ORIGINAL ARTICLE
Adenocarcinomas of the Distal Esophagus and ‘‘Gastric
Cardia’’ Are Predominantly Esophageal Carcinomas
Parakrama Chandrasoma, MD, Kumari Wickramasinghe, MD, PhD, Yanling Ma, MD,
and Tom DeMeester, MD
Background: Adenocarcinoma of the distal esophagus and
gastric cardia are defined by the relationship of its epicenter to
the gastro-esophageal junction, which is presently defined as the
end of the tubular esophagus. We have recently suggested that
the true gastro-esophageal junction is best defined by the
proximal limit of gastric oxyntic mucosa.
Aim: To reclassify adenocarcinomas of this region by the
relationship of the tumor to the proximal limit of gastric oxyntic
mucosa.
Methods: Seventy-four patients who had esophago-gastrectomy
for adenocarcinomas in this region were classified as adenocarcinoma of distal esophagus (38 patients) and gastric cardia
(36 patients) by present criteria. The epithelial type at the
epicenter and distal edge of these tumors was assessed.
Results: The epicenter of the tumor in 64 patients with
noncircumferential tumors had squamous (5 cases), cardiac
(21 cases), oxynto-cardiac (4 cases), and intestinal (Barrett-type)
(34 cases) epithelia. None had gastric oxyntic mucosa. Of the 10
patients with circumferential tumors, 7 had cardiac or oxyntocardiac epithelium at the distal tumor edge.
Conclusions: If the gastro-esophageal junction is defined
histologically as the proximal limit of oxyntic mucosa, 71/74
patients would be classified as adenocarcinoma of the distal
esophagus. The other 3 patients were questionable as to gastric
or esophageal origin. We suggest that this reclassification based
on the proposed new definition of the gastro-esophageal
junction provides an explanation for the epidemiologic relationship that exists between adenocarcinoma of the ‘‘gastric cardia’’
and gastro-esophageal reflux disease.
Key Words: gastro-esophageal junction, esophagus, adenocarcinoma, gastric cardia, Barrett esophagus
(Am J Surg Pathol 2007;31:569–575)
From the Departments of Surgical Pathology and Foregut Surgery,
Keck School of Medicine and University of Southern California,
Los Angeles, CA.
Supported by any external funding source.
Reprints: Parakrama Chandrasoma, MD, Department of Surgical
Pathology, LAC+USC Medical Center, GH 16-905, 1200 N. State
Street, Los Angeles, CA 90033 (e-mail: ptchandr@usc.edu).
Copyright r 2007 by Lippincott Williams & Wilkins
Am J Surg Pathol
Volume 31, Number 4, April 2007
A
denocarcinoma of the distal esophagus is a recognized complication of gastro-esophageal reflux.15 Its
incidence has increased 6-fold in the past 3 decades in the
United States and Western Europe.4,5,13,18,19,20 A similar
increase has been shown in the incidence of adenocarcinoma of the gastric cardia4,5,13,20 with a recent trend
suggesting a flattening of the incidence curve for this
location that has not been seen for esophageal adenocarcinoma.19 Somewhat surprisingly, epidemiologic
studies have shown that there is a correlation between
adenocarcinoma of the gastric cardia and symptomatic
gastro-esophageal reflux, although this correlation is
weaker than that for adenocarcinoma of the distal
esophagus.15
Classifying tumors of this region into distal
esophageal and gastric cardiac is based on endoscopic
and radiologic criteria15,24,25 or pathologic examination
of resected specimens.10 Endoscopically, the gastroesophageal junction is defined as the proximal limit of
rugal folds.16,22 In 2000, the Association of Directors of
Anatomic and Surgical Pathology (ADASP) made
recommendations for standardizing the classification of
these tumors in resected specimens.2 They advocated the
use of the relationship of the epicenter of the tumor to the
grossly defined gastro-esophageal junction. This group of
experts defined the gastro-esophageal junction as the
horizontal line drawn across the end of the tubular
esophagus. When classified by the present definitions of
the gastro-esophageal junction, there is evidence that
gastric cardiac adenocarcinomas commonly arise in
intestinal metaplasia of the gastric cardia,21 and that they
bear similarities to distal esophageal adenocarcinoma.6
We have suggested that the gastro-esophageal
junction is most accurately defined by histologic determination of the proximal limit of gastric oxyntic mucosa.7–10
The area proximal to this, which is esophagus, is lined by
squamous epithelium in normal people and a variable
extent of metaplastic esophageal columnar epithelium
(oxynto-cardiac, cardiac, and intestinal) in patients with
reflux damage. In our recent study of 10 esophagectomy
specimens,10 we showed that there was a region between
the end of the tubular esophagus (the present definition of
the gastro-esophageal junction) and the proximal limit
of gastric oxyntic mucosa (the true gastro-esophageal
junction) that was identified as esophagus rather than
stomach by the presence of submucosal esophageal
glands (Fig. 1). We designated this area as the ‘‘dilated
569
Chandrasoma et al
Am J Surg Pathol
Volume 31, Number 4, April 2007
FIGURE 1. Definition of the dilated end-stage esophagus,
which is the area distal to the end of the tubular esophagus
(the present definition of the gastro-esophageal junction) and
the proximal limit of gastric oxyntic mucosa (the true gastroesophageal junction) (gray = squamous epithelium; black =
cardiac mucosa with and without intestinal metaplasia;
white = gastric oxyntic mucosa. The submucosal glands are
shown as yellow circles).
