American Journal of Gastroenterology
C ?2004 by Am. Coll. of Gastroenterology
Published by Blackwell Publishing
Heterotopic Gastric Mucosa of the Esophagus:
Literature-Review and Proposal of a Clinicopathologic
Burkhard H. A. von Rahden, M.D., Hubert J. Stein, M.D., F.A.C.S., Karen Becker, M.D.,
Dorothea Liebermann-Meffert, M.D., F.A.C.S., and J. R¨ udiger Siewert, M.D., F.A.C.S.
Department of Surgery; and Department of Pathology, Klinikum rechts der Isar, Technical University Munich,
The prevalence of heterotopic gastric mucosa (HGM) in the cervical esophagus is frequently
underestimated. Tiny microscopic foci have to be distinguished from a macroscopically visible
patch, also called “inlet patch.” Symptoms as well as morphologic changes associated with HGM
are regarded as a result of the damaging effect of acid, produced by parietal cells in the mostly
fundic type of HGM.
We herein review the literature and propose a new clinicopathologic classification of esophageal
HGM: Most of the carriers of esophageal HGM are asymptomatic (HGM I). Some individuals with
HGM in the esophagus complain of dysphagia, odynophagia, or “extraesophageal manifestations”
(hoarseness and coughing), without further morphologic findings (HGM II). Still fewer patients are
symptomatic due to morphologic changes, i.e., esophageal strictures, webs, or esophagotracheal
fistula (HGM III). Malignant transformation via dysplasia (intraepithelial neoplasia, HGM IV) to
cervical esophageal adenocarcinoma (HGM V) is exceedingly rare (only 24 reported cases). In
contrast to Barrett’s esophagus, HGM should not be regarded as a precancerous lesion.
Symptoms are more likely to occur in patients with inlet patch, whereas malignant transformation
and adenocarcinogenesis can also occur in microscopic HGM foci. Asymptomatic HGM requires
neither specific therapy nor endoscopic surveillance. Only in symptomatic cases treatment, i.e.,
dilatation for (benign) strictures or acid suppression for reflux symptoms, can be recommended.
Patients with low-grade dysplasia in HGM might be candidates for surveillance strategies, whereas
in cases of high-grade dysplasia and invasive adenocarcinoma oncological treatment strategies
must be employed.
it can be responsible for local morphologic alterations (e.g.,
webs, strictures, ulcers, fistula) causing local symptoms (es-
pecially pain and dysphagia). Furthermore, in exceedingly
rare cases, HGM can be the origin of malignant progression
to cervical esophageal adenocarcinoma.
HGM is not exclusively found in the esophagus as it has
trointestinal tract, like the tongue (1), the duodenum (2), the
jejunum (3), the gall bladder (4), and the rectum (5).
macroscopically visible areas of red or salmon-colored vel-
vety patches. Predominant localization of esophageal HGM
ter. Such patches of macroscopically visible HGM are also
called “inlet patches.”
Although the first description of a gastric inlet patch in the
esophagus dates back 200 yr when Schmidt in 1805 was the
ology, pathophysiology, and treatment remain unanswered.
Selection of articles for this review was based on a comput-
erized MEDLINE database search for relevant literature, us-
ing the search terms “ectopic gastric mucosa,” “heterotopic
gastric mucosa,” “gastric inlet patch,” and “gastric hetero-
topia.” Articles were checked and included if relevant new
information on the topic were provided. The literature search
encompassed the years available online. Additionally, prior
articles cited in the papers were included if relevant.
Epidemiologic data concerning HGM are scarce. The ex-
act prevalence, the frequency of symptomatic cases, and the
544 von Rahden et al.
incidence of malignant progression to cancer are vaguely
Historical investigations revealed a prevalence of 0.67%
(7) to 70% when microscopically visible foci were included
Rector and Connerly revealed abberant gastric mucosa in the
upper esophagus in 4.5% of the cases (9). Unfortunately this
interesting question has not been addressed in more recent
of the cases (10–14), but the frequency tends to be clinically
The latter is due to the predominant localization in the re-
area is not easily accessible by endoscopy as it is just below
the scope of the otolaryngologist and exploration by flexible
upper gastrointestinal endoscopy is difficult: The region is
quickly passed protruding the endoscope over the sphincter’s
an inlet patch be detected (12, 13).
to 0.3 cm to 3 × 4 cm (12). They can be unique or multiple,
round or oval, can extent transversally or circumferentially.
