Endocrine Cell Hyperplasia Research Articles

Pulmonary endocrine cell hyperplasia and papilloma in rats induced by intratracheal injections of extract from particulate air pollutants

We investigated the effect of intratracheal injections of an extract of suspended particulate matter (SPM) obtained from the urban ambient air of Tokyo, upon the development of proliferative lesions of pulmonary endocrine cells (PECs) in the rat. We also examined the modification effects of nitrogen dioxide, sulfur dioxide, or both of them on the PEC lesions. Male F344 rats were divided into six experimental groups of 5 animals each. Twenty animals were treated with intratracheal instillations of SPM admixed with carbon once a week for 4 weeks with or without additional gaseous exposure (6 ppm nitrogen dioxide or 4 ppm sulfur dioxide) 16 hrs a day for 11 months. Five animals were given intratracheal injections of carbon suspended in saline and the other five were untreated. The subcardiac lobes of the right lung were fixed with 4% paraformaldehyde, and embedded in paraffin. PEC hyperplasias and papillomas were counted in 200 serial sections, 4 microns thick. The average incidences of PEC hyperplasia in the untreated animals and in those treated with carbon were 194 and 200/cm3, respectively. The average incidences of PEC hyperplasia in the animals exposed to SPM tar only, SPM tar plus nitrogen dioxide and sulfur dioxide, SPM tar with nitrogen dioxide and SPM tar with sulfur dioxide were 376, 378, 372 and 349/cm3, respectively. These were significantly higher than the levels of the control animals, and additional gaseous stimuli had no effect on the incidence of PEC hyperplasia. Besides PEC hyperplasia, a few PEC papillomas were found in the animals treated with SPM tar, regardless of gaseous exposure, but in the control animals no papilloma was evident. Thus, compounds in airborne particulates are considered to be responsible for the development of PEC hyperplasias and papillomas.

Pattern of gastric endocrine cells in microcarcinoidosis--an immunohistochemical study of 14 gastric biopsies.

A total of 14 gastric biopsy specimens from patients with microcarcinoidosis were analysed by immunohistochemical methods to evaluate the pattern of endocrine cell hyperplasia and dysplasia. All the patients had type A gastritis (autoimmune gastritis). Nonantral proliferations of gastric endocrine cells were classified according to Solcia et al. All 14 cases had hyperplasia and 13 (92.9%) of them, dysplasia of gastric endocrine cells; 9 (64.3%) of the 14 were found to have showed a coexisting invasive gastric carcinoid at the time of diagnosis of microcarcinoidosis. The patients with invasive carcinoids had higher degrees and more complex forms of endocrine dysplasia (precarcinoid lesions). The average size of the foci of the microcarcinoidosis in gastric biopsies was 0.14 +/- 0.09 cm in the patients without invasive carcinoid, as against to 0.5 +/- 0.24 cm in the group of patients with associated invasive carcinoid. Microcarcinoid gastric biopsies about 0.5 cm in size, are suggestive of adjacent invasive carcinoid. However, even frankly invasive ECL carcinoids seem to be clinically less dangerous than was thought until recently.

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.

The Histopathological Spectrum of Type A Gastritis

It has been recently shown that type A gastritis can be histologically diagnosed in the preatrophic stage. In order to evaluate whether parietal cell atrophy in AG might correlate with other histopathological findings in the antral and body mucosa, we retrospectively investigated 171 consecutive cases of histologically diagnosed preatrophic (active) or atrophic type A gastritis (H&E, Warthin-Starry). The prevalences of intestinal metaplasia (75% vs 44.4%) and micronodular hyperplasia (86.1% vs 52.4%) of endocrine cells in the oxyntic mucosa were significantly higher of parietal cell atrophy was present (p < 0.001 and p < 0.0001, respectively), whereas the prevalence of nodular lymphoid aggregates (77.8% vs 48.1%) and of Helicobacter pylori (14.3% vs 1.9%) in the oxyntic mucosa was significantly higher if parietal cell atrophy could not be detected (p < 0.001 and p < 0.01, respectively). In the antral mucosa, altered patterns of the inflammatory reaction could be demonstrated independent of the parietal cell mass possibly caused by impaired gastric acid production. Our data support the notion that the development of parietal cell atrophy in type A gastritis represents a stepwise process including initial pseudohypertrophy of these cells.

