Clinical significance of heterotopic gastric mucosal patch of the proximal esophagus

Abstract

Heterotopic gastric mucosa of the proximal esophagus (HGMPE), also referred to as “inlet patch” or “cervical inlet patch”, is a salmon colored patch that is usually located just distal to the upper esophageal sphincter. HGMPE is uncommon with endoscopic studies reporting a prevalence ranging from less than one percent to 18%. Most HGMPE are asymptomatic and are detected incidentally during endoscopy for evaluations of other gastrointestinal complaints. Most consider HGMPE as clinically irrelevant entity. The clinical significance of HGMPE is mainly acid related or neoplastic transformation. The reported prevalence of laryngopharyngeal reflux symptoms varies from less than 20% to as high as 73.1%. However, most of these symptoms are mild. Clinically significant acid related complications such as bleeding, ulcerations, structure and fistulization have been reported. Although rare, dysplastic changes and malignancies in association with HGMPE have also been reported. Associations with Barrett’s esophagus have also been reported but the findings so far have been conflicting. There are still many areas that are unknown or not well understood and these include the natural history of HGMPE, risk factors for complications, role of Helicobacter pylori infection and factors associated with malignant transformations. Follow-up may need to be considered for patients with complications of HGMPE and surveillance if biopsies show intestinal metaplasia or dysplastic changes. Despite the overall low incidence of clinically relevant manifestations reported in the literature, HGMPE is a clinically significant entity but further researches are required to better understand its clinical significance.

Key Words: Cervical inlet patch, Laryngopharyngeal reflux, Globus pharyngeus, Neoplasms, Barrett’s esophagus

INTRODUCTION

Heterotopic gastric mucosa of the esophagus (HGMPE), also commonly referred to as “inlet patch” or “cervical inlet patch”, is an island of ectopic gastric mucosa that is found in the proximal esophagus[1,2]. Rarely, they can also been found in the other part of the esophagus[2,3]. HGMPE is widely considered to be congenital in nature. However, it has also been proposed to be an acquired condition[1,4,5].

The reported incidence varies from less than one percent[6] to 13.8% in endoscopic studies[7]. Autopsy study has reported higher incidence of up to 70%[1,2]. Commonly reported symptoms include laryngopharyngeal reflux (LPR) symptoms and the prevalence has been reported to be as high as 73.1%[8]. However, most of these symptoms are mild and the management depends on the severity of symptoms. A clinico-pathologic classification has been proposed which categorized HGMPE into five distinct groups based on their clinical, endoscopic and histological characteristics (Table 1)[1]. Serious and significant complications of HGMPE have been reported in both adults and the pediatric population[1,2,9]. Interestingly, other common upper aero-digestive disorders have also been linked to HGMPE[2,9]. The clinical significance of HGMPE remains debated due to the limited number of publications. This article reviews the literature and discusses the clinical manifestations and significance of HGMPE in clinical practice.

Table 1 Clinico-pathological classification for heterotopic gastric mucosa of the proximal esophagus.

Category	Description	Symptoms/findings
I	Asymptomatic	None
II	Symptomatic	Laryngopharyngeal reflux
III	Symptomatic with benign complications	Strictures/webs/fistula/bleeding
IV	Intra-epithelial dysplasia	None/non-specific
V	Malignant transformation	Asymptomatic/dysphagia

BACKGROUND

Pathogenesis

Currently, there are three proposed theories on the development of HGMPE[1,2,4,5]. The most widely accepted theory is that HGMPE is congenital in origin. During the development of the esophagus and at 24 wk of gestation (equivalent to 90 mm crown rump length during fetal development), squamous lining replaces the columnar lining starting from the mid esophagus moving in both directions. The proximal esophagus is usually the last part to get stratification and this account for the common finding of heterotopic gastric mucosa in the proximal esophagus[1,2]. Although less common, ectopic mucosa can also be found in the other parts including the distal esophagus[2,3]. Another proposed theory involves metaplastic transformation of the squamous lining to columnar from chronic acid injury as seen in Barrett’s esophagus[4]. Proliferation of remnant pluripotent cells as result of acid injury has been proposed as the underlying pathogenesis. The third theory involves rupture of proximal esophageal retention cystic glands[5].