The surface can be flat, slightly raised, or depressed, some-
times with heaped margins (15) (see Figs. 1 and 2)
The histologic appearance of HGM is fairly characteris-
tic (see Figs. 3 and 4) although esophageal mucosal glands
can be mistaken for HGM (16). Mostly the gastric mucosa
is uniformly of the fundic-type, containing parietal cells
(10, 12). Less frequently, histopathologic examination of
HGM shows a “transitional” cell type with random admix-
Figure 1. Development of the Mucosa in the human esophagus (from (17)).
by the absence of chief cells and only few parietal cells (10).
(infiltration of inflammatory cells) may be present and varies
in extent (10, 15). Infiltration with granulocytes as well as
common is the coexistence of esophagitis in the squamous
mucosa adjacent to the HGM (12).
Inherited Condition or Metaplastic Change?
Esophageal HGM is generally regarded as a congeni-
tal condition, resulting from an incomplete embryologic
esophageal epithelization process: The columnar epithelium
of the embryo’s esophagus is gradually replaced by squa-
mous cell epithelium. This process starts in the mideso-
phagus and extents vertically in both directions with the
cervical esophagus being the last region to get stratified
(17, 9, 18). If the squamous epithelization remains incom-
plete, the persisting columnar-lined area differentiates to
The development of the esophageal lumen and the pattern
of epithelization is illustrated in Figure 5. Cell types (colum-
nar/squamous cells), cell layers and special features of the
cells (vacuoles/cilia/glands), and the size of the esophageal
lumen at the certain stages of mucosal development are il-
lustrated. The features are correlated with the length of the
Barrett’s esophagus has formerly also been regarded as a
congenital condition, but nowadays it is generally accepted
that it is an acquired metaplastic change due to chronic gas-
troesophageal reflux. Repeatedly attempts have been under-
taken to find an association between Barrett’s esophagus and
HGM (19, 14). Avidan et al. judged from their findings in
a large case control study (53 patients with inlet patch and
4,882 control subjects) that the coincidence of the cervical
Heterotropic Gastric Mucosa of the Esophagus 545
after limited resection of the cervical esophagus succeeding neoadjuvant radiochemotherapy of an esophageal squamous cell cancer with
inlet patch and Barrett’s esophagus could suggest a shared
embryonic etiology (14).
Malhi-Chowla et al. reported, that in patients treated for
high-grade dysplasia in Barrett’s epithelium, the prevalence
of HGM in the cervical esophagus is much higher and ac-
counts for one-third of these patients (19). The authors con-
cluded that patients with HGM might be at higher risk for
Figure 3. Microscopic examination shows the glandular differentiated tissue, interposed between normal esophageal squamous cell
epithelium (H.E., 12x).
developing high-grade dysplasia in Barrett’s esophagus and
thus HGM might be a suitable marker.
physiologic and morphologic characteristics with Barrett’s
esophagus: Areas of intestinal metaplasia have been re-
ported to occur within ectopic gastric mucosa (20, 15). Sim-
ilarities of the mucin profile of HGM and Barrett were
546 von Rahden et al.
Figure 4. HGM consisting of well-differentiated gastric tissue with mucus-secreting columnar cells, chief cells, and parietal cells (H.E.,
regarded as suggestive of a pathogenic link between these
Since it has been suggested by Ormsby et al. that Bar-
rett’s esophagus can reliably be distinguished from intestinal
metaplasia of the stomach according to a specific cytokeratin
staining pattern (21), much interest has been focused on the
immunohistochemical characterization of esophageal glan-
dular epithelia. Although different authors have thus far sup-
ported the findings by Ormsby, the diagnostic significance
of the CK7 positive/CK20 negative phenotype is not gen-
erally accepted (e.g., (22)). Recently Chatelain et al. have
Figure 5. Fiberoptic endoscopic view of a large inlet patch, size 2.5 × 1 cm, localized immediately below the upper esophageal sphincter.
staining pattern in HGM of a patient with associated cervi-
cal esophageal adenocarcinoma (23). The authors concluded
from these findings (in addition to the considerations that
HGM shares “some common clinical features with Barrett’s
esophagus”) that both—Barrett and HGM—have a common
pathogenesis, related to gastroesophageal reflux disease.
Others hypothesized that some features reminding of
a superimposed acquired component to an underlying con-
genital lesion (16).
Heterotropic Gastric Mucosa of the Esophagus547
not been finally determined as yet, and further investigations
are needed to resolve these questions.
