Normal Oxyntic Mucosa Research Articles

Gastric inverted hyperplastic polyp with typical endoscopic feature.

A 37-year-old woman received gastroscopy for compliant of upper abdominal discomfort for six months. A polyp with size in 10 mm was found in the upper third of stomach. The polyp with a papilla-like depression in the top and smooth surface similar to surrounding non-atrophic mucosal characterized by regular arrangement of collective veins (Fig. 1A and B). Endoscopic ultrasound showed the lesion was hypo –equal echo in the mucosal layer, displayed expansive growth nature and oppressing submucosal layer (Fig. 1C). Histology of biopsy showed inflamed mucosa with submucosal atypic oxyntic gland, considering histological diagnosis of ectopic gastric glands with atypia, but adenocarcinoma of fundic gland type cannot be ruled out (Fig. 1D and E). Thus, the polyp was removed by endoscopic submucosal dissection for accurate histological diagnosis. The histology showed the benign hyperplastic glands with inverted growth manner with communication with mucosal at the top, the surround area was covered by normal oxyntic mucosa (Fig. 2), and diagnosed as gastric inverted hyperplastic polyp (GIHP). GIHPs are rare gastric polyps and typically appeared as rounded subepithelial lesions with normal overlying mucosa, more than half of cases with surface erosion, depression, or orifice exuding mucin [ [1] Kim JY Ahn S Kim KM et al. Gastric inverted polyps—distinctive subepithelial lesions of the stomach: clinicopathologic analysis of 12 cases with an emphasis on neoplastic potential. Am J Surg Pathol. 2021 May 1; 45: 680-689 Crossref PubMed Scopus (3) Google Scholar ]. GIHPs had the potential to develop adenocarcinoma, but histological diagnosis based on biopsy is challenging, endoscopic resection may be a wise choice for accurate diagnosis. Fig. 2Histology based on the resected specimen. (A) Scanning image of the lesion showed inverted growth manner; (B) Hyperplastic glands without dysplasia at high magnification. View Large Image Figure Viewer Download Hi-res image

The cytoprotective protein clusterin is overexpressed in hypergastrinemic rodent models of oxyntic preneoplasia and promotes gastric cancer cell survival

The cytoprotective protein clusterin is often dysregulated during tumorigenesis, and in the stomach, upregulation of clusterin marks emergence of the oxyntic atrophy (loss of acid-producing parietal cells)-associated spasmolytic polypeptide-expressing metaplasia (SPEM). The hormone gastrin is important for normal function and maturation of the gastric oxyntic mucosa and hypergastrinemia might be involved in gastric carcinogenesis. Gastrin induces expression of clusterin in adenocarcinoma cells. In the present study, we examined the expression patterns and gastrin-mediated regulation of clusterin in gastric tissue from: humans; rats treated with proton pump (H+/K+-ATPase) inhibitors and/or a gastrin receptor (CCK2R) antagonist; H+/K+-ATPase β-subunit knockout (H/K-β KO) mice; and Mongolian gerbils infected with Helicobacter pylori and given a CCK2R antagonist. Biological function of secretory clusterin was studied in human gastric cancer cells. Clusterin was highly expressed in neuroendocrine cells in normal oxyntic mucosa of humans and rodents. In response to hypergastrinemia, expression of clusterin increased significantly and its localization shifted to basal groups of proliferative cells in the mucous neck cell-chief cell lineage in all animal models. That shift was partially inhibited by antagonizing the CCK2R in rats and gerbils. The oxyntic mucosa of H/K-β KO mice contained areas with clusterin-positive mucous cells resembling SPEM. In gastric adenocarcinomas, clusterin mRNA expression was higher in diffuse tumors containing signet ring cells compared with diffuse tumors without signet ring cells, and clusterin seemed to be secreted by tumor cells. In gastric cancer cell lines, gastrin increased secretion of clusterin, and both gastrin and secretory clusterin promoted survival after starvation- and chemotherapy-induced stress. Overall, our results indicate that clusterin is overexpressed in hypergastrinemic rodent models of oxyntic preneoplasia and stimulates gastric cancer cell survival.

