Ovarian carcinoma as a cause of Zollinger-Ellison syndrome. Natural history, secretory products, and response to provocative tests

Zollinger-Ellison syndrome is usually caused by a gastrin-secreting tumor in or near the pancreas. We describe a patient in whom an ovarian cystadenocarcinoma was the cause of the syndrome. The patient presented with a short history of peptic ulceration and development of a large pelvic mass. Investigations demonstrated a basal acid output of 37.8 mEq/h and a maximal acid output of 36.0 mEq/h, and the plasma concentration of gastrin was 830 pg/ml (normal less than 100). Secretin and calcium infusion tests were positive, and a meal test was compatible with Zollinger-Ellison syndrome. Imaging studies demonstrated a normal liver and pancreas but a large cystic right ovarian mass. Resection of the mass resulted in a marked reduction in gastric acid output, a fall in plasma gastrin concentration to normal, negative calcium and secretin tests, and a normal (positive) meal test. Histology of the mass showed it to be a mucinous cystadenocarcinoma. The tumor stained with immunoperoxidase technique was positive for gastrin, and the cyst fluid contained high concentrations of gastrin and calcitonin. One year later, the patient has no biochemical or imaging evidence of tumor. Ovarian, gastrin-producing tumors and pancreatic gastrinomas cannot be distinguished by provocative tests, and negative imaging studies do not exclude a pancreatic tumor. Patients with an ovarian mass and Zollinger-Ellison syndrome should have a bilateral oophorectomy and a careful exploration of the pancreatic area.     

An enucleated duodenal gastrinoma with multiple type 1 endocrine neoplasia located by selective arterial calcium injection

We report a duodenal gastrinoma in a 50-year-old man who was admitted to our hospital with tarry stools. Esophagogastroduodenoscopy revealed multiple ulcers in the duodenal bulb and a submucosal tumor in the descending duodenum. His serum gastrin level was 1400pg/ml. We suspected Zollinger-Ellison syndrome and performed selective arterial calcium injection to locate the gastrinoma. Increase in the hepatic venous gastrin level was seen only in the gastroduodenal artery area. We diagnosed a gastrinoma located in the pancreaticoduodenal area. Genetic examination showed a single-base deletion in the MEN-1 gene. At operation, the tumor was found in the submucosal layer of the descending duodenum and was extirpated. He is alive without recurrence 3 years after surgery.     

Gastrinoma in a Mesenteric Lymph Node

A 36-yr-old man was admitted to our hospital complaining of severe vomiting and diarrhea. Upper gastrointestinal series showed deformity of the duodenum. Serum gastrin level was very high (1,829 pg/ml) and secretin provocative test presented a positive result (peak 4,535 pg/ml). We diagnosed his illness as Zollinger-Ellison syndrome, but failed to identify the site of tumor. His symptoms were controlled with cimetidine 1,600 mg qid, but serum gastrin level was increasing. A year after the first admission, computed tomographic scan and selective angiography demonstrated the tumor, and surgery was performed. A solitary 2-cm tumor was noted at the surface of mesenterium of the duodenum. Frozen and paraffin section of the tumor revealed islet cell tumor apparently within a lymph node. Immunohistological examination revealed positive staining for gastrin alone. No other tumors were detectable by inspection and palpation during the operation. After excision of the tumor, serum gastrin and secretion test were normalized, and the patient remains asymptomatic 1 yr after surgery.     

Case of Zollinger-Ellison syndrome diagnosed three years after ulcer perforation in the third portion of the duodenum]

A 61-year-old woman was referred to our hospital for a double balloon endoscopy (DBE) examination of small intestine. She had undergone laparotomy for a perforated ulcer of the 3rd portion in the duodenum 3 years prior to this admission. Esophagogastroduodenoscopy at the previous hospital revealed multiple ulcers in the 2nd and 3rd portions in the duodenum. DBE revealed multiple ulcer scars in the proximal jejunum. Zollinger-Ellison syndrome was suspected from the distribution of the ulcers and scars. Serum gastrin was high and a selective arterial calcium injection test showed a step up of gastrin level only in the gastroduodenal artery area. We diagnosed a gastrinoma located on the ventral side of the 2nd portion of the duodenum from imaging studies. The tumor was extirpated and histologically found to be a neuroendocrine tumor in a lymph node. Serum gastrin level decreased to the normal range a day after surgery.     

