Pathologic changes of endocrine cells in chronic atrophic gastritis. An ultrastructural study on peroral gastric biopsy specimens

In the course of an ultrastructural study on peroral gastric biopsy specimens that were obtained from patients with chronic atrophic gastritis, peculiar pathological changes of endocrine cells were observed and correlated with functional and hormonal data on the patients. An increased number of G (gastrin) cells was found in hypergastrinemic patients. These cells could be divided into a "light" (probably hyperfunctioning) and a "dark" (probably exhausted) type. The light type of cell was prominent regardless of the concomitant gastrin blood levels. The G cells found within the fundic region were always localized within the areas of pyloric metaplasia. Focal micronodular proliferation of antral enterochromaffin cells (EC) was often seen. A proliferation of the closed type of endocrine cells of the fundic mucosa was observed only in patients with elevated gastrin concentrations. In the present study, these cells were identified as enterochromaffin-like cells (ECL). No substantial changes were found in the D and D1 cells. The endocrine cells seen in metaplastic intestinal epithelium exhibited ultrastruct characteristics of at least three different types of intestinal endocrine cells (EC, L, and S cells).     

Gastric Carcinoids of Argyrophil ECL Cells

Histochemical and ultrastructural studies were carried out in four gastric carcinoids, two of which were associated with atrophic gastritis and pernicious anemia. All tumors showed intense argyrophilia and vesicular granules resembling those of endocrine enterochromaffinlike (ECL) cells in normal human gastric mucosa. Tumor cells were found to be unreactive to all the 18 available antiserums to gut hormones, including gastrin, somatostatin, glucagon, and pancreatic polypeptide. The tumors were interpreted as ECL cell argyrophil carcinoids with various degrees of differentiation and atypia.     

Gastric Carcinoids of Argyrophil ECL Cells

Histochemical and ultrastructural studies were carried out in four gastric carcinoids, two of which were associated with atrophic gastritis and pernicious anemia. All tumors showed intense argyrophilia and vesicular granules resembling those of endocrine enterochromaffinlike (ECL) cells in normal human gastric mucosa. Tumor cells were found to be unreactive to all the 18 available antiserums to gut hormones, including gastrin, somatostatin, glucagon, and pancreatic polypeptide. The tumors were interpreted as ECL cell argyrophil carcinoids with various degrees of differentiation and atypia.     

Endocrine Precursor Lesions of Gastroenteropancreatic Neuroendocrine Tumors

This review focuses on precursor lesions of gastrointestinal and pancreatic neuroendocrine tumors (GEP-NETs). There are three conditions that are associated with hyperplastic changes in endocrine cells preceding GEP-NETs: autoimmune chronic atrophic gastritis or multiple endocrine neoplasia type 1 (MEN1) with gastric enterochromaffin-like (ECL) cell hyperplasia; MEN1 with gastrin and somatostatin cell hyperplasia in the duodenum and glucagon cell hyperplasia in the islets of the pancreas; and inflammatory bowel disease with endocrine cell hyperplasia in the colon. In gastric ECL cell hyperplasia, it is assumed that hypergastrinemia promotes the growth of the ECL cells of the corpus mucosa and leads to hyperplasia and neoplasia. In the duodenum and the pancreas, the MEN1-associated germline mutation of the menin gene obviously causes hyperplasia of the gastrin and somatostatin cells (duodenum) and the glucagon cells (pancreas), resulting in multifocal development of tumors. These tumors show allelic deletion of the MEN1 gene, whereas the precursor lesions retain their heterozygosity. The endocrine cell hyperplasia in the colon described in inflammatory bowel disease has neither a genetic nor a definite hormonal background.     

Multicentric gastric carcinoids complicating pernicious anemia. Origin from the metaplastic endocrine cell population

We report three cases of multicentric carcinoid tumors of the stomach in patients with long-standing pernicious anemia and severe atrophic gastritis (type A). The tumor nodules arose in nonantral gastric mucosa showing marked intestinal metaplasia. Diffuse endocrine cell hyperplasia was present in both fundus and antrum. Antral G-cell hyperplasia was observed. A widely accepted pathogenesis of this syndrome suggests that the proliferating cell type is the argyrophilic, enterochromaffinlike cell native to the gastric body and fundus. Our findings conflict with this view, in that focal argentaffin staining was also present within tumor cells, as well as immunoreactivity for serotonin and substance P (more characteristic of small-intestinal enterochromaffin or Kulchitsky's cells and small-intestinal carcinoids). Findings in these cases at least suggest an alternative possibility: the tumors may derive from small-intestinal-type metaplastic endocrine cells within the atrophic mucosa, rather than the hypertrophic native endocrine cell population.     

