gastrins and Multiple-Endocrine-Neoplasia-Type-1

Zollinger-Ellison syndrome (ZES) is a distinct syndrome characterized by hyperchlorhydria-induced peptic ulcer disease and chronic diarrhea. It is the result of a gastrin-excess state caused by a duodenal or pancreatic neuroendocrine tumor referred to as gastrinoma. This gastrin-secreting neuroendocrine tumor is usually sporadic in nature, or part of multiple endocrine neoplasia type 1 syndrome. The high rate of malignancy associated with gastrinomas substantiates the need for early diagnosis. In order to diagnose ZES with laboratory tests, patients under antacid medication are required to stay off proton pump inhibitors for at least one week and H2 receptor antagonists for 48 h. Fasting serum gastrin level measurement serves as an initial and fundamental diagnostic test, boasting a sensitivity of 99%. Gastrinoma patients will present with a gastrin level greater than 100 pg/mL, while a serum gastrin level higher than 1000 pg/mL, in the presence of gastric pH <2, is considered diagnostic. Since more common causes of hypergastrinemia exist in the setting of hypochlorhydria, ruling those out should precede ZES consideration. Such causes include atrophic gastritis, Helicobacter pylori (H. pylori)-associated pangastritis, renal failure, vagotomy, gastric outlet obstruction and retained antrum syndrome. The secretin stimulation test and the calcium gluconate injection test represent classic adjuvant diagnostic techniques, while alternative approaches are currently being introduced and evaluated. Specifically, the secretin stimulation test aids in differentiating ZES cases from other hypergastrinemic states. Its principle is based on secretin stimulation of gastrinoma cells to secrete gastrin, while inhibiting normal G cells. The rapid intravenous infusion of 4 μg/kg secretin over 1 min is followed by gastrin level evaluation at specific intervals post-infusion. Localization of the primary tumor and its metastases is the next diagnostic step when gastrinoma-associated ZES is either suspected or biochemically confirmed. Endoscopic ultrasound has showcased sensitivity as high as 83% for pancreatic gastrinomas and is considered the primary modality in such cases, although its tumor detection rates are substantially lower in duodenal lesions. Gallium-68 radiotracers, especially DOTATOC with positron emission tomography, are currently setting the standard in tumor localization, enhancing traditional imaging techniques and showcasing high sensitivity and specificity.

Topics: Gastrinoma; Gastrins; Humans; Multiple Endocrine Neoplasia Type 1; Proton Pump Inhibitors; Secretin; Zollinger-Ellison Syndrome

The Multiple Endocrine Neoplasia I (MEN1) locus encodes the protein MENIN, which functions as a tumor suppressor protein in neuroendocrine tissues. Gastrinomas are neuroendocrine neoplasms that overproduce the hormone gastrin and can arise sporadically or as part of the MEN1 syndrome, in which mutations in the MEN1 gene lead to loss or inactivation of MENIN protein. Gastrin is a peptide hormone that is primarily synthesized in the gastric antrum and stimulates the secretion of histamine from enterochromaffin-like (ECL) cells and subsequently acid from parietal cells in the gastric corpus. In addition, gastrin exerts a mitogenic function primarily on ECL cells and progenitor cells in the gastric isthmus. Current studies seek to understand how MEN1 mutations generate a mutant MENIN protein that abrogates its tumor suppressor function. Mutations in the MEN1 gene are broadly distributed throughout its nine protein-coding exons, making it difficult to correlate protein structure with its function. Although disruption of the Men1 locus in mice causes functional neuroendocrine tumors in the pituitary and pancreas, gastrinomas do not develop in these transgenic animal models. Prior studies of human gastrinomas suggest that tissue-specific microenvironmental cues in the submucosal foregut may contribute to tumorigenesis by reprogramming of epithelial cells toward the neuroendocrine phenotype. Accordingly, recent studies suggest that neural crest-derived cells are also sensitive to reprogramming when MEN1 is deleted or mutated. Thus, the goal of this report is to review our current understanding of how MENIN modulates gastrin gene expression while highlighting its role in the prevention/suppression of neuroendocrine cell transformation.

Topics: Animals; Gastrinoma; Gastrins; Gene Expression; Humans; Mice; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Proto-Oncogene Proteins; Transcription Factors

Gastric neuroendocrine tumours (NET) are rare. Clinically they are classified in tumours type 1 to 3. The histological classification is according to the WHO 2000 classification for endocrine tumours. NET type 1 occur in coincidence with chronic atrophic gastritis, as single or multiple small tumours. The prognosis of type 1 tumours is excellent, with no tumour related death reported during follow-up. NET type 2 are part of the MEN-1 syndrome. These tumours may be more aggressive and even develop metastasis. However, in most patients with MEN-1 the prognosis is due to other manifestations of the disease as duodenal or pancreatic neuroendocrine tumours. Gastric neuroendocrine tumours type 3 are sporadic tumours without relationship to other gastric pathology. They tend to occur earlier, without sex preference. These tumours may develop an aggressive course, with metastatic disease and an overall poor prognosis. Thus, aggressive surgical therapy is recommended.

Topics: Biopsy; Chronic Disease; Diagnosis, Differential; Duodenal Neoplasms; Enterochromaffin-like Cells; Gastric Mucosa; Gastrinoma; Gastrins; Gastritis, Atrophic; Humans; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Pancreatic Neoplasms; Prognosis; Stomach Neoplasms

Gastrinomas are defined as gastrin producing tumors that are associated with an elevated fasting gastrin serum level, a positive gastrin secretin stimulation test and certain clinical symptoms, e.g. recurrent peptic ulcer disease and occasionally diarrhea, the so-called Zollinger-Ellison syndrome. Most gastrinomas occur in the duodenum (approx. 70%) and not in the pancreas. The duodenal gastrinomas are small, and when they occur in association with the genetic syndrome of multiple endocrine neoplasia type 1 (MEN1), they are multicentric and originate from precursor lesions. The prognosis of duodenal gastrinomas is better than that of pancreatic gastrinomas, since despite early lymph node metastasis they progress slowly to liver metastasis.

Topics: Duodenal Neoplasms; Duodenum; Gastrin-Secreting Cells; Gastrinoma; Gastrins; Humans; Hyperplasia; Multiple Endocrine Neoplasia Type 1; Pancreas; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

Cross sectional imaging in the assessment of gastrinomas has three major applications: Tumor localization (sporadic gastrinoma, MEN I) in patients undergoing primary or secondary surgery. Staging of metastasized tumors, especially assessment of lymph nodes and liver metastases, possibly including a risk analysis prior to liver resection. Post-surgery follow-up and monitoring of bio- or chemotherapy. Detection of primary tumors is strongly correlated with their size. However, the sensitivity of surgical assessment of the mostly small tumors by experienced surgeons is much higher than that of any imaging modality. Of all imaging modalities, endoultrasonography (EUS) followed by Somatostatin receptor scintigraphy (SRS) is the most sensitive modality for the assessment of pancreatic tumors in asymptomatic patients suffering from a MEN-I syndrome. Scintigraphy has the highest sensitivity in tumors of symptomatic patients and in the assessment of metastases. CT and MRI are only second line diagnostic modalities. Their sensitivity is largely dependent on the selection of patients. As a potential application, 3D reconstruction of nearly isotropic CT data sets for the risk assessment prior to liver resection is currently developing. Due to the absent radiation exposure, MRI is increasingly utilized to monitor the response of metastases under systemic therapy, e.g. in clinical trials.

Topics: Angiography; Clinical Trials as Topic; Duodenal Neoplasms; Duodenum; Gastrinoma; Gastrins; Humans; Liver; Liver Neoplasms; Lymphatic Metastasis; Magnetic Resonance Imaging; Multiple Endocrine Neoplasia Type 1; Neoplasm Staging; Pancreas; Pancreatic Neoplasms; Tomography, X-Ray Computed; Ultrasonography; Zollinger-Ellison Syndrome

Somatostatin receptor scintigraphy (SRS) is a valuable method for the detection of somatostatin receptor-positive lesions. Most gastrinomas (over-)express the somatostatin receptor subtype 2 which can be targeted by In-111 labeled Octreotide. Different studies show a high sensitivity of SRS for the localization and staging of gastrinomas. SRS seems to be superior to other non-invasive imaging modalities and has been proven to significantly contribute to patient management. However, the sensitivity depends on the size and exact localization of the tumors. Smaller lesions and lesions located in the duodenum show a significantly lower sensitivity. In any case, SRS belongs to the routine imaging procedure for gastrinomas for localization and staging and can also be used for evaluation of the tumor progression.

Topics: Disease Progression; Duodenal Neoplasms; Gastrinoma; Gastrins; Humans; Indium Radioisotopes; Multiple Endocrine Neoplasia Type 1; Neoplasm Staging; Octreotide; Pancreatic Neoplasms; Radionuclide Imaging; Receptors, Somatostatin; Sensitivity and Specificity

Gastrinoma is the most frequent functional pancreaticoduodenal endocrine tumor in patients with multiple endocrine neoplasia type 1 (MEN1) and one major determinant of mortality in this syndrome. Whether routine surgical exploration should be performed in a patient with MEN1 associated Zollinger-Ellison syndrome (ZES) to possibly reduce the malignant spread and eventually increase survival still remains controversial. There is not only disagreement about the indication for surgical exploration, but also what type of procedure should be performed, since sufficient evidence-based data are not available. The article discusses the available data on treatment strategies of MEN1 associated ZES.

