Chapter 12, Page 5  

ENDOCRINE CELL PROLIFERATIONS OF THE STOMACH ENDOCRINE CELL HYPERPLASIA Endocrine Cell Hyperplasia Secondary to Gastric Disease Pathogenesis. The major pathogenetic mechanisms of gastric endocrine cell hyperplasia are hypochlorhydria secondary to atrophic gastritis, partial gastrectomy with resection of the body and fundic mucosa, or rarely, the Zollinger-Ellison syndrome (3, 6, 9 , 13, 19, 21, 25, 37, 42, 46, 72, 74, 81, 82, 85, 87, 100). Gastric acid normally suppresses gastrin production; hypochlorhydria results in gastrin cell hyperplasia and hypergastrinemia (fig. 12-4a). The latter is trophic for the fundic endocrine cells and results in a predominantly argyrophil cell hyperplasia (figs. 12-4b, 12-4c, 12-4d). A number of distinctive cell types have been demonstrated in endocrine cell hyperplasia by immunohistochemistry and electron microscopy, such as enterochromaffin-like (ECL) (which are by far the most common), enterochromaffin (EC), gastrin, pancreatic polypeptide (PP), somatostatin (D), and D1 cells (13, 37, 39, 72). The major cause of hypochlorhydria is severe atrophic gastritis of the fundus, for example, in pernicious anemia and partial gastrectomy (4, 19, 42, 74). Hypochlorhydria may also be induced iatrogenically with acid-suppressing drugs such as the H2 blockers or the newer proton pump inhibitors such as omeprazole, which suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system. In animals, omeprazole has been shown to result in endocrine cell hyperplasia and even carcinoid tumors. Hyperplasia of ECL cells, but not tumors, have also been demonstrated in humans treated with proton pump inhibitors although the clinicopathologic evidence suggests that the hyperplasia is more likely related to the atrophic gastritis than the acid suppressors (4, 44, 95, 96). A rare cause of hypergastrinemia is a gastrinoma. A recent study has shown that hyperplastic endocrine cells express BCL-2 oncoprotein which may expose them to oncogenic factors, leading to further proliferation of these cells (4a). Clinical Features. There are no significant clinical symptoms related to endocrine cell hyperplasia (7, 18). Occasionally, fundic endocrine cell hyperplasia progresses to dysplasia or, rarely, carcinoid tumors. Regular gastroscopic screening for carcinoid tumor in the stomach is not considered worthwhile other than in high-risk groups, namely, those with juvenile pernicious anemia and those with multiple endocrine neoplasia (MEN) (8, 88). Microscopic Findings. The histologic findings in endocrine cell hyperplasia secondary to gastric disease are G-cell hyperplasia of the antrum and endocrine cell proliferations of the gastric body and fundus (figs. 12-4a, fig. 12-4b). In our experience, the latter usually originate from the atrophic glands (often showing features of pseudopyloric metaplasia or mucous cell metaplasia) rather than from areas of intestinal metaplasia. Proliferation of the fundic endocrine cells may occur in a diffuse manner, most commonly in Zollinger-Ellison syndrome associated with the MEN syndrome, in a sleeve-like manner around gastric glands (fig. 12-5), or as small balls or nests of cells budding from the base of glands and often lying free within the lamina propria (figs. 12-4b, 12-4c, 12-4d). These proliferations are best appreciated with silver stains or immunostains for chromogranin (figs. 12-4d, 12-5). In hematoxylin and eosin-stained sections, the endocrine cells are not readily apparent; the nodular proliferations appear pale with a somewhat basophilic cytoplasm and are often confused with gastric chief cells (fig. 12-4d). The G-cell proliferations secondary to atrophic gastritis may be as numerous as those in primary G-cell hyperplasia but clinically the two entities differ since the gastric fundus and body are atrophic and patients do not develop symptoms due to excess acid production (3, 19, 74).