Ultrastructural characterization of fundic endocrine cell hyperplasia associated with atrophic gastritis and hypergastrinaemia

Summary Clinical and experimental evidence indicates that carcinoid tumours of the stomach fundic mucosa represent another example of hormone-dependent neoplasm, gastrin being the hormone involved in tumour induction. In this context hyperplasia of fundic endocrine cells associated with chronic atrophic gastritis (CAG) and hypergastrinaemia is regarded as the most frequent preneoplastic lesion. However, the cell type involved in this hyperplasia has not been clarified. To elucidate this problem fundic endocrine cells were characterized ultrastructurally in 9 patients from which endoscopic gastric biopsies were obtained. ECL cells were the most frequent cell type in 8 cases, in 4 of which they were more numerous than all other cell types taken together. D₁ cells were the most frequent type in one case while they were inconspicuous in the other cases. P cells were found with a frequency in each case intermediate between that of ECL cells and that of D₁ cells. These results indicate that fundic endocrine cell hyperplasia occurring in hypergastrinaemic CAG is in most cases cytologically similar to that found in other hypergastrinemic conditions, in which the gastrin-dependent ECL cells were already found to prevail. They also explain why fundic carcinoids arising in CAG are mostly composed of ECL cells. The relation between ECL, D₁ and P cells, if any, remains obscure.Abbreviations EC enterochromaffin cells, producing 5-hydroxytryptamine - ECL enterochromaffin-like cells - D somatostatin producing cells - D₁ cells with small granules showing some characteristics of granules of D cells - P cells with small granules similar to those of pulmonary (P) endocrine cells - X gastric endocrine cells with large, dense granules. Unless specified, the secretory product of these cells is unknown Supported by grants from the Italian Ministry of Public Education and from the A.I.R.C. (Associazione Italiana per la Ricerca sul Cancro)     

Enterochromaffin-like cell populations in human fundic mucosa: quantitative studies of their variations with age, sex, and plasma gastrin levels

The human gastric fundal mucosa contains a variety of endocrine cells, the most numerous of which are the so-called enterochromaffin-like (ECL) cells. We have studied the variations with age and sex of the ECL cell populations, utilizing an assessment based on multiple endoscopic biopsies from four groups of subjects. Plasma gastrin levels were also determined in these subjects. In males, endocrine cell densities declined with age but the ECL cell numbers in females opposed this trend. ECL cell counts showed no appreciable differences between young and old females. In older females, there was a high rate of gastritis and increased levels of circulating gastrin. Concentrations in older females (29.6 +/- 8.7 pmol/l) were higher than in both younger (less than 45 years) males (5.3 +/- 1.1 pmol/l) and older (greater than 55 years) males (6.3 +/- 0.6 pmol/l) (P less than 0.05). The plasma gastrin level was also higher in older females than in young females (13.1 +/- 4.5 pmol/l), although this difference failed to reach statistical significance. In conclusion, clinically silent gastritis, raised gastrin levels, and maintenance or rise of ECL cells numbers, in opposition to a general decrease in endocrine cells with age, appear to be features of women of more than 55 years of age. The variations in ECL cell populations reported here should be taken into account when evaluating possible pathological alterations of the stomach.     

Influence of hypergastrinemia secondary to long-term proton pump inhibitor treatment on ECL cell tumorigenesis in human gastric mucosa

Proton pump inhibitor (PPI) therapy causes hypergastrinemia, which could promote the development and progression of neuroendocrine tumors (NETs). Concerns have been raised about the safety of long-term PPI use due to a possible increased risk of NETs. This study aimed to investigate the association between hypergastrinemia and the risk of NETs. Twenty outpatients presenting with serum gastrin levels greater than 400 pg/mL after long-term PPI treatment were registered in this study. Immunohistochemical analyses for chromogranin A (CgA), Ki67, gastrin and CCK/B gastrin receptor (CCKBR) were performed, and positive cell numbers were counted. There were no NET or gastric epithelial neoplasia cases observed among any of the 20 patients examined throughout the PPI treatment period. Histologically, ECL cell hyperplasia were shown in all patients. However, no relationship was found between serum gastrin levels and the number of CgA positive ECL cells. There was also no relationship between serum gastrin levels and the proportion of Ki67 positive cells or the density of CCKBR positive cells. The data indicate no relationship may exist between NETs and hypergastrinemia secondary to PPI treatment in patients having no, or mild, atrophic gastritis.     

