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Evolution of gastrinoma tumoral mass, fasting serum gastrin concentrations, and gastric endocrine cells has been analyzed in 21 patients with the Zollinger-Ellison syndrome committed to long-term omeprazole treatment (up to 7.75 years, median 37 months). Gastrinoma growth was seen in eight patients. Significant increase in serum gastrin was only observed in the group of patients with gastrinoma growth. Fundic argyrophil cell densities were correlated with serum gastrin (r' = 0.68, P = 0.002). Argyrophil and antral gastrin cell densities significantly increased during the survey, but increases were greater in the group with gastrinoma growth (respectively, +136% and +131%) than in the other group (respectively, +34% and +43%). Progression in the degree of argyrophil cell hyperplasia, noted qualitatively, was observed in 11 patients. Fundic carcinoids developed in three of these 11 patients, all three having multiple endocrine neoplasia type 1 (MEN 1). Positive linear individual correlations (r > or = 0.85) between argyrophil cell densities and corresponding durations of omeprazole treatment were found in nine of the 10 patients studied at least three times and who had a clear-cut increase in those cell densities. Thus, increase in serum gastrin and fundic argyrophil cell densities appeared closely associated with gastrinoma growth; however, duration of drug-induced hypochlorhydria may also affect cell proliferation.

During the three decades since the recognition of the Zollinger-Ellison syndrome (ZES), major progress has been made in the diagnosis and treatment of this disease. However, the many failed operations in patients with ZES, the existence of primary lymph node gastrinomas, and the surgical approach of patients with ZES and multiple endocrine neoplasia type I (MEN-I) have remained controversial issues. In this review, our experience with the pathology of immunocytochemically identified gastrinomas in 44 patients with ZES is presented and related to the relevant literature. (1) Gastrinomas occur frequently in the duodenum (> 40%) and are commonly small (< 1 cm). They can therefore easily be missed at surgical exploration; lymph node metastases from such occult gastrinomas may be mistaken for primary tumors. (2) Most pancreatic gastrinomas reside in the head of the gland and have a diameter of 1 to 3 cm. (3) Gastrinomas associated with MEN-I are predominantly of duodenal origin and frequently multicentric; sporadic gastrinomas are single and more often pancreatic. Because MEN-I associated pancreatic tumors seldom contain gastrin, ZES in MEN-I patients is almost never cured by resection of the pancreatic tumors. (4) The metastatic potential of most small duodenal gastrinomas seems to be restricted to the regional lymph nodes.

The clinical evolution of type I multiple endocrine neoplasia (MEN I) was studied in 45 patients among a consecutive series of 172 with Zollinger-Ellison syndrome (ZES). These 172 patients were seen in our hospital between 1959 and 1989. Diarrhea was half as frequent in ZES-MEN I as in sporadic ZES cases. At diagnosis, mean basal acid output and serum gastrin levels in MEN I patients (28.8 +/- 6.6 mmol/h and 587 +/- 487 pg/ml, respectively) were not different from those observed in the others with sporadic ZES. Laparotomy was performed in all 36 patients with no diffuse liver involvement to attempt the removal of gastrinomas. Twenty-nine patients had adenomas, located in the pancreas in 21, in the duodenal wall in 3, and in both in 5. Adenomas were multiple in 23 cases (78%). No tumor was found in seven patients. Twenty-nine of the 36 operated patients were tumor-free after surgery; 7 died in the postoperative period between 1959 and 1970. Median follow-up of the 38 other patients was 95 months (range 17-278 months). Among the 24 patients without residual tumor at discharge (group I), biological and/or morphological evidence of a persistent or recurrent source of gastrin was obtained in 22. Among the 14 patients with residual tumor (group II), an increase in tumor size was seen in 5 after a median of 27 months (range 9-36 months), while no change occurred in 9 after 54 months (3-100 months). Actuarial survival curves were not different, either in group I versus group II patients (67 and 72% at 5-year follow-up, respectively) or in MEN I versus sporadic ZES patients. Apparently, complete resection of primary tumor did not reduce the incidence of subsequent liver metastases. In all, 21 of the 45 patients had malignant gastrinomas (47%), consisting of liver metastases in 14 (31%), metastatic lymph nodes in 11 (24%), and lung metastases in 2 (4%). Monitoring of fundic argyrophil cells disclosed hyperplasia in 13 of the 14 MEN I patients (92%), and 5 had invasive carcinoid tumors. Taken together, these results prompt us to recommend that in ZES-MEN I patients, surgery should be avoided and oxyntic mucosa regularly monitored.

