The origin of sporadic gastrinomas within the gastrinoma triangle: a theory.
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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.
Duodenal Neoplasms↗
[The role of total gastrectomy in the management of gastrinoma syndrome].
Total gastrectomy used to be considered as a standard operation in the surgical treatment for gastrinoma syndrome. Although this end organ resection is a good palliation, to cure this ulcerogenic disease, gastrinoma resection is preferred. It remains a question if a total gastrectomy is necessary when a gastrinoma is found and resected. In a period of 12 years, nine out of 17 patients with gastrinoma syndrome were surgically treated. Fifteen gastrinomas were removed without histologic evidence of malignancy. Total gastrectomy was added in three, Whipple's operation was done in one and tumor resection alone in five. Serial examination of the resected stomach didn't find any gastrinoma. Eight gastrinomas of seven patients were found located in the pancreas, duodenum and lymph nodes within the gastrinoma triangle. These patients except one were followed up for six months to five years (mean 32 months). One died of post-operative hepatic failure, and one died of hypophysectomy for a co-existent huge prolactinoma (MEN I) four years later. Cure of the disease in terms of normal fasting serum gastrin levels, symptom free without medication, endoscopic evidence of healed ulcer, and a negative conversion of secretin provocative test was found in 2/3 of the patients with additional total gastrectomy, and 4/6 of the others. All cured patients had their gastrinomas located in the gastrinoma triangle, and six of the seven (85.7%) patients with gastrinomas in the triangle were cured. It is our conclusion that total gastrectomy was retrospectively unnecessary in most of the patients with gastrinomas in the gastrinoma triangle. Staged operations should be planned.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Prospective study of the ability of computed axial tomography to localize gastrinomas in patients with Zollinger-Ellison syndrome.
The ability of routine computed tomography (CT) performed with oral and intravenous contrast to localize gastrinomas in 61 consecutive patients with Zollinger-Ellison syndrome was evaluated prospectively. The results of CT scanning were subsequently evaluated in all patients by either surgery, autopsy, or percutaneous biopsy. Thirteen of 14 patients with CT scans positive for hepatic metastases and 5 of 13 patients with CT scans negative for hepatic metastases were found to have gastrinoma in the liver. For gastrinoma metastatic to the liver, CT scanning had a specificity of 98%, a sensitivity of 72%, a positive predictive value of 93%, and a negative predictive value of 90%. Twenty-two of 23 patients with positive extrahepatic CT scans and 15 of 33 patients with negative extrahepatic CT scans were found to have extrahepatic gastrinomas. For extrahepatic gastrinoma, CT scanning had a specificity of 95%, a sensitivity of 59%, a positive predictive value of 96%, and a negative predictive value of 54%. The ability of CT scan to detect gastrinomas both in the liver and extrahepatically was directly related to tumor size, detecting 0% of tumors less than 1 cm and 83%-95% of tumors greater than 3 cm. The location of the extrahepatic gastrinoma was also an important determinant in that approximately 80% of pancreatic gastrinomas but only 35% of extrapancreatic gastrinomas were detected. The present results indicate that because of its convenience and accuracy, CT scanning with oral and intravenous contrast material should be the initial procedure to evaluate the extent of gastrinoma. A positive CT scan is almost always correct; therefore, a CT scan detecting metastatic gastrinoma to the liver would avoid unnecessary surgery and, if positive for extrahepatic gastrinoma, would assist the surgeon in finding the gastrinoma. A negative CT is less reliable; therefore, patients should undergo other localizing studies before exploratory laparotomy.
Biopsy↗
Surgical pathology of gastrinoma. Site, size, multicentricity, association with multiple endocrine neoplasia type 1, and malignancy.
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.
Duodenal Neoplasms↗
Surgical treatment of localized gastrinoma within the liver: a prospective study.