end-stage esophagus.’’ The use of the end of the tubular
esophagus resulted in a discrepancy of 0.31 to 2.05 cm
between what is presently called the gastro-esophageal
junction and what we have shown is the true gastroesophageal junction.10 Sarbia et al,23 in a similar study of
esophagectomy specimens, showed that cardiac and
oxynto-cardiac mucosa can extend to 2.8 cm beyond the
end of the tubular esophagus. This error would have the
potential of distal esophageal adenocarcinomas being
incorrectly designated as gastric cardiac adenocarcinomas.
We undertook this study to compare how adenocarcinomas of this region would be classified on the basis
of the presently accepted gross definition of the gastroesophageal junction for use in resected specimens and the
new histologic definition of the gastro-esophageal junction that we have proposed. We were unable to test these
tumors against the presently accepted endoscopic definition of the gastro-esophageal junction; in many of these
cases, the rugal folds are greatly distorted in this region by
the presence of the tumor.
FIGURE 2. Adenocarcinoma of the distal esophagus by
present definition. The tumor extends focally across the line
of the end of the tubular esophagus but has its epicenter
slightly above the line.
to the tumor, and at the lateral edge of the epicenter of
the tumor. The last determination was not possible in 10
cases where the tumor involved the full circumference of
the esophagus.
MATERIALS AND METHODS
Seventy-four patients who underwent esophagogastrectomy for adenocarcinoma of the distal esophagus
and gastric cardia (proximal stomach) during the years of
1997 to 2000 were selected for study. The relationship of
the epicenter of the tumor to the grossly defined gastroesophageal junction was used to classify these tumors as
distal esophageal (Fig. 2) and gastric cardiac (Fig. 3). The
gastro-esophageal junction was defined as a horizontal
line drawn between the end of the tubular esophagus and
the saccular stomach as recommended by the ADASP.2
The specimen was sectioned extensively in a manner that
permitted evaluation of the mucosal types present
immediately proximal to the tumor, immediately distal
570
FIGURE 3. Adenocarcinoma of the gastric cardia, by present
definition. The tumor presents as an ulcerated mass whose
epicenter is clearly below the end of the tubular esophagus.
r
2007 Lippincott Williams & Wilkins
Am J Surg Pathol
Volume 31, Number 4, April 2007
Origin of Adenocarcinomas of the GEJ Region
FIGURE 4. Cardiac mucosa, consisting entirely of mucous
cells in surface, foveolar region and glands. Parietal and goblet
cells are absent.
FIGURE 6. Cardiac mucosa with intestinal metaplasia, characterized by the presence of well-defined goblet cells on
hematoxylin and eosin-stained section. No parietal cells are
seen.
The epithelial types were classified by previous
reported criteria7,9 into squamous, cardiac (epithelium
composed only of mucous cells without any parietal cells,
Fig. 4), oxynto-cardiac (containing glands composed of a
mixture of parietal and mucous cells, Fig. 5), intestinal
(defined by the presence of goblet cells in cardiac mucosa,
Fig. 6), and oxyntic (containing glands composed of
parietal and chief cells without mucous cells, Fig. 7). The
type of epithelium at the proximal, distal, and central
lateral edge of each tumor was recorded. Where more
than one epithelial type was present, priority was given as
follows: intestinal, cardiac, oxynto-cardiac, squamous,
and oxyntic, on the basis of our belief that the first 3
represents the gradation of these epithelial types in this
region from most to least abnormal of reflux-induced
columnar epithelia of the esophagus, and the last 2 are
normal epithelia of esophagus and stomach, respectively.8
FIGURE 5. Oxynto-cardiac mucosa, showing a mixture of
parietal cells and mucous cells in glands under the foveolar
region. Goblet cells are absent.