The normal neuroendocrine cells of the upper gastrointestinal tract lack E-cadherin

Objective. E-cadherin plays a crucial role in the adhesion between epithelial cells and thus epithelial integrity. Moreover, germline mutations in the E-cadherin gene (CDH1) causing loss of E-cadherin function (adhesion) leads to hereditary gastric cancer of the diffuse type, according to Laurén. Even sporadic gastric carcinomas of the diffuse type often lose E-cadherin expression due to mutations. Lack of E-cadherin has been recorded at an early phase in such carcinomas. For 25 years, we have provided evidence for neuroendocrine (NE) cell origin of gastric carcinomas of diffuse type. The present study was, therefore, done to examine whether normal NE cells in the gastrointestinal tract express E-cadherin or not. Methods. During upper gastrointestinal endoscopy, biopsies were taken from normal oxyntic mucosa, gastric carcinoids, gastric carcinomas, and from normal duodenal mucosa. Tissues were examined by immunohistochemistry (IHC) using antibodies toward chromogranin A, synaptophysin, and E-cadherin. Isolated mucosal cells were prepared from biopsies of normal mucosa and examined by antibodies against the same markers by immunofluorescence. Results. Normal gastrointestinal NE cells did not express E-cadherin as assessed by IHC or immunocytochemistry. No expression of E-cadherin was found on tumor cells from gastric carcinoids or cancer of diffuse type examined by IHC. Conclusion. Our findings, which are in contrast to some previous studies, may explain why there is a discrepancy between lack of atypia and malignant biological behavior of such tumors. Since they normally lack the adhesion molecule E-cadherin, reflected in their spread occurrence, only minor changes may result in malignant behavior.

Spasmolytic polypeptide-expressing metaplasia (SPEM) in the gastric oxyntic mucosa does not arise from Lgr5-expressing cells

ObjectiveMetaplastic lineages in the oxyntic mucosa of the stomach are critical preneoplastic precursors of gastric cancer. Recent studies have demonstrated that spasmolytic polypeptide-expressing metaplasia (SPEM) in the mouse oxyntic mucosa...

Gastric neuroendocrine carcinoma after long-term use of proton pump inhibitor

We present a case of a gastric neuroendocrine carcinoma in a patient with a history of long-term proton pump inhibitor (PPI) use. A 49-year-old man using PPI for the last 15 years due to gastroesophageal reflux disease developed progressive dysphagia, dyspepsia and weight loss. Upper gastrointestinal endoscopy, endoscopic ultrasonography and abdominal CT diagnosed a malignant tumor localized to a hiatal hernia. Fasting serum chromogranin A and gastrin concentrations were elevated (32 nmol/l and 159 pmol/l, respectively). Helicobacter pylori PCR analysis of antral biopsies was negative. Biopsies from endoscopically normal oxyntic mucosa showed enterochromaffin-like (ECL) cell hyperplasia. Tumor biopsies revealed a poorly differentiated neuroendocrine carcinoma. Sevier-Munger staining, immunohistochemistry and electron microscopy indicated ECL cell as origin of the tumor cells. Concerns have previously been raised about the safety of long-term PPI use due to a possible increased risk of cancer. This case illustrates a patient with a poorly differentiated neuroendocrine carcinoma with ECL cell characteristics probably induced by hypergastrinemia secondary to long-term PPI use.

The Transcription Factor MIST1 Is a Novel Human Gastric Chief Cell Marker Whose Expression Is Lost in Metaplasia, Dysplasia, and Carcinoma

The lack of reliable molecular markers for normal differentiated epithelial cells limits understanding of human gastric carcinogenesis. Recognized precursor lesions for gastric adenocarcinoma are intestinal metaplasia and spasmolytic polypeptide expressing metaplasia (SPEM), defined here by ectopic CDX2 and TFF2 expression, respectively. In mice, expression of the bHLH transcription factor MIST1, normally restricted to mature chief cells, is down-regulated as chief cells undergo experimentally induced metaplasia. Here, we show MIST1 expression is also a specific marker of human chief cells. SPEM, with and without MIST1, is present in human lesions and, akin to murine data, likely represents transitional (TFF2(+)/MIST1(+) = "hybrid"-SPEM) and established (TFF2(+)/MIST1(-) = SPEM) stages. Co-visualization of MIST1 and CDX2 shows similar progressive loss of MIST1 with a transitional, CDX2(+)/MIST1(-) hybrid-intestinal metaplasia stage. Interinstitutional analysis and comparison of findings in tissue microarrays, resection specimens, and biopsies (n > 400 samples), comprising the entire spectrum of recognized stages of gastric carcinogenesis, confirm MIST1 expression is restricted to the chief cell compartment in normal oxyntic mucosa, rare in established metaplastic lesions, and lost in intraepithelial neoplasia/dysplasia and carcinoma of various types with the exception of rare chief cell carcinoma ( approximately 1%). Our findings implicate MIST1 as a reliable marker of mature, healthy chief cells, and we provide the first evidence that metaplasia in humans arises at least in part from the chief cell lineage.

