric acid.7–9
This
introduced the possibility that the formation of
cardiac mucosa may be the first step in the
development of Barrett’s esophagus.10,11
Others
reject this possibility, leading to controversy re-
garding the nature and etiology of cardiac mu-
cosa.12–14
Unfortunately, limitations as to the
accurate location of endoscopic biopsies13,15
and
the rapid autolysis of the mucosa of the gastro-
esophageal junction in autopsy specimens5
have
made it difficult to resolve this controversy.14
In this study, we used the cervical esophagus
afteresophagectomy reconstructedwithagastroeso-
phagostomy as a model for de novo gastroesoph-
ageal reflux. In this situation, it can be confirmed
histologically that the squamous-lined cervical eso-
phagus is anastomosed to the gastric fundus lined
with oxyntic mucosa because any previously present
cardiac mucosa was removed with the surgical
specimen. Further, the cervical esophagus is not
normally exposed to gastric juice. Even in patients
diagnosed with gastroesophageal reflux disease
(GERD), acid exposure in the cervical esophagus
is relatively infrequent—less than 1% of a 24-hour
period.16
Consequently, even in patients with
severe GERD, the cervical esophagus is normally
lined by squamous epithelium. In contrast, after
esophagectomy and gastric pull-up, free reflux into
the cervical esophagus occurs.17
Esophagectomy
and cervical esophagogastrostomy is thus a unique
in vivo human model for de novo reflux disease.
This study was undertaken to test the hypothesis
that cardiac mucosa is an acquired, metaplastic
epithelium that arises from squamous mucosa in
response to exposure to gastric acid. If this hypo-
thesis is correct, reflux into the cervical esophagus
after esophagectomy should result in the develop-
ment of cardiac mucosa in the remnant esophagus,
as reported in other studies.18–20
We also sought to
characterize with immunohistochemistry the ac-
quired mucosa and to compare it with cardiac
mucosa at the gastroesophageal junction and
Barrett’s mucosa in the distal esophagus.
MATERIAL AND METHODS
After obtaining approval for this study from the
Institutional Review Board of the University of
Southern California Keck School of Medicine, the
medical records of 100 patients with esophageal
adenocarcinoma or squamous cell carcinoma who
had undergone esophagectomy with gastric tube
reconstruction were retrospectively reviewed.
Patients who had received chemotherapy or radi-
ation therapy were excluded because of the re-
ported association between these treatments and
the development of Barrett’s esophagus and
esophageal cancer. Of the 100 patients, 20 had an
endoscopic evaluation, which included a biopsy of
the remnant cervical esophagus taken from above
the gastroesophageal anastomosis 9 months or
more after esophagectomy. The endoscopies were
performed to investigate symptoms, including
regurgitation, dysphagia, chest pain, and either
loss or failure to gain weight; thus, these patients
were somewhat selected and may not be represen-
tative of the entire group of 100 patients reviewed.
The supra-anastomotic biopsies were performed to
conduct studies such as the present one. All
biopsies were performed by members of the sur-
gery faculty. The hematoxylin and eosin (H&E)
stained slides of all postoperative endoscopic
biopsies from these 20 patients were reviewed,
and patients with cardiac mucosa in the cervical
esophagus were identified. Formalin-fixed, paraffin-
embedded blocks of the esophageal biopsies
and the gastric biopsies, if obtained, from the
patients with cardiac mucosa in the cervical
esophagus were retrieved from the pathology
archives. In these selected patients, the pathology
report on the surgical margin before anastomosis
was reviewed.
Histopathology. The H&E-stained slides of the
supra-anastomotic cervical esophageal biopsies
were examined using the criteria of Paull et al,21
as modified by Chandrasoma et al.22
The diagnosis
of pure cardiac mucosa was made when the glands
were composed of mucous cells only, with no
parietal cells. Pure cardiac mucosa is thus similar
to the junctional epithelium of Paull et al.21
Oxyntic mucosa was recognized by the presence
of glands containing both mucous and parietal
cells, equivalent to the fundic epithelium described
by Paull et al.21
The diagnosis of IM required the
presence of definitive goblet cells. When visible
macroscopically, IM (or specialized epithelium)21
is
referred to as Barrett’s esophagus. Information in
the medical records was insufficient to be certain of
the endoscopic appearance of the cervical esoph-
Surgery
September 2004
634 Lord et al

3. agus in some patients, and therefore, macroscopic
data were not collected.