Results of cell culture and cytogenetic analysis (standard and fluorescent in situ hybridization, FISH) of two sporadic gastrinomas are reported. Maintenance of hormonal activity was assessed by detection of gastrin levels during the first 3 months in culture. Case 1 showed clonal aberrations consisting of two marker chromosomes: marker 1 is a large metacentric chromosome and marker 2 is a small acrocentric chromosome. Case 2 showed a constitutional polymorphism with chromosome 15p+ and a clone in the tumor cell culture with trisomy for chromosome 3. To our knowledge, this is the first cytogenetic report of sporadic gastrinomas (Zollinger-Ellison syndrome).

The introduction of modern cytological techniques has provided the pathologist of tools that considerably improved his analysis of pancreatic endocrine tumors and that are discussed in this review. Hormonal characterization of the tumors by immunohistochemistry significantly contributed to the definition of the current functional classification of the tumors and proved that ectopic tumors (producing extrapancreatic hormones) are as common as entopic tumors synthesizing pancreatic hormones. The identification of neuroendocrine markers and of other active non-hormonal substances extended our knowledge on the functional properties of tumor cells often with significant fall out on the biology of the corresponding normal cells. Current studies are mostly oriented toward the analysis of cell proliferation and appear to open promising perspectives for the prognostic evaluation of the tumor course.

Background: We have previously reported the first establishment and characterization of a functioning human gastrinoma (PT) xenograft. Bombesin, the equivalent of the mammalian gastrin-releasing peptide, has trophic effects on normal and neoplastic tissues of the gastrointestinal tract; the effects of gut hormones on the growth of gastrinoma are not known. The purpose of this study was twofold: (1) to determine the presence of various gut peptides in PT and (2) to determine the effect of bombesin on the growth of PT xenografts., Methods: PT tumors were examined for expression (mRNA and protein) of various gut peptides by Northern hybridization and immunohistochemistry. In addition, PT xenografts were implanted as 3 mm2 pieces bilaterally subcutaneously in athymic nude mice. Mice were divided into two groups to receive either bombesin (5 micrograms/kg) or saline administered as intraperitoneal injections every 8 hours. Tumor area was measured twice weekly until mice were sacrificed (day 28), when tumor and normal pancreas were removed, weighed, and assayed for DNA and protein content., Results: Both mRNAs and peptides of gastrin and chromogranin A were present in PT tumors. Bombesin significantly stimulated growth of PT tumors from day 18 until mice were sacrificed (day 28). As expected, bombesin stimulated pancreatic growth., Conclusions: We have demonstrated for the first time that bombesin is a trophic hormone for gastrinoma. The unique cell line PT contains gastrin and chromogranin A and will be a useful model to define the biologic mechanisms controlling the growth of human gastrinomas.

The case of a patient who had Zollinger-Ellison syndrome caused by a primary peripancreatic lymph node gastrinoma is presented. Accompanying diffuse pancreatic islet cell hyperplasia, a well-documented occurrence in hypergastrinemia, was present. A perforated esophageal ulcer in a Barrett's esophagus led to right-sided necrotizing pleuritis, septicemia, and death. The diffuse parathyroid hyperplasia also noted in the patient is thought to be secondary to chronic hypertensive renal failure rather than MEN-I syndrome.

One hundred fifteen gastroenteropancreatic (GEP) patients with malignant endocrine tumors entered a prospective multicenter trial (12 patients with gastrinoma, 53 with carcinoid syndrome, 45 with nonfunctioning tumors, and five with other endocrine GEP tumors) to determine the efficacy of 200 micrograms Sandostatin three times a day in the control of tumor growth. This interim report describes the results in 85 patients. Thirty-four patients died, 14 before and 20 after the first follow-up investigation, indicating a "negative" selection of patients included in the trial and suggesting that Sandostatin cannot prevent disease progress when it is far advanced. In the evaluation of 68 patients monitored for at least 3 months, partial regression was observed in 4.4%, stable disease in 50%, and tumor progression in 45%. However, an initially favorable response frequently occurred with a decrease in response later: 54.4% at 3 months to 38% at 12 months for the whole group of patients. Proven inhibition of tumor growth was mirrored by suppression of serum and urine hormone parameters. It is concluded that Sandostatin exerts a beneficial effect on tumor growth in patients with metastatic endocrine GEP tumors. This beneficial effect decreases with time and is as yet unpredictable in the individual patient.

