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.     

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.     

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.     

Gastrinomas associated with MEN-1 syndrome: new insights for the diagnosis and management in a series of 11 patients

BACKGROUND/AIMS: Approximately, 25-30% of patients (pts) have gastrinomas, (Zollinger-Ellison syndrome, ZES), as part of the inherited syndrome, multiple endocrine neoplasia 1 (MEN-1). The identification of MEN-1 syndrome in these pts is always important, as there are some differences in their management and prognosis. Among 33 pts with ZES, we present in this study 11 pts with ZES and MEN-1 syndrome, describing our diagnostic and therapeutic approach. METHODOLOGY: Eleven pts with ZES and MEN-1 syndrome (6 females and 5 males) were included (mean age 51.8 years). The diagnosis of ZES was based upon: a) clinical features and b) high serum gastrin levels, while in 7/11 pts diagnosis was confirmed histopathologically. A variety of other gastrointestinal peptides, as well as the general neuroendocrine tumor marker, Chromogranin-A (CgA) were also estimated. All pts underwent conventional imaging methods (CT, MRI) and OCTREOSCAN or EUS when necessary, in order to localize the primary lesion or the metastases. The diagnosis of MEN-1 was based upon the presence of the other two MEN-1 related endocrinopathies (hyperparathyroidism, pituitary adenomas), revealed by estimation of several hormones (PTH, Prolactin, ACTH etc.) and performance of imaging studies of the pituitary and parathyroid glands. When MEN-1 syndrome was established, a familiar screening of pts was also performed, when possible. The mean duration of pts' follow-up was 6.1 years (range: 2.1-8.5 years). RESULTS: At the time of presentation, 91% pts, had symptoms of peptic ulcer disease, refractory to treatment, while a history of colicky abdominal pain due to nephrolithiasis was also reported by 45% pts. Four of our pts had a blood relation. Serum gastrin levels at the time of diagnosis were greater than 1000pg/mL in 63.5% pts, while at the same time serum CgA levels were greater than 10 times the upper normal limit (<98ng/mL) in all pts. OCTREOSCAN and EUS revealed the primary tumor (in duodenum or pancreas) in 64% pts, in whom conventional methods showed no abnormalities at the same time. Parathyroid adenomas, pituitary adenomas and bronchial carcinoids were revealed in 11, 3 and 1 pts respectively, which were treated surgically. Also, surgical treatment of pancreatic or duodenal gastrinomas was performed in 54.5% pts, while pts who already had metastases (45%), or developed them during the follow-up period (18%), were treated by somatostatin analogues (63.6%) and chemotherapy (27.3%). Ten out of 11 pts are alive and in a good condition, whereas 1 patient died 2.8 years after diagnosis. Familiar screening revealed parathyroid adenomas in 4 children of our pts, which were treated surgically. CONCLUSIONS: MEN-1 syndrome should always be considered in pts with ZES. A precise preoperative localization of all pancreaticoduodenal lesions, in combination with a surgical exploration and management by experienced surgeons, seems to be curative in pts without distal metastases. Non-surgical treatment with somatostatin analogues and chemotherapy in pts with progressive disease seem to stabilize the disease, although further studies are needed. A close clinical and biochemical follow-up of all pts, as well as their family members, is necessary in order to reveal and treat all MEN-1 related endocrinopathies and especially PETs, in an early stage.     

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.     

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.     

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.     

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)     

Sporadic versus hereditary gastrinomas of the duodenum and pancreas： Distinct clinico-pathological and epidemiological features

INTRODUCTION Gastrinomas are de?ned as gastrin-producing tumors that are associated with Zollinger-Ellison syndrome (ZES) due to inappropriate gastrin secretion. ZES is characterized by elevated fasting gastrin serum levels, positive gastrin secretin stim…     

Thymic carcinoids in multiple endocrine neoplasia type 1

Teh BT (Karolinska Hospital, Stockholm, Sweden). Thymic carcinoids in multiple endocrine neoplasia type 1 (Minisymposium: MEN & VHL). J Intern Med 1998; 243 : 501–4.
Thymic carcinoid is a rare malignancy with about 150 cases reported to date. It is associated with multiple endocrine neoplasia type 1 (MEN-1), but compared with other MEN-1-related neoplasia little is known about it. We have recently described and studied 20 MEN-1-related cases and found that up to 25% of all reported thymic carcinoids are MEN-1 related. It is an insidious tumour not associated with Cushing's syndrome or carcinoid syndrome. Local invasion, recurrence and distant metastasis are common with no known effective treatment. Its male predominance, the absence of loss of heterozygosity (LOH) in the MEN1 region, clustering in some MEN-1 families and the findings of different MEN1 mutations in these clustered families suggest the involvement of additional aetiological factors. We propose that computed tomography (CT) or magnetic resonance imaging (MRI) of the chest should be included as part of the clinical workup for all MEN-1 patients. Prophylactic thymectomy should be considered during subtotal or total parathyroidectomy on MEN-1 patients to reduce the risk of this malignancy.     