Immunohistochemistry. Immunohistochemical
stains were performed to assess similarity to
Barrett’s mucosa (cytokeratins [CK] 7 and 20 and
DAS-1), cellular proliferation (topoisomerase 2a),
and the potential for dysplasia (cyclo-oxygenase 2
[COX-2], and ornithine decarboxylase [ODC]).
Archival formalin-fixed, paraffin-embedded
blocks were cut into 6-lm sections, mounted onto
polylysine-coated slides, dewaxed in xylene, and
rehydrated through graded alcohol steps at room
temperature. Pretreatment by immersion in 10
mmol/L citrate buffer pH 6.0 with microwave,
pressure cooker heating was performed for all the
antibodies used. A 0.05M Tris-HCl buffer solution
(pH 7.6) was used to prepare solutions and for
washes between steps. The sections were peroxi-
dase-blocked using 3% hydrogen peroxide in 0.05
mol/L TRIS-hydrochloric acid buffer, incubated
for 15 minutes with normal horse serum, and
incubated with primary antibody (all overnight
at room temperature). The primary antibodies
used were: topoisomerase 2a Mab (diluted 1:100;
Neomarkers, Clone JH2.7, Fremont, Calif), cyto-
keratin (CK) 7 and CK 20 (both 1:100; DAKO,
Carpinteria, Calif), ornithine decarboxylase (ODC-
29, 1:50; Sigma Chemical, St. Louis, Mo), DAS-1
(1:5, kindly provided by Dr Kiron M. Das, University
of Medicine and Dentistry of New Jersey, Robert
Wood Johnson Medical School), and cyclo-
oxygenase 2 Mab (COX-2 clone 33, 1:50;
Transduction Laboratories, Lexington, Ky).
Biotinylated horse antimouse secondary antibody
(1:200 dilution for 40 minutes; Vector Labs, Burlin-
game Calif), peroxidase-conjugated-streptavidin
complex reagent (1:100 dilution, 30 minutes,
VectaStain Elite ABC Kit, Vector Labs), and 3,39-
diaminobenzidine (DAB, 10 mg in 10 ml tris buffer
for 20 minutes) were used to visualize binding of
the first antibody. Positive controls included
sections of colon cancer (CK-20), breast cancer
(CK-7), lymph node (topoisomerase 2a), and
normal colon (DAS-1). Negative controls used the
study sections without primary antibody. Immuno-
reactivity was graded as positive when there was
moderate or strong staining of at least 5% of the
mucosal cells of interest.
RESULTS
Cardiac mucosa was present in the cervical
esophagus in 10 of the 20 (50%) patients who
underwent biopsy. The indications for esopha-
gectomy in these 10 patients were adenocarci-
noma in 7, squamous cell carcinoma in 2, and
stricture in 1. In 4 of the 7 patients with adeno-
carcinoma, IM was identified in the esophagectomy
specimen. In all patients, the surgical margins prior
to anastomosis showed no IM or cardiac mucosa.
Figure 1 shows the endoscopic appearance of
an area of IM in the cervical esophagus in 1
patient.
Seven of the 10 patients who showed cardiac
mucosa on biopsy of the remnant cervical esoph-
agus were males, and the median interval between
esophagectomy and biopsy of cardiac mucosa was
36 months (range, 9 months–42 years). Cardiac
mucosa was found on the first endoscopy after
esophagectomy in 9 patients. These are the only
biopsies that were available for these patients. One
patient had 2 post-esophagectomy endoscopies
with biopsy. At the first endoscopy, performed 15
months after esophagectomy, only squamous epi-
thelium was present in the biopsy of the cervical
esophagus. At the second endoscopy, performed 9
months later, cardiac mucosa was found in the
cervical esophagus.