FIGURE 7. Gastric oxyntic mucosa with only parietal and chief
cells without mucous cells in the glands below the foveolar
region.
r
2007 Lippincott Williams & Wilkins
RESULTS
There were 58 men and 16 women in this series for a
M:F ratio of 3.6:1. By the present criterion for the gastroesophageal junction (a line drawn across the end of the
tubular esophagus), 38 (51%) of these tumors were
classified as distal esophageal (Fig. 2) and 36 (49%) as
gastric cardiac (Fig. 3). Of the 38 distal esophageal
cancers, 30 were men and 8 (21%) were women. Eight
571
Chandrasoma et al
(25%) of the 36 patients with gastric cardiac tumors were
women. The mean age was 64.1 years (median: 66 y;
range: 31 to 86 y). The tumor size ranged from grossly
invisible carcinomas to large tumors exceeding 15 cm in
greatest dimension. Histologically, they were all pure
adenocarcinomas and ranged from well differentiated to
poorly differentiated and showed many different histologic subtypes including tubular, mucinous, papillary,
signet ring cell, solid, microcystic, and clear cell types of
adenocarcinoma. The depth of invasion of the tumor was
intramucosal in 14 (18.9%), submucosal in 8 (10.8%),
intramural in 4 (5.4%), and transmural in 48 cases
(64.9%).
Helicobacter pylori gastritis was present in ten of 74
(14%) patients which is similar to the reported prevalence
of H. pylori infection in our previous study of carditis in
our study population.12 These 10 patients included 5 of 38
with distal esophageal tumors and 5 of 25 with gastric
cardiac tumors. Only one of these, a patient with a distal
esophageal tumor, had multifocal atrophic gastritis with
intestinal metaplasia in the gastric part of their resection
specimen. This patient had cardiac mucosa without
intestinal metaplasia at the distal edge of the tumor.
Lymph node involvement correlated with depth
of tumor invasion. There was 1 patient among the 14
intramucosal tumors that was node positive; this patient
had a poorly differentiated intramucosal carcinoma that
measured 3 cm with 1 positive node out of 45 nodes. Two
(25%) of 8 patients with submucosal tumors, 3 (75%) of
4 patients with intramural tumors, and 43 (90%) of 48
patients with transmural tumors had positive lymph
nodes.
The epithelial type at the proximal and distal edges
of the tumor was determined by examination of the
section immediately above the upper edge and below the
distal edge of the tumor, respectively (Table 1). Of interest
is the fact that 25 patients had nondysplastic intestinal
metaplasia proximal to the tumor, suggesting that the
carcinomas arose in the more distal part of the segment
of Barrett esophagus. No tumors had oxynto-cardiac or
oxyntic mucosa proximal to the tumor.
The epithelial type at the lateral edge of the
epicenter of the tumor was determined by examination
of the section across the center of the tumor in the 64
cases where taking such a section was feasible (Fig. 8).
The epithelial type at the center of the tumor was
squamous in 5 patients, intestinal in 34 (53%) patients,
cardiac in 21 (33%) patients, and oxynto-cardiac in 4
patients. None of the 64 noncircumferential tumors had
oxyntic mucosa at the epicenter (Table 1).
