Diagnostic and therapeutic criteria in patients with Zollinger–Ellison syndrome and multiple endocrine neoplasia type 1

: Mignon M, Cadiot G (Bichat and Claude Bernard Hospital, Paris, France). Diagnostic and therapeutic criteria in patients with Zollinger–Ellison syndrome and multiple endocrine neoplasia type 1 (Minisymposium: MEN & VHL). J Intern Med 1998; 243 : 489–94. About 25% of patients with ZES have MEN-1. Except for diarrhoea, less frequent in patients with ZES MEN-1 than in sporadic ZES, and specific MEN-1-related signs, clinical characteristics are similar in both ZES types. Acid output and gastrin level are also similar whether in the basal state or after secretin. Primary hyperparathyroidism (pHPT) exists in the majority of ZES MEN-1 patients, 30% have pituitary adenoma (prolactinomas for half), 30% adrenal involvement, 25–30% have ECLomas: bronchial and thymic carcinoids have probably been underevaluated. Gastrinomas are multiple predominantly located in the duodenal wall, but also in the pancreas in association with clinically silent endocrine tumours. The spread of the disease metastases to the liver (LM), mediastinum, bones, is evaluated best by Octreoscan. Associated endoscopic ultrasonography evaluates the number, size and anatomical characteristics of gastrinomas. Patients without LM have an excellent prognosis. Surgery never cures ZES, but is necessary in cases of associated life-threatening conditions such as insulinoma. Although the size of the tumour, when located in the pancreas >3 cm, favours metachronous LM occurrence, surgery in our experience has not been able to prevent LM development.     

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.     

Surgical treatment and prognosis of gastrinoma

Zollinger-Ellison syndrome (ZES) is a clinical syndrome with severe peptic ulcer disease and diarrhea caused by gastric acid hypersecretion secondary to a neuroendocrine tumour that secretes excessive amounts of the hormone gastrin (gastrinoma). Gastrinomas occur in a familial and a sporadic form. Patients with gastrinoma in the familial setting of Multiple Endocrine Neoplasia type 1 (MEN-1) are seldom, if ever, cured of Zollinger-Ellison syndrome by the current non-Whipple operations to remove duodenal and pancreatic gastrinoma. Surgery is currently used in these patients to deal with the malignant nature of pancreatic or duodenal neuroendocrine tumours. Malignant potential is best determined by tumour size. Tumours that are greater than 2 cm in size should be excised. In the sporadic setting, cure occurs in a significant proportion of patients (50%) by surgical resection of gastrinoma. Duodenotomy has improved both the tumour detection rate and the cure rate and should be routinely done. Whipple pancreaticoduodenectomy results in the highest probability of cure in both sporadic and MEN-1 gastrinoma patients as it removes the entire gastrinoma triangle. However, the excellent long-term survival of these patients with lesser operations and the increased operative mortality and long-term morbidity of Whipple make its current role unclear until further studies are done.     

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.     

Use of omeprazole in patients with Zollinger-Ellison syndrome

Omeprazole, a substituted benzimidazole, has been shown to be a potent inhibitor of gastric acid secretion in patients with Zollinger-Ellison syndrome (ZES). We review our experience, as well as the published data on 210 patients with ZES who have required omeprazole for control of gastric acid hypersecretion over the past seven years. The dose of omeprazole required in individual patients ranged from 10 to 180 mg/24 hr with 20-60% requiring a split dosage regimen. Omeprazole was effective in approximately 99% of the patients over a period ranging from 0.5 to 54 months. Twenty-four percent of patients required an increase in omeprazole dose, while 26% required a decrease in dose. Adverse effects attributable to omeprazole were reported in 2% of patients, and in all cases, they were mild (ie, rash, constipation, headache). There was no effect of omeprazole on serum gastrin concentration or on gastric endocrine cells in three studies. Although one patient with multiple endocrine neoplasia, type-I syndrome (MEN-I) in this series developed a gastric carcinoid while taking omeprazole, evidence is presented that suggests the presence of MEN-I per se may be important in determining the development of gastric carcinoid in patients with ZES. It is concluded that omeprazole is safe and effective in patients with ZES, and in these patients, it is the drug of choice for the management of gastric acid hypersecretion. However, yearly assessment is indicated to clearly evaluate the long-term risk of gastric carcinoid as well as therapy directed at the gastrinoma itself.     