Topics: Disease Progression; Duodenal Neoplasms; Gastrinoma; Gastrins; Humans; Laparoscopy; Multiple Endocrine Neoplasia Type 1; Pancreatectomy; Pancreatic Neoplasms; Pancreaticoduodenectomy; Prognosis; Reoperation; Survival Rate; Zollinger-Ellison Syndrome

The physiologic sequelae of a gastrinoma can be well controlled with medical therapy. The role of surgery has shifted from managing acid hyper-secretion and ulcer complications to preventing metastatic disease and managing symptomatic metastases. With improved methods of imaging for the detection of occult gastrinomas, the prospective evaluation of the role for surgery in altering the natural history of these tumors is now possible.

Topics: Algorithms; Diagnosis, Differential; Disease-Free Survival; Gastrinoma; Gastrins; Humans; Liver Neoplasms; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Sensitivity and Specificity; Tomography, X-Ray Computed; Zollinger-Ellison Syndrome

Gastrinomas are defined as gastrin secreting tumors that are associated with Zollinger-Ellison syndrome (ZES). ZES is characterized by elevated fasting gastrin serum levels, positive secretin stimulation test and clinical symptoms such as recurrent peptic ulcer disease, gastroesophageal reflux disease and occasional diarrhea. Genetically, nonhereditary (sporadic) gastrinomas are distinguished from hereditary gastrinomas, which are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome. In general, duodenal gastrinomas are small and solitary if they are sporadic and multiple as well as hereditary. The sporadic gastrinomas occur in the duodenum or in the pancreas while the hereditary gastrinomas almost all occur in the duodenum. Our series of 77 sporadic duodenal neuroendocrine tumors (NETs) includes 18 patients (23.4%) with gastrinomas and ZES. Of 535 sporadic NETs in the pancreas collected from the NET archives of the departments of pathology in Zurich, Switzerland, and Kiel, Germany, 24 patients (4.5%) suffered from sporadic pancreatic gastrinomas and ZES. These NETs have to be distinguished from tumors with immunohistochemical positivity for gastrin but without evidence of ZES. An additional 19 patients suffered from MEN1 and ZES. These patients showed exclusively duodenal gastrinomas, but not pancreatic gastrinomas. The prognosis of sporadic and MEN1-associated duodenal gastrinomas is better than that of pancreatic gastrinomas, since they progress slowly to liver metastasis. In summary, sporadic and MEN1-associated gastrinomas in the duodenum and pancreas show different clinico-pathological and genetic features. The incidence of sporadic duodenal gastrin-producing tumors is increasing, possibly due to optimized diagnostic procedures. In contrast, pancreatic MEN1-associated gastrinomas seem to be extremely rare. A considerable subset of tumors with immunohistochemical expression of gastrin but without evidence of ZES should be designated as functionally inactive NETs expressing gastrin, but not as gastrinomas.

Topics: Duodenal Neoplasms; Gastrinoma; Gastrins; Germany; Humans; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Prognosis; Switzerland; Zollinger-Ellison Syndrome

In two-thirds of patients with Zollinger-Ellison syndrome (ZES), fasting serum gastrin (FSG) levels overlap with values seen in other conditions. In these patients, gastrin provocative tests are needed to establish the diagnosis of ZES. Whereas numerous gastrin provocative tests have been proposed, only the secretin, calcium, and meal tests are widely used today. Many studies have analyzed gastrin provocative test results in ZES, but they are limited by small patient numbers and methodologic differences. To address this issue, we report the results of a prospective National Institutes of Health (NIH) study of gastrin provocative tests in 293 patients with ZES and compare these data with those from 537 ZES and 462 non-ZES patients from the literature. In 97%-99% of gastrinoma patients, an increase in serum gastrin post secretin (Delta secretin) or post calcium (Delta calcium) occurred. In NIH ZES patients with <10-fold increase in FSG, the sensitivity/specificity of the widely used criteria were as follows: Delta secretin > or =200 pg/mL (83%/100%), Delta secretin >50% (86%/93%), Delta calcium > or =395 pg/mL (54%/100%), and Delta calcium >50% (78%/83%). A systematic analysis of the sensitivity and specificity of other possible criteria for a positive secretin or calcium test allowed us to identify a new criterion for secretin testing (Delta > or =120 pg/mL) with the highest sensitivity/specificity (94%/100%) and to confirm the commonly used criterion for calcium tests (Delta > or =395 pg/mL) (62%/100%). This analysis further showed that the secretin test was more sensitive than the calcium test (94% vs. 62%). Our results suggest that secretin stimulation should be used as the first-line provocative test because of its greater sensitivity and simplicity and lack of side effects. In ZES patients with a negative secretin test, 38%-50% have a positive calcium test. Therefore the calcium test should be considered in patients with a strong clinical suspicion of ZES but a negative secretin test. Furthermore, we found that some clinical (diarrhea, duration of medical treatment), laboratory (basal acid output), and tumoral (size, extent) characteristics correlate with the serum gastrin increase post secretin and post calcium. However, using the proposed criteria, the result of these provocative tests (that is, positive or negative) is minimally influenced by these factors, so secretin and calcium provocative tests are reliable in patients with different clinical,

Topics: Calcium; Eating; Female; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Multivariate Analysis; Prospective Studies; Secretin; Sensitivity and Specificity; Zollinger-Ellison Syndrome

The assessment of fasting serum gastrin (FSG) is essential for the diagnosis and management of patients with the Zollinger-Ellison syndrome (ZES). Although many studies have analyzed FSG levels in patients with gastrinoma, limited information has resulted from these studies because of their small size, different methodologies, and lack of correlations of FSG levels with clinical, laboratory, or tumor features in ZES patients. To address this issue, we report the results of a prospective National Institutes of Health (NIH) study of 309 patients with ZES and compare our results with those of 2229 ZES patients in 513 small series and case reports in the literature. In the NIH and literature ZES patients, normal FSG values were uncommon (0.3%-3%), as were very high FSG levels >100-fold normal (4.9%-9%). Two-thirds of gastrinoma patients had FSG values <10-fold normal that overlap with gastrin levels seen in more common conditions, like Helicobacter pylori infection or antral G-cell hyperplasia/hyperfunction. In these patients, FSG levels are not diagnostic of ZES, and gastrin provocative tests are needed to establish the diagnosis. Most clinical variables (multiple endocrine neoplasia type 1 status, presence or absence of the most common symptoms, prior medical treatment) are not correlated with FSG levels, while a good correlation of FSG values was found with other clinical features (prior gastric surgery, diarrhea, duration from onset to diagnosis). Increasing basal acid output, but not maximal acid output correlated closely with increasing FSG. Numerous tumoral features correlated with the magnitude of FSG in our study, including tumor location (pancreatic > duodenal), primary size (larger > smaller) and extent (liver metastases > local disease). In conclusion, this detailed analysis of FSG in a large number of patients with ZES allowed us to identify important clinical guidelines that should contribute to improved diagnosis and management of patients with ZES.

Topics: Adult; Diagnosis, Differential; Fasting; Female; Gastrinoma; Gastrins; Humans; Liver Neoplasms; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Multivariate Analysis; Pancreatic Neoplasms; Prospective Studies; Zollinger-Ellison Syndrome

Topics: Diagnosis, Differential; Gastrinoma; Gastrins; Humans; Indium Radioisotopes; Lymph Node Excision; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Secretin; Survival Rate

Duodenal and pancreatic endocrine tumors are uncommon and their surgical treatment is often difficult. The management of these tumors has changed with recent advancements in tumor localization, intraoperative hormone measurements, standardized surgical techniques, and a better understanding of the genetic basis of multiple endocrine neoplasia syndrome. We present our experience with 191 endocrine tumors and elaborate the contemporary management of functioning duodenopancreatic endocrine tumors.

Topics: Duodenal Neoplasms; Endosonography; Gastrinoma; Gastrins; Gastrointestinal Agents; Humans; Insulinoma; Liver Neoplasms; Magnetic Resonance Imaging; Multiple Endocrine Neoplasia Type 1; Octreotide; Pancreatectomy; Pancreatic 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

Topics: Diagnosis, Differential; Gastrinoma; Gastrins; Humans; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Prognosis; Zollinger-Ellison Syndrome

The role of gastrin in the pathophysiology of two diseases affecting the human stomach, the Zollinger Ellison syndrome (ZES) and the pernicious anemia (PA), is reviewed. Both diseases present chronic hypergastrinemia but from different origins. The ZES is characterized by the occurrence of ectopic endocrine gastrin-secreting tumors and PA by a fundic atrophic gastritis leading to complete atrophy of fundus and resulting in achlorhydria. In PA, the lack of acid induces continuous gastrin cell activation and is responsible for the subsequent gastrin hypersynthesis and secretion. In ZES, hypergastrinemia causes hypertrophy of the oxyntic mucosa, which, in addition, displays hyperplasia of parietal and mucus cells. In both diseases, hypergastrinemia also induces the hyperproliferation of enterochromaffin-like endocrine cells in the fundic mucosa, which can offer all aspects from hyperplasia, then dysplasia, until true carcinoid tumor. The influence of antisecretory treatments and MEN 1 in the ZES as well as that of several other factors and antrectomy in PA on the behavior of the different gastric cells is evoked. Finally, the role that gastrin and its receptor play in the maintenance of the normal development of gastric mucosa and gastric acid secretion is emphasized by results observed in gene knockout models.