An Unusual Case of Multiple Gastric Carcinoids Associated with Diffuse Endocrine Cell Hyperplasia and Parietal Cell Hypertrophy.

We describe a case of multiple gastric carcinoid tumors in a 47 year-old Japanese man. The patient had markedly elevated serum gastrin levels (>800 pg/mL), which were suppressed by secretin-pancreozymin administration. In the partial gastrectomy specimen, a total of 19 carcinoids arose from diffuse linear and micronodular hyperplasia of the oxyntic mucosal endocrine cells. The carcinoid cells were chromogranin A-positive. Except for a very small number of serotonin-positive cells in several carcinoids, none of the 19 reacted with a battery of antibodies to other bioactive neuroendocrine substances. The most prominent findings in this case were peculiar fundic glands that were distended with a proteinaceous substance and lined with large hypertrophic parietal cells. At the ultra-structural level, these cells showed poorly developed intracytoplasmic canaliculi and vesicotubular profiles, yet their large cytoplasm had numerous mitochondria. On the basis of our histological and ultrastructural findings we suggest that an intrinsic HCI secretion abnormality of the parietal cells may be responsible for the patient's hypergastranemia. Since there have been no reports on similar parietal cells changes, it is possible that our case may represent a pathological entity not previously described.

Endocrine cells of the human gastrointestinal tract have no proliferative capacity

There is compelling evidence that the epithelial cell lineage of the gastrointestinal tract are derived from a common stem cell precursor, but the details of the subsequent cellular hierarchies remain uncertain. In this context, it is important to know the arrangement of cell proliferation that gives rise to the final cell populations. In rodents, a number of studies have been performed examining the possible proliferative capacity of endocrine cells, but a wide range of technical problems makes interpretation of these data difficult. Continuous labelling studies suggest there is potential for proliferation in endocrine cells but flash labelling studies have not been conclusive. In man there are no data on this issue. We have taken advantage of the ability to perform double immunostaining for operational markers of proliferation (Ki67 antigen) and endocrine cell phenotype (chromogranin expression). We demonstrate that there are no double-labelled cells in the normal stomach, small intestine or colon of fetal, neonatal or adult humans. Moreover, no double-labelled cells are found in pathological states associated with endocrine cell hyperplasia (gastritis, ulcerative colitis). These data indicate that the normal endocrine cells of the human gut have no proliferative capacity and that, in this cell lineage, population expansion precedes differentiation.

Smooth Muscle Cell Abnormalities Associated with Gastric ECL Cell Carcinoids.

The histologic and immunohistochemical study of 45 ECL cell gastric carcinoids and of the extratumoral gastric mucosa revealed four variants of smooth muscle cell abnormalities: (1) hypertrophy of muscularis mucosae trapped within the tumors, a finding occurring in 76.5% of cases; (2) proliferation of stromal smooth muscle cells originating from the muscularas mucosae and mostly associated with tumor invasion of the submucosa (seen in 93.9% of cases with abundant stromal component of the tumors); (3) occurrence of frequent, prominent aggregates of smooth muscle cells in the lamina propria of the antral (but not of the fundic) mucosa of the stomach (found in 41.7% of cases); and (4) increased thickness of the extratumoral muscularis mucosae in the fundic (but not in the antral) mucosa of patients with gastric carcinoids. In addition, localized muscle cell proliferation was also associated with foci of micronodular hyperplasia of endocrine cells in the extratumoral mucosa. These findings were neither observed in control cases of gastric adenocarcinoma, gastric peptic ulcer, and duodenal peptic ulcer (10 unselected cases from each group) nor were they observed in 10 subjects with normal gastric mucosa collected at autopsy. With the possible exception of the increased thickness of the extratumoral fundic muscularis mucosae, which may be influenced by the mucosal inflammatory process, it is suggested that the present findings represent a proliferative response of smooth muscle cells to basic fibroblastic growth factor whose production by gastric carcinoids and their precursor lesions has recently been demonstrated.

