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Background: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of multiple epithelial neuroendocrine tumors (NETs) and non-NETs in various organs. MEN1 encodes a 610-amino acid-long tumor suppressor protein, menin. The optimal treatment for multiple tumors, identification of the most critical tumors for patient prognosis, and menin immunohistochemistry findings remain controversial. Therefore, we aimed to elucidate these issues through a histological analysis of tumors and tumor-like lesions in a Japanese family, comprising a father and his two sons, who had MEN1 with Zollinger-Ellison syndrome (ZES)., Patients and Methods: All family members had a germline alteration in exon 10, c.1714-1715 del TC of MEN1 , and exhibited multiple synchronous and metachronous tumors. The patients had pulmonary NETs, hyperparathyroidism, hypergastrinemia, pituitary adenomas, pancreaticoduodenal NETs, adrenocortical adenoma with myelolipoma, nodular goiter of the thyroid, lipomas, and angiofibroma. Most tumors were resected and histologically examined. We compared their clinical courses and tumor histology, and conducted menin immunohistochemistry (IHC)., Results: Two patients died of pulmonary NET G2. One patient who underwent pancreaticoduodenectomy was cured of ZES; however, the two other patients who did not undergo pancreaticoduodenectomy suffered persistent ZES despite treatment with octreotide. Menin IHC revealed varying NET intensities, ranging from positive to negative stains., Conclusion: Pancreaticoduodenectomy is the most effective treatment for ZES. Long-term follow-up is essential for pulmonary NET G2 owing to the risk of distant metastasis and/or multiplicity. Moreover, the variability of menin IHC in MEN1-related tumors may indicate the pattern of tumor formation rather than the diagnostic utility of menin in MEN1., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kimura, Hirata, Iwashiro, Kijima, Takayasu, Yamagata, Sakihara, Uchino and Ohara.)

The journey of gastrinomas had its beginnings in 1955 when Zollinger and Ellison published their seminal paper (Zollinger and Ellison, Ann Surg 1955; 142: 709-723). The evolution of the diagnosis and management of this syndrome has paralleled many important advances in medicine, including the development of various diagnostic tools to the major impact of medical treatment on the management of an inherently surgical pathology. There are numerous excellent review articles on the most current developments and treatment options of gastrinomas available in the literature today. The purpose of this paper is to present a historical perspective on this most fascinating condition. This article will illustrate the way in which the discovery of gastrinomas evolved and how its management has developed with it. The evolution of the surgical treatment of gastrinomas has evolved over the last 50 years., ((c) 2009 Wiley-Liss, Inc.)

Context/objectives: The diagnosis of Zollinger-Ellison syndrome requires secretin testing in 60% of patients. Even with secretin, the diagnosis may be difficult because variable responses occur, and 6-30% have negative testing. The basis for variability or negative responses is unclear. It is unknown whether the tumor density of secretin receptors or the presence of a secretin-receptor-variant, which can act as a dominant negative, is important. The aim of this study was to investigate these possibilities., Patients/methods: Secretin-receptor and variant mRNA expression was determined in gastrinomas using real-time PCR from 54 Zollinger-Ellison syndrome patients. Results were correlated with Western blotting, secretin-receptor immunohistochemistry, with gastrin-provocative test results and tumoral/clinical/laboratory features., Results: Secretin-receptor mRNA was detectible in all gastrinomas but varied 132-fold with a mean of 0.89 +/- 0.12 molecules per beta-actin. Secretin-receptor PCR results correlated closely with Western blotting (r = 0.95; P < 0.0001) and receptor immunohistochemistry (P = 0.0015; r = 0.71). The variant was detected in all gastrinomas, but levels varied 102-fold and were 72-fold lower than the total. Secretin-receptor levels correlated with variant levels, Deltasecretin, but not Deltacalcium and with tumor location, but not growth, extent, or clinical responses. Variant levels did not correlate with the Deltasecretin. Detailed analysis provides no evidence that variant expression modified the secretin-receptor response or accounted for negative tests., Conclusions: Secretin-receptor and secretin-receptor-variant expressions occur in all gastrinomas. Because the expression of the total, but not variant, correlated with the secretin results and no evidence for dominant negative activity of the variant was found, our results suggest that the total secretin-receptor density is an important determinant of the secretin test response.

