**2.1.2 Acquired origins theories**

#### *Metaplastic transformation of squamous mucosa to columnar mucosa from chronic acid injury*

It has also been proposed that the HGMP/CIP is an acquired condition as result of chronic inflammation from exposure to acid as part of gastroesophageal reflux disorders (Avidan et al., 2001; Lauwers et al., 2005). It is postulated that chronic acid exposure results in inflammation that leads to reactivation or proliferation of remnant columnar mucosa. These remnants columnar mucosa are present as microscopic foci in the esophageal lining or are covered by squamous mucosa. With chronic irritations, these foci develop into larger patch resulting in the formation of island of columnar mucosa, HGMP (Figure 2).

al., 2004). The management strategies of HGMP/CIP are not well defined and are dependent on the severity of symptoms. However, other newer treatment modalities have also been

This chapter discusses the pathogenesis, the endoscopic features, clinical symptoms and the management of HGMP/CIP, an entity that is still under-recognised and is frequently missed

HGMP is widely considered to be congenital in nature, as result of incomplete esophageal squamous epithelization during the embryogenic development stage (von Rahden et al., 2004). Reports of HGMP in the esophagus of young children and even babies support this theory (Boybeyi et al., 2008; Georges et al., 2011; Macha et al., 2005; Surana et al., 1993). However, it has also been proposed to be acquired in nature, similar to Barrett's esophagus (Avidan et al., 2001; Lauwers et al., 2005). There are based on similarities in the mucin and staining characteristics with CK7 and CK20 (Bogomoletz et al., 1988; Lauwers et al., 2005) between Barrett's esophagus and HGMP/CIP. Reports of higher incidence of Barrett's esophagus in patients with HGMP/CIP also suggested a link. Some has even proposed that the origins of HGMP/CIP may be different, congenital in children and acquired in adult (Lauwers et al., 2005). A recently proposed hypothesis suggested that HGMP/CIP developed

from rupture retention cyst of the proximal esophagus (Meining & Baubouj, 2010).

**2.1 Origin of heterotopic gastric mucosal patch of the proximal esophagus** 

The development of the esophagus starts at the beginning of embryogenesis (Lieberman-Meffert et al., 2002). The upper aerodigestive tract (oro, naso and largyngopharynx), respiratory tract, esophagus and stomach and duodenum arise from the same embryogenic segment. The stages of development are correlated with the length of the embryo. At 3 mm crown-rump length, the esophagus is mainly lined with columnar mucosa and during development at 110 CR length (equivalent to 24 weeks gestation), the squamous lining begin to replace the columnar lining starting at the mid esophagus, migrating in both directions. The cervical region of the esophagus is the last area to get stratification and this account for the common findings of HGMP in the proximal esophagus. The embryogenic development

*Metaplastic transformation of squamous mucosa to columnar mucosa from chronic acid injury* 

resulting in the formation of island of columnar mucosa, HGMP (Figure 2).

It has also been proposed that the HGMP/CIP is an acquired condition as result of chronic inflammation from exposure to acid as part of gastroesophageal reflux disorders (Avidan et al., 2001; Lauwers et al., 2005). It is postulated that chronic acid exposure results in inflammation that leads to reactivation or proliferation of remnant columnar mucosa. These remnants columnar mucosa are present as microscopic foci in the esophageal lining or are covered by squamous mucosa. With chronic irritations, these foci develop into larger patch

during upper gastrointestinal endoscopy examinations.

reported.

**2. Pathogenesis** 

**2.1.1 Congenital origin theory**  *Embryogenesis of the esophagus* 

of the esophagus is shown in Figure 1.

**2.1.2 Acquired origins theories** 

Fig. 1. Embryogenesis of the esophagus: solidification of the hollow tubular esophagus occur with rapid cellular proliferation followed by vacuoles formations (recanalization), columnarization (cilia phase shaded rippled pink) and the final stage of squamous cell mucosa formation (keratinizing followed by dekeratinizing phase-shaded gray). HGMP form when the final phase is incomplete

Fig. 2. Proposed acquired pathway through chronic reflux injury: Chronic acid (+/- pepsin and bile injury) leads to reflux esophagitis and reflux may reach the proximal esophagus resulting in similar changes. Chronic esophagitis leads to adaptive changes resulting in metaplasia metaplasia of the distal esophagus. Chronic injury in the proximal esophagus lead to reactivation of buried columnar cells resulting in formation of HGMP

Heterotopic Gastric Mucosal Patch of the Proximal Esophagus 129

Others have proposed that development of HGMP/CIP in adult and children may be different based on differences in the mucin protein (MUC) staining. It has been suggested that two pathogenetic pathways maybe involved: focal upper esophageal mucosal misdevelopment in pediatric population and patchy metaplastic replacement of squamous

HGMP/CIP consists of columnar mucosa found in the stomach (Figure 4). HGMP/CIP can contain glandular mucosa of different types similar to those found in the stomach. One study showed that the body or fundus mucosa type parietal cells is the most common accounting for 50 to 65% with the antral type and mixed transition type accounting for 20 to 25% respectively (Borhan-Manesh & Franum, 1991). Presence of acid producing parietal mucosa have been associated with acid production (Galan et al., 1998; Hamilton et al., 1986; Korkut et al., 2010; Yüksel et al., 2008). Mucin is also secreted (Bajbouj et al., 2009; Bogomoletz et al., 1988). The cytokeratin staining pattern of HGMP/CIP is similar to those seen with Barrett's esophagus with surface epithelium staining for CK7 and CK20 (Figure 5). The staining pattern of the esophagus and stomach is shown in Figure 6 (Latchford et al.,

Fig. 4. High power view showing boundary between squamous esophageal mucosa and the

Apart from CK, only one study had assessed the MUC protein profiles (Lauwers et al., 2005). This study showed that MUC5AC was strongly expressed on the surface and pits but not in the glands of HGMP/CIP and antral mucosa. In contrast, MUC5AC positivity was noted on the surface, pits and the glands of Barrett's esophagus. MUC6 similarly decorated the glands of HGMP/CIP and Barrett's esophagus. MUC2 was expressed rarely in HGMP/CIP with goblet cells but conspicuously on the surface and pits of Barrett's esophagus. MUC5B was seen in both HGMP/CIP and Barrett's esophagus and rarely in

mucosa in adults with gastroesophageal reflux disease. (Lauwers et al., 2005)

**2.1.3 Others** 

**3. Histology** 

2001).

glandular mucosa of the HGMP/CIP

#### *Formation from ruptured retention cyst of the proximal esophagus*

This proposed theory suggested that HGMP/CIP formed from ruptured proximal esophageal glandular retention cysts (Meining & Baubouj, 2010). The initial process starts with occlusion of esophageal glands in the proximal esophagus resulting in formation of retention cysts which is internally covered by columnar epithelium. With further enlargement of the cysts, they eventually rupture resulting in the formation of HGMP (Figure 3).

Fig. 3. Proposed acquired pathway through rupture of esophageal glandular retention cysts in the proximal esophagus
