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Download PDF (4844K) 119 J. St. Marianna Univ. Original Article Vol. 6, pp. 119–130, 2015 Histopathologic and Immunohistochemical Characterization of Human Gastric Oxyntic Mucosa with Parietal Cell Protrusions and Investigation into the Association Between Such Mucosal Changes of the Stomach and Use of Proton Pump Inhibitors Saeko Naruki1, Takashi Fujino1, Shigeko Ohnuma1, Akira Endo1, Hirotaka Koizumi1, Yo Kato2, and Masayuki Takagi1 (Received for Publication: June 25, 2015) Abstract With widespread use of proton pump inhibitors (PPIs) has come characteristic gastric mucosal changes such as parietal cell protrusions (PCPs) and so-called fundic gland polyps (FGPs). Nevertheless, whether these lesions are actually PPI-related gastric mucosal lesions has not been fully clarified. The present study focused on this issue. We firstly examined the purported relation between the emergence of PCPs and PPI use. We also investigated the relation between PPI use and the emergence of cystically dilated glands (CDGs) that can give rise to elevated mucosal lesions such as FGPs. In addition, we performed histopathologic and immunohisto‐ chemical analyses to clarify the characteristics of PCPs and PCP-affected gastric oxyntic mucosa. A significant relation between the emergence of PCPs and PPI use was confirmed. In contrast, no significant relation was found between the emergence of CDGs and PPI use. Histologic and immunohistochemical analyses showed PCPs to be hyperplastic lesions. In the PCP-affected oxyntic mucosa, the isthmus-and-neck region of the fundic glands was elongated and the base region was shortened in relation to the total mucosal thickness. These changes were accompanied by an increase in the number of parietal cells and a decrease in the number of chief cells. Immunohistochemical analysis suggested impairment of both parietal cell differentiation and mucous neck-to-chief cell differentiation．Furthermore, our study reinforced the notion that elevated hydrostatic pres‐ sure and cytoplasmic edema due to movement of water from interstitial space toward the lumen of oxyntic glands via parietal cells give rise to the formation of PCPs, oxyntic dilatation, and CDGs. The detailed mecha‐ nism of PCP formation and its clinical implications are expected to be clarified in future studies. Key words stomach, proton pump inhibitor, oxyntic mucosa, parietal cell protrusion, dilated fundic gland composed mainly of oxyntic epithelial progenitors Introduction (proliferating cells). The neck is composed of a mix‐ Human gastric oxyntic mucosa is characterized ture of mucous neck cells and parietal cells (gastric by pits (foveolae), which are invaginations of the sur‐ acid-secreting cells), and the base is composed face epithelium that open into long glands. Each mainly of chief cells (pepsinogen-secreting cells). gland is made up of 3 regions: an isthmus, neck, and The parietal cells extend mainly from the isthmus to base1). As illustrated in Figure 1, the pit is lined by the base. foveolar cells (mucus-secreting cells). The isthmus is Proton pump inhibitors (PPIs) are a class of 1 Department of Pathology, St. Marianna University School of Medicine 2 Department of Pathology, Nikko Medical Center, Dokkyo Medical University 17 120 Naruki S Fujino T et al ways. PPIs, marketed as omeprazole or lansoprazole, became widely available in the early 1990s and, with their potent suppression of gastric acid secretion, pre‐ vailed over H2 blockers2). PPIs are now commonly used in the treatment of gastric acid-related diseases including gastric ulcer, duodenal ulcer, and reflux esophagitis. PPIs are also used adjuvantly in the erad‐ ication of H. pylori3). With widespread use of PPIs came reports of gastric mucosal changes including fundic gland hy‐ perplasia4), cystic dilation of fundic glands (oxyntic dilatation)5)6), emergence and enlargement of so- called fundic gland polyps (FGPs)7–11), and morpho‐ logic changes in parietal cells12). The parietal cell pro‐ trusions (PCPs) found in patients treated with omeprazole are thought to be an especially character‐ istic change13–15). PCP describes marked convex pro‐ trusion of parietal cell cytoplasm into the lumen of the oxyntic glands. Oxyntic glands affected by PCP tend to dilate (oxyntic dilatation) (Figure 2A), and the cytoplasm of the involved parietal cells often ap‐ pears vacuolated (Figure 2B). PCPs have been ob‐ served frequently in patients receiving maintenance therapy with omeprazole or lansoprazol13–16). So- called FGPs, which are characterized histologically by cystically dilated glands (CDGs), are also ob‐ served in patients receiving maintenance PPI ther‐ Figure 1. Schematic diagram (anatomy) of oxyntic mu‐ apy7–11),17). In fact, Cats et al. reported that most of cosa. their patients with