Heterotopic Gastric Mucosa in the Proximal Esophagus (Inlet Patch): Endoscopic Prevalence, Clinico-pathological Characteristics and Its Association with Helicobacter pylori

Abstract

Objective To determine the prevalence of the inlet patch (IP), its clinico-pathological features, and its association with Helicobacter pylori.

Materials and Methods A prospective observational study was performed on 1,889 patients referred for esophagogastroduodenoscopy for various reasons, primarily for the evaluation of dyspepsia. All patients were enquired about the presence of symptoms and carefully examined for the presence of IP during upper gastrointestinal (GI) endoscopy. Biopsies were taken from the patients who had IP.

Statistical Analysis All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) 13.0 software for Windows XP. Categorical variables were compared using the chi-squared test or Fisher's exact test and continuous variables were compared using Student's t-test and univariate analysis. A P-value of less than 0.05 was considered to be statistically significant.

Results Inlet patches were found in 34 of 1,889 patients (1.8%). H. pylori was identified in 23.52% of patients (8/34) with IP. Gastric H. pylori infection was positive in all (08/08) patients who had IP. Colonization of H. pylori was more common in antral type mucosa (6/8). H. pylori positivity in the IP correlated with globus sensation symptom in our study, 87.5% of patients with IP and H. pylori positive had globus sensation.

Conclusion The prevalence of IP seems to be underestimated. H. pylori colonization of the IP is common and it positively correlates with globus sensation and is closely related to the H. pylori density in the stomach. Though preneoplasia within IP is rare, which does not support the recommendation to regularly obtain biopsies for histopathology, it might be beneficial in a subset of patients with persistent globus sensation.

Keywords

cervical heterotopic gastric mucosa - globus sensation - Helicobacter pylori - inlet patch

Introduction

Islands of heterotopic gastric mucosa are found throughout the gastrointestinal tract, the most common site being the cervical esophagus. IP is not always an acquired condition; several studies suggest an embryologic origin. During normal embryonic development, the squamous cell epithelium of the esophagus is replaced by columnar epithelium starting from the mid esophagus to the cervical esophagus. However, persistent columnar-lined areas that result from incomplete squamous epithelialization can further differentiate into an inlet patch (IP).[1]

Patients with cervical heterotopic gastric mucosa (CHGM) have various laryngeal and oropharyngeal symptoms, ranging from asymptomatic to protracted symptoms such as globus sensation and chronic cough due to acid secretion from the IP.[2] [3] [4] [5] The usual complaint in patients with globus sensation or globus pharyngeus is the sensation of a ball or lump in the throat, generally not accompanied by dysphagia. Globus sensation is felt medially deep in the throat during dry swallowing (empty swallow), and almost never while drinking or eating. It is not painful, and there is no obstruction of food.[3] [4] Helicobacter pylori (H. pylori) produces chronic inflammation in the CHGM (as in non-ulcer dyspepsia). H. pylori infection plays a role in altered gastric perception in non-ulcer dyspepsia. H. pylori in CHGM may cause altered cervical perception such as globus sensation.

In this prospective study, we aimed to determine the association between H. pylori and globus sensation in patients with CHGM. Some experts recommend taking biopsies from IP to detect neoplastic or preneoplastic alterations[6] [7] [8] or advise follow-up examinations.[8] [9] Before such recommendations can be generalized, more data on the prevalence of preneoplastic alterations in IP are needed.

Materials and Methods

Subjects: A prospective observational study was performed on 1,889 patients referred for esophagogastroduodenoscopy for various reasons, primarily for the evaluation of dyspepsia between October 2019 and February 2021 at our hospitals (Kilpauk Medical college; Government Peripheral Hospital, Anna Nagar; Royapettah Government Hospital).

All patients were enquired about the presence of symptoms of globus sensation (lump in the throat), hoarseness, sore throat, frequent clearing of the throat, cough, dysphagia were questioned prior to endoscopy.

Informed consent was obtained from all subjects and the study was approved by the ethical review committee of Kilpauk Medical College.