Topics: Anemia, Pernicious; Animals; Atrophy; Autoimmune Diseases; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Hypertrophy; Mice; Mice, Knockout; Multiple Endocrine Neoplasia Type 1; Zollinger-Ellison Syndrome

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

With insulinoma, Zollinger-Ellison syndrome is one of the most common functional islet-cell tumour. Since it is a life-threatening condition, needing appropriate management, the diagnosis must be accurately established. This paper reviews the clinical situations leading to suspect the diagnosis and the biological tests, mainly the secretin test, that confirm the diagnosis. The different ways of performing the secretin test and the respective results are presented. This review will also focus on some aspects of the diagnosis of multiple endocrine neoplasia type 1 in these patients.

Topics: Age of Onset; Diagnosis, Differential; Female; Gastric Acid; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Prognosis; Zollinger-Ellison Syndrome

Gastrinomas secrete gastrin and cause symptoms related to gastric acid hypersecretion that can be controlled by antisecretory medications. Primary tumors are located within the pancreas or duodenum and 60% metastasize. Liver metastases are associated with decreased survival. Localization studies especially somatostatin receptor scintigraphy are indicated to image the extent of disease. Surgery is indicated to potentially cure the patient, or control the malignant tumoral process and prolong survival.

Topics: Diagnostic Imaging; Duodenal Neoplasms; Gastric Acid; Gastrinoma; Gastrins; Humans; Liver Neoplasms; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin; Survival Rate; Zollinger-Ellison Syndrome

The rationale for a multifaceted operative procedure in all MEN 1 patients with pancreaticoduodenal neuroendocrine disease who present without liver metastases is presented. The results in 36 patients with MEN 1 ZES are encouraging in that more than two-thirds are eugastrinemic and none have liver metastases after follow-up as long as 20 years.

Topics: Adult; Duodenal Neoplasms; Female; Follow-Up Studies; Gastrins; Hormones; Humans; Liver Neoplasms; Male; Mass Screening; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Octreotide; Pancreatectomy; Pancreatic Neoplasms; Radionuclide Imaging; Radiopharmaceuticals; Zollinger-Ellison Syndrome

Gastrin is synthesized and secreted mostly in a heptadecapeptide form from neurocrine G cells located in the antrum. The biologically active sequence of the molecule is a C-terminal pentapeptide, which has been conserved across many species. Transcriptional regulation of gastrin mRNA synthesis is positively regulated by transforming growth factor-alpha (TGF-alpha) and inhibited by somatostatin (SST). The inactive precursor form is converted to the active molecule by several post-translation processing steps which include cleavage, C-terminal amidation, glycosylation, phosphorylation and sulfation. Aberrations in processing steps generate incompletely processed forms, particularly glycosylated progastrin, which may act as autocrine growth factors for gastrointestinal neoplasms. Gastrin release is stimulated by luminal aromatic amino acids and inhibited by a decrease in luminal pH. Other gastrin agonists include beta-adrenergic agents, acetylcholine, gastrin-releasing peptide (bombesin), TGF-alpha, and possibly the gastric pathogen, Helicobacter pylori. The principal peptide inhibitor of gastrin release is SST. The major physiological roles of gastrin include stimulation of acid secretion, regulation of mucosal cell lineage and mucosal cell proliferation. The fundic enterochromaffin-like (ECL) cell is the principal cellular transducer of the gastrin-acid signal. Activation of its gastrin/CCKB receptor results in histamine synthesis and release with consequent activation of the fundic parietal cell H2 receptor. An increase in luminal pH caused by acid inhibitory pharmacotherapy agents (particularly proton pump inhibitors) results in hypergastrinemia and ECL cell hyperplasia. Gastric carcinoids however appear occur in patients with multiple endocrine neoplasia type I syndrome, suggesting that an associated genomic defect is necessary. Gastrin is thus both a potent gastrointestinal trophic and histamine secretory agent. As a hormone it is a paradigm in the elucidation of both cellular secretory and growth factor induced cell proliferation.

Topics: Enterochromaffin-like Cells; Gastric Acid; Gastrin-Secreting Cells; Gastrins; Humans; Multiple Endocrine Neoplasia Type 1

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

Use of a standardized meal stimulation test has been recommended for the early diagnosis of pancreaticoduodenal endocrine tumours (PETs) in patients with multiple endocrine neoplasia type 1 (MEN 1). The diagnostic value of this test was re-evaluated.. In a prospective, controlled trial 58 standardized meal stimulation tests (563 kcal) were performed in 12 patients with MEN 1 and histologically, biochemically and/or radiologically confirmed PETs (group 1), 11 carriers of an MEN 1 mutation with no evidence of PETs (group 2) and in 27 healthy controls (group 3). Serum pancreatic polypeptide (PP) and gastrin concentrations were measured before and during the test meal.. Patients in group 1 had significantly higher mean basal serum PP and gastrin concentrations than patients in group 2 and controls (P < 0.05). In all three groups an increase in serum PP was observed after meal stimulation, but there was no significant difference between the groups. No increase in gastrin level was found in any of the groups after meal stimulation.. The standardized meal stimulation test does not reliably indicate the presence of PETs in patients with MEN 1, whereas raised basal serum PP and gastrin levels do. The expensive and time-consuming meal test can be excluded from MEN 1 screening programmes.

Topics: Adult; Aged; Duodenal Neoplasms; Female; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Mutation; Pancreatic Neoplasms; Pancreatic Polypeptide; Prospective Studies

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

Loss of the tumor suppressor protein menin is a critical event underlying the formation of neuroendocrine tumors (NET) in hormone-expressing tissues including gastrinomas. While aberrant expression of menin impairs its tumor suppression, few studies explore the structure-function relationship of clinical multiple endocrine neoplasia, type 1 (. We examined the function of somatic and germline mutations and a variant of

Topics: Animals; Gastrins; Hormones; Humans; Mice; Multiple Endocrine Neoplasia Type 1; Mutation; Pancreatic Neoplasms; Proto-Oncogene Proteins; Transcription Factors

Patients with multiple endocrine neoplasia 1 syndrome (MEN1) often develop multifocal duodenopancreatic neuroendocrine tumors (dpNETs). Nonfunctional pancreatic neuroendocrine tumors (PanNETs) and duodenal gastrinomas are the most frequent origins of metastasis. Current guidelines recommend surgery based on tumor functionality, size ≥2 cm, grade or presence of lymph node metastases. However, in case of multiple primary tumors it is often unknown which specific tumor metastasized. This study aims to unravel the relationship between primary dpNETs and metastases in patients with MEN1 by studying endocrine differentiation. First, it was shown that expression of the endocrine differentiation markers ARX and PDX1 was concordant in 18 unifocal sporadic neuroendocrine tumors (NETs) and matched metastases. Thereafter, ARX, PDX1, Ki67 and gastrin expression, and the presence of alternative lengthening of telomeres were determined in 137 microscopic and macroscopic dpNETs and 36 matched metastases in 10 patients with MEN1. ARX and PDX1 H-score clustering was performed to infer relatedness. For patients with multiple metastases, similar intrametastases transcription factor expression suggests that most metastases (29/32) originated from a single NET of origin, while few patients may have multiple metastatic primary NETs. In 6 patients with MEN1 and hypergastrinemia, periduodenopancreatic lymph node metastases expressed gastrin, and clustered with minute duodenal gastrinomas, not with larger PanNETs. PanNET metastases often clustered with high grade or alternative lengthening of telomeres-positive primary tumors. In conclusion, for patients with MEN1-related hypergastrinemia and PanNETs, a duodenal origin of periduodenopancreatic lymph node metastases should be considered, even when current conventional and functional imaging studies do not reveal duodenal tumors preoperatively.

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma, Neuroendocrine; Databases, Factual; Duodenal Neoplasms; Female; Gastrins; Homeodomain Proteins; Humans; Ki-67 Antigen; Lymphatic Metastasis; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Neoplasm Grading; Pancreatic Neoplasms; Trans-Activators; Transcription Factors

Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited endocrine cancer syndrome. Multiple gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) affect 30% to 80% of MEN1 patients, with the most common functioning GEP-NET being gastrinoma. Biochemical identification of hypergastrinemia may help to recognize the presence of gastrinomas before they are detectable by instrumental screening, enabling early diagnosis and start of therapy, preferably before tumor progression and metastases occurrence.. Evaluate the effectiveness of secretin stimulation test to precociously diagnose the presence of gastrin-secreting tumors.. Results of secretin stimulation tests, performed between 1991 and February 2020, were retrospectively analyzed, as aggregate, in a cohort of MEN1 patients with GEP-NETs.. Data were extracted from the MEN1 Florentine database.. The study included 72 MEN1 patients with GEP-NETs who underwent a secretin stimulation test for the evaluation of gastrin secretion.. A positive secretin stimulation test was assumed with a difference between basal fasting serum gastrin (FSG) and the maximum stimulated value of gastrin over 120 pg/mL.. The secretin stimulation test showed a secretin-induced hypergastrinemia in 27.8% (20/72) of patients with GEP-NETs, and a positive test in 18 cases. The test allowed the identification of a positively stimulated hypergastrinemia in 75.0% (3/4) of patients who presented a basal FSG within the normal range.. Diagnosis of gastrinoma is complex, difficult, and controversial. Results of this study confirm that a positive secretin stimulation test allows early diagnosis of gastrinomas, even in the presence of borderline or normal levels of nonstimulated FSG.