In 10 patients, circumferential involvement of the
esophagus precluded the evaluation of the epithelial type
at the lateral edge of the epicenter of the tumor. These
included 4 distal esophageal tumors and 6 gastric cardiac
tumors. Examination of the epithelium distal to the distal
limit of these tumors showed cardiac mucosa in 3 cases
and oxynto-cardiac mucosa in 4 cases; the other 3 patients
had oxyntic mucosa at the distal tumor edge. These 3
tumors were all large (4, 6.5, and 11 cm), with transmural
572
Am J Surg Pathol
Volume 31, Number 4, April 2007
TABLE 1. Epithelial Types Found at Proximal Edge, Distal
Edge, and Lateral Edge at the Epicenter of Distal Esophageal
and Gastric Cardiac Adenocarcinomas Classified by its
Relationship to the end of the Tubular Esophagus
Epithelial Type
Distal Esophageal
Tumors (n = 38)
At proximal edge of tumor
Squamous
16 (42%)
Intestinal
20 (53%)
Cardiac
2 (5%)
Oxynto-cardiac
0
Oxyntic
0
At the lateral edge of epicenter of tumor
Squamous
2 (5%)
Intestinal
25 (66%)
Cardiac
5 (13%)
Oxynto-cardiac
2 (5%)
Oxyntic
0
Circumferential
4 (11%)
tumor
At the distal edge of tumor
Squamous
0
Intestinal
12 (32%)
Cardiac
13 (34%)
Oxynto-cardiac
7 (18%)
Oxyntic
6 (16%)
Gastric Cardiac
Tumors (n = 36)
27 (75%)
5 (14%)
4 (11%)
0
0
3
9
16
2
(8%)
(25%)
(44%)
(6%)
0
6 (17%)
4
14
8
10
0
(11%)
(39%)
(22%)
(28%)
invasion and positive lymph nodes (17 of 62, 8 of 26, and
9 of 36 lymph nodes positive), lymphovascular invasion,
undermining of proximal squamous epithelium and distal
oxyntic mucosa and with satellite nodules in the mucosa
away from the main tumor.
The epithelial type at the distal edge of the tumor
was determined by examination of the vertical section
taken across the distal edge of the tumor and are shown in
Table 1. Sixteen patients, which included 6 distal
esophageal tumors and 10 gastric cardiac tumors, had
gastric oxyntic mucosa at the distal tumor edge. These
were characterized by being large tumors (size range from
2 to 11 cm; mean size 6 cm; median size 5.5 cm), deeply
FIGURE 8. Lateral edge at the epicenter of a moderately
differentiated adenocarcinoma of the gastric cardia showing
cardiac mucosa at the edge of the tumor.
r
2007 Lippincott Williams & Wilkins
Am J Surg Pathol
Volume 31, Number 4, April 2007
Origin of Adenocarcinomas of the GEJ Region
invasive (all 16 tumors were transmural) with evidence of
lymph node involvement (all 16 tumors showed lymph
node involvement). These tumors also showed frequent
undermining of the proximal squamous epithelium (15
cases), undermining of distal oxyntic mucosa (10 cases),
lymphovascular involvement (14 cases), and the presence
of satellite tumor nodules in squamous or oxyntic mucosa
(12 cases).
DISCUSSION
In 1953, Allison and Johnstone1 described the
columnar lined esophagus interposed between the squamocolumnar junction and the gastro-esophageal junction.
Before this, columnar lined esophagus was called a
tubular intrathoracic stomach by virtue of the fact that
the esophagus was believed to end at the squamocolumnar junction.3 In a masterful dissection of one of their
resection specimen, the pathologist, Dr D. H. Collins,
proved that what was being called ‘‘tubular stomach’’ was
in fact esophagus.1 He reports: ‘‘The esophagus was
separated with a knife from the stomach along the line of
peritoneal reflection. A vertical slice was then made
through the centre of the reconstituted specimenyy,
and three vertically contiguous blocks were preparedy’’
The histologic examination is reported: ‘‘The stomach
below the anatomical junction with the esophagus is lined
by gastric mucosa of fundal typey.. Cardiac glands and
cardiac gastric mucosa do not appear until 0.6 cm up the
anatomic esophagus’’ (Fig. 9).
Allison and Johnstone1 identify the features that
prove that the columnar lined structure is esophagus
rather than stomach: ‘‘it has no peritoneal covering, that
the musculature is that of the normal esophagus, that
there may be islands of squamous epithelium within it,
that there are no oxyntic cells in the mucosa, and that in
addition to gastric glands there are present typical
esophageal mucous glands’’ (Fig. 9).
When the validated definition of the true gastroesophageal junction (the peritoneal reflection) is used,
there is no confusion. The epithelium at and distal to the
gastro-esophageal junction is gastric fundal ( = oxyntic)
mucosa. The columnar lined esophagus is defined by an
epithelium that is largely cardiac. This is true whenever a
validated definition of the true gastro-esophageal junction
is used. De Hertogh et al,11 in a study of fetal specimens
showed that the epithelium at the gastro-esophageal
junction (the angle of His) contained parietal cells. Paull
et al,17 in a study of columnar lined esophagus showed
that the epithelium in and above the upper end of the
lower esophageal sphincter contained parietal cells.