Duodenal carcinoma is a rare disease and is encountered in no more than 10% of cases of the Zollinger-Ellison syndrome. The article discusses a rare case in which an isolated duodenal gastrinoma was removed endoscopically with subsequent recovery from the Zollinger-Ellison syndrome. Study of the serum gastrin concentration with provocative tests allowed the Zollinger-Ellison syndrome to be diagnosed and the radicality of duodenal gastrinoma removal to be controlled. Retrograde duodenoscopy conducted after resection of the gastric stump by the Billroth II method localized the source of hypergastrinemia and made possible radical removal of the duodenal gastrinoma, which was confirmed by normalization of the blood serum gastrin concentration. The work includes a brief literature reference on the subject.

CT examinations of 25 patients with proved primary or metastatic duodenal neoplasms were retrospectively reviewed to determine if morphologic features seen on CT scans could be used to predict the benign or malignant nature of these neoplasms and to assess the effectiveness of using CT findings to predict tumor resectability. We studied 19 malignant and six benign tumors. Histologic proof was obtained by means of surgery in 20 patients and by endoscopic biopsy in five. CT features of tumor morphology were assessed in the 22 cases in which a duodenal tumor was seen on CT. These features included central necrosis, ulceration or excavation, and the location of the tumor with respect to the bowel wall. The specific morphologic features used to predict that a tumor was malignant included the presence of an exophytic or intramural mass, central necrosis, and ulceration. The only criterion used to predict that a tumor was benign was that the mass be entirely intraluminal. Whenever vascular encasement, invasion of contiguous organs other than the head of the pancreas, distant lymphadenopathy, or metastases were present, the tumor was predicted to be unresectable for cure. With the exception of three benign smooth muscle tumors, all tumors with one or more CT morphologic features indicative of a malignant neoplasm were malignant (n = 16). Three of four intraluminal masses were benign. In three cases of polypoid tumors smaller than 2 cm, a duodenal tumor was not seen on CT. Whenever extraduodenal disease was found (15 cases), the neoplasms were malignant. In the 22 cases in which a tumor was detected on CT, the sensitivity of using the presence of one or more morphologic features associated with a malignant neoplasm as a predictor was 94%; the specificity was 50%, and the accuracy was 82%. If the presence of any morphologic feature indicative of a malignant neoplasm was combined with the presence of any finding of extraduodenal disease, CT was 100% sensitive and 86% accurate for predicting that the tumor was malignant. CT appears to be reliable for predicting duodenal tumor resectability. On the basis of CT findings, 10 tumors were correctly predicted as being unresectable for cure, and 12 were predicted as being resectable; no surgery was performed in the remaining three cases. In conclusion, evaluation of the morphologic features of duodenal neoplasms is a sensitive, but nonspecific, method for predicting that a tumor is malignant.(ABSTRACT TRUNCATED AT 400 WORDS)

Duodenal gastrinomas do not seem to behave as malignantly as sporadic pancreatic gastrinomas. Statistical analysis of 49 patients with sporadic pancreatic gastrinoma and 21 patients with sporadic duodenal gastrinoma reported since 1980 in Japan revealed that the incidence of hepatic metastasis was 57% in patients with sporadic pancreatic gastrinoma and only 9% in patients with sporadic duodenal gastrinoma (p less than 0.01). These findings suggest that there is an essential biological differences between duodenal and pancreatic gastrinoma. Five patients with sporadic duodenal microgastrinoma (tumor diameter less than 5mm) in our hospital had no hepatic metastases; however, 4 patients had lymph node metastases. Immunohistochemical study of 5 sporadic duodenal microgastrinomas and 6 sporadic pancreatic gastrinomas revealed that the sporadic duodenal gastrinomas contained significantly fewer insulin-producing or glucagon-producing cells than sporadic pancreatic gastrinomas. The cellular composition of the metastatic lymph nodes from duodenal microgastrinomas was similar to that of the primary tumor. This difference in cellular composition between the duodenal microgastrinomas and the pancreatic gastrinomas suggests that the process of development and differentiation of gastrinoma cells is different.