Histologic classification of patients based on mapping biopsies of the gastroesophageal junction.

This study consists of 959 consecutive patients in whom endoscopic biopsies were taken according to a protocol that permitted mapping and measurement of epithelial types in the gastroesophageal region. The epithelial types were classified as normal (oxyntic and squamous) and questionably abnormal (oxyntocardiac, cardiac, intestinal) by strict histologic criteria. Patients were classified into four groups based on the length of histologically defined abnormal glandular epithelium in the measured biopsies. A total of 811 (84.6%) patients had 0 to 0.9 cm of questionably abnormal columnar epithelium between normal oxyntic mucosa and squamous epithelium. Of these, 161 (19.9%) patients had no abnormal epithelium, 158 (19.4%) patients had oxyntocardiac mucosa, 372 (45.9%) patients had cardiac mucosa, and 120 (14.8%) patients had intestinal metaplasia. A total of 148 (15.4%) patients had >or=1 cm of abnormal columnar epithelium. All but one patient in this group had cardiac or intestinal epithelia. The prevalence of intestinal epithelium increased progressively with increasing length of abnormal columnar epithelium, being present in 70.4% in the 1- to 2-cm group, 89.5% in the 3- to 4-cm group, and 100% with in the >or=5 cm group. We propose a histologic grading system of biopsies based on these findings.

Oxyntic mucosa pseudopolyps: a presentation of atrophic autoimmune gastritis.

Gastric polyps are often present in the setting of atrophic gastritis. Although the majority of these polyps are nonneoplastic, such as hyperplastic polyps, neoplastic polyps may be present. We discuss nine cases that illustrate an additional nonneoplastic cause of polyps in atrophic gastritis. Specifically, preserved islands of relatively normal oxyntic mucosa in a background of gastric atrophy may appear polypoid endoscopically. The patients (seven women, two men, mean age 64 years) presented with nonspecific abdominal or reflux symptoms (n = 8) and diarrhea (n = 1). Five of five patients tested were confirmed to have hypergastrinemia, and three of three patients tested had antiparietal cell antibodies. Biopsies from the gastric body or fundus of our nine patients showed fragments of atrophic mucosa and separate fragments of preserved oxyntic mucosa. Based upon the histologic characteristics of the atrophic fundic and relatively normal antral biopsies, the gastric atrophy appeared to be of autoimmune-type. The relatively preserved oxyntic glands showed parietal cell hypertrophy and focal mild chronic inflammation. The number of polyps observed endoscopically ranged from less than five to multiple/diffuse. Three patients had persistent nodularities in their stomachs for 1, 3, and 7 years of their follow-up. Our study shows that some patients with atrophic gastritis, autoimmune-type, may present with gastric polyps/nodules that represent relatively preserved oxyntic mucosa. This presentation may be more common than is presently recognized because biopsies of the polyps alone will not show histologic features of atrophic gastritis or reveal the etiology of the polyp itself. Although a limited number of previous studies have suggested this type of polypoid presentation may represent "early" atrophic gastritis, its persistence in three of our patients argues against this hypothesis.

Spontaneous ECLomas in cotton rats (Sigmodon hispidus): tumours occurring in hypoacidic/hypergastrinaemic animals with normal parietal cells.

