The Relationship of Gastrinoma in MEN 1 to Helicobacter pylori infection.

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

Cromogranina A y tumores neuroendocrinos / Chromogranin A and neuroendocrine tumors

La cromogranina A (CgA) es la granina más abundante en los tumores neuroendocrinos gastroenteropancreáticos (TNE-GEP). Como marcador tumoral es moderadamente sensible y poco específico. A pesar de las limitaciones de los métodos de medida que requieren una interpretación cuidadosa, especialmente en el caso de los gastrinomas, pacientes tratados con análogos de somatostatina y tumores pobremente diferenciados, es el mejor marcador tumoral en los TNE-GEP y puede ser útil en otros tumores con diferenciación neuroendocrina. La CgA puede ser usada como marcador en sangre o en muestra tisular mediante inmunohistoquímica. Las concentraciones se relacionan con la carga y la extensión tumoral y puede ser usada en el diagnóstico y seguimiento de los TNE-GEP, especialmente en los derivados del intestino delgado y neuroendocrinos del páncreas. Además es útil como marcador pronóstico en la detección de recidivas y en la monitorización de la respuesta a los distintos tratamientos (AU)

Chromogranin A (CgA) is the most abundant granin in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). As a tumor marker is moderately sensitive and nonspecific. Despite the limitations of testing methods, which require careful interpretation, especially in the case of gastrinomas, patients treated with somatostatin analogues, and poorly differentiated tumors, it is the best tumor marker in GEP-NETs and may be of value in other tumors with neuroendocrine differentiation. CgA may be used as a marker in blood or tissue samples through immunohistochemical techniques. CgA levels correlate with tumor burden and extension and may be used for diagnosis and monitoring of GEP-NETs, especially midgut carcinoids and endocrine pancreatic tumors. It is also useful as a prognostic marker for detection of recurrence and monitoring of response to different treatments (AU)

Population-based study of islet cell carcinoma.

BACKGROUND: We examine the epidemiology, natural history, and prognostic factors that affect the duration of survival for islet cell carcinoma by using population-based registries. METHODS: The Surveillance, Epidemiology, and End Results (SEER) Program database (1973-2003 release, April 2006) was used to identify cases of islet cell carcinoma by histology codes and tumor site. RESULTS: A total of 1310 (619 women and 691 men) cases with a median age of 59 years were identified. The annual age-adjusted incidence in the periods covered by SEER 9 (1973-1991), SEER 13 (1992-1999), and SEER 17 (2000-2003) were .16, .14, and .12 per 100,000, respectively. The estimated 28-year limited duration prevalence on January 1, 2003, in the United States was 2705 cases. Classified by SEER stage, localized, regional, and distant stages corresponded to 14%, 23%, and 54% of cases. The median survival was 38 months. By stage, median survival for patients with localized, regional, and distant disease were 124 (95% CI, 80-168) months, 70 (95% CI, 54-86) months, and 23 (95% CI, 20-26) months, respectively. By multivariate Cox proportional modeling, stage (P < .001), primary tumor location (P = .04), and age at diagnosis (P < .001) were found to be significant predictors of survival. CONCLUSIONS: Islet cell carcinomas account for approximately 1.3% of cancers arising in the pancreas. Most patients have advanced disease at the time of diagnosis. Despite the disease's reputation of being indolent, survival of patients with advanced disease remains only 2 years. Development of novel therapeutic approaches is needed.

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

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.

50-year appraisal of gastrinoma: recommendations for staging and treatment.