Topics: Early Detection of Cancer; Gastrinoma; Gastrins; Humans; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Retrospective Studies; Secretin; Zollinger-Ellison Syndrome

Efforts to characterize the signaling mechanisms that underlie gastroenteropancreatic neoplasms (GEP-NENs) are precluded by a lack of comprehensive models that recapitulate pathogenesis. Investigation into a potential cell-of-origin for gastrin-secreting NENs revealed a non-cell autonomous role for loss of menin in neuroendocrine cell specification, resulting in an induction of gastrin in enteric glia. Here, we investigated the hypothesis that cell autonomous Men1 inactivation in glial fibrillary acidic protein (GFAP)-expressing cells induced neuroendocrine differentiation and tumorigenesis.. Transgenic GFAP. GFAP. GFAP-directed Men1 inactivation exploits glial cell plasticity in favor of neuroendocrine differentiation.

Topics: Animals; Carcinogenesis; Cell Differentiation; Cell Plasticity; Gastrins; Glial Fibrillary Acidic Protein; Hedgehog Proteins; Hyperplasia; Mice; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Cells; Neuroglia; Proto-Oncogene Proteins; RNA, Small Interfering

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

Helicobacter pylori and Multiple Endocrine Neoplasia Type 1 (MEN 1) are risk factors for hypergastrinemia. Gastrin-secreting neoplasms of the foregut mucosa are both a source of, and potentially stimulated by, hypergastrinemia.. To determine the relationship between H pylori exposure and the prevalence and severity of hypergastrinemia in patients with MEN 1.. Cross-sectional analysis of patients with a common MEN1 gene mutation managed at a tertiary referral hospital that underwent fasting serum gastrin and H pylori serum IgG measurement.. H pylori IgG and serum gastrin concentration, determined via immunoassay.. The prevalence and severity of hypergastrinemia and its relationship to past H pylori exposure.. Thirty-four of 95 (36%) patients were H pylori IgG seropositive. H pylori seropositive patients were significantly more likely to exhibit hypergastrinemia compared with seronegative patients (relative risk [RR] 1.72, P = .023). H pylori exposure also predicted severe hypergastrinemia (RR 3.52, P = .026 and RR 9.37, P = .031 for patients with gastrin ≥ ×4 and ≥ ×8 the upper limit of normal [ULN], respectively). Gastrin concentrations ≥ ×10 ULN occurred exclusively in H pylori seropositive patients (0/61 vs 6/34, P = .001). Serum gastrin and alpha subunit were positively associated in H pylori-exposed (β = 0.69, P = .001), but not in H pylori-unexposed patients.. Past H pylori exposure was associated with increased prevalence and severity of hypergastrinemia in MEN 1 patients. Past H pylori-related hypergastrinemia may contribute to the pathogenesis of ongoing gastrin hypersecretion by susceptible foregut neuroendocrine tissues.

Topics: Adolescent; Adult; Aged; Cross-Sectional Studies; Female; Gastrinoma; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Prevalence; Severity of Illness Index; Tasmania; Young Adult

Zollinger-Ellison syndrome is a rare cause of tumoral hypergastrinemia; 1 of 5 patients with this syndrome also has multiple endocrine neoplasia type 1. The diagnosis of this disease is complicated by the widespread use of proton pump inhibitors that can elevate serum gastrin levels, the cornerstone for biochemical diagnosis. Abrupt discontinuation of proton pump inhibitors could lead to adverse outcomes. Clinician awareness of the relationship between Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1 could lead to a safer diagnostic pathway.. We conducted a retrospective review of a cohort of patients with multiple endocrine neoplasia type 1.. There were 287 patients with multiple endocrine neoplasia type 1 (73 with gastrinoma) evaluated between 1997 and 2014. Two patients experienced adverse events after proton pump inhibitor therapy was discontinued to re-measure serum gastrin level during the evaluation of severe peptic ulcer disease. In both cases, the diagnosis of multiple endocrine neoplasia type 1 was made after proton pump therapy was discontinued.. Abrupt discontinuation of proton pump therapy can lead to adverse outcomes in patients with Zollinger-Ellison syndrome. Clinical assessment for features of multiple endocrine neoplasia type 1 (eg, serum calcium levels, personal and family history of hypercalcemia, pituitary or pancreatic tumors) could identify patients with higher risk for a tumoral source of hypergastrinemia where imaging studies can help support the diagnosis without the potential side effects of abrupt discontinuation of proton pump inhibitor therapy.

Topics: Adult; Duodenal Ulcer; Female; Gastrins; Gastroesophageal Reflux; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Proton Pump Inhibitors; Retrospective Studies; Withholding Treatment; Zollinger-Ellison Syndrome

Pancreatic neuroendocrine tumours (PNETs) are the major source of disease-specific mortality in multiple endocrine neoplasia type 1 (MEN1) patients. Chromogranin A (CgA), pancreatic polypeptide (PP), glucagon and gastrin have some diagnostic value in sporadic PNETs, but there is very little evidence for their efficacy in diagnosing PNETs in MEN1 patients.. We performed a retrospective chart review of the existing MEN1 database in our institution.. One hundred and thirteen patients were eligible for diagnostic value analysis of tumour markers. Patients were excluded if measurement of tumour markers was missing, either 3 months prior to PNET diagnosis (PNET patients) or prior to abdominal imaging (non-PNET patients).. Clinicopathologic characteristics and of tumour marker measurements were analysed.. Of 293 confirmed MEN1 cases, 55 PNETs and 58 non-PNETs met inclusion criteria. The area under the curve (AUC) for CgA, PP, glucagon and gastrin in MEN1 cases was 59·5%, 64·1%, 77·0% and 75·9%, respectively. The AUC for the combination of CgA, PP and gastrin was 59·6%. PP, but not CgA, glucagon or gastrin was significantly associated with both age and PNET functional status (P = 0·0485 and 0·0188, respectively). No markers were significantly associated with sex, PNET size, tumour number, tumour location, American Joint Committee on Cancer (AJCC) stage, presence of lymph node metastasis, lymphovascular invasion or overall survival. CgA values were not significantly lower following PNET resection than pre-operatively (P = 0·554).. The value of blood markers for diagnosing PNETs in MEN1 patients is relatively low, even when used in combination.

Topics: Adolescent; Adult; Aged; Area Under Curve; Biomarkers, Tumor; Chromogranin A; Female; Gastrins; Glucagon; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Pancreatic Neoplasms; Pancreatic Polypeptide; Retrospective Studies; Young Adult

Topics: Collagen Diseases; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Neoplastic Syndromes, Hereditary; Pancreatic Neoplasms; Skin Neoplasms

Somatostatin analogues (SSA) represent one of the main therapeutic option in patients affected with functioning well-differentiated neuroendocrine tumours (NETs). There are no studies specifically focusing on NETs associated with Multiple Endocrine Neoplasia type 1 (MEN1).. To evaluate the efficacy of the long-acting SSA octreotide in MEN1 patients with early-stage duodeno-pancreatic NETs.. Forty patients with MEN1 were retrospectively evaluated. Twenty patients with evidence of one or more MEN1-related duodeno-pancreatic NETs < 20 mm in size (age range 26-61 years) were treated with octreotide long-acting octreotide (LAR) as first-line therapy. Treatment duration ranged 12-75 months. At the baseline radiological evaluation, multiple duodeno-pancreatic NETs (range 1-8, size 3-18 mm) were detected.. An objective tumour response was observed in 10%, stable disease in 80% and progression of disease in 10% of cases. In six patients with abnormally increased CgA, gastrin and/or insulin serum concentrations, a significant clinical and hormonal response occurred in 100% of cases and was stable along the time.. Therapy with SSA is highly safe and effective in patients with early-stage MEN1 duodeno-pancreatic NETs, resulting in long-time suppression of tumour and hormonal activity and 10% objective response. This suggests to early start therapy with SSA in patients with MEN1-related NETs.

Topics: Adult; Cell Differentiation; Disease Progression; Endocrine System; Female; Gastrins; Humans; Insulin; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Octreotide; Retrospective Studies; Somatostatin; Time Factors; Treatment Outcome

Zollinger-Ellison syndrome (ZES) is characterized by gastrinoma and resultant hypergastrinemia, which leads to recurrent peptic ulcers. Because gastrinoma is the most common pancreatic endocrine tumor seen in multiple endocrine neoplasia type I (MEN 1), the possibility of gastrinoma should be investigated carefully when patients exhibit symptoms associated with hormonal changes. Ureteral stones associated with hyperparathyroidism in the early course of MEN 1 are known to be its most common clinical manifestation; appropriate evaluation and close follow-up of patients with hypercalcemic urolithiasis can lead to an early diagnosis of gastrinoma. We report a patient with ZES associated with MEN 1, and urolithiasis as the presenting entity. A 51-year-old man visited the emergency department with recurrent epigastric pain. He had a history of calcium urinary stone 3 years ago, and 2 years later he had 2 operations for multiple jejunal ulcer perforations; these surgeries were 9 months apart. He was taking intermittent courses of antiulcer medication. Multiple peripancreatic nodular masses, a hepatic metastasis, parathyroid hyperplasia, and a pituitary microadenoma were confirmed by multimodal imaging studies. We diagnosed ZES with MEN 1 and performed sequential surgical excision of the gastrinomas and the parathyroid adenoma. The patient received octreotide injection therapy and close follow-up.