Pathophysiology: Acid is the Evil Agent
Acid is the damaging agent in the pathophysiology of symp-
tomatic esophageal HGM. Gastric parietal cells of the ec-
topic gastric tissue have been proven to be able to secrete a
pathophysiologically effective amount of acid (10, 24–26).
This acid can induce chronic inflammation and ulceration.
The subsequent healing process can lead to formation of
esophageal strictures and webs (24, 27–29).
ing after stimulation with pentagastrin (25). The secretion
has also been demonstrated using a pH electrode attached to
a standard fiberoscope (26) or by continuous ambulatory pH
It has been shown that the pH in the area of the inlet patch
is less than 4, but the pH milieu in the distal esophagus is not
is neutralized by saliva (24). Furthermore a meal-related se-
revealed by the study.
It has been assumed that in view of the functional capacity
of the HGM patches to produce acid, larger patches are more
likely to produce symptoms (12).
Symptoms (dysphagia) as well as presumable “extrae-
sophageal” manifestations of the acid production (coughing,
hoarseness) are resolved by acid suppression therapy with a
proton pump inhibitor (24).
rings and webs associated with iron-deficiency anemia has
been subsumed under Paterson–Kelly or Plummer–Vinson
syndrome or termed sideropenic dysphagia (30–32). Later,
HGM has been suggested as a possible cause of this syn-
drome (28, 33): Functionally active (acid secreting) HGM
causes peptic lesions in the cervical esophagus, which may
heal through a reparative process with formation of ring-like
mia can result from chronic blood loss due to erosive lesions.
The clinical importance of HGM is limited to symp-
tomatic cases. Symptoms, signs, and complications are acid-
related. Predominant symptoms are dysphagia (34) and
pain/odynophagia. These result from different pathologic
changes, like formation of stenosis/strictures or webs (for
review see Ward et al. (29, 35, 26, 27)), esophageal spasms
and esophagotracheal fistula (36), and colonization/infection
with Helicobacter pylori (37, 38).
Malignant progression to adenocarcinoma is exceedingly
rare, with only 24 cases reported in the world literature to
date (the literature on published cases is listed in Table 1).
Macroscopic suspicion of malignant transformation requires
histological confirmation by means of biopsy. The specimen
should be collected—as in most suspect lesions—from the
immediately below the sphincter (33).
Histologic confirmation of malignant behavior can appear
difficult as well: Sperling and Grendell (39) as well as Car-
rie (40) reported about adenocarcinomas proven only during
subsequent surgical resection.
The association between H. pylori and pathogenesis of ac-
ism to colonize gastric type mucosa has been demonstrated.
By contrast HGM has been shown to be only colonized with
H. pylori, when the bacterium is also present in the stomach
(37, 38). Colonization of HGM was not observed in absence
of HP in the stomach. Furthermore in this study there was
no apparent correlation between positivity of HP and acute
or chronic inflammation in HGM patches. Thus it is unlikely
colonization, although this question has not been answered
in this study.
Another recent endoscopic biopsy study on H. pylori
colonization of inlet patches (38) confirmed these results
and found a prevalence of 73% (in 27 of 37 patients with
H. pylori gastritis and HGM in the esophagus the inlet patch
was also colonized). Interesting hypotheses have been pro-
reservoir for oral–oral transmission or a niche where antibi-
otics might have difficulty reaching (38).
Malignant Transformation and Adenocarcinoma
in the Cervical Esophagus
The low frequency of malignant transformation of HGM in
the distal esophagus suggests that it may not be regarded as
a premalignant lesion. Malignant progression of HGM is—
compared to its high prevalence—an exceedingly rare and
sporadic event, which is much less frequent than malignant
transformation of other tissues more commonly involved in
carcinogenesis, e.g., colonic mucosa.
Presumably, malignant progression within HGM occurs in
ithelia: The heterotopic, but otherwise “normal” epithelium
initially may change to low- and then high-grade dysplasia
(“intraepithelial neoplasia” according to the new nomencla-
ture recently introduced by the WHO (42)) and finally ad-
vance to invasive carcinoma: This might be similar to ma-
lignant transformation of Barrett’s esophagus, following a
metaplasia-dysplasia-carcinoma-sequence and for colorectal
cancer, for which an adenoma-carcinoma sequence has been
well described (43). However, so far only exceedingly few
cases of high-grade dysplasia in esophageal HGM have been
New Clinicopathologic Classification
We propose a new clinicopathologic classification of
esophageal HGM that summarizes current knowledge about