Esophagogastroduodenoscopy

After an overnight fast, a routine esophagogastroduodenoscopy was performed using a standard white light endoscope. During the procedure when slowly withdrawing the scope, the esophagus was carefully examined for the presence of the IP. Inlet patch was defined as the presence of salmon-red mucosa with well-defined margins within the surrounding grayish pearl-colored esophageal mucosa within the first 3 cm from the UES. As per the literature, IPs are generally found between the first 3 cm and the upper esophageal sphincter, on the lateral or posterior wall and sometimes encroaching on the upper sphincter.[10]

Biopsies were taken from the patients who had IPs. A minimum of two biopsies were obtained from the IP and antral gastric mucosa. Histological slides were stained with hematoxylin–eosin and a modified Giemsa stain (2%) to detect H. pylori. In cases with doubtful H. pylori status, Warthin–Starry stain was used in addition. Detection of goblet cells led to the diagnosis of intestinal metaplasia.

Statistical Analysis

All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) 13.0 software for Windows XP. Categorical variables were compared using the chi-squared test or Fisher's exact test, and continuous variables were compared using Student's t-test and univariate analysis. A p-value of less than 0.05 was considered to be statistically significant.

Results

Prevalence, Demographic Characteristics

Inlet patches were found in 34 of 1,889 patients. The endoscopic prevalence of IP was determined to be 1.8%. The female/male ratio was 1.25 in 34 patients with patches and 0.75 in those without. There was no significant difference between the mean age of the patients with CHGM with and without H. pylori (p > 0.05). Female patients with IPs had higher colonization of H. pylori than male patients (p < 0.05). Demographic characteristics of the patients with and without patches are shown in [Table 1].

Table 1 Demographic characteristics of the patients with and without inlet patch

	With IP	Without IP	Level of statistical significance
Number	34	1855
Gender
Female	18 (52.9%)	766 (40.55%)	p = 0.09
Male	16 (47.1%)	1,089 (59.44%)
Age
Age range (y)	17–62	18–80	p = 0.44
Mean age (±SE)	37.29 ± 1.85	47.9 ±  0.3

Abbreviation: IP, inlet patch.

Histological Characteristics

In the IP, fundic type mucosa was the most common histologic type (22/34), followed by antral type of mucosa (10/34). Two specimens of the inlet patch contained only foveolar epithelium. Intestinal metaplasia was found in three patients with IP(two in fundic type and one in antral type). None of the patient with IP had dysplasia. Histological characteristics of patients with IPs are shown in [Table 2].

Table 2 Histological characteristics of patients with inlet patch

Histological characteristics	Number	Percentage
Type of mucosal pattern
Fundic type mucosa	22/34	64.75
Antral type mucosa	10/34	29.41
Foveolar epithelium	02/34	5.88
Intestinal metaplasia	03 (2 fundic type, 1 antral type)
Dysplasia	00

Association of IP with H. pylori

H. pylori was identified in 23.52% of patients (8/34) with IP. Gastric H. pylori infection was positive in all (08/08) of these patients. Colonization of H. pylori was more common in antral type mucosa (6/8). Female patients with IP had higher colonization of H. pylori than male patients (p < 0.05). Comparison of the H. pylori (+ ve) and H. pylori (−ve) patients with IP are shown in [Table 3].

Table 3 Comparison of the H.pylori (+ve) and H.pylori (−ve) patients with inlet patch

	HP + (8/34)	HP − (26/34)	p-Value
Age (y)	35.6 ±  2.3	37.3 ± 3.2	0.09
Female n (%)	5 (62.5%)[*]	12 (46.1%)	< 0.05
Male n (%)	3 (37.5%)	14 (53.8%)	0.10
Fundic type	02 (25%)	7 (26.9%)	0.08
Antral type	06 (75%)[*]	11 (42.3%)	< 0.05
Intestinal metaplasia	–
Foveolar epithelium	–

Abbreviation: HP, Helicobacter pylori.

^* p < 0.05.

Symptomatic Characteristics

In our study, globus sensation was present in 18/34 patients with IP and 75/1,855 patients without IP (p < 0.05). Globus sensation symptom was significantly associated with H. pylori infection (p < 0.05). Among patients with IP and H. pylori infection, 87.5% of patients had globus sensation (7/8), compared with only 38.4% of patients with IP and without H. pylori infection. Comparison of symptoms between patients with and without IP and H. pylori infection co-infection are shown in [Table 4].

