gastrins and Carcinoid-Tumor

Neuroendocrine tumors (NETs) were initially identified as a separate entity in the early 1900s as a unique malignancy that secretes bioactive amines. GI-NETs are the most frequent type and represent a unique subset of NETs, because at least 75% of these tumors represent gastrin stimulation of the enterochromaffin-like cell located in the body of the stomach. The purpose of this review is to understand the specific role of gastrin in the generation of Gastric NETs (G-NETs).. We review here the origin of enterochromaffin cells gut and the role of hypergastrinemia in gastric enteroendocrine tumorigenesis. We describe generation of the first genetically engineered mouse model of gastrin-driven G-NETs that mimics the human phenotype. The common mechanism observed in both the hypergastrinemic mouse model and human carcinoids is translocation of the cyclin-dependent inhibitor p27

Topics: Animals; Carcinoid Tumor; Cyclin-Dependent Kinase Inhibitor p27; Cytoplasm; Disease Models, Animal; Enterochromaffin-like Cells; Gastrins; Humans; Mice; Neuroendocrine Tumors; Phenotype; Receptor, Cholecystokinin B; Stomach Neoplasms

Gastrin has been identified as the principal effector of gastric secretion, but several studies have demonstrated its role as a biomarker of cancer risk and as a growth factor for colorectal, stomach, liver, and pancreatic cancer. Hypergastrinemia characterizes autoimmune gastritis, with body and fundic gland atrophy and increased risk for both gastric adenocarcinoma and neuroendocrine tumors. Gastric type I carcinoids develop in the context of autoimmune gastritis because of the stimulus exerted by gastrin on enterochromaffin-like cells and remain gastrin-sensitive for long durations because the removal of hypergastrinemia leads to tumor regression. The treatment of gastric carcinoid is still open to debate, but when the disease frequently relapses, or is multicentric or infiltrating, surgery is advocated or, in the alternative, a costly and long-lasting treatment with long-acting somatostatin analogues is prescribed. A technology allowing the preparation of an immunogen eliciting an immune system response with generation of antibodies against G17 has been developed. This vaccine has been tested in patients with colorectal, pancreatic or advanced gastric cancer. The vaccine has also been used in the treatment of gastric type I carcinoids, and the administration of G17DT in patients harboring these lesions leads to carcinoid regression. Antigastrin vaccination in the treatment of gastrointestinal cancer obviously needs validation, but this immunotherapy may well represent a simple, inexpensive, and active 'adjuvant' treatment.

Topics: Adenocarcinoma; Autoimmune Diseases; Cancer Vaccines; Carcinoid Tumor; Colorectal Neoplasms; Gastrins; Gastritis; Humans; Liver Neoplasms; Pancreatic Neoplasms; Stomach Neoplasms

Gastric neuroendocrine neoplasms of the stomach can be divided into the usually well-differentiated, hypergastrinemia-dependent type I and II lesions and the more aggressively behaving gastrin-independent type III lesions. Studying menin and its complex interrelationship with gastrin may provide insight into tumor biology at the clinical level and in terms of basic cell biology (eg, the role of the epigenome in neuroendocrine cell proliferation), and lead to potential consideration of other targets that are known candidates for molecular-based therapies in other adenocarcinomas.

Topics: Animals; Carcinoid Tumor; Disease Models, Animal; Gastrins; Humans; Stomach Neoplasms

Topics: Carcinoid Tumor; Female; Gastrectomy; Gastrins; Humans; Laparoscopy; Middle Aged; Pyloric Antrum; Stomach Neoplasms; Treatment Outcome

Gastric carcinoid tumors comprise 7% of all gastrointestinal carcinoids and have significantly increased in incidence over the past few decades. Seventy to 80% of gastric carcinoids are type I, which usually are clinically asymptomatic and found incidentally at endoscopic evaluation for abdominal pain or anemia. In this review, advances in understanding the pathophysiology of type I gastric carcinoid are highlighted. In addition, various current diagnostic and treatment options are discussed. Although type I carcinoids generally hold a benign course, rigorous investigation is needed to ensure accurate diagnosis and optimal treatment. This includes appropriate diagnostic procedures and imaging and accurate staging of tumor. Tumor size, depth of invasion, presence of metastasis, and the tumor's gastrin dependency dictate treatment options. Appropriate treatments can consist of endoscopic resection, antrectomy, medical management, or frequent follow-up. This article provides a systematic method of evaluating and treating type I gastric carcinoid.

Topics: Carcinoid Tumor; Enterochromaffin Cells; Gastrectomy; Gastric Acidity Determination; Gastric Fundus; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Neoplasm Staging; Polyps; Prognosis; Pyloric Antrum; Radionuclide Imaging; Risk Factors; Stomach Neoplasms

Several circulating or urinary tumour markers can be used for the diagnosis and follow-up of functioning and clinically non-functioning neuroendocrine tumours of the pancreatic islet cells and intestinal tract. Among the specific tumour markers are serotonin and its metabolites--e.g. 5-hydroxyindoleacetic acid (5-HIAA)--in carcinoid tumours and the carcinoid syndrome, insulin and its precursors or breakdown products in insulinoma, and gastrin in gastrinoma. Plasma vasointestinal polypeptide (VIP) determinations have been used in the diagnosis of VIPoma, plasma glucagon for glucagonoma, and serum somatostatin for somatostatinoma. Among the tumour-non-specific markers are: chromogranins, neuron-specific enolase (NSE), alpha-subunits of the glycoprotein hormones, catecholamines, pancreatic polypeptide (PP), ghrelin and adrenomedullin.

Topics: Biomarkers; Biomarkers, Tumor; Carcinoid Tumor; Gastrinoma; Gastrins; Humans; Insulin; Insulinoma; Malignant Carcinoid Syndrome; Neuroendocrine Tumors; Pancreatic Neoplasms; Serotonin

The most frequent conditions of hypergastrinemia in man are the Zollinger-Ellison syndrome with autonomous gastrin hypersecretion by the tumour cell and reactive hypergastrinemia in type A autoimmune chronic atrophic gastritis with achlorhydria causing unrestrained gastrin release from the gastrin-producing antral G-cells. Both entities differ with respect to the pH in the gastric fluid, which is < 2 in patients with Zollinger-Ellison syndrome and neutral in type A gastritis. Other conditions with moderate hypergastrinemia as treatment with proton pump inhibitors, gastric outlet obstruction, previous vagotomy, chronic renal failure or short bowel syndrome are of minor clinical importance.

Topics: Autoimmune Diseases; Carcinoid Tumor; Diagnosis, Differential; Duodenal Neoplasms; Enterochromaffin-like Cells; Gastric Mucosa; Gastrinoma; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Pancreatic Neoplasms; Stomach Neoplasms; Zollinger-Ellison Syndrome

Proton pump inhibitors are being increasingly used and for longer periods of time, especially in patients with gastroesophageal reflux disease. Each of these trends has led to numerous studies and reviews of the potential risk-benefit ratio of the long-term use of proton pump inhibitors. Both long-term effects of hypergastrinaemia due to the profound acid suppression caused by proton pump inhibitors as well as the effects of hypo-/achlorhydria per se have been raised and studied. Potential areas of concern that have been raised in the long-term use of proton pump inhibitors, which could alter this risk-benefit ratio include: gastric carcinoid formation; the development of rebound acid hypersecretion when proton pump inhibitor treatment is stopped; the development of tolerance; increased oxyntic gastritis in H. pylori patients and the possibility of increasing the risk of gastric cancer; the possible stimulation of growth of non-gastric tumours due to hypergastrinaemia; and the possible effect of the hypo/achlorhydria on nutrient absorption, particularly iron and vitamin B12. Because few patients with idiopathic gastro-oesophageal reflux disease/peptic ulcer disease have been treated long-term (i.e., >10 years), there is little known to address the above areas of potential concern. Most patients with gastrinomas with Zollinger-Ellison syndrome have life-long hypergastrinaemia, require continuous proton pump inhibitors treatment and a number of studies report results of >5-10 years of tratment and follow-up. Therefore, an analysis of Zollinger-Ellison syndrome patients can provide important insights into some of the safety concerns raised above. In this paper, results from studies of Zollinger-Ellison syndrome patients and other recent studies dealing with the safety concerns above, are briefly reviewed.

Topics: Animals; Carcinoid Tumor; Cell Transformation, Neoplastic; Drug Tolerance; Enterochromaffin-like Cells; Gastric Acid; Gastric Mucosa; Gastrinoma; Gastrins; Gastritis; Gastroesophageal Reflux; Gastrointestinal Agents; Helicobacter pylori; Humans; Malabsorption Syndromes; Peptic Ulcer; Proton Pump Inhibitors; Stomach Neoplasms; Time Factors; Zollinger-Ellison Syndrome

Gastric carcinoid tumours are classified in 3 types depending on whether they are sporadic (type III), or they are associated with a chronic atrophic gastritis (type I) or a multiple endocrine neoplasia type I-associated Zollinger-Ellison syndrome (type II). For type I tumours, the role of antrectomy, which aims to suppress the causative hypergastrinemia, has not been determined.. To determine, from literature review the role of antrectomy in the management of type I gastric carcinoid tumours.. Bibliographic study searching for published observations of antrectomy for type I gastric carcinoid tumours. Data regarding postoperative evolution of gastrinemia and carcinoid tumours were collected.. Thirty-eight published cases were identified. Preoperative gastrinemia was elevated in the 32 patients in whom it was measured. It came to normal ranges in the 19 patients in whom it was postoperatively assessed. With a mean follow-up of 34 months (1 to 120), disappearance of carcinoid tumours was observed in 27 of 38 patients (71%), the 11 others having tumour recurrence or persistence. When postoperatively assessed, hyperplasia of fundic enterochromaffine-like cells persisted in 7 patients, regressed in 4 and disappeared in the 6 others. No antrectomy-related complication was reported.. Antrectomy can be considered as a worthwhile alternative for the treatment of gastric carcinoid tumours related to chronic atrophic gastritis and hypergastrinemia.

Topics: Carcinoid Tumor; Gastrins; Humans; Postoperative Period; Preoperative Care; Pyloric Antrum; Stomach Neoplasms

Despite general awareness of Zollinger-Ellison syndrome (ZES) by most physicians and more than 3000 articles written about it since 1955, the diagnosis of ZES is still delayed for a mean of 5 years. Recent studies show it is being delayed even more with the widespread use of proton pump inhibitors. A number of tumor markers, in addition to assessing serum gastrin, such as chromogranin A, neuron-specific enolase, and subunits of chorionic gonadotropin, have been proposed for use in either the diagnosis of pancreatic endocrine tumors, such as gastrinomas, or for assessment of tumor extent and growth. In this article important recent insights into the diagnosis of ZES as well as the clinical usefulness of assessing tumor markers for diagnosis and determination of disease extent and growth are discussed. Approximately 25% of ZES cases are due to multiple endocrine neoplasia type 1 (MEN1). A number of important studies in this group of patients are also reviewed. Finally, almost every patient with ZES has marked gastric acid hypersecretion, and its current treatment as well as the long-term possible side effects are reviewed briefly.

Topics: Algorithms; Biomarkers, Tumor; Carcinoid Tumor; Chorionic Gonadotropin; Chromogranin A; Chromogranins; Gastric Acid; Gastrinoma; Gastrins; Gastrointestinal Agents; Humans; Hyperparathyroidism; Multiple Endocrine Neoplasia Type 1; Octreotide; Pancreatic Neoplasms; Phosphopyruvate Hydratase; Proton Pump Inhibitors; Stomach Neoplasms; Zollinger-Ellison Syndrome

Several case reports have emphasized that esophageal carcinoid tumors are associated with a poor prognosis. To expand our knowledge about the pathology and biologic behavior of these rare tumors, we reviewed the clinicopathologic and immunohistochemical findings of four cases of primary esophageal carcinoid. The age of the patients ranged from 48 to 82 years (mean 63 years; median 61 years). The lower segment of the esophagus was involved in two cases and the mid segment was involved in one case. The sizes of the tumors ranged from 0.3 cm to 3.5 cm. Two tumors were confined to the lamina propria and two invaded into the muscular wall. Two tumors appeared polypoid, whereas the remaining two were incidental findings and associated with adenocarcinoma arising in a background of Barrett esophagus. The adenocarcinoma was superficially invasive in one case, whereas it penetrated the muscular wall in the other. All four carcinoid tumors were immunoreactive with chromogranin and synaptophysin. There was focal expression of serotonin in two cases, glucagon in one case, and pancreatic polypeptide in one case. Endocrine cell hyperplasia was noted in both the Barrett esophagus and the invasive adenocarcinoma. One patient died secondary to postoperative pneumonia. Three patients are alive and disease free at 1, 6, and 23 years status post therapy. None of the patients had metastatic disease. These findings show that esophageal carcinoids are associated with a favorable prognosis. They arise in two settings: (1) a single large polypoid tumor or (2) an incidental finding and in association with adenocarcinoma arising in the background of Barrett esophagus. The presence of endocrine cell hyperplasia in the Barrett mucosa and the adenocarcinoma supports the hypothesis that these lesions arise from a common stem cell.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Barrett Esophagus; Carcinoid Tumor; Chromogranins; Esophageal Neoplasms; Female; Gastrins; Glucagon; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Pancreatic Polypeptide; Polyps; Prognosis; Synaptophysin

Topics: Adenoma; Carcinoid Tumor; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Neoplasms, Multiple Primary; Parathyroid Glands; Parathyroid Neoplasms; Stomach; Stomach Neoplasms; Zollinger-Ellison Syndrome

The recent recognition of the nature of gastric carcinoids and the elucidation of the biological events associated with enterochromaffin-like cell transformation has provided an opportunity to advance the understanding of this particular type of neuroendocrine tumour. The relationship between hypergastrinaemia present in low acid disease states and the development of gastric carcinoids has led to an appreciation of the role of gastrin as a growth mediator in the evolution of this type of neoplasia. In addition, evidence exists to support a genetic predisposition to this tumour type in individuals with Multiple Endocrine Neoplasia type 1 syndrome, and in an experimental model--the African rodent species, Mastomys. The recent development of an isolated pure enterochromaffin-like cell preparation has facilitated the elucidation of the molecular physiology of the naive enterochromaffin-like cell and, in addition, allowed the evaluation of the cellular events associated with enterochromaffin-like cell transformation from the naive state to the neoplastic phenotype. This synopsis seeks to present information relevant to both the animal model and the human disease state. The aim is to facilitate an appreciation of the regulatory mechanisms of the enterochromaffin-like cell and delineate the changes consequent to the development of the neoplastic phenotype.

Topics: Animals; Apoptosis; Carcinoid Tumor; Cell Transformation, Neoplastic; Cytoplasm; Enterochromaffin-like Cells; Gastric Mucosa; Gastrins; Histamine Release; Histidine Decarboxylase; Humans; Immunohistochemistry; Rats; Receptors, Growth Factor; Rodentia; Sensitivity and Specificity; Somatostatin; Stomach Neoplasms

Four cases of primary hepatic carcinoid were identified during a retrospective study of liver resections for primary tumor. The cases included two adult males, one adult female, and a 9-year-old boy in whom gastrin levels were documented. The estimation of gastrin levels was prompted by symptoms suggestive of acid-peptic disease. One patient died postoperatively. The other three are alive and well at 3 years, 2 years, and at 1 year, respectively, after surgery, outcomes distinctly different from hepatocellular carcinomas. Diagnostic difficulties may be experienced in histologic assessment, and this may require recourse to immunohistochemistry and electron microscopy. Long-term follow-up and careful exclusion of a possible primary elsewhere are necessary for establishing the primary nature of liver carcinoids.

Topics: Adult; Carcinoid Tumor; Child; Fatal Outcome; Female; Gastrins; Hepatectomy; Humans; Liver; Liver Neoplasms; Male; Middle Aged

Gastrin is a well known endogenous stimulator of gastric acid. In addition, recent studies have revealed that gastrin has a growth promoting effect on gastric ECL cells. Indeed, development of ECL carcinoid tumor occurs almost exclusively in patients with hypergastrinemia such as autoimmune gastritis and Zollinger-Ellison syndrome with MEN type I. We have recently cloned human gastrin receptor gene, and by using it, we found that both gastric carcinoid tumor and endocrine cell carcinoma of the stomach express significant amount of gastrin receptor gene whereas none of gastric cancer tissue shows gastrin receptor gene expression. Thus, it is clear that gastrin plays important roles in the development of gastric carcinoid tumor as well as endocrine cell carcinoma of the stomach.

Topics: Animals; Carcinoid Tumor; Duodenal Ulcer; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Receptors, Cholecystokinin; Stomach Neoplasms

The enterochromaffin-like (ECL) cell of the oxyntic, acid-secreting mucosa is at present the most extensively studied endocrine cell type in the gastrointestinal tract. It is functionally related to acid secretion through paracrine release of histamine. Its ability to undergo proliferation in response to the trophic stimulus of hypergastrinemia has important implications in pathology, being involved in the development of ECL-cell carcinoid tumors of rodents treated with powerful inhibitors of acid secretion as well as in that of most human gastric carcinoids which, with rare exceptions, are composed of ECL cells. The various aspects of the ECL-cell response to hypergastrinemia in humans are discussed in this review. The trophic effect of gastrin is specific for ECL cells and its sensitivity is enhanced by the female sex and by the genetic background of the multiple endocrine neoplasia type 1 (MEN-1) syndrome. Exposure of ECL cells to hypergastrinemia induces peculiar changes in the structure of cytoplasmic granules and triggers the phenotypic expression of a novel protein, the alpha subunit of glycoprotein hormones, absent in normal cells. The ECL-cell hyperplasia driven by hypergastrinemia may influence the hypersecretory gastric state of patients with Zollinger-Ellison syndrome (ZES) by inappropriate intramucosal secretion of histamine and may contribute to the high circulating levels of basic fibroblast growth factor (bFGF), an ECL-cell product responsible for parathyroid mitogenic effects in MEN-1 patients. However, hypergastrinemia per se cannot promote evolution of hyperplasia into carcinoid tumors, for which additional unknown factors, particularly associated with atrophic gastritis or MEN-1 syndrome, are required. ECL-cell carcinoids developing within these backgrounds have a strikingly more favorable course than their gastrin-independent counterpart. Suppression of hypergastrinemia, either by antrectomy or treatment with somatostatin analogues, may induce regression of both ECL-cell hyperplasia and gastrin-sensitive ECL-cell carcinoids.

Topics: Carcinoid Tumor; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Stomach Neoplasms; Zollinger-Ellison Syndrome

In the Zollinger-Ellison syndrome, fundic argyrophil carcinoid tumors occur almost exclusively in the small subgroup of patients who also have multiple endocrine neoplasia type 1. In these patients, tumor development seems related to the same genetic alterations as those observed in other endocrine tumors related to multiple endocrine neoplasia type 1. We report here the second detailed case of a patient with sporadic Zollinger-Ellison syndrome who developed an argyrophil carcinoid tumor in nonatrophic fundic mucosa, suggesting that chronic hypergastrinemia may lead to fundic carcinoid development in nongenetically predisposed patients.

Topics: Aged; Biopsy; Carcinoid Tumor; Chronic Disease; Diagnosis, Differential; Female; Gastric Fundus; Gastric Mucosa; Gastrins; Humans; Multiple Endocrine Neoplasia Type 1; Silver Staining; Stomach Neoplasms; Zollinger-Ellison Syndrome

Gastric carcinoid tumors were previously believed to be rare lesions, representing less than 2% of all carcinoid tumors and less than 1% of all stomach neoplasms. More recent studies have demonstrated that they may constitute as much as 10-30% of carcinoid tumors. Patients with conditions associated with hypergastrinemia, such as chronic atrophic gastritis, Zollinger-Ellison syndrome with multiple endocrine neoplasia type 1 (ZES-MEN-1), and pernicious anemia, display a markedly elevated incidence of gastric carcinoid tumor formation. A classification system distinguishing three types of gastric carcinoid tumor has been proposed: 1) tumors associated with chronic atrophic gastritis, 2) tumors associated with Zollinger-Ellison syndrome, and 3) sporadic lesions. Tumors that develop in association with hypergastrinemia are usually composed of enterochromaffin-like (ECL) cells, in contrast to sporadic lesions that contain a variety of endocrine cell types (enterochromaffin, ECL, X). In both intact animal models such as the rat and Praomys (mastomys) natalensis and in isolated purified ECL cell preparations, gastrin has been demonstrated to exert a powerful trophic effect on ECL cells, in addition to stimulating histamine secretion. It is apparent that hypergastrinemia-associated gastric carcinoids display relatively benign biological behavior. Sporadic lesions require aggressive surgical management on diagnosis. Type I and type II (hypergastrinemia-associated) lesions can be managed initially by endoscopic excision of accessible tumors, followed by endoscopic surveillance. If tumors recur, antrectomy and local excision may be used to remove the source gastrin, resulting in cure in the vast majority of patients.

Topics: Animals; Carcinoid Tumor; Decision Trees; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Incidence; Multiple Endocrine Neoplasia Type 1; Stomach Neoplasms; Zollinger-Ellison Syndrome

The gastrointestinal neuroendocrine cell proliferations are comprised of a few hyperplasias and various neoplasias. The better characterized hyperplasias include G-cell hyperplasia, either primary or secondary, enterochromaffin-like (ECL)-cell hyperplasias, generally secondary to hypergastrinemia, and EC-cell hyperplasias. The neoplasias include carcinoid tumors, demonstrating low malignancy and divided into foregut, midgut, and hindgut varieties, poorly differentiated neuroendocrine carcinomas resembling their pulmonary counterparts the "oat cell" carcinomas both in histological pattern and in their highly malignant behavior mixed endo-exocrine tumors, which in turn can be divided into composite tumors formed by a population of endocrine cells and a population of exocrine cells, and amphicrine tumors formed by a uniform population of cells with a mixture of endocrine and exocrine phenotypic traits. Although some of these mixed tumors show a degree of malignancy intermediate between the classical carcinoid and an adenocarcinoma, more information must be gathered to establish firm prognostic parameters for these relatively new entities.

Topics: Carcinoid Tumor; Enterochromaffin Cells; Gastrinoma; Gastrins; Gastrointestinal Neoplasms; Humans; Hyperplasia; Neuroendocrine Tumors

ECL cells are argyrophilic endocrine cells of the stomach. Their distribution is species specific, however they are consistently located in the oxyntic mucosa and, in particular, in very close contact with the adenomeres of acidopeptic glands. ECL cells store histamine and are considered a key element in the mechanisms of gastric acid secretion as controlled by gastrin stimulus. Their peculiar anatomical disposition and secretory properties strongly suggest that ECL cells exert their function by a paracrine mechanism, i.e. by releasing histamine in the extracellular spaces surrounding acid-producing parietal cells. ECL cell activity is strongly stimulated by gastrin, which, once applied as a long-standing stimulus, also exerts a potent proliferating effect. Long-lasting hypergastrinaemia has been demonstrated to elicit ECL cell proliferation in laboratory animals, inducing ECL cell hyperplasia, dysplasia and ECL cell tumours, i.e. argyrophilic gastric carcinoids. However, in experimental rodents it is believed that hypergastrinaemia is not per se a stimulus capable of inducing ECL cell transformation, a predisposing genetic background being required for tumour development in endocrine organs. In man, long-standing hypergastrinaemia exerts the same proliferative pressure on ECL cells and is associated with hyperplasia with or without dysplastic changes and carcinoid development. Clinical evidence suggests that other factors, both genetic and environmental, are required to induce ECL cell transformation and carcinoid development. For this reason human gastric argyrophilic ECL carcinoids are subdivided into three main groups depending on their clinical background: (1) gastric carcinoids in patients with chronic atrophic gastritis; (2) gastric carcinoids in patients with Zollinger-Ellison and multiple endocrine neoplasia type 1 syndrome (MEN-ZES); and (3) solitary, sporadic gastric carcinoids. The clinical assessment of carcinoid-bearing patients is strongly recommended for better diagnosis and management of patients.

Topics: Animals; Carcinoid Tumor; Enterochromaffin Cells; Gastric Acid; Gastric Mucosa; Gastrins; Gastritis; Histamine Release; Humans; Multiple Endocrine Neoplasia; Omeprazole; Parietal Cells, Gastric; Stomach Neoplasms; Zollinger-Ellison Syndrome

In hormone-producing tumors such as the carcinoids, overproduction of certain hormones may activate proto-oncogenes. Hormones, or growth factors, thus can be of importance for growth regulation. Information is presented on some growth factors and their receptors in this respect and on the involvement of gastrin and its receptor on tumor development in the experimental Mastomys model. The relevance of differential expression of cell adhesion molecules in endocrine tumors is discussed also.

Topics: Animals; Carcinoid Tumor; Cell Adhesion Molecules; Disease Models, Animal; Gastrins; Gastrointestinal Neoplasms; Growth Substances; Humans; Muridae

A 42-yr-old woman presented with multiple carcinoid tumors in her stomach and a markedly elevated serum gastrin level. Total gastrectomy was performed, and 22 small carcinoid tumors were found in the gastric fundus and body. A high serum gastrin level was revealed in the gastric drainage veins; still more gastrin was detected in the carcinoid tumors by the immunohistochemical method, and many secretory granules were found in the tumor cells with an electron microscope. The fundic gland showed marked atrophy, and there was some conglobation of endocrine cells (ECL cells). This case suggests a hypothetic sequence of anacidity due to atrophic gastritis----hypergastrinemia----proliferation of ECL cells----multiple carcinoids. A search of the Japanese literature revealed that 26 cases of multiple carcinoid tumors in the stomach have been reported so far, and most of them support this hypothesis.

Topics: Adult; Carcinoid Tumor; Female; Gastrins; Humans; Neoplasms, Multiple Primary; Stomach Neoplasms

Topics: Achlorhydria; Carcinoid Tumor; Gastrectomy; Gastrins; Gastritis, Atrophic; Humans; Stomach Neoplasms

Topics: Carcinoid Tumor; Enterochromaffin Cells; Female; Gastrins; Humans; Male; Omeprazole; Pyloric Antrum; Sex Factors; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Adenocarcinoma; Carcinoid Tumor; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Omeprazole; Stomach Neoplasms; Zollinger-Ellison Syndrome

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.

Topics: Animals; Anti-Ulcer Agents; Carcinoid Tumor; Endocrine Glands; Gastric Mucosa; Gastrins; Humans; Models, Biological; Stomach Neoplasms

A 42-year-old white woman was seen by her physician because of somatic complaints of the neck and right arm discomfort, difficulty in swallowing, and "heartburn." Findings of the workup led to the diagnosis of metastatic ossified gastric carcinoid. Review of the literature suggests that this is the third report of ossified gastric carcinoid. However, this is the only case in which such a tumor was associated with hypergastrinemia, gastric (antiparietal cell), and thyroid (antimicrosomal) autoantibodies.

Topics: Adult; Autoantibodies; Carcinoid Tumor; Female; Gastrins; Humans; Ossification, Heterotopic; Parietal Cells, Gastric; Stomach Neoplasms

Newer potent and long-acting inhibitors of acid secretion, such as the proton pump inhibitor omeprazole, are becoming available for general use. These drugs promise to control acid-peptic disease effectively in patients who do not respond adequately to conventional short-acting H2-receptor antagonists. The safety of chronic administration of these drugs has come into question, however. Lifelong profound inhibition of acid secretion in rats induced by superpotent inhibitors of acid secretion or subtotal fundectomy is associated with the development of carcinoid tumors of enterochromaffin-like (ECL) cells in the gastric corpus. Available evidence supports a role of gastrin, which becomes chronically elevated in animals subjected to prolonged and profound hypochlorhydria. In humans, hypergastrinemic states such as Zollinger-Ellison syndrome and atrophic gastritis are associated with an increased risk of ECL-cell carcinoid tumors. Such observations have raised concern that humans may also be susceptible to carcinoid tumor formation in response to potent inhibitors of acid secretion. To date, however, no cases of carcinoid tumor have been attributed to the use of omeprazole in humans. If achlorhydric doses are not used, significant hypergastrinemia can be avoided while effectiveness of treatment is maintained. Such measures should minimize any risk of ECL-cell carcinoid tumors in humans taking potent long-term antisecretory drugs.

Topics: Achlorhydria; Animals; Carcinoid Tumor; Cell Transformation, Neoplastic; Enterochromaffin Cells; Gastrins; Humans; Omeprazole; Rats; Stomach Neoplasms

Three cases of gastric carcinoid polypi associated to atrophic gastritis and high levels of seric gastrin, are presented. One of the cases was a multiple micropolyposis the literature regarding this association is reviewed and the therapy discussed. Tumors of greater than 2 cm have to be considered potentially malignant and be treated likewise. The treatment of the micropolyposis is not well established.

Topics: Achlorhydria; Adult; Autoimmune Diseases; Carcinoid Tumor; Female; Follow-Up Studies; Gastrins; Gastritis, Atrophic; Humans; Male; Middle Aged; Neoplasms, Multiple Primary; Polyps; Pyloric Antrum; Stomach Neoplasms

Although carcinoid tumors only infrequently (2-6%) have a gastric localization, in recent years several cases have been described of this tpe of neoplasm in association with atrophic gastritis (with or without pernicious anemia). A possible carcinogenetic effect of sustained hypergastrinemia on the enterochromaffin-like cells (ECL) of the gastric mucosa has been postulated. A new case of these characteristics in reported, and a review is made of the pathogenic hypotheses in the literature on this peculiar type of tumors and their possible clinical implications.

Topics: Adult; Carcinoid Tumor; Gastrins; Gastritis; Gastritis, Atrophic; Humans; Male; Stomach Neoplasms

Based on the experience from more than 10,000 individuals omeprazole has been found to be safe and is well tolerated. Side effects are few and do not differ from those observed during H2-blocker treatment. Effects on endocrine cells observed in animals during toxicological studies include increase of antral G cells, decrease of antral D cells and increase of fundic ECL cells. The increase of G cells and the decrease of D cells is the consequence of achlorhydria achieved by very high omeprazole dosages and results in hypergastrinaemia. Hypergastrinaemia is responsible for ECL cell hyperplasia. Lifelong hypergastrinaemia in rats has been found to induce carcinoid tumours. This gastrin-carcinoid sequence is unlikely to occur in man with an omeprazole dosage recommended for treatment of peptic diseases. Therapeutic doses in man do not produce complete achlorhydria. Therefore, serum gastrin levels increase in man during omeprazole treatment only moderately and are similar in magnitude as after selective proximal vagotomy. Available results on gastric endocrine cells in patients treated with omeprazole for up to 2 years could not demonstrate significant changes in G, D and ECL cell densities. It is concluded that omeprazole is, in man, as safe as H2 blockers if administered in doses recommended for treatment of peptic diseases.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Achlorhydria; Animals; Carcinoid Tumor; Clinical Trials as Topic; Drug Administration Schedule; Enterochromaffin Cells; Gastrins; Humans; Omeprazole

Topics: Achlorhydria; Adenocarcinoma; Animals; Anti-Ulcer Agents; Carcinoid Tumor; Gastric Acid; Gastric Mucosa; Gastrins; Humans; Male; Rats; Serotonin; Stomach Neoplasms

We have described a 40-year-old woman whose classic adrenal insufficiency, achlorhydria, and hypergastrinemia was complicated by the development of a gastric carcinoid. There is now evidence that patients with elevated serum gastrin levels are at increased risk for this rare tumor.