Pathophysiological effects of long-term acid suppression in man.

A critical evaluation has been made of the available evidence in man of the effects of prolonged low acid states on the structure and function of the stomach. Various human models have been examined. 1. Ageing does not affect acid output from the normal male stomach, and there may be an increase in women. With progressive atrophy of the corpus mucosa, which is more frequent and rapid in patients with gastric ulcer, there is an associated loss of secretory function. Chronic gastritis and atrophy are the most important age-related changes, which in many cultures are hypothesized to develop via a prior Helicobacter pylori-related gastritis. However, H. pylori colonization of the mucosa decreases with increasing grades of gastric atrophy probably because intestinal metaplasia provides a hostile environment. Atrophy and intestinal metaplasia are associated with precancerous lesions and gastric cancer. Apparent hyperplasia of the gastric argyrophil endocrine cells is a common and spontaneous phenomenon in patients with atrophic gastritis, which in part may be related to the preferential loss of nonendocrine cells. 2. Pernicious anemia is associated with a complete lack of acid production, marked hypergastrinemia, and endocrine cell hyperplasia in the majority of patients. ECL-cell carcinoids and gastric cancer occur with a prevalence of 3-7%, and endoscopic surveillance in routine clinical practice is not warranted. 3. Gastric ECL-cell carcinoids are rare events that have been described in association with two diseases in man, pernicious anemia and Zollinger-Ellison syndrome as part of multiple endocrine neoplasia syndrome type I, and usually relate to marked hypergastrinemia and the presence of chronic atrophic gastritis with gastric antibodies or a genetic defect rather than the presence or absence of acid. Regression or disappearance of ECL-cell carcinoids, either spontaneously or after removal of the gastrin drive, has been recorded. Lymph node, and rarely hepatic, metastases are documented but death in these cases has been anecdotal. 4. Therapy with H2 antagonists may result in up to a twofold rise in serum gastrin levels but in man no endocrine cell hyperplasia has been recorded. However, the data for H2 antagonists on these aspects are very limited. There is no drug-related risk of gastric or esophageal cancer, although the incidence of the latter may be raised. Long-term treatment with omeprazole is associated with a two- to fourfold increase in gastrin levels over baseline values in one third of patients and apparent endocrine cell hyperplasia in 7% of cases overall.(ABSTRACT TRUNCATED AT 400 WORDS)

Current approach to the management of gastrinoma and insulinoma in adults with multiple endocrine neoplasia type I.

The difficult and controversial diagnostic and therapeutic management of patients having gastrinoma or insulinoma with multiple endocrine neoplasia type I (MEN-I) has been discussed by reference to the literature and a personal series of 45 gastrinoma/MEN-I patients followed consecutively at Bichat Hospital. In both gastrinoma/ and insulinoma/MEN-I patients, anatomic distribution and morphology of tumoral process(es) are usually multiple, diffuse, of small size, and associated with endocrine cell hyperplasia and even nesidioblastosis. These features enhance the difficulty of tumor localization and eradication. Despite the dramatic development of modern medical imagery and surgical experience, the real possibility, on a long-term basis, of curing the patients from their disease remains limited, especially in the gastrinoma/MEN-I patients. In the latter group, according to our experience, persistence or recurrence of the disease after surgery is usual, and metachronous hepatic metastasis development is frequently observed when the follow-up is long enough. Patients with liver metastases, however, seem to undergo a more indolent course than sporadic gastrinoma cases. In insulinoma/MEN-I patients, removal of the functionally dominant islet cell area(s) is essential. Various preoperative and intraoperative localization techniques allow efficacious selective pancreatic surgery in many cases. The latter refinements and the promises of long-acting somatostatin analogs, if confirmed, might restrict to exceptional circumstances the indication of near-total or total pancreatectomy.