BACKGROUND: Gastrinoma is a rare neuroendocrine tumor associated with ulcerogenic syndrome. The purpose of this study was to provide information on current controversies related to treatment, including staging, patient selection, and outcomes for surgical resection. STUDY DESIGN: A retrospective review of 106 patients with gastrinoma. Patients were classified as sporadic gastrinoma (SG) or MEN. End points of analysis included disease-free and disease-specific survival. Kaplan-Meier survival analysis was performed and significance (p < 0.05) was determined by Mantel-Haenszel log-rank test. RESULTS: Gastrinoma can be staged by TNM criteria into four groups (stage 0, I, II, and III), which had notably different survival curves, dependent on tumor size and distant metastases (p < 0.0001), but independent of lymph node metastases (p = 0.324). Surgical resection was possible in 72 patients (SG, n = 50; MEN, n = 22). Durable cure rate for SG was 26%, compared with 4% for MEN-1. Surgical resection achieving gross removal of all tumor resulted in improved survival in both SG and MEN patients (p < 0.0001). Improved survival was independent of a normal postoperative serum gastrin. Stage III was highly predictive of incomplete resection and the associated failure to improve survival (p = 0.0001). CONCLUSIONS: Staging provides a reliable method for the clinician to select patients for operation and to provide a prognosis, and should permit better comparisons of treatment between institutions. In the management of gastrinoma, it is recommended that SG and MEN patients with clinical stage I and II disease have surgical exploration, patients with stage III disease not have mandatory surgical treatment, and some stage 0 patients might not need routine surgical exploration.

Endocrine tumours of the pancreas.

Endocrine pancreatic tumours (EPTs) are uncommon tumours occurring in approximately 1 in 100,000 of the population, representing 1-2% of all pancreatic neoplasms. Some of the tumours may be part of multiple endocrine neoplasia type one (MEN-1) syndrome or von Hippel-Lindau (vHL) disease. EPTs are classified as functioning or non-functioning tumours on the basis of their clinical manifestation. The biochemical diagnosis of EPT is based on hormones and amines released. Besides specific markers such as insulin, there are also general tumour markers such as chromogranin A, which is the most valuable marker and has been reported to be increased in plasma in 50-80% of patients with EPTs and correlates with tumour burden. The location of endocrine tumours of the pancreas includes different techniques, from endoscopic investigations to scintigraphy (e.g. somatostatin receptor scintigraphy) and positron emission tomography. The medical treatment of endocrine pancreatic tumours consists of chemotherapy, somatostatin analogues and alpha-interferon. None of these can cure a patient with malignant disease. In future, therapy will be custom-made and based on current knowledge of tumour biology and molecular genetics.

Multiple endocrine neoplasia type 1 variant with frequent prolactinoma and rare gastrinoma.

No variant of multiple endocrine neoplasia type 1 (MEN1) has been reproducible among families. We examined two large kindreds with MEN1 variants, and we compared these to past reports. The two kindreds were followed up for 20-30 yr with MEN1 tumors in 30 members. Results in cases from two kindreds were that 93% showed parathyroid adenoma, 40% pituitary tumor (always prolactinoma), and 27% enteropancreatic endocrine tumor. The latter included 10% insulinoma, 7% nonfunctioning islet tumor, but only 10% gastrinoma. Compared with prior large series, this lower prevalence of gastrinoma (10% vs. 42%, P < 0.01) and higher prevalence of prolactinoma (40% vs. 22%, P < 0.01) define this variant. Many possible biases of retrospective analyses were excluded as possible explanations. Previously sequenced DNA showed no characteristic MEN1 mutation in these two kindreds and in a third, reported previously; the lack of any shared MEN1 mutation also excluded common ancestry for MEN1 among the three kindreds. The causes for differences between this variant and typical MEN1 are unknown. In conclusion, this variant shows more frequent prolactinoma and less frequent gastrinoma than typical MEN1; the variant is reproducible among kindreds. MEN1 carriers in such families should have periodic monitoring adjusted for the expected penetrance of tumors.

Possible primary lymph node gastrinoma: occurrence, natural history, and predictive factors: a prospective study.