A 63-year-old male was admitted to our department for further examination of hypergastrinemia. Secretin provocation test and calcium infusion test suggested Zollinger-Ellison syndrome and percutaneous transhepatic portal venous sampling (PTPVS) demonstrated gastrinoma in the jejunum, although CT, ultrasonography and angiography could not accurately detect the location of the gastrinoma. Laparotomy findings showed a solid tumor 1.5 cm in diameter in the jejunal mesentery 5 cm distal to the ligament of Treitz, and primary gastrinoma was confirmed in the submucosa of the jejunum immediately adjacent to this tumor. An immunohistochemical study using the PAP method revealed gastrin secreting cells in the tumor. In addition to this case of jejunal gastrinoma, a review of literature in Japan and other countries was presented.

During the past seven years we have diagnosed and treated 12 patients with the Zollinger-Ellison syndrome (ZES), some of whom have had virtually unique manifestations. Among these are a 74-year-old man who was cured after endoscopic removal of a submucosal duodenal gastrinoma, suggesting the usefulness of an operative approach using intraoperative endoscopic transillumination; a 33-year-old man in whom the manifestations of ZES brought him into conflict with the law; and a 10-year-old domestic cat who was cured surgically, the gastrinoma providing material for the first determination of the sequence of cat gastrins.

A total of 24 patients with endocrine neoplasms of the pancreas were clinicopathologically and immunohistochemically studied. They consisted of 18 patients with adenoma and 6 with carcinoma. Of the 24 patients, 13 developed attacks of hypoglycemia due to hyperinsulinemia, and 1 developed an uncontrollable duodenal ulcer caused by the hypersecretion of gastrin, however, the remaining 10 were asymptomatic. No prediction could be made as to the site of origin of the tumors. A clear difference was seen between adenoma and carcinoma in the size of the mass, the mean greatest diameter of the 18 adenoma cases being 1.7 cm, while that of the 6 carcinoma cases was 7.3 cm. One of the 13 insulinomas and a gastrinoma was malignant, while all 24 tumors were positive for neuron-specific enolase. The 13 insulinomas were diffusely positive for insulin and 5 were also shown to be focally immunoreactive for gastrin, with 3 also being immunoreactive for somatostatin and 2 for pancreatic polypeptide. The gastrinoma showed immunoreactivity for somatostatin, insulin, pancreatic polypeptide, and glucagon in addition to a positivity to gastrin. The above findings thus indicate the multiple hormone synthesis of endocrine neoplasms of the pancreas.

Specimens from the pancreas and duodenum of 26 patients with sporadic Zollinger-Ellison syndrome (ZES) and 18 patients with multiple endocrine neoplasia type 1 (MEN-1) and hypergastrinemia (17 with ZES) were screened immunocytochemically for gastrinomas. Location, size, multicentricity, and malignancy of the gastrinomas were evaluated. The MEN-1 patients had gastrinomas in the duodenum (nine of 18), pancreas (one of 18), and periduodenal lymph nodes (two of 18). No gastrinoma was identified in six patients. Most duodenal gastrinomas were multiple (five of nine) and smaller than 0.6 cm (six of nine). Lymph node metastases were present in eight of 12 patients. All 26 patients with sporadic ZES had a solitary gastrinoma; 14 were found in the pancreas and had a diameter greater than 2 cm. Ten patients had a duodenal gastrinoma, two with a diameter less than 0.6 cm. In two patients, only periduodenal "lymph node gastrinomas" were detected. Eighteen of the sporadic gastrinomas were malignant. These results suggest that duodenal location and multicentricity of gastrinomas are associated with the MEN-1 syndrome, and solitary gastrinomas, either in the pancreas or the duodenum, are predominantly seen in sporadic ZES.

The authors reported a case of giant solitary pancreatic gastrinoma. A 29-year-old woman complaining of upper abdominal pain and loss of weight of 6 months duration. Four months later she noticed moving abdominal tumor. At the surgery a tumor was identified on pancreatic body measuring 20 centimeters of dimension and it was completely removed. A partial pancreatectomy with pancreatic tail preservation was performed in addition to this the Wirsung duct was joined on pancreatic head. No abdominal metastasis was found. The gastrointestinal transit was re-established by end-to-side Roux-en-Y jejunum-pancreatic anastomosis. The final diagnosis was confirmed by immunohistochemical test (immunoperoxidase). The follow-up was made until 40th postoperative month and after surgery the plasma level of gastrin was 120 pg/ml but at present day is normal. The authors concluded that it was a benign giant solitary pancreatic gastrinoma.