Topics: Achlorhydria; Addison Disease; Adult; Carcinoid Tumor; Female; Gastrins; Humans; Stomach Neoplasms

The accumulating evidence of an association between antrum-sparing hypergastrinaemic atrophic gastritis, frequently associated with pernicious anaemia, and the occurrence of gastric carcinoid tumours is briefly reviewed. The development of argyrophil cell carcinoid tumours in the atrophic fundic mucosa seems to be related to argyrophil cell hyperplasia caused by hypergastrinaemia. Epidemiologic considerations indicate that the gastric carcinoid generally is underdiagnosed and that the incidence of this tumour is higher than previously recognized. The clinical relevance of minute gastric carcinoids, or endocrine cell 'adenomas', is obscure. However, larger tumours should be regarded as potentially malignant. These findings are relevant to the aspect of long-term medically induced achlorhydria leading to hypergastrinaemia.

Topics: Achlorhydria; Adenoma; Anemia, Pernicious; Atrophy; Carcinoid Tumor; Cell Division; Epidemiologic Methods; Gastrins; Gastritis; Humans; Stomach Neoplasms

The stomach is rich in endocrine cells, most of which are still unidentified with respect to the peptide hormones they produce. The endocrine cell populations in the antrum usually differ from those in the oxyntic mucosa. Gastrin cells are found in the antrum and respond readily to stimuli from the gastric lumen, such as changes in the pH and the presence of food. In order to study the functional control of the antral gastrin cell, rats were subjected to different kinds of surgery. The serum gastrin concentrations in the various experimental groups were measured 8-10 weeks after the operations. Elevated antral pH raised the serum gastrin concentration. The combination of elevated antral pH and the passage of food over the pyloric glands produced gastrin cell hyperplasia. The operation that was most effective in inducing gastrin cell hyperplasia was removal of the acid-producing part of the stomach. Interestingly, gastrin cell hyperplasia was seen also after bilateral truncal vagotomy, indicating that an intact vagal innervation is not essential for the development of gastrin cell hyperplasia. Enterochromaffin-like (ECL) cells are endocrine/paracrine cells that are numerous in the acid-producing part of the stomach in many species. In the rat, they occur predominantly in the basal half of the oxyntic mucosa and produce and store histamine. The ECL cells have an unknown function and do not seem to respond to stimuli from the gastric lumen. They are activated by circulating gastrin and by vagal excitation. Gastrin mobilises histamine from these cells and activates the histamine-forming enzyme, histidine decarboxylase. Long-term hypergastrinaemia produces diffuse ECL cell hyperplasia, whereas hypogastrinaemia (following removal of the endogenous stores of gastrin by antrectomy) reduces the ECL cell number. Portacaval shunt brings about a marked increase in the number of ECL cells through an unknown mechanism. Also neuronal stimuli are important for the trophic control of the ECL cells. Studies of unilaterally vagotomised rats showed reduced weight and thickness of the oxyntic mucosa as well as a markedly reduced number of ECL cells on the denervated side. Gastric carcinoids in man are rare tumours predominantly made up of ECL cells. The incidence of such tumours is increased in patients with hypergastrinaemia (pernicious anaemia, Zollinger-Ellison syndrome). A diffuse ECL cell hyperplasia is a common finding in such patients, which is in keeping with the know

Topics: Animals; Carcinoid Tumor; Chromaffin System; Enterochromaffin Cells; Gastrins; Humans; Hydrogen-Ion Concentration; Hyperplasia; Microscopy, Electron; Portacaval Shunt, Surgical; Rats; Stomach; Stomach Neoplasms

Histopathological and experimental observations indicate that tumors composed wholly or in part of neuroendocrine elements may arise in tissues derived from ectoderm (including neuroectoderm), mesoderm, and endoderm. These tumors frequently exhibit multidirectional differentiation as manifested by multihormonality and by the presence of morphological features indicative of divergent differentiation both in vivo and in vitro. The existence of stem cells, plasticity of differentiated cells, microenvironmental influences, and random events are factors which might all interact to determine the characteristics of any particular tumor. The production of characteristic regulatory peptide products in association with tumors of specific histological subtypes and with other neuroendocrine markers suggests mechanisms for nonrandom activation of multiple genes common to neuroendocrine-programmed cells. Future studies applying new molecular biological techniques to intact tissues and to in vitro models may help to clarify the mechanisms that regulate the expression of the neuroendocrine phenotype in normal and neoplastic states.

Topics: Adrenal Gland Neoplasms; Animals; Apudoma; Calcitonin; Carcinoid Tumor; Cricetinae; Female; Gastrins; Hormones, Ectopic; Humans; Neurotensin; Ovarian Neoplasms; Pancreatic Neoplasms; Pheochromocytoma; Rats; Somatostatin; Thyroid Neoplasms; Uterine Neoplasms; Vasoactive Intestinal Peptide

Topics: Adenoma; Carcinoid Tumor; Endocrine System Diseases; Gastrins; Gastrointestinal Diseases; Glucagonoma; Histocytochemistry; Humans; Hyperinsulinism; Immunochemistry; Insulinoma; Islets of Langerhans; Pancreatic Diseases; Pancreatic Neoplasms; Peptic Ulcer; Somatostatinoma; Stomach; Vipoma

The identification and description of a widely dispersed group of cells of common origin and biochemical characteristics, APUD cells, has allowed a better understanding and classification of endocrine tumors of the pancreas. Similarly, it has enabled the relationships between the endocrine tumors of the multiple endocrine neoplasia type I syndrome and the endocrine tumors of the pancreas to be better appreciated. This has facilitated both diagnosis and management of these conditions. The pluripotentiality of the cells of the APUD system combined with the certain existence of many unidentified peptides suggests the likelihood of other undescribed pancreatic endocrine tumors. Many of these are probably part of the heterogenous group of neoplasms currently designated as carcinoids, since their secretory products and exact cell types are not known. The recognition of the physiologic characteristics and cells of origin of these peptides, amines or other bioactive agents will allow delineation of the symptom complex and the identification of further functional tumors of the pancreas. The development of plasma radioimmunoassays for the various hormones and the appreciation of the specific clinical syndromes related to each tumor have enabled earlier diagnosis. The understanding of the hormonal physiopathologic functions has led to the evolution of specific therapeutic maneuvers. Provocative tests have allowed increased precision of the differential diagnosis, while selective arteriography and pancreatic venous sampling have greatly enhanced the accuracy of topical localization. The role of operation in tumor removal is still prominent, but malignant and recurrent tumors may now also be controlled with specific pharmacotherapy or appropriate endocrine cytotoxic agents. The use of peptides with antagonistic actions or the administration of specific antibodies to the active tumor products are areas of therapy that require further exploration.

Topics: Adult; Apudoma; Carcinoid Tumor; Child; Diagnosis, Differential; Gastrins; Glucagon; Humans; Infant; Insulin; Insulin Secretion; Islets of Langerhans; Neoplasms, Multiple Primary; Pancreatic Neoplasms; Pancreatic Polypeptide; Somatostatin; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Topics: Acute Kidney Injury; Adenoma, Islet Cell; Adolescent; Adult; Aged; Carcinoid Tumor; Child; Dehydration; Female; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Glucagon; Humans; Hyperplasia; Hypokalemia; Insulin; Insulin Secretion; Male; Middle Aged; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Precancerous Conditions; Serotonin; Somatostatin; Syndrome; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Topics: Appendiceal Neoplasms; Carcinoid Tumor; Carcinoma, Small Cell; Cholecystokinin; Digestive System; Duodenum; Endocrine Glands; Fetus; Gastric Mucosa; Gastrins; Humans; Ileum; Peptides; Rectal Neoplasms; Respiratory System; Secretin; Substance P; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Animals; Biogenic Amines; Carcinoid Tumor; Decarboxylation; Gastric Mucosa; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Histocytochemistry; Intestinal Mucosa; Islets of Langerhans; Pancreatic Neoplasms; Serotonin; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Carcinoid Tumor; Cholecystokinin; Diarrhea; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Glucagon; Hormones, Ectopic; Humans; Insulin; Insulin Secretion; Neurosecretory Systems; Pancreatic Hormones; Paraneoplastic Endocrine Syndromes; Prostaglandins; Serotonin; Syndrome; Vasoactive Intestinal Peptide; Werner Syndrome; Zollinger-Ellison Syndrome

Topics: Animals; Biogenic Amines; Carcinoid Tumor; Cholecystokinin; Chromaffin System; Diabetes Mellitus; Digestive System; Digestive System Physiological Phenomena; Gastric Juice; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Glucagon; Humans; Insulin; Insulin Secretion; Intestines; Pancreas; Pancreatic Neoplasms; Peptic Ulcer; Secretin; Syndrome

Patients with chronic atrophic gastritis have long-term gastric hypoacidity, and secondary hypergastrinaemia. Some also develop gastric ECL cells carcinoids (type 1 GC). Most type 1 GC remain indolent, but some metastasise. Patients undergo surveillance, and some are treated with somatostatin analogues, endoscopic resection or surgery. Netazepide (YF476) is a highly selective, potent and orally active gastrin receptor antagonist, which has anti-tumour activity in various rodent models of gastric neoplasia driven by hypergastrinaemia. Netazepide has been studied in healthy volunteers.. To assess the effect of netazepide on type 1 GC.. Eight patients with multiple type 1 GC received oral netazepide once daily for 12 weeks, with follow-up at 12 weeks in an open-label, pilot trial. Upper endoscopy was performed at 0, 6, 12 and 24 weeks, and carcinoids were counted and measured. Fasting serum gastrin and chromogranin A (CgA) and safety and tolerability were assessed at 0, 3, 6, 9, 12 and 24 weeks.. Netazepide was well tolerated. All patients had a reduction in the number and size of their largest carcinoid. CgA was reduced to normal levels at 3 weeks and remained so until 12 weeks, but had returned to pre-treatment levels at 24 weeks. Gastrin remained unchanged throughout treatment.. The gastrin receptor antagonist netazepide is a promising new medical treatment for type 1 gastric carcinoids, which appear to be gastrin-dependent. Controlled studies and long-term treatment are justified to find out whether netazepide treatment can eradicate type 1 gastric carcinoids.

Topics: Aged; Benzodiazepinones; Carcinoid Tumor; Chromogranin A; Female; Gastrins; Humans; Male; Middle Aged; Phenylurea Compounds; Receptor, Cholecystokinin B; Stomach Neoplasms; Treatment Outcome

Chromogranin A (CgA) is a neuroendocrine tumor (NET) marker. Modest CgA elevation is found in subjects with enterochromaffin-like (ECL) cell hyperplasia due to hypergastrinemia. Somatostatin analogs reduce CgA levels in patients with NET. Meals may affect serum CgA levels. The aims of the study were to investigate meal-induced CgA release and the short-term effect of octreotide on serum CgA levels. Four groups were studied: group A, seven patients with ECL cell hyperplasia secondary to use of proton pump inhibitors (PPIs); group B, six patients with gastric carcinoid type 1/ECL hyperplasia due to chronic atrophic gastritis (CAG); group C, six patients with nongastric NETs; group D, seven controls. The subjects were studied on three separate days with the use of three exposures: a test meal, pentagastrin subcutaneously (not group C), and octreotide intravenously. Serum CgA and gastrin were analyzed. A test meal induced a significant CgA increase in long-term PPI users and in healthy controls. The meal did not affect CgA levels in patients with gastric carcinoid type 1 or patients with NETs. The test meal increased gastrin levels in all groups except in those with CAG. Pentagastrin increased CgA levels in all groups tested except in those with CAG, while octreotide, reduced CgA and gastrin levels in all groups. Serum CgA should be determined in fasting individuals. A test meal may distinguish between increased CgA levels in PPI users from nongastric NET patients. Concomitant gastrin determination may help to discriminate between nongastric NETs and CAG. Intravenous octreotide rapidly reduces serum CgA.

Topics: Aged; Biomarkers, Tumor; Carcinoid Tumor; Carcinoma, Neuroendocrine; Chromogranin A; Diagnostic Techniques, Digestive System; Enterochromaffin-like Cells; Female; Gastrins; Gastrointestinal Agents; Humans; Hyperplasia; Male; Middle Aged; Octreotide; Pentagastrin; Proton Pump Inhibitors; Radioimmunoassay; Stomach Neoplasms

Patients with chronic atrophic gastritis (CAG) and hypergastrinaemia are at risk of developing hyperplasia of the enterochromaffin-like (ECL) cells and ECL-cell-derived tumours. The effect of the somatostatin analogue octreotide on ECL cell carcinoids is examined.. Five patients with hypergastrinaemia and ECL cell carcinoids were enrolled in a 1-year study of octreotide LAR (long-acting release) 20 mg given at monthly intervals. Biopsies from tumours and from flat oxyntic mucosa were done at the start and 3, 6 and 12 months thereafter. Sections were stained with haematoxylin-erythrosin, immunostained with chromogranin A (CgA) and doublestained with CgA and Ki-67. Serum gastrin and CgA were measured.. The number of visible tumours was reduced by more than 50 %. Sections from both tumours and flat mucosa showed a reduced number of CgA immunoreactive cells. Mean serum gastrin decreased from 421 to 186 pM (normal <40 pM); P > 0.05, and serum CgA from 73 to 25 ng/ml (normal < 30 ng/ml); P < 0.001.. During treatment the patients were still markedly hypergastrinaemic, whereas the serum CgA showed normalization. A diminished tumour load and reduced ECL cell density were found, indicating an antiproliferative effect of octreotide directly on the ECL cells.

Topics: Aged; Antineoplastic Agents, Hormonal; Carcinoid Tumor; Cell Proliferation; Chromogranin A; Chromogranins; Delayed-Action Preparations; Enterochromaffin-like Cells; Female; Gastric Mucosa; Gastrins; Gastroscopy; Humans; Male; Middle Aged; Octreotide; Stomach Neoplasms; Time Factors

Body-predominant atrophic gastritis is considered a risk factor for gastric cancer and carcinoid. Timing of follow-up for patients with this disorder has not been defined. This study was undertaken to determine the optimal time for the first endoscopic/histologic follow-up in patients with body-predominant atrophic gastritis.. Forty-two patients with body-predominant atrophic gastritis were randomly assigned to 1 of 2 follow-up intervals: group A (n = 22) at 24 months and group B (n = 20) at 48 months. At baseline and follow-up patients underwent gastroscopy at which biopsies were obtained from the antrum and body for histopathology and evaluation for enterochromaffin-like cells.. In group A patients, 2 antral hyperplastic polyps (9.1%) were present at baseline and 4 antral hyperplastic polyps (18.2%) were found at follow-up. In group B patients, baseline gastroscopy revealed 2 antral hyperplastic polyps (10%) and follow-up 2 antral hyperplastic polyps (10%) and 1 carcinoid tumor (5%) in the body. Atrophy and intestinal metaplasia scores in gastric body and antral mucosa in both groups did not change significantly between baseline and follow-up, except an increase in antral mucosa atrophy in group B patients (p = 0.02) was revealed.. The results of this study indicate that performing the first follow-up in patients with body-predominant atrophic gastritis need not be earlier than at 4 years after diagnosis. This interval is satisfactory for detection of potential neoplastic lesions.

Topics: Adult; Aged; Anemia, Pernicious; Biopsy; Carcinoid Tumor; Enterochromaffin-like Cells; Female; Follow-Up Studies; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Pepsinogen A; Polyps; Prospective Studies; Pyloric Antrum; Random Allocation; Stomach Neoplasms; Time Factors

Serum chromogranin A levels (CgA) are reported by some authors to be of clinical utility for assessing the presence or absence of a pancreatic endocrine tumor and tumor extent or growth. The aim of the current study was to assess this finding and compare the results with those from serum gastrin determinations (FSG) in a large cohort of patients with gastrinomas.. In 112 consecutive patients with the Zollinger-Ellison syndrome serum CgA and FSG levels were measured and correlated with disease activity, extent of disease, and the presence of multiple endocrine neoplasia type-1 (MEN-1) or gastric carcinoid tumors.. Serum CgA levels drawn on 2 consecutive days correlated closely (P < 0.00001) as did serum gastrin levels. Serum CgA levels correlated significantly with FSG levels (P < 0.00001). Serum CgA and FSG levels were significantly higher in patients with active disease than in disease free patients (P < 0.00001). The sensitivity for the presence of disease was higher for CgA compared with FSG (92% vs. 80%; P = 0.021). However, the specificity of CgA was 67%. Serum CgA levels were not significantly different in the four disease categories (stable extrahepatic disease, increasing extrahepatic disease, stable liver metastases, and increasing liver metastases). FSG levels were significantly lower in patients with stable extrahepatic disease compared with those with increasing extrahepatic disease. However, both tumor markers decreased significantly with a gastrinoma resection in five patients. The presence of MEN-1 or a gastric carcinoid tumor did not influence the results.. The results of the current study showed that serum CgA and FSG levels both are sensitive tumor markers for the detection of a gastrinoma; however, CgA levels have a relatively low specificity. Neither the magnitude of the serum CgA nor gastrin level correlated with tumor growth or tumor extent and therefore cannot be used to determine these variables. However, in contrast to some other studies, the results of the current study show that changes in serum CgA or gastrin in a given patient with time are related to the tumor extent and not to gastric mucosal changes due to hypergastrinemia.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoid Tumor; Chromogranin A; Chromogranins; Female; Gastrinoma; Gastrins; Humans; Liver Neoplasms; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Prospective Studies; Sensitivity and Specificity; Stomach Neoplasms; Zollinger-Ellison Syndrome

To evaluate the response of endocrine cells of the gastric oxyntic mucosa in hypergastrinaemic patients to either antrectomy or treatment with the somatostatin analogue octreotide.. (a) Two patients with enterochromaffin-like (ECL) cell carcinoid and chronic atrophic gastritis, treated with antrectomy; (b) four patients with Zollinger-Ellison syndrome, treated with octreotide.. Oxyntic endocrine cells were examined by ultrastructural morphometry on full thickness biopsy specimens taken: (a) before and four months after antrectomy, (b) before and after three months' treatment with octreotide 200 micrograms daily.. Both treatments induced prompt, significant reduction of gastrinaemia and a significant decrease of the volume density of the whole endocrine cell mass and of the cross sectional area of all nucleated endocrine cell profiles (antrectomy: -38%, p < 0.04 and -31%, p < 0.04, respectively; octreotide: -59%, < 0.007 and -26%, < 0.04, respectively). Assessment of the relative proportion of individual endocrine cell types showed a different response to antrectomy or octreotide. After antrectomy, in fact, only the volume fraction of ECL cells was significantly reduced, from 56.5% to 22.5% (-60%, p < 0.04). After octreotide treatment, in contrast, the proportion of all endocrine cell types remained remarkably constant, showing that all cell types took part in the observed overall decrease.. Postantrectomy reduction of oxyntic endocrine cells mostly reflects the withdrawal of the specific trophic stimulus of hypergastrinaemia on ECL cells. In contrast, the inhibitory response to octreotide seems to be exerted on virtually all types of oxyntic endocrine cells, probably reflecting a universal occurrence of somatostatin receptors.

Topics: Adult; Aged; Carcinoid Tumor; Female; Gastrins; Gastritis, Atrophic; Gastrointestinal Agents; Humans; Male; Microscopy, Electron; Middle Aged; Octreotide; Parietal Cells, Gastric; Pyloric Antrum; Stomach Diseases; Stomach Neoplasms; Zollinger-Ellison Syndrome

Although patients with neuroendocrine tumors typically exhibit an indolent clinical course, the pace of disease accelerates and the prognosis deteriorates once objective progression of disease begins. Thirty-four patients with advanced neuroendocrine tumors were treated with octreotide as antineoplastic therapy. This treatment was begun only after documentation of clear objective progression of disease.. A Phase II trial was performed at a tertiary comprehensive cancer center.. The median survival for this patient population from the start of octreotide therapy has not been reached, with a median follow-up of 29 months (range, 1-47 months). No major objective tumor regressions were seen. Seventeen patients (50%) experienced a computed tomography-documented stabilization of disease that was maintainable for a minimum of 2 months (median, 5 months; range, 0-27 months). Of the 34 patients, 20 patients received octreotide as their first antineoplastic therapy. The median survival for these 20 patients has not been reached, with a median follow-up also of 29 months (range, 12-41 months).. Octreotide may influence the natural history of neuroendocrine tumors. The survival in patients treated with octreotide, as measured from the time of progression of disease, compares favorably with that of historical controls. Proof of a survival advantage for patients treated with octreotide would require a multicenter, randomized trial.

Topics: Adenoma, Islet Cell; Adult; Aged; Carcinoid Tumor; Female; Gastrins; Humans; Male; Middle Aged; Neoplasm Staging; Octreotide; Pancreatic Neoplasms; Survival Analysis

Based on the experience from more than 10,000 individuals omeprazole has been found to be safe and is well tolerated. Side effects are few and do not differ from those observed during H2-blocker treatment. Effects on endocrine cells observed in animals during toxicological studies include increase of antral G cells, decrease of antral D cells and increase of fundic ECL cells. The increase of G cells and the decrease of D cells is the consequence of achlorhydria achieved by very high omeprazole dosages and results in hypergastrinaemia. Hypergastrinaemia is responsible for ECL cell hyperplasia. Lifelong hypergastrinaemia in rats has been found to induce carcinoid tumours. This gastrin-carcinoid sequence is unlikely to occur in man with an omeprazole dosage recommended for treatment of peptic diseases. Therapeutic doses in man do not produce complete achlorhydria. Therefore, serum gastrin levels increase in man during omeprazole treatment only moderately and are similar in magnitude as after selective proximal vagotomy. Available results on gastric endocrine cells in patients treated with omeprazole for up to 2 years could not demonstrate significant changes in G, D and ECL cell densities. It is concluded that omeprazole is, in man, as safe as H2 blockers if administered in doses recommended for treatment of peptic diseases.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Achlorhydria; Animals; Carcinoid Tumor; Clinical Trials as Topic; Drug Administration Schedule; Enterochromaffin Cells; Gastrins; Humans; Omeprazole

Gastric enterochromaffin-like cell (ECL) tumours can occur in patients with multiple endocrine neoplasia type 1 (MEN1), especially in those affected by Zollinger Ellison syndrome (ZES). Since the prevalence of ECL lesions is not well defined yet, the present study evaluated the presence and extent of ECL lesions in MEN1 patients with and without ZES.. Multiple endocrine neoplasia type 1 patients being part of a regular screening program (2014-2018) underwent gastroduodenoscopies with biopsies of the stomach and determination of serum gastrin and chromogranin A levels. Haematoxylin- and immunostaining with chromogranin A, gastrin and VMAT I and II (vesicular monoamine transporter I and II) of the biopsies were performed.. Thirty-eight MEN1 patients, of whom 16 (42%) were diagnosed and treated earlier for ZES, were analysed. In ten of 16 (62.5%) ZES patients, a locally scattered, mixed image of diffuse, linear and micronodular mild hyperplasia was present. In addition, two of these patients (13%) showed small (max 1.5 mm in size) intramucosal ECL tumours. Neither ECL changes, nor tumours were found in MEN1 patients without ZES (n = 22). In MEN1/ZES patients, the median serum gastrin level was significantly elevated compared to MEN1 patients without ZES (206 pg/ml vs. 30.5 pg/ml, p < .001). A subgroup analysis of the serum gastrin and chromogranin A levels of MEN1/ZES patients with or without ECL hyperplasia did not show significant differences (gastrin level: p = .302, chromogranin A: p = .464).. Enterochromaffin-like cell hyperplasia and gastric carcinoids occur only in MEN1 patients with ZES, but less frequently than reported.

Topics: Carcinoid Tumor; Enterochromaffin-like Cells; Gastrins; Humans; Multiple Endocrine Neoplasia Type 1; Stomach Neoplasms; Zollinger-Ellison Syndrome

Gastric carcinoids are slow growing neuroendocrine tumours arising from enterochromaffin-like (ECL) cells in the corpus of stomach. Although most of these tumours arise in the setting of gastric atrophy and hypergastrinemia, it is not understood what genetic background predisposes development of these ECL derived tumours. Moreover, diffuse microcarcinoids in the mucosa can lead to a field effect and limit successful endoscopic removal.. To define the genetic background that creates a permissive environment for gastric carcinoids using transgenic mouse lines.. The multiple endocrine neoplasia 1 gene locus (Men1) was deleted using Cre recombinase expressed from the Villin promoter (Villin-Cre) and was placed on a somatostatin null genetic background. These transgenic mice received omeprazole-laced chow for 6 months. The direct effect of gastrin and the gastrin receptor antagonist YM022 on expression and phosphorylation of the cyclin inhibitor p27. The combination of conditional Men1 deletion in the absence of somatostatin led to the development of gastric carcinoids within 2 years. Suppression of acid secretion by omeprazole accelerated the timeline of carcinoid development to 6 months in the absence of significant parietal cell atrophy. Carcinoids were associated with hypergastrinemia, and correlated with increased Cckbr expression and nuclear export of p27. Gastric carcinoids require threshold levels of hypergastrinemia, which modulates p27

Topics: Adenocarcinoma; Adult; Animals; Benzodiazepines; Carcinogenesis; Carcinoid Tumor; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p27; Female; Gastrins; Gene Deletion; Hormone Antagonists; Hormones; Humans; Male; Mice; Mice, Transgenic; Omeprazole; Phosphorylation; Proto-Oncogene Proteins; Proton Pump Inhibitors; Receptor, Cholecystokinin B; RNA, Messenger; Signal Transduction; Somatostatin; Stomach Neoplasms

Topics: Aged; Biopsy, Fine-Needle; Carcinoid Tumor; Chromogranins; Duodenal Neoplasms; Duodenoscopy; Duodenum; Endosonography; Gastrinoma; Gastrins; Humans; Immunohistochemistry; Male; Stomach Neoplasms; Synaptophysin

To review the presentation, treatment and outcome of patients with type 1 gastric carcinoid tumours.. We retrospectively reviewed medical records and re-evaluated histopathological specimens of 26 patients with type 1 gastric carcinoids treated at a single tertiary referral centre from 1993 to 2013, with median time of follow-up 52.5 months (IQR 90.8).. Seven patients (27%) had single tumours and 19 patients (73%) multiple tumours at the time of diagnosis. The median number of tumours and median diameter of largest tumour were 2.5 (IQR 3.2) and 6.0 mm (IQR 9.5) respectively. Median serum gastrin was 321.0 pmol/l (IQR 604.0) and median serum chromogranin A 7.7 nmol/l (IQR 5.3). Three patients had metastatic disease at the time of diagnosis and two developed metastases during follow-up. Patients with metastatic disease had larger primary tumours than the others (20.0 mm (IQR 28.5) vs. 5.0 mm (IQR 5.5), p = 0.04). There was a positive correlation between age and tumour size (r = 0.44, p = 0.03) and between serum chromogranin A and serum gastrin at diagnosis (r = 0.76, p = 0.001). Patients were either treated with surgery (n = 8 (31%)), a long-acting somatostatin analogue and/or gastrin receptor antagonist (n = 10 (39%)) for a period of time, or were observed without treatment (n = 8 (31%) with close endoscopic follow up.. Although gastric carcinoids have an overall good prognosis, a significant proportion develops metastatic disease. As partial and total gastrectomy is associated with major side effects, treatment with long-acting a somatostatin analogue or gastrin antagonist should be considered.

Topics: Aged; Antineoplastic Agents, Hormonal; Carcinoid Tumor; Chromogranin A; Comorbidity; Enterochromaffin-like Cells; Female; Follow-Up Studies; Gastrectomy; Gastric Mucosa; Gastrins; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Norway; Octreotide; Receptor, Cholecystokinin B; Retrospective Studies; Somatostatin; Stomach Neoplasms; Tertiary Care Centers; Tomography, X-Ray Computed; Treatment Outcome

Optimal management and treatment of type-1 gastric carcinoids is under debate.. This prospective study evaluates the outcome of patients with recurrent type-1 gastric carcinoids treated with somatostatin analogues.. From 2000 to 2013, among a population of 107 chronic atrophic gastritis patients, 25 (20% males, median age 62 years) developed type-1 gastric carcinoids and underwent regular clinical and endoscopic follow-up (median 77 months, range 6-165) after the initial treatment. Those patients showing recurrent disease were treated with somatostatin analogues until carcinoid disappearance.. 12/25 patients (33% males, median age 65 years) showed recurrent gastric carcinoids and were treated with somatostatin analogues for a median duration of 12 months. Median gastrin and chromogranin A levels, which were 802 pg/mL and 33 U/L, respectively, decreased to 299 pg/mL (p=0.002) and 15.6 U/L (p=0.001) at the end of the treatment. Gastric carcinoids disappeared after a median length of treatment of 12 months. After a median time of 19.5 months from somatostatin analogues discontinuation, 4/12 patients (25% males, median age 56 years) showed a further recurrence. A new cycle of treatment was performed successfully.. This study confirms that type-1 gastric carcinoids are a recurring disease and somatostatin analogues, administered on 12-month cycles, represent an effective treatment.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Autoimmune Diseases; Carcinoid Tumor; Chromogranin A; Cohort Studies; Female; Gastrins; Gastritis, Atrophic; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Octreotide; Peptides, Cyclic; Prospective Studies; Somatostatin; Stomach Neoplasms; Treatment Outcome

To describe disease characteristics and treatment modalities in a group of rare patients with metastatic gastric carcinoid type 1 (GCA1).. Information on clinical, biochemical, radiological, histopathological findings, the extent of the disease, as well as the use of different therapeutic modalities and the long-term outcome were recorded. Patients' data were assessed at presentation, and thereafter at 6 to 12 monthly intervals both clinically and biochemically, but also endoscopically and histopathologically. Patients were evaluated for the presence of specific symptoms; the presence of autoimmune disorders and the presence of other gastrointestinal malignancies in other family members were also recorded. The evaluation of response to treatment was defined using established WHO criteria.. We studied twenty consecutive patients with a mean age of 55.1 years. The mean follow-up period was 83 mo. Twelve patients had regional lymph node metastases and 8 patients had liver metastases. The primary tumor mean diameter was 20.13 ± 10.83 mm (mean ± SD). The mean Ki-67 index was 6.8% ± 11.2%. All but one patient underwent endoscopic or surgical excision of the tumor. The disease was stable in all but 3 patients who had progressive liver disease. All patients remained alive during the follow-up period.. Metastatic GCA1 carries a good overall prognosis, being related to a tumor size of ≥ 1 cm, an elevated Ki-67 index and high serum gastrin levels.

Topics: Adult; Aged; Carcinoid Tumor; Chemotherapy, Adjuvant; Disease Progression; Europe; Female; Gastrectomy; Gastric Bypass; Gastrins; Gastroscopy; Humans; Israel; Ki-67 Antigen; Liver Neoplasms; Lymph Node Excision; Lymphatic Metastasis; Male; Middle Aged; Multimodal Imaging; Positron-Emission Tomography; Retrospective Studies; Stomach Neoplasms; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Tumor Burden

Multiple Endocrine Neoplasia type 1 syndrome (MEN1) is characterized by the presence of tumors in parathyroid glands, anterior pituitary gland, endocrine pancreas and duodenum. However, other tumors may also occur. One of them is the carcinoid tumor, which in this context, is more common in the gastrointestinal tract. Less common is the presence of carcinoid tumors of bronchial origin, which with histologic confirmation, may occur in 5-8% of cases and that appears more frequently in patients with hypergastrinemia. We report a patient with MEN1 syndrome, hypergastrinemia and an incidental finding in a somatostatin receptor scintigraphy of an unsuspected bronchial carcinoid tumor that was confirmed histologically.