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.     

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.     

Catching the Zebra: Clinical Pearls and Pitfalls for the Successful Diagnosis of Zollinger–Ellison Syndrome

Zollinger–Ellison syndrome (ZES) results from an ectopic gastrin-secreting tumor leading to peptic ulcer disease, reflux, and chronic diarrhea. While early recognition portends an excellent prognosis with >80% survival at 15 years, symptoms are often nonspecific making the diagnosis difficult to establish. Diagnosis involves a series of tests, including fasting gastrin, gastric pH, chromogranin A, and secretin stimulation. Performing these tests in the correct sequence and at the proper time is essential to avoid inaccurate results. Tumor localization is equally nuanced. Although providers have classically used ¹¹¹indium-radiolabeled octreotide with somatostatin receptor scintigraphy to evaluate tumor size and metastases, recent studies have shown superior results with newer imaging modalities. In particular, ⁶⁸gallium (⁶⁸Ga)-labeled somatostatin radiotracers (i.e., ⁶⁸Ga-DOTATOC, ⁶⁸Ga-DOTANOC and ⁶⁸Ga-DOTATATE) used with positron emission tomography/computed tomography can provide excellent results. Endoscopic ultrasound is another useful modality, particularly in patients with ZES in the setting of multiple endocrine neoplasia type 1. This review aims to provide clinicians with an overview of ZES with a focus on both clinical presentation and the proper utilization of the various biochemical and imaging tests available.     

The effect of Zollinger-Ellison syndrome and neuropeptide-secreting tumors on the stomach

Zollinger-Ellison syndrome (ZES) is caused by a tumor that secretes gastrin and is the most common of the malignant islet cell tumors. ZES leads to hypergastrinemia, which, in turn, causes an overproduction of gastric acid and results in complications of peptic ulcer disease. Of all the islet cell tumors, gastrinoma tumors have undergone the most extensive study, providing a model of tumor management. Increased awareness and improved biochemical and radiologic techniques mean that these disorders are being recognized in more patients. Advances in the management of gastric acid secretion and new localization methods have significantly reduced the morbidity and mortality associated with ZES. The use of intravenous proton pump inhibitors such as pantoprazole will make surgical and perioperative management more favorable for patients. Radiologic and nuclear medicine studies permit the detection of the majority of islet cell tumors and improve the ability for surgical resection. With the recent cloning of the gene for multiple endocrine neoplasia type I (MEN- I) and the recognition of tumor markers associated with the development of islet cell tumors, early detection of these tumors may someday be possible.     

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.     

Digestive hormones and gastric diseases. Facts and hypotheses (author's transl)]

Relationships between hormonal secretions from the GI tract and gastric functional and/or pathological abnormalities could be studied according to 2 main lines : 1) gastric secretory changes could be the main symptom of hormonal secretory tumors, i.e. acid hypersecretion in the Zollinger Ellison syndrome, acid hyposecretion in pancreatic cholera and in somatostatinoma. In these cases, hormonal hypersecretion is directly responsible for the functional disturbances and the related symptoms; 2) gastric pathological conditions are sometimes accompanied by changes in hormonal secretion, but the level of interdependence is variable : high blood gastrin is directly depending upon the atrophic gastritis in pernicious anemia; this mechanism was also suggested in case of gastric carcinoma. Concerning ulcer disease, numerous problems are unsolved in respect to blood gastrin (basal and stimulated) abnormalities, as well as somatostatin and GIP secretions.     

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.     