Table 4 Comparison of symptoms between patients with and without inlet patch and H.pylori co-infection

	IP + (34)	IP – (1855)	HP + (8/34)	HP – (26/34)
Globus sensation	18 (52.9%) *	75 (4.04%)	7 (87.5%) *	11 (38.4%)
	* p < 0.05		* p < 0.05

Abbreviations: HP, Helicobacter pylori; IP, inlet patch.

Clinico-pathologic Classification

Clinico-pathologic classification was performed according to the classification reported by von Rahden et al[2] in patients with CHGM ([Table 5]). Asymptomatic carriers of esophageal CHGM were classified as CHGM I. Also, 7/34 patients were classified with CHGM I in our study. Symptomatic individuals with esophageal CHGM complaining of globus sensation, cough, hoarseness or “extra esophageal manifestations” were classified as CHGM II without morphologic changes. Next, 27/34 patients were classified with CHGM II. Patients with additional morphologic changes (IP complications) were classified as CHGM III. If dysplasia was present, this was classified as CHGM IV. If the diagnosis was invasive cancer and originated within the IP, this was classified as CHGM V. None of the patients belonged to CHGM category 3, category 4, or category 5.

Table 5 Clinico-pathologic classification according to the classification reported by von Rahden et al

	Number (%)	Symptoms/findings
CHGM 1	7/34 (20.58)	Asymptomatic
CHGM 2	27/34 (79.41)	Globus sensation, cough, hoarseness
CHGM 3	0
CHGM 4	0
CHGM 5	0

Abbreviation: CHGM, cervical heterotopic gastric mucosa.

Discussion

The usual endoscopic appearance of CHGM is a salmon rose-colored mucosal patch with a sharp border or edge in the upper esophagus. The patches vary in diameter from 1 to 20 mm or more. Inlet patches are recognized endoscopically as one or two patches mostly in the lateral walls between the level of the cartilage and the fifth tracheal ring and are seen as sharply demarcated, salmon rose-colored oval or round patches.

The prevalence of CHGM varied between 0.29% and 2.27% in one prospective study.[7] Akbayir et al[6] reported a prevalence of 1.67% and Tang et al[11] reported a prevalence of 1.1%. In our prospective study, over a period of 17 months, 34 cases (1.8%) of CHGM were documented and confirmed by histology.

Microscopically, gastric mucosa containing either cardiac, antral, or potentially acid-secreting fundic mucosa can be found. In general, CHGM is uniform of the fundic type, containing both parietal and chief cells. Less frequently, histopathologic examination of CHGM shows an “antral pattern,” defined by the absence of chief cells and only a few parietal cells.[2] [11] [12] In our series, fundic type mucosa was found in 22 of 34 (64.75%) patients examined histologically. There are controversial reports regarding the type of mucosa reported in IP.

The oxyntic mucosa cell type is most commonly reported[11] but cardiac, antral, and mixed types (both oxyntic and antral) have also been detected.[13]

H. pylori is a well-known pathogenic microorganism responsible for chronic inflammation. Ectopic gastric mucosa of the IP is an ideal location for H. pylori colonization.[13] Borhan–Manesh et al[14] found H. pylori in the IP in 35% of patients in a subset with gastric H. pylori. Among our 34 patients with inflamed IPs, 8 were positive for H. pylori (23.52%), and all these 8 patients also had H. pylori in the antrum. Co-infection with H. pylori in the IP and gastric antrum has also been reported by others.[13] 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 colonize heterotopic mucosa[13]. Because the infection by H. pylori is through the oral route, IP may be an important site of H. pylori infection in the upper gastrointestinal tract because of its more proximal location. The IP may function as reservoirs for H. pylori. Inlet patch colonization by H. pylori can occur during the ingestion of food, and the presence of gastric H. pylori may play a role in the development of IPs. We believe that the elimination of H. pylori in both the IP and antrum is very important in the treatment of patients with coinfection.