The most common histological type is the cardia or oxyntic type mucosa followed by the antral mucosa. Depending on the mucosa type, some HGMPE can produce acid[10-12], and given their close proximity to the laryngopharyngeal complex can easily reflux into this area to cause symptoms. The laryngeal mucosa is also particularly susceptible to acid injury, even with mildly acidic secretion. Non-acidic secretions such as mucus have also been shown to induce laryngopharyngeal symptoms[13].

HGMPE can be colonized by Helicobacter pylori (H. pylori) and the prevalence have been reported to be as high as 82%[14]. The infection rates probably correlate with the prevalence of H. pylori infection in the general population. Although the role of H. pylori in HGMPE remains uncertain, one can probably surmise that it can cause changes similar to those seen in the stomach. Inflammatory and histological changes such as atrophy, metaplasia, dysplasia and carcinoma of the HGMPE have also been reported[2,15].

Endoscopic characteristics

HGMPE is often missed during endoscopy as the proximal esophagus is often neglected or briefly examined during routine endoscopic examination. On endoscopy, HGMPE appears as a salmon colored ovoid or round patch that is usually distinct from the surrounding esophageal squamous mucosa (Figure 1A and B). It can be flat, elevated or depressed and the surface can be smooth or nodular. Most HGMPE are located on the lateral walls typically a few centimetres distal to the upper esophageal sphincter (16 and 21 cm from the incisors)[1,2]. The sizes can vary from microscopic to as large as three to five centimeters. Most patients have a single patch while those with multiple patches, the patches tend to be small and are usually found within close proximity of other patches. On specialized imaging such as narrow band imaging, the HGMPE is clearly more visible (Figure 1C).

Figure 1 Endoscopic images of heterotopic gastric mucosa of the proximal esophagus. A: A large heterotopic gastric mucosa of the proximal esophagus (HGMPE) on the left lateral wall; B: A large HGMPE located on the right lateral wall; C: Small patch with a brownish hue located on the left lateral wall on neutral beam injection.

CLINICAL MANIFESTATIONS

The clinical manifestations of HGMPE can be broadly divided into non-neoplastic and neoplastic. The majority of patients found to have HGMPE are asymptomatic and the HGMPE are detected incidentally during evaluation for other gastrointestinal complaints. These patients are categorized to have type I HGMPE. The non-neoplastic manifestations (type II and III) such as LPR symptoms and strictures and bleeding are probably related to the acid produced by the patch. The least common manifestations are the histological or neoplastic changes (type IV and V)[1,2]. With the exception of malignancy in the pediatric population, all these have been reported both in the adult[1,2] and pediatric population[16-20]. Acid related symptoms are often seen in younger patients whereas neoplastic manifestations have been reported mainly in the elderly population.

Acid-related manifestations

Symptoms associated with HGMPE include LPR symptoms such as regurgitation, dysphagia, hoarseness, globus, throat discomfort and chronic cough[1,2]. Often dysphagia is located in the proximal esophagus or throat level. Associations with chronic ear or sinus problem have also been reported.

Symptoms in adult population

To date, there have only been a few studies that have reported comparisons of symptoms between patients with and without HGMPE. Published studies have so far reported mixed findings, some showing significantly higher LPR symptoms[8,21-24] whilst others reported no significant difference[15,25] (Table 2). The symptoms enquired and reported were not consistent between studies. Some reported the overall prevalence or limited to only one or few symptoms. However, most of the symptoms reported were mild. Prevalence rate of LPR symptoms as high as 73.1% has been reported[8]. The largest study to date based on a database of 487  229 endoscopies carried out in non-referral centers in the United States showed that dysphagia or odynphagia, upper respiration symptoms suggestive of LPR and globus were significantly more common in patients with HGMPE[24]. However, this study was limited by its retrospective nature and the assessment of only referral indications. The other studies were mainly from referral or specialized centers.

Table 2 Prevalence of symptoms reported to be associated with heterotopic gastric mucosa of the proximal esophagus in adult.

