Helicobacter pylori and Hetertopic Gastric Mucosa
in the Upper Esophagus (the Inlet Patch)
Oscar Gutierrez, M.D., Taiji Akamatsu, M.D., Hector Cardona, M.D., David Y. Graham, M.D., and
Hala M.T. El-Zimaity, M.D.
Gastrointestinal Mucosa Pathology Laboratory, Department of Medicine, Department of Pathology, Veterans
Affairs Medical Center and Baylor College of Medicine, Houston, Texas, USA; Department of Endoscopy,
Shinshu University Hospital, Matsumoto, Japan; and Department of Gastroenterology, National University of
Colombia, Bogota, Colombia
OBJECTIVES: Helicobacter pylori (H. pylori) may colonize
gastric mucosa wherever it is found in the GI tract. Heter-
otopic gastric mucosa in the upper esophagus (inlet patch) is
a potential site for H. pylori infection and may provide a
reservoir for oral-oral transmission or a niche where antibi-
otics might have difficulty reaching. The aim of this study
was to analyze the intensity and distribution of H. pylori in
the inlet patch.
METHODS: Whenever a cervical inlet patch was observed,
mucosal biopsy samples were taken to confirm the endo-
scopic diagnosis and to search for H. pylori and active
inflammation. In addition, mucosal biopsy samples were
also taken from the gastric mucosa. Formalin-fixed biopsy
specimens were cut and stained with a new dual stain
developed in our laboratory. The stain is a combination of
periodic acid-Schiff and a silver stain that allows simulta-
neous visualization of H. pylori and gastric type epithelium.
The density of H. pylori was scored using a visual analog
scale of 0 to 5. The type of mucosa in the inlet patch was
RESULTS: The study included 48 patients; 37 had H. pylori
gastritis and 27 of these (73%) had H. pylori identified on
their heterotopic gastric mucosa. A higher density of H.
pylori in the stomach was associated with a higher preva-
lence in the inlets. Active inflammation correlated with
active infection in the inlet patch and the presence of antral
CONCLUSION: H. pylori colonization of heterotopic gastric
mucosa in the upper esophagus is common and is closely
related to the H. pylori density in the stomach. The fact that
H. pylori was not found in all cases suggests that another
event such as reflux may be required for H. pylori to colo-
nize heterotopic mucosa. (Am J Gastroenterol 2003;98:
1266–1270. © 2003 by Am. Coll. of Gastroenterology)
Gastric type mucosa occurring in the upper one third of the
esophagus within 3 cm of the upper esophageal sphincter is
designated the “inlet patch.” Macroscopically, the inlet
patch typically has a deep pink, velvety appearance; it
presents either as a single patch or as multiple patches of
gastric mucosa situated just below the upper esophageal
sphincter. Microscopically, the patch can be lined with
either cardiac type glands or gastric body type mucosa. As
inlet patches are typically small (size range, ?1 cm to ?5
cm) (1), the presence of an inlet patch is often overlooked at
endoscopy; the chance of it being discovered is related to
Inlet patches are found in approximately 2–4% of esoph-
agi (2, 3) in all age groups. They are generally considered an
incidental congenital finding, and most patients have no
symptoms referable to the inlet patch. Nonetheless, the
patch can become the site of small peptic erosions/ulcers,
stenosis, fistula, intestinal metaplasia (4), high grade dys-
plasia (5, 6), or adenocarcinoma (7–11). We report a pro-
spective observational study designed to examine the rela-
tionship of Helicobacter pylori (H. pylori) colonization of
heterotopic gastric mucosa at the upper esophagus (i.e., inlet
MATERIALS AND METHODS
Over a 1-yr recruitment period, cervical inlet patches were
specifically looked for in patients undergoing upper GI
endoscopy at the University Hospital of the National Uni-
versity of Colombia, Bogota, Colombia. Patients were re-
ferred for endoscopy for a variety of reasons, primarily for
evaluation of dyspepsia. Heterotopic gastric mucosa of the
upper esophagus was identified as salmon-rose patches that
were clearly distinct from the adjacent grayish-pearly
esophageal mucosa (Fig. 1). Mucosal biopsy samples were
taken from the inlet patch (before the endoscope entered the
stomach) and from the gastric mucosa. Gastric mucosal
THE AMERICAN JOURNAL OF GASTROENTEROLOGY
© 2003 by Am. Coll. of Gastroenterology
Published by Elsevier Inc.