BACKGROUND: Studies demonstrate that liver metastases of gastrinoma significantly reduce survival. METHODS: Since 1982 we have prospectively studied 213 patients with Zollinger-Ellison syndrome. For this report the results of surgery for localized liver gastrinoma were analyzed. RESULTS: Zollinger-Ellison syndrome was diagnosed biochemically in all patients and acid output was controlled with medications. Imaging studies demonstrated liver gastrinoma in 69 patients (32%). Fifty-two had diffuse unresectable disease, whereas 17 (10%) had localized disease. All patients with localized liver gastrinoma and 2 patients with diffuse disease who needed surgery are the subject of this report. Major hepatic lobectomy was performed in 10 patients and wedge resections in 9. Three patients had apparent liver primary gastrinomas and 16 had metastatic disease. Seventeen of 19 patients were able to have all identifiable gastrinoma resected. Extrahepatic tumor was also removed at the same procedure. Extirpation of liver gastrinoma required hepatic lobectomy in 10 patients and wedge resections in the others. Five-year survival was 85%. Five of 17 completely resected patients (29%) remained disease free. CONCLUSIONS: Resectable localized liver gastrinoma is rare. Primary liver gastrinomas can occur. Surgical resection of localized liver gastrinoma provides a cure rate similar to that of extrahepatic gastrinoma and an excellent long-term survival.
Female↗
Genotype/phenotype correlation of multiple endocrine neoplasia type 1 gene mutations in sporadic gastrinomas.
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.
Base Sequence↗
Alterations in the p16INK4a/CDKN2A tumor suppressor gene in gastrinomas.
The p16INK4a/CDKN2A gene (p16INK4a) is frequently altered by homozygous deletion, mutation, or methylation in many nonendocrine tumors, and these alterations may be predictive of recurrence, tumor growth, or aggressiveness. Whether this is true of neuroendocrine tumors such as gastrinomas is unclear. To address this question we analyzed the gastrinomas from 44 patients for p16INK4a gene mutations and correlated the results to the tumor's biological behavior, growth pattern, and aggressiveness. No gastrinomas had mutations of exon 1 or exon 2 of the p16INK4a gene, although polymorphisms were found in 54%. No homozygous deletions were found. In 52% of the gastrinomas, hypermethylation of a 5'-CpG island of the p16INK4a gene promoter was found. To assess the growth behavior of the gastrinomas, all patients were assessed yearly with at least three conventional imaging studies (computed tomography scan, magnetic resonance imaging, and ultrasound), and since 1994 have been assessed with radionuclide scanning using [111In-diethylenetriamine pentaacetic acid,DPhe1]octreotide. The mean follow-up was 5.1+/-0.4 yr (range, 1.2-11.7). The presence or absence of methylation of the p16INK4a gene did not correlate with clinical characteristics of the gastrinoma, biological behavior (gastrin release and basal or maximal acid output), the presence or absence of known prognostic factors (tumor size, gastrinoma location, lymph node metastases, liver metastases, and curability), or growth pattern of the gastrinoma postresection. These results indicate that methylation of the p16INK4a gene is the most common gene alteration described to date in gastrinomas. Furthermore, because it is independent of disease stage it is probably an early event in the pathogenesis and because it is independent of the primary gastrinoma location, which is now thought to have different origins, methylation of the p16INK4a gene is probably a central process in the molecular pathogenesis of these tumors.
Adolescent↗
Localization, malignant potential, and surgical management of gastrinomas.
Between 1987 and 1996 a total of 25 patients with proved Zollinger-Ellison syndrome (ZES) have been treated in our department. If preoperative imaging studies did not show diffuse metastatic disease, patients were scheduled for operation with a standardized surgical approach including thorough exploration and intraoperative ultrasonography (IOUS) of the pancreas and a longitudinal duodenotomy, with separate palpation of the anterior and posterior walls. Postoperatively, patients were followed up by physical examination, fasting gastrin levels, and the secretin stimulation test. Altogether 10 patients had duodenal wall gastrinoma, 14 patients pancreatic gastrinoma, and the tumor was not found in 1 patient. Only 15 tumors (60%) (2 duodenal wall and 13 pancreatic gastrinomas) could be visualized preoperatively. Intraoperatively, 24 of 25 primary gastrinomas were localized. The mean size of duodenal wall gastrinomas (9.6 mm) was significantly smaller than that of pancreatic gastrinomas (28.7 mm) (p < 0.05). At the time of surgical exploration, five duodenal and seven pancreatic gastrinomas had metastasized. The incidence of lymph node metastases was similar for both tumor sites, whereas patients with pancreatic gastrinomas more frequently had liver metastases. The presence of liver metastases was the most important determinant for survival. Four patients (40%) with duodenal and seven with pancreatic (50%) gastrinomas (mean follow-up 5.2 years) were biochemically cured by operation. Of the remaining patients, eight are still alive with recurrent disease. Our results suggest that preoperative localization of gastrinomas often fails despite all modern imaging methods. Therefore a standardized surgical exploration of the pancreas including IOUS and a duodenal exploration should be performed to achieve optimal results. Preoperative diagnostic imaging tests should include computed tomography, ultrasonography, and somatostatin receptor scintigraphy to exclude diffuse metastases. In contrast to liver metastases, lymph node metastases do not have a significant influence on survival.