Ref.	Symptoms reported	Prevalence of LPR symptoms		P value
		HGMPE (+ve)	HGMPE (-ve)
Chong et al[8]	Overall LPR symptoms	73.1%	25.9%	< 0.001
	Chronic cough	29.2%	10.6%	< 0.01
	Sore throat/hoarseness	54.2%	11.7%	< 0.01
	Globus	23.1%	7.1%	< 0.01
	Regurgitation	42.3%	13.1%	< 0.01
	Heartburn	50.0%	22.5%	< 0.01
Akbayir et al[15]	Upper esophageal and laryngopharyngeal symptoms	45%	21.5%	= 0.07
Baudet et al[21]	Dysphagia	21%	4.0%	< 0.001
Poyrazoglu et al[22]	Dysphagia	39.4%	0%	< 0.05
Alagozlu et al[23]	Globus	78.6%	0%	< 0.05
	Dyspepsia	88.2%	97.8%	NS
1Neumann et al[24]	Dysphagia/odynophagia	20.8%	16.4%	< 0.001
	Upper respiratory symptoms	2.5%	0.9%	< 0.001
	Globus	1.6%	0.3%	< 0.001
Weickert et al[25]	Recurrent hoarseness	9.1%	5.6%	= 0.5
	Dysphagia (any grade upper and lower)	15.2%	9.4%	NS
	Heartburn (any grade upper and lower)	15.2%	9.4%	NS

¹In the study by Neumann et al, the symptoms presented are symptom recorded as indications for endoscopy. HGMPE: Heterotopic gastric mucosa of the proximal esophagus; LPR: Laryngopharyngeal reflux; NS: Not significant.

Symptoms in pediatric population

Currently, there are only a few studies on HGMPE in the pediatric population and are usually limited by small sample sizes[9,16,18-20]. Most are in the form of case reports[16-20]. To date, there is no endoscopic study that has assessed HGMPE in this population. Clinical manifestations are different from the adult population. Common manifestations include laryngospasm[16], respiratory symptoms[17] and dysphagia from reflux or stricture[9,20]. In one multicentre study that had looked at 15 patients with a median age 9.5 years (range: 3.3-15 years) found that five patients had esophageal atresia, nine with gastroesophageal reflux disease (GERD) and asymptomatic in one. Dysphagia and food impaction were the most common manifestations reported in 14 patients. Six patients had respiratory or ear, nose, and throat symptoms[9]. An autopsy study in the pediatric population showed that HGMPE was more common in younger age and was more significantly associated with unexplained death. Variend et al[26] speculated that pulmonary aspiration of esophageal contents may have been the cause of death in some of the children.

Barrett’s esophagus

Similarly to clinical symptoms, the association between HGMPE and Barrett’s esophagus remains debated. Studies have reported conflicting results (Table 3). Avidan et al[4] showed that patients with HGMPE had up to fivefold higher risk of Barrett’s esophagus compared to patients without HGMPE. Three other studies[23,24,27] have reported significant positive correlations while five studies that included more than 20 patients with HGMPE have not found any correlations[3,8,22,25,28]. Two histological studies reported similar mucin staining patterns in Barrett’s esophagus and HGMPE suggesting possible shared pathogenesis[29,30]. However, Fuerle et al[31] found some differences and postulated that the specialized columnar epithelium of Barrett's esophagus originates from a very immature multipotent gastrointestinal stem cell whereas HGMPE originates from remnant embryonic gastric mucosa located in the proximal esophagus

Table 3 Endoscopic studies reporting the associations between heterotopic gastric mucosa of the proximal esophagus and other endoscopic findings with special attention to Barrett’s esophagus n (%).

