Zollinger-Ellison syndrome

Opinion statement Zollinger-Ellison syndrome (ZES) is caused by a gastrin-producing tumor called a gastrinoma, which results in gastric acid hypersecretion. Gastrin stimulates the parietal cell to secrete acid directly and indirectly by releasing histamine from enterochromaffin-like (ECL) cells, and induces hyperplasia of parietal and ECL cells. ZES should be suspected in patients with severe erosive or ulcerative esophagitis, multiple peptic ulcers, peptic ulcers in unusual locations, refractory peptic ulcers, complicated peptic ulcers, peptic ulcers associated with diarrhea, and a family history of multiple endocrine neoplasia type 1 (MEN-1) or any of the endocrinopathies associated with MEN-1. The initial diagnostic test for ZES should be a fasting serum gastrin level when antisecretory medications are discontinued. If the gastrin level is elevated, gastric acidity should be assessed through pH or gastric analysis. It should be noted that hypochlorhydria causes feedback stimulation of antral gastrin secretion. In suspected cases of ZES with mild hypergastrinemia, the secretin stimulation test may be useful. Initial treatment for ZES should be oral high-dose proton pump inhibitors. If parenteral therapy is needed, intermittent bolus injection of pantoprazole is recommended. Total gastrectomy and antisecretory surgery is rarely required. Somatostatin receptor scintigraphy (SRS) is the initial localization study of choice. Endoscopic ultrasound (EUS) may have a similar sensitivity for identifying primary tumors. A combination of SRS and EUS detects greater than 90% of gastrinomas. In patients without metastasis and without MEN-1, surgical cure is possible in 30%. It has been suggested that patients with gastrinomas larger than 2.5 cm, irrespective of whether they have MEN-1, should undergo surgical resection in an effort to decrease the risk for metastasis.     

Localization of islet cell tumors

In summary, although similar imaging techniques are used for the localization of insulin and gastrin secreting islet cell tumors, the success rates are very different. Fortunately, the best results are obtained in the tumor for which effective medical treatment is less available, namely insulinomas, which can be found and successfully resected in over 90 per cent of patients. Both portal venous sampling and experienced intraoperative ultrasound are critical for successful surgery of small insulin-secreting tumors. Facilities without these resources should not explore patients when the conventional imaging studies are negative. Gastrinomas, on the other hand, will elude detection by even the most experienced surgeons in over 20 per cent of patients with sporadic Zollinger-Ellison syndrome in spite of positive portal venous sampling and intra-arterial secretin studies. The very small size of these tumors and their occurrence in more difficult to explore extrapancreatic sites provides the basis for this difference. However, patients with negative imaging studies and negative surgical explorations have an excellent prognosis on long-term follow-up when gastric acid hypersecretion is controlled. An annual computed tomographic scan is recommended since the appearance of a tumor would mandate surgical resection because of the significant incidence of malignancy in larger tumors. However, progression to imageable tumors has been unusual in our experience with this group of patients. There remains a small group of patients with highly malignant, rapidly metastasizing, gastrin-secreting islet cell carcinomas for whom localization is simple but of little relevance. However, locally invasive gastrinomas may often be resectable and provide prolonged remission and even cure. Aggressive surgery, supported by detailed cross-sectional and angiographic localization, has a role in this small group of patients.     

Gastrinoma and Zollinger Ellison syndrome: A roadmap for the management between new and old therapies

Zollinger-Ellison syndrome (ZES) associated with pancreatic or duodenal gastrinoma is characterized by gastric acid hypersecretion, which typically leads to gastroesophageal reflux disease, recurrent peptic ulcers, and chronic diarrhea. As symptoms of ZES are nonspecific and overlap with other gastrointestinal disorders, the diagnosis is often delayed with an average time between the onset of symptoms and final diagnosis longer than 5 years. The critical step for the diagnosis of ZES is represented by the initial clinical suspicion. Hypergastrinemia is the hallmark of ZES; however, hypergastrinemia might recognize several causes, which should be ruled out in order to make a final diagnosis. Gastrin levels > 1000 pg/mL and a gastric pH below 2 are considered to be diagnostic for gastrinoma; some specific tests, including esophageal pH-recording and secretin test, might be useful in selected cases, although they are not widely available. Endoscopic ultrasound is very useful for the diagnosis and the local staging of the primary tumor in patients with ZES, particularly in the setting of multiple endocrine neoplasia type 1. Some controversies about the management of these tumors also exist. For the localized stage, the combination of proton pump inhibitory therapy, which usually resolves symptoms, and surgery, whenever feasible, with curative intent represents the hallmark of gastrinoma treatment. The high expression of somatostatin receptors in gastrinomas makes them highly responsive to somatostatin analogs, supporting their use as anti-proliferative agents in patients not amenable to surgical cure. Other medical options for advanced disease are super-imposable to other neuroendocrine neoplasms, and studies specifically focused on gastrinomas only are scant and often limited to case reports or small retrospective series. The multidisciplinary approach remains the cornerstone for the proper management of this composite disease. Herein, we reviewed available literature about gastrinoma-associated ZES with a specific focus on differential diagnosis, providing potential diagnostic and therapeutic algorithms.     