We have identified cotton rats with a high female-predominant occurrence of spontaneous gastric carcinomas localized to the oxyntic mucosa, classified as malignant enterochromaffin-like (ECL) omas. The present study was made to further characterize these ECLomas and surrounding oxyntic mucosa, both morphologically using histochemical and immunohistochemical methods, and for gene expression by northern blot analysis. Among eight female cotton rats, three had an irregularly thickened oxyntic mucosa, increased stomach weight and a high serum gastrin level. Histopathological examination showed adenomatous hyperplasia of the thickened oxyntic mucosa with areas of an invasive neoplastic tumour. Immunohistochemistry, using the general neuroendocrine cell marker chromogranin A (CgA) and the specific ECL cell marker histidine decarboxylase (HDC), showed a considerably increased ECL cell density. These ECL cells displayed active proliferation, with hyperplasia, dysplasia and neoplasia. Parietal cells were not found in the tumour tissue. Parietal cell density was only slightly reduced in the surrounding oxyntic mucosa. The antral mucosa was histopathologically normal with a normal number of gastrin-immunoreactive cells. Likewise, somatostatin-immunoreactive cells did not show any differences in the antral and oxyntic mucosa between rats with pathological and normal oxyntic mucosa. Northern blot analysis revealed increased expression of CgA and HDC mRNA in the thickened oxyntic mucosa, whereas H(+)/K(+) ATPase mRNA was similar in the oxyntic mucosa of those with thickened and normal oxyntic mucosa. Gastrin mRNA in the antral mucosa was high in animals with thickened oxyntic mucosa. Somatostatin mRNA expression was similar in the antral mucosa of control animals and animals with a thickened oxyntic mucosa. We conclude that the spontaneous gastric carcinoma occurring in female cotton rats is an ECLoma developing secondary to hypergastrinaemia due to reduced intragastric pH. The mechanism for reduced acidity is not known, but is not gastric atrophy.

Involvement of BCL-2 Oncoprotein in the Development of Enterochromaffin-like Cell Gastric Carcinoids

To evaluate the involvement of the apoptosis-suppressing protein BCL-2 in the gastrin-dependent mechanism of induction of gastric enterochromaffin-like (ECL) cell carcinoids, the endocrine cell of the oxyntic mucosa were immunohistochemically investigated in (a) 10 normogastrinemic subjects with histologically normal gastric mucosa; (b) 22 patients with endocrine cell hyperplasia and affected by hypergastrinemic conditions with different risk of gastric carcinoid development, such as sporadic Zollinger-Ellison syndrome (sZES; n = 9), ZES associated with multiple endocrine neoplasia-1 (MEN-1; n = 4), and atrophic fundal gastritis (AFG; n = 9); (c) 14 patients with ECL gastric carcinoids accounting for a total of 31 tumors investigated. In the normal oxyntic mucosa, BCL-2 was consistently expressed by a subset of endocrine cells accounting for 50.0% (median; range, 24.6-74.0%) of the total number of endocrine cells immunostained for chromogranin A (CgA) in consecutive sections. BCL-2 immunoreactive cells were located mostly in the middle mucosal layer, suggesting a role for the protein during downward migration of maturing endocrine cells. No BCL-2 immunoreactivity was found in other specialized gastric epithelial cells. Expression of BCL-2 by hyperplastic oxyntic endocrine cells (mostly ECL cells) varied in parallel with the risk of carcinoid development. In fact, the ratio of BCL-2- to CgA-immunoreactive cells was reduced (median, 4.6%; p less than 0.0001; range, 0.9-42.0%) in sZES, a condition showing virtually no risk, unchanged (median, 55.6%; range 29.4-83.8 %) in cases of MEN-1/ZES with intermediate risk, and increased (median 87.6%; p less than 0.014; range, 48.8-199.4%) in cases of AFG, a condition at the highest risk of carcinoid. In ECL cell carcinoids, BCL-2 expression varied markedly from one tumor to another even in the same patient and was low or absent in most cases. In both hyperplastic and neoplastic ECL cells, an inverse relation between BCL-2 expression and CgA immunoreactivity, that is, the cell granule content, was found. These results suggest that BCL-2 expression by hyperplastic ECL cells is independent of the influence of serum gastrin and may contribute to the development of ECL cell carcinoid tumors by extending cell exposure to oncogenic factors. Once a carcinoid tumor is established, BCL-2 expression becomes inconsistent.