Vol. 98, No. 6, 2003
biopsy samples were obtained from predetermined, anatom-
ically defined locations along the greater and lesser curva-
ture of the stomach (12). The samples were taken using
large cup forceps (RADIAL JAW, MicroVasive, Water-
At endoscopy, patients were classified according to the
presence of erosive esophagitis, gastroesophageal reflux dis-
ease (GERD), and/or hiatal hernia. GERD patients were
classified into five grades according to the criteria of Savary
and Miller (13).
The investigation conformed to principles outlined in the
Declaration of Helsinki. Informed consent was obtained
from all subjects, and the ethical review committee of the
Universidad Nacional de Colombia in Bogota, Colombia,
approved the study.
Each biopsy specimen was placed in a separate bottle of
formalin and routinely processed. Serial sections were cut at
4 ?m and stained with a triple stain, either the Genta triple
stain (14) or El-Zimaity triple stain (15). Each specimen was
reviewed by one pathologist and scored using a visual
analog scale from 0 (absent/normal) to 5 (maximal inten-
sity) for H. pylori, polymorphonuclear leukocytes, and in-
testinal metaplasia (16). The type of epithelium in the inlet
patch biopsy sample was recorded. In addition, all biopsy
samples from the inlet patch were stained with El-Zimaity
dual stain (17) with hematoxylin as the counterstain (Figs. 1
and 2). The dual stain uses a combination of periodic acid-
Schiff and a silver stain, thus allowing simultaneous visu-
alization of H. pylori and gastric type epithelium (18). This
stain reliably allows recognition of even one or two bacteria
present on the entire section. Briefly, slides are deparaf-
finized, hydrated to water, oxidized in 0.5% periodic acid
for 5 min, and then placed in Schiff’s reagent for 3–5 min.
They are stained with a modified silver method using he-
matoxylin as counterstain (17).
All scores were entered into a database and analyzed using
SPSS 10 (SPSS, Chicago, IL) or STATA 7 (Stata, College
Station, TX). Analysis was done in several steps. First,
variables were screened independently for association with
presence of H. pylori or active inflammation in the inlet
patch. Fisher’s exact test or, when appropriate, the ?2test
(both two-tailed) were used for comparison of proportions.
Next, the results were used to construct a model (or models)
to predict the presence of H. pylori or active inflammation
in the inlet patch. All variables were treated as categorical
variables in the univariate as well as the multivariate anal-
ysis stage. Variables with statistical significance at the uni-
variate level, as well variables with particular clinical inter-
est, were entered in the final model. A model was developed
through consecutive steps of backward elimination of non-
significant variables and using goodness of fit tests. Statis-
tical significance of differences and relationships were de-
termined by p values of ?0.05. Odds ratios were derived
from the coefficients of the model.
Figure 1. Inlet patches are located in the upper esophagus and has
antral type, transitional mucosa, or fundic type epithelium sur-
rounded with esophageal squamous epithelium (El-Zimaity dual
Figure 2. H. pylori density is typically lower than that seen in the
corresponding stomach with few bacilli seen in the inlet patch
(El-Zimaity dual stain, ? oil immersion).
AJG – June, 2003
H. pylori in the Upper Esophagus
Over a 1-yr period, a total of 1495 patients undergoing
upper GI endoscopy were screened endoscopically for the
presence of “inlet patch.” In all, 57 patients (29 male and 28
female; median age 41 yr, range 17–75 yr) were identified.
In nine patients the inlet biopsy samples were too small and
superficial for detailed analyses, and these patients were
excluded from the analyses. Clinical information was not
available in three patients. The prevalence of the evaluated
clinical characteristics of patients with inlet patch, as well as
characteristics of an age- and sex-matched control group,
are summarized in Table 1.