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

Background: Patients with a multiple endocrine neoplasia type 1 (MEN1)-associated Zollinger-Ellison syndrome (ZES) show multifocal duodenal gastrinomas and precursor lesions., Aims: To test these lesions for loss of heterozygosity (LOH) of the MEN1 gene locus on chromosome 11q13, and to investigate whether the MEN1-related endocrine cell changes also involved somatostatin cells., Material and Methods: Tissue specimens from six patients with MEN1 and ZES were analysed by immunohistochemistry and immunofluorescence. LOH analysis was performed by fluorescence in situ hybridisation (FISH), using probes containing the MEN1 gene locus and the centromere 11 (C11) region. For simultaneous analysis of hormones and allelic deletions, a combined FISH/immunofluorescence protocol was established., Results: 28 of a total of 33 duodenal neuroendocrine tumours (NETs) were gastrin-producing tumours; 13/28 (46.4%) revealed LOH on 11q13 and/or C11. Five of the NETs were somatostatin-expressing tumours, two revealing LOH. Allelic loss was detected in tumours as small as 300 microm (gastrin) and 400 microm (somatostatin) in diameter. The gastrin-producing tumours showed different deletion/retention patterns. Hyperplastic somatostatin cell lesions, similar to those of the gastrin cells, were present in all patients. The hyperplastic lesions of both cell lines consistently retained both 11q13 alleles., Conclusions: Allelic deletion of the MEN1 gene may reflect a pivotal event in the development of multifocal gastrin and somatostatin cell neoplasms in the duodenum of patients with MEN1. The observation of distinct deletion patterns in small synchronous tumours supports the concept that each gastrin-producing tumour in an individual MEN1 patient arises from an independent cell clone.

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

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

Background: Recent studies have shown that tumor growth, rather than hormone overproduction, is the leading cause of death among patients with gastrinomas and other malignant gastrointestinal endocrine tumors. No patient/laboratory characteristics accurately predict which tumors will exhibit aggressive growth. Furthermore, little is known regarding the molecular pathogenesis of these tumors. X-chromosome loss of heterozygosity (LOH) occurs in some nonendocrine tumors, and its presence can be associated with aggressive growth/decreased survival. Data on X-chromosome LOH in gastrointestinal endocrine tumors are conflicting. Therefore, the purpose of the current study was to determine whether X-chromosome LOH occurred in gastrinomas and, if so, whether it was correlated with tumor growth, tumor behavior, and/or prognosis., Methods: X chromosome allelotyping was performed using 12 microsatellite markers spaced throughout the chromosome using DNA from leukocytes and microdissected gastrinoma specimens from 16 female patients. The presence of X-chromosome LOH was analyzed for correlations with clinical and laboratory tumor characteristics as well as tumor growth characteristics., Results: Nine gastrinoma specimens (56%) had X-chromosome LOH, ranging from 6% to 23% at the 12 different loci studied. X-chromosome LOH was significantly associated with aggressive postoperative tumor growth, increased primary tumor size, and pancreatic primaries. In 6 tumor specimens, LOH occurred on Xp22.1-22.3 over a 28.4-centimorgan region., Conclusions: X-chromosome LOH was common in gastrinoma specimens from female patients, and its presence was found to be a potentially useful molecular/genetic prognostic factor for aggressive growth.