We have shown that the use of the end of the
tubular esophagus or proximal limit of the rugal folds to
define the gastro-esophageal junction place the gastroesophageal junction at a point that can be over 2 cm
proximal to the true gastro-esophageal junction.10 The
effect of this error is to mis-label the most distal part of
the columnar lined esophagus as the proximal stomach.
This area that is presently mis-labeled proximal stomach
r
2007 Lippincott Williams & Wilkins
FIGURE 9. Diagrammatic representation of the dissection in
Allison and Johnstone of their case 1 by the pathologist, Dr
Collins. The epithelium at the peritoneal reflection (the true
gastro-esophageal junction) was gastric oxyntic mucosa.
Submucosal glands were present in the nonoxyntic mucosa
above this line that defined the columnar lined esophagus for
the first time (gray = squamous epithelium; black = cardiac
mucosa with and without intestinal metaplasia; white = gastric
oxyntic mucosa. The submucosal glands are shown as yellow
circles).
can be recognized as esophagus by the fact that it is not
covered by a peritoneal lining, it sometimes contains
squamous islands within it,14 it is proximal to gastric
oxyntic mucosa and lined by cardiac mucosa (with and
without intestinal metaplasia) and oxynto-cardiac mucosa
identical to that seen in the columnar lined esophagus,
and it contains submucous esophageal glands.10 These are
the same criteria that Allison and Johnstone1 used to
convince Norman Barrett that what he was calling the
tubular stomach was actually esophagus. We should
recognize that this is true today as well: these same
criteria should convince the reader that what we are
calling proximal stomach today is actually esophagus
when it displays these criteria.
If this is true, pathologic entities that are presently
classified as lesions of the gastric cardia, potentially
demand reclassification as esophageal lesions. These
include adenocarcinoma of the gastric cardia and
intestinal metaplasia of the gastric cardia. The 2 entities
are troublesome entities at present because, although they
are classified as gastric diseases, they have strong evidence
to indicate that they are associated with gastro-esophageal reflux disease. It is difficult to understand how
gastro-esophageal reflux disease can result in gastric
pathology. Also, adenocarcinoma of the gastric cardia
has epidemiologic similarities to esophageal rather than
gastric adenocarcinoma.
Our division of these tumors in the present study
into adenocarcinoma of the esophagus and gastric cardia
conforms to the International Classification of Diseases.
In this classification, tumors of the gastro-esophageal
junction are classified within the definition of gastric
573
Chandrasoma et al
cardiac tumors. When so classified, 38 patients had
distal esophageal tumors and 36 had gastric cardiac
tumors.
We applied the same recommendation presently
recommended by the ADASP to classify the tumor by the
relationship of its epicenter to the newly proposed gastroesophageal junction (the histologically defined proximal
limit of gastric oxyntic mucosa). The epithelium at the
epicenter of the tumor was defined by a lateral section
across the center of the tumor. If the epithelium at the
epicenter of the tumor was gastric oxyntic mucosa, the
tumor was classified as gastric; if it was squamous or
cardiac mucosa (with and without intestinal metaplasia)
and oxynto-cardiac mucosa, the tumor was classified as
esophageal. In 10 patients, this was not possible because
the tumor was circumferential.
When so reclassified, all 64 tumors (34 distal
esophageal and 30 proximal gastric) that were noncircumferential had cardiac mucosa (with and without
intestinal metaplasia) and oxynto-cardiac mucosa at their
epicenter and were classified as esophageal. This meant
that 30 of 36 tumors previously called gastric cardiac in
location were now reclassified as esophageal tumors.