Ref.	Prevalence of HGMPE	Findings
Positive association
Avidan et al[4]	53 (1.1)	Significantly more reflux esophagitis (77 vs 50, P = 0.023), Barrett’s esophagus (34 vs 9, P < 0.001), hiatus hernia (49 vs 30, P < 0.05) and gastric ulcer (P < 0.05) On multivariate analysis, hiatus hernia, gastric ulcer and Barrett’s esophagus remained significant
Alagozlu et al[23]	68 (1)	Significantly more (P < 0.05) endoscopic Barrett’s esophagus in patients with HGM (13.2 vs 2.4) but not with reflux esophagitis (10.3 vs 9.5) Hiatus hernia and duodenal ulcer were reported in 13.2% and 10.3% respectively but no comparisons were made
1Neumann et al[24]	870 (0.18)	Significantly more Barrett’s mucosa on biopsy (9.7 vs 6.5, P < 0.001), adenocarcinoma arising from Barrett’s mucosa (3.6 vs 0.7, P < 0.01) and reflux esophagitis (41.8 vs 49.7, P < 0.001)
Yuksel et al[27]	171 (1.8)	Significantly more reflux esophagitis (25.1 vs 5.6, P < 0.001) and histologically proven Barrett’s esophagus (3.5 vs 0.5, P < 0.000) No difference in hiatus hernia
No association
Borhan-Monesh et al[3]	64 (10)	No significant difference (all P = NS) between reflux esophagitis (34.3 vs 38.1) and Barrett’s esophagus
Chong et al[8]	26 (5.6)	No significant difference (all P = NS) between esophageal, gastric and duodenal findings including Barrett’s esophagus (3.8 vs 3.7), hiatus hernia (15.4 vs 12.2) and ulcers
Akbayir et al[15]	11 (1.67)	No significant difference (all P = NS): Barrett’s esophagus (0 vs 0.9), hiatus hernia (0 vs 10), reflux esophagitis (27 vs 16) and duodenal ulcer (9 vs 7)
2Poyrazoglu et al[22]	33 (3.6)	No significant difference (all P = NS): Barrett’s esophagus (0 vs 0.8), hiatus hernia (3 vs 9.1), reflux esophagitis (36.4 vs 34.8), gastric ulcer (3 vs 3) and duodenal ulcer (6.1 vs 6.8)
Weickert et al[25]	33 (11)	Overall prevalence: hiatus hernia (n = 92, 30.7%), reflux esophagitis (n = 41, 13.7%), Barrett’s esophagus (n = 3, 1%), gastric ulcer (n = 24, 8%) and duodenal ulcer (n = 22, 7%), all P = NS
Jacobs et al[28]	33 (4.9)	Significant difference for reflux esophagitis (27.3 vs 11.4) but not for hiatus hernia (15.2 vs 12.5), Barrett’s esophagus (6.1 vs 1.1) and any gastric or duodenal ulcer (15.2 vs 6.1)

Studies included are those with more than 10 patients with heterotopic gastric mucosa of the proximal esophagus (HGMPE).

¹The study by Neumann et al was based on analysis clinic-pathologic records of patients who had undergone upper gastrointestinal endoscopy with biopsies between January 2008 and December 2010 in private outpatient clinics and endoscopy centres in the United States;

²The study by Poyrazoglu et al compared the prevalence of other endoscopic findings between 33 patients with HGMPE with 132 matched controls without HGMPE. NS: Not significant.

Non-laryngopharyngeal symptoms

Reports on symptoms associated with HGMPE are mainly on LPR symptoms[2]. There is currently little information to suggest whether HGMPE is associated with non-LPR symptoms. Heartburn has been shown to be common in patients with HGMPE, even in those not found to have any erosive esophagitis[4,8,32]. Explanations offered included symptoms induced by acid secretion flowing downward or increased sensitivity as seen in non-erosive esophagitis. Apart from proximal acid reflux independent of distal acid reflux, Korkut et al[11] also showed that some patients with HGMPE have signs of esophageal motor dysfunction based on manometry and 24 h dual probe pH study. They concluded that these abnormalities may be responsible for some of the symptoms experienced by patients with HGMPE. In another study, Rosztoczy et al[32] reported several differences between patients with and without HGMPE. Patients with HGMPE had more and prolonged acid exposure in both proximal and distal esophagus, longer bile exposure time in the distal esophagus, reduced lower esophageal sphincter pressure with prolonged relaxation and decreased peristaltic wave amplitude. There was also increased number of simultaneous contractions in the esophageal body of patients with HGMPE. These suggest that patients with HGMPE also have motility disorders contributing to their symptoms.

Other non-neoplastic complications

Complications of HGMPE reported in the literature range from formations of strictures[33-35], web[36-38], ulceration with bleeding[39], fistula formation with or without subcutaneous abscesses[19,40-42], perforation[43,44] and polyps[45-47] (Table 4). HGMPE have been reported to be the possible cause of Plummer Vinson or Paterson Kelly Brown syndrome[1,2,38]. The underlying pathogenesis is probably similar to those seen in acid-related gastric pathologies. In the pediatric population, HGMPE has also been associated with unexplained infant deaths[26], dysphagia from strictures in the proximal esophagus[9,18,20] or spasm[16] and recurrent neck abscesses secondary to fistula[19].