Crypt Cell Proliferative Micronests in Rectal Carcinoids

Gastrointestinal endocrine cells are situated both in the epithelium as well as in the subepithelium, especially in relation to enteric nerves. This has complicated efforts at delineating the histogenesis of gastrointestinal carcinoids. However, gastrointestinal carcinoids themselves are a heterogeneous group made up of various subsets, and as such may have different modes of origin. The present study investigated the histogenesis of rectal carcinoids because this has not been adequately addressed. Nine rectal carcinoids together with sex- and age-matched controls were stained with silver stains and various immunoreagents. The number of intraepithelial endocrine cells per unit length of mucosa in the carcinoid group was compared with the controls using the Student t test. Our results showed that there was no evidence of diffuse intraepithelial endocrine cell hyperplasia associated with these carcinoids. In six of the cases, however, there were focal areas where the carcinoids abutted onto the mucosal epithelium, and in another two cases there were focal areas depicting crypt cell proliferative micronests. These findings suggest that most conventional rectal carcinoids arise from localized areas of crypt cell proliferation rather than from diffuse areas of intraepithelial endocrine cell hyperplasia. Furthermore, rectal carcinoids appear to be constituted of a heterogenous population of endocrine cells rather than a monoclonal population of cells with each cell expressing a multiplicity of hormones.

Development of gastric carcinoids inmastomys during histamine2-receptor blockade

We have investigated the effect of histamine2-receptor blockade on gastric carcinoid formation inMastomys, a rodent prone to develop gastric carcinoids. During long-term treatment (8–24 weeks) with loxtidine, a 3–5 fold increase in plasma gastrin levels was observed. Oxyntic mucosal histamine and histidine decarboxylase activity were increased 2 times and 4–10 times respectively in loxitidine-treated animals, as compared to controls. An increase in oxyntic mucosal thickness was also noted in all treated animals, while gross tumors were only observed in animals treated for 24 weeks. Immunocytochemical analysis of treated animals revealed a marked proliferation of chromogranin-positive cells in the oxyntic mucosa. These cells were identified as ECL cells because they were labeled by histamine antibodies, but not by gastrin-, somatostatin-or serotonin-antibodies. Hyperplasia of endocrine cells was noted after 8 weeks of treatment, while dysplastic lesions were seen after 16 weeks and the first micro- or macrocarcinoids after 24 weeks of treatment. No tumors, or hyperplastic changes, were observed in control animals. The results demonstrate that histamine2-receptor blockade significantly enhances the development of gastric carcinoids inMastomys and suggest that hypergastrinemia may be important for the development of these tumors.

Gastroscopic follow up of pernicious anaemia patients.

To assess the value of gastroscopic cancer surveillance of patients with pernicious anaemia, 56 patients were re-endoscoped and biopsied after three years. In addition, changes in the density of fundic mucosal endocrine cells were evaluated morphometrically. Two cases (3.6%) of early gastric cancer and two cases of small gastric carcinoid tumours (3.6%) were detected in addition to the five carcinoids that had been found at the initial endoscopic screening. Nodular argyrophil cell hyperplasia and morphometric density of argyrophil cells were not stable phenomena: nodular hyperplasias regressed in five patients, remained similar in six, and progressed to a small carcinoid tumour in one. Serum gastrin concentrations did not correlate well with changes in the endocrine cell density. Regular endoscopic surveillance for gastric cancer may be beneficial and realistic in young patients with pernicious anaemia while the importance of fundic endocrine cell hyperplasia and that of small gastric carcinoids need further study.