Zollinger-Ellison syndrome revisited: Diagnosis,biologic markers,associated inherited disorders,and acid hypersecretion

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, neuronspecific 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 longterm possible side effects are reviewed briefly.     

Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature

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.     

Treatment of endocrine tumors of the pancreas

Many advances have been made in the recognition, diagnosis, and management of patients with functional islet cell tumors during the past three decades. Improved results should occur in those patients with functional islet cell tumors causing recognizable syndromes. The likelihood of this occurring is predicated upon an awareness, high index of suspicion, the use of immunoassays, provocative tests, and appropriate localization studies. Earlier diagnosis is providing the opportunity to cure many patients who could be treated only with palliative procedures or drugs in the past. Figure 1 summarizes the current management plan utilized in evaluating patients whose findings suggest the possibility of a functional islet cell tumor syndrome. Nonfunctional islet cell tumors continue to be a therapeutic problem because their detection (with the exception of those discovered incidentally during upper abdominal explorations, CT scanning for other indications, or CT scanning of the pancreas in MEN-1 patients) usually does not occur until the tumor is locally invasive or associated with liver metastases. The treatment of these tumors has usually been palliative, utilizing chemotherapy and medical therapy including the somatostatin analogue Sandostatin or an operation to bypass an obstruction of the biliary tract or duodenum.     

Diagnosis and treatment of Zollinger-Ellison syndrome

A diagnostic and therapeutic strategy for the management of patients with Zollinger-Ellison syndrome has been developed, based on the review of a large personal experience and the most recent literature. The mainstay of a modern ZES management is the eradication of tumoral processes whenever feasible. Diagnosis is centred upon gastric acid and gastrin secretion measurements both in basal conditions and on secretin stimulation. Recognition of other endocrine involvement and familial inheritance is of the utmost importance in distinguishing sporadic ZES patients from those who have the condition known as multiple endocrine neoplasia type I. Blood calcium and phosphorus levels, parathyroid hormone concentration, combined if necessary with urinary cyclic AMP excretion measurement, should be performed routinely once ZES diagnosis is established or highly suspected. Localization of the tumour is the next essential step, and this has been considerably facilitated by the recent development in imaging techniques: it involves computerized axial tomography and selective abdominal angiography, a combination of which allows tumour detection in 60-70% of sporadic gastrinoma patients, with a maximal sensitivity for well-developed hepatic metastases. In sporadic ZES exploratory laparotomy is legitimate when preoperative localization of the tumour has failed; this laparotomy will allow further detection and then eradication of gastrinomas in a significant number of patients. Control of gastric acid secretion is mandatory throughout the work-up period; modern antisecretory agents are efficacious in most cases; total gastrectomy, when control of acid hypersecretion has failed, is now exceptional. Eradication of the tumour should be attempted in cases of sporadic ZES in the absence of recognizable liver involvement. The chance of a definite cure provided by surgery when performed by an experienced surgeon varies from 20% to 60% in pancreatic and ectopic gastrinomas respectively. In ZES patients with MEN I, exploratory laparotomy is seldom indicated (other than for symptomatic associated endocrine secretion), as the chance of a definite cure by surgery is very rare. Parathyroid surgery is often indicated and should take place before any form of abdominal surgery. In cases of hepatic metastases, chemotherapy with streptozocin and fluorouracil is indicated and soon, perhaps, chemo-embolization.     