Topics: Adult; Bronchial Neoplasms; Carcinoid Tumor; Gastrins; Humans; Incidental Findings; Male; Multiple Endocrine Neoplasia Type 1; Neoplasms, Multiple Primary; Radionuclide Imaging; Receptors, Somatostatin

To study the clinical presentation, diagnostic approach, response to treatment, and the presence of other pathologies in patients with gastric carcinoid type 1 (GC 1) tumors.. Retrospective analysis of 111 patients from four institutions and a mean follow-up of 76 months.. The main indications for gastroscopy were upper gastrointestinal tract symptoms. The mean number of lesions, maximum tumoral diameter, and percentage of cells expressing Ki-67 labeling index were 3.6±3.8, 8±12.1 mm and 1.9±2.4% respectively. Serum gastrin and chromogranin A (CgA) levels were elevated in 100/101 and 85/90 patients respectively. Conventional imaging studies demonstrated pathology in 9/111 patients. Scintigraphy with radiolabeled octreotide was positive in 6/60 without revealing any additional lesions. From the 59 patients who had been followed-up without any intervention, five developed tumor progression. Thirty-two patients were treated with long-acting somatostatin analogs (SSAs), leading to a significant reduction of gastrin and CgA levels, number of visible tumors, and CgA immune-reactive tumor cells in 28, 19, 27, and 23 treated patients respectively. Antrectomy and/or gastrectomy were initially performed in 20 patients and a complete response was achieved in 13 patients. The most common comorbidities were vitamin B12 deficiency, thyroiditis, and parathyroid adenomas.. Most GCs1 are grade 1 (82.7%) tumors presenting with stage I (73.9%) disease with no mortality after prolonged follow-up. Ocreoscan did not provide further information compared with conventional imaging techniques. Treatment with SSAs proved to be effective for the duration of administration.

Topics: Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Carcinoid Tumor; Chromogranin A; Female; Follow-Up Studies; Gastrins; Humans; Male; Octreotide; Prognosis; Retrospective Studies; Stomach Neoplasms; Treatment Outcome

Autophagy has dual roles in tumorigenesis: tumor-promoting or tumor-suppressing. The aim of the present study was to examine autophagy-related markers by immunohistochemistry in gastric carcinoids and adenocarcinomas in rodent models and patients.. Gastric carcinoids in Mastomys were induced by loxtidine treatment. Spontaneously developed gastric adenocarcinomas in Japanese cotton rats and INS-GAS transgenic mice were included. Patient tissue samples of gastric carcinoids or adenocarcinomas were collected. Immunohistochemistry was performed against autophagy-related gene protein-6 (ATG-6, also called beclin-1), ATG-5 and ATG-16.. In tumor-free Mastomys, ATG-5, ATG-16 and beclin-1 were immunepositive in the gastric mucosa. In tumor-bearing Mastomys, ATG-5 and ATG-16 were negative in the tumors, whereas beclin-1 was positive in four of five animals. In carcinoid patients, ATG-5 was negative in six of ten, ATG-16 negative in nine of ten, and beclin-1 negative in three of ten patients. In cotton rats, ATG-5 and ATG-16 were negative in all tumors. Beclin-1 was negative in three of five rats. In INS-GAS mice, ATG-5 and beclin-1 were positive in the tumor area, but the numbers of immunopositive cells per gland were reduced by about 50% in comparison with wild-type mice. In adenocarcinoma patients, ATG-5 and ATG-16 were negative in eight of ten, and beclin-1 positive in all ten patients.. An impaired autophagy took place at the stage of formation of ATG-5-ATG-12-ATG-16 complex in both gastric carcinoids and adenocarcinoma of both rodent models and patients. ATG-5 and ATG-16 might be better markers than beclin-1 in assessing autophagy in these lesions.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Animals; Apoptosis Regulatory Proteins; Autophagy; Autophagy-Related Protein 5; Beclin-1; Biomarkers, Tumor; Carcinoid Tumor; Female; Gastric Mucosa; Gastrins; Humans; Immunohistochemistry; Insulin; Male; Membrane Proteins; Mice; Mice, Transgenic; Microtubule-Associated Proteins; Middle Aged; Murinae; Promoter Regions, Genetic; Sigmodontinae; Stomach Neoplasms; Triazoles

We show that the gastric hormone gastrin induces the expression of the prosurvival secretory clusterin (sCLU) in rat adenocarcinoma cells. Clusterin mRNA was still upregulated in the presence of the protein synthesis inhibitor cycloheximide, although at a lower level. This indicates that gastrin induces clusterin transcription independently of de novo protein synthesis but requires de novo protein synthesis of signal transduction pathway components to achieve maximal expression level. Luciferase reporter assay indicates that the AP-1 transcription factor complex is involved in gastrin-mediated activation of the clusterin promoter. Gastrin-induced clusterin expression and subsequent secretion is dependent on sustained treatment, because removal of gastrin after 1-2 h abolished the response. Neutralization of secreted clusterin by a specific antibody abolished the antiapoptotic effect of gastrin on serum starvation-induced apoptosis, suggesting that extracellular clusterin is involved in gastrin-mediated inhibition of apoptosis. The clusterin response to gastrin was validated in vivo in hypergastrinemic rats, showing increased clusterin expression in the oxyntic mucosa, as well as higher levels of clusterin in plasma. In normal rat oxyntic mucosa, clusterin protein was strongly expressed in chromogranin A-immunoreactive neuroendocrine cells, of which the main cell type was the histidine decarboxylase-immunoreactive enterochromaffin-like (ECL) cell. The association of clusterin with neuroendocrine differentiation was further confirmed in human gastric ECL carcinoids. Interestingly, in hypergastrinemic rats, clusterin-immunoreactive cells formed distinct groups of diverse cells at the base of many glands. Our results suggest that clusterin may contribute to gastrin's growth-promoting effect on the oxyntic mucosa.

Topics: Adenocarcinoma; Animals; Apoptosis; Carcinoid Tumor; Cell Line, Tumor; Chromogranin A; Clusterin; Enterochromaffin Cells; Female; Gastrins; Histidine Decarboxylase; Humans; Neuroendocrine Cells; Pancreatic Neoplasms; Parietal Cells, Gastric; Promoter Regions, Genetic; Rats; Rats, Sprague-Dawley; Stomach Neoplasms; Transcription Factor AP-1; Up-Regulation

Autoimmune gastritis (AIG) may predispose to gastric carcinoid tumors or adenocarcinomas and may also cause unexplained iron and/or vitamin B(12) deficiency. The aims of this study were to explore clinical manifestations, endoscopic findings and laboratory features of patients with AIG.. 109 patients with AIG were enrolled into the study. In addition to demographic and clinical data, gastric lesions, serum gastrin, vitamin B(12), antiparietal cell antibody (APA), current Helicobacter pylori status, and anti-H. pylori IgG were also investigated.. The mean age of the patients was 53.06 ± 12.7 years (range 24-81; 72 (66.1%) women). The most common main presenting symptom was abdominal symptoms in 51 patients, consultation for iron and/or vitamin B(12) deficiency in 36, and non-specific symptoms including intermittent diarrhea in 15 patients. Endoscopic lesions were detected in 17 patients, hyperplastic polyps in 8, gastric carcinoid tumor in 4, fundic gland polyps in 3, and adenomatous polyps in 2 patients. H. pylori was negative in all patients in biopsy specimens; however, anti-H. pylori IgG was positive in 30 (27.5%) patients. 91 patients (83.4%) were positive for APA.. In patients with AIG, the main symptoms prompted for clinical investigation were: abdominal symptoms, iron/B(12) deficiency and non-specific symptoms. 20% of patients with AIG had various gastric lesions including type I gastric carcinoids. None of the patients were positive for H. pylori by means of invasive tests; however, anti-H. pylori IgG was found in 27.5% of patients. Patients referring with non-specific abdominal symptoms such as bloating, diarrhea and iron/B(12) deficiency should be investigated for the presence of AIG.

Topics: Adenomatous Polyps; Adult; Age Factors; Aged; Aged, 80 and over; Antibodies, Bacterial; Autoimmune Diseases; Carcinoid Tumor; Diarrhea; Female; Gastrins; Gastritis; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Immunoglobulin G; Iron; Iron Deficiencies; Male; Middle Aged; Parietal Cells, Gastric; Polyps; Sex Factors; Stomach Neoplasms; Vitamin B 12 Deficiency; Young Adult

Gastric neuroendocrine neoplasms of the stomach can be divided into the usually well-differentiated, hypergastrinemia-dependent type I and II lesions and the more aggressively behaving gastrin-independent type III lesions. Mainly due to better diagnostics and awareness of this tumor, the observed incidence has increased more than tenfold over the last 30 years. Small (<15-20 mm) localized type I and II lesions that are slowly proliferating (Ki67<2%) can usually be managed conservatively with endoscopic surveillance. Reducing hypergastrinemia by surgical removal of an underlying gastrinoma is important in inhibiting growth and induce reduction of type II lesions, while the specific gastrin receptor antagonist YF476 or gastrin antibodies may become useful for both type I and II lesions. Infiltrating and metastasized tumors and type III lesions require a more aggressive approach with surgical resection and consideration of modalities such as somatostatin analogs, cytotoxics, and peptide receptor targeted treatment.

Topics: Carcinoid Tumor; Gastrinoma; Gastrins; Humans; Neuroendocrine Tumors; Stomach Neoplasms

Gastric carcinoids type 1 (GC1) are neuroendocrine tumors (NETs) arising from the enterochromaffin-like (ECL) cells in patients with chronic atrophic gastritis (CAG). The treatment of GC1 has been endoscopic polypectomy or surgical tumor excision and antrectomy. One year treatment with somatostatin analogs (SSAs) diminished tumor load and ECL cell density. The effect persisted 1 year after treatment was discontinued. However, the optimal SSA dose and treatment duration are unknown.. The aim of the present work was to study macroscopic and histopathological changes in the stomach and serum markers gastrin and chromogranin A (CgA) in GC1 patients 5 years after 1 year of octreotide long-acting release (LAR) treatment.. Five patients with GC1 were included 5 years after the initial year of octreotide LAR treatment. All patients underwent upper gastrointestinal endoscopy including tumor and mucosal biopsies from oxyntic mucosa, chest and abdominal computer tomography and octreotide scintigraphy. Fasting serum gastrin and CgA were also measured.. At 5 years, one patient had a highly malignant gastric tumor, one patient had an increased number of GCs, regional and distant metastases and three patients had an increased number of GCs. Serum gastrin and CgA increased to pre-treatment levels after 1 year of follow-up and were unchanged at the 5-year follow-up.. The disease had progressed in all five GCs patients treated with octreotide for 12 months at 5 years of follow-up. This suggests that, if started, octreotide treatment should not be discontinued in these patients.

Topics: Aged; Antineoplastic Agents, Hormonal; Biopsy; Carcinoid Tumor; Chromogranin A; Disease Progression; Enterochromaffin-like Cells; Female; Follow-Up Studies; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Male; Middle Aged; Octreotide; Stomach Neoplasms; Tomography, X-Ray Computed; Tumor Burden

Gastric type I carcinoid is a rare neoplasm, deriving from enterochromaffin-like cells (ECL), mainly affecting women with autoimmune gastritis. The approach to treatment, either endoscopic, medical or surgical, is not well defined, particularly in multifocal tumours or carcinoids with rapid growth/frequent recurrence.. To determine whether an anti-G17 vaccination might interfere on the natural history of gastric type I carcinoid.. Padua teaching Hospital, outpatient clinic.. Three patients with type I gastric carcinoid in autoimmune gastritis were administered, after informed consent and ethic committee approval, with a vaccine against gastrin 17 (G17), a synthetic peptide that stimulates specific and high-affinity anti-G17 antibodies, and followed up endoscopically and clinically for a mean of 36 months.. Gastric histology and specifically carcinoid growth/recurrence and trend in time in gastrin, G17, pepsinogens, chromogranin A and clinical parameters.. Following vaccination, carcinoid regression was observed in 2/3 patients and, in one of the patients, even the disappearance of ECL hyperplasia, with a reduced ECL cells stimulation, confirmed by a significant reduction in chromogranin A levels. Regression was observed in the two patients that showed a more clear local response to the vaccine. Increased autoantibody titre was observed, but no appearance of new autoimmune diseases.. Anti-G17 vaccination induced regression of type I gastric carcinoid and could be considered for the treatment of this tumour, when endoscopic removal is not indicated.

Topics: Aged; Cancer Vaccines; Carcinoid Tumor; Female; Gastrins; Gastritis, Atrophic; Humans; Immunoenzyme Techniques; Male; Pilot Projects; Prognosis; Stomach Neoplasms; Survival Rate; Tumor Microenvironment; Vaccination

Topics: Carcinoid Tumor; Female; Gastrins; Humans; Middle Aged; Prognosis; Stomach Neoplasms

Carcinoid tumors are the most common neuroendocrine tumors. Gastric carcinoids represent 2% of all carcinoids and 1% of all gastric masses. Due to the widespread use of Esophagogastroduodenoscopy for evaluating a variety of upper gastrointestinal symptoms, the detection of early gastric carcinoids has increased. We highlight an alternative management of a young patient with recurrent type 1 gastric carcinoids with greater than 5 lesions, as well as lesions intermittently greater than 1 cm. Gastric carcinoids have a variable presentation and clinical course that is highly dependent on type. Type 1 gastric carcinoids are usually indolent and have a metastasis rate of less than 2%, even with tumors larger than 2 cm. There are a number of experts as well as organizations that recommend endoscopic resection for all type 1 gastric carcinoid lesions less than 1 cm, with a follow-up every 6-12 mo. They also recommend antrectomy for type 1 gastric carcinoids with greater than 5 lesions, lesions 1 cm or greater, or refractory anemia. However, the American Society of Gastrointestinal Endoscopy guidelines state that type 1 gastric carcinoid surveillance is controversial based on the evidence and could not make an evidence-based position statement on the best treatment modality. Our report illustrates a rare cause of iron deficiency anemia in a young male (without any medical history) due to multiple recurrent gastric carcinoid type 1 lesions in the setting of atrophic gastritis causing hypergastrinemia, and in the absence of a vitamin B12 deficiency. Gastric carcinoid type 1 can present in young males without an autoimmune history, despite the known predilection for women aged 50 to 70 years. Type 1 gastric carcinoids can be managed by endoscopic resection in patients with greater than 5 lesions, even with lesions larger than 1 cm. This course of treatment enabled the avoidance of early antrectomy in our patient, who expressed a preference against more invasive measures at his young age.

Topics: Adult; Anemia, Iron-Deficiency; Carcinoid Tumor; Endoscopy, Gastrointestinal; Female; Gastrectomy; Gastrins; Humans; India; Male; Neoplasm Recurrence, Local; Stomach Neoplasms

There are limited data on response and long-term follow-up of octreotide therapy in type-I gastric neuroendocrine tumors. The objective of the present study was to assess the response of type-I gastric neuroendocrine tumors to octreotide-long acting, repeatable (LAR) therapy and evaluate long-term follow up of such patients after therapy.. Three patients with documented type-I gastric neuroendocrine tumors from a tertiary gastroenterology centre were studied. Octreotide-LAR therapy 20 mg intramuscularly every 28 days was administered for one year. Serum gastrin and chromogranin levels, gastroscopies and biopsies from tumor nodules at 6 months and one year on therapy and every 6 months after completion of drug therapy were taken. Follow-up after completion of therapy extended for 3 years in two and 2.5 years in one patient.. During octreotide therapy there was normalization of serum gastrin levels and serum chromogranin levels. Tumors in all three patients had regressed at 6 months of treatment. Following cessation of therapy, there was progressive rise of serum gastrin to pre-treatment levels. Serum chromogranin levels remained within normal limits. Gastroscopic and histologic examination of gastric biopsies did not reveal recurrence of tumors in any patients. All patients tolerated therapy well and became asymptomatic soon after drug therapy.. Octreotide-LAR therapy causes regression of type-I gastric neuroendocrine tumors. After completion of drug therapy there was no recurrence of tumors even with continued hypergastrinemia. Octreotide therapy should be considered as one of the treatment options in such patients.

Topics: Adult; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Carcinoid Tumor; Chromogranins; Female; Follow-Up Studies; Gastrins; Humans; Injections, Intramuscular; Male; Middle Aged; Octreotide; Stomach Neoplasms; Treatment Outcome

We report the case of a patient demonstrating multiple gastric carcinoids with hypergastrinemia. A 50-year-old Japanese woman was admitted to our hospital for the further examination of multiple carcinoids of the stomach with hypergastrinemia, although she was asymptomatic. However, based on our clinical examination, this case seemed to be neither type I nor II carcinoid. We performed a total gastrectomy with D1 lymph node dissection. A pathological examination showed numerous endocrine micronests, hyperplasia of the parietal cells extending to the foveolar neck region, and numerous dilated oxyntic glands filled with eosinophilic secretions. Many parietal cells exhibited vacuolated cytoplasms and apical snouts. Furthermore, the dilated glands at the base of the mucosa had hyperchromatic nuclei and ciliated surfaces. The postoperative serum gastrin level was soon normalized to 47 pg/ml. This is only the third reported case of multiple gastric carcinoids with hypergastrinemia due to an intrinsic abnormality in the acid secretion of the parietal cells.

Topics: Carcinoid Tumor; Female; Gastrectomy; Gastric Acid; Gastrins; Humans; Lymph Node Excision; Middle Aged; Parietal Cells, Gastric; Stomach Neoplasms

While the optimal treatment for type I gastric carcinoid tumors remains controversial, there is evidence to suggest that in multifocal disease, antrectomy may not only control local disease but also may lead to enterochromaffin-like cell (ECL) hyperplasia regression compared to medical and endoscopic treatments.. A single institution retrospective review of eight consecutive patients with multifocal type I gastric carcinoid tumor patients with no evidence of metastatic disease was performed from 2005 to 2006. All of these patients underwent laparoscopic antrectomy with Billroth II reconstruction. Patients' preoperative gastrin, chromogranin A levels, and biopsy and surgical specimen slides were compared with postoperative laboratory and biopsy slides. Pathology slides were reanalyzed by a blinded pathologist from our institution for evidence of tumor and ECL hyperplasia regression.. All patients tolerated the procedure well with no reoperations or mortalities. Six of eight patient complained of mild reflux which was treated medically. One of eight had a mild wound infection which resolved with a course of cephalexin. Gastrin levels significantly decreased (98.9%) in all patients (P = 0.001). Furthermore, chromogranin A levels also significantly decreased (81.4%). Eight of eight patients showed no evidence of carcinoid tumor after surgery at mean biopsy follow-up of 17 mo (range 2-35 mo), however there was ECL hyperplasia after resection. Four of eight patients (50%) showed regression of ECL hyperplasia on postop biopsy, while the remaining four of eight showed no evidence of regression.. This is the largest case series to investigate the surgical, clinical, and histologic outcomes of laparoscopic antrectomy in type I gastric carcinoid. Our data suggest that laparoscopic antrectomy is a safe and minimally invasive approach to treat nonmetastatic type I gastric carcinoid. All patients had no evidence of gross or microscopic disease at follow-up biopsy and almost half had regression of ECL hyperplasia at follow-up suggesting that antrectomy may be sufficient to prevent tumor recurrence. However, continued regular endoscopic surveillance and medical follow-up of patients with ECL hyperplasia are recommended.

Topics: Adult; Aged; Carcinoid Tumor; Enterochromaffin-like Cells; Female; Gastrins; Humans; Hyperplasia; Laparoscopy; Male; Middle Aged; Pyloric Antrum; Retrospective Studies; Stomach Neoplasms

Carcinoid is a rare gastrointestinal tumor, with an incidence varying from 1 to 2.5 per 100,000 in the general population. In this article, we report an elevated incidence of carcinoid tumor in an obese population, showing the importance of performing an endoscopic procedure before bariatric surgery.

Topics: Adult; Bariatric Surgery; Carcinoid Tumor; Duodenal Neoplasms; Endoscopy, Digestive System; Female; Gastrectomy; Gastrins; Hepatectomy; Humans; Hysterectomy; Incidental Findings; Liver Neoplasms; Male; Middle Aged; Obesity, Morbid; Preoperative Care; Stomach Neoplasms; Uterine Neoplasms; White People

We have previously demonstrated that gastric and intestinal endocrine cell (End-cell) marker expression is important for assessment of the histogenesis of endocrine cell tumors. However, the End-cell phenotypes of carcinoid tumors in the rectum remain largely unclear. We therefore examined marker expression of rectal carcinoid tumors. We evaluated 20 rectal carcinoid tumors (as well as 8 from the stomach for comparison) phenotypically, using gastrin, gastric inhibitory polypeptide (GIP) and glucagons-like peptide-1 (GLP-1) as End-cell markers. Rectal carcinoid tumors were divided into 3 endocrine-gastric (e-G), 16 endocrine-gastric-and-intestinal mixed (e-GI), 1 endocrine-intestinal (e-I), and 0 endocrine-null (e-N) types, thus 19 (e-G+ e-GI types, 95%) had gastric phenotypic expression, while 17 (e-GI+ e-I types, 85%) harbored intestinal elements. Stomach carcinoid tumors were classified as 6 e-G and 2 e-N types, respectively. In conclusion, most rectal carcinoid tumors exhibited the e-GI type, suggesting the importance of gastric End-cell marker expression for histogenesis of the rectal carcinoid tumors. Further studies of pathological and biological analyses are needed to clarify the histogenesis of the carcinoid tumors.

Topics: Animals; Biomarkers, Tumor; Carcinoid Tumor; Endocrine Cells; Female; Gastric Inhibitory Polypeptide; Gastrins; Glucagon-Like Peptide 1; Humans; Immunohistochemistry; Male; Middle Aged; Phenotype; Rectal Neoplasms

Gastric carcinoid tumors are rare but increasing in incidence. Current recommendations suggest endoscopic resection for type I carcinoids found in the stomach, however reports of incomplete resection have led to difficulty planning future management. Our purpose was to describe the application of the endoscopic multi-band mucosectomy (MBM) device to achieve en-bloc resection of multiple gastric carcinoid tumors.. Over a 30-month period (June 2006-January 2009) eight patients attending for endoscopic assessment of gastric carcinoid tumors were identified at two tertiary referral centers. Patients underwent endoscopic resection of the carcinoids with an MBM device. En-bloc specimens underwent histological evaluation for identification and tumor resection margins. Patients with type I carcinoids were subsequently enrolled in an endoscopic follow-up program.. A total of 34 gastric carcinoid tumors were removed from eight patients. On histological analyses seven out of eight patients were diagnosed with type I tumors. In the remaining patient a single, sporadic (type III) gastric carcinoid was diagnosed. No complications of severe bleeding or perforation occurred. All specimens were shown to have clear deep and peripheral histological resection margins.. Complete 'en-bloc' endoscopic resection of multiple 'type I' gastric carcinoid tumors can be safely and easily performed with an MBM technique.

Topics: Adult; Aged; Australia; Biomarkers; Biopsy; Carcinoid Tumor; Female; Gastric Mucosa; Gastrins; Gastroscopy; Humans; Male; Middle Aged; Neoplasms, Multiple Primary; Stomach Neoplasms; Treatment Outcome; Vitamin B 12

We describe a 30-year-old man in whom upper endoscopy revealed multiple gastric carcinoids. The peripheral blood gastrin level was 2400 ng/ml (normal range, <200 ng/ml). Mucosal biopsy of the gastric body and fundus showed no atrophy; typical type A chronic atrophic gastritis was thus unlikely. Neither abdominal computed tomography nor selective angiography showed any evidence of tumor in the pancreas or at its periphery. However, the possibility of microgastrinoma could not be ruled out. We performed radioguided surgery with a somatostatin analog, diethylenetriamine pentaacetic acid-D-Phe1-octreotide labeled with (111)In (Octreo Scan). The location of the carcinoids was confirmed. Gastrinoma was ruled out. Total gastrectomy was performed, and the gastrin level decreased to the normal range. Macroscopically, 20 carcinoid tumors, measuring 30 mm in maximum diameter, were confirmed. Microscopic examination showed large numbers of endocrine cell micronests. Hyperplasia of parietal cells was observed, suggesting early-stage type A chronic atrophic gastritis. The antrum contained increased numbers of gastrin-positive cells, which probably caused the preoperative hypergastrinemia.

Topics: Adult; Carcinoid Tumor; Gastrectomy; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Male; Parietal Cells, Gastric; Radiopharmaceuticals; Somatostatin; Stomach Neoplasms; Surgery, Computer-Assisted

Elevated serum concentrations of the hormone gastrin are associated with the development of gastric carcinoid tumors, but the mechanisms of tumor development are not fully understood. We hypothesized that the antiapoptotic effects of gastrin may be implicated and have therefore investigated the role of antiapoptotic members of the bcl-2 family of proteins. AGS-G(R) human gastric carcinoma cells stably transfected with the CCK-2 receptor were used to assess changes in the expression of bcl-2 family members following gastrin treatment and the function of mcl-1 during apoptosis was investigated by use of small-interfering RNA (siRNA). Treatment of AGS-G(R) cells with 10 nM gastrin for 6 h caused maximally increased mcl-1 protein abundance. Gastrin-induced mcl-1 expression was inhibited by the transcription inhibitor actinomycin D and by the protein synthesis inhibitor cycloheximide. Downstream signaling of mcl-1 expression occurred via the CCK-2 receptor, protein kinase C, and MAP kinase pathways, but not via PI 3-kinase. Transfection with mcl-1 siRNA significantly suppressed mcl-1 protein expression and abolished the antiapoptotic effects of gastrin on serum starvation-induced apoptosis. Mcl-1 protein expression was also specifically increased in the type I enterochromaffin-like cell carcinoid tumors of 10 patients with autoimmune atrophic gastritis and hypergastrinemia. Gastrin therefore signals via the CCK-2 receptor, protein kinase C, and MAP kinase to induce expression of antiapoptotic mcl-1 in AGS-G(R) cells, and mcl-1 expression is also increased in human hypergastrinemia-associated type I gastric carcinoid tumors. Gastrin-induced mcl-1 expression may therefore be an important mechanism contributing toward type I gastric carcinoid development.

Topics: Adult; Aged; Aged, 80 and over; Blotting, Western; Carcinoid Tumor; Cell Line, Tumor; Female; Gastrins; Humans; Immunohistochemistry; Male; Middle Aged; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; Receptor, Cholecystokinin B; Stomach Neoplasms

Gastrointestinal stromal tumor is the most common mesenchymal tumor in the gastrointestinal tract. It may coexist with other type of cancers, and if so, the tumors usually involve the stomach. The most common associated cancers are gastrointestinal carcinomas. We report a 65-year-old woman with a history of gastric gastrointestinal stromal tumor who had undergone subtotal segmental gastrectomy. New polypoid lesions were detected on a follow-up gastroscopy one year later. The lesions were biopsied and found to be carcinoid tumors. There was serum hypergastrinemia, and type 1 gastric carcinoid tumor was diagnosed. A total gastrectomy was performed. Pathologic examination revealed both carcinoid tumors and a recurrent gastrointestinal stromal tumor.

Topics: Aged; Biopsy; Carcinoid Tumor; Female; Gastrectomy; Gastrins; Gastrointestinal Stromal Tumors; Gastroscopy; Humans; Lymph Node Excision; Lymphatic Metastasis; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Reoperation; Stomach Neoplasms; Up-Regulation

Topics: Adult; Biopsy; Carcinoid Tumor; Chronic Disease; Female; Follow-Up Studies; Gastrectomy; Gastrins; Gastritis, Atrophic; Humans; Lymph Node Excision; Neoplasms, Multiple Primary; Radiography, Abdominal; Stomach; Stomach Neoplasms; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

Topics: Carcinoid Tumor; Female; Gastrins; Gastritis, Atrophic; Humans; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Remission Induction; Stomach; Stomach Neoplasms

Multiple endocrine neoplasia type 1 (MEN1) patients frequently develop Zollinger-Ellison syndrome (ZES). These patients can develop proliferative changes of gastric enterochromaffin-like (ECL) cells and gastric carcinoids (ECL-cell tumors). ECL-cell changes have been extensively studied in sporadic ZES patients and can be precursor lesions of gastric carcinoids, but little is known about factors influencing their severity or development of carcinoids in MEN1/ZES patients.. Our objective was to prospectively analyze ECL-cell changes and gastric carcinoids (ECL-cell tumors) in a large series of MEN1/ZES patients to detect risk factors and deduct clinical guidelines.. Fifty-seven consecutive MEN1/ZES patients participated in this prospective study at two tertiary-care research centers.. Assessment of MEN1, gastric hypersecretion, and gastroscopy with multiple biopsies was done according to a fixed protocol and tumor status. ECL-cell changes and alpha-human chorionic gonadotropin staining were assessed in each biopsy and correlated with clinical, laboratory, and MEN1 features.. ECL-cell proliferative changes were universally present, advanced changes in 53% and carcinoids in 23%. Gastric nodules are common and are frequently associated with carcinoids. Patients with high fasting serum gastrin levels, long disease duration, or a strong alpha-human chorionic gonadotropin staining in a biopsy are at higher risk for an advanced ECL-cell lesion and/or gastric carcinoid.. Gastric carcinoids and/or advanced ECL-cell changes are frequent in MEN1/ZES patients, and therefore, regular surveillance gastroscopy with multiple routine biopsies and biopsies of all mucosal lesions are essential. Clinical/laboratory data and biopsy results can be used to identify a subgroup of MEN1/ZES patients with a significantly increased risk for developing gastric carcinoids, allowing development of better surveillance strategies.

Topics: Adolescent; Adult; Aged; Carcinoid Tumor; Enterochromaffin-like Cells; Female; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Prospective Studies; Risk Factors; Stomach Neoplasms; Zollinger-Ellison Syndrome

Gastric endocrine tumors associated with autoimmune chronic atrophic gastritis (gastric carcinoid type I) are almost exclusively benign lesions with little risk of deep invasion of the gastric parietal wall. For this reason, the role of octreotide in the treatment of these neoplastic lesions is controversial. Nine patients with more than five type I gastric endocrine tumors each <1 cm in size, without invasion of the muscularis propria and with Ki-67 index lower than 3%, were treated with long-acting somatostatin analogs for 12 months. After 6 months and again after 12 months, all the patients underwent upper gastrointestinal (GI) endoscopy with multiple biopsies. The plasma chromogranin A (CgA) levels and the gastrin levels in the serum were also determined. In all patients, the gastric neoplastic lesions disappeared after 12 months of somatostatin analog therapy. We also observed a significant reduction of CgA and gastrin levels at 6 and at 12 months of therapy as compared with the baseline values. We demonstrate that somatostatin analog treatment provokes the pathological regression of type I gastric carcinoids. This therapeutic approach should be considered as a valid option in selected patients with multiple type I gastric endocrine tumors.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Carcinoid Tumor; Chromogranin A; Chronic Disease; Endosonography; Female; Gastrins; Gastritis, Atrophic; Humans; Immunoenzyme Techniques; Male; Middle Aged; Octreotide; Parietal Cells, Gastric; Stomach Neoplasms; Treatment Outcome

Chronic hypergastrinemia is associated with enterochromaffin-like (ECL) cell hyperplasia, which may progress to gastric carcinoid tumors. The latter consists of epithelial cells and stroma, and both compartments usually regress after normalization of hypergastrinemia. We previously showed that matrix metalloproteinase (MMP)-7 in gastric epithelial cells was upregulated by Helicobacter pylori and described MMP-7-dependent reciprocal signaling between the epithelium and a key stromal cell type, the myofibroblast. Here, we describe the regulation of gastric MMP-7 by gastrin and the potential significance for recruiting and maintaining myofibroblast populations. Biopsies of the gastric corpus and ECL cell carcinoid tumors were obtained from hypergastrinemic patients. Western blot analysis, ELISA, immunohistochemistry, and promoter-luciferase (luc) reporter assays were used to study MMP-7 expression. Gastric myofibroblasts were identified by alpha-smooth muscle actin (alpha-SMA) expression, and the effects of MMP-7 on myofibroblast proliferation were investigated. In hypergastrinemic patients, there was an increased abundance of MMP-7 and alpha-SMA in gastric corpus biopsies and ECL cell carcinoid tumors. In the latter, MMP-7 was localized to ECL cells but not stromal cells, which were nevertheless well represented. Gastrin stimulated MMP-7-luc expression in both AGS-G(R) and primary human gastric epithelial cells. Conditioned medium from gastrin-treated human gastric glands stimulated myofibroblast proliferation, which was inhibited by neutralizing antibodies to MMP-7. MMP-7 increased the proliferation of myofibroblasts via the MAPK and phosphatidylinositol 3-kinase (PI3K) pathways. In conclusion, stimulation of gastric MMP-7 by elevated plasma gastrin may activate epithelial-mesenchymal signaling pathways regulating myofibroblast function via MAPK and PI3K pathways and contribute to stromal deposition in ECL cell carcinoid tumors.