Table 4 Complications of heterotopic gastric mucosa of the proximal esophagus reported in the literature.

Clinico-pathological classification	Conditions	Status	Numbers based on PubMed literature search
Type III	Stricture	Reported	6
	Web	Reported	4
	Bleeding	Reported	1
	Fistula	Reported	4
	Perforation	Reported	2
	Polyp1	Reported	4
Type IV2	Dysplasia
	Low grade	Reported	None
	High grade	Reported	3[32-34]
Type V2	Adenocarcinoma
	Early (pT1 tumor)	Reported	13[35-48]
	Advanced	Reported	19[33,49-54]

References for type III cases reported in the literature not included in the reference list.

¹Not included in the original classification proposed by von Rahden et al[1];

²Number of cases of neoplastic transformation identified through literature searches up till December 2011.

Histology progressions or neoplastic transformation

Overall, significant histological non-malignant changes or malignancies in HGMPE are extremely rare. Histological changes such as chronic inflammation[3,14], atrophy, intestinal metaplasia[14], and dysplasia[48-50] as seen in the stomach have been reported mainly in the adult population. However intestinal metaplasia has also been reported in children[17]. Macha et al[17] reported that 8.3% (n = 2/24) of their pediatric patients with HGMPE had intestinal metaplasia detected on histology. Neoplastic transformations have only been reported in the adult population[2,36-39]. A summary of the reported significant histological or malignancies in association with HGMPE are shown in Table 4.

Since the first case reported by Carrie et al[51] in 1950, there have only been 43 cases of adenocarcinoma[52-54] in association with HGMPE reported in the literature to date (Table 4). To date, Neumann et al[24] in the largest series of endoscopies done in non-specialised centers did not encounter any cases of HGMPE with malignancy whereas Alagozlu et al[23] encountered a case each of adenocarcinoma and low grade dysplasia among 64 patients with HGMPE. Based on these two studies, it can be estimated that the incidence of malignancies among patients with HGMPE ranges between 0 and 1.56%[23,24]. However, the incidence is likely to be much lower than the estimate from the latter study.

Based on a review of 43 cases reported in the literatures by Akanamu et al[54], majority of those affected were men (88.4%) with a median age of 60.4 years (range 35 to 85 years). Most of the lesions were advanced at diagnosis especially in the earlier reported. Early lesions (T1 lesion) accounted for 14 cases[54]. The lesions were ulcerated in 31.2%, protruding in 30.2% and polypoidal in 18.6%. Dysphagia was the most common compliant (74.4%) with smaller proportion detected through surveillance. Interestingly, acid-related symptoms were not common. Smoking appeared to be a risk factor.

Associations with extra-esophageal neoplasms

To date, association with extra-esophageal neoplasms have only been reported twice[55,56]. Basseri et al[55] reported the case of a 22-year-old lady with asthma and GERD diagnosed with laryngeal adenocarcinoma. She later developed a stricture proximal to a HGMPE (type III). In another report, Satoh et al[56] reported the case of a 44-year-old lady with hypopharyngeal carcinoma with a HGMPE (2.0 cm × 1.5 cm) bordering the tumor. Chronic irritation from acid was proposed as the contributing cause to the development of the tumors.

OVERVIEW

HGMPE was first reported by Schmidt et al[1] as an aberrant gastric fundus-type epithelium located in the proximal esophagus. Despite this, the number of publications on this entity has remained low compared to the other esophageal disorders. Therefore it is not surprising that controversies remain regarding the clinical significance of this entity. Despite the lack of data, HGMPE is clinically significant and the clinical significance is related to acid-related manifestations, mucosal changes and malignant transformations.

The clinical manifestations of HGMPE are best summarized by the classification proposed by von Rahden et al[1]. Clinically significant manifestations which have been reported in only a small proportion of patients are categorized as type II, III, IV and V HGMPE. The most common is the type II with clinical symptoms of LPR[1,8]. However, some do not consider type II HGMPE as significant as the symptoms experienced are mostly mild[8,13]. On the other hand, these symptoms are chronic and very troublesome for a small minority of patients.