Four of the 10 patients with cardiac mucosa also
had goblet cells characteristic of IM in the supra-
anastomotic biopsies. One of the 4 patients, a
Fig 1. Endoscopic photograph showing a tongue of
intestinal metaplasia (Barrett’s esophagus) in the cervical
esophagus above the gastroesophageal anastomosis.
Surgery
Volume 136, Number 3
Lord et al 635

4. 57-year-old man who had undergone esopha-
gectomy at age 15 for an esophageal stricture
secondary to ingesting a coin at 9 months of age,
had Barrett’s esophagus with dysplasia and an
intramucosal adenocarcinoma in the remnant
cervical esophagus 42 years after esophagectomy.
Immunohistochemistry. The immunohisto-
chemistry results are shown in the Table. Rep-
resentative images are shown in Figures 2, 3, 4, 5,
and 6. CK7 staining of the cervical esophagus with
cardiac mucosa, IM, and dysplasia was similar to
Barrett’s esophagus in the distal esophagus and was
seen consistently in both the surface epithelium
and the deep glandular cells (Fig 2, A). The
staining was typically more intense in areas of IM
and dysplasia. In contrast to the columnar meta-
plasia pattern, CK7 staining of squamous mucosa
showed focal staining in the deep glandular cells
without staining in the superficial squamous cells.
Also similar to the pattern seen in Barrett’s
esophagus, CK20 staining of the cervical esophagus
containing columnar mucosa occurred in the
surface cells, but there was little or no staining of
the deep glandular cells (Fig 2, B). In contrast,
squamous mucosa did not stain. Again as found in
Barrett’s esophagus, DAS-1 antibody in cervical
cardiac mucosa stained intensely the mucin within
goblet cells and faintly the cytoplasm of some of the
columnar cells (Fig 3). Squamous epithelium did
not stain. All the cervical cardiac mucosa, including
sections with IM and dysplasia, showed positive
topoisomerase 2a staining, which was typically
stronger at the bases of crypts and in glands than
in the surface epithelium (Fig 4). The staining was
stronger in goblet cells and dysplastic cells than in
cardiac columnar cells. Normal squamous epithe-
lium showed topoisomerase 2a staining in the basal
layer.
Table. Immunohistochemistry findings in different tissue types from the 10 patients with
cardiac mucosa in the remnant cervical esophagus
Immunohisto-
chemistry
stain Purpose
Normal
squamous
mucosa
Normal
gastric antral
mucosa
Cardiac
mucosa
Cardiac mucosa
with IM
Cardiac mucosa with
IM, dysplasia,
adenocarcinoma
Number of
patients
10 5 10 4 1
CK 7 Similarity to
Barrett’s
esophagus
in the distal
esophagus
No superficial
staining.
Focal deep
glandular
staining.
Superficial
staining
in 2/5.
Deep glan-
dular
staining
in 5/5.
Superficial
staining
in all.
Deep glan-
dular
staining
in all.
Superficial
staining in all.
Deep glandular
staining in all.
Superficial
staining. Deep
glandular
staining.
CK 20 No superficial
staining.
No deep
glandular
staining.
Superficial
staining
in 2/5.
No deep
glandular
staining.
Superficial
staining
in all. No
or little deep
glandular
staining
Superficial
staining in all.
No deep
glandular
staining
Superficial
staining in all.
No deep
glandular
staining
DAS-1 No staining. Staining of
oxyntic
cells.
Weak cytoplasmic
staining of
columnar
cells in 2/10.
Staining of
mucin within
goblet cells.
Staining of
mucin within
goblet cells.
Topoiso-
merase
2a
Cellular
proliferation
Staining in
basal layer.
Staining of
basal layer
of crypts
and super-
ficial glands.
Staining in all
with more
intense
staining
in 5/10.
Staining in all
with more
intense staining
in goblet cells
than in cardiac
mucosa.
Intense staining
in dysplastic
and tumor cells.
COX-2* Potential for
dysplasia
No staining. Staining of
oxyntic cells.
Staining
in 2/10.