A case of Zollinger-Ellison syndrome produced by gastrinoma in the duodenum accompanied with multiple endocrine neoplasia type 1

A case of Zollinger-Ellison syndrome produced by gastrinoma in the duodenum accompanied by multiple endocrine neoplasia type-1 (MEN-1) is reported. A 46 year-old female underwent distal gastrectomy due to gastric ulcer 5 years ago. As ulceration of the residual stomach recurred, further examination was performed. Hyperprolactinemia, hypergastrinemia, primary hyperparathyroidism, pancreatic tumor, and duodenal carcinoid were evident, and the diagnoses of Zollinger-Ellison syndrome and MEN-1 were established. The origin of the gastrin secretion was suspected to be from the pancreatic tumor, so sampling of the portal blood was performed. As lesion on the gastrinoma in the pancreas could not be identified, total parathyroidectomy was performed for primary hyperparathyroidism. The level of the gastrin secretion, however, remained high. Partial resection of the duodenum for the duodenal carcinoid and a distal pancreatectomy were carried out concurrently. Immunohistochemical study of the anti-gastrin antibody revealed duodenal tumor cells. Initially, the gastrinoma was thought to be in the pancreas, however, the lesion accompanied with MEN-1 and the Zollinger-Ellison syndrome had occurred in the duodenum.     

The ultimate biochemical diagnosis of endocrine pancreatic tumours in MEN-1

Öberg K, Skogseid B (University Hospital, Uppsala, Sweden). The ultimate biochemical diagnosis of endocrine pancreatic tumours in MEN-1 (Minisymposium: MEN & VHL). J Intern Med 1998; 243 : 471–6. Multiple endocrine neoplasia type 1 (MEN-1) is a well characterized hereditary syndrome with the occurrence of primary hyperparathyroidism (HPT) in combination with pancreatic-duodenal endocrine and anterior pituitary tumours. The diagnosis of MEN-1, the possible probands, necessitates the recognition of at least two or three lesions classically associated with the syndrome whilst only one of them is required for individuals belonging to established MEN-1 kindreds. A distinct feature of MEN-1 comprises the multiplicity of organ involvement, the multicentricity of tumours within the affected organs as well as the complex pattern of the clinical signs of these tumours and their sometimes temporarily variable profile of hormone excess. Thorough screening studies have demonstrated that the MEN-1 trait is biochemically detectable virtually two decades prior to clinically overt disease. The primary biochemical screening programme for MEN-1 includes serum prolactin and insulin growth factor 1 (IGF-1) for pituitary lesions, intact PTH and albumin corrected total serum calcium for the parathyroids and for duodenal/pancreatic tumours serum glucose, insulin, proinsulin, pancreatic polypeptide, glucagon, gastrin and plasma chromogranin A. Furthermore a standardized meal stimulatory test analysing serum polypeptides (PP) and gastrin is recommended. Our current primary screening procedure has yielded about 10% false positives when compared with RFLP data. Pancreatic endocrine tumour diagnosis must be biochemically established since radiology fails to show lesions in half of the patients. Pancreatic involvement in young MEN-1 patients is most consistently demonstrated by analysing serum insulin, proinsulin, PP as well as plasma glucagon chromogranin A levels, which have exhibited sensitivities of 56, 67, 37 and 60%, respectively. Serum PP is a non-specific marker of islet cell tumours that should be applied in conjunction with other peptide markers. Elevation of basal serum gastrin generally indicates the presence of advanced pancreatic tumour involvement or duodenal carcinoids. Early diagnosis of pancreatic endocrine tumours in MEN-1 is enhanced by the use of a standardized meal stimulation test with measurements of serum PP and gastrin response. This test was the most sensitive test and substantiated the presence of tumour in 75% of individuals whose mean age was 25 years. False-positive stimulation due to the meal test has been found in about 10% of previous investigated individuals. The diagnosis of MEN-1 pancreatic tumours is based on biochemical screening alone and it has been substantiated that an unequivocal rise in pancreatic tumour markers precedes radiological detection of these lesions by at least five years.     