Purpose: Recently, an increased incidence of some nonendocrine tumors are reported in patients with multiple endocrine neoplasia type 1 (MEN 1). There are rare reports of meningiomas and other central nervous system tumors in these patients, but it is unknown if they are more frequent or if allelic loss of the MEN1 gene is important in their pathogenesis. The aim of this study was to address these two latter questions., Experimental Design: Results from a prospective study of 74 MEN 1 patients with suspected/proven pancreatic endocrine tumors (PETs) were analyzed, as well as molecular studies performed on a resected meningioma. All patients had serial brain imaging studies (computed tomography, magnetic resonance imaging, and octreoscanning since 1994) and yearly studies evaluating MEN 1 involvement with a mean follow-up of 7.2 years. Results were compared with 185 patients with sporadic Zollinger-Ellison syndrome., Results: Six patients (8%) had meningiomas. Meningiomas were single and found late in the MEN 1 course (mean age = 51 years). Magnetic resonance imaging/computed tomography were more sensitive than octreoscanning. Their diagnosis averaged 18 years after the onset of hyperparathyroidism, 10-15 years after pituitary disease or PETs. Meningiomas were 11 times more frequent in patients with PETs with MEN 1 than without MEN 1 (P = 0.017). No clinical, laboratory, or MEN 1 feature distinguished patients with meningiomas. Meningiomas were asymptomatic and 60% showed no growth. A resected meningioma showed loss of heterozygosity at 11q13 and 1p, including at p73 and ARHI/NOEY2 locus, but not at the neurofibromatosis 2 gene locus., Conclusions: These results show meningiomas are not an infrequent occurrence in MEN 1, and loss of the function of the MEN1 gene product plays a role in their pathogenesis in these patients.

A proportion of gastrinomas demonstrates aggressive growth, and most deaths occur in this group. Little is known about the molecular pathogenesis of growth of this tumor, and there are no predictive factors that are useful in an individual patient. Chromosome 1 (Chr 1) loss of heterozygosity (LOH) is frequent in a number of nonendocrine tumors and in a few endocrine tumors, and its presence can correlate with tumor aggressiveness and survival. In gastrointestinal endocrine tumors including gastrinomas, little data are available on Chr 1 LOH, and the limited results are contradictory. In the present study we determine whether Chr 1 LOH occurs in gastrinomas and is associated with aggressive growth by performing Chr 1 allelotyping with microsatellite markers in microdissected tumor tissue from 27 human gastrinomas and the leukocyte DNA of the patients. Detailed clinical pathological correlations were possible, because tumor growth in all of the patients was prospectively assessed with yearly imaging studies. Twelve gastrinomas (44%) had Chr 1 LOH, and in all of the cases 1q LOH occurred. 1q LOH was associated with aggressive growth (P = 0.0004), presence of liver metastases (P = 0.019), and postoperative development of hepatic metastases (P = 0.017). Eight (75%) of the 12 tumors with 1q LOH had 1q31-32 LOH over a 17.3 cM region, whereas LOH in 6 tumors (50%) occurred at 1q21-23 over a 12.3 cM area. The presence of 1q31-32 LOH and 1q21-23 LOH correlated with aggressive tumor growth (P = 0.0056 and P = 0.0031, respectively), and with postoperative development of liver metastases (P = 0.0114 and P = 0.011, respectively). These data suggest that 1q LOH is not infrequent in gastrinomas and could be a molecular/genetic prognostic factor for aggressive growth that could be useful clinically. The high frequent allelic loss at 1q31-32 as well as 1q21-23, which was associated with tumor aggressive growth, suggests these two regions harbor putative tumor suppressor gene(s) that are important for aggressive growth of this tumor.

Purpose: Growth factor receptor expression and activation, particularly for epidermal growth factor (EGF) and hepatocyte growth factor (HGF), in many endocrine and nonendocrine tumors is important in determining tumor recurrence, growth, and aggressiveness. Whether this is true of neuroendocrine tumors such as gastrinomas is unclear., Experimental Design: To address this question, we analyzed the extent of EGFR and HGFR expression in gastrinomas from 38 patients with Zollinger-Ellison syndrome and correlated it with clinical and tumor characteristics. EGFR (n = 38) and HGFR (n = 22) mRNA levels were determined by competitive PCR, and immunohistochemistry was performed on a subset., Results: In each of the gastrinomas studied, detectable levels of EGFR and HGFR mRNA were present. Low levels of EGFR protein expression were detected in 40% of gastrinomas and HGFR protein expression in 90%. EGFR mRNA expression varied by 1050-fold and HGFR by 375-fold. Eighteen percent of gastrinomas overexpressed EGFR mRNA and 14% overexpressed HGFR mRNA, compared with normal pancreas. Maximal EGFR and HGFR mRNA levels were 4- and 1.2-fold increased and correlated with the presence of liver metastases (P = 0.034) and decreased long-term curability (P = 0.027) but not tumor location, size, or tumor functional characteristics., Conclusions: These above results indicate that EGFR and HGFR mRNA are universally expressed in gastrinomas. Furthermore, each is overexpressed in a minority (15-20%) of the gastrinomas, and the overexpression correlates with aggressive growth and lower curability.