OBJECTIVE: To analyze the results of a prospective study of 176 patients with Zollinger-Ellison syndrome (ZES) (138 sporadic, 38 MEN1) undergoing 207 operations over a 17-year period. SUMMARY BACKGROUND DATA: The existence of lymph node (LN) primary gastrinoma causing ZES is controversial. METHODS: Three groups of patients were compared: LN only resected, cured, and no relapse (likely LN primary); same criteria but relapse (unlikely LN primary); and duodenal primary and LN metastases (Duo-LN). RESULTS: Forty-five (26%) had only LN(s) as the initial tumor found. Twenty-six of the 45 (58%) fit the definition of a likely LN primary because they were apparently cured postresection. At 10.4 +/- 1.2 years, 69% of the 26 patients with likely LN primary tumors have remained cured and have LN primaries. In the 8 of 26 with recurrent ZES, it occurred at 5 +/- 1 years, and 3 had duodenal gastrinoma that had been missed. Ten percent (13/138) of all patients with sporadic ZES and 0% (0/38) with ZES and MEN1 remained cured with only a LN tumor removed. In patients with sporadic gastrinomas no clinical, laboratory, or radiographic localization feature differed among patients with likely LN primary (n = 16) and those with unlikely LN primary (n = 6) or those with Duo-LN (n = 37). In the likely LN primary group, the largest LN was 2.2 +/- 0.2 cm, the number of LNs removed was 1.3 +/- 0.1 (25% > or =1 LN), and 78% were in the gastrinoma triangle, which also did not differ from the other 2 groups. Disease-free survival was similar in the likely LN primary group, patients with Duo-LN, and those with pancreatic primaries. CONCLUSIONS: These results support the conclusion that primary LN gastrinomas occur and are not rare (approximately 10% of sporadic cases). These results suggest that a proportion (25%) of these tumors are either multiple or malignant. Because no clinical, laboratory, or tumoral characteristic distinguishes patients with LN primary tumors, all patients with ZES undergoing surgery should have an extensive exploration to exclude duodenal or pancreatic tumors and routine removal of lymph nodes in the gastrinoma triangle.

Gastrinoma.

Gastrinoma treatment has evolved considerably in the last 20 years. In particular, the advent of effective acid-reducing pharmacologic agents has changed the primary morbidity of this disease entity from one of acid hypersecretion to one of tumor growth and spread. Thus, while symptoms can be temporized using histamine receptor antagonists, proton pump inhibitors, or somatostatin analogs, cure can be effected only by surgical means. Recent advances in operative techniques and pre- and intra-operative imaging studies, including routine duodenotomy, somatostatin-receptor scintigraphy, and intraoperative ultrasound, have allowed for identification and subsequent resection of more than 95% of gastrinoma tumors. Most experts agree that all sporadic cases of localized gastrinoma should be excised. In addition, debulking of metastatic tumor may improve symptoms and survival when cure cannot be ascertained. There is, however, some controversy as to the surgical approach for gastrinoma found in the setting of multiple endocrine neoplasia, type 1. Because of the usual multiplicity and particular indolence of these tumors, two primary strategies have emerged: aggressive approaches have been advocated in an effort to eradicate all present and potential tumor; and less aggressive, or nonoperative, approaches have been suggested because it is unclear whether intervention offers survival or disease-free benefit in this population. We advocate surgical intervention for patients with gastrinoma and multiple endocrine neoplasia, type 1 when tumors exceed 2.5 cm in size. This tumor size has been associated with a higher likelihood of hepatic metastases, which ultimately affects survival. The role of adjuvant therapies for gastrinoma remains limited.

Specificity of somatostatin receptor scintigraphy: a prospective study and effects of false-positive localizations on management in patients with gastrinomas.