Zollinger-Ellison syndrome. Clinical presentation in 261 patients

We prospectively evaluated the initial presenting symptoms in 261 patients with Zollinger-Ellison syndrome (ZES) over a 25-year period. Twenty-two percent of the patients had multiple endocrine neoplasia-type 1 (MEN-1) with ZES. Mean age at onset was 41.1 +/- 0.7 years, with MEN-1 patients presenting at a younger age than those with sporadic ZES (p < 0.0001). Three percent of the patients had onset of the disease < age 20 years, and 7% > 60 years. A mean delay to diagnosis of 5.2 +/- 0.4 years occurred in all patients. A shorter duration of symptoms was noted in female patients and in patients with liver metastases. Abdominal pain and diarrhea were the most common symptoms, present in 75% and 73% of patients, respectively. Heartburn and weight loss, which were uncommonly reported in early series, were present in 44% and 17% of patients, respectively. Gastrointestinal bleeding was the initial presentation in a quarter of the patients. Patients rarely presented with only 1 symptom (11%); pain and diarrhea was the most frequent combination, occurring in 55% of patients. An important presenting sign that should suggest ZES is prominent gastric body folds, which were noted on endoscopy in 94% of patients; however, esophageal stricture and duodenal or pyloric scarring, reported in numerous case reports, were noted in only 4%-10%. Patients with MEN-1 presented less frequently with pain and bleeding and more frequently with nephrolithiasis. Comparing the clinical presentation before the introduction of histamine H2-receptor antagonists (pre-1980, n = 36), after the introduction of histamine H2-receptor antagonists (1981-1989, n = 118), and after the introduction of proton pump inhibitors (PPIs) (> 1990, n = 106) demonstrates no change in age of onset; delay in diagnosis; frequency of pain, diarrhea, weight loss; or frequency of complications of severe peptic disease (bleeding, perforations, esophageal strictures, pyloric scarring). Since the introduction of histamine H2-receptor antagonists, fewer patients had a previous history of gastric acid-reducing surgery or total gastrectomy. Only 1 patient evaluated after 1980 had a total gastrectomy, and this was done in 1977. The location of the primary tumor in general had a minimal effect on the clinical presentation, causing no effect on the age at presentation, delay in diagnosis, frequency of nephrolithiasis, or severity of disease (strictures, perforations, peptic ulcers, pyloric scarring). Disease extent had a minimal effect on symptoms, with only bleeding being more frequent in patients with localized disease. Patients with advanced disease presented at a later age and with a shorter disease history (p = 0.001), were less likely to have MEN-1 (p = 0.0087), and tended to have diarrhea more frequently (p = 0.079). A correct diagnosis of ZES was made by the referring physician initially in only 3% of the patients. The most common misdiagnosis made were idiopathic peptic ulcer disease (71%), idiopathic gastroesophageal reflux disease (GERD) (7%), and chronic idiopathic diarrhea (7%). Other less common misdiagnosis were Crohn disease (2%) and various diarrhea diseases (celiac sprue [3%], irritable bowel syndrome [3%], infectious diarrhea [2%], and lactose intolerance [1%]). Other medical disorders were present in 55% of all patients; patients with sporadic disease had fewer other medical disorders than patients with MEN-1 (45% versus 90%, p < 0.00001). Hyperparathyroidism and a previous history of kidney stones were significantly more frequent in patients with MEN-1 than in those with sporadic ZES. Pulmonary disorders and other malignancies were also more common in patients with MEN-1. These results demonstrate that abdominal pain, diarrhea, and heartburn are the most common presenting symptoms in ZES and that heartburn and diarrhea are more common than previously reported. The presence of weight loss especially with abdominal pain, diarrhea, or heartburn is an important clue suggesting the presence of gastrinoma. The presence of prominent gastric body folds, a clinical sign that has not been appreciated, is another important clue to the diagnosis of ZES. Patients with MEN-1 presented at an earlier age; however, in general, the initial symptoms were similar to patients without MEN-1. Gastrinoma extent and location have minimal effects on the clinical presentation. Overall, neither the introduction of successful antisecretory therapy nor widespread publication about ZES, attempting to increase awareness, has shortened the delay in diagnosis or reduced the incidence of patients presenting with peptic complications. The introduction of successful antisecretory therapy, however, has dramatically decreased the rate of surgery in controlling the acid secretion and likely led to patients presenting with less severe symptoms and fewer complications. (ABSTRACT TRUNCATED)     