Zollinger-Ellison syndrome type 1: clinical and pathological correlations in a case

Some patients with the Zollinger-Ellison syndrome appear to have hypergastrinaemia and hyperplasia of the antral G cells but no tumour. This subgroup has been classified as Zollinger-Ellison syndrome type 1. We have treated such a patient by vagotomy and antrectomy, the fasting plasma gastrin and acid secretion subsequently returning to normal.A 17-year-old male had a four-year history of duodenal ulcer. Gastric secretion tests showed acid hypersecretion. Fasting plasma gastrin was 8350 pg/ml (normal 50-170 pg/ml). At laparotomy duodenal ulceration was confirmed but no pancreatic or other tumours were found. Truncal vagotomy and antrectomy was performed with distal pancreatectomy. Immunofluorescent staining showed hyperplasia of G cells in the resected antrum but a normal pancreas and duodenum.Six months after operation he was symptom free and acid secretion was reduced by 92%. The fasting plasma gastrin at two months was <50 pg/ml.These findings suggest that type 1 Zollinger-Ellison syndrome may be a clinical entity.     

A case of Zollinger-Ellison syndrome produced by gastrinoma in the duodenum accompanied with multiple endocrine neoplasia type 1

A case of Zollinger-Ellison syndrome produced by gastrinoma in the duodenum accompanied by multiple endocrine neoplasia type-1 (MEN-1) is reported. A 46 year-old female underwent distal gastrectomy due to gastric ulcer 5 years ago. As ulceration of the residual stomach recurred, further examination was performed. Hyperprolactinemia, hypergastrinemia, primary hyperparathyroidism, pancreatic tumor, and duodenal carcinoid were evident, and the diagnoses of Zollinger-Ellison syndrome and MEN-1 were established. The origin of the gastrin secretion was suspected to be from the pancreatic tumor, so sampling of the portal blood was performed. As lesion on the gastrinoma in the pancreas could not be identified, total parathyroidectomy was performed for primary hyperparathyroidism. The level of the gastrin secretion, however, remained high. Partial resection of the duodenum for the duodenal carcinoid and a distal pancreatectomy were carried out concurrently. Immunohistochemical study of the anti-gastrin antibody revealed duodenal tumor cells. Initially, the gastrinoma was thought to be in the pancreas, however, the lesion accompanied with MEN-1 and the Zollinger-Ellison syndrome had occurred in the duodenum.     

Gastrin-producing ovarian cystadenocarcinoma: sensitivity to secretin and SMS 201-995

We report a patient with severe peptic ulcer disease and a right ovarian mass that was found to be a gastrin-producing cystadenocarcinoma. Gastrin production by the tumor was stimulated by secretin and inhibited by the long-acting somatostatin analogue SMS 201-995. Following resection of the tumor, serum gastrin levels and the gastrin response to secretin returned to normal. Histologic examination, including Alcian blue staining for mucin and immunoperoxidase staining for gastrin, revealed gastrin at the base and mucin at the apex of the tumor cells. This report demonstrates secretin stimulation and somatostatin inhibition of gastrin secretion from a cell that is apparently not of endocrine origin.     

Pseudo Zollinger-Ellison syndrome in a patient with duodenal stenosis caused by tuberculosis

We report the case of a 32-year-old Indian man with symptoms suggesting Zollinger-Ellison syndrome including abdominal pain, esaphagitis, duodenal stenosis that did not improve with antisecretory medication, elevated fasting gastrin serum levels that increased after intravenous secretin injections, elevated chromogranin A serum levels and tumoral aspect of pancreatic uncus on CT scan examination. A pancreaticoduodenectomy was performed. Histological examination of the resected specimen showed that there was no endocrine tumour of the pancreas or the duodenum, but identified marked lesions of follicular and caseous tuberculosis. The final diagnosis retained pseudo Zollinger-Ellison syndrome due to gastric outlet obstruction caused by duodenal stenosis of a tuberculosis origin.     