A total of 152 slides were examined from the 48 patients
included in the study: 103 from the stomach (median two,
range two to eight), and 49 from the inlet patch (median one,
range one to two). The inlet patch had antral type mucosa in
25 cases (54%), fundic type epithelium in five (11%), and
transitional mucosa in 16 (35%). In two patients, inlet patch
mucosa was replaced with intestinal metaplasia.
H. pylori was identified in the inlet patch 73% (27/37) of
patients with active H. pylori infection and in none (0/11) of
the patients who were negative for gastric H. pylori infec-
tion (p ? 0.001) (Table 2). When H. pylori were seen, the
density of infection was lower than that seen in the corre-
sponding stomach (inlet H. pylori mean and median 2, range
1–4 vs gastric H. pylori mean and median 3, range 1–5)
The type of mucosa did not influence its colonization with
H. pylori. For example, among the 27 patients who were
positive for both gastric and inlet patch H. pylori, the inlet
patch mucosa was antral type in 15, oxyntic type in three,
and transitional type in nine. Of the 10 patients who were
positive for gastric H. pylori but negative for inlet H. pylori,
the inlet patch had antral type mucosa in six cases and
transitional type mucosa in four (p ? 0.548).
With univariate analysis in the logistic model, significant
predictors of the presence of H. pylori in the inlet patch were
gastric H. pylori density (p ? 0.008), age (p ? 0.05), and
presence of a hiatal hernia (p ? 0.06). The type of mucosa
(antral type vs corpus-like) was not a significant predictor
factor for the presence of H. pylori (p ? 0.816). GERD was
not a significant predictor factor for the presence of H.
pylori in the inlet patch. We evaluated for possible interac-
tion of the various factors (e.g., reflux and/or hiatal hernia
with H. pylori density in the stomach). None of these factors
were found to be significant. The final logistic model in-
cluded gastric H. pylori density, age, and presence of a
hiatal hernia. Gastric H. pylori density in the stomach was
the only significant predictor of H. pylori status in the inlet
patch (p ? 0.03). For a SD increase in gastric H. pylori
density, a finding of H. pylori in the inlet patch was two
times more likely (OR ? 2.284; 95% CI ? 1.066–4.89)
Acute and Chronic Inflammation
ACTIVE INFLAMMATION IN THE INLET PATCH.
Active inflammation correlated well with active infection
and mucosa type. Patients with active infection and antral
type mucosa in the inlet patch were more likely to have
active inflammation (p ? 0.01). This relationship was also
confirmed using a logistic regression model. At the univar-
iate level, the presence of H. pylori in the inlet (p ? 0.047),
as well as the type of mucosa (p ? 0.008), were significant
predictors of the presence of active inflammation in the inlet
patch. Other factors such as age, sex, and the presence of a
hiatal hernia or reflux did not influence the presence of
active inflammation in the inlet. Possible interactions among
various factors (e.g., reflux and/or hiatal hernia with H.
pylori density in the stomach) were examined, and none was
significant. The final logistic model included inlet H. pylori
density, inlet mucosa type, presence of reflux and/or hiatal
hernia, and age. At the multivariate level (final model), inlet
H. pylori density and type of mucosa were the only predic-
tors of the presence of active inflammation in the inlet,
holding all other factors in the model constant (p ? 0.01)
(Table 3). The odds of having active inflammation were two
to three times higher in patients with active H. pylori infec-
tion in the inlet in nonoxyntic mucosa (antral or transitional)
(OR ? 2.48; 95% CI ? 1.13–9.31).
CHRONIC INFLAMMATION IN THE INLET PATCH.
The scores for chronic inflammation (mononuclear cells)
were similar in patients with and without H. pylori infection,
irrespective of inlet patch mucosa type (p ? 1.00).
Table 1. Prevalence of Clinical Features Evaluated
H. pylori infection
Table 2. Correlation of Active Inflammation in Inlet Patch With
H. pylori Infection
Inlet Patch Active
Gastric H. pylori Absent
Gastric H. pylori Present 14
1268 Gutierrez et al.
AJG – Vol. 98, No. 6, 2003
Inlet Intestinal Metaplasia
Intestinal metaplasia was identified in the inlet patch in
seven patients. H. pylori was present in the gastric and inlet
mucosa in four patients. Two patients had complete replace-
ment of the underlying mucosa with intestinal metaplasia.