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.

Extracellular calcium levels are able to influence the secretion of gastrin by gastrinomas and possibly affect the growth pattern. The molecular mechanisms of these functions are not known. The purpose of the present study was to investigate the presence of the calcium-sensing receptor (CaR) in 10 gastrinomas and determine the extent of expression in the tumors. The amounts of CaR messenger ribonucleic acid in eight tumors were determined by quantitative RT-PCR. Protein expression was analyzed by Western blot and immunohistochemistry using a monoclonal antibody (ADD). CaR messenger ribonucleic acid was detected in all gastrinomas with levels ranging from 0.04-3.16 times the amount of beta-actin transcripts. The Western blot showed a major immunoreactive band at 250 kDa and a minor at 140 kDa, corresponding to the receptor dimer and monomer, respectively. Immunohistochemistry demonstrated variable membranous staining in all gastrinomas and normal pancreatic islets. No staining was observed in the normal liver, lymph node, or exocrine pancreas. We conclude that the CaR is present in all gastrinomas, with expression varying by 80-fold. It probably contributes to the calcium-stimulated gastrin release by gastrinomas. Whether the density of the CaR is a determining factor of the magnitude of this gastrin release or plays a role in regulating the growth pattern of the gastrinoma, as it does in other cells, remains unclear at present.

Multiple endocrine neoplasia type 1 (MEN1) gene mutations are reported in some gastrinomas occurring in patients without MEN1 as well as in some other pancreatic endocrine tumors (PETs). In some inherited syndromes phenotype-genotype correlations exist for disease severity, location, or other manifestations. The purpose of the present study was to correlate mutations of the MEN1 gene in a large cohort of patients with sporadic gastrinomas to disease activity, tumor location, extent, and growth pattern. DNA was extracted from frozen gastrinomas from 51 patients and screened by dideoxyfinger-printing (ddF) for abnormalities in the 9 coding exons and adjacent splice junctions of the MEN1 gene. Tumor DNA exhibiting abnormal ddF patterns was sequenced for mutations. The findings were correlated with clinical manifestations of the disease, primary tumor site, disease extent, and tumor growth postoperatively. Tumor growth was determined by serial imaging studies. Sixteen different MEN1 gene mutations in the 51 sporadic gastrinomas (31%) were identified (11 truncating, 4 missense, and 1 in-frame deletion). Nine of the 16 mutations were located in exon 2 compared to 7 of 16 in the remaining 8 coding exons (P = 0.005 on a per nucleotide basis). Primary pancreatic or lymph node gastrinomas with a mutation had only exon 2 mutations, whereas duodenal tumors uncommonly harbored exon 2 mutations (P = 0.011). Similarly, small primary tumors (<1 cm) more frequently contained a nonexon 2 mutation (P = 0.02). There was no difference between patients with or without a mutation with respect to clinical characteristics, primary tumor site, disease extent, or proportion of patients disease free after surgery. Postoperative tumor growth tended to be more aggressive in patients with a mutation (P = 0.09). No correlation in the rate of disease-free status or postoperative tumor growth in patients with active disease to the location of the mutation was seen. These results demonstrate that the MEN1 gene is mutated in 31% of sporadic gastrinomas, and mutations are clustered between amino acids 66-166, which differs from patients with familial MEN1, in whom mutations occur throughout the gene. The presence of an MEN1 gene mutation does not correlate with clinical characteristics of patients with gastrinomas, gastrinoma extent, or growth pattern; however, the location of the mutation differed with gastrinoma location. These data suggest that mutations in the MEN1 gene are important in a proportion of sporadic gastrinomas, but the presence or absence of these mutations will not identify the clinically important subgroups with different growth patterns.

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 (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.

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.