UNLABELLED: Somatostatin receptor scintigraphy (SRS) is being increasingly used both for localization and, in some cases, diagnosis of various diseases. There are no prospective studies of its specificity or occurrence of false-positive results and their effects on management. This study was designed to address both of these issues. METHODS: Over a 40-mo period, 146 consecutive patients with Zollinger-Ellison syndrome (ZES) undergoing 480 SRS examinations were studied prospectively. Patients were admitted at least yearly and underwent SRS as well as conventional imaging studies (ultrasonography, CT, MRI) and angiography, if necessary. All admissions were assigned to one of five different clinical categories in which imaging studies had different purposes. SRS localizations were classified as true-positive or false-positive based on preset criteria. A false-positive result was determined to change clinical management based on five preset criteria. RESULTS: Of all SRS examinations, 12% resulted in a false-positive localization for a neuroendocrine tumor or its metastases, resulting in a sensitivity of 71%, specificity of 86% and positive and negative predictive values of 85% and 52%, respectively. Extra-abdominal false-positive localizations (2/3) were more common than intra-abdominal (1/3). Thyroid disease, breast disease and granulomatosis lung disease were the most frequent causes of extra-abdominal false-positive localizations. Accessory spleens, localization to previous operative sites, renal parapelvic cysts and various procedural aspects were the most frequent causes of intra-abdominal false-positive localizations. Of all SRS studies, 2.7% resulted in a false-positive result that altered management. CONCLUSION: False-positive SRS localization occurs in 1 of 10 patients with ZES. By having a thorough understanding of diseases or circumstances that result in false-positive localization and comparing the SRS result with the clinical context, the percentage of patients in whom false-positive localization results in altered management can be reduced to below 3% and the correct diagnosis made in almost every case.

The gastrinoma/Zollinger-Ellison syndrome: statistical evaluation of a Japanese series of 359 cases.

The diagnostic modalities and management of gastrinoma/Zollinger-Ellison syndrome (ZES) have been markedly modified and improved over the past 15 years. To evaluate the present status of this disease, in terms of various clinicopathologic features, we collected 359 Japanese cases of gastrinoma/ZES from the literature. We found a decreasing incidence (from 74.7% in 1965-1980 to 34.2% in 1981-1995) of multiple surgeries and a decreasing rate (from 94.3% in 1965-1980 to 83.5% in 1981-1995) of ZES associated with gastrinoma. There was an increasing rate (from 12.6% in 1965-1980 to 48.9% in 1981-1995) of correct preoperative diagnosis. (All these differences were significant; P < 0.01). In 1981-1995, there was a high incidence (51. 1%) of small tumors (20 mm or less) and a high rate (39.5%) of metastases, and a relatively favorable postoperative outcome (10-year survival rate of 63.7%); P < 0.05. The diagnosis and treatment of gastrinoma/ZES have been markedly improved by increased rates of curative surgery, and more favorable postoperative outcomes will be expected in decades to come.

Processing-independent analysis in the diagnosis of gastrinomas.

BACKGROUND: This study evaluates whether a new analytic principle, processing-independent analysis (PIA), offers better specificity and sensitivity than the conventional gastrin radioimmunoassay in the diagnosis of gastrinomas. METHODS: Plasma concentrations of alpha-amidated gastrins and the total progastrin product were measured with radioimmunoassay and with PIA, respectively, in 512 samples taken for gastrin measurement and in a selected group of gastrinoma patients (n=10). RESULTS: Among the 512 patients were 9 with gastrinomas. In plasma from these patients the median degree of amidation (ratio of alpha-amidated gastrins to total progastrin product) was 75% (range, 25-98%), whereas in the other groups the medians varied from 41% to 86%. In the second group of gastrinoma patients all had a degree of amidation of less than 50%. CONCLUSIONS: In screening for gastrinomas PIA offered no diagnostic advantages in comparison with conventional gastrin radioimmunoassay. However, in selected patients who in spite of normal or slightly increased concentrations of amidated gastrins were still suspected of having gastrinoma, additional measurement of the total progastrin product showed incomplete processing of progastrin and thus proved helpful in establishing the diagnosis.

[Endocrine tumors of the pancreas at a Mexican institution]. / Los tumores endocrinos del páncreas en una institución mexicana.