Cushing's syndrome due to ectopic adrenocorticotropic hormone production by a non-metastatic gastrinoma after long-term conservative treatment of Zollinger-Ellison syndrome

This report concerns a case of a Cushing's syndrome 10 years after first diagnosis of a Zollinger-Ellison syndrome within the same patient. In a 69-year-old female patient symptoms of hypergastrinaemia have been successfully treated with a proton pump inhibitor. Cushing's syndrome was the result of ectopic adrenocorticotropic hormone production by a large cystic gastrin-producing tumour of the pancreatic tail. After resection by subtotal pancreatectomy serum adrenocorticotropic hormone, cortisol, gastrin levels and secretin infusion test returned to normal. In contrast to all other previously published cases of ectopic adrenocorticotropic hormone syndrome associated with Zollinger-Ellison syndrome, this tumour had not metastasized into the liver and did not show local invasive growth.     

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

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

Insulinoma with subsequent association of Zollinger-Ellison syndrome

We report a patient with insulinoma associated with Zollinger-Ellison syndrome. A 67-year-old woman was first admitted to our hospital for an abdominal mass. Abdominal computed tomography (CT) revealed a large pancreatic tumor, which was then diagnosed as an unresectable pancreatic adenocarcinoma. At the age of 71, she presented symptoms of hypoglycemia. Fasting blood glucose was 21 mg/dl and plasma immunoreactive insulin level was 846 microU/ ml. Plasma gastrin, glucagon, vasoactive intestinal polypeptide and somatostatin levels were all normal. At the age of 73, hypoglycemic attacks occurred more frequently and she was admitted to our hospital. Abdominal CT scan showed multiple liver metastases. Chemotherapy with 5-fluorouracil and doxorubicin was performed. Three months later, she had an emergency laparotomy because of a perforated duodenal ulcer. Plasma gastrin level was 1,960 pg/ml at that time. Gastric hypersecretion was well controlled with a proton pump inhibitor (lansoprazole) but she died of widespread cancer dissemination 8 years after her first admission. On autopsy, histologic examination revealed a mixed acinar-endocrine carcinoma of the pancreas. Immunohistochemical stains were positive for insulin, gastrin, and alpha1-antitrypsin.     

Allelic deletion of the MEN1 gene in duodenal gastrin and somatostatin cell neoplasms and their precursor lesions

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

A case of jejunal gastrinoma diagnosed by percutaneous transhepatic portal venous sampling.

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.     

A case of jejunal gastrinoma diagnosed by percutaneous transhepatic portal venous sampling

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. Laparatomy 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.     

Zollinger-Ellison phenotype in the absence of hypergastrinemia and islet-cell tumor

Patients with the Zollinger-Ellison syndrome are characterized by islet-cell tumors, striking gastric acid hypersecretion, and peptic ulcer disease. They often experience severe abdominal pain, diarrhea, and gastrointestinal bleeding with potentially life-threatening consequences. It is a rare syndrome caused by nonbeta cell islet-cell tumors (gastrinomas) located in or in proximity to the pancreas. These tumors freely secrete gastrin, a peptide hormone that serves as a powerful stimulant of gastric acid secretion. Exuberant secretion of gastrin from the gastrinomas produces severe gastric acid hypersecretion that often leads to impressive peptic ulcer disease and the constellation of symptoms listed above. We describe a patient presenting with clinical manifestations characteristic of the ZES with strikingly elevated gastric acid secretion, multiple ulcers in the first and second portions of the duodenum and diarrhea, but in absence of islet-cell tumor and/or hypergastrinemia.     

Selective intra-arterial methylene blue injection: a novel method of localizing gastrinoma.

A 40-year-old woman had persistent Zollinger-Ellison syndrome despite excision of a 4-cm duodenal gastrinoma. Localizing studies including ultrasonography, computed tomography, magnetic resonance imaging, duodenal endoscopy, endoscopic ultrasonography, and intraoperative endoscopic transillumination of the duodenum failed to detect a tumor. Selective intra-arterial methylene blue injection was used to identify a 6-mm gastrinoma in the duodenum, which was locally excised. Postoperatively, the patient had a negative secretin provocative test result. This novel method uses selective arterial secretin injection with hepatic venous gastrin sampling to identify the vessel feeding the gastrinoma. An angiographic catheter is then positioned in this artery. At laparotomy, methylene blue is injected through this catheter to selectively stain the gastrinoma, facilitating its identification. Selective intra-arterial methylene blue injection can enhance intraoperative detection of small gastrinomas and may improve the rate of curative resection in the Zollinger-Ellison syndrome. Further evaluation of this novel localizing technique is warranted.     