Topics: Gastrinoma; Gastrins; Humans; Immunohistochemistry; Liver; Magnetic Resonance Imaging; Male; Mesenteric Artery, Superior; Middle Aged; Multimodal Imaging; Multiple Endocrine Neoplasia Type 1; Pancreas; Pituitary Gland; Positron-Emission Tomography; Radiopharmaceuticals; Thyroid Gland; Tomography, X-Ray Computed; Ultrasonography; Urolithiasis; Zollinger-Ellison Syndrome

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

Controversy exists regarding the role and extent of operation for patients with multiple endocrine neoplasia type 1 (MEN1) and hypergastrinemia.. An institutional MEN1 database was reviewed to identify patients with evidence of hypergastrinemia. The relationship of extent of resection to achievement of eugastrinemia was evaluated.. Operation was performed in 20 patients with MEN1 and hypergastrinemia with a median follow-up of 71 months. Duodenal gastrinomas were identified in 85% of patients who underwent duodenal evaluation. Nodal metastases were identified in 80%. Patients who underwent anatomic regional lymph node dissection (RLND) had a median of 16 nodes removed, vs 1 in patients who did not undergo a formal regional lymphadenectomy. Eugastrinemia was achieved in 12 patients (60%), and 8 (40%) had persistent hypergastrinemia. Compared with patients with persistent hypergastrinemia, patients rendered eugastrinemic more often underwent duodenal evaluation (11/12 vs 2/8; P = .01) and RLND (11/12 vs 3/8; P = .03); there was no relationship between pancreatic resection and achievement of eugastrinemia (P = .32).. For patients with MEN1-associated hypergastrinemia selected for operative treatment, a strategy including duodenal evaluation and anatomic regional lymphadenectomy is associated with long-term eugastrinemia. In contrast, the extent of pancreatic resection should be dictated by the extent and distribution of pancreatic neuroendocrine neoplasms, rather than by the presence of hypergastrinemia.

Topics: Abdomen; Adult; Duodenal Neoplasms; Female; Gastrinoma; Gastrins; Humans; Lymph Node Excision; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatectomy; Pancreatic Neoplasms; Pancreaticoduodenectomy; Retrospective Studies; Treatment Outcome

Recent advances in localization techniques, such as the selective arterial secretagogue injection test (SASI test) and somatostatin receptor scintigraphy have promoted curative resection surgery for patients with pancreatic neuroendocrine tumors (PNET). For patients with sporadic functioning PNET, curative resection surgery has been established by localization with the SASI test using secretin or calcium. For curative resection of functioning PNET associated with multiple endocrine neoplasia type 1 (MEN 1) which are usually multiple and sometimes numerous, resection surgery of the pancreas and/or the duodenum has to be performed based on localization by the SASI test. As resection surgery of PNET has increased, several important pathological features of PNET have been revealed. For example, in patients with Zollinger-Ellison syndrome (ZES), duodenal gastrinoma has been detected more frequently than pancreatic gastrinoma, and in patients with MEN 1 and ZES, gastrinomas have been located mostly in the duodenum, and pancreatic gastrinoma has been found to co-exist in 13% of patients. Nonfunctioning PNET in patients with MEN 1 becomes metastatic to the liver when it is more than 1 cm in diameter and should be resected after careful observation. The most important prognostic factor in patients with PNET is the development of hepatic metastases. The treatment strategy for hepatic metastases of PNET has not been established and aggressive resection with chemotherapy and trans-arterial chemoembolization have been performed with significant benefit. The usefulness of octreotide treatment and other molecular targeting agents are currently being assessed.

Topics: Animals; Diagnosis, Differential; Gastrins; Humans; Liver Neoplasms; Male; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Pancreatic Neoplasms; Secretin; Zollinger-Ellison Syndrome

The purpose of this study is to describe outcomes of MEN-1 patients with recurrence requiring completion pancreatectomy and duodenectomy after initial treatment of pancreatic endocrine neoplasms (PENs) and hypergastrinemia with distal pancreatectomy, enucleation of pancreatic head PENs, and duodenotomy.. After undergoing this initial operation, 8 of 49 patients (16%) have required completion pancreatectomy and duodenectomy for recurrent PENs and hypergastrinemia. Retrospective review was performed.. Median age was 39 years (27-51) at completion pancreatectomy compared to 31 years (20-40) at initial operation. Pathology revealed multiple PENs in 100%, duodenal neoplasms in 63%, and metastatic lymph nodes in 75%. There was no operative mortality and 88% of patients are currently alive. Preoperative gastrin levels were 934 +/- 847 pg/mL while postoperative levels are 93 +/- 79 pg/mL (normal 25-111 pg/mL). Mean Hemoglobin A1C levels are 8.3 +/- 3.3% (normal 3.8%-6.4%). Mean follow-up is 44 +/- 25 months.. This initial operation may provide tumor control and prevent metastases but recurrent PENs are multifocal and progressive. Completion pancreatectomy and duodenectomy is arduous but outcomes are acceptable. Considering the radical nature of this treatment, individual consideration should be given to MEN-1 patients amenable to initial alternative pancreatic resections that preserve pancreatic mass and allow future pancreas-preserving reoperations.

Topics: Adult; Duodenal Neoplasms; Duodenum; Female; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Neoplasm Recurrence, Local; Pancreatectomy; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

The observations that the peptide hormone gastrin interacts with transferrin in vitro and that circulating gastrin concentrations are increased in the iron-loading disorder hemochromatosis suggest a possible link between gastrin and iron homeostasis. This study tested the hypothesis that gastrin and iron status are interrelated by measurement of iron homeostasis in mice and humans with abnormal circulating gastrin concentrations. Intestinal iron absorption was determined by (59)Fe uptake following oral gavage, and concentrations of duodenal divalent metal transporter-1 (DMT-1) and hepatic hepcidin mRNAs were determined by quantitative real-time PCR in agastrinemic (GasKO), hypergastrinemic cholecystokinin 2 receptor-deficient (CCK2RKO), or wild-type mice. Iron status was measured by standard methods in the same mice and in hypergastrinemic humans with multiple endocrine neoplasia type 1 (MEN-1). Iron absorption was increased sixfold and DMT-1 mRNA concentration fourfold, and transferrin saturation was reduced 0.8-fold and hepcidin mRNA expression 0.5-fold in juvenile GasKO mice compared with age-matched wild-type mice. In mature mice, few differences were observed between the strains. Juvenile CCK2RKO mice were hypergastrinemic and had a 5.4-fold higher DMT-1 mRNA concentration than wild-type mice without any increase in iron absorption. In contrast to juvenile GasKO mice, juvenile CCK2RKO mice had a 1.5-fold greater transferrin saturation, which was reflected in a twofold increase in liver iron deposition at maturity compared with wild-type mice. The correlation between transferrin saturation and circulating gastrin concentration observed in mutant mice was also observed in human patients with MEN, in whom hypergastrinemia correlated positively (P = 0.004) with an increased transferrin saturation. Our data indicate that, in juvenile animals when iron demand is high, circulating gastrin concentrations may alter iron status by a CCK2R-independent mechanism.

Topics: Animals; Antimicrobial Cationic Peptides; Cation Transport Proteins; Duodenum; Female; Ferritins; Gastrins; Hepcidins; Homeostasis; Humans; Iron; Liver; Male; Mice; Mice, Knockout; Middle Aged; Multiple Endocrine Neoplasia Type 1; Receptor, Cholecystokinin B; RNA, Messenger

Topics: Adult; Biomarkers; Diagnosis, Differential; Female; Gastrinoma; Gastrins; Gluconates; Humans; Injections, Intra-Arterial; Multiple Endocrine Neoplasia Type 1; Mutation; Pancreatic Neoplasms; Proto-Oncogene Proteins

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

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

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

Gastric neuroendocrine tumors are rare neoplasms that originate from gastric enterochromaffin-like (ECL) cells in the oxyntic mucosa. Gastrin and its derivates have been reported to regulate epithelial cell proliferation, migration, and differentiation. Mutations in the epithelial cadherin (E-cadherin) gene have been shown to be associated with the occurrence of diffuse gastric carcinomas in affected families.. In this study we investigated the histopathological and molecular findings in the gastrointestinal wall of a patient with multiple endocrine neoplasia type 1 with malignant duodenal gastrinoma and multiple gastric ECL cell tumors, who additionally developed a signet-ring cell carcinoma of the stomach.. Biopsies from the gastrointestinal tract of a patient with multiple endocrine neoplasia type 1 were immunostained for vesicular monoamine transporter-2 and E-cadherin. Nonamidated gastrin products were measured in the serum of the patient using antibodies that react with progastrin, Gly-extended, and amidated gastrins. Genetic analyses were performed to exclude germ-line mutations within the E-cadherin gene.. Immunohistochemical studies of gastric ECL cell tumors showed a largely diminished E-cadherin expression in comparison to gastric surface mucosa cells and a loss of E-cadherin expression in the cells of the signet-ring carcinoma. Detailed biochemical measurements revealed progastrin concentrations that were approximately 20%, and Gly-gastrin concentrations that were approximately 10% the amidated gastrin concentrations in plasma. Molecular analyses revealed no E-cadherin germ-line mutation.. Our immunohistochemical studies might suggest that the gastrinoma-associated excessive progastrin tissue concentrations led to diminished expression of E-cadherin within the gastric mucosa and promoted tumor development of a signet-ring cell carcinoma.