The type of mucosa was evaluated in the remaining five
patients; two had antral type and three transitional type.
Active inflammation was present in two patients (scores 2
and 3); both were positive for inlet H. pylori. Clinical
information was available in the seven patients. Three pa-
tients had clinical and endoscopic evidence of GERD (H.
pylori negative), and one patient had a hiatal hernia (H.
pylori positive). Clinical and endoscopic evidence of GERD
or hiatal hernia were not present in the remaining three
patients; two were positive for H. pylori. The number of
patients with intestinal metaplasia in the inlet patch was too
small for further analysis.
Correlation With Clinical and Endoscopic Findings
The presence of clinical or endoscopic evidence of reflux
and/or hiatal hernia had no influence on mucosal coloniza-
tion with H. pylori or on the presence of active inflamma-
tion. In both models that were developed to assess differ-
ences in having inlet mucosa colonized with H. pylori or
active inflammation, the presence of reflux and/or hiatal
hernia did not influence disease outcome (Table 3). These
results were consistent irrespective of GERD or hiatal her-
Heterotopic gastric mucosa has been described throughout
the GI tract including the tongue, floor of the mouth, sub-
mandibular gland, small intestine, pancreas, gallbladder,
and Meckel’s diverticulum (19–24). The term “inlet patch”
is given to small islets of glandular tissue resembling gastric
glands that are found in the esophagus within 3 cm of the
upper esophageal sphincter (hence the designation “inlet
patch”) (1). Although some autopsy studies have been done
(25), no systematic approach is used to identify such cases,
and the incidence is thus probably higher than the reported
prevalence of 2–4% (2, 3).
Although the origin of heterotopic gastric mucosa had
been a subject of debate (4, 26), most agree that it is likely
caused by entrapment of undifferentiated endodermal cells
during development (27). At approximately 10 wk of ges-
tation, a single layer of columnar cells lines the esophagus.
Stratified squamous epithelium appears at 5 months of ges-
tation in the middle third of the esophagus and extends
proximally and distally (28). If this process is not complete,
some columnar cells may persist at birth, usually distally
over the esophageal cardiac glands or proximally over the
upper one third of the esophagus (4, 27). Although most
changes such as high grade dysplasia (5, 6) and adenocar-
cinoma (7–11) have been described within the inlet patch.
Considering H. pylori’s affinity for gastric-type mucosa
(29–31), the importance of studying the relationship be-
tween such mucosa and H. pylori seems obvious. Yet, most
studies have either ignored the issue (4) or have examined
H. pylori in heterotopic mucosa without providing informa-
tion regarding the individual’s H. pylori status in the stom-
ach (2, 32).
In the current study, H. pylori colonization of heterotopic
gastric mucosa in the upper esophagus was common and
closely related to H. pylori density in the stomach (p ?
0.01). We took special care to biopsy the inlet patch before
examining the stomach to exclude the possibility that the
presence of H. pylori in the esophagus was related to con-
tamination when the endoscope was withdrawn. Active in-
flammation in the inlet patch was related to H. pylori pres-
ence in the inlet patch. Superficially, our study is somewhat
at odds with prior studies reporting that H. pylori was rarely
observed in inlet patch mucosa (2, 33, 34) and that the
presence of H. pylori had no apparent correlation with acute
or chronic inflammation in the inlet patch (34). It is likely
that the difference between results relates to the background
prevalence of H. pylori infection in the population. This
study was performed in Colombia, where H. pylori is very
prevalent. In prior studies, H. pylori was found in the inlet
patch in 35% (34) and 50% (33) of the subset with gastric
H. pylori. The low score of H. pylori in the inlet patch (mean
and median 2) indicates that it would be easy to miss the
bacteria histologically unless a specific stain such as the dual
stain was used.