The regulation of gastric acid secretion – clinical perspectives

The purpose of this review, based upon 40 years of research, is to clear old controversies. The gastric juice is a strong acid with active enzymes (pepsin and lipase); ideal for killing swallowed microorganisms. Totally isolated rat stomach and histamine determination. Human gastric carcinomas were examined for ECL cell differentiation because tumours found in rodents after dosing with inhibitors of acid secretion were reclassified to be of ECL cell origin. The gastrin receptor is localized to the ECL cell only, where gastrin stimulates the function and growth. Drug‐induced hypo‐acidity induces hypergastrinaemia and ECL cell hyperplasia responsible for rebound acid hypersecretion. Every condition with long‐term hypergastrinaemia disposes to ECL cell neoplasia. In man, both atrophic gastritis and gastrinoma lead to ECL cell carcinoids. Proton pump inhibitors induce hypergastrinaemia with ECL cell hyperplasia and ECL cell carcinoids that disappear when stopping treatment. The gastrin antagonist netazepide induces regression of ECL cell carcinoids due to atrophic gastritis. Human gastric carcinomas of diffuse type, particularly the signet‐ring subtype, show ECL cell differentiation, suggesting involvement of gastrin in the carcinogenesis. Helicobacter pylori (Hp) causes gastritis and peptic ulcer, and when infecting the antrum only gives a slight hypergastrinaemia with acid hypersecretion predisposing to duodenal ulcer, but protecting from gastric cancer. When Hp infection spreads to oxyntic mucosa, it induces atrophy, reduced acid secretion and marked hypergastrinaemia and cancer.It is remarkable that the interaction between Hp and gastrin may explain the pathogenesis of most diseases in the upper gastrointestinal tract.     

Autoimmune gastritis. A clinicopathologic study of 25 cases

The histopathological diagnosis of autoimmune gastritis (AG) in its early stages can be a diagnostic challenge. Even some advanced cases with complete atrophy of the corpus mucosa may be difficult to recognize. To establish the diagnosis of autoimmune gastritis, several histological features should be assessed and combined with immunostains for enterochromaffin cell-like (ECL) cells and G-cells. The main histological criteria include a mononuclear infiltrate within the lamina propria, foci of destruction of oxyntic glands, intestinal metaplasia (IM), pyloric metaplasia, and parietal cell pseudohypertrophy. These criteria were evaluated in our series of 25 patients with achlorhydria and/or megaloblastic anemia. Some of our patients presented with nonspecific gastrointestinal symptoms. The age ranged between 46 and 79 years; one male patient was only 31 years old. Histologically, the corpus mucosa displayed in all cases chronic inflammation with focal complete IM and advanced pyloric metaplasia. In 4 patients, oxyntic glands were destructed in some sites. There was a pancreatic metaplasia of acinar type in 2 patients and a minimal focal pseudohypertrophy of parietal cells in the 31-year-old man. A tubular adenoma with a low-grade dysplasia was found in one female patient. Immunohistochemically, chromogranin-A highlighted linear or nodular hyperplasia of ECL cells in 19 patients, and adenomatoid ECL hyperplasia in one case (80%). In the remaining cases hyperplasia of ECL cells could not be recognized from their normal count. In 13 cases (52%) a few ECL cells were seen also in IM. Regarding associated pathology, in one woman with nodular ECL cell hyperplasia, a gastric carcinoid was removed endoscopically. The reaction with gastrin antibody revealed in 11 cases (44%) a small number of G cells in IM in the corpus mucosa. In 18 patients, antral mucosa was examined as well. In 8 patients, the mucosa was normal; in 10 cases, a mild chronic inactive gastritis was diagnosed, and in 15 patients G-cell hyperplasia was found. In accordance with other studies, we show that the diagnosis of AG may be established microscopically in endoscopic specimens of the gastric body mucosa when histologic features and immunohistochemical detection of ECL and G cell hyperplasia are combined.     

Expression of glycoprotein hormone alpha-subunit by endocrine cells of the oxyntic mucosa is associated with hypergastrinemia