Diagnostic Imaging↗
Evaluation of NH2-terminus gastrins in gastrinoma syndrome.
Forty-six patients with the gastrinoma syndrome were divided into 2 categories: 1) benign sporadic gastrinoma (n = 30), and 2) gastrinoma with metastases to liver (n = 16). Thirteen of the 46 patients had multiple endocrine neoplasia type I syndrome. Serum gastrin levels in patients fasted overnight were determined by RIA using antisera directed toward the NH2- and COOH-terminals of heptadecapeptide gastrin (G17) and the NH2-terminus of the triacontatetrapeptide (G34). These results were compared with findings in 50 normal subjects. In the normal subjects, the mean COOH-terminal gastrin-17 level was higher [65 +/- 8 (+/- SEM) pg/ml] than the NH2-terminal gastrin-17 level (11 +/- 0.2 pg/ml) and lower than the NH2-terminal gastrin-34 level (134 +/- 20 pg/ml). The levels of NH2-terminal gastrin-17 were higher in patients with metastatic disease than in those with benign gastrinoma, whereas the COOH-terminal gastrin-17 and the NH2-terminal gastrin-34 levels were similarly high in both groups. The mean ratio of NH2-terminal gastrin-17 to COOH-terminal gastrin-17 was less than 1 in normal subjects (0.22 +/- 0.02) and benign gastrinoma patients (0.2 +/- 0.04), and it was 2.2 +/- 0.41 in the patients with metastatic gastrinoma. An NH2 to COOH gastrin-17 ratio greater than 1 was found in 13 of 16 patients with metastatic gastrinoma, but in none of the patients with benign gastrinoma or normal subjects. Similar results were found in multiple endocrine neoplasia type I patients with benign and metastatic disease. A high NH2 to COOH gastrin-17 ratio is suggestive of metastatic gastrinoma. In 4 patients with metastatic gastrinoma, the NH2 to COOH gastrin-17 ratio fell in parallel with the response to chemotherapy.
Chromatography, Gel↗
The dichotomous distribution of gastrinomas.
Our experience with 47 sporadic gastrinomas suggests that no less than 85% of these tumors are located to the right of the superior mesenteric artery. This finding is unexpected because approximately 75% of insulinomas and glucagonomas are located to the left of the superior mesenteric artery. All of our extrapancreatic gastrinomas have been located to the right. These observations prompted us to determine if other extrapancreatic gastrinomas were also predominantly located to the right side. We searched the world's literature and found 10 cases of ovarian gastrinomas and one case of a renal gastrinoma. Nine of these remote extrapancreatic gastrinomas were located on the right side. This distribution of remote extrapancreatic gastrinomas is similar to our experience with peripancreatic gastrinomas. This unexpected right-sided preponderance of both remote and peripancreatic gastrinomas suggests a common origin for both.
Adult↗
Benefit of resection of metastatic gastrinoma in multiple endocrine neoplasia type I.
Although gastrinoma resection is generally advocated for patients with the sporadic form of nonmetastatic Zollinger-Ellison syndrome, there is controversy regarding the surgical management of the gastrinoma among patients with multiple endocrine neoplasia type I (MEN-I). Using strict criteria, to date no biochemical cures of the Zollinger-Ellison syndrome lasting greater than 5 months have been achieved by gastrinoma resection among patients with MEN-I. Whereas resections of hepatic metastases have been performed in patients with sporadic gastrinoma, none have been reported among patients with MEN-I. The current report describes a patient with MEN-I, closely followed up for 30 years, in whom enlargement of pancreatic gastrinoma and development of hepatic gastrinoma was observed to occur over 3 years. After preoperative localization, an 80% pancreatectomy and a left lateral segmentectomy of the liver were performed. Sixteen months after the operation, secretin and calcium provocative testing showed that the patient's fasting gastrin and stimulated plasma gastrin concentrations were normal; also, results of computerized tomographic angiography, selective abdominal angiography, and hepatic venous sampling for gastrin after intra-arterial secretin injection were negative for gastrinoma. By achieving a 16-month cure of gastrinoma, this case shows that an aggressive surgical approach can benefit certain patients with gastrinoma who have MEN-I even in the presence of hepatic metastases.