No staining. Staining.
ODC No staining. Staining of
oxyntic cells.
Weak staining
in 6/10.
Staining
in 3/4.
Staining.
CK, Cytokeratin; COX, cyclo-oxygenase; ODC, ornithine decarboxylase.
*Excludes staining of inflammatory cells.
Surgery
September 2004
636 Lord et al

5. The staining pattern for COX-2 and ODC was
similar. In the cervical esophagus, cytoplasmic
COX-2 epithelial staining was faint and was present
in only 2 of 10 patients with cardiac mucosa (Fig 5).
It was not present in those with IM but was present
in the tumor cells in the patient with cancer.
Intense ODC cytoplasmic epithelial staining was
present in the cervical esophageal mucosa with
dysplastic and tumor cells (Fig 6). Weak ODC
cytoplasmic staining was present in 6 of 10 patients
with cervical cardiac mucosa. It also was present in
goblet cells in 3 of the patients with IM. Squamous
mucosa did not stain for both antibodies, except
COX-2 stained inflammatory cells in the lamina
propria.
DISCUSSION
Our study shows that cardiac mucosa can be
an acquired, metaplastic epithelium.18,19
In the
remnant cervical esophagus of patients who had
esophagectomy with esophagogastrostomy, an op-
eration that provides a unique human model for de
novo reflux disease, we found cardiac mucosa in
the supra-anastomotic biopsy in half the patients
who had biopsy at this site. This indicates that the
columnar mucosa in these selected patients was
Fig 2. Immunohistochemistry images showing the ‘‘Barrett’s’’ cytokeratin 7/20 (CK 7/20) staining
pattern in a section of cardiac mucosa with IM biopsied from the supra-anastomotic cervical esophagus. A,
CK 7 staining is seen in both the surface epithelium and the deep glandular cells. B, CK 20 staining, in
contrast, is seen in the surface cells but not the deep glandular cells.
Fig 3. Immunohistochemistry image showing intense
DAS-1 staining of the mucin in goblet cells in a section of
cardiac mucosa with intestinal metaplasia in the supra-
anastomotic cervical esophagus.
Fig 4. Immunohistochemistry image showing moder-
ately intense topoisomerase 2a staining in a section of
cardiac mucosa with intestinal metaplasia in the supra-
anastomotic cervical esophagus.
Surgery
Volume 136, Number 3
Lord et al 637

6. acquired after the operation because at the time of
surgery, oxyntic mucosa was anastomosed to squa-
mous mucosa. The stimulus for this metaplastic
process is almost certainly acid reflux into the rem-
nant esophagus. This is supported by a study from
Sweden by O¨ berg et al in which pH probes
measuring 24-hour acid exposure were placed
in the cervical esophagus 1 cm above the eso-
phagogastric anastomosis in patients who had
esophagectomy.20
All patients with columnar mu-
cosa in the remnant esophagus had abnormal acid
exposure, and there was a direct correlation be-
tween the length of the metaplastic segment and
the percentage of time the cervical esophagus was
exposed to a pH less than 4.0.20
Interestingly, there
was no association between the presence of cervical
columnar metaplasia and exposure to bilirubin,
a marker for non-acid reflux, although the few
patients with IM in the cardiac mucosa had
abnormal esophageal exposure of both acid and
bilirubin. These results are similar to those found
in the distal esophagus, as indicated by a study that
found that similar proportions of patients with
cardiac mucosa and IM had abnormal esophageal
acid exposure (79% and 83%, respectively), but
abnormal esophageal bilirubin exposure was more
frequent in the patients with IM.9
Based on these
results, the hypothesis may be advanced that acid
reflux is sufficient to stimulate the development of
cardiac mucosa, but non-acid reflux may be
particularly important for the development of IM.
We found that cardiac mucosa in the remnant
esophagus shares some definitive characteristics
with cardiac mucosa and Barrett’s esophagus in the
distal esophagus. Most importantly, we found a CK
7/20 expression pattern similar to that of Barrett’s
esophagus23,24
in a majority of the patients with
cardiac mucsosa with or without IM and dysplasia.