Background & Aims: Both gastrin and genetic factors were suggested to underlie the pathogenesis of multiple gastric enterochromaffin-like (ECL) cell carcinoids. To assess the role of genetic alterations in carcinoid tumorigenesis, loss of heterozygosity (LOH) at the locus of the multiple endocrine neoplasia type 1 (MEN-1) gene was studied in gastric carcinoids of patients with MEN-1 and chronic atrophic type A gastritis (A-CAG), as well as in sporadically arising intestinal carcinoids., Methods: DNA extracted from archival tissue sections of 35 carcinoid tumors was assessed for LOH with eight polymorphic markers on chromosome 11q13. A combined tumor and family study was performed in 1 patient with MEN-1-Zollinger-Ellison syndrome (ZES)., Results: LOH at 11q13 loci was detected in 15 of 20 (75%) MEN-1-ZES carcinoids, and each ECL-cell carcinoid with LOH showed deletion of the wild-type allele. Only 1 of 6 A-CAG carcinoids displayed LOH at the MEN-1 gene locus, and none of the 9 intestinal and rectal carcinoids showed 11q13 LOH., Conclusions: Gastric ECL-cell carcinoid is an independent tumor type of MEN-1 that shares a common developmental mechanism (via inactivation of the MEN-1 gene) with enteropancreatic and parathyroid MEN-1 tumors. Further analysis of sporadic and A-CAG carcinoids is needed to elucidate genetic factors involved in their tumorigenesis.

The surgical management of multiple endocrine neoplasia type 1 (MEN1) parathyroid disease and involvement of the endocrine pancreas remains controversial. Hyperparathyroidism, usually the first clinical manifestation of the syndrome, requires surgical treatment in nearly all patients. We favour a subtotal parathyroidectomy and cervical thymectomy rather than a total parathyroidectomy and autotransplant because of good long-term results and the absence of permanent hypoparathyroidism. The results of treating 34 MEN1 patients during a 20-year period are reported. The most common functional pancreatic or duodenal tumours in MEN1 patients are gastrinomas and insulinomas. In addition to the management of functional syndromes, another major concern is the malignant potential of the neuroendocrine tumours that frequently develop. Our surgical management of gastrinomas and the ZES has evolved over a period of 15 years. We have found that distal pancreatectomy, enucleation of any neoplasms in the head, and duodenotomy and excision of any neuroendocrine tumours (gastrinomas) combined with a regional node dissection are effective in the majority of patients. The results of treating 21 MEN1 patients with ZES are reported.

The surgical treatment of patients with the Zollinger-Ellison syndrome has undergone a dramatic evolution since the syndrome was originally described. It is now recognized that an aggressive surgical approach is mandatory because of the malignant potential of gastrinomas in both the sporadic and the familial forms of the syndrome. Although initially regarded as an incurable neoplasm, it is now known that complete surgical resection of gastrinomas can result in eugastrinemia even in the presence of lymph node metastases. It is now recognized that extrapancreatic gastrinomas are more common than pancreatic gastrinomas, and the most common location for an extrapancreatic gastrinoma is the duodenal wall. Major improvements in preoperative imaging and intraoperative localization techniques combined with an increased awareness of the anatomic distribution of gastrinomas have markedly increased the surgeon's ability to care for and cure patients with the Zollinger-Ellison syndrome.

Background: With successful means of controlling gastric acid secretion in patients with Zollinger-Ellison syndrome, the gastrinoma itself is becoming the major determinant of long-term survival. No methods have yet been described to predict which tumors will have more malignant courses thereby indicating which patients should undergo aggressive surgery or antitumor therapy. Because DNA analysis, using flow cytometry, has proved helpful in this regard in other tumors, the current study was designed to evaluate its utility in gastrinoma patients., Methods: Flow cytometry was performed on 81 paraffin-embedded gastrinoma specimens from 59 patients. Results were compared with preoperative patient characteristics, findings at surgery, and postoperative follow up., Results: Tumors were diploid in 54% of patients, near diploid in 15%, pure tetraploid in 0%, nontetraploid aneuploid in 25%, and multiple stem line aneuploid in 5%. All patients with multiple stem line aneuploid tumors had wide-spread metastases whereas all patients with nontetraploid aneuploid tumors had localized or regional disease. Median S phase percentage was 3.6. S phase percentages were higher in patients with widespread metastatic disease than in patients with localized or regional disease. Disease extent also correlated closely with fasting serum gastrin level. After removing this variable with logistic regression analysis, the significant correlation between disease extent and DNA analysis persisted., Conclusions: DNA analysis of gastrinoma tissue specimens correlates independently with the extent of disease and may be useful in planning therapeutic strategies for patients with Zollinger-Ellison syndrome.