In this study, the female/male ratio in the H. pylori (+ve) CHGM group was higher than that in the H. pylori (−ve) CHGM group. Females had higher IP colonization with H. pylori than males (p < 0.05). Epidemiological studies on the general population show a male preponderance in the infection rate by H. pylori [15]; Although there are controversial reports representing comparable rates. In our study, we found that female patients with IPs had higher colonization of H. pylori than male patients. Similar results were seen in a study done by Alagozlu et al.[16] The mechanism of H. pylori colonization in female IP is unclear.

A clinicopathological classification of CHGM as proposed by von Rahden et al[2] was performed on all 34 patients, 7 patients were classified as CHGM 1 and 27 patients were classified as CHGM 2. Theoretically, laryngeal and oropharyngeal symptoms should be common due to acid secretion from the IP. Several studies have reported cases of esophageal IP presenting with various laryngeal and oropharyngeal symptoms, ranging from asymptomatic to protracted symptoms such as chronic cough and globus sensation.[5] [17] [18] [19] In addition, CHGM can cause stricture, ulcer, perforation, web or polyp in the esophagus because of the its capability to secrete acid.[20] [21] None of our patients with IPs had any local complications.

The usual complaint in GS is that of a ball or lump in the throat generally not accompanied by dysphagia. This sensation is often more pronounced when taking an “empty swallow.” In our study, seven of eight patients with H. pylori in cervical IPs had globus sensation. A study[16] done by Hakan et al showed similar results.

H. pylori infection plays a role in causing symptoms in patients fulfilling the criteria for non-ulcer dyspepsia. There is an agreement that H. pylori infection causes changes in gastric physiology. In addition, H. pylori infection plays a role in altered gastric perception in non-ulcer dyspepsia. We speculate that the disturbances in globus sensation are like non-ulcer dyspepsia. H. pylori produces chronic inflammation in the CHGM (as in non-ulcer dyspepsia). It could be speculated that globus sensation is non-ulcer dyspepsia of CHGM. H. pylori is a potential cause of GS in patients with CHGM.

One case report, in particular, found that H. pylori eradication was able to ameliorate the extragastric symptoms associated with CHGM and resulted in beneficial histopathological changes.[22] However, this report was limited by the fact that the patient had both gastric and esophageal IP H. pylori colonization. Thus, it is impossible to determine if the improvement in globus sensation and heartburn are due exclusively to the eradication of H. pylori or to the proton pump inhibitor (PPI) that is commonly included in the treatment as well.

However, there was no significant difference in the improvement in globus symptoms in patients who received only PPI treatment.[23] Additional studies are needed to understand the fundamental mechanisms leading to globus sensation in CHGM. These patients might benefit from H. pylori eradication therapy to alleviate this potentially aggravating factor. Based on these important findings, we expect to see more studies on IP in the near future.

Conflict of Interest

None declared.