In contrast, a ‘‘non–Barrett’s-like’’ CK pattern was
present in specimens of normal squamous and gas-
tric mucosa. The similarity between supra-anasto-
motic cardiac mucosa, distal esophageal cardiac
mucosa, and Barrett’s esophagus25
supports the
likelihood that IM may result from the develop-
ment of goblet cells within the cardiac mucosa.
Further, the ‘‘Barrett’s’’ CK staining pattern also
has been shown to be associated with a reflux
etiology.26
This study further supports the likeli-
hood of a reflux etiology for cardiac mucosa in the
remnant esophagus after esophagectomy.
The DAS-1 MAb reacts against colonic epithelial
cells, but not with normal small-bowel enterocytes
or esophageal mucosa.27
The antibody does react
intensely with an unknown epitope in Barrett’s
esophagus, particularly the incomplete (II and III)
type of IM.27,28
In the present study, intense DAS-1
staining of the mucin in goblet cells was observed in
cervical esophagus with intestinalized cardiac mu-
cosa. Further, the pattern of DAS-1 staining in both
the IM and cardiac columnar cells was similar to
that found in the lower esophagus.24
Cellular proliferation was assessed with
topoisomerase 2a immunohistochemistry. As ex-
pected, the proliferative zones in normal gastric and
esophageal mucosa, dysplastic Barrett’s cells, and
cancer cells were strongly positive for topoisomerase
2a. There was also evidence of increased prolifera-
tion in some of the cardiac mucosa, suggesting the
possibility of disease progression in some patients
Fig 5. Immunohistochemistry image showing only faint
cytoplasmic COX-2 epithelial staining in a section of
cardiac mucosa in the supra-anastomotic cervical esoph-
agus. Stronger COX-2 staining is seen in some in-
flammatory cells in the lamina propria.
Fig 6. Immunohistochemistry image showing moderately
strong ODC cytoplasmic staining in an area of low grade
dysplasia in the supra-anastomotic cervical esophagus.
Surgery
September 2004
638 Lord et al

7. with non-IM columnar metaplasia. The protein
expressions of ODC and COX-2 were also exam-
ined. Both of these genes have putative roles in
tumorigenesis. ODC is the initial and rate-limiting
enzyme in the biosynthetic pathway of polyamines,
which have essential roles in cell growth and dif-
ferentiation. Increased ODC protein and mRNA
expression have been reported in Barrett’s esoph-
agus and adenocarcinoma.29
Similarly, the pros-
taglandin synthesis enzyme COX-2, which has
been implicated as a fundamental factor in many
tumorigenic processes,30
is upregulated in some
Barrett’s tissues.31,32
The low ODC and COX-2
expressions found in cardiac mucosa in this study
support the clinical observation that cardiac mucosa
has very little malignant potential.
Cardiac mucosa is frequently present at the
gastroesophageal junction in adults in Western
society, raising the possibility that we have merely
taken biopsies of long-standing cardiac mucosa
from the distal, gastric side of the anastomosis.
This possibility is extremely unlikely because we
included only patients in whom it was noted that
the biopsies were from above the anastomosis,
and because at least 2 cm of proximal stomach, and
thus the gastroesophageal junction and all cardiac
mucosa, was resected at the time of esophagectomy.
The possibility that columnar mucosa was present
in the cervical esophagus before esophagectomy is
also excluded because only normal squamous
epithelium was seen at the proximal resection
margin at the time of operation. Furthermore, the
supra-anastomotic biopsies were performed for the
specific purpose of conducting studies such as the
present one. In this respect, although the methods
of data collection and specimen retrieval make this
a retrospective study, the biopsies were collected
prospectively.
In summary, cardiac mucosa can be an acquired,
metaplastic epithelium. It is likely that it develops
commonly after esophagectomy with gastric re-
construction and its presence very likely signifies at
least some reflux into the esophagus. This obser-
vation supports the hypothesis that cardiac mucosa
at the gastroesophageal junction in unoperated
individuals, despite the prevalence of this finding,
is also an acquired epithelium. CK 7/20 character-
ization shows that the cardiac mucosa in the
remnant esophagus is similar to Barrett’s in the
distal esophagus. This supports the possibility that
IM could arise from cardiac mucosa. Dysplastic
Barrett’s and adenocarcinoma developed in 1 pa-
tient in our study 42 years after esophagectomy.