Apoptosis

Maintenance of gastric mucosal structure depends on a dynamic balance between cell loss and cell renewal. The surface epithelial cells exfoliate at a rapid rate (usually in response to luminal contents) and are entirely replaced within 3-5 days. The loss of parietal, chief, and endocrine cells is much slower, but there is little information concerning the morphologic aspects of this process. Because in other tissues cells are physiologically eliminated through a process of apoptosis--genetically programmed cell self-destruction and loss--we studied whether this process occurs in normal gastric mucosa and in the mucosa of recently healed gastric ulcers in the rat. Degeneration and loss of the surface epithelial cells into the gastric lumen occurs in normal oxyntic mucosa, and more extensive desquamation of poorly differentiated mucous cells in the dilated gastric glands takes place within mucosal scars of grossly healed gastric ulcers. Apoptosis of parietal, chief, and endocrine cells in normal oxyntic mucosa and apoptosis of poorly differentiated cells lining dilated glands in mucosal scar were assessed and characterized by electron microscopy. Apoptosis affects single glandular cells and involves a rapid initial condensation of both nucleus and cytoplasm, with subsequent fragmentation. Finally, the cell is converted into a cluster of membrane-bound apoptotic bodies, which usually are engulfed by adjacent cells or disposed into a glandular lumen. Desquamation of surface epithelium and apoptotic self-destruction of glandular epithelium stimulate a constant cell renewal and thus contribute to the maintenance of the ulcer healing process. Rapid and "excessive" proliferation of regenerating gastric epithelium enables re-epithelialization of ulcer crater.(ABSTRACT TRUNCATED AT 250 WORDS)

The structure of normal and regenerating rat oxyntic mucosa.

The morphology of the normal oxyntic mucosa is described. Different animal models for the production of gastric ulcers are briefly reviewed. In a series of rats, wounds were produced by cauterisation of the oxyntic mucosa. The mucosal regeneration process was then followed by morphometrical methods using light and electron microscopy. In particular, the regeneration of the acid-producing parietal cells was followed. Initially, the ulcer area is covered by primitive epithelial cells originating from the mucosa in the wound margin. These cells form the new gastric glands. With time, all specialised epithelial cell types which normally occur in the oxyntic mucosa can be recognised and, if regeneration is allowed to continue, the structure and function of these cells will normalise. However, the amount of glands and the number of parietal cells within the glands remain subnormal.

Immunohistochemical studies on glucagon, glicentin and pancreatic polypeptide in human stomach: normal and pathological conditions.

Endocrine-like cells containing glucagon, glicentin or pancreatic polypeptide immunoreactivity in human foetal and adult stomach, with or without disease, were studied with the indirect immunoperoxidase method and mirror sectioning technique. In foetal and neonatal oxyntic mucosae, there were endocrine-like cells with glucagon and glicentin immunoreactivities and argyrophilia. Cells containing glicentin immunoreactivity alone were detected earlier than glucagon cells during foetal development, and were also distributed throughout foetal to neonatal life. Bovine pancreatic polypeptide immunoreactivity coexisted in a subpopulation of the glucagon-glicentin cells. These cells were absent from normal oxyntic mucosa in the postneonatal period and from normal antral mucosa throughout life. Hamartomatous polyp in adult oxyntic mucosa, hyperplastic oxyntic mucosa in Menetrier's disease and atrophic oxyntic mucosa in a remnant stomach with cancer showed scattered glucagon-glicentin cells, but few or no cells containing bovine pancreatic polypeptide. Intestinalized mucosa showed plentiful glicentin cells with occasional glucagon and/or bovine pancreatic polypeptide immunoreactivity. Some gastric cancer cells of both diffuse and adenoplastic types contained immunoreactive glicentin and, less frequently, glucagon. Bovine pancreatic polypeptide immunoreactivity was detected in a few adenoplastic cancer cells, but not in diffuse type cells. Three different anti-pancreatic polypeptide sera against bovine, porcine or human pancreatic polypeptide detected basically the same cells mentioned above, but pancreatic polypeptide cells lacking human pancreatic polypeptide immunoreactivity were also present in foetal oxyntic mucosa. Immunoabsorption tests revealed that the bovine pancreatic polypeptide immunoreactivity was remote from peptide YY and neuropeptide Y.

Polyps in the acid-secreting area of the stomach

The relation of gastric polyps to acid-secreting mucosa was examined in 120 patients with gastric polyps. Studies were made by the endoscopic Congo red test developed in this clinic. In 23 patients (19.1%) gastric polyps were located in acid-secreting mucosa and may have arisen from normal oxyntic mucosa. These polyps were of two histological types: oxyntic gland polyps containing many parietal cells, and nonoxyntic gland polyps without parietal cells. Only the former type appeared to secrete acid, judging endoscopically from the change of Congo red from red to blue-black on the surface of the polyps after administration of gastrin.