The "serendipitous" surgical cure of the Zollinger-Ellison syndrome in a patient with multiple endocrine neoplasia type 1 despite an unsuspected diagnosis of either disease

Zollinger-Ellison syndrome (ZES) is a relatively uncommon disease that usually presents with peptic ulcer disease or refractory diarrhea. It occurs as a component of multiple endocrine neoplasia type 1 (MEN-1) syndrome in more than 25% of cases. Surgical management of MEN-1 ZES remains controversial. In this case report, we describe the serendipitous cure of ZES in a patient with recurrent peptic ulcer disease who underwent two surgical procedures. The diagnosis of MEN-1 ZES syndrome was neither suspected nor recognized during either operation. This case is presented to highlight the important principles in the diagnosis and current management of patients with MEN-1 ZES.     

Biliary tree gastrinomas in multiple endocrine neoplasia type 1 syndrome

AIM:To describe our patients affected with ectopic biliary tree gastrinoma and review the literature on this topic.METHODS:Between January 1992 and June 2012,28 patients affected by duodenopancreatic endocrine tumors in multiple endocrine neoplasia type 1(MEN1)syndrome underwent surgery at our institution.This retrospective review article analyzes our experience regarding seventeen of these patients subjected to duodenopancreatic surgery for Zollinger-Ellison syndrome(ZES).Surgical treatment consisted of duodenopancreatectomy(DP)or total pancreatectomy(TP).Regional lymphadenectomy was always performed.Any hepatic tumoral lesions found were removed during surgery.In MEN1 patients,removal of duodenal lesions can sometimes lead to persistence or recurrence of hypergastrinemia.One possible explanation for this unfavorable outcome could be unrecognized ectopic localization of gastrin-secreting tumors.This study described three cases among the seventeen patients who were found to have an ectopic gastrinoma located in the biliary tree.RESULTS:Seventeen MEN1 patients affected with ZES were analyzed.The mean age was 40 years.Fifteen patients underwent DP and two TP.On histopathological examination,duodeno pancreatic endocrine tumors were found in all 17 patients.Eighty-one gastrinomas were detected in the first three portions of the duodenum.Only one gastrinoma was found in the pancreas.The mean number of gastrinomas per patient was 5(range 1-16).Malignancy was established in 12 patients(70.5%)after lymph node,liver and omental metastases were found.Three patients exhibited biliary tree gastrinomas as well as duodenal gastrinoma(s).In two cases,the ectopic gastrinoma was removed at the same time as pancreatic surgery,while in the third case,the biliary tree gastrinoma was resected one year after DP because of recurrence of ZES.CONCLUSION:These findings suggest the importance of checking for the presence of ectopic gastrinomas in the biliary tree in MEN1 patients undergoing ZES surgery.     

Determinants of metastatic rate and survival in patients with zollinger-ellison syndrome: A prospective long-term study

It is unclear whether tumor location, size, or the presence of multiple endocrine neoplasia type 1 (MEN-1) alters metastatic rate and survival in patients with pancreatic endocrine tumors. The purpose of this study was to determine the prognostic factors of survival and metastatic rate in patients with Zollinger-Ellison syndrome (ZES). Data were analyzed from 185 consecutive patients with ZES who were followed up prospectively. Liver metastases were present in 24% of patients and correlated with the size of the primary tumor. Duodenal tumors were smaller than pancreatic tumors. Liver metastases occurred more often (P < 0.00001) with pancreatic than duodenal tumors, whereas the metastatic rate to lymph nodes was not different. Survival of patients with liver but not lymph node metastases was shortened. In patients with sporadic ZES, liver metastases were more common during the initial evaluation and survival was decreased compared with patients with MEN-1; however, during follow-up, an equal percentage of patients with and without MEN-1 developed liver metastases. Survival was primarily determined by the presence of liver metastases. The frequency of liver metastases depends on the size and location of the primary tumor and on the presence of MEN-1 at the initial presentation. Metastases to the lymph nodes do not depend on these factors. A benign and malignant form of ZES exists.     