In the Zollinger-Ellison syndrome, fundic argyrophil carcinoid tumors have been described only in the small genetically defined subgroup of patients who have the multiple endocrine neoplasia type 1 syndrome (MEN-1). Allelic losses on 11q13, on which MEN-1 gene has been localized, have been noted in parathyroid and pancreatic tumors of patients with MEN-1, suggesting that the MEN-1 gene could act as a recessive tumor suppressor gene. One fundic argyrophil carcinoid tumor from a patient with the Zollinger-Ellison syndrome and MEN-1 was studied. Loss of heterozygosity in the tumor DNA at loci close to MEN-1 locus was looked for using Southern technique with six DNA probes. Segregation of alleles was examined in relatives. In the tumor DNA, we found the loss of one allele with PYGM, the closest probe to the MEN-1 locus. The allele lost in the tumor had been transmitted by the unaffected parent. This suggests that in patients with the Zollinger-Ellison syndrome and MEN-1, the promotion of fundic argyrophil carcinoid tumors results from the inactivation of the two copies of MEN-1 gene and that fundic argyrophil carcinoid tumors may be included in the spectrum of MEN-1-related tumors.

Gastrinomas from 25 patients were examined by immunohistochemistry (IHC) and in situ hybridization histochemistry (ISH). Most patients (84%) presented with the Zollinger-Ellison syndrome. Six had multiple endocrine neoplasia type I (MEN-I). Twelve patients (48%) had duodenal primaries and 11 of 12 of these had metastases to regional lymph nodes and/or liver in spite of the small sizes of the primary tumors (mean size of 0.9 cm). Five patients had pancreatic gastrinomas and eight patients had metastatic tumor in regional lymph nodes or liver at surgery but a primary was not found. IHC and ISH analyses showed that all cases were positive for gastrin protein and 24 of 25 (96%) expressed gastrin mRNA that was easily detected in formalin-fixed, paraffin-embedded tissue sections. Both benign and malignant tumors expressed alpha subunit of human chorionic gonadotropin protein (alpha-HCG). However, only malignant gastrinomas (29%) expressed adrenocorticotropic hormone protein or proopiomelanocortin (POMC) mRNA. ISH and Northern hybridization analysis revealed that chromogranin A mRNA was the most common member of the chromogranin/secretogranin (Cg/Sg) family which was expressed in both benign and malignant gastrinomas. These results indicate that duodenal gastrinomas are common in both sporadic and MEN-1-associated cases, and small duodenal primaries may be associated with extensive regional lymph node and liver metastases. Expression of ACTH/POMC protein and mRNA was consistently associated only with malignant gastrinomas while gastrin protein, gastrin mRNA and Cgs/Sgs mRNAs were readily detected in both benign and malignant gastrinomas.

Gastrinomas are pancreatic endocrine neoplasms that arise either sporadically or are inherited as part of the multiple endocrine neoplasia type I syndrome (MENI). Loss of heterozygosity (LOH) in the region flanking the MENI gene at chromosome 11q13 has been documented in a few sporadic and familial pancreatic endocrine tumors, but not previously in sporadic gastrinomas. It has therefore been suggested that gastrinomas develop by a mechanism different from other tumors associated with the MENI syndrome. We report LOH on chromosome 11 in 5 of 11 sporadic gastrinomas. Four of these tumors have LOH for markers flanking the MENI region. Molecular evaluation of segments of chromosomes 3, 13, and 17 known to contain cloned or putative tumor suppressor genes fail to show LOH except at one locus in one tumor. These data suggest that a tumor suppressor DNA segment exists at 11q13 that may be involved in the development of sporadic gastrinomas.