dilated fundic glands showed PCP The luminal surface of the oxyntic mucosa during omeprazole maintenance therapy15). It is our displays orifices that lead to tubular invagina‐ understanding that the morphology of parietal cells in tions called pits, at the bottom of which open CDGs in patients taking PPIs clearly differs from that 1 or more glands. Each gland is divided into 3 of sporadic FGPs in patients not taking PPIs (Figure regions: isthmus, neck, and base. The pit is 3), indicating that the formation of CDGs with PCP lined by foveolar cells (mucus-producing differs etiologically from the formation of sporadic cells). The isthmus is composed mainly of FGPs. oxyntic epithelial progenitors (proliferating We know of no reported investigation of PCP cells). The neck is characterized by a mixture development in patients taking PPIs versus patients of mucous neck cells and parietal cells (gastric not taking PPIs. We conducted a comparative study acid secretion cells). The base is composed to clarify the characteristics and histogenesis of PCP mainly of chief cells (pepsinogen secretion itself and of oxyntic mucosa with PCPs in humans. cells). Parietal cells extend mainly from the Materials and Methods isthmus to the base. Case selection medicines used to control and treat gastrointestinal We reviewed all endoscopically obtained biopsy peptic ulcer disease by blocking acid secretion2). In‐ specimens of gastric oxyntic mucosa from 468 pa‐ troduced in the 1980s, PPIs suppress secretion of gas‐ tients examined for various gastrointestinal disorders tric acid by parietal cells, and they do this by target‐ at St. Marianna University School of Medicine Hos‐ ing the enzymatic function of gastric H+/K+-ATPase pital, Kanagawa, Japan, in 2013. In addition, we re‐ (proton pump) without influencing histamine recep‐ viewed the records of these patients to determine tor, gastrin receptor, or acetylcholine receptor path‐ which had been prescribed a PPI (omeprazole, lanso‐ 18 Characterization of PCP in Humans 121 Figure 2. Characteristics of PCPs. Representative histologic images of oxyntic mucosa with PCPs. A, Parietal cells show marked intraluminal protrusion of cytoplasm resulting in a serrated glandular lumen. The affected fundic glands tend to dilate (oxyntic dilatation) (H&E stain, low magnification). B, Parietal cells show tongue-like convex protrusion. Note the protrusion of parietal cell cytoplasm into the lumen and the accompanying vacuolation (arrow) (H&E stain, high magnification). Each black bar = 100 µm Figure 3. Histologic comparison of CDGs with PCPs and with sporadic FGPs. Representative histologic images of CDGs with PCPs (H&E stain). A, Low magnification. B, High magnification. Note the protruding parietal cells (ar‐ rows). Representative histologic images of a sporadic FGP (H&E stain). C, Low magnification. D, High magnification. Note the flattening of epithelial cells in the CDGs. Each black bar = 100 µm 19 122 Naruki S Fujino T et al prazole, sodium rabeprazole, esomeprazole) during The sections were incubated with the primary anti‐ the 1-year period before the biopsy was performed, bodies for 1 hour at room temperature and then and we classified these patients according to whether washed 3 times in PBS, stained with horseradish per‐ they had (n = 127) or had not (n = 341) used PPIs. oxidase-labeled polymer-conjugated anti-mouse or We also reviewed surgical specimens containing anti-rabbit secondary antibodies (EnVision+ System, gastric oxyntic mucosa from 52 patients who under‐ Dako), and color developed with 3′-diaminobenzidine went open gastrectomy at St. Marianna University tetrahydrochloride. School of Medicine Hospital or Toyoko Hospital, Ka‐ nagawa, Japan, between January 2011 and December Histologic evaluation of biopsy specimens 2013. These patients, none of which had atrophic We reviewed H&E-stained slides of the biopsy gastritis, were divided into 2 groups: those in whom specimens and divided them into 4 groups according PCPs were present (n = 26, PCP(+) group) and those to the presence or absence of PCP, observed as dis‐ in whom PCPs were not present (n = 26, PCP(−) tinct intraluminal protrusion of parietal cell cyto‐ group). The PCP(+) group included 22 men (85%) plasm at 3 or more glands, and the presence or ab‐ and 4 women (15%) with a median age of 67 years sence of CDGs, observed as gland dilatation and (range: 27–84 years), and the PCP(−) group included cystic change (≥250 µm in diameter) at 3 or more 19 men (73%) and women (27%) with a median age glands. Findings were recorded as PCP(−) CDG(−), of 70 years (range: 40–87 years). Only specimens ob‐ PCP(+) CDG(−), PCP(−) CDG(+), or PCP(+) tained from the lesser curvature of the corpus were CDG(+) and were further classified according to examined. whether
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