Modulation of the incidence of hamster pulmonary endocrine cell hyperplasia by unilateral collapse of the lung.

We evaluated the effects of the unilateral collapse of the left lung on the formation of pulmonary endocrine cell hyperplasia (PECH) induced by 4-nitroquinoline 1-oxide (4NQO) in Syrian golden hamsters. Ten hamsters were injected subcutaneously with 20 mg/kg body weight of 4NQO, once a week for 4 weeks and treated with injection of silicone rubber into the left thorax at the 8th experimental week. Another 30 animals were divided into three groups: treated with 4NQO only, left lung collapse only, and vehicle only. All animals were sacrificed at the 30th week. The lung tissues were embedded in paraffin; 50 serial sections were made from the tissues of each animal and were studied histologically and immunohistochemically. PECH showed a positive immunostain for calcitonin and/or serotonin. In the uncollapsed right lungs of the animals treated with both 4NQO and unilateral collapse, the mean incidence of PECH was 12.2 x 10(-2)/mm3 lung volume; the incidences of PECH in the animals treated with 4NQO only, collapse only, and vehicle only were 4.1, 3.8, and 1.4 x 10(-2)/mm3, respectively. In the collapsed left lungs, PECH did not form, regardless of 4NQO treatment. This study demonstrates that unilateral collapse of the lung modulates the incidence of PECH induced by 4NQO in hamsters.

Gastric endocrine cell hyperplasia in chronic atrophic gastritis

Gastric endocrine cell hyperplasia in chronic atrophic gastritis

Inter-Relationship between Serum Gastrin Levels, Gastric Mucosal Histology and Gastric Endocrine Cell Growth

The development of gastric enterochromaffin-like (ECL)-cell hyperplasia in humans may be associated with extreme hypergastrinaemia, as occurs in Zollinger-Ellison syndrome (ZES) and pernicious anaemia (type A gastritis). More recently, endocrine cell hyperplasia has been found in all forms of chronic atrophic gastritis and even in cases of focal atrophy. Serum gastrin levels, non-antral gastric endocrine (argyrophil) cell growth, and the severity and type of concomitant gastritis were monitored in 66 unoperated and 8 antrectomized patients with poorly responsive peptic ulcer or reflux oesophagitis during up to 5 years' treatment with high-dose omeprazole, 40 mg daily. A small subgroup of patients (23%) had serum gastrin concentrations of more than four times the normal upper limit. These patients also had hyperplasia of the gastric argyrophil cells. More importantly, the same subgroup of patients had high-grade (atrophic) gastritis. Micronodular hyperplasia of argyrophil cells was significantly more frequent in biopsies showing atrophic gastritis (48%) than in biopsies showing only superficial gastritis (3.6%). It is concluded that, as previously demonstrated in untreated patients with gastric ulcer, the argyrophil cell hyperplasia observed during high-dose omeprazole therapy is related to the progression of chronic atrophic gastritis rather than to serum gastrin levels.

Stereologic Investigations of Human Gastric Mucosa: II. Oxyntic Mucosa from Patients with Zollinger-Ellison Syndrome

Biopsy specimens from the oxyntic mucosa were obtained on 210 occasions from 76 patients with the Zollinger-Ellison syndrome (ZES) before and during omeprazole treatment. One-micrometer sections were examined by light microscopy, and in 5% linear hyperplasia of endocrine cells was observed. Morphometry was carried out in 91 of the specimens and showed a significant increase of the mean endocrine cell density in comparison with both young, healthy subjects and patients suffering from active peptic ulcer disease (PUD). No metaplasia, dysplasia, or neoplasia was detected in patients with ZES, and the mean mucosal thickness and parietal cell density remained normal. The parietal cells often displayed endosome-like structures, and occasionally there were lingulate cytoplasmic projections into the gland lumen. Electron microscopic morphometry was carried out in specimens from nine patients with ZES and did not show any significant differences in the parietal cells in comparison with healthy subjects.