Avidan et al. (4), while studying 53 patients with cervical
inlet patch, found a significant association with Barrett’s
Table 3. OR Stratified by the Dependent Variable
Inlet H. pylori
Gastric H. pylori
Inlet H. pylori
Inlet H. pylori, mucosa type*
Inlet active inflammation
* Inlet H. pylori mucosa type is an interactive term. *Delta ? 1 SD rather than 1 unit.
AJG – June, 2003
H. pylori in the Upper Esophagus
esophagus as well as with gastric ulcer. Although none of
our patients had Barrett’s esophagus, active inflammation in
the inlet patch correlated with both H. pylori infection and
the presence of antral type mucosa (p ? 0.019). In this
study, the presence of GERD or hiatal hernia did not cor-
relate with inlet patch colonization by H. pylori or with the
presence of active inflammation. The mechanism of H.
pylori colonization of the inlet patch is unclear. Although
contamination can occur during ingestion of food, the cor-
relation between gastric and inlet H. pylori suggest that
some degree of reflux might play a role (35). It is not known
what effect cure of H. pylori infection might have on an inlet
patch. Such a study is currently underway.
Reprint requests and correspondence: Hala M.T. El-Zimaity,
M.D., Veterans Affairs Medical Center (111-D), Room 3A-320,
2002 Holcombe Boulevard, Houston, TX 77030.
Received July 11, 2002; accepted Jan. 24, 2003.
1. Owen DA. Stomach. In: Sternberg S, ed. Histology for pa-
thologists, second ed. Philadelphia: Lippincott-Raven, 1997:
2. Jacobs E, Dehou MF. Heterotopic gastric mucosa in the upper
esophagus: A prospective study of 33 cases and review of
literature. Endoscopy 1997;29:710–5.
3. Borhan-Manesh F, Farnum JB. Incidence of heterotopic gas-
tric mucosa in the upper oesophagus. Gut 1991;32:968–72.
4. Avidan B, Sonnenberg A, Chejfec G, et al. Is there a link
between cervical inlet patch and Barrett’s esophagus? Gastroi-
ntest Endosc 2001;53:717–21.
5. Klaase JM, Lemaire LCJM, Rauws EAJ, et al. Heterotopic
gastric mucosa of the cervical esophagus: A case of high-grade
dysplasia treated with argon plasma coagulation and a case of
adenocarcinoma. Gastrointest Endosc 2001;53:101–4.
6. Mion F, Lambert R, Partensky C, et al. High-grade dysplasia
in an adenoma of the upper esophagus developing on hetero-
topic gastric mucosa. Endoscopy 1996;28:633–5.
7. Berkelhammer C, Bhagavan M, Templeton A, et al. Gastric
inlet patch containing submucosally infiltrating adenocarci-
noma. J Clin Gastroenterol 1997;25:678–81.
8. Sperling RM, Grendell JH. Adenocarcinoma arising in an inlet
patch of the esophagus. Am J Gastroenterol 1995;90:150–2.
9. Lauwers GY, Scott GV, Vauthey JN. Adenocarcinoma of the
upper esophagus arising in cervical ectopic gastric mucosa:
Rare evidence of malignant potential of so-called “inlet
patch.” Dig Dis Sci 1998;43:901–7.
10. Goodwin WJ, Larson DL, Sajjad SM. Adenocarcinoma of the
cervical esophagus in a patient with extensive columnar cell-
lined (Barrett’s) esophagus. Otolaryngol Head Neck Surg
11. Takagi A, Ema Y, Horii S, et al. Early adenocarcinoma arising
from ectopic gastric mucosa in the cervical esophagus. Gas-
trointest Endosc 1995;41:167–70.
12. El-Zimaity HMT, Al-Assi MT, Genta RM, Graham DY. Con-
firmation of successful therapy of Helicobacter pylori infec-
tion: Number and site of biopsies or a rapid urease test. Am J
13. Ollyo JB, Fontolliet CH, Brossard E, Lang F. Savary’s new
endoscopic classification of reflux esophagitis. Acta Endosc
14. Genta RM, Robason GO, Graham DY. Simultaneous visual-
ization of Helicobacter pylori and gastric morphology: A new
stain. Hum Pathol 1994;25:221–6.