Angiography↗
Gastrinomas demonstrate amplification of the HER-2/neu proto-oncogene.
OBJECTIVE: This study determined whether genomic amplification of HER-2/neu or mutations of the p53 and ras genes were present in gastrinomas. SUMMARY BACKGROUND DATA: Amplification of HER-2/neu, a proto-oncogene related to the epidermal growth factor receptor, and mutation of the ras proto-oncogene and p53 tumor suppressor gene appear to play a role in the pathogenesis of some human cancers. Little is known about possible molecular alterations in gastrinomas, tumors that may be particularly virulent because of gastrin overproduction, resulting in the severe ulcer diathesis, the Zollinger-Ellison syndrome. METHODS: The differential polymerase chain reaction (PCR) procedure was used to detect amplification of the HER-2/neu gene in DNA samples from the novel human gastrinoma cell line (PT) and from paraffin-embedded samples of gastrinomas. Sequencing techniques were used to determine whether mutations of the p53 or ras (Ha-ras, N-ras, Ki-ras) genes were present. RESULTS: Amplification (> twofold) occurred in all gastrinoma tumor samples. Compared with normal pancreas or ileum, a 4- to 12-fold amplification of HER-2/neu was found in 3 gastrinomas, 3 to 3.3-fold in four samples and 2.1- to 2.4-fold in the remaining five tumors. A heterozygous point mutation in the p53 gene (codon 273) was found in a single sample; none of the gastrinomas contained a mutation of the ras genes. CONCLUSIONS: Amplification of the HER-2/neu gene, but not alterations of either p53 or ras, may be involved in the pathogenesis of gastrinomas. The unique PT cell line will be a useful model to further elucidate the molecular mechanisms that contribute to gastrinoma formation and growth.
Base Sequence↗
A prospective study of perioperative and postoperative control of acid hypersecretion in patients with Zollinger-Ellison syndrome undergoing gastrinoma resection.
Fifty-five consecutive patients with Zollinger-Ellison syndrome who underwent exploratory laparotomies for gastrinoma resection were evaluated prospectively to determine the effect of gastrinoma resection on acid secretion and to establish criteria for safe and effective perioperative management of gastric acid hypersecretion. In 15 patients (27%) no tumor was found and postoperative serum gastrin, basal acid output (BAO), and maximal acid output (MAO) were unchanged. Twenty-one patients (38%) had gastrinomas resected and were biochemically cured. Median fasting gastrin, median delta secretin, mean BAO, and mean MAO decreased 89%, 94%, 80%, and 43%, respectively, at 3-month follow-up in these patients. In 19 patients gastrinomas were resected, but patients were not cured, and median fasting gastrin, median delta secretin, mean BAO, and mean MAO decreased 47%, 10%, 26%, and 25%, respectively. Forty percent of patients with gastrinoma resected and cured and 81% of patients with gastrinoma resected but not cured continued to hypersecrete acid (BAO greater than 10 mEq/hr) at 3- to 6-month follow-up. Acid control was managed perioperatively during gastrinoma resection by continuous intravenous infusion of H2 receptor antagonists at a dose established by preoperative titration to decrease acid output to less than 10 mEq/hr. Thirty patients were treated with cimetidine at a mean dose of 3.2 mg/kg/hr for a mean of 13.8 days. Twenty-one patients were treated with ranitidine at a mean dose of 1.1 mg/kg/hr for a mean of 8 days. No patients suffered any complications related to acid hypersecretion or side effects of the H2 antagonists. Patients undergoing gastrinoma resection can be managed safely by continuous infusion of H2 antagonists. Successful gastrinoma resection can reduce acid output, but even 40% of biochemically cured patients will continue to hypersecrete acid at short-term follow-up and will require continuation of antisecretory medication.
Adult↗
Pathologic aspects of gastrinomas in patients with Zollinger-Ellison syndrome with and without multiple endocrine neoplasia type I.
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.