Advanced gastrointestinal endocrine tumors respond poorly to conventional chemotherapy. In this study we examined the effects of two agents that promote cellular differentiation, sodium butyrate and hexamethylene bisacetamide, on the in vitro growth and secretory responses of a human pancreatic carcinoid (BON) and human gastrinoma (PT-2 and PT-SM) cell lines that have been established in our laboratory. We found that both sodium butyrate and hexamethylene bisacetamide strongly inhibited growth of BON, PT-2, and PT-SM cells. With continuous exposure of BON cells to sodium butyrate (2 mmol/L), the doubling time was prolonged, from 60 hours in controls to 156 hours, and saturation density was reduced to 28% that of controls. Hexamethylene bisacetamide (4 mmol/L) reduced saturation density to 37% that of controls in BON cells and prolonged the doubling time, from 60 hours to 103 hours. Antiproliferative effects of similar magnitudes were observed in the gastrinoma cell lines. In contrast, differential effects were produced on amine biosynthesis in BON cells; sodium butyrate stimulated levels of 5-hydroxytryptamine in the cells, whereas hexamethylene bisacetamide caused a profound dose-dependent inhibition of amine biosynthesis. The significant antiproliferative activity of sodium butyrate and hexamethylene bisacetamide and the inhibitory effects of hexamethylene bisacetamide on amine biosynthesis warrant evaluation of these agents or analogues for treatment of metastatic carcinoid and gastrinoma.

The main advances in the management of carcinoid and gastrointestinal neuroendocrine tumors have been in the areas of imaging and therapy. New techniques have been developed to detect and identify the sites of tumor so that correct therapeutic decisions can be made. Although surgery remains the mainstay of treatment of localized and some cases of advanced disease, the use of biologic agents and new drugs has proven valuable in those patients in whom surgery is not indicated. These include interferon-alpha, the somatostatin analogue octreotide, omeprazole. Different methods of delivery have been investigated with mixed success. Future progress in the understanding and management of neuroendocrine tumors is likely to be slow due to their rarity and long natural history.

Extensive experience from patients with gastrinoma as part of the multiple endocrine neoplasia type 1 (MEN 1) syndrome has revealed that MEN 1-gastrinoma patients show important differences from patients with sporadic gastrinoma. These differences comprise clinical, pathological and biochemical features, but are especially pertinent to the therapeutic approach. Therefore, the diagnosis of the MEN 1 syndrome is of great clinical importance to the gastrinoma patient and his family.

Percutaneous aspiration to measure hormone levels in suspected functioning endocrine adenomas has been performed in 23 suspected cases of parathyroid adenomas, 7 cases of ACTH-producing thoracic carcinoid tumors, and 1 case of gastrinoma. When tumors secrete hormone or peptide markers, the biochemical assay can replace cytology to identify the lesion with greater specificity and at less expense.

The case of a 55-year-old woman with a duodenal ulcer developing since 6 months is reported, in whom the surgical indication was early established on the basis of increasing of suffering and inefficacy of the medical treatment. Intraoperatively an exophytic pancreatic tumour sited on the upper border of the isthmus, sized 5/6/4 cm, was found. In view of the suspicion of gastrinoma and considering that total gastrectomy or splenopancreatectomy would be excessive taking into account the patient's state, option was made for exeresis of the tumour. The ulcerous suffering disappeared and the histological examination of the specimen (weighting 70 g) confirmed a benign gastrinoma. The peculiarities of the case and data from the literature dealing with gastrinomas are discussed.

Extracellular matrices have recently been demonstrated to alter cell morphology in culture. Altered cell morphology has been associated with changes in gene transcription and translation, but it is not known whether it also affects posttranslational processing. Using tyrosine-O-sulfation as a marker of processing, we studied the effects of various substrates on biologically active gastrin (IRG) production and sulfation in gastrin-containing tumor cells (GT cells). Dispersed GT cells were plated onto different substrates and then incubated. Culture media from days 4, 7, and 28 were assayed with specific antibodies that recognize total IRG and nonsulfated IRG. Cells cultured on plastic and dried films of laminin, collagen, and Matrigel (Collaborative Research Inc., Lexington, Mass.) flattened and formed monolayers of GT cells. Cells cultured on a porous membrane and hydrated gels of collagen and Matrigel did not flatten but formed spheroids of GT cells. The monolayer cultures showed an increase in sulfation with time but a decrease in IRG production. The spheroid cultures maintained a constant level of sulfation over time and, with the exception of Matrigel (gel), also showed a decrease in IRG production. These results indicate that the level of sulfation was unchanged from that of the original tumor when cells were grown in spheroids but increased when cultured as monolayers. It appears that alteration of the cellular milieu alters colony morphology, which in turn alters gastrin processing.