The use of the relationship of the epicenter of a
tumor to the gastro-esophageal line to classify tumors of
this region, as suggested by most experts, is reasonable. It,
however, assumes equivalent growth of the tumor
proximally and distally. For example, if a tumor arises
1 mm above the gastro-esophageal junction and infiltrates
distally into the stomach in preference to proximally into
the esophagus, it is liable to be mis-classified as a gastric
cancer when it becomes large. A more specific criterion
for classification would be the relationship of the distal
edge of the tumor to the gastro-esophageal line. If the
distal edge of the tumor was proximal to the gastroesophageal line, there can be no argument about the
esophageal derivation of the tumor. In the present study,
the distal edge of the tumor showed oxyntic mucosa only
in 16 patients; in the other 58 patients, the mucosa distal
to the tumor was metaplastic esophageal epithelia
(oxynto-cardiac in 15 patients, cardiac in 27 patients
and intestinal in 16 patients). By our new proposed
definition of the proximal limit of oxyntic mucosa as the
true gastro-esophageal junction, the entire tumor in these
58 patients was esophageal. These 58 patients unquestionably have esophageal cancers because no part of their
tumor is in the stomach.
Ten patients had circumferential tumors, precluding
assessment of the epithelium at the epicenter of the
tumor. Examination of the epithelium at the distal edge of
these 10 circumferential tumors showed metaplastic
glandular epithelium in 7 patients (cardiac mucosa in 3
cases and oxynto-cardiac mucosa in 4 cases). In these 7
cases, therefore, the entire tumor was proximal to the
proximal limit of oxyntic mucosa, and therefore esophageal. Three patients had oxyntic mucosa at the distal
tumor edge; these tumors could be either true gastric
adenocarcinomas or esophageal adenocarcinomas extending into the stomach distally.
574
Am J Surg Pathol
Volume 31, Number 4, April 2007
The 16 patients who had oxyntic mucosa at the
distal edge of the tumor may have an adenocarcinoma of
the esophagus infiltrating across the gastro-esophageal
junction to involve gastric oxyntic mucosa or they
may have gastric adenocarcinoma infiltrating the esophagus. The epicenter in 13 of these tumors that were
noncircumferential showed squamous (3 cases), cardiac
(6 cases), oxynto-cardiac (1 case), or intestinal (3 cases)
epithelia. This indicates that in these 13 cases more than
half the tumor was in the esophagus but it does not prove
that the origin was esophageal because of the possibility
of nonuniform growth. By the present ADASP criterion
of classifying these tumors to the relationship of the
epicenter,2 these tumors would also be esophageal.
These tumors were all large (mean size 6 cm) and
extensively infiltrating tumors. They all showed transmural invasion with evidence of lymph node involvement
(all cases were node positive) and showed undermining of
the proximal squamous epithelium (15 cases), undermining of distal oxyntic mucosa (13 cases), lymphovascular involvement (14 cases), and the presence of
satellite tumor nodules (12 cases) in squamous lined
and oxyntic mucosa. The 3 circumferential tumors
with oxyntic mucosa distally also had all of these
features.
Using our new proposed criterion of the proximal
limit of oxyntic mucosa as the true gastro-esophageal
junction had the effect of shifting this line distally to the
extent that 58 of these cancers were entirely in the
esophagus. Thirteen of the other 16 tumors that had
oxyntic mucosa at its distal edge would have been
classified as esophageal if one applied the presently
accepted standard of taking the epicenter of the tumor
and its relationship to the gastro-esophageal junction to
indicate origin. It is only in the 3 circumferential cases
with oxyntic mucosa at the distal end that there is any
reasonable doubt about origin from esophagus or
stomach.
The reclassification of these tumors is based on a
newly proposed definition of the gastro-esophageal
junction: the proximal limit of gastric oxyntic mucosa.
We believe that this is more accurate than the presently
used definitions because it has been validated by the
criterion of submucosal esophageal glands. We suggest it
is worthy of examination and attempted duplication by
other workers because it provides an explanation for the
anomaly that adenocarcinomas presently classified as
‘‘gastric cardiac’’ have an epidemiologic association
with symptomatic gastro-esophageal reflux disease. This
correction would result in the probability that the
finding of intestinal metaplasia in cardiac mucosa distal
to the presently accepted gastro-esophageal junction is
equivalent to Barrett esophagus and therefore the
precursor lesion for most tumors presently believed
to be gastric cardiac.11 Whether this means that
surveillance is indicated when intestinal metaplasia is
found in this region will depend on the magnitude of
cancer risk associated with this finding. This is presently
unknown.
r
2007 Lippincott Williams & Wilkins
Am J Surg Pathol
Volume 31, Number 4, April 2007
REFERENCES
1. Allison PR, Johnstone AS. The oesophagus lined with gastric
mucous membrane. Thorax. 1953;8:87–101.