Gastrin immunocytochemistry and non-radioactive in situ hybridization, using biotinylated oligonucleotide probes, for gastrin mRNA have been used for studying a retrospective material of six gastrin-producing (Zollinger-Ellison) tumors. Hybridization results for gastrin mRNA were positive in all six, while gastrin immunoreactivity could be detected in five tumors. In one of the patients, different areas of the same tumor displayed differences in immunoreactivity to gastrin, but were uniformly hybridization positive. Weak hybridization signals were detected in liver metastases from a necropsy case, while the gastrin immunostaining was more pronounced. The results show that non-radioactive hybridization methods are applicable to routine clinical specimens stored for as long as 16 years and that in situ hybridization may be a useful complement to immunocytochemical diagnosis, particularly in cases where high synthesis and little storage of hormonal products occur.

We report four cases of gastric argyrophil carcinoidosis arising in the oxyntic mucosa of patients with Zollinger-Ellison syndrome as part of type 1 multiple endocrine neoplasia (MEN) syndrome. Multiple mucosal and submucosal carcinoids were seen in combination with innumerable hyperplastic and dysplastic growths of argyrophil endocrine cells disseminated in the entire acidopeptic mucosa. Histochemical and ultrastructural investigation indicated that the argyrophil enterochromaffin-like (ECL) cell, a type of endocrine cell normally restricted to the oxyntic mucosa and very sensitive to gastrin stimulation, was a major component of the carcinoidosis. Five similar cases were found in the literature. Because argyrophil ECL cell carcinoid or carcinoidosis is unusual in patients who have the Zollinger-Ellison syndrome but do not have MEN, we believe that the genetic trait of the MEN syndrome has an important permissive role in the promotion of gastric carcinoids through the hypergastrinemia inherent to Zollinger-Ellison syndrome.

Four cases of endocrine tumors of the pancreas and, more generally, of the diffuse endocrine system, are presented here. Included are all the data relative to the inherited character of the disease covering two generations. Two brothers had Zollinger-Ellison syndrome--one of them probably, the other one proven (first case recorded in France). Both patient's only sons are currently treated for endocrine tumor of the pancreas and Zollinger-Ellison syndrome, respectively.

The potential for malignancy of an islet cell tumor of the pancreas is difficult to cytologically judge when one evaluates only the primary lesion, because a malignant condition is usually determined by the presence of regional or distant metastases. Nuclear DNA cytometric measurements have proved helpful both in the evaluation of the malignant potential of other endocrine and nonendocrine lesions and in the determination of the "aggressiveness" of these tumors. Thirty-six islet cell tumors or their metastases from 25 patients were studied. Eleven patients had insulinomas and typical insulinoma syndromes, and 14 others had gastrinomas with the Zollinger-Ellison syndrome. Tissue from each tumor was stained by the Feulgen technique, and nuclear DNA cytometry was performed by means of the microTICAS system designed by the Cytopathology Laboratory of the University of Chicago. Ploidy measurements of insulinomas, taken alone, did not discriminate well between benign and malignant states. However, the single malignant insulinoma could be clearly recognized, for it was one of only two lesions in that group with 5N-exceeding rate (5N-ER) values of 1% or greater. (5N-ER is defined as the percentage of aneuploid nuclei with nuclear DNA content greater than 5N.) On the other hand, seven of eight malignant gastrinomas had ploidy values of 2.5N or greater (our definition of an aneuploid state) and/or had 5N-ER values of 1% or greater, while five of six benign gastrinomas had ploidy values of less than 2.5N and had 5N-ER values of 0%. In addition, the two most aggressive tumors had the highest ploidy and 5N-ER values. Nuclear DNA cytometric studies appear to offer promise as an aid in the evaluation of pancreatic islet cell tumors, particularly gastrinomas.

To evaluate the frequency of associated endocrine disorders, 26 patients with the Zollinger-Ellison syndrome were restudied in a uniform screening programme. The examinations were directed primarily against disorders in the pituitary, parathyroid, thyroid, adrenal cortex, and endocrine pancreas. Fourteen endocrine disorders were found in 10 patients (38%). Ten of these were newly diagnosed. Five patients had hyperparathyroidism, and in two of these a pituitary adenoma was also suspected. Two had pituitary adenomas, one was suspected of having a pituitary adenoma and one of having adrenocortical hypofunction, and one showed multiple hormone production with hypoglycaemia and flushing. It is concluded that most cases of associated endocrinopathies are not diagnosed until specifically looked for. In the Danish population of patients with the Zollinger-Ellison syndrome the prevalence is about 38%.