This observation does not indicate the need for
routine post-esophagectomy surveillance of the
remnant esophagus, except perhaps in long-term
survivors.
REFERENCES
1. Der R, Tsao-Wei DD, DeMeester T, Peters J, Groshen S, Lord
RV, Chandrasoma P. Carditis: a manifestation of gastro-
esophageal reflux disease. Am J Surg Pathol 2001;25:245-52.
2. Hayward J. The lower end of the oesophagus. Thorax
1961;16:36-55.
3. Lord RV. Norman Barrett, ‘‘doyen of esophageal surgery’’.
Ann Surg 1999;229:428-39.
4. O¨ berg S, Peters JH, DeMeester TR, Chandrasoma P, Hagen
JA, Ireland AP, et al. Inflammation and specialized intestinal
metaplasia of cardiac mucosa is a manifestation of gastro-
esophageal reflux disease. Ann Surg 1997;226:522-30.
5. Chandrasoma PT, Der R, Ma Y, Dalton P, Taira M. Histology
of the gastroesophageal junction: an autopsy study. Am J
Surg Pathol 2000;24:402-9.
6. Zhou H, Greco MA, Kahn E. Origin of cardiac mucosa.
Ontogenic considerations. Mod Pathol 1999;12:499A.
7. Csendes A, Maluenda F, Braghetto I, Csendes P, Henriquez
A, Quesada MS. Location of the lower oesophageal
sphincter and the squamous columnar mucosal junction
in 109 healthy controls and 778 patients with different
degrees of endoscopic oesophagitis. Gut 1993;34:21-7.
8. Csendes A, Smok G, Burdiles P, Sagastume H, Rojas J,
Puente G, Q, et al. ÔCarditisÕ: an objective histological
marker for pathologic gastroesophageal reflux disease. Dis
Esoph 1998;11:101-5.
9. O¨ berg S, Peters JH, DeMeester TR, Lord RV, Johansson J,
DeMeester SR, et al. Determinants of intestinal metaplasia
within the columnar-lined esophagus. Arch Surg 2000;135:
651-5.
10. Chandrasoma P. Pathophysiology of Barrett’s esophagus.
Semin Thorac Cardiovasc Surg 1997;9:270-8.
11. Csendes A, Smok G, Flores N, Rojas J, Quiroz J, Henriquez
A. Comparison of clinical, endoscopic and functional
findings in patients with intestinal metaplasia at the cardia,
carditis and short-segment columnar epithelium of the
distal esophagus with and without intestinal metaplasia. Dis
Esoph 2000;13:61-8.
12. Chen YY, Antonioli DA, Spechler SJ, Zeroogian JM, Goyal
RK, Wang HH. Gastroesophageal reflux disease versus
Helicobacter pylori infection as the cause of gastric carditis.
Mod Pathol 1998;11:950-6.
13. Spechler SJ. The role of gastric carditis in metaplasia and
neoplasia at the gastroesophageal junction. Gastroenterol-
ogy 1999;117:218-28.
14. Kilgore SP, Ormsby AH, Gramlich TL, Rice TW, Richter JE,
Falk GW, et al. The gastric cardia: fact or fiction? Am J
Gastroenterol 2000;95:921-4.
15. Kim SL, Waring JP, Spechler SJ, Sampliner RE, Doos WG,
Krol WF, et al. Diagnostic inconsistencies in Barrett’s
esophagus. Department of Veterans Affairs Gastroesopha-
geal Reflux Study Group. Gastroenterology 1994;107:945-9.
16. Dobhan R, Castell DO. Normal and abnormal proximal
esophageal acid exposure: results of ambulatory dual-probe
pH monitoring. Am J Gastroenterol 1993;88:25-9.