The pathology of insulinoma and gastrinoma was studied in 81 patients (31 men, 50 women, mean age 48.4 years) suffering from persistent hyperinsulinaemic hypoglycaemia, and in 44 patients (28 men, 16 women, mean age 48.5 years) with Zollinger-Ellison syndrome. Insulinomas were seen in the pancreas of all patients with persistent hyperinsulinaemic hypoglycaemia. In 70 of the 81 patients the insulinoma was solitary, whereas six patients had multiple insulinomas. In five patients with multiple endocrine neoplasia type I, multiple endocrine tumours of the pancreas were visible, only one of them in each case being an insulinoma. 75% of all insulinomas were less than 2 cm in size and 15% were malignant. 18 of the 44 Zollinger-Ellison syndrome patients also had multiple endocrine neoplasia type I. Nine of these patients presented with duodenal gastrinomas which were often multiple and smaller than 0.5 cm. The gastrinoma was located in the pancreas of one of the patients with multiple endocrine neoplasia, in two patients in lymph nodes, and no gastrinoma was identified in the specimens from six patients. 33% of the duodenal gastrinomas had metastasised. Solitary gastrinomas were found in all 26 patients with sporadic Zollinger-Ellison syndrome, 14 being located in the pancreas (diameter over 2 cm in eight cases) and ten in the duodenum (diameter less than 1 cm in seven cases). 16 of these gastrinomas were malignant.

In two patients with malignant gastrinoma and the Zollinger-Ellison syndrome, we were able to use selective arterial stimulation with secretin as a technique to localize the lesions accurately, allowing resection. The technique of selected arterial secretin stimulation is one of measuring variations in gastrin levels in both the hepatic vein and a peripheral artery at specified times after injection of secretin into a specific artery. When the criteria for localization have been met, one can plot the presence of the gastrinoma within the blood supply of the injected artery and, using angiograms, thus accurately localize the lesion. This method promises to be a valuable additional tumor-localizing procedure, particularly when gastrinomas are extrapancreatic.

Montpellier Cancer Institute strategy and experience in surgical treatment of multi-bilateral hepatic metastases from digestive tract cancers is presented based on retrospective case by case analysis of survival time of 38 patients. The mean age was 46.2 years and the primaries were colorectal (22 patients) and endocrine (16 patients). Liver surgery was synchronous to the resection of primary lesions in 8 patients and metachronous in 22 patients. Two-step liver surgery was performed in 8 patients. Overall thirty-days postoperative mortality was 7.8% and morbidity 15.7% (wound sepsis, subphrenic abscess, transitory jaundice, biliary fistula). The analysis of survival time evidenced that with reasonable risk-benefit ratio the aggressive surgical approach can be justified especially in patients with endocrine primaries.

The nuclear DNA content of 17 pancreatic neuroendocrine tumors was measured from paraffin-embedded tissue with flow cytometry. The tumors were classified by immunostaining with antisera for synaptophysin, insulin, gastrin, glucagon, pancreatic polypeptide, somatostatin, and vasoactive intestinal polypeptide. Eight (47%) of the 17 tumors were aneuploid, and two (12%) were multiploid (had two aneuploid stemlines of cells). Seven of the eight insulinomas, one of the four gastrinomas, and two of the four nonspecified neuroendocrine tumors had an abnormal nuclear DNA content. The DNA indices of the aneuploid and multiploid cases ranged from 1.13 to 1.93, and three cases had a DNA index greater than 1.50. During the follow-up for up to 16 years (mean, 7 years), one patient with diploid nonspecified tumor died of the disease, another patient with a multiploid gastrinoma had metastatic disease develop, and a third patient with a multiploid nonspecified tumor was alive with the disease. The authors conclude that many neuroendocrine tumors of the pancreas have an abnormal nuclear DNA content as measured by DNA flow cytometry. DNA multiploid pancreatic neuroendocrine tumors may be associated with a less favorable clinical course, but this needs to be confirmed in additional studies.