Topics: Actins; Animals; Carcinoid Tumor; Cell Line, Tumor; Cell Proliferation; Culture Media, Conditioned; Dose-Response Relationship, Drug; Enterochromaffin-like Cells; Enzyme Induction; Epithelial Cells; Fibroblasts; Gastric Mucosa; Gastrins; Humans; MAP Kinase Signaling System; Matrix Metalloproteinase 7; Mice; Mice, Inbred C57BL; Mice, Knockout; Multiple Endocrine Neoplasia Type 1; Paracrine Communication; Phosphatidylinositol 3-Kinases; Signal Transduction; Stomach; Stomach Neoplasms; Time Factors; Tissue Culture Techniques; Transcription, Genetic; Transfection

A 70-year-old man was found to have at least 12 type I gastric carcinoids and microcarcinoidosis. We performed an extended octreotide suppression test to determine if the tumors were gastrin-dependent and would likely regress after antrectomy. He was given an octreotide infusion at 12.5-25 mcg/h for 86 hr followed by depot octreotide 20 mg intramuscularly every four weeks for eight months. Fasting serum gastrin and chromogranin A levels were measured, and endoscopy with biopsies was performed before and after the infusion and at five months and eight months. Total RNA was extracted for quantitation of histidine decarboxylase mRNA using real-time PCR. Fasting serum gastrin decreased from 306 pg/ml pretreatment to 31 pg/ml at the end of infusion and 115 pg/ml at eight months. Chromogranin A decreased from four to six times the upper limit of normal to normal. Tissue histidine decarboxylase mRNA decreased 50-fold. At eight months, only a few diminutive nodules were present on endoscopy. These results demonstrated that the carcinoid tumors in this patient were under neuroendocrine control and were expected to respond to antrectomy.

Topics: Aged; Carcinoid Tumor; Gastrins; Humans; Male; Octreotide; Stomach Neoplasms

Topics: Adult; Anemia, Iron-Deficiency; Carcinoid Tumor; Gastrins; Humans; Male; Multiple Endocrine Neoplasia Type 1; Stomach Neoplasms

Topics: Anti-Ulcer Agents; Carcinoid Tumor; Gastrins; Humans; Proton Pump Inhibitors; Stomach Neoplasms

Topics: Carcinoid Tumor; Female; Gastrins; Humans; Male; Prognosis; Stomach Neoplasms

The aim of this study was to review the presentation, treatment, and outcome of patients with Type 1 gastric carcinoid tumors.. A retrospective review of 1,600 carcinoid patients was analyzed to identify patients with gastric carcinoid tumors.. Eighteen patients were found to have biopsy-confirmed Type 1 gastric carcinoid tumors on upper endoscopy. Reasons for endoscopy included abdominal pain (n = 4), gastrointestinal bleeding (n = 4), surveillance for pernicious anemia (n = 8), and other (n = 2). The mean pre-treatment serum gastrin and chromogranin A levels were 1,436 ng/ml (+/-771 ng/ml) and 91.6 ng/ml (+/-68.6 ng/ml), respectively. Imaging revealed evidence of gastric carcinoid in 4 of 10 patients undergoing CT scanning and 3 of 10 patients undergoing octreotide scintigraphy. Of the 18 patients, 8 were treated medically (acidification or octreotide) and 10 were treated with surgery (laparoscopic antrectomy or partial gastrectomy). Mean gastrin levels decreased by 37.2% in the medically treated group (median follow-up 6 months), versus 94.0% in the surgically treated patients (median follow-up 5 months). Mean chromogranin A levels decreased by 56.2% in patients undergoing surgery.. Gastric antrectomy is the most efficacious treatment for Type 1 gastric carcinoid, leading to a significant reduction in serum gastrin levels and regression of carcinoid tumors.

Topics: Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Carcinoid Tumor; Chromogranin A; Chromogranins; Enterochromaffin-like Cells; Female; Gastrectomy; Gastrins; Humans; Male; Middle Aged; Octreotide; Pyloric Antrum; Retrospective Studies; Somatostatin; Stomach Neoplasms; Treatment Outcome

Type I gastric carcinoid tumors result from hypergastrinemia in 1%-7% of patients with pernicious anemia. We diagnosed pernicious anemia in a 48-year-old female patient with complaint of fatigue for three months. She had no gastrointestinal symptoms. Endoscopic examination ot the upper gastrointestinal tract revealed atrophic gastritis and a polypoid lesion in the corpus of 3-4 mm in size. Endoscopic polypectomy was performed. Histopathological examination of the specimen revealed positive chromogranin A and synaptophysin stainings compatible with the diagnosis of a carcinoid tumor. Serum gastrin level was increased, urinary 5-hydroxyindoleacetic acid was within the normal range. There was no other symptom, sign, or laboratory finding of a carcinoid syndrome in the patient. No metastasis was found with indium-111 octreotide scan, computed tomographies of abdomen and thorax. Type I gastric carcinoid tumors are only rarely solitary and patients with tumors < 1 cm in size may benefit from endoscopic polypectomy.

Topics: Anemia, Pernicious; Carcinoid Tumor; Endoscopy; Female; Gastrins; Humans; Middle Aged; Polyps; Stomach Neoplasms

We reviewed the clinicopathologic profile of a series of recently diagnosed sporadic duodenal gastrin-cell (G-cell) tumors. All cases were discovered incidentally and had a unique clinicopathologic profile: all 18 cases were gastrin-positive tumors located in the duodenal bulb, were small in size (mean size 5.4 mm), demonstrated an insular architectural pattern, and were localized to the lamina propria and submucosa. None of the patients had Zollinger-Ellison or carcinoid syndrome. The behavior was indolent and there was no evidence of metastasis at diagnosis or during follow-up. In our sampled population, the presence of Helicobacter pylori gastritis and the use of proton pump inhibitors (PPIs) were significantly associated with the presence of G-cell tumors. Both the presence of H. pylori gastritis and use of PPI remained significant in a logistic regression model adjusted for age, race/ethnicity, and sex with P values of 0.0016 (odds ratio=10.1, 95% confidence interval: 2.3 to 42.4) and 0.008 (odds ratio=8.9, 95% confidence interval: 1.76 to 45.4), respectively. Most patients with tumors showed G-cell hyperplasia in the nontumorous regions of the duodenum. The high incidence of sporadic duodenal G-cell tumors in patients with H. pylori gastritis and long-term PPI use suggests an association that needs to be further explored. Presence of G-cell hyperplasia in the nontumorous duodenal mucosa suggests that these may originate from a proliferative phase, similar to the hyperplasia-dysplasia-neoplasia sequence seen in other endocrine tumors.

Topics: Aged; Aged, 80 and over; Anti-Ulcer Agents; Carcinoid Tumor; Duodenal Neoplasms; Duodenum; Female; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Histamine H2 Antagonists; Humans; Male; Middle Aged; Proton Pump Inhibitors

Little is known about the natural course of multiple gastric carcinoids associated with type A gastritis. Between 1993 and 2003, we enrolled eight patients, diagnosed as having multiple gastric carcinoids associated with type A gastritis, in a follow-up program without surgical resection. In these patients, endoscopy showed multiple small polyps on the gastric body, with nonantral atrophic gastritis. Histologically, biopsy specimens obtained from the polyps revealed carcinoid tumors. The serum gastrin level was found to be very high in all patients, and testing for anti-parietal cell antibody was positive in seven. The mean follow-up was 5.8 years (range, 1.5-10.8 years). The levels of serum gastrin increased in all patients, but, endoscopically, the carcinoid tumors did not change in size. Neither hepatic nor lymphatic metastasis was detected on abdominal computed tomography (CT). These patients were free of the development or metastasis of carcinoids, in spite of their continuous hypergastrinemia. It was concluded that multiple gastric carcinoids associated with type A gastritis may be indolent.

Topics: Aged; Biopsy; Carcinoid Tumor; Endoscopy, Gastrointestinal; Female; Follow-Up Studies; Gastrins; Gastritis; Humans; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Stomach Neoplasms

To analyze tumor biology and the outcome of differentiated treatment in relation to tumor subtype in patients with gastric carcinoid.. Gastric carcinoids may be subdivided into ECL cell carcinoids (type 1 associated with atrophic gastritis, type 2 associated with gastrinoma, type 3 without predisposing conditions) and miscellaneous types (type 4). The biologic behavior and prognosis vary considerably in relation to type.. A total of 65 patients from 24 hospitals (51 type 1, 1 type 2, 4 type 3, and 9 type 4) were included. Management recommendations were issued for newly diagnosed cases, that is, endoscopic or surgical treatment of type 1 and 2 carcinoids (including antrectomy to abolish hypergastrinemia) and radical resection for type 3 and 4 carcinoids.. Infiltration beyond the submucosa occurred in 9 of 51 type 1, 4 of 4 type 3, and 7 of 9 type 4 carcinoids. Metastases occurred in 4 of 51 type 1 (3 regional lymph nodes, 1 liver), the single type 2 (regional lymph nodes), 3 of 4 type 3 (all liver), and 7 of 9 type 4 carcinoids (all liver). Of the patients with type 1 carcinoid, 3 had no specific treatment, 40 were treated with endoscopic or surgical excision (in 10 cases combined with antrectomy), 7 underwent total gastrectomy, and 1 underwent proximal gastric resection. Radical tumor removal was not possible in 2 of 4 patients with type 3 and 7 of 9 patients with type 4 carcinoid. Five- and 10-year crude survival rates were 96.1% and 73.9% for type 1 (not different from the general population), but only 33.3% and 22.2% for type 4 carcinoids.. Subtyping of gastric carcinoids is helpful in the prediction of malignant potential and long-term survival and is a guide to management. Long-term survival did not differ from that of the general population regarding type 1 carcinoids but was poor regarding type 4 carcinoids.

Topics: Adult; Aged; Aged, 80 and over; Carcinoid Tumor; Cohort Studies; Female; Gastrectomy; Gastric Mucosa; Gastrins; Gastroscopy; Humans; Male; Middle Aged; Neoplasm Staging; Probability; Prognosis; Proportional Hazards Models; Prospective Studies; Risk Assessment; Stomach Neoplasms; Survival Rate; Treatment Outcome

Topics: Carcinoid Tumor; Female; Gastrins; Gastritis; Humans; Middle Aged; Multiple Endocrine Neoplasia Type 1; Proto-Oncogene Proteins; Stomach Neoplasms

Ghrelin, a recently discovered peptide isolated from the gastric corpus mucosa, is believed to be important in the regulation of growth hormone secretion and has been shown to increase appetite and food intake as well. It may also have other gastrointestinal and cardiac functions. Because a cell of origin for ghrelin has not been convincingly identified in the gastric mucosa thus far, we studied the immunohistochemical expression of ghrelin in proliferative lesions of the enterochromaffin-like (ECL) cells-a cell that is not only exclusively confined to the gastric corpus mucosa but is its dominant endocrine cell type as well. Formalin-fixed, paraffin embedded tissues from three cases of gastric ECL cell hyperplasia and five ECL carcinoids (three with coexisting foci of diffuse, linear, and micronodular hyperplasia) were immunohistochemically stained for ghrelin, using a commercially available antibody. The Sevier-Munger stain for ECL cells and immunohistochemical stains for chromogranin, gastrin, serotonin, somatostatin, and vesicular monoamine transporter-2 (VMAT-2) were performed on parallel sections for correlation with the ghrelin staining results. All ECL cell carcinoids and hyperplastic lesions were positive for both the Sevier-Munger and the immunohistochemical stains for chromogranin and VMAT-2. Immunoreactivity for ghrelin was seen in 4/5 ECL carcinoids, all cases of ECL cell hyperplasia, as well as in all areas with linear and micronodular hyperplasia adjacent to the ECL cell carcinoids. In each instance, such staining was confined to the Sevier-Munger, and VMAT-2 positive cells only. Our findings indicate that the ECL cells are either the ghrelin-producing cells of the gastric mucosa or acquire the capability to synthesize ghrelin during proliferative states encompassing the entire hyperplasia to neoplasia spectrum. In view of the orexigenic and other known actions of ghrelin, the functional and/or biologic significance of ghrelin production in such ECL cell proliferations needs to be investigated further.

Topics: Carcinoid Tumor; Chromogranins; Enterochromaffin-like Cells; Gastric Mucosa; Gastrins; Ghrelin; Humans; Hyperplasia; Immunohistochemistry; Membrane Glycoproteins; Membrane Transport Proteins; Peptide Hormones; Retrospective Studies; Serotonin; Somatostatin; Stomach Neoplasms; Vesicular Biogenic Amine Transport Proteins; Vesicular Monoamine Transport Proteins

Topics: Aged; Carcinoid Tumor; Female; Gastrins; Humans; Neoplastic Processes; Stomach Neoplasms

Hypergastrinemia in patients with pernicious anemia is a major regulator contributing to enterochromaffin-cell hyperplasia and, ultimately, to gastric carcinoids.. Between 1990 and 2003, we studied 8 women and 10 men with pernicious anemia and gastric carcinoids; their mean age was 50 years. Serum gastrin levels ranged from 740 to 4,000 pg/mL (mean 1,000 pg/mL). Six patients underwent antrectomy, four total gastrectomy, and eight endoscopic resection or biopsy. During the same period, 22 patients with Zollinger-Ellison tumors and hypergastrinemia (20 men and 2 women, mean age 49 years) had no gastric carcinoids, but 1 of 7 patients with Zollinger-Ellison and multiple endocrine neoplasia (MEN1) tumors had hypergastrinemia and gastric carcinoids.. Mean followup for pernicious anemia patients was 6 years after antrectomy and 1 to 10 years after endoscopic resection or biopsy. Tumor regression was observed in one patient after antrectomy and one patient after biopsy. There were no deaths in this group in spite of lymph node metastasis in two patients. The patient with Zollinger-Ellison and MEN1 syndrome has been followed 3 years after diagnosis and 2 years after total gastrectomy.. Gastric carcinoids are indolent tumors occurring with increasing frequency in patients with pernicious anemia. Antrectomy or biopsy and observation are preferred methods of treatment. Total gastrectomy is reserved for patients with extensive tumor involvement of the gastric wall or for emergency bleeding.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Pernicious; Biopsy; Carcinoid Tumor; Female; Gastrectomy; Gastric Mucosa; Gastrinoma; Gastrins; Gastroscopy; Humans; Hyperplasia; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Retrospective Studies; Stomach Neoplasms; Zollinger-Ellison Syndrome

We have encountered an unusual case of gastric carcinoid tumors. Gastroscopic examination of a 71-year-old male patient showed eight smooth protrusions at the greater curvature of the gastric body, some of which had central depressions. Endoscopic ultrasonography demonstrated that the largest tumor (2.6 cm in diameter) was located in the submucosal layer. The patient had a normal serum gastrin level and was negative for antiparietal cell antibody. The patient was also found to have a pituitary tumor, an adenomatous goiter, and bilateral Warthin's tumors of the parotid glands. Histological examination of the resected stomach identified 12 discrete carcinoid tumors. There was no evidence of atrophic gastritis or of endocrine cell micronests. No mutations of the MEN1 gene were found on genomic DNA analysis. Despite the multiplicity of carcinoid tumors, we diagnosed type 3 gastric carcinoid in this patient.

Topics: Aged; Carcinoid Tumor; Endosonography; Gastrins; Gastroscopy; Humans; Laparoscopy; Male; Stomach Neoplasms

Topics: Adult; Carcinoid Tumor; Duodenal Diseases; Endoscopy, Gastrointestinal; Female; Gastrectomy; Gastrins; Hematemesis; Humans; Neoplasm Recurrence, Local; Polyps; Prolapse; Stomach Neoplasms

To study the clinicopathological features of gastric neuroendocrine tumors.. Twenty cases were reviewed. The specimens were formalin-fixed, paraffin-embedded and immunostained by S-P method.. Among the twenty cases, one case was carcinoid, three were malignant carcinoids, six had small cell carcinomas and ten had mixed extocrine--endocrine carcinomas. Immunohistological examination of tumor cells found 80% positive for S-100, NSE (85%), CgA (50%), SY (50%), gastrin (30%), serotonin (65%), AE1/AE3 (50%), and CEA (80%).. In the WHO classification, there are five histological types in endocrine tumors of gastrointestinal tract. They are carcinoid, malignant carcinoid, small cell carcinoma, mixed exocrine--endocrine carcinoma and tumor-like lesions. But some cases in our paper were so different that they could not be classified. The gastric endocrine tumors are different from intestinal endocrine tumors and in classification, treatment and prognosis.

Topics: Adult; Aged; Carcinoembryonic Antigen; Carcinoid Tumor; Carcinoma, Small Cell; Female; Gastrins; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Neuroendocrine Tumors; Phosphopyruvate Hydratase; Prognosis; Stomach Neoplasms

Topics: Atrophy; Biopsy; Carcinoid Tumor; Endoscopy, Digestive System; Fatal Outcome; Female; Gastrins; Gastritis; Humans; Immunohistochemistry; Middle Aged; Pulmonary Emphysema; Stomach Neoplasms; Tomography, X-Ray Computed

Gastric carcinoid is a rare tumour that is associated with chronic atrophic gastritis in the majority of cases. It usually occurs in the 6th or 7th decade of life and is rarely diagnosed in patients under 30 years of age.. We describe a case of multiple gastric carcinoids in a 23-year-old woman with systemic lupus erythematosus and atrophic autoimmune gastritis--an association that has not been reported previously.. The combination of atrophic autoimmune gastritis and gastric carcinoid with other autoimmune disorders has rarely been reported in the English medical literature.. The fact that it mostly concerns (relatively) young patients may suggest a potential causative relation between those autoimmune disorders and the early development of atrophic gastritis with hypergastrinaemia, which subsequently leads to the occurrence of gastric carcinoid tumours at a young age.

Topics: Adult; Antiphospholipid Syndrome; Carcinoid Tumor; Female; Gastrectomy; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Lupus Erythematosus, Systemic; Stomach; Stomach Neoplasms

Patterns of elevated serum peptides may reveal additional markers and permit better classification of tumors based on (secondary) peptide secretion.. Fasting peptide profiles were obtained from 31 carcinoid patients. vasoactive intestinal peptide (VIP), pancreatic polypeptide (PP), neurotensin, substance P, gastrin-releasing polypeptide (GRP), calcitonin, gastrin, and pancreastatin were measured. Peptide elevation patterns were correlated with disease sites, syndrome, and survival.. Elevations in patients were as follows: VIP 0%, PP 13%, neurotensin 10%, substance P 20%, GRP 3%, calcitonin 10%, and gastrin 3%. There were no consistent patterns of elevated peptides with regard to site or syndrome. Pancreastatin was elevated in 81% of profiles and was the only abnormal peptide in 57% of patients.. Peptide profile results do not permit improved classification, predict syndrome development, or correlate with survival. In contrast, pancreastatin is elevated in most cases and may be utilized to monitor disease progression and evaluate response to therapy.

Topics: Biomarkers, Tumor; Calcitonin; Carcinoid Tumor; Chromogranin A; Disease Progression; Female; Gastrin-Releasing Peptide; Gastrins; Humans; Male; Neurotensin; Pancreatic Hormones; Pancreatic Polypeptide; Peptides; Predictive Value of Tests; Substance P; Vasoactive Intestinal Peptide

Until recently, the association of primary hyperparathyroidism and gastric carcinoid, with or without hypergastrinaemia, had been considered an incomplete form of multiple endocrine neoplasia type 1. This is because it seemed unlikely that the rare joint appearance of these diseases could occur only by chance. It is now possible to evaluate the pathogenetic involvement of the multiple endocrine neoplasia type 1 gene in many, apparently sporadic, clinical conditions. This is a case report of a female mimicking multiple endocrine neoplasia type 1 due to the presence of hyperparathyroidism, gastric carcinoid, and hypergastrinaemia. However, involvement of the MEN-1 gene (exons 2-10) was not detected, whereas hypergastrinaemia was attributed to a chronic atrophic gastritis.

Topics: Aged; Carcinoid Tumor; Diagnosis, Differential; Female; Gastrins; Gastritis, Atrophic; Gene Expression; Humans; Hyperparathyroidism; Multiple Endocrine Neoplasia Type 1; Stomach Neoplasms

Gastric carcinoids are strongly associated with chronic atrophic gastritis A, and it is suggested that hypergastrinemia plays a critical role in development of gastric carcinoids. Since Helicobacter pylori infection causes hypergastrinemia, it is held that H. pylori infection produces gastric carcinoids. We followed the histological changes of H. pylori-infected stomachs of Mongolian gerbils for a long time.. Five-week-old-male Mongolian gerbils were infected with H. pylori ATCC 43504 with cagA gene, expressing vacuolating cytotoxin. Determination of the serum gastrin and histopathological examination of the stomach at 6, 12, 18, and 24 months after H. pylori inoculation was studied and compared with uninfected animals.. In infected animals, the gastric carcinomas appeared 18 and 24 months after infection. Endocrine cell dysplasias and carcinoids with marked atrophic gastritis of the oxyntic mucosa were observed in the infected animals 24 months after H. pylori inoculation. The serum gastrin level in the infected group increased from an average of 86.2 pg/ml at the beginning of the study to an average of 498 pg/ml and 989 pg/ml at 18 and 24 months after infection, respectively. These changes in the serum gastrin levels were significant compared with uninfected controls that showed no changes.. H. pylori infection caused not only gastric carcinomas but also enterochromaffin-like cell tumors in Mongolian gerbils, due to hypergastrinemia. This model is thought to be useful to study the relationship between hypergastrinemia and gastric carcinoids.

Topics: Adenocarcinoma; Animals; Carcinoid Tumor; Disease Models, Animal; Gastric Mucosa; Gastrins; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Male; Stomach Neoplasms

In Japan, most cases of gastric carcinoid tumor (GCT) are unassociated with either autoimmune gastritis (AIG) showing type-A chronic atrophic gastritis (CAG-A) or Zollinger-Ellison syndrome (ZES). However, the pathogenesis of this tumor remains unknown. Recent studies have determined that Helicobacter pylori infection induces gastric carcinoid in Mongolian gerbils and that H. pylori lipopolysaccharide exerts a mitogenic effect on ECL cells. We examined five patients with histologically diagnosed GCT, 40 patients with H. pylori-positive gastric ulcer (Hp+GU), 24 patients with H. pylori-positive duodenal ulcer (Hp+DU), and 12 patients with AIG showing CAG-A topographically. We compared the prevalence of H. pylori infection, and the levels of gastrin and pepsinogen (PG) in the serum of patients with GCT with those of patients with Hp+GU, or Hp+DU, and AIG. We also investigated the histological characteristics of the tumor and the gastric corpus mucosa in the GCT patients. The levels of serum gastrin and PG I and II were measured using an RIA kit. In all five (100%) patients with GCT, H. pylori infection was present, without any evidence of AIG or ZES. The serum levels of gastrin in the GCT patients were higher than those in either Hp+GU or Hp+DU patients and lower than those in the AIG patients. In contrast, serum PG I levels and the PG I/II ratio were lower in the GCT group than in the Hp+GU or Hp+DU groups. Histologically, all GCTs were ECL cell tumors and peritumoral corporal mucosal atrophy was observed in four of the five patients with GCT. In conclusions, H. pylori infection and hypergastrinemia were found in the patients with GCT without AIG. This finding suggests that H. pylori infection may induce corporal mucosal atrophy and hypergastrinemia that can produce a GCT with time.

Topics: Adult; Aged; Aged, 80 and over; Autoimmune Diseases; Carcinoid Tumor; Duodenal Ulcer; Female; Gastrins; Gastritis; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Pepsinogen A; Pepsinogen C; Peptic Ulcer; Stomach Neoplasms

The gastric hormone gastrin regulates the organization of the gastric epithelium, but the cellular control mechanisms are yet unknown. Epithelial remodelling typically involves extracellular proteolysis mediated by the matrix metalloproteinases (MMPs). Since a gene-array analysis of the gastric cancer cell line AGS-G(R) suggested that gastrin increased MMP-9 expression, we examined the control of MMP-9 expression by gastrin. Gelatin zymography confirmed gastrin induction of MMP-9 in AGS-G(R) cells, but showed a small inhibition of MMP-2. Immunocytochemical studies showed that MMP-9 was localized to vesicles that appeared to traffic along the processes that were extended in response to gastrin. Gastrin stimulated the invasion of AGS-G(R) cells through artificial basement membrane, which was reduced by an inhibitor of MMP-2/-9. There was also an increase in MMP-9 in the stomach of patients with elevated plasma gastrin and multiple-endocrine neoplasia type 1 (MEN-1) syndrome, suggesting in vivo regulation of MMP-9 expression by gastrin. Finally, we showed that the expression of 1.9 kb of human MMP-9 gene promoter coupled with luciferase (MMP-9-luc) was increased 7.65+/-1.2-fold by gastrin, via a pathway which includes stimulation of protein kinase C, and activation of Raf and the mitogen-activated protein (MAP) kinase pathway. The tumour suppressor menin (which is mutated in MEN-1 syndrome) inhibited the expression of MMP-9-luc by gastrin. These results suggest that gastrin increases MMP-9 expression, which is associated with increased invasion, and this is a putative mechanism regulating remodelling of the gastric epithelium.

Topics: Animals; Carcinoid Tumor; Epithelial Cells; Female; Gastric Mucosa; Gastrins; Gene Expression Regulation, Enzymologic; Genes, Reporter; Humans; Male; Matrix Metalloproteinase 9; Middle Aged; Multiple Endocrine Neoplasia Type 1; Neoplasm Invasiveness; Neoplasm Proteins; Proto-Oncogene Proteins; Recombinant Fusion Proteins; Transcription Factor AP-1; Tumor Cells, Cultured

Gastrointestinal carcinoids are derived from the diffuse intestinal endocrine system and may produce amines and many peptides, including serotonin, chromogranin A (CGA), and tachykinins. Most peptide hormones are synthesized as bigger prohormones, which are processed to smaller active hormones by prohormone convertases (PCs). A total of 35 cases of gastrointestinal carcinoids, including gastric, duodenal, small intestinal, appendiceal, and large intestinal carcinoids, were immunocytochemically stained for serotonin, CGA, and PC 1/3 and 2, in order to colocalize CGA and PCs in the carcinoids. All carcinoids were positive for CGA and PCs. Carcinoids that stained strongly for CGA were generally weakly stained for PCs and those weakly staining for CGA were more strongly stained for PCs in the majority of the small and large intestinal tumors. Gastrointestinal carcinoids were positive for CGA and PCs, and the presence of PCs may suggest that the conversion of peptide prohormones to smaller peptide hormones occurs in gastrointestinal carcinoids. PCs immunocytochemistry may be added as a new phenotypic characterization for gastrointestinal carcinoids.

Topics: Adult; Aged; Appendiceal Neoplasms; Aspartic Acid Endopeptidases; Carcinoid Tumor; Child; Chromogranin A; Chromogranins; Duodenal Neoplasms; Female; Gastrins; Gastrointestinal Neoplasms; Humans; Immunohistochemistry; Intestinal Neoplasms; Intestine, Large; Intestine, Small; Male; Middle Aged; Proprotein Convertase 2; Proprotein Convertases; Serotonin; Stomach Neoplasms; Subtilisins

In the presence of atrophic body gastritis, gastric carcinoid develops from gastric-body mucosa enterochromaffin-like cells. Few data exist on the prevalence of enterochromaffin-like dysplastic lesions in atrophic body gastritis patients and their presumed risk of evolution to carcinoid has never been assessed prospectively in humans. The aim of the present study was to investigate the prevalence and incidence of dysplastic and neoplastic enterochromaffin-like cell lesions in a consecutive series of patients with atrophic body gastritis.. A total of 130 atrophic body gastritis patients at diagnosis and 96 atrophic body gastritis patients at follow-up (median 30 months) underwent gastroscopy with multiple biopsies and fasting gastrinaemia evaluation. In patients with enterochromaffin-like cell dysplasia, a more detailed bioptic sampling at follow-up was performed.. Of the 130 atrophic body gastritis patients, only one (0.7%) had a gastric carcinoid polyp, whereas enterochromaffin-like cell dysplasia was found in five patients (3.8%). At follow-up only one out of the 96 atrophic body gastritis patients (1%) was diagnosed as having a carcinoid polyp at 41 months. Enterochromaffin-like cell dysplasia was present in four additional patients (4.2%). Two atrophic body gastritis pernicious anaemia patients with enterochromaffin-like cell dysplasia developed a gastric carcinoid in the follow-up. Among nine atrophic body gastritis patients with enterochromaffin-like cell dysplasia, the incidence of carcinoid tumour was 22% compared to 1.1% of atrophic body gastritis patients without dysplasia (odds ratio: 26.00; 95% confidence interval: 2.089-323.52). During the follow-up, fasting gastrin levels increased significantly only in atrophic body gastritis patients with enterochromaffin-like cell dysplasia (mean 677.4 +/- 66.1 vs 1112.2 +/- 185.6; P = 0.0287).. This study provides the first clinical evidence that, in hypergastrinaemic atrophic body gastritis patients, enterochromaffin-like cell dysplasia carries a markedly increased risk for development of type I gastric carcinoid. This suggests that a more detailed endoscopic/bioptic procedure in this subgroup of atrophic body gastritis patients is able to detect gastric carcinoid at an early stage.

Topics: Adult; Aged; Aged, 80 and over; Carcinoid Tumor; Enterochromaffin-like Cells; Female; Follow-Up Studies; Gastrins; Gastritis, Atrophic; Humans; Immunohistochemistry; Male; Middle Aged; Odds Ratio; Precancerous Conditions; Prevalence; Prospective Studies; Risk; Stomach Neoplasms

Topics: Adult; Antineoplastic Agents; Carcinoid Tumor; Female; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Octreotide; Peptides, Cyclic; Somatostatin; Stomach Neoplasms; Zollinger-Ellison Syndrome

Hypergastrinemia secondary to low acid secretion is associated with gastric carcinoid formation in Mastomys. We investigated the effect of gastrin on oxyntic epithelial apoptosis and proliferation in this model.. Hypergastrinemia and mucosal hyperplasia were induced by irreversible H(2) receptor blockade with loxtidine. Gastrin levels were normalised in some animals by 10 days' loxtidine withdrawal. Serum gastrin was determined by radioimmunoassay, proliferative, enterochromaffin-like cells and Bcl-2 protein family expression by immunohistochemistry, and apoptotic cells by terminal deoxyuridine nucleotide nick end labeling (TUNEL).. Proliferating cells were increased 4-fold in loxtidine-treated animals, and returned to normal upon loxtidine withdrawal. Enterochromaffin-like cell number increased 2-fold with loxtidine, and did not decrease after withdrawal. Apoptotic epithelial cells were located at the luminal surface and increased 1.8-fold with loxtidine, returning to control levels upon withdrawal. The ratio of proliferative to apoptotic cells was lower in the control and withdrawn groups than in the loxtidine group (0.26+/-0.05 and 0.26+/-0.08 vs. 0.77+/-0.12). With hypergastrinemia, the expression of Bcl-2 and Bak was increased and Bax decreased in the middle of the gland.. Hypergastrinemia is associated with alterations in both proliferation and apoptosis in Mastomys gastric mucosa. This may contribute to the pathogenesis of mucosal hyperplasia in this model.