Previous studies have shown that hyperplastic endocrine cells of the oxyntic mucosa in patients with atrophic gastritis may express immunoreactivity for the alpha-subunit of human chorionic gonadotropin (alpha-HCG, common to all glycoprotein hormones). Since this endocrine proliferation is regarded as dependent on the trophic effect of the concomitant hypergastrinemia, the relation between immunohistochemical expression of alpha-HCG by oxyntic endocrine cells and serum levels of gastrin were investigated. The study was performed on endoscopic gastric biopsies of the oxyntic mucosa from 49 patients subdivided into the following groups: A) with histologically normal mucosa and normogastrinemia (22 cases), B) with atrophic gastritis and normogastrinemia (12 cases), C) with normal mucosa and hypergastrinemia (Zollinger-Ellison syndrome, retained antrum) (7 cases) and D) with atrophic gastritis and hypergastrinemia (with or without pernicious anemia) (8 cases). The alpha-HCG immunoreactive cells were found in all hypergastrinemic patients (groups C and D), regardless of the concomitant pathological condition of the mucosa. These cells accounted for 7.8% to 44.7% of the number of Grimelius argyrophil cells in consecutive serial sections. In contrast, alpha-HCG-containing cells were exceptional or absent in most normogastrinemic patients. Their number was sizable in only two cases of group A and three cases of group B, where it ranged from 2.5% to 14.8% of the number of argyrophil cells. It was concluded that expression of alpha-HCG is another feature of oxyntic endocrine cells associated with hypergastrinemia in addition to those previously recognized such as development of hyperplasia and/or carcinoid tumors.     

Vesicular monoamine transporter 2 as a marker of gastric enterochromaffin-like cell tumors

The vesicular monoamine transporter 2 (VMAT2) facilitates the ATP-dependent accumulation of biogenic amine inside the secretory granules of endocrine cells and neurons and was demonstrated in the histamine-producing enterochromaffin-like (ECL) cells of the stomach. In the present investigation, VMAT2 immunohistochemistry was tested in 85 endocrine tumors, of which 60 were well differentiated gastrointestinal and pancreatic growths, 5 poorly differentiated (neuro)endocrine carcinomas (PDEC) and 1 mixed PDEC/ECL cell carcinoma of the stomach, 12 pheochromocytomas/paragangliomas, 3 adrenocortical lesions, 2 parathyroid and 2 lung neuroendocrine tumors. Extensive and intense VMAT2 immunoreactivity was observed in 16 of 16 gastric ECL cell tumors, 6 of 6 adrenal pheochromocytomas, 2 of 2 chromaffin paragangliomas and in 3 of the 4 carotid body paragangliomas investigated. Rare VMAT2-positive cells were observed in 12 of 21 intestinal enterochromaffin (EC) cell tumors, in 9 of 11 pancreatic neuroendocrine tumors, and in the mixed PDEC/ ECL cell carcinoma of the stomach (differentiated cells only). No VMAT2 immunoreactivity was observed in five gastrin, four somatostatin and three enteroglucagon/peptideYY tumors of the gastrointestinal tract, in six gastric PDECs, in three adrenocortical growths, and two parathyroid and two lung neuroendocrine tumors. These data support VMAT2 immunohistochemistry as being a useful tool for the diagnosis of gastric ECL cell tumors, separating them from all other endocrine tumors arising in the gastroduodenal area i.e., gastrin, somatostatin, EC cell and PDEC tumors, all of which proved essentially negative. Received: 28 June 1999 / Accepted: 20 October 1999     

52例胃神经内分泌肿瘤临床病理分析

目的 对胃内分泌肿瘤进行分型,并探讨其临床病理意义。方法 收集５２例胃神经内分泌肿瘤,应用组织学及免疫组织化学学ＡＢＣ法及透射电镜技术对肿瘤及其瘤旁粘膜进行观察。参照Ｂｏｒｄｉ和Ｒｉｎｄｉ分类将肿瘤分成Ⅰ、Ⅱ、Ⅲ型,并设有阳性、阴性和替代对照组。结果 胃神经内分泌肿瘤可分为３个临床病理类型,其病理学特点、生物学行为及治疗方案均有不同。Ⅰ型伴有萎缩性胃炎型类癌（２６例）：分为单发及多发两型。单发型多     

Gastric neuroendocrine carcinoma associated with atrophic gastritis in the norwegian lundehund

In humans and rodents the association between atrophic gastritis, hypergastrinemia and gastric neoplasia is well-documented. Gastric tumours are rare in dogs, but the Norwegian Lundehund (puffin dog) appears predisposed to the development of gastric neoplasia associated with chronic atrophic gastritis. The present study describes 8 Lundehunds with gastric neoplasia. Seven of these animals had concurrent chronic atrophic gastritis characterized by reduction in parietal cells and hyperplasia of neuroendocrine cells. Four of the tumours displayed neuroendocrine (enterochromaffin-like cell; ECL) differentiation, suggesting that hypergastrinemia secondary to fundic atrophy may be important in carcinogenesis. The Norwegian Lundehund may therefore represent a further animal model for the study of the role of gastrin in the induction of gastric neoplasia.     