Functional gastrin-containing tumor cells were maintained for up to 8 wk without fibroblastoid cell overgrowth. Short-term cultures consisted mainly of colonies composed of small polygonal cells, 70%-90% of which stained positive for immunoreactive gastrin. Cultures exhibited limited growth but viability remained high for 2-3 wk. Culture medium contained component I, and gastrin 34, 17, and 14. With time the major C-terminal gastrin species in medium changed from gastrin 17 at 3 days to gastrin 34 at 5 wk. Extracts of cultured cells contained gastrin 34, 17, and 14; gastrin 17 was the major form detected at all times. Ultrastructurally, cultured tumor cells retained morphological integrity for several weeks; however, with time changes in the appearance of the secretory granules accompanied by evidence of cellular retrodifferentiation were gradually observed. Secretin, gastrin-releasing peptide, 8-bromoadenosine 3':5'-cyclic monophosphate, and phorbol, 12-myristate, 13-acetate stimulated the release of gastrin from cultured cells in a time-dependent fashion. Secretin, bombesin, gastrin-releasing peptide, L-tryptophan, and ethylamine stimulated gastrin release in a dose-dependent fashion. Somatostatin 14 inhibited secretin, bombesin, and gastrin-releasing peptide stimulated gastrin release but did not alter basal release. Cultured cells demonstrated de novo gastrin synthesis, evidenced by their ability to incorporate radiolabeled amino acids into immunoadsorbable gastrinlike material. Primary cultures of gastrin-containing tumor cells free from stromal contamination offer unique advantages for studies of factors that regulate the synthesis and secretion of gastrin and may prove of potential value for studies on cell differentiation and growth.

In patients with multiple endocrine neoplasia type 1 (MEN-1), gastrinomas are common and thought to occur predominantly in the pancreas. We describe eight patients with MEN-1 and hypergastrinemia (seven with the Zollinger-Ellison syndrome) in whom we searched for neuroendocrine tumors in the pancreas and duodenum. Tumors were found in the proximal duodenum in all eight patients: solitary tumors (diameter, 6 to 20 mm) in three patients and multiple microtumors (diameter, 2 to 6 mm) in the other five. Paraduodenal lymph-node metastases were detected in four patients. Immunocytochemical analysis revealed the presence of gastrin in all the duodenal tumors and in their lymph-node metastases. In contrast, no immunoreactivity for gastrin was present in the endocrine tumors found in the seven pancreatic specimens available for study, except for one tumor with scattered gastrin-positive cells. In four of the six patients whose duodenal gastrinomas were removed, serum gastrin levels returned to normal; in the other two patients gastrin concentrations decreased toward normal. We conclude that in patients with MEN-1 and the Zollinger-Ellison syndrome, gastrinomas occur in the duodenum, but the tumors may be so small that they escape detection.

Endoscopic ultrasonography (EUS) can provide high resolution images of the pancreatic parenchyma. Complete visualization of the pancreas requires scanning from positions in the duodenum and stomach. Current clinical experience indicates that EUS is a useful adjunct to standard imaging in the evaluation of suspected pancreatic tumors. Improvements in technique and instruments are necessary to broaden the clinical application of EUS in pancreatic disease.

Pancreatic endocrine tumors are grouped together by their common histologic, cytochemical, and ultrastructural features. Although useful conceptually, this paradigm has been unable to predict the anatomic location of different tumor types. Successful surgical excision of these tumors would be facilitated by an improved understanding of their anatomic distribution. Based on the available data, a bimodal distribution of pancreatic endocrine tumors was identified. Cluster 1 (gastrinomas, pancreatic polypeptide (PP)-secreting tumors, somatostatinomas) had 75% of tumors to the right of the superior mesenteric artery, whereas cluster 2 (insulinoma, glucagonoma) had 75% of tumors to the left of the superior mesenteric artery (p less than 0.05). This distribution is similar to that distribution predicted based on the volume density of the corresponding islet cells for insulinoma, glucagonoma, and PP-secreting tumors, but not for somatostatinoma. These findings suggest that pancreatic endocrine tumors are derived from similar cytologic precursors as pancreatic islet cells, and their distribution may be a consequence of embryologic development from either the ventral (cluster 1) or dorsal (cluster 2) pancreatic buds.

We present here an unusual case of a pancreatic gastrinoma that caused recurrent episodes of clinical pancreatitis secondary to complete obstruction of the main pancreatic duct. The patient did not manifest signs or symptoms of peptic ulcer disease.