Topics: Animals; Apoptosis; Carcinoid Tumor; Cell Division; Disease Models, Animal; Female; Gastric Acid; Gastric Mucosa; Gastrins; Immunohistochemistry; Male; Muridae; Proto-Oncogene Proteins c-bcl-2; Stomach Neoplasms

The authors report seven patients with carcinoid tumors of the extrahepatic bile ducts (EHBDs). All patients were women, with an average age at diagnosis of 49.8 years (range, 37-67 yrs). The most common presenting symptom was painless jaundice with or without pruritus. Although one patient had peptic ulcer disease before the onset of obstructive jaundice, none had systemic endocrine manifestations. These neoplasms were most often located in the common bile duct. Grossly, the carcinoid tumors were usually nodular and poorly demarcated, and ranged from 1.1 to 2.7 cm in size. Only one of the neoplasms was polypoid. Microscopically, the tumors had a trabecular or nesting pattern with occasional tubule formation, and were composed of relatively small cells with granular chromatin. All of the neoplasms expressed chromogranin and two expressed synaptophysin. Three expressed serotonin and two of the three were also immunoreactive for pancreatic polypeptide or somatostatin. Two tumors were focally positive for gastrin and one of these two tumors was also positive for serotonin and pancreatic polypeptide. All seven carcinoid tumors showed no immunoreactivity for p53, and assays for p53 loss of heterozygosity analysis were negative in two, suggesting that p53 mutations do not play a role in the pathogenesis of EHBD carcinoids. A mutation in codon 12 of K-ras was found in one carcinoid tumor whereas two of two showed immunoreactivity for Dpc4 protein. In view of the small number of carcinoids studied, the importance of these findings in the pathogenesis of these tumors is unclear. Ultrastructural examination of three of the tumors revealed numerous membrane-bound, round neurosecretory granules. Clinically, these lesions had an indolent course. Even in the presence of lymph node metastases (noted in two patients), all of the patients remained disease free 2 to 11 years (average follow up, 6.6 yrs) after segmental resection or pancreaticoduodenectomy (Whipple's procedure). Because carcinoid tumors of the EHBD are of low malignant potential, they should be separated from the more common adenocarcinomas in this location.

Topics: Adult; Aged; Bile Duct Neoplasms; Bile Ducts, Extrahepatic; Carcinoid Tumor; Chromogranins; Cytoplasmic Granules; DNA-Binding Proteins; DNA, Neoplasm; Female; Follow-Up Studies; Gastrins; Humans; Immunoenzyme Techniques; Loss of Heterozygosity; Lymph Nodes; Lymphatic Metastasis; Microsatellite Repeats; Middle Aged; Neurosecretory Systems; Pancreatic Polypeptide; Pancreaticoduodenectomy; Serotonin; Smad4 Protein; Somatostatin; Synaptophysin; Trans-Activators; Treatment Outcome

We have experienced a case of the stomach with hypergastrinemia and type A gastritis with multiple carcinoids in a 37-year-old woman. An upper gastrointestinal series revealed multiple minute polyps in the upper body of the stomach. All polyps were diagnosed as carcinoid using endoscopic biopsies. She had neither symptom or signs of typical carcinoid disease. The serum gastrin level was as high as 725 pg/ml. Total gastrectomy was performed, and the diagnosis of multiple gastric carcinoids (sm, no) with type A gastritis was histologically confirmed. After the operation, the serum gastrin level returned to normal, and the patient has been doing well and is disease-free to date at 7 years after the operation. This case suggested that multiple gastric carcinoid lesions may be precipitated by chronic atrophic gastritis accompanying hypergastrinemia. In the treatment of multiple gastric carcinoids with type A gastritis, total gastrectomy with lymph node dissection should be standard operative procedure, in order to resect the fundic gland area completely which could be the origin of carcinoids and endocrine cell micronest.

Topics: Adult; Carcinoid Tumor; Female; Gastrins; Gastritis; Humans; Stomach Neoplasms

The RegIalpha gene (Reg) encodes a secretory protein proposed to regulate islet beta-cell and gastric mucous cell growth. Reg is expressed in rat gastric enterochromaffin-like (ECL) cells. The aim of this study was to examine Reg expression in human corpus and to determine the identity of Reg in ECL cell carcinoid tumors in hypergastrinemic patients.. Reg messenger RNA (mRNA) abundance was quantified by Northern blot in extracts of gastric corpus from patients with and without ECL cell tumors and in AR4-2J cells stimulated by gastrin; cellular origins were determined by immunocytochemistry. Mutations of Reg were determined by reverse-transcription polymerase chain reaction, cloning, and sequencing, and the mutated protein was expressed in HIT-T15 cells.. Reg mRNA abundance was increased approximately threefold in the corpus of hypergastrinemic patients compared with controls, and was enriched in 3 of 7 ECL cell carcinoid tumors but not in non-endocrine cell gastric polyps. In AR4-2J cells, gastrin stimulated Reg mRNA abundance; this was eliminated by the gastrin/cholecystokinin B antagonist L-740,093 (10(-9) mol/L). Immunocytochemistry indicated that Reg was located in both chief cells and ECL cells in human corpus. Mutations of Reg were identified in 3 of 5 patients with ECL cell carcinoid tumors; in 2 cases, mutation of the initiator methionine residue led to exclusion of the protein from the secretory pathway.. Gastrin regulates Reg mRNA abundance in human corpus. Mutations of Reg that prevent secretion are associated with ECL cell carcinoids, suggesting a function as an autocrine or paracrine tumor suppressor.

Topics: Adult; Aged; Aged, 80 and over; Calcium-Binding Proteins; Carcinoid Tumor; Endocrine Gland Neoplasms; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Humans; Lithostathine; Male; Methionine; Middle Aged; Mutation; Nerve Tissue Proteins; Protein Biosynthesis; RNA, Messenger; Stomach Neoplasms; Tissue Distribution

We present a 57-year-old man with Zollinger-Ellison syndrome who had undergone total gastrectomy 12 years previously. At that time, a cystic mass in the left lobe of the liver was palpated but was not removed. The patient currently had high serum gastrin levels. Abdominal ultrasound, CT and MR images showed a well defined liver mass with solid and cystic components. The lesion was resected and a primary hepatic carcinoid tumour was diagnosed. Post-operatively, serum gastrin levels were normal. A primary liver carcinoid may appear as multicystic liver mass with solid components. Careful exclusion of a primary tumour elsewhere is required to establish the diagnosis of this rare entity.

Topics: Carcinoid Tumor; Gastrins; Humans; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Zollinger-Ellison Syndrome

A Mongolian gerbil model was used to clarify whether long-term colonization by Helicobacter pylori is an important risk factor for the development of gastric cancer. Fifty-nine gerbils (3 controls and 56 gerbils inoculated with H. pylori) were killed at various times (average, 23 months) more than 12 months after H. pylori inoculation. In the H. pylori-inoculated group, poorly differentiated adenocarcinoma was observed in the pylorus of 1 gerbil, and carcinoid was observed in the fundus of the stomach in 18 gerbils. No lesions were found in the stomachs of the 3 control gerbils. The results imply that long-term colonization by H. pylori is an important risk factor for the development of gastric adenocarcinoma and carcinoid.

Topics: Adenocarcinoma; Animals; Antibodies, Bacterial; Carcinoid Tumor; Disease Models, Animal; Duodenum; Gastrins; Gerbillinae; Helicobacter Infections; Immunoglobulin G; Intestinal Mucosa; Metaplasia; Stomach Neoplasms; Time

Gastrin is one of the main factors controlling enterochromaffin-like (ECL) cell endocrine function and growth. Long-standing hypergastrinemia may give rise to ECL cell carcinoids in the gastric corpus in man and in experimental models. We have analysed the expression and function of CCK-B/gastrin receptors in normal ECL cells and in ECL cell tumours (gastric carcinoids) of the African rodent Mastomys natalensis. Hypergastrinemia induced by short-term (5 days) histamine2-receptor blockade (loxtidine) resulted in increased histidine decarboxylase (HDC) mRNA expression in the gastric oxyntic mucosa. This increase was significantly and dose-dependently reversed by selective CCK-B/gastrin receptor blockade (YM022). Long-term (12 months) hypergastrinemia, induced by histamine2-receptor blockade, gave rise to ECL cell carcinoids in the gastric oxyntic mucosa. CCK-B/gastrin receptor mRNA was only slightly elevated while HDC mRNA expression was eight-fold elevated in ECL cell carcinoids and was not influenced by CCK-B/gastrin receptor blockade. Thus CCK-B/gastrin receptor blockade of hypergastrinemic animals reduces the HDC mRNA expression in normal mucosa but not in ECL cell carcinoids. These results demonstrate that HDC mRNA expression in neoplastic ECL cells is not controlled by CCK-B/gastrin receptors.

Topics: Animals; Benzodiazepines; Carcinoid Tumor; Cell Transformation, Neoplastic; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Gene Expression; Histamine H2 Antagonists; Histidine Decarboxylase; Hormone Antagonists; Humans; Muridae; Receptors, Cholecystokinin; RNA, Messenger; RNA, Neoplasm; Stomach Neoplasms; Triazoles

The aims of this study were to illustrate the malignant potential of gastric enterochromaffin-like (ECL) cell carcinoids (ECLomas) associated with hypergastrinemia, and the gradual neoplastic progression of such tumours. In addition, we examined whether the tyramide signal amplification (TSA) technique could visualize immunohistochemical (IHC) neuroendocrine (NE) features in the dedifferentiated neoplastic ECL cells which were not detected by conventional methods.. Conventional histopathological and IHC methods for visualizing ECL cells and cell proliferation were used in addition to the TSA technique.. Our patient was followed for 5 years. During that period, her ECLoma displayed all the signs of classical tumour progression, ultimately with the appearance of metastases in the regional lymph nodes, the liver and the skin. The neoplastic ECL cells became progressively dedifferentiated with an increasing number of Ki-67 immunoreactive (IR) cell nuclei. In addition, there was a substantial decrease in argyrophil and IR NE cells that could be visualized by conventional methods. By applying the TSA technique, however, the number of IR tumour cells increased considerably.. ECLomas secondary to hypergastrinemia should be closely followed for signs of clinical and histopathological tumour progression. Such ECLomas deserve early, active, radical surgical treatment. The TSA technique is a valuable tool for visualizing the characteristic IHC features in dedifferentiated NE cells.

Topics: Aged; Carcinoid Tumor; Cell Differentiation; Chromogranin A; Chromogranins; Enterochromaffin Cells; Female; Gastrins; Gastritis, Atrophic; Histidine Decarboxylase; Humans; Immunohistochemistry; Ki-67 Antigen; Serotonin; Stomach Neoplasms

Topics: Carcinoid Tumor; Cell Line; Enterochromaffin Cells; Gastrins; Humans; Multiple Endocrine Neoplasia Type 1; Stomach Neoplasms

We present here familial occurrence of two patients with gastric carcinoid. Both patients, a sister and older sister, had type A chronic atrophic gastritis with hypergastrinemia. This is the first case report of familial occurrence of gastric carcinoid associated with type A chronic atrophic gastritis in the world literature. The possible mechanism of familial occurrence in the patients is discussed.

Topics: Adult; Carcinoid Tumor; Chronic Disease; Female; Gastrins; Gastritis, Atrophic; Humans; Pedigree; Stomach Neoplasms

In gastric adenocarcinoma the gastrin autocrine-paracrine pathway is activated. As enterochromaffin-like (ECL) cells originate from the same stem as epithelial cells, the aim of this study was to determine if the gastrin autocrine pathway is present in gastric carcinoid.. Samples from ten patients with gastric carcinoid were assessed by immunocytochemistry using primary antibodies directed against gastrin precursors and the gastrin/cholecystokinin B receptor and detected using the avidin-biotin immunoperoxidase system.. A high level of expression of precursor and mature gastrin peptides, together with the gastrin receptor, was seen in all carcinoids screened.. In common with the glandular epithelium of the stomach the gastrin gene is activated during the neoplastic process in ECL cells. This finding may explain why some carcinoids do not regress after surgical procedures that lower serum gastrin. Antigastrin agents may be a useful treatment for carcinoid either in their own right or as an adjunct to surgery.

Topics: Adult; Aged; Carcinoid Tumor; Cholecystokinin; Female; Gastric Acid; Gastrins; Humans; Immunohistochemistry; Male; Middle Aged; Stomach Neoplasms

Topics: Abdominal Pain; Adult; Anemia, Pernicious; Carcinoid Tumor; Diagnosis, Differential; Female; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Hyperplasia; Precancerous Conditions; Pyloric Antrum; Stomach Neoplasms

It is not known whether plasma chromogranin analysis could be a complement to histology for detection and grading of gastric fundic mucosal endocrine cell proliferation in hypergastrinemic (type-A) atrophic gastritis.. Gastric biopsy sections (body and antrum) from 43 patients with type-A gastritis (9 with gastric carcinoid) were examined for density and micronodules of argyrophil endocrine cells. Fasting blood samples were analyzed for chromogranin A and B, gastrin, and somatostatin.. All patients with carcinoid and 17 of the 34 without carcinoid had micronodules in the gastric fundic mucosa. The median plasma chromogranin A concentration was 5.7 (3.5-40.0) nmol/l in patients with carcinoid, 4.5 (3.0-9.5) nmol/l in patients with micronodules, and 3.7 (0.8-6.0) nmol/l in patients without micronodules. Overall, chromogranin A concentrations correlated to endocrine cell densities in the fundic mucosa (r = 0.64, P < 0.001) and to gastrin concentrations (r = 0.71, P < 0.001). Plasma somatostatin and chromogranin B concentrations did not differ significantly between the groups.. In type-A gastritis, analysis of plasma chromogranin A may be a useful complement to histology in estimating the endocrine cell mass. Moreover, subclinical type-A gastritis may be a source of error when chromogranin A analysis is used in the search for neuroendocrine neoplasia.

Topics: Aged; Anemia, Pernicious; Biopsy; Carcinoid Tumor; Chromogranin A; Chromogranins; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Male; Stomach Neoplasms

Thirty-two cases of so-called sclerosing hemangioma of the lung observed by light microscopy were further studied by electron microscopy and/or immunohistochemistry. Three histologic patterns were seen: hemangioma-like, papillary, and solid. The only significant component representing the nature of the lesion is characteristic round cells within the stroma in all these patterns, whereas the surface cells lining the papillary projections or cystic spaces are normal or are hyperplastic bronchioloalveolar cells with a few neuroendocrine cells. Immunohistochemical findings showed that the "stromal cells" (tumor cells) were positive for neuroendocrine markers, namely, chromogranin A (19 of 22 cases), neuron-specific enolase (24 of 24), synaptophysin (six of 10), adrenocorticotropic hormone (14 of 15), growth hormone (14 of 15), calcitonin (11 of 15), and gastrin (11 of 14). Besides, some tumor cells were positive for epithelial membrane antigen (four of four), carcinoembryonic antigen (one of four), and vimentin (one of one). All tumor cells were negative for polyclonal antikeratin antibody (25 cases), AE1 (one case), and AE3 (one case). However, in contrast to the "stromal cells," the surface cells of the cystic spaces stained positively for keratin (25 of 25 cases), AE1 (one of one), AE3 (one of one), epithelial membrance antigen (four of four), and carcinoembryonic antigen (four of four); only a few of them expressed neruoendocrine markers. Both surface and tumor cells were negative for factor VIII-related antigen (25 cases), CD31 (one case), and alpha1-antitrypsin (25 cases). Ten cases further studied by electron microscopy and six examined by ultrastructural morphometry showed that the surface cells were mainly type 2 pneumocytes containing many lamellar bodies in the cytoplasm. Lying among them, neuroendocrine cells were occasionally seen. The stromal tumor cells had no lamellar body, but dense core granules (neurosecretory granules) and microtubules. In six cases, 92.3% (345 of 374) of tumor cells contained neurosecretory granules, which were pleomorphic and 73 to 1056 nm in diameter (mean, 302 nm). Two to 193 (mean, 12) neurosecretory granules were found in each tumor cell. Both immunohistochemical findings and ultrastructural evidence indicate that so-called sclerosing hemangioma of the lung is a benign lesion composed of neoplastic neuroendocrine cells with areas of sclerosis. A suggested name for this tumor is benign neuroendocrine tumor of the lung

Topics: Adenocarcinoma, Bronchiolo-Alveolar; Adenoma; Adrenocorticotropic Hormone; Adult; Aged; Biomarkers, Tumor; Calcitonin; Carcinoembryonic Antigen; Carcinoid Tumor; Cell Transformation, Neoplastic; Chromogranin A; Chromogranins; Diagnosis, Differential; Female; Gastrins; Histiocytoma, Benign Fibrous; Human Growth Hormone; Humans; Immunohistochemistry; Lung Neoplasms; Male; Microscopy, Electron; Middle Aged; Neuroendocrine Tumors; Phosphopyruvate Hydratase; Synaptophysin; von Willebrand Factor

We report a case of a gastric carcinoid tumor in an anemic woman with chronic atrophic gastritis and hypergastrinemia. An antrectomy with excision of a carcinoid tumor was performed; afterwards, gastrinemia was normal. Gastric carcinoids were considered uncommon gastric cancers; however, in recent years they have been studied with increasing interest because, as in chronic atrophic gastritis, it has been suggested that they might be produced by prolonged hypergastrinemia associated with therapeutic use of gastric acid supressors. We discuss the gastrin hypothesis, the different clinical types of gastric carcinoids and its therapeutical management.

Topics: Adult; Carcinoid Tumor; Female; Gastrins; Gastritis; Humans; Stomach Neoplasms

Topics: Adult; Carcinoid Tumor; Duodenal Neoplasms; Gastrins; Humans; Male; Somatostatin; Tomography, Emission-Computed, Single-Photon; Zollinger-Ellison Syndrome

A 48-year-old male with type A atrophic gastritis developed multiple gastric carcinoids and a pituitary adenoma. Laboratory tests revealed high levels of serum gastrin and growth hormone (GH). He underwent subtotal gastrectomy, resulting in a return of the previously elevated gastrin level to normal. Serum GH concentration remained high. Three months after the surgery, the pituitary tumor, composed greatly of GH-immunoreactive cells, was partially removed. Since hypergastrinemia plays a pivotal role in gastric carcinoid formation and induces GH-releasing factor (GHRH) release resulting in GH-producing pituitary tumor formation, GH-producing pituitary adenoma might be a clinical manifestation in type A gastritis.

Topics: Adenoma; Carcinoid Tumor; Follow-Up Studies; Gastrectomy; Gastrins; Gastritis, Atrophic; Gastroscopy; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasms, Multiple Primary; Pituitary Neoplasms; Stomach Neoplasms; Tomography, X-Ray Computed

A case of MEN type I in a 64-year-old man is reported. He had undergone partial duodenectomy because of gastric ulcer and multiple duodenal polyps (gastrin secreting carcinoid). Blood examination revealed hypercalcemia, hyperPTHemia, and hyperprolactinemia. Neck US and CT showed enlargement of 4 parathyroid glands. Brain MRI revealed the microadenoma in left pituitary gland. Total parathyroidectomy with auto-transplantation in the left forearm were performed. Histological examination showed the hyperplasia of the parathyroid. Three and a half year after parathyroidectomy, there was no evidence of recurrence of gastrin secreting tumor and hyperparathyroidism, and enlargement of pituitary microadenoma. This is the first MEN type I case in Japan which have detected 3 endocrine tumors clinically with gastrin secreting duodenal carcinoid.

Topics: Adenoma; Carcinoid Tumor; Duodenal Neoplasms; Gastrins; Humans; Hyperparathyroidism; Hyperplasia; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Parathyroid Glands; Pituitary Neoplasms; Prolactin

Topics: Adult; Carcinoid Tumor; Gastrins; Humans; Male; Neoplasms, Multiple Primary; Pancreatic Diseases; Stomach Neoplasms

The genesis of human gastric carcinoma is ill understood but is invariably related to achlorhydria. Gastrin secretion is negatively regulated by luminal acid and hypergastrinaemia is thus associated with low acid states which may be natural (atrophic gastritis) or owing to acid inhibitory therapy. Apart from its acid secretory activity, gastrin is trophic to the mucosa, via stimulation of the fundic enterochromaffin-like (ECL) cells to secrete histamine. In conditions of elevated gastrin levels, ECL cell hyperplasia and even neoplasia have been noted. The relationship between low acid, hypergastrinaemia, ECL cell hyperplasia, and neoplasia may be of relevance since ECL cells secrete histamine and TGF alpha which are both recognised mitogens. We studied the rodent mastomys, which spontaneously develop gastric carcinoid tumours, which can be generated in 4 months under conditions of drug-induced acid inhibition and inhibited by octreotide administration. A pure (90-95%) cell preparation was used to evaluate ECL cell physiology and trophic regulation. A gastrin/CCKB receptor responsible for histamine secretion and DNA synthesis was identified, cloned and sequenced. Octreotide lowers plasma gastrin levels, decreases ECL cell neoplasia and, in vitro, inhibits ECL cell DNA synthesis. H1 receptor antagonists inhibited DNA synthesis in vitro and ECL neoplasia in vivo without altering gastrin levels. Hypergastrinaemia increased TGF alpha/EGF receptor and TGF alpha production and TGF alpha massively stimulated ECL cell DNA synthesis. Since ECL cells produce both histamine and TGF alpha and regulate parietal cells which produce TGF alpha, it is possible that achlorhydria-generated ECL cell dysfunction may play an initiative role in the pathobiology of gastric adenocarcinoma. The long-term clinical consequences of drug-induced sustained acid inhibition are worthy of further consideration.

Topics: Animals; Base Sequence; Carcinoid Tumor; Cell Transformation, Neoplastic; DNA; DNA, Neoplasm; Enterochromaffin Cells; Gastrins; Histamine Release; Molecular Sequence Data; Polymerase Chain Reaction; Rats; Receptors, Cholecystokinin; Stomach Neoplasms; Transforming Growth Factor alpha; Tumor Cells, Cultured

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.

Topics: Adult; Aged; Aged, 80 and over; Biopsy; Carcinoid Tumor; Endocrine Glands; Female; Gastrins; Humans; Hyperplasia; Immunohistochemistry; Male; Middle Aged; Stomach; Stomach Neoplasms

Topics: Carcinoid Tumor; Diagnostic Errors; Diarrhea; Female; Gastrins; Gastritis; Humans; Liver Neoplasms; Middle Aged; Pain; Stress, Psychological

A now 54-year-old woman was 32 years ago found to have immune thrombocytopenia and 3 years ago ANA-positive and HBsAg-negative hepatitis with cirrhotic metaplasia. Numerous small asymptomatic carcinoids with marked hypergastrinaemia (1626 ng/l) were also first found 3 years ago. No gastrinoma could be found. Severe arthralgia was the main symptom on admission.. Gastroscopy revealed a polypoid carcinoid, 1 cm in diameter. There was total achlorhydria. No pernicious anaemia or carcinoid syndrome was found.. Total gastrectomy with construction of a jejunal substitute stomach was performed. Histology showed typical chronic-atrophic gastritis type A, all stages of an argyrophilic endocrine cell hyperplasia, as well as microcarcinoidosis and multicentric carcinoid, in part with submucosal infiltration and lymph node metastases. Immunohistology revealed immune reaction for the global endocrine marker. No specific hormones were demonstrable in the carcinoid cells. The postoperative course was without complications. Serum gastrin levels have since been normal.. The case confirms the possibility of an achlorhydria-hypergastrinaemia-carcinoid sequence. Now new stage-related therapeutic guidelines for this disease are needed.

Topics: Achlorhydria; Autoimmune Diseases; Carcinoid Tumor; Female; Follow-Up Studies; Gastrectomy; Gastrins; Gastritis, Atrophic; Gastroenterostomy; Humans; Jejunum; Lymphatic Metastasis; Middle Aged; Stomach; Stomach Neoplasms; Time Factors

Histamine is an important stimulator of gastric acid secretion. In experimental animals, inhibition of acid secretion by long term histamine2 receptor blockade causes hypergastrinemia, proliferation of enterochromaffin-like (ECL) cells, and formation of histamine-producing gastric carcinoids. The aim of this study was to examine the role of gastrin in histamine synthesis and metabolism of the oxyntic mucosa of normal, hyperplastic, and carcinoid-bearing Mastomys natalensis. Administration of exogenous gastrin to normal animals increased histidine decarboxylase (HDC) messenger RNA (mRNA) expression in the oxyntic mucosa within 30 min, indicating that gastrin stimulates histamine synthesis by regulating HDC mRNA abundance. Endogenous hypergastrinemia, induced by short term histamine2 receptor blockade (loxtidine) for 3-29 days, did not induce tumors, but enhanced the expression of HDC mRNA (2- to 4-fold elevated) and histamine contents (2-fold elevated) in the oxyntic mucosa. Long term histamine2 receptor blockade (7-21 months) resulted in sustained hypergastrinemia and ECL tumor formation. Tumor-bearing animals had a 4-fold increase in HDC mRNA expression and histamine contents of the oxyntic mucosa. Urinary excretion of the histamine metabolite methyl-imidazole-acetic acid was 2-fold elevated. Tumor-bearing animals recovering from histamine2 receptor blockade were normogastrinemic and had normal levels of HDC mRNA and histamine in the oxyntic mucosa as well as normal excretion of methyl-imidazole-acetic acid. The results indicate that ECL cell carcinoids developing during hypergastrinemia are well differentiated tumors that respond to high gastrin levels with increased histamine synthesis and secretion.

Topics: Animals; Carcinoid Tumor; Female; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Histamine Release; Histidine Decarboxylase; Male; Muridae; Parietal Cells, Gastric; RNA, Messenger; Stomach Neoplasms; Time Factors; Tissue Distribution; Triazoles

Carcinoid tumors of the biliary tract are rare. We report a 47 year-old man who was unexpectedly found to have a nonobstructing carcinoid tumor of the common bile duct during orthotopic liver transplantation for decompensated cirrhosis. No metastases were noted. Five months after resection of the common bile duct and liver transplantation, the patient had no evidence of residual tumor. The carcinoid was a sclerotic tumor of insular type and was immunoreactive for gastrin and serotonin, but nonfunctional. We review the literature on carcinoids of the extrahepatic bile duct.

Topics: Adult; Carcinoid Tumor; Common Bile Duct; Common Bile Duct Neoplasms; Gastrins; Humans; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Serotonin

Malignant transformation in bile duct hamartomas has been previously reported in very rare instances. Here, we describe a unique case of a neuroendocrine tumor of the liver arising within an area of unusually large hamartoma with predominant bile duct component, hitherto unreported and distinct from the conventional von Meyenburg complex. The tumor was apparently secreting gastrin and chromogranin, with associated gastrinoma syndrome over several years. The histologic picture was reminiscent of a moderately differentiated adenocarcinoid, with positive mucin staining in a signet ring pattern. Tumor cells showed positive staining for neuron-specific enolase, chromogranin A, gastrin, and serotonin. Staining for pancreatic hormone peptides was negative. Resection of the tumor was apparently curative, with complete resolution of the patient's symptoms.

Topics: Bile Duct Diseases; Carcinoid Tumor; Chromogranin A; Chromogranins; Female; Gastrins; Hamartoma; Humans; Immunohistochemistry; Liver Diseases; Liver Neoplasms; Magnetic Resonance Imaging; Middle Aged; Radionuclide Imaging; Tomography, X-Ray Computed

A patient with long-standing Zollinger-Ellison syndrome, treated for 14 years with antisecretory agents, underwent computed tomography and upper gastrointestinal examination because of upper gastrointestinal bleeding. Radiologic and pathologic examinations showed multiple nodular masses arising from the wall of the stomach that were determined to be mucosal carcinoid tumors. A gastrin-producing islet cell tumor of the pancreatic head was also present. Gastric carcinoid tumors occurred as a consequence of chronic hypergastrinemia.

Topics: Carcinoid Tumor; Gastrins; Humans; Male; Middle Aged; Stomach Neoplasms; Tomography, X-Ray Computed; Zollinger-Ellison Syndrome

Gastric carcinoids evolved from enterochromaffin-like (ECL) cell hyperplasia are usually associated with high pH and hypergastrinemia. The Mastomys species exhibits a genetic propensity to gastric carcinoid formation that can be accelerated by acid inhibition-induced hypergastrinemia. Although gastrin is critical in the initiation of the ECL cell transformation, the role of other growth factors involved in the evolution of the tumor autonomy has not been established. The aim of this study was to evaluate the role of transforming growth factor (TGF) alpha in the regulation of ECL cell transformation.. Mastomys were orally administered an irreversible H2-receptor antagonist loxtidine for 0, 8, and 16 weeks, and ECL cell transformation was monitored by assessing gastrin levels, mucosal histamine content, and chromogranin immunoreactivity. The ECL cells were purified, and cell proliferation at each stage in response to gastrin and TGF alpha was measured by bromodeoxyuridine uptake. TGF-alpha expression was evaluated by radioimmunoassay and Northern blot, and epidermal growth factor (EGF) receptor expression was determined by Western blot, immunoprecipitation, and immunocytochemistry.. Although the response to gastrin decreased during hypergastrinemia, the proliferative effect of TGF-alpha on ECL cells was specifically amplified during the development of hyperplasia. TGF-alpha and EGF receptor expression increased steadily in the transformed cells.. During low acid-induced hypergastrinemia, the expression of TGF-alpha and EGF receptor may constitute an autocrine regulatory mechanism in ECL cell tumor transformation.

Topics: Animals; Carcinoid Tumor; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; Enterochromaffin Cells; Epidermal Growth Factor; ErbB Receptors; Gastrins; Histamine; Muridae; Stomach Neoplasms; Transforming Growth Factor alpha

A 38-year-old female was admitted for investigation of the cause of hypergastrinemia, hypercalcemia and an elevated plasma parathyroid hormone (PTH) level. Her siblings, elder brother and sister who had duodenal carcinoid tumor with hypergastrinemia and parathyroid adenomas, were diagnosed as multiple endocrine neoplasia (MEN) type 1. In the present patient, endoscopic examination showed a carcinoid tumor of the duodenum, but examinations by computed tomography (CT) and ultrasonography of the abdomen failed to reveal pancreatic lesions. Serum gastrin levels of this patient and her siblings improved to the normal level after resection of carcinoid tumors. The hypergastrinemia accompanying MEN type 1 in these cases might be due to carcinoid tumor of the duodenum.

Topics: Adult; Carcinoid Tumor; Duodenal Neoplasms; Female; Gastrins; Humans; Male; Multiple Endocrine Neoplasia Type 1; Pedigree

A 41-year-old woman with a chronic atrophic gastritis after endoscopic investigation diagnosed a carcinoid at the corpus of the stomach. There were more lesions in the mucosa of the stomach in the form of dysplasias. The labor investigation indicated an hypergastrinaemia. We performed a resection of the basis of the carcinoid. It has shown to be histologically tumor-free as the rest of the stomach. A gastrectomy was not necessary. After resection the patient was under therapy with vitamin B-12. The level of gastrin in blood was normal under this treatment. Two years later the patient remained symptom-free. Regular endoscopic investigations show a stagnation of the growth of the dysplastic lesions of the mucosa of the stomach.