• References

• 1 Orosey M, Amin M, Cappell MSA. A 14-year study of 398 esophageal adenocarcinomas diagnosed among 156,256 EGDs performed at two large hospitals: an inlet patch is proposed as a significant risk factor for proximal esophageal adenocarcinoma. Dig Dis Sci 2018; 63 (02) 452-465
• 2 von Rahden BH, Stein HJ, Becker K, Liebermann-Meffert D, Siewert JR. Heterotopic gastric mucosa of the esophagus: literature-review and proposal of a clinicopathologic classification. Am J Gastroenterol 2004; 99 (03) 543-551
• 3 Lancaster JL, Gosh S, Sethi R, Tripathi S. Can heterotopic gastric mucosa present as globus pharyngeus?. J Laryngol Otol 2006; 120 (07) 575-578
• 4 Alaani A, Jassar P, Warfield AT, Gouldesbrough DR, Smith I. Heterotopic gastric mucosa in the cervical oesophagus (inlet patch) and globus pharyngeus–an under-recognised association. J Laryngol Otol 2007; 121 (09) 885-888
• 5 Meining A, Bajbouj M, Preeg M. et al. Argon plasma ablation of gastric inlet patches in the cervical esophagus may alleviate globus sensation: a pilot trial. Endoscopy 2006; 38 (06) 566-570
• 6 Akbayir N, Alkim C, Erdem L. et al. Heterotopic gastric mucosa in the cervical esophagus (inlet patch): endoscopic prevalence, histological and clinical characteristics. J Gastroenterol Hepatol 2004; 19 (08) 891-896
• 7 Klaase JM, Lemaire LC, Rauws EA, Offerhaus GJ, van Lanschot JJ. 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 (01) 101-104
• 8 Poyrazoglu OK, Bahcecioglu IH, Dagli AF, Ataseven H, Celebi S, Yalniz M. Heterotopic gastric mucosa (inlet patch): endoscopic prevalence, histopathological, demographical and clinical characteristics. Int J Clin Pract 2009; 63 (02) 287-291
• 9 Abe T, Hosokawa M, Kusumi T. et al. Adenocarcinoma arising from ectopic gastric mucosa in the cervical esophagus. Am J Clin Oncol 2004; 27 (06) 644-645
• 10 Shah KK, DeRidder PH, Shah KK. Ectopic gastric mucosa in proximal esophagus. Its clinical significance and hormonal profile. J Clin Gastroenterol 1986; 8 (05) 509-513
• 11 Tang P, McKinley MJ, Sporrer M, Kahn E. Inlet patch: prevalence, histologic type, and association with esophagitis, Barrett esophagus, and antritis. Arch Pathol Lab Med 2004; 128 (04) 444-447
• 12 Jabbari M, Goresky CA, Lough J, Yaffe C, Daly D, Côté C. The inlet patch: heterotopic gastric mucosa in the upper esophagus. Gastroenterology 1985; 89 (02) 352-356
• 13 Gutierrez O, Akamatsu T, Cardona H, Graham DY, El-Zimaity HM. Helicobacter pylori and hetertopic gastric mucosa in the upper esophagus (the inlet patch). Am J Gastroenterol 2003; 98 (06) 1266-1270
• 14 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 (01) 142-146
• 15 Ibrahim A, Morais S, Ferro A, Lunet N, Peleteiro B. Sex-differences in the prevalence of Helicobacter pylori infection in pediatric and adult populations: Systematic review and meta-analysis of 244 studies. Dig Liver Dis 2017; 49 (07) 742-749
• 16 Alagozlu H, Simsek Z, Unal S, Cindoruk M, Dumlu S, Dursun A. Is there an association between Helicobacter pylori in the inlet patch and globus sensation?. World J Gastroenterol 2010; 16 (01) 42-47
• 17 Chevalier JM, Brossard E, Monnier P. Globus sensation and gastroesophageal reflux. Eur Arch Otorhinolaryngol 2003; 260 (05) 273-276
• 18 Tokashiki R, Yamaguchi H, Nakamura K, Suzuki M. Globus sensation caused by gastroesophageal reflux disease. Auris Nasus Larynx 2002; 29 (04) 347-351
• 19 Akbayir N, Sökmen HM, Caliş AB. et al. Heterotopic gastric mucosa in the cervical esophagus: could this play a role in the pathogenesis of laryngopharyngeal reflux in a subgroup of patients with posterior laryngitis?. Scand J Gastroenterol 2005; 40 (10) 1149-1156
• 20 Ward EM, Achem SR. Gastric heterotopia in the proximal esophagus complicated by stricture. Gastrointest Endosc 2003; 57 (01) 131-133
• 21 Jerome-Zapadka KM, Clarke MR, Sekas G. Recurrent upper esophageal webs in association with heterotopic gastric mucosa: case report and literature review. Am J Gastroenterol 1994; 89 (03) 421-424
• 22 Wüppenhorst N, Viebahn B, Theile A, Radü HJ, Kist M. Culture and successful eradication of Helicobacter pylori from heterotopic gastric mucosa. Z Gastroenterol 2012; 50 (07) 677-679
• 23 Kasap E, Ayhan S, Yüceyar H. Does Helicobacter pylori treatment improve the symptoms of globus hystericus?. Turk J Gastroenterol 2012; 23 (06) 681-685

Publication History

Article published online:
20 April 2022