Duodenal Neoplasms↗
Preoperative detection of duodenal gastrinomas and peripancreatic lymph nodes by somatostatin receptor scintigraphy. Groupe D'etude Du Syndrome De Zollinger-Ellison.
BACKGROUND & AIMS: Duodenal gastrinomas and peripancreatic lymph nodes are difficult to localize. The aim of this study was to evaluate the ability of Octreoscan scintigraphy to detect such tumors. METHODS: Results of Octreoscan scintigraphy in 21 consecutive patients with Zollinger-Ellison syndrome were compared with those of conventional imaging techniques, including endoscopic ultrasonography, and with the surgical findings. RESULTS: Surgical exploration found 27 duodenal and/or lymph node gastrinomas in 19 patients. None had pancreatic gastrinoma. Octreoscan scintigraphy was the only positive preoperative technique in 32% of the patients. The sensitivities of conventional techniques, Octreoscan scintigraphy, and their association were 58%, 58%, and 90%, respectively, for all resected gastrinomas. The smallest duodenal gastrinoma detected by Octreoscan scintigraphy measured 3 mm. Endoscopic ultrasonography detected all the tumors visualized by any other conventional technique and was considered falsely positive, as was Octreoscan scintigraphy, in 1 patient. Follow-up and comparison between the number of resected gastrinomas and the number of preoperative hot spots suggested that surgeons should find at least as many tumors as the number of hot spots. CONCLUSIONS: Octreoscan scintigraphy improved the preoperative detection of extrapancreatic gastrinomas, mainly by endoscopic ultrasonography. Surgeons should find at least as many gastrinomas as the number of hot spots.
Adult↗
Human gastrinoma cells express calcium-sensing receptor.
The intravenous calcium injection test has been reported to be useful for the diagnosis of gastrinoma. However, the mechanism underlying calcium-evoked gastrin release is not fully understood. We investigated the mechanism of calcium-stimulated gastrin release from gastrinoma cells in vitro with a particular focus on the calcium-sensing receptor (CaR). Human gastrinoma cells were taken from mechanically minced gastrinoma tissues obtained at surgery. In the perifusion system, high [Ca2+]o induced gastrin release from gastrinoma cells. As [Ca2+]o increased, [Ca2+]i rapidly increased, as monitored by fluorometry. The response was not inhibited by nifedipine, a blocker of the voltage-dependent calcium channel. Reverse transcriptase-polymerase chain reaction and subsequent Southern blot hybridization revealed the presence of the CaR gene in human gastrinoma tissues. Moreover, the expression of CaR in gastrinoma tissues was confirmed by immunohistochemistry. Our results demonstrated that CaR was expressed in human gastrinoma cells and could be involved in the mechanism of calcium-evoked gastrin release.
Blotting, Southern↗
A prospective analysis of the frequency, location, and curability of ectopic (nonpancreaticoduodenal, nonnodal) gastrinoma.
BACKGROUND: Extrapancreatic, extraduodenal and extralymphatic (ectopic) gastrinomas have been reported only rarely. The frequency, locations, and surgical outcome of these lesions are unknown. METHODS: From 1982 to 1997, 215 patients with Zollinger-Ellison syndrome were evaluated prospectively at the National Institutes of Health and 142 patients (66%) underwent standardized surgical exploration and resection. Eight patients (5.6%) (six men and two women; mean age, 41 years) had primary gastrinoma located in ectopic sites. Long-term follow-up was derived from a prospective database. RESULTS: Ectopic gastrinoma tissue was identified and resected in the liver (three patients), common bile duct (one patient), jejunum (one patient), omentum (one patient), pylorus (one patient), and ovary (one patient). Seven patients (88%) were cured biochemically after resection and five patients (63%) have sustained cures, with a mean follow-up of 7.5 years (range, 0.4 to 11.7 years). One patient with a jejunal primary gastrinoma had a biochemical recurrence at 2 years, and another with a primary hepatic gastrinoma had a recurrence 6 years after resection. A patient with a pyloric primary gastrinoma was not cured. CONCLUSIONS: Extraduodenal, extrapancreatic, and extranodal gastrinomas are encountered in 5.6% of patients who undergo exploration with curative intent. If no gastrinoma is found in the usual locations, other ectopic sites should be examined carefully. Resection of these primary ectopic tumors can lead to durable biochemical cures.
Adult↗