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 The Esophageal
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Volume: Barrett's Esophagus
Chapter: Etiology and origins of Barrett's epithelium

What epidemiological considerations on Barrett's esophagus development can be drawn from salivary epidermal growth factor output?

M. Marcinkiewicz, C. Poplawski, T. Zbroch, J. Sarosiek (Kansas City)

Esophageal squamous cell carcinoma demonstrates the largest variation in incidence among different populations in the world of any cancer monitored in humans [1]. For example, in Nigeria, there are 1.5 cases in males and 1.1 in females per 100,000 population per year, whereas in the North Gonbad region or Iran, there are 165.5 cases in males and 195.3 cases in females per 100,000 population per year, strongly implying that other factors than difference in reporting must play the role in the development of this fatal disease [1].

Esophageal adenocarcinoma also exhibits a high variation in its incidence in terms of geography, race and gender [1, 2]. Esophageal adenocarcinoma develops predominantly in the setting of Barrett's esophagus, therefore, an insight into its pathogenetic mechanisms may help to better understand its epidemiological patterns throughout the world [1, 3-7]. Extensive research targeting Barrett's esophagus and conducted by clinicians, pathologists, molecular biologists and epidemiologists demonstrates the importance of significant potential within the specialized columnar epithelium for malignant transformation [8-11].

There is ample evidence that both Barrett's esophagus and esophageal adenocarcinoma predominantly affect Caucasian males, whereas less likely to arise within the esophageal mucosa of African-American males and least likely to affect African-American females [5,12,13]. Furthermore, prevalence of Barrett's esophagus in Hispanics is similar to Caucasians in the United States [3]. Also in Europe, dominated by Caucasian population, the prevalence of Barrett's esophagus among patients undergoing upper endoscopy for gastroesophageal reflux disease (GERD) symptoms is similar to United States. Barrett's esophagus on the other hand, is uncommon among Asian populations, as for example in Japan or Singapore, but more prevalent among Chinese population in Taiwan [4]. Also Africa and Middle East represent geographical regions with low prevalence of both Barrett's esophagus and adenocarcinoma, although these regions are highly affected by squamous cell esophageal cancer [3-5, 12, 13].

In our recent studies we have demonstrated that patients with endoscopic reflux esophagitis exhibit impairment in the rate of secretion of salivary and esophageal epidermal growth factor (EGF) and that this impairment persists after healing of endoscopic changes [14-16]. Furthermore, among our investigated African-American controls we have revealed significantly higher rate of salivary and esophageal EGF secretion than in control Caucasians [17,18]. Therefore, salivary EGF seems to be critical in prevention of the development of Barrett's esophagus and potentially adenocarcinoma. A similar variation in the rate of secretion of salivary EGF could potentially take place among various populations worldwide, and could potentially contribute to differences in prevalence and incidence of Barrett's esophagus and adenocarcinoma. Exploration of the rate of secretion of salivary EGF among various ethnic populations in the United States and in various regions of African, American, Asian, Australian, and European continents could provide some new insights into Barrett's esophagus and adenocarcinoma pathophysiology and potentially benefit their preventive measures and strategies.

An impairment in the rate of secretion of salivary EGF in patients with Barrett's esophagus has also been demonstrated by Gray et al. [19]. In addition, in our preliminary data we have also demonstrated that patients with Barrett's esophagus, which develops in the setting of GERD, also exhibited an impairment in esophageal EGF secretion when compared to controls [20]. This impairment in the rate of secretion of esophageal EGF could be attributed to lower expression of EGF gene at its peptide level within the esophageal submucosal mucous glands or to a lower number of submucosal mucous glands. A variation in the number of submucosal mucous glands in human esophagus from as low as 62 to as high as 741 glandular lobules has been reported by Goetsch [21].

A similar phenomenon of diminished expression of EGF peptide or a smaller size of salivary glands could also lead to decline of salivary EGF in both populations. Only approximately 1/3 of patients with reflux esophagitis exhibited low EGF in both salivary and esophageal secretion, the remaining showed decline in salivary or esophageal secretion only. The clinical importance of this phenomenon of the most severe impairment in salivary and esophageal EGF secretion requires further investigation.

These data strongly suggest that although gastroesophageal reflux (GER) is prerequisite of the development of the esophageal mucosal pathology, the quality of mucosal protective mechanisms are significant, and could be decisive in determining the development of complications.

Dietary factors may at least partly explain geographical variation in prevalence and incidence of Barrett's esophagus and esophageal adenocarcinoma, and one may assume that the normal squamous epithelium, since it exhibits a high density of EGF receptor even on the apical cell membrane, requires a steady supply of EGF from salivary glands and esophageal submucosal mucous glands which also release their content into esophageal lumen through the ducts [21, 22]. This hypothesis is supported by recently published data demonstrating esophageal squamous epithelial hyperplasia after chronic administration of EGF [23]. Deficiency of EGF hampers physiological functions of the esophageal squamous epithelium and leads to enhanced permeability of the esophageal mucosa to hydrogen ion [24, 25]. This in turn may accelerate damage to the esophageal epithelium by apoptosis or cell necrosis, depending on pH changes within the intercellular milieu in the esophageal mucosa under the impact of GER, decreasing cell-cell adhesion and adhesion of squamous cells to basement membranes hampering their migratory and firm attachment potential. This in turn may promote migration of columnar cells which are phylogenetically well equipped, within their cytoskeleton network, with all molecules necessary to maintain their integrity under the impact of gastric or gastroduodenal milieu. This may explain the receding zone of squamous epithelium and expanding columnar compartment. The borderline between these two distinct morphological compartment is probably determined by 1) the quantity and quality of duodenogastroesophageal refluxate, 2) the intensity of esophageal propulsive primary and secondary peristalsis, 3) the quantity and the quality of protective components within salivary secretion, 4) the density and distribution of esophageal submucosal mucous glands and quality of their protective potential.

Grade IV esophagitis is more common in males than females and Caucasians than African-Americans [2]. It is therefore conceivable that these sex- and race-specific variations reflect inborn differences in tissue resistance or mucosal protective mechanisms operating within the esophageal pre-epithelial, epithelial or postepithelial compartments [2, 26].

Most national data concerning esophageal carcinoma not always well distinguish between the histologic type of cancer or anatomic location. Therefore, the numerical data in most of publications represent all esophageal cancers and requires caution in their interpretation [1].


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18. Marcinkiewicz M, Zbroch T, Scheurich J, Sarosiek J, McCallum R. Potential contribution of enhanced salivary EGF output to the lower prevalence of reflux esophagitis and complications in African-Americans. Gastroenterology 1997;112:A211.

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Publication date: August 2003 OESO©2015