OBJECTIVE: To analyze characteristics of patients with endocrine tumors of the pancreas seen between 1960 and 1992 at the Instituto Nacional de la Nutrición. MATERIAL & METHODS: The clinical records of 38 patients with endocrine tumors of the pancreas were reviewed. Overall characteristics, diagnostic studies, intraoperative findings, treatment and outcome were analyzed. The archival histological specimens were revised and immunohistochemical stainings were performed in the non-functioning tumors. RESULTS: Twenty patients had hyperinsulinism, 10 non-functioning tumors, and eight a Zollinger-Ellison syndrome. The mean age of patients with hyperinsulinism was 38 years (8 males and 12 females); 18 were sporadic and two associated with MEN I syndrome. In 16 patients an insulinoma was removed: (6 in the head, 5 in the body, 5 in the tail of the pancreas). A cure was documented in 14 patients with sporadic tumors but not in the two cases associated with MEN I; 15 tumors were benign. Three patients with the Zollinger-Ellison syndrome were males and five females with a mean age of 41 years. Seven tumors were sporadic and one associated with the MEN I syndrome; 70% were located in the gastrinoma triangle. Local excision was performed in five and gastrectomy in three. The cure rate was 60% and malignancy was documented in 40%. Two males and eight females with a mean age of 30 years had non-functioning tumors (9 sporadic and one associated to MEN I). There was a positive immunohistochemistry in 60% of the tumors; 90% were malignant and the cure rate was 10%. CONCLUSIONS: Insulinoma is the most common endocrine tumor of the pancreas in our hospital. The cure rate for insulinomas, gastrinomas and non-functioning tumors was 90%, 60% and 10% and malignancy was documented in 5%, 40% and 90% respectively.

Liver metastases of digestive endocrine tumours: natural history and response to medical treatment.

BACKGROUND: Few data are available about the natural history of liver metastases of digestive endocrine tumours. Moreover, results of studies on treatment with intravenous chemotherapy, hepatic arterial chemoembolization and somatostatin analogues are conflicting. AIMS OF THE STUDY: To assess the progression of liver metastases of digestive endocrine tumours before antitumoral treatment, and to evaluate a stepwise therapeutic strategy in these patients. PATIENTS AND METHODS: 22 patients with histologically-confirmed liver metastases were studied. Primary tumours were carcinoids in nine, gastrinomas in five, non-functioning pancreatic tumours in six and calcitonin-secreting tumours in two patients. The progression of liver metastases was assessed according to the World Health Organization criteria in 10 patients before treatment, and during treatment in all patients. Intravenous (i.v.) chemotherapy with streptozotocin and 5-fluorouracil was used in patients with more than 25% progression in tumour size or with more than 50% liver involvement. Hepatic arterial chemoembolization was performed if i.v. chemotherapy failed, or as a first-choice treatment after 1993. The somatostatin analogues octreotide or lanreotide were used as a third-choice treatment. RESULTS: Progression (+90%, range 28-600%) of liver metastases was identified in the 10 patients studied before treatment, after a median follow-up of 11.5 months. Objective and minor responses were obtained in 2/10 patients (20%) and 1/10 patients (10%) receiving i.v. chemotherapy. Corresponding figures were 3/7 (43%) and 2/7 (29%) for hepatic arterial chemoembolization. No objective response was observed with somatostatin analogues, although 2 patients experienced a minor response. CONCLUSION: Untreated liver metastases of digestive endocrine tumours show an objective increase (their size approximately doubles after 1 year of follow-up). Among the currently available therapeutic modalities, hepatic arterial chemoembolization provides the highest response rates. An increase in patient survival as a result of this procedure remains to be determined.

Surgery in Zollinger-Ellison syndrome alters the natural history of gastrinoma.

OBJECTIVE: The authors assessed the impact of gastrinoma resection on the subsequent development of hepatic metastases in Zollinger-Ellison syndrome. SUMMARY BACKGROUND DATA: The symptoms of acid hypersecretion can be controlled medically in Zollinger-Ellison syndrome with high-dose pharmacologic therapy. The current role of surgery is curative excision of the gastrinoma. Because biochemical cure is obtained only in a portion of the patients and the neoplastic disease may be indolent in this syndrome, the ability of surgical resection of gastrinoma to alter or improve the subsequent development of hepatic metastases and mortality has not been defined. METHODS: One hundred twenty-four patients with the biochemical diagnosis of Zollinger-Ellison syndrome and no hepatic metastases on initial imaging studies were evaluated. Ninety-eight patients underwent surgical exploration for curative gastrinoma resections while 26 patients were managed medically. Long-term follow-up regarding development of hepatic metastases and survival were evaluated. RESULTS: Surgical exploration with gastrinoma excision resulted in a significantly decreased incidence of hepatic metastases 3% (3/98) compared with patients managed medically 23% (6/26) with comparable follow-up (p < 0.003). Two deaths due to metastatic gastrinoma occurred in the nonoperative group compared with no disease-specific deaths in the surgical group (p = 0.085). CONCLUSIONS: For the patient with Zollinger-Ellison syndrome without metastatic disease, surgical exploration with attempted curative gastrinoma resection is recommended because it may alter the natural history of this syndrome.