Composite Gastric Carcinoma and Precursor Lesions with Amphicrine Features in Chronic Atrophic Gastritis

A composite carcinoma of the gastric body consisting of endocrine and mucous epithelial cells with interspersed amphicrine cells is reported together with ultrastructural and immunocytochemical documentation of endocrine and nonendocrine differentiation. The tumor was associated with hypergas-trinemia related to chronic atrophic gastritis (achlorhydria) and with multiple proliferative lesions, such as intramucosal microcarcinoid (IMCI and endocrine cell proliferations of the micronodular and linear type, which are currently regarded as carcinoid precursor changes. Ultrastructurally, a composite architecture with amphicrine features was demonstrated in the primary tumor, IMC, and liver metastases. On the other hand, the endocrine cell proliferations exclusively contained gastrin and enterochromaffinlike cells. Immunostaining with antibodies to calcitonin documented a number of positive cells both in the primary and in the metastatic sites. This is the first report of mixed exocrine-endocrine-amphicrine components both in a metastasizing carcinoma and in its precursor lesions in a chronic hypergastrinemic state. Unlike previously reported lesions, the endocrine component was unexpectedly composed of calcitonin cells, which are not usually present in the gastric mucosa.     

Coexistence of gastric- and intestinal-type endocrine cells in gastric and intestinal mixed intestinal metaplasia of the human stomach

Intestinal metaplasia (IM) in the human stomach has previously been classified into a gastric and intestinal mixed (GI-IM) and a solely intestinal phenotype (I-IM). The phenotypes of mucous and endocrine cells were evaluated in 3034 glandular ducts associated with chronic gastritis. In the pyloric region, the relative expression of gastric endocrine cell markers, such as gastrin and somatostatin, decreased gradually from glandular ducts with only gastric mucous cell phenotype (G type) to GI-IM toward I-IM, while that of the intestinal endocrine cell markers, glicentin, gastric inhibitory polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) was inversely correlated. In the fundic region, gastrin-positive cells emerged in the pseudo-pyloric and GI-IM glands, whereas I-IM glands did not possess any gastrin-positive cells, suggesting the presence of a distinct pathway of intestinalization. Double staining revealed coexistence of gastrin- and GLP-1-positive cells in the same gland and occasionally in the same cell in GI-IM glands. These results suggest that the phenotypes of endocrine cells are in line with those for mucous counterparts and support the concept that all of the different types of mucous and endocrine cells in normal and IM glands might be derived from a single progenitor cell in each gland.     

Endocrine neoplasm of the stomach. Study of thirteen cases

A Thirteen patients with primary endocrine neoplasm of the stomach were studied for 20 years. Six patients were male and 7 female with an age range of 33 to 77, mean age 57 years. Nine cases corresponded to well differentiated carcinoids and four to neuroendocrine carcinomas. Of the former, three were sporadic and six were associated with atrophic gastritis. These two forms of neoplasm showed important differences: those associated with atrophic gastritis had hypergastrinemia, all of the multiple small tumors confined to the corpus and fundus were well differentiated carcinoids associated with intestinal metaplasia and G cell hyperplasia in antrum and ECL cell hyperplasia in corpus and fundus. Tumors were clinically benign, with an excellent prognosis. All patients are currently alive with no evidence of neoplasm. In only one of these cases, antiparietal cell antibodies were documented; in three of them, extensive intestinal metaplasia probably due to Helicobacter pylori infection was found. In contrast, sporadic carcinoids were large isolated tumors originating in the antrum or corpus. Two patients died as a consequence of the neoplasm; all of them were moderately differentiated and in none of the cases we found evidence of endocrine hyperplasia. All were positive for generic endocrine markers and were focally positive to some of the specific hormone markers. Al four neuroendocrine carcinomas had a clinical course similar to that of gastric adenocarcinomas and were poorly differentiated large tumors. We conclude that gastric carcinoids associated with atrophic gastritis have an excellent prognosis. On the other hand, neuroendocrine carcinomas have a very poor prognosis with fatal outcome of patients. Sporadic carcinoids have an intermediate prognosis.     

A histological study of the effect of chronic gastritis on gastrin cell distribution in the human stomach.

To determine the effect of varying degrees of gastritis on the distribution of immuno-reactive gastrin cells 38 partial gastrectomy specimens have been studied. Routinely stained histological sections of mucosa were compared with serial and adjacent sections stained by specific immunohistochemistry using peroxidase and fluorescent techniques. While chronic superficial gastritis had no obvious effect, mild atrophic gastritis was associated with an uneven distribution of gastrin cells which became more marked with increasing severity of gastritis. In the region of intestinal metaplasia gastrin cells were almost totally absent. Small numbers of gastrin cells were found within areas of pseudopyloric metaplasia in the fundus, a region where those cells are not normally seen. Similarly, gastrin cells were detected within regenerative gastric polypi in both antrum and fundus.