Topics: Adult; Biomarkers, Tumor; Carcinoid Tumor; Chromogranins; Diagnosis, Differential; Female; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Stomach Neoplasms; Synaptophysin

A rapid induction of enterochromaffinlike (ECL) cell tumours has been shown in Praomys (Mastomys) natalensis subjected to histamine2-receptor blockade. In the present study the reversibility of ECL cell proliferation induced by acid inhibition was investigated. Short-term treatment (8 weeks) with the histamine2-receptor antagonist loxtidine caused a moderate hypergastrinemia, accompanied by a minor increase in histamine contents and a 2-fold increased volume density of the endocrine cells in gastric oxyntic mucosa. Eight weeks after withdrawal of treatment the volume density of endocrine cells was normalised as were the tissue levels of histamine, indicating a total reversibility of ECL cell hyperplasia. Long-term treatment (24 weeks) caused severe changes in the endocrine cell population of the oxyntic mucosa with neoplasia (5/21), dysplasia (11/21) and nodular hyperplasia (5/21). The endocrine cell density increased twofold and tissue histamine levels fourfold. 24 weeks after cessation of treatment, the endocrine cell density had decreased to 136% of controls, while histamine concentrations were normalised. The frequency of invasive carcinoids after recovery (4/23) differed only slightly from that seen after treatment for 24 weeks (5/21). Dysplastic lesions were only seen in 1/23 and hyperplastic lesions were of less severe type after recovery. The results demonstrate that ECL cell hyperplasia and dysplasia, induced by acid inhibition, are reversible after cessation of treatment. However, ECL cell tumours did not disappear, within the given observation period. One may therefore speculate that ECL cell proliferation is no longer reversible once the neoplastic (transformed) phenotype has developed.

Topics: Animals; Carcinoid Tumor; Cell Count; Cell Division; Cell Transformation, Neoplastic; Enterochromaffin Cells; Female; Gastrins; Histamine; Histamine H2 Antagonists; Hyperplasia; Male; Muridae; Parietal Cells, Gastric; Stomach Neoplasms; Triazoles

To document our experience with gastric carcinoids over the past decade and to identify lesion frequency and the existence of a relationship to low acid states.. Retrospective case series.. Tertiary care referral center.. A consecutive sample of 16 patients with gastric carcinoids was evaluated over the last decade. Only two cases were recorded in the prior decade. Ages ranged from 30 to 93 years (mean, 65.9 years). There were eight men and eight women. Three patients were unavailable for follow-up.. Therapy included total gastrectomy (n = 4), subtotal gastrectomy (n = 3), endoscopic polypectomy (n = 3), and endoscopic surveillance (n = 6).. Pathobiological tumor characteristics and survival.. All carcinoids were of gastric fundic origin. None of the patients exhibited the carcinoid syndrome. Chronic atrophic gastritis was the most frequently observed comorbid pathologic condition (63%). Half of the patients had multiple polypi. Mean follow-up was 4.7 years (n = 13). There were 10 survivors. The only related death occurred in a patient with a solitary tumor.. Diagnosis of the complex and ill-defined entity of gastric carcinoid is increasing. This may be due to an increased awareness and increased upper gastrointestinal endoscopy rate rather than an increase in real incidence. Criteria for prediction of malignant progression are not available. Multiple gastric carcinoids associated with hypergastrinemia predominantly display nonaggressive behavior. Conservative gastric surgery may be appropriate therapy for such patients.

Topics: Adult; Aged; Aged, 80 and over; Carcinoid Tumor; Comorbidity; Connecticut; Female; Follow-Up Studies; Gastrectomy; Gastric Acid; Gastric Fundus; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Incidence; Male; Middle Aged; Polyps; Retrospective Studies; Stomach Neoplasms; Survival Rate

A 48-year-old woman with type II diabetes developed fatigue, arthralgia and myalgia. A few weeks later she was found to have hepatomegaly. The erythrocyte sedimentation rate was raised (53/93 mm), as were liver enzyme activities (GOT 186 U/l; GPT 240 U/l; gamma-GT 199 U/l), the gamma-globulin levels (40.7%;IgG 4470 mg/dl, IgA 698 mg/dl, IgM 245 mg/dl), antinuclear antibodies and antibodies against double-strand DNA, smooth muscles and actin. Laparoscopy revealed small-nodular liver cirrhosis. The autoimmune hepatitis was treated with prednisolone (initially 60 mg daily, then reduced to 10 mg daily) and azathioprine (initially 100 mg daily, reduced to 50 mg daily). The symptoms markedly improved. But one year later, during follow-up examination, gastric polyps were found, excised and histologically found to be carcinoid. The gastrin level was raised to 765 pg/ml. Another year later the liver cirrhosis had advanced further and the type A gastritis was still present, but there was no sign of carcinoid recurrence.

Topics: Autoimmune Diseases; Azathioprine; Carcinoid Tumor; Cholangiopancreatography, Endoscopic Retrograde; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Endoscopy, Digestive System; Female; Follow-Up Studies; Gastrins; Gastritis; Hepatitis; Humans; Liver Cirrhosis; Middle Aged; Prednisolone; Stomach Neoplasms

Topics: Animals; Carcinogenicity Tests; Carcinogens; Carcinoid Tumor; Gastric Mucosa; Gastrins; Liver; Liver Neoplasms, Experimental; Mice; Rats; Risk Assessment; Stomach; Stomach Neoplasms

Topics: Animals; Blotting, Northern; Carcinogens; Carcinoid Tumor; Chromaffin System; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Muridae; Receptors, Cholecystokinin; Reference Values; Stomach; Stomach Neoplasms; Triazoles

Topics: Carcinoid Tumor; Esophagitis, Peptic; Gastrins; Humans; Omeprazole; Stomach Neoplasms

Profound and sustained inhibition of gastric acid secretion has been associated with development of carcinoid tumors of the fundic enterochromaffin-like (ECL) cells in rodents. While ECL cell hyperplasia has been recognized in humans, the development of carcinoid tumors is rare and often confined to patients under treatment for gastrinoma related to the multiple endocrine neoplasia type I (MEN1) syndrome. The Mastomys was utilized as a model for the rapid induction of ECLomas by insurmountable acid secretory blockade induced by the pharmacologically irreversible H2-receptor antagonist, loxtidine. Loxtidine-induced ECL cell hyperplasia and neoplasia were compared in the absence of presence of cyproheptadine (0.5 mg/kg), an H1-receptor antagonist. Loxtidine administration resulted in a significant increase in ECL cell hyperplasia and neoplasia as well as an increase in ECL cell number, mucosal thickness, plasma gastrin levels, and stomach weight. Cyproheptadine ameliorated loxtidine-induced ECL cell hyperplasia and neoplasia and significantly decreased loxtidine-stimulated increases in ECL cell number. Nevertheless, cyproheptadine failed to alter the loxtidine-induced increase in plasma gastrin, stomach weight or mucosal height. The results indicate that cyproheptadine, an H1-receptor antagonist, inhibits loxtidine-induced ECL cell hyperplasia independent of any effects on serum gastrin.

Topics: Animals; Carcinoid Tumor; Cell Count; Cyproheptadine; Enterochromaffin Cells; Gastric Acid; Gastric Fundus; Gastrins; Growth Substances; Histamine; Muridae; Stomach Neoplasms

Topics: Aged; Anemia, Pernicious; Carcinoid Tumor; Female; Gastrectomy; Gastrins; Gastroscopy; Humans; Stomach Neoplasms

In the rat, hypergastrinaemia induced by drug treatment with omeprazole or potent H2-receptor antagonists leads to the development of gastric enterochromaffin-like cell carcinoids. In man, gastric carcinoids induced by hypergastrinaemia have been described only in patients with chronic atrophic gastritis type A and in patients with the multiple endocrine neoplasia syndrome type 1. This patient with Zollinger-Ellison syndrome without gastric mucosal atrophy and without evidence of the multiple endocrine neoplasia syndrome developed an argyrophil gastric carcinoid tumour. This observation indicates that hypergastrinaemia in the sporadic Zollinger-Ellison-syndrome may induce gastric carcinoids.

Topics: Adult; Carcinoid Tumor; Female; Gastric Mucosa; Gastrins; Humans; Stomach Neoplasms; Zollinger-Ellison Syndrome

Enterochromaffinlike (ECL) cell carcinoids recently observed in rats stimulated new interest in gastric endocrine tumors arising in humans.. Paraffin-embedded sections of 55 endocrine tumor cases were stained with H&E, mucin tests were performed, and immunoperoxidase was used for detecting endocrine markers; 23 cases were also investigated ultrastructurally.. Forty-five argyrophil carcinoids, 9 neuroendocrine carcinomas, and 1 gastrinoma were identified. Three clinicopathologic subtypes of carcinoids were characterized: (1) twenty-eight cases, none metastatic, arose in a background of body-fundus atrophic gastritis and hypergastrinemia; (2) seven cases, 2 locally metastatic, were associated with hypertrophic gastropathy and hypergastrinemia due to multiple endocrine neoplasia/Zollinger-Ellison syndrome; and (3) ten were sporadic cases, 7 of which were deeply invasive, 6 metastatic, and 5 histologically atypical. All carcinoids showed histochemical and ultrastructural patterns of ECL cells. The 9 neuroendocrine carcinomas, all deeply invasive and metastatic, were composed of anaplastic, small- to intermediate-sized cells with high mitotic index and focal necrosis.. Gastrin-promoted carcinoids represent a benign or low grade tumor disease, whereas sporadic carcinoids and neuroendocrine carcinomas are life-threatening neoplasms, independent of gastrin promotion.

Topics: Adult; Aged; Antigens, Neoplasm; Biomarkers; Biomarkers, Tumor; Carcinoid Tumor; Chromogranin A; Chromogranins; Female; Gastrins; Glycoprotein Hormones, alpha Subunit; Humans; Immunoenzyme Techniques; Immunohistochemistry; Male; Membrane Glycoproteins; Microscopy, Electron; Middle Aged; Mucin-1; Multiple Endocrine Neoplasia; Neoplasm Invasiveness; Neoplasm Metastasis; Pancreatic Polypeptide; Phosphopyruvate Hydratase; Serotonin; Somatostatin; Stomach Neoplasms; Thiolester Hydrolases; Ubiquitin Thiolesterase

Topics: Carcinoid Tumor; Dyspepsia; Gastrins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Ranitidine; Self Administration; Stomach Neoplasms

Topics: Adenocarcinoma; Carcinoid Tumor; Gastric Acid; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Peptic Ulcer; Stomach Neoplasms

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.

Topics: Adenocarcinoma; Adult; Aged; Anemia, Pernicious; Carcinoid Tumor; Female; Follow-Up Studies; Gastric Fundus; Gastric Mucosa; Gastrins; Gastroscopy; Humans; Hyperplasia; Male; Middle Aged; Stomach; Stomach Neoplasms

Recently, we identified the specific binding site for gastrin on the gastric carcinoid tumor of Mastomys (Praomys) natalensis. In this study, precise characterization of the gastrin binding site on these tumors was performed. Both 125I-human gastrin I (gastrin) and 125I-CCK-8 bound specifically to the cell membrane, and Scatchard analysis revealed a high affinity binding site for each ligand with similar Kd and Bmax values. The specific binding of both 125I-gastrin and 125I-CCK-8 was displaced in a concentration-dependent manner by various related peptides with a relative potency order of CCK-8 > or = gastrin < des(SO3)CCK-8. In addition, L364,718 as well as L365,260 displaced the binding of both ligands with similar potencies. Furthermore, not only gastrin but also CCK-8 increased [Ca2+]i in these tumor cells, the action of both being inhibited by L364,718 as well as by L365,260 (10(-7) M). These results suggest that the carcinoid tumor of Mastomys possesses a high affinity gastrin/CCK binding site coupled to the increase of [Ca2+]i.

Topics: Animals; Carcinoid Tumor; Female; Gastrins; Humans; Kinetics; Male; Muridae; Neoplasm Transplantation; Receptors, Cholecystokinin; Sincalide; Stomach Neoplasms

Hypergastrinemia has been claimed to cause first hyperplasia and then dysplasia/neoplasia of enterochromaffin-like (ECL) cells in rat stomach. The growth is thought to reflect an accelerated self replication rate of mature ECL cells. The cytokinetics and the histidine decarboxylase (HDC) activity of the ECL cells were investigated during sustained hypergastrinemia.. Hypergastrinemia was evoked by omeprazole (400 mumol.kg-1 x day-1 orally) for up to 1 year. Immunocytochemistry for histamine was used to determine the ECL cell density and combined with [H3]-thymidine autoradiography to establish the labeling index (LI), i.e., the proportion of the ECL cells that has incorporated [H3]thymidine.. The ECL cell density increased progressively for 10-20 weeks in response to the hypergastrinemia and remained at a plateau for the remainder of the study. The hyperplasia was diffuse with additional micronodules at 52 weeks. The ECL cell Ll was maximally elevated after 1-2 weeks and declined to control values after 10-20 weeks of treatment. In contrast, the HDC activity remained elevated for the duration of the study.. The ECL cell hyperplasia reflects the transiently elevated ECL cell Ll during the early phase but is not associated with an accelerated rate of mitosis during the 10-52 weeks period. Even though with time gastrin seems to loose its ability to sustain a high ECL cell Ll it retains its ability to maintain a high HDC activity.

Topics: Animals; Carcinoid Tumor; Cell Division; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Histidine Decarboxylase; Hyperplasia; Kinetics; Male; Rats; Rats, Sprague-Dawley; Stem Cells; Stomach Neoplasms

The concentrations of immunoreactive (IR) corticotropin-releasing hormone (CRH) in 218 neuroendocrine tumors were determined by CRH radioimmunoassay. The tumors examined were 86 pancreatic endocrine tumors (PET), 22 neuroblastic tumors (NBT), 26 carcinoid tumors (CA), 24 pheochromocytomas (PHEO), 40 small cell lung carcinomas (SCLC) and 20 medullary thyroid carcinomas (MTC). IR-CRH was detectable in 21 neuroendocrine tumors (10 PET, four NBT, three CA, two PHEO and two SCLC) at levels of 10-2,700 ng/g wet weight (9.6%). The 21 patients with these CRH-producing tumors showed no clinical symptoms suggestive of Cushing's syndrome. The levels of plasma IR-CRH extracted by immunoaffinity chromatography were < 7.5 pg/ml in five normal subjects and a patient with a neuroblastic tumor containing 55 ng/g wet weight IR-CRH, but in a patient with a thymic carcinoid tumor containing 1,000 ng/g wet weight IR-CRH, the plasma level was elevated to 180 pg/ml. This patient did not have Cushing's syndrome nor an elevated plasma adrenocorticotropic hormone (ACTH) level. The concentrations of nine peptides (growth hormone-releasing hormone, somatostatin, ACTH, calcitonin, gastrin-releasing peptide, glucagon, vasoactive intestinal peptide, neuropeptide tyrosine and pancreatic polypeptide) were determined in extracts of the 21 IR-CRH-producing tumors. Some of these peptides were frequently found to be produced concomitantly with CRH. The results indicate IR-CRH to be produced by various neuroendocrine tumors, but Cushing's syndrome, due to the CRH, to be very rare. The results also show that CRH-producing tumors produce multiple hormones.

Topics: Adenoma, Islet Cell; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Bombesin; Calcitonin; Carcinoid Tumor; Carcinoma, Small Cell; Chromatography, Gel; Corticotropin-Releasing Hormone; Gastrin-Releasing Peptide; Gastrins; Humans; Hypothalamus; Lung Neoplasms; Neoplasms; Neuroblastoma; Pancreatic Neoplasms; Peptides; Pheochromocytoma; Somatostatin; Thyroid Neoplasms; Vasoactive Intestinal Peptide

We report here the cDNA cloning of a putative gastrin receptor from enterochromaffin-like (ECL) carcinoid tumor of Mastomys natalensis. For this study, we used the polymerase chain reaction technique to amplify transmembrane domain sequences related to rat pancreatic cholecystokinin (CCK)-A receptor from the ECL tumor cDNA library. The amino acid sequence deduced from the cloned cDNA showed 85.7% and 49.0% identity to canine parietal cell gastrin receptor and rat pancreatic CCK-A receptor, respectively. Ligand binding studies using COS-7 cells transfected with the cDNA showed the same binding specificity for gastrin and CCK-8 as the gastrin receptor on the Mastomys carcinoid tumor membrane. Both gastrin and CCK-8 elevated free cytosolic calcium concentration in COS-7 cells expressing the cloned receptor. RNA blot analysis revealed the expression of the gastrin receptor in both Mastomys stomach and brain.

Topics: Amino Acid Sequence; Animals; Base Sequence; Calcium; Carcinoid Tumor; Cloning, Molecular; DNA; Dogs; Female; Gastrins; Molecular Sequence Data; Muridae; Pancreas; Parietal Cells, Gastric; Rats; Receptors, Cholecystokinin; Sequence Homology, Nucleic Acid; Sincalide; Stomach Neoplasms; Transfection

In rats, hypergastrinemia due to achlorhydria produced by antisecretory drugs or resection of the gastric fundus leads to enterochromaffinlike (ECL) cell hyperplasia and gastric carcinoids. In humans, achlorhydria due to pernicious anemia may also lead to ECL cell hyperplasia and multicentric gastric carcinoids in as many as 5% of cases. To examine the apparent gastrin dependence of gastric ECL carcinoids, three patients were studied (2 men aged 59 and 73 years; 1 woman aged 45 years) who had pernicious anemia, serum gastrin concentrations of greater than 1000 ng/L (greater than 1000 pg/mL), and multicentric gastric carcinoids. Antrectomy resulted in normalization of serum gastrin levels within 8 hours and disappearance of carcinoids in 6-16 weeks. In each of the three patients, a focus of microcarcinoid was found at 12-18 months. Further follow-up in each of the three patients 21-30 months after antrectomy again showed no carcinoids or ECL cell hyperplasia. It is concluded that multicentric ECL gastric carcinoids in patients with pernicious anemia and achlorhydria appear to be gastrin dependent and disappear after normalization of serum gastrin by antrectomy. Antrectomy rather than total gastrectomy may be the most appropriate treatment for this condition.

Topics: Aged; Anemia, Pernicious; Carcinoid Tumor; Enterochromaffin Cells; Female; Gastrins; Gastroscopy; Humans; Hyperplasia; Male; Middle Aged; Pyloric Antrum; Stomach Neoplasms

The regulation of gastrin secretion from antral G-cells is of major importance in the physiologic control of acid secretion. Gastrin secretion is highly dependent upon gastric intraluminal pH and is inhibited significantly by a pH of less than 3.0. Acute gastric alkalinization greater than pH 6.0 with antisecretory agents such as H2-receptor antagonists or H+/K+ ATPase inhibitors has little impact on fasting serum gastrin levels but promotes an enhanced sustained rise in meal-stimulated gastrin release. Courses of standard therapy with both H2-antagonists and H+/K+ inhibitors cause a significant rise in 24 h integrated plasma gastrin levels that is inversely correlated to the 24-h integrated gastric acidity. The rise in fasting or integrated plasma gastrin levels observed in patients treated with H2-antagonists is small and of unclear clinical significance. Therapy with antisecretory agents leads to earlier ulcer relapse than with other agents. A variety of factors have been proposed to explain the earlier ulcer relapse rate, including secondary hypergastrinemia with rebound acid hypersecretion after discontinuation of the drug. Secondary hypergastrinemia may also lead to tolerance to prolonged courses of H2-antagonists therapy with a decrease in acid inhibition. This may contribute to break-through ulcer recurrence during maintenance H2-antagonist therapy. However, the relative importance of hypergastrinemia and tolerance to H2-antagonists compared with other factors such as baseline gastric acid secretion, smoking status, nonsteroidal anti-inflammatory drug use, and Helicobacter pylori status is difficult to assess.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphatases; Carcinoid Tumor; Gastrins; H(+)-K(+)-Exchanging ATPase; Histamine H2 Antagonists; Humans; Peptic Ulcer; Stomach Neoplasms

A histologic and immunohistochemical study was carried out in 23 unselected nonantral gastric carcinoids and their precursor lesions classified according to Solcia et al. None of the patients showed Zollinger-Ellison syndrome. Two variants of carcinoids showing distinctive pathologic and pathogenetic characteristics were identified on the basis of presence or absence of associated chronic atrophic gastritis type A (A-CAG). Chronic atrophic gastritis type A was found in 19 cases showing either single or multiple neoplasms, tumor extension limited to the mucosa or submucosa, consistent endocrine cell precursor changes in extratumoral mucosa, and consistent hypergastrinemia and/or G cell hyperplasia. Associated precursor lesions were only hyperplastic in all but two cases with single carcinoids whereas they were also dysplastic in all but one case with multiple carcinoids. The four tumors arising in nonatrophic mucosa were all single, more aggressive, and not associated with extratumoral endocrine cell proliferations or with signs of gastrin hypersecretion. Tumor cells were diffusely immunoreactive for chromogranin A and synaptophysin but usually negative for chromogranin B or HISL-19. Scattered serotonin cells were found in ten carcinoids. They were more frequent in infiltrating than in intramucosal tumors as were the less represented pancreatic polypeptide cells whereas the reverse was found for alpha-subunit-containing cells. These results are of relevance for tumor pathogenesis and may provide the rationale for a less aggressive therapeutic approach in the patients.

Topics: Adolescent; Adult; Aged; Carcinoid Tumor; Chromogranin A; Chromogranins; Female; Gastric Mucosa; Gastrins; Glycoprotein Hormones, alpha Subunit; Humans; Hyperplasia; Immunohistochemistry; Male; Membrane Proteins; Middle Aged; Neoplasms, Multiple Primary; Nerve Tissue Proteins; Pancreatic Polypeptide; Precancerous Conditions; Serotonin; Stomach Neoplasms; Synaptophysin

The authors have established a long-term tissue culture cell line (BON) derived from a metastatic human carcinoid tumor of the pancreas. The cells have been in continuous passage for 46 months. Tissue culture cells produce tumors in a dose-dependent fashion after SC inoculation of cell suspensions in athymic nude mice. BON tumors, grown in nude mice, are histologically identical to the original tumor; they possess gastrin and somatostatin receptors, synthesize serotonin and chromogranin A, and have a doubling time of approximately 13 days. The antiproliferative effects of the long-acting somatostatin analogue, SMS 201-995 (300 micrograms/kg, t.i.d.), and 2% alpha-difluoromethylornithine on BON xenografts in nude mice were examined. Tumor size was significantly decreased by day 14 of treatment with either agent and at all points of analysis thereafter until the animals were killed (day 33). In addition, tumor weight, DNA, RNA, and protein contents were significantly decreased in treated mice compared with controls. Establishment of this human carcinoid xenograft line, BON, provides an excellent model to study further the biological behavior of carcinoid tumors and the in vivo effect of chemotherapeutic agents on tumor growth.

Topics: Animals; Binding Sites; Carcinoid Tumor; Cell Division; Cell Line; DNA; Eflornithine; Gastrins; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Octreotide; Pancreatic Neoplasms; Proteins; Receptors, Somatotropin; RNA; Tumor Cells, Cultured

Forty-five patients with metastatic neuroendocrine tumors were treated with a regimen of etoposide 130 mg/m2/d for 3 days plus cisplatin 45 mg/m2/d on days 2 and 3. Both drugs were given by continuous intravenous infusion. Among 27 patients with well-differentiated carcinoid tumors or islet cell carcinomas, only two partial objective tumor regressions were observed (7%). Among 18 patients prospectively classified as having anaplastic neuroendocrine carcinomas, however, there were nine partial regressions and three complete regressions, an overall regression rate of 67%. For anaplastic disease, the median duration of regression was 8 months (range to 21 months). Tumor response was unrelated to primary site, endocrine hyperfunction, or prior therapy experience. The median survival of all patients with anaplastic tumors was 19 months; this seemed favorable when considering the small experiences with these rare tumors reported in the literature. Toxicity, which was severe for most patients, consisted primarily of vomiting, leukopenia, thrombocytopenia, anemia, alopecia, and neuropathy. The anaplastic neuroendocrine tumor is strongly responsive to therapy with combined etoposide and cisplatin. Patients with undifferentiated carcinomas, originating in typical neuroendocrine tumor sites (small and large bowel, pancreas, and stomach) or of unknown origin, who have consistent histologic findings by light microscopy should be evaluated for this possibility with appropriate immune staining or electron microscopy.

Topics: Adenoma, Islet Cell; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoid Tumor; Carcinoma; Cisplatin; Etoposide; Female; Gastrins; Glucagon; Humans; Hydroxyindoleacetic Acid; Male; Middle Aged; Pancreatic Neoplasms; Prospective Studies; Remission Induction; Survival Rate

We have evaluated the peripheral blood natural killer (NK) cell activity and the in vitro effect of recombinant gamma-interferon (r gamma-IFN) on NK cell activity in 23 patients with a neuroendocrine tumour of the pancreas, small intestine or liver, and 23 healthy controls. Patients with a gastrinoma showed a NK cell activity which was not different from that of the control group, whereas patients with another type of neuroendocrine tumour had a decreased NK cell activity compared to the controls (p less than 0.05) and the gastrinoma patients (p less than 0.02). The impaired NK cell activity in these patients was as such not related to the presence of liver metastasis or performance status of the patients. r gamma-IFN significantly stimulated the NK cell activity in patients and controls. However, the cytotoxic response of the patients with a hormone production other than gastrin remained lower than in the two other groups. Follow-up studies in 8 patients showed NK cell activities not to vary with stable disease, to decrease with progressive disease, and to increase with regression of disease. In conclusion, NK cell activity is suppressed in patients with neuroendocrine tumours that produce hormones other than gastrin. This impairment is not related to the presence of metastasis but seems to be related to the course of the disease.

Topics: Adult; Aged; Carcinoid Tumor; Cell Line; Female; Gastrinoma; Gastrins; Gastrointestinal Hormones; Humans; Interferon-gamma; Intestinal Neoplasms; Killer Cells, Natural; Lipoma; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Recombinant Proteins; Somatostatinoma; Tumor Cells, Cultured

Topics: Animals; Carcinoid Tumor; Female; Gastrins; Humans; Neoplasms, Hormone-Dependent; Rats; Stomach; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Carcinoid Tumor; Gastrectomy; Gastric Mucosa; Gastrins; Humans; Neoplasm Staging; Prognosis; Stomach Neoplasms

Mastomys is a rodent with a high incidence of spontaneous carcinoids in the acid-producing part of the stomach. The present study was conducted to examine whether hypergastrinemia could promote tumor formation in this species. Mastomys, 4 months of age, were treated for 5 months with omeprazole subcutaneously, 100 mumol/kg body weight daily, and compared with mastomys given the vehicle only. The plasma gastrin concentration and the number of antral gastrin cells were increased in the omeprazole-treated group. The hypergastrinemia was associated with elevated histidine decarboxylase activity and histamine content in the oxyntic mucosa and with a trophic effect on the oxyntic mucosa and the enterochromaffin-like cells. However, no carcinoid tumors were observed, possibly because the strain of mastomys studied does not produce carcinoids spontaneously.

Topics: Animals; Carcinoid Tumor; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Histamine; Histidine Decarboxylase; Injections, Subcutaneous; Male; Muridae; Omeprazole; Radioimmunoassay; Stomach Neoplasms; Time Factors

Topics: Age Factors; Carcinoid Tumor; Esophagitis, Peptic; Female; Gastrins; Humans; Male; Middle Aged; Omeprazole; Peptic Ulcer; Risk Factors; Sex Factors; Stomach Neoplasms

Topics: Achlorhydria; Animals; Carcinoid Tumor; Gastrins; Humans; Omeprazole; Rats; Stomach Neoplasms

Studies in the rat have shown that partial gastric corpectomy, in which about 75% of the acid-producing oxyntic mucosa was removed, leads to markedly reduced acid secretion and a feedback increase in the plasma gastrin levels. Ten weeks after operation, the gastric enterochromaffin (ECL)-like cell density in the remaining part of the oxyntic mucosa had increased significantly. In the present study, the effects on the gastric ECL cells of lifelong persistent hypergastrinemia induced by partial (75%) corpectomy have been investigated. Seventy-five partially corpectomized rats and 40 control rats were investigated for plasma gastrin and oxyntic mucosal changes in a 124-week study. The partially corpectomized rats showed increased plasma gastrin levels after the operation; the mean increase compared with the controls was almost 10-fold during the entire study. The remaining oxyntic mucosa of the partially corpectomized rats differed from that of control rats in two respects, showing first general hypertrophy and second a marked hyperplasia of argyrophil ECL cells. The degree and incidence of these changes increased towards the end of the study, i.e., in the aging rats. An age-related increase in ECL-cell density occurred spontaneously also in the control rats but to a lesser extent than in the partially corpectomized group. ECL-cell carcinoids were found in the oxyntic mucosa of 26 of the 75 partially corpectomized rats. The first carcinoid was found 78 weeks after the beginning of the study. Six rats with carcinoids (23%) were found before week 104 (2 years) and the remainder, 20 (77%), were discovered later. No carcinoid tumor was found in the control rats. It is concluded that lifelong hypergastrinemia induced by partial corpectomy leads to the development of ECL-cell carcinoids in the oxyntic mucosa of some rats towards the end of their life span. This observation strongly supports the hypothesis that the gastric ECL-cell carcinoids found in rats treated with antisecretory drugs are caused by long-standing hypergastrinemia developing secondary to inhibition of gastric acid secretion.

Topics: Animals; Body Weight; Carcinoid Tumor; Enterochromaffin Cells; Feedback; Female; Gastric Mucosa; Gastrins; Hyperplasia; Hypertrophy; Parietal Cells, Gastric; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms; Time Factors

A 51 year-old woman with vomitus, intermittent epigastric pain and heartburn had chronic sideropenic anemia. Gastroscopy revealed a subcardial, submucosal tumor. The tumor was removed totally by endoscopic polypectomy. Histologically it was identified as a carcinoid. The endocrinologic examination showed hypergastrinemia caused by chronic atrophic gastritis. The association of this gastric carcinoid with chronic atrophic gastritis type A, hypergastrinemia, hyperplasia of the gastrin-producing antral cells and micronodular hyperplasia of endocrine cells in the gastric fundus, confirms the hypothesis about the pathogenesis of these extremely rare gastric tumors.

Topics: Carcinoid Tumor; Chronic Disease; Female; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Middle Aged; Stomach; Stomach Neoplasms

Specific binding sites for human gastrin I (gastrin) were identified in a crude membrane preparation from the gastric carcinoid tumor of Mastomys (Praomys) natalensis. The binding of 125I-gastrin to the carcinoid tumor membrane was saturable, and Scatchard analysis of the data revealed a single class of binding site with a dissociation constant of 139.2 pM and a maximal binding capacity of 23.5 fmol/mg protein. Gastrin and CCK8 equipotently and dose-dependently displaced the binding of 125I-gastrin to the membrane. GTP but not ATP decreased 125I-gastrin binding to the membrane, and removal of Mg2+ attenuated this inhibitory action of GTP. The GTP-induced reduction of 125I-gastrin binding was found to be due to a decrease in binding affinity without a change in binding capacity. These results clearly indicate the presence of specific binding sites for gastrin, probably coupled to guanine nucleotide-binding protein, in the carcinoid tumor membrane of Mastomys, and suggest that gastrin has possible biological actions on these tumors.