15. El-Zimaity HMT, Ota H, Scott S, et al. A new triple stain for
Helicobacter pylori suitable for the autostainer. Arch Pathol
Lab Med 1998;122:732–6.
16. El-Zimaity HMT, Graham DY, Al-Assi MT, et al. Interob-
server variation in the histopathological assessment of Heli-
cobacter pylori gastritis. Hum Pathol 1996;27:35–41.
17. El-Zimaity HMT, Wu J, Akamatsu T, Graham DY. A reliable
method for the simultaneous identification of H. pylori and
gastric metaplasia in the duodenum. J Clin Pathol 1999;52:
18. El-Zimaity HMT, Wu J, Akamatsu T, Graham DY. A reliable
method for the simultaneous identification of H. pylori and
gastric metaplasia in the duodenum. J Clin Pathol 1999;52:
19. Taylor AL. The epithelial heterotopias of the alimentary tract.
J Pathol Bacteriol 1927;30:415–49.
20. Wolff M, Rankow RM. Heterotopic gastric epithelium in the
head and neck region. Ann Plast Surg 1980;4:53–64.
21. Devereaux CE, Devereaux RG. Heterotopic gastric mucosa of
the rectum with a review of the literature. J Clin Gastroenterol
22. Shim YT, Kim SY. Heterotopic gastric mucosa and pancreatic
tissue in the skin of the abdominal wall. J Pediatr Surg 1992;
23. Lamont N, Winthrop AL, Cole FM, et al. Heterotopic gastric
mucosa in the gallbladder: A cause of chronic abdominal pain
in a child. J Pediatr Surg 1991;26:1293–5.
24. Kalman PG, Stone RM, Phillips MJ. Heterotopic gastric tissue
of the bile duct. Surgery 1981;89:384–6.
25. Variend S, Howat AJ. Upper oesophageal gastric heterotopia:
A prospective necropsy study in children. J Clin Pathol 1988;
26. Rattner HM, McKinley MJ. Heterotopic gastric mucosa of the
upper esophagus. Gastroenterology 1986;90:1309 (letter).
27. Gray SW, Skandalikis JE. The esophagus. In: Gray SW, Skan-
dalikis JE, eds. Embryology for surgeons. Philadelphia: WB
28. Enterline H, Thompson J. The normal esophagus—embryol-
ogy, structure, and function. In: Enterline H, Thompson JS,
eds. Pathology of the esophagus. New York: Springer-Verlag,
29. Kestemberg A, Marino G, de Lima E, et al. Gastric heterotopic
mucosa in the rectum with Helicobacter pylori-like organisms:
A rare cause of rectal bleeding. Int J Colorectal Dis 1993;8:
30. Stermer E, Hardoff D, Zuckerman E, Miselevich I. Helico-
bacter pylori-associated peptic ulcer in heterotopic gastric
mucosa within ileal duplication. J Clin Gastroenterol 1994;18:
31. Chan GS, Yuen ST, Chu KM, et al. Helicobacter pylori in
Meckel’s diverticulum with heterotopic gastric mucosa in a
population with relatively high H. pylori prevalence rate. J
Gastroenterol Hepatol 1999;14:313–6.
32. Cuddihy PJ, Maheshwar A, Griffith H. Symptomatic hetero-
topic gastric mucosa in the upper oesophagus. J Laryngol Otol
33. Flejou JF, Potet F, Molas G, et al. Campylobacter-like organ-
isms in heterotopic gastric mucosa of the upper oesophagus.
J Clin Pathol 1990;43:961 (letter).
34. Borhan-Manesh F, Farnum JB. Study of Helicobacter pylori
colonization of patches of heterotopic gastric mucosa (HGM)
at the upper esophagus. Dig Dis Sci 1993;38:142–6.
35. Leung W-K, Siu KLK, Kwok CKL, et al. Isolation of Heli-
cobacter pylori from vomitus in children and its implication in
gastro-oral transmission. Am J Gastroenterol 1999;94:2881–4.
1270Gutierrez et al.
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