Pathophysiological responses to meals in the Zollinger-Ellison syndrome: I. Paradoxical postprandial inhibition of gastric secretion.

The gastric acid, pepsin, and secretory volume output in response to a mixed meal were measured in six patients with Zollinger-Ellison syndrome caused by a gastrin-producing tumour proved subsequently at surgery. The patients were all normocalcaemic, and none had previous abdominal surgery. In four of the six patients, ingestion of the meal markedly inhibited the gastric secretory output, which decreased to below fasting levels, returning later to basal values. In two other patients, whose fasting acid output was considerably lower, the secretory output increased after the meal, but some inhibiton of gastric secretion was also apparent for variable intervals of time. The serum gastrin concentration in all patients remained essentially unchanged or increased after the meal. Two patients were restudied after successful removal of the duodenal gastrin-producing tumour, and in each the normal gastric secretory and gastrin-releasing responses were completely restored. Our studies suggest that, in patients with the Zollinger-Ellison syndrome caused by a gastrinoma, physiological regulatory mechanisms triggered by food reduce the continuous stimulation of gastric secretion caused by their tumoural hypergastrinaemia.     

A new cause of Zollinger-Ellison syndrome: non-small cell lung cancer

Numerous epidemiologic studies suggest a relationship between lung cancer and peptic ulcer disease. Furthermore, various lung cancers synthesize and release a number of peptides such as gastrin and gastrin-releasing peptide that could cause acid hypersecretion; however, Zollinger-Ellison syndrome (ZES), because of a lung tumor, has never been described. We report such a patient for the first time. A 60-year-old man with a non-small cell lung carcinoma (large cell type) presented with diarrhea, heartburn, abdominal pain, and duodenal ulcers. Evaluation showed ZES was present (fasting hypergastrinemia, hyperchlorhydria) and control of all symptoms by omeprazole. No abdominal or cardiac tumor, the other known locations of gastrinomas causing ZES, was found on detailed tumor imaging studies. Resection of the lung tumor resulted in a decrease in gastrin levels to normal values. Plasma radioimmunoassays showed elevated gastrin, chromogranin A and normal levels of gastrin-releasing peptide, and 9 other hormones. The tumor showed similar immunocytochemical results. The characteristics of this case are compared with 100 cases of sporadic abdominal gastrinomas, and the evidence reviewed suggests why ZES should be considered in patients with lung cancer with peptic symptoms.     

Hormone-mediated watery diarrhea in a family with multiple endocrine neoplasms.

A father and son each presented with severe watery diarrhea. The son was found to have a pancreatic islet-cell tumor associated with the pancreatic cholera syndrome, as well as a parathyroid adenoma. The father was found to have multiple islet-cell adenomas and the Zollinger-Ellison syndrome. Pancreatic tumor tissue from each patient contained detectable gastrin and vasoactive intestinal peptide; however, a much higher gastrin concentration was found in the tumor tissue from the father and a much higher vasoactive intestinal peptide content in the tumor tissue from the son. Thus, watery diarrhea may be mediated by different hormones in families having multiple endocrine neoplasia; the precise cause of the diarrheal syndrome should be defined to ensure the proper therapy.     

Regression of a large malignant gastrinoma on treatment with Sandostatin LAR: a case report

Gastrinomas may occur in the pancreas, duodenum or peripancreatic lymph nodes. The gastrin overproduction leads to the Zollinger-Ellison syndrome with multiple gastric and duodenal ulcers and diarrhea. About two thirds of gastrinomas are malignant. Diagnosis is made by clinical history, gastroscopy, and measurement of serum gastrin, gastric juice pH, CT scan, endoscopic ultrasonography and somatostatin receptor scintigraphy. Surgery should always be considered if the liver is not involved. Proton pump inhibitors offer symptomatic relief. Medical therapy for tumor control includes biotherapy with alpha-interferon and somatostatin analogs yielding a response rate of about 10-15%, chemotherapy or targeted radiotherapy. We describe a patient with almost complete response on treatment with Sandostatin LAR, a long-acting somatostatin analog. In patients with metastatic gastrinomas not suitable for chemotherapy, interferon or targeted radiotherapy, single therapy with somatostatin analogs may be an alternative.