A family of multiple endocrine neoplasia type I with five confirmed cases in three generations is described. All of them have primary hyperparathyroidism in common. The propositus is 51 year-old male. After a year of symptoms of gastroduodenal ulcer, he was found to have elevated levels of serum gastrin and PTH. The serial imaging studies revealed a tumor in pancreatic head, and Zollinger-Ellison syndrome was diagnosed. The gastrin level was reduced into normal range after extirpation of the tumor, but post surgical elevation of Calcium put the patient under parathyroidectomy, which normalized serum PTH and Calcium levels. His two sisters (I and II), the mother of them, and the daughter of sister I, had neither signs nor symptoms until family study showed hypercalcemia in all. Sister I is a 54 year-old female with enlarged parathyroid. The hyperparathyroidism is of chemical type, but no other endocrinological abnormality is found. The Calcium level decreased after parathyroidectomy. Sister II is a 56 year-old female. The only sign was galactorrhea. Serum PTH and Calcium decreased after parathyroidectomy. The prolactinoma was diagnosed by the increased prolactin levels and enhanced mass lesion in sella turcica. Her serum prolactin levels is now within normal range since she is on bromocryptine. The mother of the above three siblings and the daughter of the sister I are now under further study.

There are three well-delineated multiple endocrine neoplasia syndromes, all of which are inherited as autosomal dominant traits. Available evidence suggests that still more such entities exist. Despite intensive study, the nature of the genetic defect that results in these syndromes remains obscure.

To evalute the frequency of associated and hereditary endocrinopathies in the Zollinger-Ellison syndrome, 10 patients with the syndrome were studied. In seven of them, coexisting endocrine disease was found. In six, the Zollinger-Ellison syndrome was probably a feature of multiple endocrine adenomatosis type I, whereas Cushing's syndrome in the remaining patient may have been caused by the production of an ACTH-like substance by a mixed pancreatic tumor. A total of 109 family members, including all living first degree relatives over 15 years of age, were screened for endocrine abnormalities. All six patients with evidence of multiple endocrine adenomatosis type I had relatives with endocrinopathies. In the families of the four other patients with the Zollinger-Ellison syndrome, no endocrine abnormalities were found. During this study four new cases of pituitary tumor, 17 of hyperparathyroidism, seven of the Zollinger-Ellison syndrome and one of insulinoma were detected. Although most of the disorders were asymptomatic, this clearly indicates that patients suffering from Zollinger-Ellison syndrome and also their families should undergo detailed endocrine studies.

Recent advances in the medical therapy of duodenal ulcer support the long held concept that acid hypersecretion is an important pathophysiological abnormality in the majority of patients with duodenal ulcer. The origin of acid hypersecretion is heterogeneous (Table 1). Certain specific physiologic abnormalities that lead to acid hypersecretion may have a genetic basis. The various physiologic abnormalities, alone or in combination, may lead to two final common pathways: abnormally large meal-stimulated and nocturnal acid secretion. Indeed, the success of medical therapy aimed at the control of postprandial acid secretion alone or that of nocturnal acid secretion alone strongly support the significance of these two final acid hypersecretory pathways.

The complete sequence of the human gastrin gene is reported here. This gene consists of three exons. Nine Alu family sequences are found within the gene and in the surrounding region. S1 mapping study showed that the transcription of gastrin gene starts at 60, 57, or 55 bp upstream from the 3' end of the first exon. The mechanism of mRNA synthesis in a gastrinoma tissue was studied to clarify the ectopic production of gastrin. It was found that mRNA synthesis starts from the same three transcriptional start points. Southern blotting profiles for normal gastric antrum and gastrinoma DNA were indistinguishable from each other within the 18-kb region containing the gastrin gene, showing that no genomic rearrangements are associated with the gastrinoma formation. Thus, the overproduction of gastrin in this tumor is likely to be due to an aberrant expression control system of the cell, rather than a change in the control region of the gastrin gene.