Topics: Adenosine Triphosphate; Animals; Carcinoid Tumor; Cell Membrane; Female; Gastrins; Guanosine Triphosphate; Humans; Kinetics; Muridae; Receptors, Cholecystokinin; Stomach Neoplasms

Ninety-nine carcinoid tumors of the duodenum were studied. Seventy-seven patients were followed up for a mean period of 65 months, 20 tumors were autopsy findings, and two patients were unavailable for follow-up. Sixteen tumors (21%) produced metastases, all discovered initially; 3 patients (4%) died from metastatic disease (mean survival, 37 months postoperatively). Features associated with metastatic risk were involvement of muscularis propria, size greater than 2 cm, and the presence of mitotic figures. For 51 tumors, there was no correlation between immunohistochemical somatostatin and history of diarrhea, cholelithiasis, or diabetes mellitus (somatostatin syndrome). Five tumors were associated with Zollinger-Ellison syndrome and had immunohistochemical gastrin, but in the others there was no correlation between ulcer disease and gastrin positivity. Duodenal carcinoids are indolent, especially when small and localized to the submucosa. Immunohistochemical identification of somatostatin and gastrin has little clinical relevance.

Topics: Adult; Aged; Aged, 80 and over; Biopsy; Carcinoid Tumor; Duodenal Neoplasms; Endoscopy; Female; Follow-Up Studies; Gastrins; Humans; Hydroxyindoleacetic Acid; Immunohistochemistry; Male; Middle Aged; Predictive Value of Tests; Prognosis; Somatostatin; Staining and Labeling; Zollinger-Ellison Syndrome

Neuroendocrine cell (carcinoid) tumours have been reported in the acid-secreting part of the stomach of rodents after long-term administration of a range of potent chemically diverse antisecretory agents. Although evidence shows a link between the sequence of acid suppression, hypergastrinaemia, and neuroendocrine cell hyperplasia, other factors are also thought to be involved in neoplastic transformation. Prolonged hypochlorhydria or achlorhydria resulting in bacterial colonization of the stomach may allow the generation of carcinogenic substances. Other as yet unidentified trophic factors may be involved in tumour formation. In view of the potential risks associated with these agents, there must be concern about the possible consequences in man of marked suppression of acid. It seems wise to limit the use of these more potent agents to situations in which conventional therapy has failed and to short-term treatment.

Topics: Animals; Carcinoid Tumor; Female; Gastric Acid; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Humans; Hyperplasia; Male; Mice; Omeprazole; Rats; Stomach Neoplasms; Time Factors; Triazoles

Multifocal gastric carcinoid tumors occasionally develop in patients with pernicious anemia, associated with hyperplasia of endocrine cells in the atrophic and metaplastic gastric body mucosa. This constellation of findings probably requires a trophic drive from hypergastrinemia associated with antral G cell hyperplasia, a consequence of achlorhydria in these patients. We report a case in which antrectomy was performed on such a patient in order to abrogate the trophic stimulus. Antrectomy was followed by resolution of hypergastrinemia and a decrease in the size of polyps endoscopically. Nine months later, the gastric remnant was resected. Using morphometric techniques, endocrine cells in the initial antrectomy specimen (which included body mucosa at the resection line) were compared with those in the subsequently removed gastric body. Antrectomy resulted in striking decreases in number (137 versus 34/mm2; P = 0.0001) and size (93 versus 56 microns2; P = 0.0001) of endocrine cells of body mucosa. The findings suggest that antrectomy may be useful in the management of endocrine cell hyperplasia, and possibly also associated carcinoid tumors, in pernicious anemia.

Topics: Anemia, Pernicious; Carcinoid Tumor; Female; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Middle Aged; Pyloric Antrum; Reproducibility of Results; Stomach Neoplasms

A patient with pernicious anemia, atrophic non-antral gastritis, hypergastrinemia, and widespread hyperplasia of enterochromaffin-like cells and manifest enterochromaffin-like cell carcinoma was followed up during 39 months, including 15 months after gastric resection. In this case normalization of gastrin levels did not prevent the development of multiple gastric carcinoids in the fundic mucosa, suggesting that factors other than gastrin are of importance in the pathogenesis.

Topics: Anemia, Pernicious; Carcinoid Tumor; Follow-Up Studies; Gastrectomy; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Male; Middle Aged; Stomach Neoplasms

The Mastomys (Praomys natalensis) species are a unique natural model in which the bioactivity of gastric carcinoids may be studied. Several investigators have previously demonstrated that these tumors contain large amounts of histamine. In this study we investigated the presence of peptides associated with the neoplasm. The levels and location of gastrin, gastric inhibitory peptide (GIP), neurotensin, peptide YY (PYY), pancreatic polypeptide (PP), glucagon, bombesin, vasoactive intestinal peptide (VIP) and somatostatin (SRIF) were investigated by radioimmunoassay and immunocytochemistry. In addition the distribution of these peptides were evaluated in the gastrointestinal tract of young and old animals to investigate possible age-related changes. PYY and enteroglucagon (EG) were significantly (P less than 0.001) elevated in both tumor tissue (676 +/- 152, 551 +/- 164 pmol/g) and plasma (620 +/- 160, 500 +/- 147 pmol/l) of tumor-bearing animals. Immunocytochemistry revealed PYY- and EG-like immunoreactivity in 20-30% of tumor cells. A significant decrease (P less than 0.05) in bombesin was noted in older animals, but no changes in gastric tissue content of PYY or EG could be detected between young and old animals. Gastrin was not detected in tumors and there were no significant changes in tissue or plasma levels with age. Small bowel concentrations of VIP and PYY were higher in the older mastomys (P less than 0.05). In contrast, colonic levels of bombesin, VIP, somatostatin and PYY were significantly lower (P less than 0.05) in older mastomys compared with young. The age-related changes in several peptides may reflect an adaptive response to acid hypersecretion. The multi-hormonal character of these neoplasms suggests that these tumors develop from a pluripotential stem cell.

Topics: Age Factors; Animals; Bombesin; Carcinoid Tumor; Gastric Inhibitory Polypeptide; Gastrins; Immunohistochemistry; Muridae; Neoplasm Proteins; Neurotensin; Pancreatic Polypeptide; Peptide YY; Peptides; Radioimmunoassay; Stomach Neoplasms; Vasoactive Intestinal Peptide

7 gastrinomes and 1 gastrin-producer complex carcinoma-carcinoid tumor were examined by light and electron microscopical-method and by immunohistochemical method. In six cases, the tumor was in the pancreas or in the wall of duodenum; in two cases its localisation was of extra-gastroenteropancreatic (liver, lymph node). All patients developed Zollinger-Ellison syndrome, three patients bled and one had diarrhea. One patient had other tumors, besides gastrinome, which were characteristic of MEN-I syndrome. By immunohistochemical methods all tumors proved to be gastrin and neuron-specific-enolase positive. In four cases somatostatin positivity, in some cases glucagon, pancreatic polypeptide, S-100 protein, keratin and carcinoembryonal antigen positivity were detected. Relation could not be detected between other polypeptide hormones, produced besides gastrin, and biological behaviour of tumor and clinical symptoms.

Topics: Carcinoid Tumor; Carcinoma; Duodenal Neoplasms; Gastrins; Humans; Pancreatic Neoplasms; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Achlorhydria; Aged; Carcinoid Tumor; Gastrins; Humans; Male; Stomach; Stomach Neoplasms

Long-term administration of some long-acting inhibitors of gastric acid secretion has been associated with the development of gastric enterochromaffin-like (ECL)-cell carcinoids in the rat. It has been argued that short-acting, surmountable histamine H2-receptor blockers such as ranitidine do not cause carcinoids. In this study, female rats (n = 100) were treated for 2 years with the histamine H2-receptor blocker ranitidine, 2 g/kg/day in the diet. Specimens from the stomachs of all rats, including 50 controls, were stained for argyrophil cells. Plasma gastrin and ranitidine levels were measured in separate groups of rats at different times during the study. The mean plasma level of ranitidine was 37.5 mumol/l, measured at midnight when the maximal level after food intake was expected. The resulting acid inhibition was associated with an approximately 3-fold increase in plasma gastrin which persisted throughout the whole period of the study. The ranitidine treatment resulted in a pronounced hyperplasia of gastric ECL cells. In 19 rats carcinoids were found, 4 of which were micro-invasive. No carcinoids were found in the control animals. The results provide further support for the gastrin mechanism, i.e. that the development of ECL-cell carcinoids in the rat gastric mucosa is a consequence of prolonged hypergastrinaemia and is not a unique effect of any individual acid-inhibiting drug.

Topics: Animals; Carcinoid Tumor; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Ranitidine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Time Factors

A duodenal carcinoid with a diameter of 9 mm was cut serially into 5 microns thin sections from one end to the other. Every fourth section was stained with the argyrophil method of Grimelius, while representative sections in between were used for immunohistochemical analyses. The tumor displayed an argyrophil reaction and was chromogranin A immunoreactive and S-100 protein negative. Furthermore, the majority cell population was gastrin-immunoreactive, while minor cell populations stained for somatostatin and serotonin. The serial sectioning revealed that the tumor arose from differentiated endocrine cells located in the mucosal crypts. In the duodenal mucosa in the vicinity of the tumor the epithelial crypts exhibited an increased number of endocrine cells, preferentially displaying gastrin immunoreactivity. The results indicate that in this particular case the carcinoid tumor arose from hyperplastic and differentiated endocrine cells in the epithelial crypts of the duodenal mucosa.

Topics: Biogenic Amines; Carcinoid Tumor; Chromogranin A; Chromogranins; Duodenal Neoplasms; Gastrins; Humans; Immunohistochemistry; Male; Middle Aged; S100 Proteins; Serotonin; Silver; Somatostatin; Staining and Labeling

In order to compare histologic subtypes and endocrine profiles, immunohistochemical and silver stains were performed on 120 appendiceal carcinoids. Forty-three were predominantly insular; 21 were mixed insular, glandular, and trabecular; 33 were goblet cell; 17 were tubular; and five were clear cell carcinoids. Insular, mixed, and clear cell carcinoids were generally diffusely argentaffin and positive for chromogranin, neuron-specific enolase (NSE), and serotonin. Occasional tumors of insular or mixed patterns had scattered cells that stained weakly for glucagon, calcitonin, adrenocorticotrophic hormone (ACTH), somatostatin, cholecystokinin (CCK), human pancreatic polypeptide (HPP), or gastrin. Most had S-100-positive sustentacular cells. Less than half were positive for carcinoembryonic antigen (CEA). Many were cytokeratin-positive, but often focally. Goblet cell carcinoids contained few endocrine cells, but these were strongly argentaffin and positive for serotonin in nearly all, and positive for HPP in almost a third. Tubular carcinoids lacked argentaffinity and serotonin but were diffusely and strongly positive for glucagon. All goblet cell and tubular carcinoids were diffusely positive for CEA and cytokeratin. Somatostatin stained strongly in a single tumor, which had psammoma bodies and was in a patient with neurofibromatosis. In all groups, argentaffinity correlated with serotonin positivity, and argyrophilia with chromogranin positivity, although the latter was somewhat more sensitive. We conclude that among appendiceal carcinoids, the endocrine content varies according to histologic subtype.

Topics: Adrenocorticotropic Hormone; Appendiceal Neoplasms; Carcinoembryonic Antigen; Carcinoid Tumor; Cholecystokinin; Chromogranins; Diagnosis, Differential; Follow-Up Studies; Gastrins; Glucagon; Humans; Immunohistochemistry; Keratins; Pancreatic Polypeptide; Phosphopyruvate Hydratase; S100 Proteins; Serotonin; Somatostatin

The clinical, microscopic, immunohistochemical and ultrastructural features of 7 gastrinomas and 1 combined carcinoma-carcinoid tumor were evaluated. The tumors were located in the pancreas or duodenal wall in 6 cases, and on extragastro-enteropancreatic sites in 2 (liver or peripancreatic lymph node). All patients had the Zollinger-Ellison syndrome, 3 of them with additional bleeding and 1 with diarrhea. One patient with gastrinoma had additional tumors characteristic of the MEN-I syndrome. Immunohistochemistry showed gastrin and neuron-specific enolase-positivity in all of the tumors. Somatostatin was found in 4 cases, and single cell glucagon, pancreatic polypeptide. S-100 protein, keratin as well as carcino-embryonic antigen positivity in another few. Additional hormone production did not appear to be connected with biological behaviour of the tumors or with the clinical symptoms.

Topics: Adolescent; Adult; Aged; Carcinoembryonic Antigen; Carcinoid Tumor; Duodenal Neoplasms; Female; Gastrins; Glucagon; Humans; Immunohistochemistry; Keratins; Male; Microscopy, Electron; Middle Aged; Pancreatic Neoplasms; Pancreatic Polypeptide; Phosphopyruvate Hydratase; S100 Proteins; Somatostatin; Zollinger-Ellison Syndrome

Oral administration of ciprofibrate, a potent hypolipidemic compound, to rats for 2 or more weeks at doses of 20 mg/kg/day or more resulted in hypertrophy and increased eosinophilia of the oxyntic cells in the gastric mucosa. Ultrastructural evaluation revealed small secretory canaliculi with small microvilli in these cells, changes consistent with the inhibition of acid secretion. After longer administration (e.g., greater than 2 months at 20 mg/kg/day), hyperplasia of the neuroendocrine cells (in particular, the enterochromaffin-like cells) was present in the fundic mucosa of the stomach. After life-time (2-year) administration at 10 mg/kg/day, neuroendocrine cell hyperplasia was accompanied by formation of malignant carcinoid tumors in the fundus of 5 of 59 male and 1 of 60 female rats. In contrast, administration of ciprofibrate to mice at 20 mg/kg/day for 2 months was not associated with oxyntic or neuroendocrine cell changes, a finding consistent with the lack of gastric carcinoid tumors in a 2-year mouse study. Similarly, no significant changes were induced in the marmoset stomach by doses as high as 100 mg/kg/day for 6 months. These findings are consistent with the hypothesis that the formation of gastric carcinoid tumors following ciprofibrate administration is a phenomenon that occurs specifically in those species such as the rat where this compound has significant gastric antisecretory activity.

Topics: Animals; Callitrichinae; Carcinoid Tumor; Clofibrate; Clofibric Acid; Fibric Acids; Gastric Mucosa; Gastrins; Hypolipidemic Agents; Male; Mice; Microscopy, Electron; Rats; Rats, Inbred F344; Stomach Neoplasms

We report a case of gastric enterochromaffin-like carcinoid tumour associated with fundic chronic atrophic gastritis and hypergastrinaemia of antral origin. The clinical and pathological features of this association are reviewed. The probable causal relationship between these argyrophil carcinoids and hypergastrinaemia is also discussed.

Topics: Adult; Carcinoid Tumor; Female; Gastrins; Gastritis; Humans; Stomach Neoplasms

The number and density of argyrophil endocrine cells were morphometrically calculated in gastric fundal mucosal biopsy specimens taken from 64 patients with pernicious anaemia (five with gastric carcinoids, 15 with nodular argyrophil cell hyperplasia, 44 with diffuse argyrophil cell hyperplasia) and from 14 healthy controls. Similar calculations were also made on the ileal mucosa away from the tumour of 10 patients with ileal carcinoids and 10 controls. In the stomach, the argyrophil cell counts were twice as high in the patients with pernicious anaemia than in controls and the densities in the whole mucosa or in the epithelial structures were similarly three to five times higher. The cell counts in the patients showed positive correlation with the serum gastrin concentration. The patients with nodular argyrophil cell hyperplasia and gastric carcinoids formed a uniform group with the highest cell counts and serum gastrin concentrations; the difference between the groups was in the longer duration of pernicious anaemia in the patients with carcinoid tumours. On the other hand, no endocrine cell hyperplasia was seen in those with ileal carcinoids. It is concluded that fundal mucosal endocrine cells show an increase in patients with pernicious anaemia that is related to the gastrin concentration. This phenomenon may favour the development of hyperplastic endocrine cell nodules and, eventually, carcinoid tumours.

Topics: Adult; Aged; Anemia, Pernicious; Carcinoid Tumor; Cell Count; Epithelium; Female; Gastric Fundus; Gastric Mucosa; Gastrins; Gastrointestinal Neoplasms; Humans; Hyperplasia; Intestinal Mucosa; Male; Middle Aged

A clinical and anatomic analysis was made of duodenal carcinoid tumors in 5 male patients (mean age 43.2 years). The tumors were present in the areas of the major duodenal papilla (in 3 cases), those of the bulb (1) and horizontal part of the duodenum (1). They were multiple in 2 cases. Clinically, signs of gastrin activity, i. e. recurring ulcers in various segments of the gastrointestinal tract (Zollinger-Ellison syndrome), were most common. Other changes included impairments in the biliary tract and liver. The causes of death were hepatic and renal insufficiencies (2 cases), thrombohemorrhagic events (2). In the closed glands, nesidioblastosis and thyroid C cell hyperplasia were detected, one case having type I multiple endocrinal neoplasia (adrenal corticosteroma, pancreatic apudoma). In three cases, the metastases invaded into the liver and lymph nodes. Direct correlation was not established between the tumor sizes, metastases and hormonal activity signs. All the tumors had not been recognized in the patients' life. The paper discusses if it is possible to make life-time diagnosis.

Topics: Adult; Aged; Biliary Tract; Carcinoid Tumor; Duodenal Neoplasms; Gastrins; Humans; Kidney; Liver Cirrhosis; Male; Middle Aged

The histamine H2-receptor antagonist SK&F 93479 induced gastric neuroendocrine (carcinoid) ECL-cell tumor formation in 6/34 male and 8/37 female rats treated for 22-24 months at 1,000 mg/kg/day po. Focal ECL-cell hyperplasia was present in 21/34 males and 15/37 females, with local infiltration through the muscularis mucosae in half these cases. No focal hyperplasias or carcinoids were present after 200 mg/kg/day po treatment. Investigative studies showed evidence for marked and sustained hypergastrinemia increasing on chronic dosing which was capable of restoring gastric acid secretion and pH to near control values. Using morphometric analysis of immunoperoxidase anti-chromogranin A stained sections, a dose-related and time-dependent neuroendocrine ECL-cell hyperplasia was correlated with the sustained elevated hypergastrinemia. A 21-month mouse oncogenicity study showed no focal neuroendocrine cell hyperplasia or carcinoid tumor induction, but a diffuse neuroendocrine cell hyperplasia and an increase in multifocal glandular hyperplasia of the oxyntic mucosa was observed in mice treated with 1,000 mg/kg SK&F 93479 po. The morphological changes observed in both rat and mouse were considered to be secondary to the hypergastrinemia resulting from the pharmacological suppression of gastric acid secretion by SK&F 93479. These changes were also observed to a more marked degree following omeprazole treatment and were only slight following oxmetidine treatment in the rat.

Topics: Animals; Carcinogens; Carcinoid Tumor; Enterochromaffin Cells; Female; Gastric Acid; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Hydrogen-Ion Concentration; Hyperplasia; Imidazoles; Male; Mice; Omeprazole; Pyrimidinones; Rats; Stomach Neoplasms

The presence of a number of regulatory peptides (bombesin, gastrin, glucagon, somatostatin, calcitonin and ACTH) was compared in 30 typical carcinoid tumours and 27 well differentiated neuroendocrine carcinomas (atypical carcinoids) using conventional immunocytochemistry. Strong immunostaining for one or more peptide was observed in 97% of the typical carcinoids (29/30) whereas only 67% of the neuroendocrine carcinomas showed immunoreactivity. The peptide most frequently detected in typical carcinoids was bombesin (67%), while gastrin was more common in neuroendocrine carcinomas (44%). Immunoreactivity for more than one peptide was present in 33 tumours and in three cases, six different peptides were detected. The study shows that immunoreactivity to various peptides is more common in typical carcinoids than well differentiated neuroendocrine carcinomas. The significance of these findings is discussed.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Aged; Antibodies, Monoclonal; Bombesin; Bronchial Neoplasms; Calcitonin; Carcinoid Tumor; Female; Gastrins; Glucagon; Humans; Immunoenzyme Techniques; Male; Middle Aged; Peptides; Somatostatin

Multicentric gastric carcinoids develop infrequently in association with atrophic gastritis, achlorhydria, and hypergastrinemia. These unusual tumors, thought to arise from proliferation of enterochromaffin-like (ECL) cells, have not been shown to secrete any measurable biogenic amines and usually grow slowly. Hypergastrinemia, which results from antral G cell stimulation secondary to atrophic gastritis, is believed to be the trophic stimulus, but alternative explanations include production of gastrin-releasing factor (GRF) or gastrin per se by the tumor. We recently encountered two patients with pentagastrin-resistant achlorhydria and multiple gastric carcinoids. Neither had symptoms of carcinoid syndrome. Urinary 5-hydroxyindoleacetic acid and serum human pancreatic polypeptide, vasoactive intestinal peptide, and motilin values were normal. Fasting gastrin values were nearly 1800 pg/ml. Antrectomy and regional lymphadenectomy was performed in each patient. The tumors were locally invasive with penetration through the submucosa. One patient had regional lymph node involvement, and one had an isolated hepatic metastasis. Immunohistochemical stain tests were positive in both patients for neuron-specific enolase and chromogranin, with focal positive staining for gastrin and serotonin. Serum gastrin levels decreased to less than 25 pg/ml after antrectomy. Evaluation with upper gastrointestinal endoscopy and biopsy examination 4 to 6 months after antrectomy showed complete regression of disease in one patient and residual neoplasm in one patient, despite normal serum gastrin levels. Additional studies with careful long-term follow-up will be needed to determine whether antrectomy eliminates the hypergastrinemia associated with enterochromaffin-like hyperplasia and leads to regression of disease.

Topics: Adult; Carcinoid Tumor; Female; Gastrectomy; Gastrins; Gastroscopy; Humans; Male; Middle Aged; Pyloric Antrum; Stomach; Stomach Neoplasms

Among 196 patients examined in 1972-1985 because of pernicious anemia (PA), 105 patients under the age of 76 years were invited for gastroscopic screening, and 71 patients (68%) participated. Gastroscopy revealed carcinoid tumor(s) in 5 patients (7%) but no case of carcinoma. In addition, one patient with gastric carcinoid, 5 patients with adenocarcinomas and one with a concomitant carcinoid and carcinoma had already been diagnosed earlier in the overall PA group on the basis of clinical symptoms. Thus, within a follow-up of 0-20 years (mean 7 years) the total frequency of gastric carcinoid tumors was 4% and that of carcinoma 3%. Patients with carcinoid tumors had a long duration of PA and young age of onset; these cases were not necessarily those with the highest serum gastrin levels. Even though most gastric carcinoids are small subclinical tumors of uncertain clinical significance, their unexpectedly high frequency, combined within the risk of carcinoma in PA, might indicate the need for gastroscopic follow-up, at least in cases of juvenile onset PA.

Topics: Adult; Aged; Anemia, Pernicious; Carcinoid Tumor; Female; Gastrins; Gastroscopy; Humans; Male; Middle Aged; Stomach Neoplasms

Thirty-three patients with advanced, metastatic APUD tumors (islet cell, carcinoid, or medullary carcinomas of the thyroid) were treated with etoposide as a single agent. Of 29 evaluable patients, four (14%) had partial responses (95% confidence limits, 1%-26%). Toxic effects seen were those previously reported for etoposide as a single agent. Etoposide has activity in APUD tumors; further studies with this agent are indicated.

Topics: Adenoma, Islet Cell; Adult; Aged; Calcitonin; Carcinoembryonic Antigen; Carcinoid Tumor; Drug Evaluation; Etoposide; Female; Gastrins; Humans; Hydroxyindoleacetic Acid; Male; Middle Aged; Thyroid Neoplasms

Nine patients with pancreatic apudomas (seven gastrinomas, one glucagonoma, one tumor secreting a substance P-like component) and nine with metastasized carcinoid tumors were treated with a somatostatin analogue (SMS 201-995), administered subcutaneously twice daily for 3 days. Treatment was pursued for 2 to 12 months in nine patients in whom SMS was clinically and/or biologically beneficial. In gastrinomas, SMS decreased plasma gastrin in all but one patient, inhibited the residual gastric acid secretion under H2-blockers and improved diarrhea; in the glucagonoma patient, glucagonemia decreased and skin lesions disappeared. In carcinoid syndrome, clinical efficacy was partial and inconstant; daily 5-hydroxyindole acetic acid (5-HIAA) output was slightly decreased. Plasma substance P levels decreased in six patients with initially high concentrations. No antitumoral activity or side effects have been so far evidenced. SMS 201-995 is a useful, well-tolerated agent in secreting pancreatic apudomas and to a lesser extent in carcinoid syndrome, where high-dosage regimens may be required.

Topics: Adult; Aged; Carcinoid Tumor; Female; Gastric Juice; Gastrins; Glucagonoma; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Octreotide; Pancreatic Neoplasms; Somatostatin; Substance P; Zollinger-Ellison Syndrome

Topics: Adult; Carcinoid Tumor; Female; Gastrins; Glucagon; Glucagonoma; Humans; Hydroxyindoleacetic Acid; Male; Middle Aged; Pancreatic Neoplasms; Serotonin; Somatostatin; Zollinger-Ellison Syndrome

Topics: Achlorhydria; Antacids; Carcinoid Tumor; Enterochromaffin Cells; Gastrins; Gastritis, Atrophic; Histamine H2 Antagonists; Humans; Hyperplasia; Peptic Ulcer; Risk; Somatostatin; Stomach Neoplasms; Vagotomy, Proximal Gastric

We have described a case of MEN-I in association with a benign pulmonary carcinoid tumor. Two other members of our patient's family also had MEN-I and benign carcinoid or adenomatous lung tumors. Hormonal assays of our patient's carcinoid lesion showed the production of gastrin, gastrin-releasing peptide, neurotensin, and somatostatin, but not serotonin, a hormonal profile distinct from those previously reported in carcinoid lung tumors unassociated with MEN-I.

Topics: Carcinoid Tumor; Female; Gastrin-Releasing Peptide; Gastrins; Humans; Lung Neoplasms; Middle Aged; Multiple Endocrine Neoplasia; Neurotensin; Pedigree; Peptides; Somatostatin

The prevalence of gastric carcinoid in fundic atrophic gastritis is probably greater than previously recognized. To help elucidate the clinicopathology of this syndrome, we report a series of 11 patients with solitary or multicentric carcinoid tumors. In these patients, basal gastrin levels and density of fundic mucosal endocrine cells were greater than that for patients with uncomplicated fundic atrophic gastritis (p = 0.02 and p = 0.002, respectively). The polypoid tumors, of which the largest measured 30 mm, frequently showed characteristic endoscopic features. They were all situated in the fundic mucosa, which showed micronodular endocrine cell hyperplasia. Small, endoscopically evident tumorlets, or "early carcinoids," limited to the lamina propria were observed in some patients. These lesions may represent intermediate stages between micronodules and invasive carcinoids, all of which infiltrated at least into the muscularis mucosae of the gastric wall. Although some consistent characteristics features were noted, there were structural variations. The cells were argyrophil but nonargentaffin and did not stain with conventional mucus stains. They did not stain significantly for carcinoembryonic antigen (CEA). The secretory product of these tumors remains to be identified. Ultrastructurally, some tumors were mainly composed of enterochromaffinlike (ECL) cells, but in other tumors most of the cells could not be classified.

Topics: Carcinoid Tumor; Endoscopy; Gastrins; Gastritis; Gastritis, Atrophic; Humans; Microscopy, Electron; Prospective Studies; Stomach Neoplasms; Syndrome

Low gastric acid output leads to hypergastrinaemia, which results in the stimulation of dormant enterochromaffin-like cells in the gastric mucosa; these can progress to carcinoid tumours. A patient is described with this syndrome. Reduction in gastrin levels by antrectomy resulted in regression of the carcinoids.

Topics: Anemia, Pernicious; Carcinoid Tumor; Female; Gastrins; Humans; Middle Aged; Postoperative Period; Pyloric Antrum; Stomach Neoplasms

Topics: Achlorhydria; Animals; Carcinoid Tumor; Cell Division; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Humans; Stomach Neoplasms

The concomitant occurrence of neuropeptide-reactive endometrial carcinoma and ileal carcinoid tumor represents an observation that has been unreported until now. We have seen two patients with this rare combination of tumors. The endometrial carcinomas in these cases manifested focal immunoreactivity for neuron-specific enolase; in addition, one contained rare cells showing positive staining for gastrin, and the other displayed focal content of substance P. The carcinoid tumors seen in each case demonstrated immunocytochemical positivity for neuron-specific enolase and vasoactive intestinal polypeptide, and one also exhibited immunoreactivity for gastrin. Whether this association of neoplasms represents a syndromic complex or a coincidence is a matter of speculation at present.

Topics: Aged; Carcinoid Tumor; Female; Gastrins; Histocytochemistry; Humans; Ileal Neoplasms; Nerve Tissue Proteins; Substance P; Uterine Neoplasms

Topics: Bombesin; Bronchial Neoplasms; Carcinoid Tumor; Carcinoma, Small Cell; Chorionic Gonadotropin; Diagnosis, Differential; Female; Gastrin-Releasing Peptide; Gastrins; Humans; Immunoenzyme Techniques; Lung Neoplasms; Middle Aged; Peptides; Phosphopyruvate Hydratase

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.

Topics: Adolescent; Aged; Biopsy; Carcinoid Tumor; Chronic Disease; Female; Gastric Fundus; Gastric Mucosa; Gastrins; Gastritis; Gastritis, Atrophic; Humans; Hyperplasia; Male; Microscopy, Electron; Middle Aged; Precancerous Conditions

Omeprazole is a long acting inhibitor of gastric acid secretion in different species including rat and dog. Due to the long duration of action, steady state inhibition at repeated once daily administration is reaches within 4-5 days in dogs and in about 3 days in rats. Daily dosing at high dose levels results in virtually complete 24-hour inhibition of acid secretion in experimental animals. The elimination of the inhibitory feedback effect of acid on gastrin secretion leads to hypergastrinaemia. Because gastrin has a trophic effect on the oxyntic mucosa, the hypergastrinaemia results in a reversible hypertrophy of the oxyntic mucosa and an increased capacity to produce acid following maximal stimulation with exogenous secretagogues after discontinuing treatment. Despite the increased capacity to produce acid, basal acid secretion seems to be unchanged. The pronounced hypergastrinaemia which occurs during long-term treatment with high doses rapidly normalizes after discontinuing treatment. The hyperplasia of the oxyntic endocrine ECL cells, and the eventual development of gastric ECL cell carcinoids after lifelong treatment of rats with high doses, can also be attributed to the hypergastrinaemia developing after almost complete elimination of gastric acid secretion in these animals.

Topics: Animals; Anti-Ulcer Agents; Benzimidazoles; Carcinoid Tumor; Dogs; Female; Gastric Acid; Gastric Mucosa; Gastrins; Hypertrophy; Male; Omeprazole; Rats; Stomach Neoplasms; Time Factors

Gastrin is a trophic stimulant of the acid producing gastric mucosa. Experiments have been carried out in rats, in which chronic states of either low or high serum gastrin levels were induced by surgical manipulation or drug treatment. A relationship between circulating gastrin and a trophic effect could be demonstrated in the oxyntic mucosa, but not in the pancreas and small intestine. Endocrine cells in the oxyntic mucosa (the ECL cells and A-like cells) are among the target cells for the trophic action of gastrin. The functional significance of these two cell populations is unknown. There is much experimental evidence indicating that they are under functional as well as tropic control of gastrin. The vagus nerve also exerts trophic control on the oxyntic mucosa, including the endocrine cells within it. This could be demonstrated by one-sided truncal vagotomy which caused atrophy of the mucosa and hypoplasia of endocrine cells (notably the ECL cells) on the denervated side of the stomach. Conversely, portacaval shunt greatly increased the number of ECL cells. There was no hypergastrinaemia after portacaval shunt, and no trophic effect on other cell types in the oxyntic mucosa. The factors responsible for the ECL cell proliferation after portacaval shunting remain unknown. Tumours may arise spontaneously from the ECL cells. Such neoplasias have been described in Mastomys (Praomys natalensis) and in man. ECL cell hyperplasia and neoplasia in man, but not in Mastomys, are usually associated with hypergastrinaemia either as a result of a gastrin producing tumour or as a result of achylia (sometimes associated with pernicious anaemia). It is unlikely that gastrin alone is responsible for the neoplasia, though it is quite likely that long-standing hypergastrinaemia triggers or facilitates a sequence of events that ultimately leads to tumour formation, via diffuse ECL cell hyperplasia.