Cytokine gene profile in gastric mucosa in Helicobacter pylori infection and Zollinger-Ellison syndrome

OBJECTIVE: Helicobacter pylori-associated inflammation is mediated, in part, by inflammatory cytokines. In contrast, the mucosal disease associated with Zollinger-Ellison syndrome (ZES) is acid driven, and the role of cytokines is not known. The aim of this study was to elucidate the role of cytokines in these two diseases, as we quantitated proinflammatory cytokine messenger RNA (mRNA) levels in the gastric mucosa from patients with H. pylori infection and ZES. METHODS: The study population included 11 patients with H. pylori infection, 12 with ZES, 17 with both H. pylori infection and ZES, and three control subjects with neither. Using a competitive polymerase chain reaction for interleukin (IL)-1beta, IL-6, IL-8, and tumor necrosis factor-alpha, the polymerase chain reaction products in gastric biopsies were quantitated by capillary electrophoresis and laser-induced fluorescence. RESULTS: The levels of IL-1beta, IL-6, IL-8, and tumor necrosis factor-a mRNA in gastric tissue of patients with H. pylori infection only and ZES only exceeded the levels in the control gastric tissue (p < 0.05 to p < 0.005). Unexpectedly, the number of molecules of IL-1beta and IL-8 mRNA in gastric tissue from ZES patients exceeded the levels in gastric tissue from patients with H. pylori only (p < 0.05). The local levels of cytokine mRNA in patients with both diseases exceeded the levels in patients with H. pylori only (IL-6, p < 0.05; IL-8, p < 0.05) and ZES only (IL-6, p < 0.05; tumor necrosis factor-a, p < 0.05). CONCLUSIONS: Levels of proinflammatory cytokine mRNA are increased in acid-driven as well as infection-driven gastric inflammation, and the presence of both disease processes appears to have an additive effect on local cytokine message expression. Inflammatory cytokines may mediate both infection- and acid-driven gastric inflammation.     

Surgery and prognosis of duodenal gastrinoma as a duodenal neuroendocrine tumor

It has become increasingly clear that duodenal gastrinomas are the most common cause of Zollinger-Ellison syndrome (ZES). However, attempts to find these tumors before and during surgery for ZES have had limited success until duodenotomy (opening the duodenum) was described. The routine use of duodenotomy in patients with non-familial gastrinoma increases the number of duodenal tumors found, and the immediate and long-term cure-rate. The increase in cure-rate appears to be secondary to increased detection of small, previously undetectable duodenal gastrinomas. Duodenotomy detects small tumors (<1 cm) in the proximal duodenum. It does not detect more duodenal gastrinomas per patient, nor does it detect tumors in unusual duodenal locations. Duodenotomy decreases the death-rate associated with these tumors. However, it has not affected the rate of development of liver metastases. Duodenotomy is a critical method to find duodenal gastrinomas. It should be routinely performed in all surgery to find and remove gastrinoma for cure of ZES.     

Abnormal pancreatic polypeptide release by secretin infusion in Zollinger-Ellison syndrome

In 28 patients with the Zollinger-Ellison syndrome (ZES), 26 studied before and two after tumor excision, and in 26 age-matched control patients with duodenal ulcer (DU), plasma pancreatic polypeptide and serum gastrin concentrations were studied before, during, and after infusion of pure secretin (3 CU/kg/hr). In 21 ZES patients, gastric acid output was simultaneously studied. Fasting pancreatic polypeptide concentrations were over 300 pmol/liter in five of 26 gastrinomas. In DU, secretin caused a nonsignificant increase in plasma pancreatic polypeptide concentration and markedly decreased gastric acid output. In ZES, however, it resulted in a marked increase of both plasma pancreatic polypeptide concentration and gastric acid output. Basal and post secretin pancreatic polypeptide concentrations showed no correlation with gastric acid output, serum gastrin levels, or the age of the subjects, in DU patients as well as in ZES. These concentrations were not different in ZES patients who had a vagotomy compared to nonvagotomized ZES patients. Furthermore, the pancreatic polypeptide response to intravenous secretin was abolished by gastrinoma excision.A portion of this work has appeared in abstract form (Gastroenterology 82:1161, 1982) and was presented at the Annual Meeting of the American Gastroenterological Association, Chicago (Illinois), on May 18, 1982.     