Topics: Cadherins; Carcinoma, Signet Ring Cell; Gastrins; Humans; Male; Middle Aged; Models, Biological; Multiple Endocrine Neoplasia Type 1; Stomach Neoplasms; Ultrasonography; Zollinger-Ellison Syndrome

Topics: Autoimmune Diseases; Diagnosis, Differential; Duodenal Neoplasms; Early Diagnosis; Gastrinoma; Gastrins; Gastritis, Atrophic; Humans; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

The frequency of pancreaticoduodenal endocrine tumors in patients with multiple endocrine neoplasia type 1 (MEN1) remains unknown.. To evaluate prospectively with endoscopic ultrasonography (EUS) the frequency of nonfunctioning (asymptomatic) pancreaticoduodenal tumors.. MEN1 patients without functioning pancreatic involvement underwent systematic pancreaticoduodenal EUS in nine GTE (Groupe des Tumeurs Endocrines) centers. Demographic and clinical factors predictive of pancreatic involvement were sought, and standardized biochemical measurements obtained.. Between November 1997 and July 2004, 51 patients (median age: 39 [range: 16-71] yr) were studied. MEN1 had been diagnosed 3 [0-20] yr earlier, notably by genetic screening for 26 (51%) with asymptomatic disease. Twenty-five patients had minor biochemical anomalies (<2 x normal (N)) and serum somatostatin was 10.8 N in 1; EUS detected pancreatic lesions in 28 patients (54.9%; 95% CI: 41.3-68.7%). A median of three [1-9] tumors with a median diameter of 6 [2-60] mm was found per patient; for 19 (37.3%) patients a tumor measured > or =10 mm and > or = 20 mm in 7 (13.7%) patients. Only one duodenal lesion was found and three patients had peripancreatic adenopathies. Pancreatic tumors were not associated with any of the studied parameters, notably age, family history, biochemical anomalies. Sixteen of twenty-six patients underwent EUS monitoring over 50 [12-70] months; six (37.5%) had more and/or larger pancreatic lesions.. The frequency of nonfunctioning pancreatic endocrine tumors is higher (54.9%) than previously thought. The size and number of these tumors can increase over time. Pancreatic EUS should be performed once MEN1 is diagnosed to monitor disease progression.

Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Diagnosis, Differential; Disease Progression; Duodenal Neoplasms; Endosonography; Female; Follow-Up Studies; Gastrins; Glucagon; Humans; Incidence; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Pancreatic Polypeptide; Peptides; Prospective Studies; Severity of Illness Index; Vasoactive Intestinal Peptide

The preoperative localization of gastrinomas often fails despite all modern imaging methods. Therefore, after biochemical confirmation of the diagnosis and exclusion of diffuse metastases, a meticulous surgical exploration including intraoperative ultrasound (IOUS) and duodenal exploration after duodenotomy should be performed. The experienced surgeon will be able to identify more than 90% of the primary tumors. Depending on the localization, excision of the tumor in the duodenal wall or enucleation from the pancreatic head should be performed. If the tumor is localized in the tail of the pancreas, distal pancreatectomy is the treatment of choice. Complete resection of the tumor is the only curative approach for the patients. For MEN-1 gastrinomas a spleen-preserving distal pancreatectomy with enucleation of tumors of the pancreatic head and duodenotomy with excision of duodenal gastrinomas should be performed. If the source of gastrin secretion can be regionalized to the pancreatic head by a preoperative SASI angiography, a pylorus-preserving partial pancreaticoduodenectomy might be the treatment of choice.

Topics: Adult; Aged; Chromosomes, Human, Pair 11; Duodenal Neoplasms; Endosonography; Female; Follow-Up Studies; Gastrinoma; Gastrins; Genes, Dominant; Germ-Line Mutation; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Pancreaticoduodenectomy; Reoperation; Secretin; Stomach Neoplasms; Survival Rate; Zollinger-Ellison Syndrome

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

On July 2000, 127 gastrinomas (31.1%) were studied by the Endocrine Tumour Group (GTE) using a 408-patient cohort of Multiple Endocrine Neoplasia Type 1 patients. The aim of this study was to assess clinical, biological, surgical data as well as their trends over three periods (<1980-1980/1989->1990). A Zollinger-Ellison syndrome (SZE) was present in 96% of the cases. Mean age at the onset of the disease was 39.4 years. There were 55.9% of men. Synchronous liver metastasis was present in 7.1%. Taken independently, the positivity of the four main diagnosis tests decreased over the time. The diagnosis of oesophagitis increased (4.5-29.7%), as well as the size of the resected tumours (9.9-16.8 mm). There was an increase in the familial background diagnosis (73.1-80%), an increasing use of Octreoscan scintigraphy and transduodenal ultrasound with positive detection of metastasis and tumours in 81.3% and 92.3%, respectively after 1991. Patients were operated on less frequently (96-52.5%), less frequently from the pancreas (87.5-37.5%), and from the gastro-intestinal tract (70.8-30%). The relative percentage of major pancreatic resections increased (with at least removal of the duodenum and the pancreatic head) (10-26.7%). The operative mortality disappeared. Six out of the seven patients (85.7%) who benefited from major pancreatic resections normalized their gastrine level postoperatively versus 15% in less radical techniques. Overall 5 years survival was 90 +/- 4.4%. Survival increased after 1985 (85 +/- 4.8% versus 95 +/- 3.6, P = 0.1).. SZE in NEM1 were diagnosed at an earlier stage and were less frequently operated on. Nevertheless, the incidence of synchronous metastasis did not change significantly. Patients were mainly operated on for gastric emergencies and pancreatic tumours in order to prevent metastasis without mortality after 1991.

Topics: Adult; Aged; Aged, 80 and over; Female; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Prognosis

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

Patients with multiple endocrine neoplasia (MEN) type 1 risk premature death from pancreatic endocrine tumours (PETs). Endoscopic ultrasonography (EUS) is the most sensitive imaging modality for small PETs. A screening and therapeutic approach for asymptomatic patients is delineated in which EUS plays a pivotal role.. This was a retrospective study of 15 patients with MEN-1 but with no symptoms of a PET. All patients underwent serum hormone measurement, including gastrin, and EUS. The findings were used to facilitate operative treatment.. Six of 15 patients had a normal basal gastrin level and nine had a raised level. EUS demonstrated PETs in 14 patients and identified multiple lesions in 12. There was no predictive relationship between age or gastrin level and the number or size of PETs discovered. Thirteen patients have undergone enucleation or resection of PETs and two remain under observation. Nine of the 13 patients underwent transduodenal exploration to excise gastrinoma(s). One patient had lymph node metastases found at operation. There was no death. Self-limiting pancreatic fistula in five patients and biliary fistula in one.. Early and aggressive screening using EUS identifies PETs in asymptomatic patients with MEN-1. Detection of tumours at an early stage, before the development of symptoms, lymph node metastases or liver metastases, may facilitate prompt surgical intervention and improve prognosis.

Topics: Adolescent; Adult; Endoscopy, Digestive System; Endosonography; Gastrins; Humans; Linear Models; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatectomy; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Splenectomy

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

We describe a patient with multiple endocrine neoplasia type 1 characterized by the simultaneous occurrence of parathyroid cancer, parathyroid adenomas, and pancreatic gastrinoma, who presented with an episode of acute hypercalcemia. The rapid parathyroid hormone assay provided a basis for the diagnosis of parathyroid hyperfunction. Mediastinal metastasis of the parathyroid carcinoma was found at autopsy. However, the staining of pancreatic and gastric tissue for parathyroid hormone-related protein does not make it possible to exclude completely the contribution of this peptide in mediating the hypercalcemia. To our knowledge, this is the first reported case of parathyroid carcinoma as part of the multiple endocrine neoplasia type 1 syndrome.

Topics: Acute Disease; Adenoma; Adult; Carcinoma; Fatal Outcome; Gastrinoma; Gastrins; Humans; Hypercalcemia; Hyperparathyroidism; Male; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Parathyroid Hormone; Parathyroid Neoplasms

Preoperative localisation is important for successful surgical treatment of gastrinomas. However, a satisfactory method that achieves this has not been defined, and at present somatostatin receptor scintigraphy and selective intra-arterial stimulation testing with secretin have the greatest sensitivities. As secretin is now difficult to obtain, we decided to explore the use of calcium gluconate as a secretagogue. High extracellular calcium concentrations cause degranulation of neuroendocrine cells and subsequent release of hormone.. Two patients with biochemically proven gastrinomas were investigated pre-operatively. Under angiographic control calcium gluconate was injected into the arteries supplying the pancreas and duodenum, gastrin levels were then determined in hepatic vein samples obtained before and 30, 60, 90, 120 and 180 seconds after each injection. One of the patients had also previously undergone selective intra-arterial stimulation testing with secretin.. Calcium gluconate produced sharp peaks of gastrin which unequivocally localised the tumour to a specific vascular territory in each case. Furthermore, surgery confirmed the localisations of the gastrinomas. Calcium injection, unlike secretin, into vascular territories without gastrinomas caused no rise in gastrin, thereby demonstrating calcium's greater specificity.. Calcium gluconate is a highly sensitive and specific alternative secretagogue to secretin for localisation of pancreatic and duodenal gastrinomas. Furthermore calcium gluconate was found to demonstrate the territory of the tumour more accurately than secretin.