Topics: Animals; Atrophy; Carcinoid Tumor; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Parietal Cells, Gastric; Portacaval Shunt, Surgical; Stomach Neoplasms; Vagus Nerve

Nonantral gastric carcinoid tumours in association with pronounced hypergastrinaemia are reported in 6 patients. It is suggested that the hypergastrinaemia, as a result of lack of a negative acid feedback inhibition in an achlorhydric stomach, promoted the tumour development, possibly initiated by action of carcinogenic nitrosamines, in the gastric juice.

Topics: Adult; Aged; Carcinoid Tumor; Female; Gastric Mucosa; Gastrins; Humans; Middle Aged; Stomach Neoplasms

Small intramucosal tumours in the oxyntic area of the rat stomach were observed in an oncogenicity study with omeprazole. The tumours could be defined as carcinoids of enterochromaffin-like (ECL) cell origin. ECL cells occur exclusively in oxyntic mucosa and respond to the trophic hormone gastrin with a proliferation that becomes exaggerated in old rats. Inhibition of gastric acid secretion is known to induce hypergastrinaemia in rats. According to the common concept of endocrine cells, a sustained hormonal stimulation with gastrin may induce a continuous gradient between hyperplasia and neoplasia of the ECL cells. The tumours found are thus to be regarded as hormone-induced endocrine tumours of the ECL cells in the stomach. The ECL-cell tumours of the rats in the oncogenicity study appeared to belong to the low-malignancy type of carcinoids and did not make their appearance until the end-life period of the study. The sex and species differences observed may be explained by inherent differences in gastrin response, spontaneous ECL cell density or in responsiveness to gastrin-stimulated ECL cell proliferation between sexes and species.

Topics: Animals; Carcinoid Tumor; Chromaffin System; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrins; Male; Mice; Microscopy, Electron; Omeprazole; Rats; Rats, Inbred Strains; Sex Characteristics; Species Specificity; Stomach Neoplasms

Multiple polypoidal carcinoid tumours of the stomach were found in 5 patients with achlorhydria (4 of whom had pernicious anaemia) as a result of autoimmune atrophic gastritis. The tumours were small (nearly all less than 1 cm diameter) and appeared to grow very slowly, if at all; no significant enlargement or complications were seen during periods of observation of up to 6 years. No extragastric hormonal syndromes were identified. They differed from the carcinoid tumours usually found in the intestinal tract by being composed of argyrophil (not argentaffin) cells of the enterochromaffin-like (ECL) type. Fasting plasma levels of gastrin, which is believed to be trophic to ECL cells, were very high in all patients. Thus, chronic hyperplasia of gastric ECL cells (as a result of hypergastrinaemia) may have been responsible for development of the tumours. Long-term, uninterrupted achlorhydria produced by potent inhibitors of gastric acid secretion might therefore predispose to carcinoid tumours of the stomach.

Topics: Achlorhydria; Aged; Anemia, Pernicious; Carcinoid Tumor; Female; Gastrins; Humans; Male; Middle Aged; Neoplasms, Multiple Primary; Stomach Neoplasms

Neuroendocrine tumours of the lung and gut are known to possess bombesin-like immunoreactivity. The recent observation that gastrin releasing peptide (GRP), a 27 amino acid peptide isolated from the porcine intestine, may be the mammalian analogue of bombesin led us to look for this peptide in a variety of human neoplasms. Formalin-fixed tissues from 85 tumours were examined by the immunoperoxidase technique, using specific antisera to the GRP molecule (1-27) and the GRP fragment (1-16). Intense cytoplasmic GRP immunoreactivity was seen in thyroid medullary carcinomas (3/3), carcinoids of lung, pancreas, and intestine (22/36), and paragangliomas (2/3). Less frequent staining was present in pulmonary small cell (oat cell) carcinomas (1/8) and pituitary adenomas (1/6). Complete absence of immunoreactivity was observed in three phaeochromocytomas, five Merkel cell tumours, six neuroblastomas and 15 non-neuroendocrine tumours. Normal neuroendocrine cells of the thyroid (C-cells) and bronchial mucosa (Kulchitsky cells) exhibited GRP immunoreactivity; nerve fibres from all sites failed to demonstrate staining for GRP. In each positive case, the pattern of staining for GRP (1-27) and GRP (1-16) was identical, although the GRP (1-16) immunostaining was weaker. These findings indicate that bombesin immunoreactivity in human neuroendocrine cells and tumours is attributable to GRP-like molecules and that GRP is a useful marker of neuroendocrine differentiation in many tumours.

Topics: Adenoma; Adrenal Gland Neoplasms; Amino Acid Sequence; Bombesin; Carcinoid Tumor; Carcinoma, Small Cell; Gastrin-Releasing Peptide; Gastrins; Humans; Intestinal Neoplasms; Lung Neoplasms; Neoplasms; Neurosecretory Systems; Pancreatic Neoplasms; Peptides; Pheochromocytoma; Pituitary Neoplasms; Thyroid Neoplasms

Topics: Adult; Appendiceal Neoplasms; Carcinoid Tumor; Gastrins; Humans; Male; Postoperative Period; Serotonin

Clinical, histological, histochemical and ultrastructural characteristics of eight cases of carcinoid tumors of the non-antral portion of the stomach are presented. Four cases with multiple polypoid lesions are accompanied by an increased level of gastrin. A normal level of gastrin was present in the other four cases with isolated tumor and a normal component of endocrine cells in the uninvolved mucosa. In the first group with multiple lesions, the histological and histochemical analysis of the endocrine cells revealed a wide range of appearances: a) "simple hyperplasia", b) "nodular hyperplasia", and c) carcinoid tumor. These aspects suggested a different pathogenesis for the carcinoid tumors of the non-antral portion of the stomach with possible therapeutical implications.

Topics: Achlorhydria; Adult; Aged; Carcinogens; Carcinoid Tumor; Chromaffin System; Enterochromaffin Cells; Female; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Precancerous Conditions; Stomach; Stomach Neoplasms

A young woman presented with acromegaly and amenorrhea-galactorrhea with hypersomatotropinemia and hyperprolactinemia. In addition, she had hypergastrinemia with abnormal secretory dynamics and evidence of a large pituitary tumor with suprasellar extension and erosion of the floor of the sella turcica. Evaluation of secretory diarrhea revealed a large abdominal tumor, which on removal was found to be a carcinoid of the jejunum. Postoperatively, the acromegaly, amenorrhea-galactorrhea, and hypergastrinemia resolved, and the pituitary returned to normal size, with regrowth of the sella floor. The carcinoid tumor was shown by immunoperoxidase staining to contain GH-releasing hormone.

Topics: Acromegaly; Adult; Amenorrhea; Carcinoid Tumor; Diarrhea; Female; Galactorrhea; Gastrins; Humans; Jejunal Neoplasms; Lactation Disorders; Paraneoplastic Endocrine Syndromes; Pituitary Gland; Pregnancy; Tomography, X-Ray Computed

A total of 87 surgical cases of gastric carcinoma including 3 carcinoid tumors were investigated with the methods of silver reaction and immunoperoxidase stain for 8 different brain-gut hormones. Argyrophil (AP) cells were demonstrated in 38 cases (44%), argentaffin (AF) cells in 18 (21%) and endocrine cells in 13 (14%). The occurrence of endocrine cells had no relation with histological types. Glicentin cells were demonstrated in 10 cases, somatostatin in 7, motilin in 3, beta-endorphin in 2 and gastrin in one. Endocrine cells appeared generally in small numbers except one carcinoid tumor which had numerous somatostatin cells. No single cell positive for more than two kinds of hormones could be demonstrated. Two undifferentiated carcinomas looking like carcinoid tumors had argyrophil cells and endocrine cells of either somatostatin or beta-endorphin. These results suggest that carcinoid-like carcinoma or endocrine cell carcinoma may lie on the intermediate state between carcinoma and carcinoid tumor.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Carcinoid Tumor; Endorphins; Female; Gastrins; Gastrointestinal Hormones; Glucagon; Histocytochemistry; Humans; Male; Microscopy, Electron; Middle Aged; Motilin; Proglucagon; Protein Precursors; Somatostatin; Stomach Neoplasms; Vasoactive Intestinal Peptide; Vasopressins

A consecutive series of 38 lung carcinoid tumours (36 surgical and two necropsy specimens) was studied. Histopathological features and amine and peptide hormone immunoreactivity were correlated with gross characteristics (size, location) and clinical data. Peripheral carcinoids were detected a decade later than central carcinoids and tended to be bigger. In general, the histological characteristics of peripheral and central carcinoids were similar; atypical features, however, were more common in peripheral carcinoids. Most carcinoids contained many argyrophilic cells (58%). Although argentaffinic cells were not found, serotonin immunoreactive cells were present in 32% of the tumours. Peptide hormone immunoreactivity (adrenocorticotrophic hormone (ACTH), calcitonin, somatostatin, gastrin) was rare. In one case massive ACTH production had caused clinically manifest Cushing's syndrome. In two other cases few ACTH immunoreactive cells were found and in one case calcitonin immunoreactive cells were present. The relative rarity of hormone production in lung carcinoids and the predominantly benign course of the tumour preclude the use of peptide hormone production as a prognostic indicator.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Aged; Calcitonin; Carcinoid Tumor; Cushing Syndrome; Female; Gastrins; Hormones, Ectopic; Humans; Immunoenzyme Techniques; Lung Neoplasms; Male; Middle Aged; Serotonin; Somatostatin

A clinicopathological and immunohistochemical study was carried out on 32 cases of neuroendocrine tumors of the rectum. Typical carcinoids consisted of 27 cases, histologically showing uniform round to columnar cells forming solid alveolar nests and ribbon-like or trabecular arrangement. Neuroendocrine carcinomas consisted of 5 cases in which tumor cells with prominent nuclear atypism were arranged in a ribbon-like or trabecular fashion and formed gland-like structures. There were also small round tumor cells resembling lymphocytes. The prognosis of neuroendocrine carcinomas is very poor with marked tumor invasion of lymphatics and veins resulting in liver metastases and death within one year after operation. Thirty cases out of the 32 showed a positive argyrophil reaction, while immunohistochemistry of 29 cases revealed more than one peptide hormone in 23 cases. The most common hormone was somatostatin being present in 18 of the 23 tumors and glucagon in 16 of the 23 tumors. Gastrin/CCK and calcitonin were proven in 6 of the 23 tumors and in 4 of the 23 tumors, respectively. On the other hand, more than two hormones was present in 15 of the 23 tumors examined. Histologically, neuroendocrine tumors have a very wide spectrum. Histogenetically, typical carcinoids and neuroendocrine carcinomas are considered to be of the same origin with the former showing morphological and functional differentiation to endocrine cells and the latter being more undifferentiated.

Topics: Adult; Aged; Calcitonin; Carcinoid Tumor; Cholecystokinin; Female; Gastrins; Glucagon; Humans; Liver Neoplasms; Male; Middle Aged; Prognosis; Rectal Neoplasms; Somatostatin

The authors report the case of a patient with a typical carcinoid syndrome and a severe hypoglycemia due to hyperinsulinism. He was found to have an ileal carcinoid tumor with hepatic metastasis and no evidence of pancreatic insulinoma at surgery and autopsy. By assaying serotonin and insulin in the tumor and in the supernatants of the culture derived from hepatic metastasis, the authors have been able to show that both hormones were produced by the carcinoid tissue. Cultured cells also synthesized minute amounts of gastrin and thyrocalcitonin.

Topics: Blood Glucose; Calcitonin; Carcinoid Tumor; Cells, Cultured; Cytoplasmic Granules; Gastrins; Humans; Ileal Neoplasms; Insulin; Insulin Secretion; Liver Neoplasms; Male; Malignant Carcinoid Syndrome; Microscopy, Electron; Middle Aged; Serotonin

Topics: Adult; Carcinoid Tumor; Female; Gastrins; Humans; Male; Middle Aged; Serotonin; Thymus Neoplasms; Zollinger-Ellison Syndrome

Nineteen patients with primary duodenal carcinoid were analysed retrospectively, and eight of the tumors were immunocytochemically examined. One tumor contained somatostatin, two tumors gastrin, two tumors both these peptides, and one tumor contained serotonin. In two tumors no peptide or amine could be demonstrated. Eight patients had ulcer symptoms and nine had gallstone disease. Only four patients had metastatic spread in spite of long delay. Five-year survival was 75% in 12 operated patients. No patient died of the tumor per se. It is concluded that a simple excision seems justified when the tumor is smaller than 2 cm, while probably more extensive surgery is needed when the tumor is larger or when there is local spread. Modern techniques of histofluorescence and immunocytochemistry facilitating a more precise classification will probably result in a better understanding as to symptomatology, prognosis, and making possible better treatment in the heterogenous group of carcinoid tumors.

Topics: Adult; Aged; Carcinoid Tumor; Duodenal Neoplasms; Female; Gastrins; Hormones, Ectopic; Humans; Male; Middle Aged; Paraneoplastic Endocrine Syndromes; Serotonin; Somatostatin

This report presents a case of multicentric gastric carcinoid (gastrin containing) tumors of the fundus associated with achlorhydria and pernicious anemia. It is suggested that stimulation of the antral G cells and possibly fundic argyrophilic cells by achlorhydria associated with atrophic gastritis may lead to hyperplasia, and eventually to neoplasia in the latter, in the form of gastric carcinoid with gastrin production.

Topics: Achlorhydria; Anemia, Pernicious; Carcinoid Tumor; Gastric Fundus; Gastric Mucosa; Gastrins; Histocytochemistry; Humans; Immunoenzyme Techniques; Male; Middle Aged; Pyloric Antrum; Staining and Labeling; Stomach Neoplasms

A rare case with gastrin-producing carcinoid, adenocarcinoma and xanthoma of the stomach is presented. A 69-year-old male underwent total gastrectomy with splenectomy and distal pancreatectomy. The histological type of the carcinoid was poorly differentiated (type D), and argyrophil cell carcinoma. Immunoperoxidase staining of the carcinoid was positive for gastrin and negative for glucagon, somatostatin or insulin. The histological findings of the carcinoma were tub 2, medullary, INF alpha, se, ly 2, v 1, ow(-), aw(-), n 1. Histologically, the xanthoma consisted of foamy macrophages accumulated in the lamina propria.

Topics: Adenocarcinoma; Aged; Carcinoid Tumor; Gastrins; Humans; Male; Neoplasms, Multiple Primary; Stomach Diseases; Stomach Neoplasms; Xanthomatosis

A middle-aged woman with evidence of chronic cholestasis of several years and no previous abdominal surgery was initially thought to have primary biliary cirrhosis. Clinical evaluation disclosed a well-developed secondary biliary cirrhosis apparently caused by extrahepatic obstruction due to a 1 X 2 cm neoplasm of the periampullary duodenum. Electron microscopy and immunofluorescent studies showed the neoplasm to be a G-cell adenoma. Wide local excision has resolved the biliary obstruction. Bening or slow-growing duodenal tumors, if they involve the ampulla of Vater, may produce prolonged partial extrahepatic obstruction and secondary biliary cirrhosis.

Topics: Adult; Apudoma; Carcinoid Tumor; Duodenal Neoplasms; Female; Gastrins; Humans; Liver Cirrhosis, Biliary

An endocrine pancreatic tumour that had not caused any endocrine symptoms was examined by histological, immunocytochemical and electron microscopic techniques. The majority of the tumour cells were argentaffin and contained secretory granules of the enterochromaffin cell type. Immunocytochemically a minority of tumour cells reacted to antisera against beta-endorphin, met- and leu-enkephalin, gastrin, somatostatin and ACTH. The tumour was thus multihormonal, and appeared to be more closely related to the classic Carcinoid tumours of the mid-gut than to most pancreatic endocrine tumours.

Topics: Adrenocorticotropic Hormone; Aged; Carcinoid Tumor; Endorphins; Enkephalins; Female; Gastrins; Humans; Microscopy, Electron; Pancreatic Neoplasms; Somatostatin

An argentaffin carcinoid tumour of the caecum which contained serotonin (167 micrograms/g) and consisted predominantly of EC1-cells, was analysed for the presence of peptides using immunohistochemical, biochemical and pharmacological methods. A very high content of 3.9 micrograms/g of immunoreactive substance P was found. The distribution of cells staining positively for substance P matched that of cells containing serotonin. While some immunoreactive somatostatin (3.2 ng/g) was present in the tumour, neurotensin, glucagon, gastrin, and motilin were not found. Part of the substance P immunoreactivity measured most likely represents authentic substance P: it behaved like substance P in two chromatographic systems and in two bioassays, and its activity on the guinea pig ileum was abolished by specific tachyphylaxis towards substance P.

Topics: Carcinoid Tumor; Cecal Neoplasms; Female; Fluorescent Antibody Technique; Gastrins; Glucagon; Humans; Middle Aged; Motilin; Neurotensin; Serotonin; Somatostatin; Substance P

Twenty typical mid-gut carcinoid tumours were examined for the presence of gastrin immuno-reactivity to antisera specific to the C-terminal pentapeptide or to the mid-portion of gastrin-17. Pentagastrin immuno-reactivity was found in seven cases, and in one of these reactivity to antiserum against the mid-portion of gastrin-17 was also observed. The results are in accordance with the previous observation that argyrophil tumour cells are present in mid-gut carcinoid tumours and may explain why peptic ulcer disease is sometimes seen in association with the carcinoid syndrome.

Topics: Adult; Aged; Animals; Carcinoid Tumor; Enterochromaffin Cells; Female; Gastrins; Humans; Ileal Neoplasms; Immunoenzyme Techniques; Male; Middle Aged; Rabbits

Topics: Carcinoid Tumor; Female; Gastric Mucosa; Gastrins; Gastroscopy; Humans; Middle Aged; Stomach Neoplasms

Topics: Carcinoid Tumor; Gastrins; Humans; Stomach Neoplasms

Pancreas and gut hormones are involved in many endocrine and gastrointestinal diseases. Radioimmunoassays for these hormones have proved particularly valuable in diagnosis, localisation and control of treatment of endocrine tumours, of which many are mixed. An estimate based on ten years experience in a homogenous population of 5 million inhabitants (Denmark) suggests, that endocrine gut tumour-syndromes on an average appear with an incidence of 1 patient per year/syndrome/million. At present six different syndromes are known: 1) The insulinoma syndrome, 2) The Zollinger-Ellison syndrome.3) The Verner-Morrison syndrome. 4) The glucagonoma syndrome. 5) The somatostatinoma syndrome, and 6) the carcinoid syndrome. Accordingly diagnostically valuable RIAs for pancreas and gut hormones include those for insulin, gastrin, VIP, HPP, glucagon, somatostatin, and presumably also substance P. It is probably safe to predict that the need for gut and pancreas hormone RIAs within the next decade will increase greatly in order to assure proper management of tumours producing gastroentero-pancreatic hormones.

Topics: Adenoma, Islet Cell; Carcinoid Tumor; Cholecystokinin; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptides; Humans; Insulin; Intestinal Neoplasms; Motilin; Pancreatic Hormones; Pancreatic Neoplasms; Pancreatic Polypeptide; Radioimmunoassay; Secretin; Somatostatin; Substance P; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Topics: Apudoma; Carcinoid Tumor; Female; Gastrins; Gastrointestinal Neoplasms; Glucagon; Humans; Insulin; Insulin Secretion; Pancreatic Neoplasms; Pancreatic Polypeptide; Somatostatin; Vasoactive Intestinal Peptide

In a patient with a duodenal ulcer, with acid hypersecretion and moderately disturbed gastrin secretion tests, immunocytochemical examination of the vagotomy-antrectomy specimen revealed a pyloric microgastrinoma (clinically silent and apparently benign) and focal antropyloric gastrinosis. These localised lesions represent a new variant of abnormalities affecting the gastrin cells in the context of hypersecretory duodenal ulcers.

Topics: Adenoma; Carcinoid Tumor; Duodenal Ulcer; Gastric Juice; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Pyloric Antrum; Pylorus; Stomach Neoplasms

Topics: Animals; Carcinoid Tumor; Cholecystokinin; Dogs; Enterochromaffin Cells; Gastric Inhibitory Polypeptide; Gastric Mucosa; Gastrins; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptides; Humans; Intestinal Mucosa; Intestinal Neoplasms; Pancreatic Polypeptide; Rats; Secretin; Somatostatin; Stomach Neoplasms; Vasoactive Intestinal Peptide

1. Due to their common origin from the neural crest the hormonogenic cells of the intestinal tract show similar cyto-chemical and ultra-structural characteristics. 2. Hyperplasiae and tumors of these cells lead to excessive hormone production with its consequences on the reacting organs. 3. Hormone producing tumors can be confined to one organ only, but as multiple endocrine adenomatosis they can afflict several organs. 4. Diagnosis of most hormone producing tumors is possible with the adequate radio-immunologic tests. Radiologic and endoscopic examinations can contribute to the localization of the tumor. 5. Surgical resection of the tumor or of the reacting organs impaired by the overproduction of hormones from the tumor is the indicated therapy. Medicamentous therapy is rarely successful. 6. The growth of most hormonogenic tumors is relatively slow. Rates of survival of up to 30 years have been known, even after formation of metastases of the tumor. Effects of hormone overproduction on other organs can reduce the prognosis.

Topics: Adenoma; Carcinoid Tumor; Diarrhea; Gastrectomy; Gastrins; Humans; Hypokalemia; Intestinal Neoplasms; Multiple Endocrine Neoplasia; Pancreas; Paraneoplastic Endocrine Syndromes; Syndrome; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Carcinoid Tumor; Carcinoma, Small Cell; Gastrins; Gastrointestinal Neoplasms; Glucagon; Humans; Intestinal Mucosa; Islets of Langerhans; Neurosecretory Systems; Paraneoplastic Endocrine Syndromes; Peptides

The authors report three anatomoclinical studies concerning apparently moderately aggressive endocrine tumors developped in the sub-mucosa of the duodenal bulb (2 cases) and of the pyloro-bulbar region (1 case), not connected with the pancreas, and occuring in the absence of a parietal ectopic pancreas. Two of these tumors were ulcerous but the associated syndromes (pains and hemorrhage) did not evoke, clinically, a Zollinger-Ellison syndrome. However, examination with immunofluorescence showed the presence of immunoreactive gastrine in a large number of cells. Having found some similar cases in the literature, the authors precise the features of these silent pyloro-duodenal gastrinomas: it is a variety of carcinoids or of "carcinoid-islet cell tumors". The cells contain argyrophile granules (Grimelius stain) which correspond in electron microscopy to neuro-secretory granules that may be quite different from G. granules. In the absence of significant clinical signs and of a radio-immunologic blood test, the presence of immunoreactive gastrin in the cells is the main feature for the diagnostic of these tumors. These tumors seem to arise from the gastrin cells of the mucosa or from their precursors as is suggested by the transitional forms with the fundus of the glands. Whatever the reason of the peculiar functional behavior, these neoplasms can be easily isolated from the anonymous group of duodenal carcinoids.

Topics: Aged; Carcinoid Tumor; Duodenal Neoplasms; Female; Fluorescent Antibody Technique; Gastrins; Humans; Middle Aged; Pylorus; Stomach Neoplasms

As streptozocin has a toxic effect on gastrin producing cells in some patients with gastrinomas, the action of the drug upon normal gastrin release was evaluated in patients with carcinoid tumours (n=6) and malignant insulinomas (n=2). No acute effects were recorded in 22 instances where gastrin levels were followed during the first 24 hours after infusion of streptozocin. When gastrin levels were compared throughout a course of repeated infusions during months a significant increase was noted. Concentrations were doubled after 6 g streptozocin given during a four months period, and tripled after 10 g in nine months period. One patients developed bleeding duodenal ulcer after a total dose of 6 g. It is concluded that streptozocin does not damage normal G cells, but by some action seems to stimulate gastrin relase. Peptic ulceration may be an important side effect during a long term treatment.

Topics: Adenoma, Islet Cell; Carcinoid Tumor; Female; Gastrins; Humans; Male; Neoplasm Metastasis; Pancreatic Neoplasms; Stomach Neoplasms; Streptozocin

A 65-year-old man with hypergastrinemia associated with the Zollinger-Ellison syndrome was found to have a duodenal "carcinoid-islet cell tumor." Gastrin levels have remained normal for more than 1 year following total gastrectomy and removal of the duodenal tumor. Immunohistochemical studies for gastrin localization revealed positive staining of the tumor and of a population of nonneoplastic G-cells in the adjacent duodenal mucosa and Brunner's glands. These results support the hypothesis that gastrinomas may arise as primary tumors from duodenal G-cells rather than from ectopic pancreatic tissue. "Carcinoidislet cell tumors," like other tumors of APUD-cell origin, may express dual biochemical functions in the form of polypeptide hormone and/or amine secretion. Their content of specific hormonal products may be predicted on the basis of sensitive histochemical and immunohistochemical techniques.

Topics: Adenoma, Islet Cell; Aged; Carcinoid Tumor; Duodenal Neoplasms; Gastrins; Humans; Male; Zollinger-Ellison Syndrome

The neurosecretory cells of the hypothalamus, and the cells of the pituitary gland and the pineal, are here grouped together as a central neuroendocrine division of the APUD series. The larger, peripheral division comprises the remainder of the original series. All the cells are proven or presumptive derivatives of neuroectoderm so that, with the present exception of the parathyroid gland and its products, peptide hormone endocrinology becomes neuroendocrinology. It follows that the pathology of the APUD cell series must be regarded as neuroendocrine and it is suggested that it can best be expressed by the term neurocristopathy (Bolande, 1974). Tumours of the series, properly neurocristomas, are preferably called apudomas because their common cytochemical (APUD) and ultrastructural characteristics provide the pathologist with a ready means of diagnosis.

Topics: Adenoma, Islet Cell; Amines; Animals; Biological Evolution; Calcitonin; Carcinoid Tumor; Cushing Syndrome; Dehydration; Ectoderm; Endocrine System Diseases; Ganglia; Gastrins; Hormones, Ectopic; Humans; Insulin; Insulin Secretion; Neoplasms, Multiple Primary; Neurosecretory Systems; Paraneoplastic Endocrine Syndromes; Peptide Biosynthesis; Secretin; Terminology as Topic; Vertebrates; Zollinger-Ellison Syndrome

Endocrine cells in the normal glandular stomach and gastric carcinoids of mastomys were observed by electron microscopy and at least five types of endocrine cells, EC, G, D-like, R (round-granule) and ECL cells were identified. Of these, four types excepting G cells were recognized in the fundic mucosa. Characteristic in mastomys was a scarcity of endocrine cells in the fundic mucosa, where ECL and R cells were predominant types. Silver impregnation methods including SEVIER-MUNGER's argyrophil reaction of our own modifications were applied to tissue sections and the endocrine cells were examined by electron microscopy. Only EC cells revealed argentaffin granules under the light and electron microscope. R, ECL and some of the G cells were non-argentaffin and argyrophil in reaction and D-like cells and the rest of the G cells failed to show even an argyrophil reaction. Granules of mastomys carcinoid cells, as noted in the previous reports, were non-argentaffin but faintly argyrophil. Mastomys gastric carcinoids were studied by the same method, with special reference to the parent cells of this particular neoplasia. Noteworthily, mastomys gastric carcinoids arise mostly from the fundus, the area where R and ECL cells mainly occur in normal animals. The neoplasms are composed of cells containing granules resembling partly those of R cells and partly those of ECL cells. ECL cells and neoplastic cells in the present investigation have a similar reactivity to SEVIER-MUNGER's method. Considering the generally accepted fact that neoplastic cells may not fully duplicate their parent cells in cytological features, it seems reasonable to presume that R and/or ECL cells might be the parent cells of the mastomys gastric carcinoids. In connection with this assumption histamine has been demonstrated to be produced both in mastomys carcinoid cells and normal ECL cells.

Topics: Animals; Carcinoid Tumor; Enterochromaffin Cells; Gastric Mucosa; Gastrins; Golgi Apparatus; Mice; Rodent Diseases; Stomach Neoplasms

Topics: Adult; Aged; Carcinoid Tumor; Cholinesterases; Esterases; Female; Fluorescent Antibody Technique; Gastrins; Histocytochemistry; Hormones; Humans; Immunochemistry; Kidney Neoplasms; Liver Neoplasms; Male; Microscopy, Electron; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Peptide Biosynthesis; Staining and Labeling

Topics: 5-Hydroxytryptophan; Adrenocorticotropic Hormone; Aldosterone; Carcinoid Tumor; Carcinoma, Adenoid Cystic; Chromaffin System; Cortisone; Female; Gastrins; Humans; Hydroxyindoleacetic Acid; Inclusion Bodies; Insulin; Lymphatic Metastasis; Microscopy, Electron; Middle Aged; Pancreatic Neoplasms; Serotonin

Topics: Adenoma, Islet Cell; Adult; Aged; Carcinoid Tumor; Diarrhea; Female; Gastrins; Humans; Liver Neoplasms; Male; Microscopy, Electron; Middle Aged; Neoplasm Metastasis; Pancreas; Pancreatic Neoplasms; Peptic Ulcer; Zollinger-Ellison Syndrome

Topics: Adenoma; Adult; Aged; Carcinoid Tumor; Diagnosis, Differential; Duodenal Neoplasms; Endocrine Glands; Female; Gastrins; Glucagon; Humans; Hyperparathyroidism; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Parathyroid Neoplasms; Radiography; Stomach Neoplasms; Syndrome; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Adult; Aged; Angiography; Carcinoid Tumor; Celiac Artery; Cytoplasmic Granules; Duodenal Neoplasms; Female; Gastrins; Humans; Insulin; Insulin Secretion; Male; Mesenteric Arteries; Microscopy, Electron; Middle Aged; Pancreatic Neoplasms; Serotonin; Zollinger-Ellison Syndrome

Topics: Carcinoid Tumor; Gastric Acidity Determination; Gastric Juice; Gastrins; Hormones, Ectopic; Humans; Intestinal Mucosa; Intestine, Small; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Peptic Ulcer; Stomach; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Adrenal Gland Neoplasms; Adult; Aged; Biopsy; Carcinoid Tumor; Female; Gastric Mucosa; Gastrins; Humans; Hyperplasia; Male; Microscopy, Electron; Middle Aged; Pedigree; Pituitary Neoplasms; Prospective Studies; Pyloric Antrum; Thyroid Neoplasms; Zollinger-Ellison Syndrome

Topics: Adult; Aged; Carcinoid Tumor; Cholestasis; Duodenal Neoplasms; Duodenal Obstruction; Duodenal Ulcer; Female; Gastrins; Gastrointestinal Hemorrhage; Histamine Release; History, 19th Century; History, 20th Century; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Neoplasm Metastasis; Peptic Ulcer Perforation; Peptides; Prognosis; Serotonin

Topics: Adenoma, Islet Cell; Adult; Carcinoid Tumor; Diagnosis, Differential; Duodenal Neoplasms; Gastric Mucosa; Gastrins; Histamine; Humans; Male; Neoplasms; Peptic Ulcer; Postoperative Complications; Radiography; Serotonin; Tissue Extracts; Zollinger-Ellison Syndrome