Management of the Zollinger–Ellison syndrome in patients with multiple endocrine neoplasia type 1

Jensen RT (Bethesda, MD, USA). Management of the Zollinger–Ellison syndrome in patients with multiple endocrine neoplasia type 1 (Minisymposium: MEN & VHL). J Intern Med 1998; 243 : 477–88. Zollinger–Ellison syndrome (ZES) is the most common symptomatic pancreatic endocrine tumour in patients with MEN-1. Besides the treatment of the usual endocrinopathies seen in patients with MEN-1, the treatment of the ZES requires attention be paid to controlling the gastric acid hypersecretion, to dealing with the gastrinomas per se which are malignant in 18–60% of cases, and to the diagnosis and treatment of gastric carcinoid tumours, that are increasingly seen in these patients. In this article the current management of each of the areas is reviewed and what is known or uncertain discussed, based on our studies at the NIH and data from others. Data from 231 patients including 45 with MEN-1 and 186 without MEN-1 is contrasted in this report. Gastric acid hypersecretion has been controlled in all patients medically with MEN-1 and ZES at the NIH for up to 22 years. The current drugs of choice are H⁺-K⁺ ATPase inhibitors and twice a day dosing is recommended. Periods of parenteral drug therapy (surgery, etc.) and pregnancy require important modifications. The appropriate surgical therapy of the gastrinoma is controversial. Eighty per cent of patients have a duodenal gastrinoma and 20–30% have a pancreatic tumour. Recent studies suggest gastrinoma enucleation combined with duodenotomy rarely results in cure. Aggressive surgery (Whipple resection) can result in cure of gastrinoma but effect on survival is unclear. There are important differences in gastrinoma location, extent, and percentage with aggressive disease in patients with or without MEN-1, which are discussed. Confusion has occurred because of lack of information on the natural history of the gastrinoma compared to the other pancreatic endocrine tumours that occur in MEN-1 and survival data from patients with and without MEN-1 is contrasted. The occurrence of gastric carcinoids in patients with and without MEN-1 with ZES is contrasted and the areas of certainty and disagreement reviewed.     

A prospective study of gastric carcinoids and enterochromaffin-like cell changes in multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: identification of risk factors

CONTEXT: 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. OBJECTIVES: 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. SETTING AND PATIENTS: Fifty-seven consecutive MEN1/ZES patients participated in this prospective study at two tertiary-care research centers. INTERVENTIONS AND OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSIONS: 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.     

Non-functioning islet cell tumors of the pancreas--a multicentric clinical study in Taiwan

BACKGROUND/AIMS: Islet cell tumors of the pancreas are rare. Functioning tumors are characterized by the symptoms induced by the hormones they secrete. The clinical behaviors of non-functioning tumors are quite different. In this retrospective study, we scrutinized 16 patients with non-functioning islet cell tumor in three tertiary university hospitals in Taiwan during a 20-year period. METHODOLOGY: There were 12 women and 4 men with a mean age of 47 years. Body-weight loss, abdominal pain and palpable mass were the most frequent symptoms. RESULTS: The mean size of these tumors was 8.9 cm in diameter. Ten tumors were located at the tail of pancreas, the other 6 located at the head. Except for hyperbilirubinemia in 2 patients, none of the patients with non-functioning islet cell tumor showed abnormalities of laboratory data including serum tumor markers. Preoperative detection of these tumors by imaging modalities was not difficult due to the large size of the tumors. However, differentiation with functioning tumor or ductal cell carcinoma required clinical and imaging correlation. Fourteen tumors were malignant including 8 with regional lymph nodes involvement, 3 with locally microscopic invasion, 2 with hepatic metastasis and 2 with nearby organ invasion. CONCLUSIONS: Even with its malignant behavior, non-functioning islet cell tumor still possessed a good prognosis after adequate surgical removal in comparison with a higher mortality rate of ductal carcinoma of the pancreas.     

Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature

In patients with multiple endocrine neoplasia type 1 (MEN1), the most common functional pancreatic endocrine tumor (PET) syndrome is Zollinger-Ellison syndrome (ZES). ZES has been well studied in its sporadic form (that is, without MEN1); however, there are limited data on patients with MEN1 and ZES (MEN1/ZES), and the long-term natural history is largely unknown. To address this issue we report the results of a prospective long-term National Institutes of Health (NIH) study of 107 MEN1/ZES patients and compare our results with those of 1009 MEN1/ZES patients in 278 case reports and small series in the literature. Patients were clinically, radiologically, and biochemically evaluated yearly for all MEN1 manifestations (mean follow-up, 10 yr; range, 0.1-31 yr). Compared with patients from the literature, the NIH MEN1/ZES patients more frequently had pituitary (60%) and adrenal (45%) disease and carcinoid tumors (30%), but had equal frequency of hyperparathyroidism (94%), thyroid disease (6%), or lipomas (5%). Twenty-five percent of both the NIH and the literature patients lacked a family history of MEN1; ZES was the initial clinical manifestation of MEN1 in 40%. ZES onset preceded the diagnosis of hyperparathyroidism in 45%. However, ZES was rarely (8%) the only initial manifestation of MEN1 if careful testing was done. ZES occurred before age 40 years in 50%-60% of the current patients, in contrast to older studies. The diagnosis of ZES is delayed 3-5 years from its onset and is delayed as long as in sporadic ZES cases. Pituitary disease and carcinoid tumors (gastric > bronchial, thymic) are more frequent than generally reported, whereas a second functional PET is uncommon. In patients with MEN1/ZES without a family history of MEN1, the MEN1 manifestations are not as severe. This study shows that MEN1/ZES patients differ in many aspects from those commonly reported in older studies involving few MEN1/ZES patients. In this study we have identified a number of important clinical and laboratory features of MEN1/ZES that were not previously appreciated, which should contribute to earlier diagnosis and improve both short- and long-term management.     

Histopathology of the gastric oxyntic mucosa in two different patient groups during long-term treatment with omeprazole

OBJECTIVES: Hypochlorhydria, hypergastrinaemia, inflammation and Helicobacter pylori infection, dose and duration of omeprazole treatment may separately, or in combination, influence the proliferation of enterochromaffin-like (ECL) cells and parietal cell changes in gastric mucosa. To assess the effects of these variables comparisons were carried out in patients with the acid related Zollinger-Ellison syndrome (ZES) versus patients with progressive systemic sclerosis (PSS) and gastro-oesophageal reflux disease. METHODS: Twenty-five patients with PSS and 16 patients with ZES were included and received continuous omeprazole treatment for a mean of 7.5 and 9 years. The patients were investigated every 6-12 months with endoscopy, biopsies and histology, and plasma gastrin measurements. PSS patients were titrated by 24 h pH-metry to oesophageal pH>4, and all ZES patients were titrated to a basal acid output of zero H+. RESULTS: Changes towards diffuse and linear ECL cell hyperplasia were observed in 41% of the PSS patients. Micronodular hyperplasia and neoplasia were not seen. In the ZES patients changes towards linear and micronodular hyperplasia were observed in all patients. Two patients developed ECL cell carcinoids; one of these had MEN-1 syndrome. Also parietal cell changes were more pronounced in the ZES group than in the PSS group. CONCLUSIONS: In patients without intrinsic acid hypersecretion and hypergastrinaemia significant proliferation of ECL cells is not an issue irrespective of gastric mucosal inflammation, omeprazole dose, duration of treatment and acid inhibition. The level of gastrin secretion and high plasma gastrin appear to accelerate ECL cell proliferation and parietal cell changes possibly influenced by chronic gastritis and H. pylori infection.     

Fine Needle Aspiration Cytology of Submucosal Nodules in Patients with Zollinger-Ellison Syndrome

Submucosal nodules are often encountered during investigations of the upper gastrointestinal (GI) tract. This is particularly true in diseases resulting in chronic hypergastrinemia, such as Zollinger-Kllison syndrome (ZES), in which submucosal gastric and duodenal lesions can occur. Forceps biopsy of submucosal lesions often yields only normal mucosa; however, fine needle aspiration cytology (FNAC) has recently been described as having high diagnostic accuracy for submucosal tumors Therefore, we prospectively studied the use of FNAC in 43 patients with ZES. Overall, 33% of patients with ZES had nodules. In patients with the sporadic form of ZES, submucosal nodules were found in 18%, whereas submucosal nodules were found in 80% of patients who had ZES in conjunction with multiple endocrine neoplasia type I (MEN-I). FNAC identified 11/12 (92%) of the neuroendocrine tumors, and identified another 8/9 as non-neuroendocrine. Jumbo forceps biopsy was performed on 18 nodules and diagnosed one neuroendocrine tumor. Subsequently, 11 of these nodules were found to possess neuroendocrine tumor; thus only 1/11 (9%) neuroendocrine tumors removed were accurately identified by jumbo forceps biopsy. Of the first 14 nodules, sufficient tissue was left after biopsy to permit snare polypectomy on 12 nodules. Four nodules were found to contain neuroendocrine tumor. Snare polypectomy resulted in a duodenal perforation that required surgery in one patient, and thus was not performed on the final seven nodules. We conclude that 1) upper GI tract submucosal nodules are common in patients with ZES, although neuroendocrine tumor is common only in those patients with ZES and MEN-1; 2) FNAC can accurately diagnose submucosal neuroendocrine tumors in patients with ZES; 3) jumbo biopsy is not belpful in the evaluation of these submucosal nodules; and 4) snare polypectomy can result in duodenal perforation, and thus should not be routinely performed.     