Topics: Adult; Angiography; Calcium Gluconate; Duodenal Neoplasms; Duodenum; Female; Gastrinoma; Gastrins; Hepatic Veins; Humans; Injections, Intra-Arterial; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreas; Sensitivity and Specificity

Topics: Adult; Diagnosis, Differential; Duodenal Ulcer; Female; Gastrinoma; Gastrins; Humans; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Proton Pump Inhibitors

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

A 55-year-old woman, known with multiple endocrine neoplasia (MEN) type 1, had rectal bleeding and later haematemesis but colonoscopy and gastroduodenoscopy revealed no abnormalities. Due to the normal results for serum gastrin concentration, gastroduodenoscopy and CT scanning of the pancreas, Zollinger-Ellison syndrome was considered to be less likely. Yet the diagnosis could be established on the basis of persistent symptoms and a positive somatostatin receptor scintigraphy. The patient was treated with high doses of a proton pump inhibitor and temporary tube feeding due to weight loss. Follow-up will take place at the endocrinology outpatients' department. Zollinger-Ellison syndrome is a relatively common feature of patients with MEN-1. The diagnosis and localisation of the gastrinoma can be difficult: serum gastrin concentrations can be normal and the sensitivity of CT scanning is low. The primary aim of treating gastrinoma is to control gastric acid hypersecretion by means of high doses of a proton pump inhibitor. The question as to whether surgery is indicated remains controversial.

Topics: Decision Making; Female; Gastrinoma; Gastrins; Hemorrhage; Humans; Middle Aged; Multiple Endocrine Neoplasia Type 1; Proton Pump Inhibitors; Rectal Diseases; Zollinger-Ellison Syndrome

The diagnostic value of the determination of the serum pancreatic polypeptide (PP) and gastrin concentrations after a standard meal for early diagnosis of patients with multiple endocrine neoplasia type 1 (MEN 1) is controversial. The aim of this study was to clarify this issue. Thirteen patients with MEN 1, seven healthy family members, and eight healthy controls were studied. Plasma PP and serum gastrin were measured before and after the ingestion of a standardized meal. The meal caused a statistically significant (p < 0.05) increase of both PP and gastrin in all three groups studied. Concerning PP, no statistically significant difference was observed between patients and controls. In family members, the values were significantly (p < 0.05) lower than in the other two groups. On the whole, no significant differences in gastrin levels were noted between patients and controls; in family members, the values were significantly (p < 0.05) lower than in patients. All patients who had abnormally high postprandial values of PP and gastrin also had abnormally high basal values of these two peptides. The determination of serum PP and gastrin levels after a meal stimulation test in patients with MEN 1 adds no information about the presence of pancreatic endocrine tumors over that provided by basal values of the two peptides.

Topics: Adolescent; Adult; Female; Food; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Pancreatic Polypeptide; Postprandial Period

A 58-year-old patient had been treated for recurrent gastritis. Numerous gastroscopies indicated hemorrhagic gastritis combined with increasingly severe anemia. The patient was admitted with a hemoglobin of 4.4 g/dL. Gastroscopy showed marked antral angiodysplasia. Serum samples for gastrin were taken and found to be elevated (170-250 U/mL). The search for a gastrin-producing tumor with abdominal ultrasound, computed tomography, octreotide scan, and secretin test was negative, but angiography detected a pancreas tumor with a 2-cm diameter. Partial pancreatectomy and partial gastrectomy were performed. Immunohistochemical examination of the tumor did not show a gastrinoma but did show glucagon-reactive tissue. Further tumors or elevated plasma hormone levels were not detected, and a multiple endocrine neoplasia type I syndrome could be excluded. We thus found antral angiodysplasia with hypergastrinemia leading to detection of a glucagonoma diagnosed by immunohistochemistry. After more than 4 years of follow-up, the patient is without any symptoms or signs of relapse or secondary hormone syndrome.

Topics: Diagnosis, Differential; Gastric Antral Vascular Ectasia; Gastrins; Glucagon; Glucagonoma; Humans; Immunohistochemistry; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Pyloric Antrum

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

Measurement of gastrin in serum or plasma in patients with gastrinoma may be complicated by the presence of circulating biosynthetic intermediates which may not be detected by commonly available immunoassays. In contrast, the "processing-independent analysis" of gastrins developed by professor Jens Rehfeld et al in Copenhagen detects gastrin forms irrespective of their size. The authors review gastrinoma pathophysiology, the biochemistry of gastrin and other biomarkers of gastrinoma, the differential diagnosis of hypergastrinemia as well as other methods currently employed in the workup of gastrinoma patients, and illustrate with a clinical case.

Topics: Biomarkers, Tumor; Diagnosis, Differential; Gastrinoma; Gastrins; Humans; International Cooperation; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Practice Guidelines as Topic; Prostatic Neoplasms; Quality Assurance, Health Care; Radionuclide Imaging; Scandinavian and Nordic Countries

The major phenotypes of multiple endocrine neoplasia type 1 (MEN 1) consist of three lesions characterized by hyperparathyroidism, pituitary tumors, and endocrine pancreatic tumors. The endocrine pancreatic tumors are a significant cause of disease-related mortality in MEN 1. Although symptomatic pancreatic tumors such as insulinoma and gastrinoma should be resected, the management of asymptomatic pancreatic tumors is not established. In asymptomatic pancreatic tumors, the most important factor is the propensity for malignant transformation of the tumors. Although there are no means to foresee it, the size of the pancreatic tumors might be predictive of malignant development in MEN 1. We report here a patient with MEN 1 who had a large asymptomatic pancreatic tumor. The patient (72-yr-old man) was diagnosed with primary hyperparathyroidism and underwent a total parathyroidectomy. Genetic examination showed a germline mutation of the MEN1 gene (E45G). Abdominal magnetic resonance imaging revealed a large (>6 cm) tumor with a heterogeneous pattern in the tail of the pancreas. No metastases of the tumor were evident. Serum levels of insulin, gastrin, and glucagon were normal, and the patient had no symptoms. Operative resection was performed, and microscopic examination revealed that the tumor was an islet cell tumor stained with multiple hormones. This is a case indicating that asymptomatic pancreatic tumors associated with MEN 1 might be indolent independent of their size.

Topics: Adenoma, Islet Cell; Aged; Angiography; Gastrins; Germ-Line Mutation; Glucagon; Humans; Hyperparathyroidism; Immunohistochemistry; Insulin; Magnetic Resonance Imaging; Male; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Parathyroidectomy; Serotonin; Spleen

Topics: Animals; Chromogranin A; Chromogranins; Enterochromaffin-like Cells; Gastrinoma; Gastrins; Humans; Multiple Endocrine Neoplasia Type 1; Prospective Studies; Sensitivity and Specificity

Multiple endocrine neoplasia type 1 (MEN-1) is an autosomal dominant tumor syndrome associated with parathyroid, gastroenteropancreatic (GEP), and pituitary neoplasia. Gastrinoma and GEP malignancy are common life-threatening endocrine complications of MEN-1. An effective management strategy for these disorders remains to be determined. The authors attempted to determine the role of the somatostatin analogue, octreotide, in ameliorating features of hypergastrinemic GEP neoplasia associated with MEN-1.. Five MEN-1 patients with hypergastrinemia and either symptoms of GEP neoplasia or hepatic metastases received a trial of octreotide, 100 microg subcutaneously, three times daily for 3 months.. Treatment with octreotide was associated with a rapid symptomatic and biochemical response. In all patients serum gastrin fell to < 25% of the pretreatment value. The serum glycoprotein-alphasubunit (a marker of enterochromaffin-like [ECL] cell hyperplasia, gastric carcinoidosis, and disseminated enteropancreatic malignancy) was elevated at baseline in three patients. In each case the serum glycoprotein-alphasubunit normalized after treatment with octreotide. Hepatic metastases were present in two patients at baseline. The size of the metastases diminished by up to 15% during the period of octreotide treatment. Four patients reported symptoms prior to treatment: lethargy, easy fatigability, and generalized musculoskeletal discomfort. A marked symptomatic improvement occurred in each case. No patient experienced side effects related to octreotide therapy and all elected to remain on treatment after completion of the trial.. Octreotide is a safe and effective adjunct to surgical strategies for the management of GEP neoplasia in hypergastrinemic MEN-1 patients.

Topics: Aged; Antineoplastic Agents, Hormonal; Female; Gastrins; Gastrointestinal Neoplasms; Humans; Middle Aged; Models, Biological; Multiple Endocrine Neoplasia Type 1; Octreotide; Pancreatic Neoplasms

Gastrin levels have been reported to be often increased in patients with primary hyperparathyroidism (PHPT) considered to be caused by hypercalcemia. To determine the prevalence of increased basal gastrin and to investigate its causes, 52 consecutive patients with PHPT were studied prospectively, undergoing a clinical, biochemical, and gastric morphofunctional assessment before any parathyroid surgical procedure. This included evaluation of basal and secretin-stimulated gastrin, basal and pentagastrin-stimulated gastric acid secretion, upper gastrointestinal endoscopy, with histological evaluation for gastritis and Helicobacter pylori infection. Twenty of the 52 PHPT patients (38.5%) had increased fasting gastrin. Further investigation allowed us to clearly demonstrate the causes of hypergastrinemia in 16 of these 20 patients. In 7 of 20 (35%), hypergastrinemia was caused by gastric fundus atrophy; in 3 patients (15%), Zollinger-Ellison syndrome with Multiple Endocrine Neoplasia type I was diagnosed; whereas in another 20% of patients, mild hypergastrinemia was ascribed to Helicobacter pylori gastritis. Finally, in 2 patients, additional clinical history revealed an occasional use of the gastric antisecretory drug omeprazole a few days before the serum gastrin determination. This study shows that the hypercalcemic status per se is not sufficient to produce an increase in fasting gastrin levels. Furthermore, gastric fundus atrophy, and not gastrinoma, is the major cause of relevant (>160 pg/mL) hypergastrinemia.