It is currently uncertain if the symptoms are acid-related given that studies have shown that only a small proportion of symptomatic patient have documented acid secretion from the HGMPE[10,31]. However, one can probably surmise that there is a causal association. Similar to the stomach or heterotopic gastric mucosa found in Meckel’s diverticulum, excess acid production can lead to acid-related symptoms and complications. Patients with HGMPE have also been shown to have motility disorders and this may contribute to the symptomology of HGMPE[11,32].

Symptomatic patients with HGMPE typically reports LPR symptoms; globus pharyngeus, sore throat, hoarseness, chronic cough, throat clearing and dysphagia[57]. This is not surprising given the close proximity of HGMPE with the laryngopharyngeal complex. The laryngopharyngeal complex is particularly sensitive and even a small amount of weakly acidic secretion can cause symptoms[57,58]. Symptoms can also occur with non-acidic secretions[4]. Presence of gastric enzymes such as pepsin also contributes to irritations[58].

The prevalence of the various LPR symptoms in association with HGMPE varies from less than 20% to as high as 73.1%[2]. Comparisons of published studies are difficult due to differences in the study methodologies. Symptoms enquired were not always consistent with some studies enquiring on limited number of symptoms or not specifying the symptoms enquired. Furthermore, most studies had small sample sizes.

In clinical practice, we also often encounter patients with LPR symptoms without any heartburn. Such patients are categorized as having extra-esophageal manifestations of GERD. Some of these patients clearly do not have acid exposure in the distal esophagus and as such, LPR symptoms in association with HGMPE should be considered a separate entity separate from GERD.

Associations with neoplastic changes and importantly malignant transformation are reported and these represent the most significant associations of HGMPE. However, the numbers reported is still very low and are considered extremely rare. Interestingly, a large number of the reported cases especially in the non-English literatures have been from Japan[54]. Whether, HGMPE with malignant transformations is more common in the Japanese population is unknown. It may be related to better screening program and increased detection rate. Most of the reported cases were advanced at diagnosis especially in the earlier studies. However, there were more early cancers (T1 lesions) reported in the latter part. Men seem to be more at risk and smoking appears to be a risk factor[54]. Dysphagia was the main complaint leading to detection of tumors.

Association with Barrett’s esophagus is another area that remains debated. A widely accepted theory is based on a shared pathogenesis with both Barrett’s esophagus and HGMPE being congenital in origin but with differences in pathogenesis in the later part of the development. However, this had been based on western population where the prevalence of Barrett’s esophagus is much higher compared to the East. Further large population studies will be required and help shade some lights into this controversy. Associations with other acid related complications such as erosions, ulcerations, bleeding, perforation, fistula and stricture formations have been documented[1,8]. Possible link between HGMPE and unexplained death in children have also been reported[26].

Currently, there are still many issues regarding HGMPE that remain unresolved or unknown. These ranges from the origin of HGMPE, exact correlation with Barrett’s esophagus, role of H. pylori infection in symptoms manifestations, lack of natural history data and significance of mucosal changes in the HGMPE and its relation to neoplastic transformations.

Given that HGMPE mainly manifests with upper autodigestive symptoms, it is not unexpected that only clinicians from certain specialties such as the gastroenterologists, otorhinolaryngologists and rarely upper gastrointestinal surgeons will encounter such patients. However, it is important that other clinicians from the other specialties to be aware of this entity especially when they come across patients with troublesome LPR symptoms. Establishing a diagnosis is important as it can provide reassurance. This may also lead to symptoms improvement and avoid any further unnecessary investigations or consultations. As the awareness of HGMPE increase, more asymptomatic or symptomatic cases will be diagnosed and with the ageing population, it is very likely the number of cases of neoplastic transformations will also increase, albeit a small increase.

CONCLUSION

The clinical significance of HGMPE lies mainly with its capacity to produce acid and mucosal progressions to dysplasia and frank neoplastic transformation. Currently, there are still many areas of HGMPE that are not well understood and further research are required. Symptomatic patients should to be treated and those found to have metaplasia or dysplasia may need to be considered for surveillance.