17. Johansson J, Johnsson F, Groshen S, Walther B. Pharyngeal
reflux after gastric pull-up esophagectomy with neck and
chest anastomoses. J Thorac Cardiovasc Surg 1999;118:
1078-83.
18. Hamilton SR, Yardley JH. Regeneration of cardiac type
mucosa and acquisition of Barrett mucosa after esophago-
gastrostomy. Gastroenterology 1977;72:669-75.
Surgery
Volume 136, Number 3
Lord et al 639

8. 19. Lindahl H, Rintala R, Sariola H, Louhimo I. Cervical
Barrett’s esophagus: a common complication of gastric tube
reconstruction. J Pediatr Surg 1990;25:446-8.
20. O¨ berg S, Johansson J, Wenner J, Walther B. Metaplastic
columnar mucosa in the cervical esophagus after esoph-
agectomy. Ann Surg 2002;235:338-45.
21. Paull A, Trier JS, Dalton MD, Camp RC, Loeb P, Goyal RK.
The histologic spectrum of Barrett’s esophagus. N Eng J
Med 1976;295:476-80.
22. Chandrasoma PT, Lokuhetty DM, DeMeester TR, Bremmer
CG, Peters JH, Oberg S, et al. Definition of histopathologic
changes in gastroesophageal reflux disease. Am J Surg
Pathol 2000;24:344-51.
23. Ormsby AH, Goldblum JR, Rice TW, Richter JE, Falk GW,
Vaezi MF, et al. Cytokeratin subsets can reliably distinguish
Barrett’s esophagus from intestinal metaplasia of the
stomach. Hum Pathol 1999;30:288-94.
24. Glickman JN, Wang H, Das KM, Goyal RK, Spechler SJ,
Antonioli D, et al. Phenotype of Barrett’s esophagus and
intestinal metaplasia of the distal esophagus and gastro-
esophageal junction: an immunohistochemical study of
cytokeratins 7 and 20, Das-1 and 45 MI. Am J Surg Pathol
2001;25:87-94.
25. DeMeester SR, Wickramasinghe KS, Lord RV, Friedman A,
Balaji NS, Chandrasoma PT, et al. Cytokeratin and DAS-1
immunostaining reveal similarities among cardiac mucosa,
CIM, and Barrett’s esophagus. Am J Gastroenterol 2002;97:
2514-23.
26. Couvelard A, Cauvin JM, Goldfain D, Rotenberg A,
Robaszkiewicz M, Flejou JF, et al. Cytokeratin immunoreac-
tivity of intestinal metaplasia at normal oesophagogastric
junction indicates its aetiology. Gut 2001;49:761-6.
27. Das KM, Prasad I, Garla S, Amenta PS. Detection of a shared
colon epithelial epitope on Barrett epithelium by a novel
monoclonal antibody. Ann Intern Med 1994;120:753-6.
28. Griffel LH, Amenta PS, Das KM. Use of a novel monoclonal
antibody in diagnosis of Barrett’s esophagus. Dig Dis Sci
2000;45:40-8.
29. Brabender J, Lord RV, Danenberg KD, Metzger R, Schneider
PM, UetakeH, et al. Upregulation of ornithine decarboxylase
mRNA expression in Barrett’s esophagus and Barrett’s-
associatedadenocarcinoma.JGastrointestSurg2001;5:174-82.
30. Turini ME, DuBois RN. Cyclooxygenase-2: a therapeutic
target. Annu Rev Med 2002;53:35-57.
31. Wilson KT, Fu S, Ramanujam KS, Meltzer SJ. Increased
expression of inducible nitric oxide synthase and cyclo-
oxygenase-2 in Barrett’s esophagus and associated adeno-
carcinomas. Cancer Res 1998;58:2929-34.
32. Shirvani VN, Ouatu-Lascar R, Kaur BS, Omary MB, Triada-
filopoulos G. Cyclooxygenase 2 expression in Barrett’s
esophagus and adenocarcinoma: ex vivo induction by bile
salts and acid exposure. Gastroenterology 2000;118:487-96.
Surgery
September 2004
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