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.     

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.     

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.     

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.     

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.     

Usefulness of somatostatin receptor scintigraphy in the management of patients with Zollinger-Ellison syndrome. Groupe de Recherche et d''Etude du Syndrome de Zollinger-Ellison (GRESZE).

BACKGROUND: Management of patients with Zollinger-Ellison syndrome (ZES) depends on the presence of multiple endocrine neoplasia type 1 (MEN 1) or liver metastases, or both. Somatostatin receptor scintigraphy (SRS) detects previously unknown endocrine tumours. AIM AND METHODS: To evaluate SRS findings susceptible to modifying the management of patients with ZES-that is, relevant findings, and the specificity of these findings. The latter were defined according to our current therapeutic strategy in three subgroups of patients (sporadic, MEN 1, and liver metastases). PATIENTS: 85 consecutive patients without known extra-abdominal metastases were studied between September 1991 and March 1996. RESULTS: Relevant findings were found in 41% of 49 patients with sporadic disease but without liver metastases, in 22% of 18 patients with MEN 1 but without liver metastases, and in 17% of 18 patients with liver metastases. Follow up was available for 20 (74%) of 27 patients who had 23 relevant findings. Nineteen relevant findings (83%) were confirmed at a median of three (range 0.25-45) months of follow up; four (17%) were not confirmed at 30 (range 12-52) months (p = 0.025). Findings located in the duodenopancreatic area (90%), chest (100%), bone (100%), and liver (60%) were confirmed. Most findings for patients with MEN 1 involved the chest. CONCLUSION: SRS detects many anomalies susceptible to modifying management of patients with ZES, especially in those with sporadic disease. The specificity of hot spots located outside the liver seems very high. By contrast, the specificity of hot spots located in the liver remains to be evaluated when conventional imaging is negative.     

Interest of Chromogranin A for diagnosis and follow-up of endocrine tumours

OBJECTIVE: To determine the interest of Chromogranin A (CgA) determination for diagnosis and follow-up in patients with gastroenteropancreatic endocrine tumours (GEP-ET) and multiple endocrine neoplasia type 1 (MEN-1). PATIENTS AND METHODS: CgA levels were measured with an immunoradiometric assay in 124 sporadic GEP-ET, 34 MEN-1 and 127 controls. Serial determinations were performed in 56 patients (212 visits). Changes in CgA levels over 25% were considered as significant. RESULTS: Using a cut-off value of 130 micro g/l, established from a receiver-operating characteristic curve, the specificity of CgA was 98.4%, with a sensitivity of 62.9%, higher in secreting than in nonsecreting tumours (73%vs. 45%; P < 0.003) and related to the extent of metastatic spreading (P < 0.001). In nonsecreting tumours, the positive predictive value (PPV) of CgA for the presence of metastases was 100% but the negative predictive value (NPV) was only 50%. In MEN-1, high CgA levels indicated a pancreatic tumour with a 100% specificity but the sensitivity was 59%. During the follow-up, the concordance between CgA and tumour evolution was 80%, whatever the secretory status. In patients with carcinoid tumours, the concordance was higher for CgA than for serotonin (81%vs. 54%; P < 0.001). CONCLUSION: Due to its high specificity, CgA determination may help to discriminate the endocrine character of a GEP tumour and to indicate a pancreatic tumour in MEN-1. However, its low NPV in nonsecreting tumours limits its interest for diagnosis and staging. By contrast, serial evaluation of CgA seems of particular interest for the follow-up of GEP-ET tumours.     

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.     

Heredit?re neuroendokrine Tumoren

Multiple endocrine neoplasia type 1 (MEN-1) is an autosomal-dominant hereditary disease characterized by the occurrence of tumors of the parathyroids, duodenum and/or pancreas, and anterior pituitary. The syndrome is caused by germline mutations of the MEN1 tumor suppressor gene. The identification of the causative mutations is of paramount importance for the long-term management of affected individuals and their relatives. Multiple endocrine neoplasia type 2 (MEN2) is less frequent than MEN1 and represents a cancer syndrome caused by autosomal-dominant inherited mutations of the RET proto-oncogene, and displays a genotype-phenotype correlation of remarkable clinical relevance. Major components of MEN-2 comprise medullary thyroid carcinoma (MTC), pheochromocytoma, and primary hyperparathyroidism. Since 25-30% of patients with MTC display a hereditary background, genetic testing is indicated once MTC is diagnosed. Occurrence of MTC can be avoided by prophylactic thyroidectomy in early childhood in gene carriers. Early diagnosis and therapy of simultaneous pheochromocytoma avoids the development of complications caused by acute or chronic hypertension.     

Recent standardization of treatment strategy for pancreatic neuroendocrine tumors

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 prognos-tic 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.