Is endoscopy helpful in patient monitoring?

The safety issues involved in patients on long-term treatment with omeprazole will determine whether endoscopic monitoring is necessary. In a review of 646 patients who have undergone regular gastric biopsies during continuous treatment with omeprazole, 10-120 mg daily, for periods of up to 5.5 years, there were no overall patterns to the changes in gastric endocrine cells. Apparent gastric endocrine cell hyperplasia in 72% of patients correlated with the development of chronic atrophic corpus gastritis. The only macroscopic changes to be reported were endocrine tumours in 4 out of 184 patients on long-term omeprazole for Zollinger-Ellison syndrome, and at least 3 of these patients had multiple endocrine neoplasia (MEN) type 1 syndrome. In patients with other low acid states, such as pernicious anaemia or after gastric irradiation or gastric surgery, in which drug therapy is not a confounding factor, there is a very low risk of developing macroscopic lesions within the stomach, and endoscopic surveillance is not routine practice. In conclusion, upper gastrointestinal endoscopic monitoring to identify microscopic or macroscopic changes cannot be justified during at least the first 5 years of continuous treatment with omeprazole.

Carcinoid tumours of the appendix are different

The Journal of PathologyVolume 162, Issue 3 p. 189-190 EditorialFree Access Carcinoid tumours of the appendix are different Paul A. V. Shaw, Paul A. V. Shaw Department of Histopathology, Leicester Royal Infirmary, Leicester LE1 5WW, U.K.Search for more papers by this author Paul A. V. Shaw, Paul A. V. Shaw Department of Histopathology, Leicester Royal Infirmary, Leicester LE1 5WW, U.K.Search for more papers by this author First published: November 1990 https://doi.org/10.1002/path.1711620303Citations: 19AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Sjolund K, Sanden G, Hakanson R, Sundler R. Endocrine cells in human intestine: an immunocytochemical study. Gastroenterology 1983; 85: 1120– 1130. 2 Godwin JD. Carcinoid tumors. An analysis of 2837 cases. Cancer 1975; 36: 560– 569. 3 Moertel CG, Weiland LH, Nagorney DM, Dockerty MB. Carcinoid tumors of the appendix: treatment and proghosis. N Engl J Med 1987; 317: 1699– 1701. 4 Berge T, Linell F. Carcinoid tumours. Frequency in a defined population during a 12 year period. Acta Pathol Microbiol Scand Sect A 1976; 84: 322– 330. 5 Chejfec G., Falkmer S, Askensten U, Grimelius L, Gould VE. Neuroendocrine tumours of the gastrointestinal tract. Pathol Res Pract 1988; 183: 143– 154. 6 Lundqvist M, Wilander E. Subepithelial neuroendocrine cells and carcinoid tumours of the human small intestine and appendix. A comparative immunohistochemical study with regard to serotonin, neuron specific enolase and S100 protein reactivity. J Pathol 1986; 148: 141– 147. 7 Aubock L, Hofler H. Extraepithelial intraneural endocrine cells as starting points for gastrointestinal carcinoids. Virchows Arch A [Pathol Anat] 1983; 401: 17– 33. 8 Rode J, Dhillon AP, Papadaki L, Griffiths D. Neurosecretory cells of the lamina propria of the appendix and their possible relationship to carcinoids. Histopathology 1982; 6: 69– 79. 9 Kinsey WL, Shaw PAV. On the histogenesis of carcinoid tumours: evidence from the distribution of neuroendocrine cells in the normal appendix. J Pathol 1990; 161: 356A. 10 Lundqvist M,. Wilander E. A study of the histopathogenesis of carcinoid tumors of the small intestine and appendix. Cancer 1987; 60: 201– 206. 11 Cross SS, Hughes AD, Williams GT, Williams ED. Endocrine cell hyperplasia and appendiceal carcinoids. J Pathol 1988; 156: 325– 329. 12 Stanley MW, Cherwitz D, Hagen K, Snover DC. Neuromas of the appendix. A light microscopic, immunohistochemical and electron microscopic study of 20 cases. Am J Surg Pathol 1986; 10: 801– 815. 13 Lewin KJ, Ulich T, Yang K, Layfield L. The endocrine cells of the GI tract and their tumors. Part II. In: SC Sommers, PR Rosen, RE Fechner, eds. Pathology Annual, Volume 21, Part 2. Norwalk, CT: Appleton-Century-Crofts, 1986; 181– 215. 14 Lloyd RV, Blaivas M, Wilson BS. Distribution of chromogranin and S100 protein in normal and abnormal adrenal medullary tissues. Arch Pathol Lab Med 1985; 109: 633– 635. Citing Literature Volume162, Issue3November 1990Pages 189-190 ReferencesRelatedInformation