A follow-up study of patients with Zollinger-Ellison syndrome in the period 1966-2002: effects of surgical and medical treatments on long-term survival

AIM: To evaluate the clinical history of a series of patients with Zollinger-Ellison syndrome (ZES) in the period 1966 to 2002, before and after the introduction of the current antisecretive H2 receptor antagonists and proton pump inhibitors into clinical practice. PATIENTS AND METHODS: The study involved 18 ZES patients (9 males; mean age, 43 years; range, 12-70 years), 8 with Type 1 multiple endocrine neoplasia (MEN-1), diagnosed on the basis of standard criteria. We considered the type, number and effectiveness of surgical interventions before and after appropriate treatment, the localization of the gastrinoma, the presence of associated diseases, the causes of death, and the duration of survival. RESULTS: Total gastrectomy (but not antrectomy and vagotomy) and full compliance to antisecretory treatment reduced the number of operations from 29 to 9. One patient was cured (5.5%), whereas relapsing gastrinomas occurred in 4 patients and associated diseases or complications in ten. Death was related to ZES in 5 patients and to other causes in 4. CONCLUSIONS: Curing gastrinoma or appropriately inhibiting gastric acid hypersecretion in ZES patients prevent death and favors long-term survival, regardless of gastrin levels and the size or number of tumors.     

Gastric Carcinoid Tumors Without Autoimmune Gastritis in Japan: A Relationship with Helicobacter pylori Infection

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

Current concepts in the surgical management of multiple endocrine neoplasia type 1 pancreatic-duodenal disease. Results in the treatment of 40 patients with Zollinger–Ellison syndrome, hypoglycaemia or both

Thompson NW (University of Michigan, Ann Arbor, MI, USA). Current concepts in the surgical management of multiple endocrine neoplasia type 1 pancreatic-duodenal disease. Results in the treatment of 40 patients with Zollinger– Ellison syndrome, hypoglycaemia or both (Minisymposium: MEN & VHL). J Intern Med 1998; 243 : 495–500.
The management of multiple endocrine neoplasia type 1 (MEN-1) pancreatic-duodenal disease, particularly when the Zollinger–Ellison syndrome (ZES) is the presenting manifestation, has remained controversial. The management of hypoglycaemia and other syndromes as well as large tumours detected by imaging is less controversial, although standardized surgical techniques have not been generally adapted. The rationale for an aggressive operative management plan for ZES and other syndromes is based on the facts that neuroendocrine tumours of both the pancreas and the duodenum have malignant potential and that the functional manifestations can be controlled with appropriate surgical procedures based on current concepts of the MEN-1 disease. Of the ten concepts presented, the one critical to the surgical treatment of ZES is that a duodenotomy is essential in detecting the source of hypergastrinaemia in most MEN-1 patients. The complete operation is multifaceted and includes peripancreatic lymph node dissection (ZES), enucleation of any head or uncinate tumours and a distal pancreatectomy. Our results in 40 MEN-1 patients with functional syndromes treated with these procedures are encouraging. Ten patients with hypoglycaemia (four with concomitant ZES) have been 'cured' with follow-up as long as 18 years. Sixty-eight per cent of 34 patients with ZES have remained eugastrinaemic during follow-up as long as 19 years. One patient developed a solitary liver metastasis that was excised a year ago without other evidence of recurrence. There has been no operative mortality and three subsequent deaths were due to unrelated disease.     

Gallbladder and Gastric Argyrophil Carcinoid Associated with a Case of Zollinger-Ellison Syndrome

Gastric carcinoids are uncommon tumors, reportedly associated with pathological hypergastrinemic states such as Zollinger-Ellison syndrome (ZES). Gallbladder carcinoids are also very rare, but have not previously been reported in association with ZES. In this report we discuss a patient with ZES in whom both gastric and gallbladder carcinoid tumors were found.