Surgical management of Zollinger-Ellison syndrome: Classical considerations and current controversies

Zollinger-Ellison syndrome(ZES) is characterized by gastric acid hypersecretion causing severe recurrent acid-related peptic disease. Excessive secretion of gastrin can now be effectively controlled with powerful proton pump inhibitors,but surgical management to control gastrinoma itself remains controversial.Based on a thorough literature review, we design a surgical algorithm for ZES and list some significant consensus findings and recommendations:(1) For sporadic ZES, surgery should be routinely undertaken as early as possible not only for patients with a precisely localized diagnosis but also for those with negative imaging findings. The surgical approach for sporadic ZES depends on the lesion location(including the duodenum, pancreas, lymph nodes,hepatobiliary tract, stomach, and some extremely rare sites such as the ovaries,heart, omentum, and jejunum). Intraoperative liver exploration and lymphadenectomy should be routinely performed;(2) For multiple endocrine neoplasia type 1-related ZES(MEN1/ZES), surgery should not be performed routinely except for lesions 2 cm. An attempt to perform radical resection(pancreaticoduodenectomy followed by lymphadenectomy) can be made. The ameliorating effect of parathyroid surgery should be considered, and parathyroidectomy should be performed first before any abdominal surgery for ZES; and(3) For hepatic metastatic disease, hepatic resection should be routinely performed. Currently, liver transplantation is still considered an investigational therapeutic approach for ZES. Well-designed prospective studies are desperately needed to further verify and modify the current considerations.     

Prospective study of the standard meal provocative test in Zollinger-Ellison syndrome

PURPOSE: The purpose of this work was to evaluate the proposed usefulness of a standard meal-stimulated gastrin provocative test in: (1) distinguishing Zollinger-Ellison syndrome (ZES) from antral syndromes; (2) localizing duodenal gastrinomas; or (3) suggesting that patients with multiple endocrine neoplasia type I (MEN-I) may have an increased incidence of antral syndromes. PATIENTS AND METHODS: Seventy-four consecutive patients with ZES referred to the National Institutes of Health were studied prospectively. The extent and location of gastrinomas, acid secretory studies, and the presence or absence of MEN-I were determined and correlated with the results of the gastrin response to standard meal provocative testing. RESULTS: For patients with fasting serum gastrin levels less than 1,000 pg/mL (n = 43), only 44% had a less than 50% increase over the pre-meal value, which is reported to be the typical response in ZES, and 40% had a 50% to 99% increase. Furthermore 16% had a 100% or greater increase, 9% a 150% or greater increase, and 5% a 200% or greater increase, which overlaps with values reported to be characteristic of 98%, 92%, and 46% of patients with antral syndromes. Results did not differ for patients with or without MEN-I, depend on the extent of the gastrinoma (duodenal versus pancreatic gastrinomas), the presence of previous gastric surgery or type of gastric surgery, or for patients with fasting serum gastrin concentrations greater than or equal to 1,000 pg/mL or less than 1,000 pg/mL. studies of four patients before and after resection of the gastrinoma, who prior to surgery had a greater than 100% increase in gastrin secretion after the meal, demonstrated that all patients had a less than 100% increase postoperatively even though no gastric resection was done. CONCLUSIONS: Approximately half of the patients with ZES have a greater than 50% increase in serum gastrin concentration following a standard test meal and one fifth have a 100% or greater increase. Therefore, they cannot be distinguished on this basis from patients with antral syndromes. The increased serum gastrin level after the meal in these patients with ZES appears to be due to the gastrinoma. Furthermore, the current study provides no evidence for the proposals that antral syndromes are more common in patients with MEN-I, that gastric surgery affects the meal response in patients with gastrinomas, or that the meal test is useful in localizing duodenal gastrinomas.