Clinical management of gastric carcinoid tumors.

Four types of gastric carcinoids have been identified: (1) multiple small body-fundus carcinoids associated with chronic atrophic gastritis type A (A-CAG); (2) sporadic solitary lesions without specific pathogenetic background (non-A-CAG); (3) carcinoidosis associated with Zollinger-Ellison/MEN 1 syndrome, and (4) rare tumors, e.g. gastrin cell tumors, neuroendocrine carcinomas and mixed endocrine-exocrine tumors. In a retrospective study of 15 patients with gastric carcinoids (11 A-CAG, 3 non-A-CAG and 1 gastrin cell tumor) over a 10-year period, the histopathological and clinical features were assessed. The A-CAG-type carcinoids were clinically silent with lymph node metastases in 2/11 cases but no hepatic metastases. The non-A-CAG-type carcinoids were malignant with disseminated disease, hormonal symptoms and increased urinary excretion of the main histamine metabolite, MeImAA. Five patients with A-CAG tumors were subjected to antrectomy to remove hypergastrinemia, which is thought to be of pathogenetic importance for these tumors. During the observation period (1.5-8 years) 1 patient developed recurrent tumors, while the other 4 showed persistent argyrophil cell hyperplasia. A prospective treatment protocol of these tumors is suggested with endoscopic removal of less numerous, small lesions as first-step therapy, followed by antrectomy at recurrence. Larger lesions should be excised in combination with antrectomy. Gastrectomy is reserved for the rare cases of invasive tumors with lymph node metastases. As evident from the outcome of patients with non-A-CAG tumors radical surgery should be performed whenever practicable.

Multiple endocrine neoplasm, type 1. Gastrinomas, pancreatic neoplasms, microcarcinoids, the Zollinger-Ellison syndrome, lymph nodes, and hepatic metastases.

OBJECTIVE: We reviewed the age of presentation, malignant potential, and outcome of gastrinomas and pancreatic tumors in patients with multiple endocrine neoplasm, type 1. DESIGN: Screening of one very large and one smaller, possibly related family on an island, including serum gastrin estimations and, when indicated, pancreatic ultrasound. SETTING AND PATIENTS: Over 2000 family members and their family physicians were advised on screening procedures. INTERVENTION: Data were collected and reviewed retrospectively and prospectively for all medical records, investigations, surgical procedures, and available tissue samples. OUTCOME MEASUREMENTS: Criteria for diagnosis were established for radiological, biochemical, and histological studies. RESULTS: Sixty-two patients had evidence of gastrinoma or pancreatic neoplasm. In 19 patients the diagnosis was based on demonstration of a tumor. In 21 patients the diagnosis was based on elevated serum gastrin concentration in the absence of demonstrable tumor. None of these patients required gastric surgery if they first underwent parathyroidectomy. In 18 patients the diagnosis was based on the combination of demonstrated pancreatic tumor plus elevated glucagon (two patients), gastrin (11 patients), or insulin (five patients) concentration. Peptic ulcer was difficult to control in seven of the 11 patients with elevated gastrin concentrations plus demonstrated tumor. Four patients had liver metastases that appeared to be secondary to the pancreatic gastrinoma. In patients with insulinomas, the first symptoms occurred before age 20 years. Elevated serum gastrin concentrations were not seen before age 24 years and were observed to occur for the first time in two patients after age 50 years.