The effect of Zollinger-Ellison syndrome and omeprazole therapy on gastric oxyntic endocrine cells

In 1983, all trials of omeprazole in humans were stopped because rats given the drug developed gastric endocrine cell hyperplasia and carcinoid tumors. Further studies in rats showed that druginduced achlorhydria and hypergastrinemia caused these changes. Because data in humans are limited, we compared the numbers of endocrine cells, as judged by silver staining (argyrophilia), in the gastric mucosa of patients with Zollinger-Ellison syndrome, who are hypergastrinemic, and in normogastrinemic patients with idiopathic acid-peptic diseases. In addition, we analyzed the number of gastric endocrine cells in patients with Zollinger-Ellison syndrome given omeprazole for up to 3 years. Patients with Zollinger-Ellison syndrome had 15.7% ± 6.9% argyrophil cells in biopsies of gastric oxyntic mucosa, and patients with idiopathic acid-peptic disease had 7.8% ± 2.3% (P < 0.01). In patients with Zollinger-Ellison syndrome, the percentage of argyrophil cells was not related to serum gastrin concentration, duration of symptoms, time since diagnosis, basal or maximal acid output, extent of tumor, or age. There was a tendency for patients with multiple endocrine neoplasia type 1 to have a greater percent of argyrophil cells than patients with sporadic Zollinger-Ellison syndrome. Considering the biopsies from both normogastrinemic and hypergastrinemic patients, there was a significant relationship between the percentage of argyrophil cells and the serum concentration of gastrin (P < 0.01). Patients with Zollinger-Ellison syndrome given omeprazole for up to 3 years developed no significant changes in percentage of argyrophil cells, no carcinoid tumors, and no changes in serum concentrations of gastrin. The present study shows that patients with Zollinger-Ellison syndrome have an increased percentage of argyrophil cells in oxyntic mucosa and that omeprazole does not increase this percentage. In periods of up to 3 years, omeprazole had no effects on gastric morphology in patients with Zollinger-Ellison syndrome.

Proposed mechanism of induction of gastric carcinoids: the gastrin hypothesis

Novel, powerful and long-acting inhibitors of gastric acid secretion include second generation H2-blockers and so-called proton pump inhibitors, such as omeprazole. Gastric carcinoids were found to develop in experimental animals as a consequence of continuous long-term administration of several of these highly effective anti secretory drugs. This unwanted side effect is now thought to reflect the fact (1) that pharmacological blockade of acid secretion results in hypergastrinaemia, and (2) that long-standing hypergastrinaemia gives rise to hyperplasia of certain endocrine cells, the so-called ECL cells, in the gastric mucosa. The carcinoids that develop in the rat stomach after lifelong treatment with antisecretagogues arise from the ECL cells. The proposed sequence of events is acid blockade--hypergastrinaemia--ECL cell hyperplasia--carcinoid. This concept, referred to as the gastrin hypothesis, maintains that the ECL cell hyperplasia (and possibly the carcinoids) is a consequence of long-term continuous hypergastrinaemia.