The role of surgery in the treatment of gastrinoma is unclear. The purpose of this study was to determine prospectively the surgical cure rate using a controlled clinical trial. Eleven patients who fit the entry criteria underwent abdominal exploration and attempted tumor resection for cure. A historical control group was used for comparison. Cure was defined as: (1) normal serum gastrin level, (2) no response to intravenous secretin, (3) no symptoms when antisecretory medications are stopped, and (4) no tumor recurrence on follow-up examination. Tumors found in both groups tended to be small (1.5 cm vs. 2.2 cm), multiple (71% vs. 40%), and in lymph nodes (70% vs. 70%). All tumors identified were located anatomically within the gastrinoma triangle. Tumors were found in 10 of 11 patients (91%) in the study group, and significantly more patients had their tumors excised for cure as compared to controls (82% vs. 27%, p less than 0.05). The current prospective cure rate for gastrinoma is higher than previously appreciated and tumors within lymph nodes do not preclude curative resection.

Non-beta-cell adenoma of the islet apparatus in the pancreas was described. The tumor measured 8 X 4 X 4 cm. Histological examination revealed its mixed structure. The tumor was composed of trabecular and solid structures, adenoma-like rosettes, and pericytial muffs. APUD-amyloid was found in its stroma. Application of a specific immunoperoxidase technique and electron microscopy provided good evidence for the fact that the tumor consisted of gastrin-producing cells. In view of clinical features, the tumor was regarded as gastrinoma.

Recently a number of surgeons have recommended radical resection of gastrinomas in Zollinger-Ellison syndrome (ZES). We have developed a useful technique for preoperative localization of gastrinomas--the selective arterial secretin injection test (SASI)--and we recommend an intraoperative secretin test (IOS) for deciding the radicality of resection of gastrinomas. Here the results of SASI and IOS tests in 11 patients with ZES are examined and compared with the results of other techniques. The SASI test localized gastrinomas in all of the patients, while the sensitivity of ultrasonography, computed tomography, arteriography, or portal venous blood samplings was between 1/11 and 5/11. On the basis of the results of the SASI test, radical resection of gastrinoma was performed in four patients (three pancreatoduodenectomies and one extirpation). After pancreatoduodenectomy, immunohistologic study of the specimen revealed multiple microgastrinomas and lymph node metastases in two patients and the coexistence of a microgastrinoma and a gastinoma in one patient. The IOS test was useful in the estimation of the advisability of radicality, and in two patients total gastrectomy was not performed because of the results of the IOS test. These four patients are well and have returned to work, and their serum gastrin levels are below 35 pg/mL. Thus we believe SASI and IOS tests are helpful for planning curative resection of gastrinomas.

Two patients with Zollinger-Ellison Syndrome were diagnosed and treated in PUMC Hospital, the primary tumors were found in the stomach. On sectioning of the gastrectomized specimens, 85 tumors ranging from 0.1 to 1.0 cm in diameter were disclosed in Case 1, and a large ulcero-infiltrative carcinoma-like tumor in Case 2. Both tumors had already metastasized to regional lymph nodes and/or liver. Tumor cells in both cases exhibited gastrin, NSE, GH and hCG alpha immunoreactivity immunocytochemically, and abundant neurosecretory granules of 100-250 nm in diameter under electron microscope. The clinicopathological, immunocytochemical and ultrastructural findings of tumors from these two cases met the criteria of primary malignant gastrinoma of the stomach.

The characterization of the tumors and their metastasis in patients with the Zollinger-Ellison syndrome is currently based on the immunohistochemical identification of gastrin cells. However, sometimes tumoral cells fail to react with common C-terminal gastrin antibodies. In order to clarify this failure, we carried out morphologic, morphometric and immunocytochemical analyses performed on light and electron microscope levels of 6 pancreatic and 1 metastatic gastrinomas, using antibodies raised against various sequences of human progastrin. On the basis, in light microscopy, of qualitative analysis of immunostaining within cells and of immunostained cell numbers, gastrin 34 residue seemed to be the prominent form in 2 of the tumor tissues, G-17 in 1 tumor which was not responsive with C terminus progastrin and N terminus G-34 antisera, and progastrin in the metastatic tissue that did not contain typical gastrin (G-like) cells. Two tumors failed to react with all antisera used. At the electron microscope level, immunogold staining revealed that progastrin was present only in the progranules and gastrin 34 in both progranules and intermediate granules. Quantitative studies performed on 3 tumors showed that, within a given tumoral cell, about 25 percent of progranules contained progastrin while 75 percent contained gastrin 34. We concluded that different forms of gastrin can be immunodetected in a gastrinoma tissue, depending on the regions, and that the distribution of progastrin fragments is variable from tumor to tumor. So, specific antibodies to different fragments of progastrin may help to the characterization of gastrinomas.