2. Association of Directors of Anatomic and Surgical Pathology.
Recommendations for reporting of resected esophageal adenocarcinomas. Am J Surg Pathology. 2000;31:1188–1190.
3. Barrett NR. Chronic peptic ulcer of the oesophagus and ‘oesophagitis’. Br J Surg. 1950;38:175–182.
4. Blot WJ, Devesa SS, Kneller RW, et al. Rising incidence of
adenocarcinoma of the esophagus and gastric cardia. JAMA. 1991;
265:1287–1289.
5. Blot WJ, Devesa SS, Fraumeni JF. Continued climb in rates of
esophageal adenocarcinoma: an update. JAMA. 1993;270:1320.
6. Cameron AJ. Epidemiology of columnar lined esophagus and
adenocarcinoma. Gastroenterol Clin N Am. 1997;26:487–494.
7. Chandrasoma P. Controversies of the cardiac mucosa and Barrett’s
esophagus. Histopathol. 2005;46:361–373.
8. Chandrasoma PT, Der R, Ma Y, et al. Histology of the
gastroesophageal junction: an autopsy study. Am J Surg Pathol.
2000;24:402–409.
9. Chandrasoma PT, Lokuhetty DM, DeMeester TR, et al. Definition
of histopathologic changes in gastroesophageal reflux disease. Am J
Surg Pathol. 2000;24:344–351.
10. Chandrasoma P, Makarewicz K, Wickramasinghe K, et al. A
proposal for a new validated histologic definition of the gastroesophageal junction. Hum Pathol. 2006;37:40–47.
11. De Hertogh G, Van Eyken P, Ectors N, et al. On the existence and
location of cardiac mucosa; an autopsy study in embryos, fetuses,
and infants. Gut. 2003;52:791–796.
12. Der R, Tsao-Wei DD, DeMeester T, et al. Carditis. A manifestation
of gastroesophageal reflux disease. Am J Surg Pathol. 2001;25:
245–252.
13. Devesa SS, Blot WJ, Fraumeni JF. Changing patterns in the
incidence of esophageal and gastric carcinoma in the United States.
Cancer. 1998;83:2049–2053.
r
2007 Lippincott Williams & Wilkins
Origin of Adenocarcinomas of the GEJ Region
14. Fass R, Sampliner RE. Extension of squamous epithelium into the
proximal stomach: a newly recognized mucosal abnormality.
Endoscopy. 2000;32:27–32.
15. Lagergren J, Bergstrom R, Lindgren A, et al. Symptomatic
gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med. 1999;340:825–831.
16. McClave SA, Boyce HW Jr, Gottfried MR. Early diagnosis of
columnar lined esophagus: a new endoscopic diagnostic criterion.
Gastrointest Endosc. 1987;33:413–416.
17. Paull A, Trier JS, Dalton MD, et al. The histologic spectrum of
Barrett’s esophagus. N Eng J Med. 1976;295:476–480.
18. Pera M, Cameron AJ, Trastek VF, et al. Increasing incidence of
adenocarcinoma of the esophagus and esophagogastric junction.
Gastroenterology. 1993;104:510–513.
19. Pohl H, Welch HG. The role of overdiagnosis and reclassification
in the marked increase of esophageal adenocarcinoma incidence.
J Natl Cancer Inst. 2005;97:142–146.
20. Powell J, McConkey CC. The rising trend in esophageal
adenocarcinoma and gastric cardia. Eur J Cancer Prev. 1992;1:
265–269.
21. Ruol A, Parent A, Zaninotto G, et al. Intestinal metaplasia is
the probable common precursor of adenocarcinoma in Barrett
esophagus and adenocarcinoma of the gastric cardia. Cancer.
2000;88:2520–2528.
22. Sampliner RE. Practice guidelines on the diagnosis, surveillance,
and therapy of Barrett’s esophagus. Am J Gastroenterol. 1998;93:
1028–1031.
23. Sarbia M, Donner A, Gabbert HE. Histopathology of the
gastroesophageal junction. A study on 36 operation specimens.
Am J Surg Pathol. 2002;26:1207–1212.
24. Siewert JR, Stein HJ. Adenocarcinoma of the gastroesophageal
junction. Classification, pathology and extent of resection. Dis
Esoph. 1996;9:173–182.
25. Siewert JR, Stein HJ. Classification of adenocarcinoma of the
oesophagogastric junction. Br J Surg. 1998;85:1457–1459.
575