Topics: Adult; Aged; Atrophy; Female; Gastric Acid; Gastric Fundus; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Hyperparathyroidism; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pentagastrin; Prospective Studies; Secretin

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

Enteropancreatic malignancy is an important cause of morbidity and mortality associated with multiple endocrine neoplasia type 1 (MEN 1). However, the risk factors and mechanisms of the tumorigenesis of this malignancy are poorly understood.. The authors conducted a retrospective study of factors associated with the development of malignant enteropancreatic tumor in 69 patients with MEN 1 belonging to a single family.. Metastatic enteropancreatic tumor and gastrinoma were identified in 20% and 36% of patients, respectively. Compared with MEN 1 patients who did not have an immediate family history of enteropancreatic malignancy, MEN 1 patients with a first-degree relative affected by enteropancreatic malignancy had an increased risk of developing disseminated tumor (odds ratio, 3.7; P < 0.05). In addition, hypergastrinemia and advanced age were both associated with a significant increase in the risk of enteropancreatic malignancy. Elevated serum glycoprotein alpha subunit levels were associated with enterochromaffin-like cell hyperplasia, gastric carcinoid formation, and disseminated enteropancreatic tumor in hypergastrinemic patients (P < 0.05).. Disease modifier factors act in concert with the MEN 1 gene to modulate the development of enteropancreatic neoplasia. It is possible to identify MEN 1 patients at high risk for developing aggressive enteropancreatic tumors. Heritable disease modifier factor(s) affecting enteropancreatic malignancy appear to reside at loci distinct from that of the MEN 1 gene.

Topics: Adenoma; Adult; Female; Gastrinoma; Gastrins; Humans; Hyperparathyroidism; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Neoplasm Metastasis; Pancreatic Neoplasms; Retrospective Studies; Risk Factors

To improve the clinical diagnosis and treatment of gastrinoma.. Twelve cases of gastrinoma found in the recent 30 years in our hospital were analyzed.. The results indicated that in addition to the typical symptoms related to gastric acid overproduction, the frequency of certain uncommon features characteristic of the disease was unusually high in our hands i.e., (1) The majority of them (7/12) had serious diarrhea, even resulting in shock. (2) Multiple endocrine neoplasia type I (MEN) was in 3 out of 12 associated in our series. (3) Multiple nodules in the duodenum (3/12) were found and in two patients were shown to be submucosal gastrinoma confirmed by pathology. (4) Multifocal lesions were found in 9 out of 12 patients, and in 7 cases at least two organs were involved. Most gastrinomas were located in the pancreas, stomach and duodenum. (5) As reported by other authors, multiple hormone secretion was common: in five of six patients the tumor secreted more than two hormones. (6) In some cases, tumors were sensitive to chemotherapy.. In our series gastrinoma was found with the feature of multiple lesions and multiple hormone secretion in addition to the typical symptoms related to gastric acid overproduction.

Topics: Adolescent; Adult; Diarrhea; Duodenal Neoplasms; Duodenal Ulcer; Female; Gastrinoma; Gastrins; Humans; Insulinoma; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Somatostatin; Stomach Neoplasms

We have investigated the prevalence of MEN 1 in patients with recognized pituitary adenomas. Since hyperparathyroidism is present in nearly 95-100% of patients with MEN 1 and frequently is the first condition to be identified, the study was limited to the identification of patients with hyperparathyroidism while the screening for gastroenteropancreatic (GEP) lesions was carried out in patients with both pituitary and parathyroid lesions.. Serum total and ionized calcium, phosphate and intact PTH 1-84 (EASIA) were measured in 166 patients (68 with non-functioning pituitary adenoma, 42 with prolactinoma, 35 with GH-secreting adenoma, 17-with ACTH-screening adenoma, 1 with TSH-secreting adenoma, 1 with FSH-secreting adenoma and 2 with an only alpha-subunit secreting adenoma) referred to our clinic from 1990 to 1996. Plasma gastrin, somatostatin, pancreatic polypeptide and vasoactive intestinal peptide were measured by RIA in patients with hyperparathyroidism.. Eight of 166 patients (4.8%) were found to have primary hyperparathyroidism and among these 2 also had a gastrinoma while there was no evidence of other GEP tumours. Considering the tumour type, 6 had prolactinoma (14.3%), 1 GH-secreting adenoma (2.8%) and 1 non-functioning adenoma (1.5%). In most patients the diagnosis of pituitary tumour was made several years before that of hyperparathyroidism (from 1 to 15 years) although 6 patients had previously suffered from urolithiasis and one had undergone gastric resections for recurrent peptic ulcers. One patient was identified as a MEN 1 gene carrier and 2 had relatives with signs and symptoms referable to parathyroid or GEP lesions.. The study shows a prevalence of 4.8% of primary hyperparathyroidism in unselected patients with known pituitary tumours similar to that reported in a previous study. By contrast, the prevalence of MEN 1 in patients with prolactinoma was definitely high (14.3%). In most patients the diagnosis of pituitary tumours was made several years before that of hyperparathyroidism. Although the patients were believed to harbour a sporadic pituitary tumour, most of them had had signs and/or symptoms referable to one or both of the other organs involved in MEN 1, often concomitantly with those of pituitary tumours. These data indicate that the diagnosis of MEN 1 syndrome is missed in a substantial proportion of patients with prolactinomas and therefore the screening of these patients for the syndrome is strongly recommended.

Topics: Adenoma; Adolescent; Adult; Aged; Biomarkers; Calcium; Female; Gastrinoma; Gastrins; Humans; Hyperparathyroidism; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Polypeptide; Parathyroid Hormone; Phosphates; Pituitary Neoplasms; Prevalence; Prolactinoma; Somatostatin; Vasoactive Intestinal Peptide

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

During a period of 13.5 years 17 patients with a gastrinoma and an associated Zollinger-Ellison syndrome were treated. In three patients (18%) the gastrinoma was part of a multiple endocrine neoplasia type I (MEN I). The median interval from the initial symptoms to the definite diagnosis was 5.0 years. During this interval seven patients (41%) underwent gastric surgery up to four times. The preoperative imaging studies localized the primary tumor in only seven patients (41%). In five of six diagnostic laparotomies the primary site of the tumor was identified and proved by pathologic work-up. The surgical procedures (n = 13) included five resections of the pancreas (3 x pancreatic head, 2 x left pancreatic resection), two duodenal resections, three enucleations of the tumor and three palliative operations (hospital mortality: 0%). Following laparotomy the gastrinoma could be histologically proved in eleven of 17 patients (6 x pancreas, 4 x duodenum, 1 x in the hepatoduodenal ligament). The rate of metastatic spread as characteristic feature of malignancy was 59%. After complete resection of the primary tumor (n = 8) none of these patients died because of the gastrinoma during the follow-up (median: 7.3 years). In the remaining patients three deaths were caused by the metastatic spread of the gastrinoma. Considering the high rate of preceding operations, the high malignancy rate and the excellent prognosis after RO-resection the diagnostic interval in patients with ZES is too long. Despite the modern radiographic imaging the exploratory laparotomy is of high value in patients with ZES.

Topics: Adult; Aged; Duodenal Neoplasms; Duodenum; Female; Follow-Up Studies; Gastrectomy; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreas; Pancreatic Neoplasms; Postoperative Complications; Reoperation; Zollinger-Ellison Syndrome

The role of surgical resection of gastrinoma in multiple endocrine neoplasia type 1 (MEN 1) is controversial because of low biochemical cure rates, but with adequate duodenal exploration higher cure rates may be possible.. We have prospectively evaluated this proposal in ten consecutive patients with MEN 1 and Zollinger-Ellison syndrome who underwent surgical exploration for gastrinoma resection including a detailed evaluation of the duodenum by palpation, intraoperative endoscopy with transillumination, and duodenotomy.. Duodenal tumors were present in seven patients. Six of seven patients had metastatic deposits in lymph nodes, and two of seven had synchronous pancreatic tumors. Three patients had a single duodenal tumor, one patient had two tumors, and three patients had more than 20 duodenal tumors. Positive gastrin staining by use of immunohistochemistry was seen in all duodenal tumors. None of these seven patients were biochemically cured. Of three patients with negative duodenal explorations, two had single pancreatic tumors removed and one had only lymph node gastrinoma. No patients were biochemically cured.. Not all patients with MEN 1 and Zollinger-Ellison syndrome have duodenal gastrinomas. In the 70% of patients with duodenal tumors, even extensive duodenal exploration with removal of positive lymph nodes does not result in cures because 86% of tumors had metastasized to lymph nodes and 43% of patients had large numbers of tumors.

Topics: Adult; Duodenal Neoplasms; Female; Gastrinoma; Gastrins; Humans; Lymphatic Metastasis; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Prospective Studies; Zollinger-Ellison Syndrome

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