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.     

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.     

Surgical treatment and prognosis of gastrinoma

Zollinger-Ellison syndrome (ZES) is a clinical syndrome with severe peptic ulcer disease and diarrhea caused by gastric acid hypersecretion secondary to a neuroendocrine tumour that secretes excessive amounts of the hormone gastrin (gastrinoma). Gastrinomas occur in a familial and a sporadic form. Patients with gastrinoma in the familial setting of Multiple Endocrine Neoplasia type 1 (MEN-1) are seldom, if ever, cured of Zollinger-Ellison syndrome by the current non-Whipple operations to remove duodenal and pancreatic gastrinoma. Surgery is currently used in these patients to deal with the malignant nature of pancreatic or duodenal neuroendocrine tumours. Malignant potential is best determined by tumour size. Tumours that are greater than 2 cm in size should be excised. In the sporadic setting, cure occurs in a significant proportion of patients (50%) by surgical resection of gastrinoma. Duodenotomy has improved both the tumour detection rate and the cure rate and should be routinely done. Whipple pancreaticoduodenectomy results in the highest probability of cure in both sporadic and MEN-1 gastrinoma patients as it removes the entire gastrinoma triangle. However, the excellent long-term survival of these patients with lesser operations and the increased operative mortality and long-term morbidity of Whipple make its current role unclear until further studies are done.     

Duodenal gastrinoma—clinical features and usefulness of selective arterial secretin injection test

Duodenal gastrinoma is recognized as a relatively common cause of Zollinger-Ellison syndrome, but its clinical and biological features are not well known. Here we report a case of duodenal gastrinoma with lymph node metastasis which was confirmed by pathology examinations. Hypergastrinemia and gastric acid hypersecretion were documented, but the secretin test showed negative results. An enlarged peripancreatic lymph node lying close to the pancreas head was the only positive finding on preoperative imaging studies. The results of the selective arterial secretin injection (SASI) test suggested that the primary tumor was located in the gastrinoma triangle. Finally, surgical exploration was carried out and a submucosal tumor, approximately 15mm in size, was detected by intraoperative palpation at the posterior wall of the proximal portion of the duodenum. Intraoperative pathology examination demonstrated metastases to regional lymph nodes. The present case calls attention to the unique features of duodenal gastrinomas, which differ from those of pancreatic origin: a highly malignant potential for its small size, and submucosal location in the proximal duodenum. The SASI test is recommended for assessing the location of a primary lesion if it cannot be identified by various conventional imaging studies. (Received Dec. 17, 1997; accepted Jan. 23, 1998)     

The role of surgery in the management of islet cell tumors

Endocrine tumors of the pancreas are rare disorders that can cause life-threatening symptoms related to the excessive hormonal secretion and the malignant nature of the neoplasm. In addition, these neoplasms can present as part of familial endocrinopathy syndromes, especially multiple endocrine neoplasia type 1 (MEN-1). The initial step in evaluation of a patient with an islet cell tumor is definitive diagnosis of the hormonal syndrome that usually can be achieved biochemically. The next step is to reverse the life-threatening hormonal syndrome medically to allow radiographic localization of the islet cell neoplasm and to prepare the patient for elective surgery. In general, the goal of surgery is to accurately stage the extent of disease and to totally resect the tumor resulting in complete correction of the excessive hormonal condition and freedom from malignant progression of the tumor. Resection of the neoplasm should encompass metastatic disease in select individuals in whom complete or nearly complete resection can be achieved. Surgery must be performed with acceptable morbidity and mortality because the medical management of the excessive hormonal secretion in most patients is adequate and the progression rate of malignant islet cell carcinomas is usually slow. Patients with MEN-1 should be identified during evaluation by careful history and should be managed differently. These patients always have multiple islet cell tumors and may have malignant islet cell carcinomas. Large (3 cm) imageable pancreatic neoplasms in patients with MEN-1 should be resected because nearly 50 per cent are malignant. Zollinger-Ellison syndrome in patients with MEN-1 and primary hyperparathyroidism is best managed initially by surgery directed at the hyperparathyroidism. It may be impossible to correct the biochemical abnormalities of Zollinger-Ellison syndrome by islet cell tumor resection in patients with MEN-1. However, insulinoma or VIPoma syndromes can often be corrected by islet cell tumor resection. Portal venous sampling for hormones may be helpful in determining what hormone a specific tumor is secreting.     

Gastrinomas associated with MEN-1 syndrome: new insights for the diagnosis and management in a series of 11 patients

BACKGROUND/AIMS: Approximately, 25-30% of patients (pts) have gastrinomas, (Zollinger-Ellison syndrome, ZES), as part of the inherited syndrome, multiple endocrine neoplasia 1 (MEN-1). The identification of MEN-1 syndrome in these pts is always important, as there are some differences in their management and prognosis. Among 33 pts with ZES, we present in this study 11 pts with ZES and MEN-1 syndrome, describing our diagnostic and therapeutic approach. METHODOLOGY: Eleven pts with ZES and MEN-1 syndrome (6 females and 5 males) were included (mean age 51.8 years). The diagnosis of ZES was based upon: a) clinical features and b) high serum gastrin levels, while in 7/11 pts diagnosis was confirmed histopathologically. A variety of other gastrointestinal peptides, as well as the general neuroendocrine tumor marker, Chromogranin-A (CgA) were also estimated. All pts underwent conventional imaging methods (CT, MRI) and OCTREOSCAN or EUS when necessary, in order to localize the primary lesion or the metastases. The diagnosis of MEN-1 was based upon the presence of the other two MEN-1 related endocrinopathies (hyperparathyroidism, pituitary adenomas), revealed by estimation of several hormones (PTH, Prolactin, ACTH etc.) and performance of imaging studies of the pituitary and parathyroid glands. When MEN-1 syndrome was established, a familiar screening of pts was also performed, when possible. The mean duration of pts' follow-up was 6.1 years (range: 2.1-8.5 years). RESULTS: At the time of presentation, 91% pts, had symptoms of peptic ulcer disease, refractory to treatment, while a history of colicky abdominal pain due to nephrolithiasis was also reported by 45% pts. Four of our pts had a blood relation. Serum gastrin levels at the time of diagnosis were greater than 1000pg/mL in 63.5% pts, while at the same time serum CgA levels were greater than 10 times the upper normal limit (<98ng/mL) in all pts. OCTREOSCAN and EUS revealed the primary tumor (in duodenum or pancreas) in 64% pts, in whom conventional methods showed no abnormalities at the same time. Parathyroid adenomas, pituitary adenomas and bronchial carcinoids were revealed in 11, 3 and 1 pts respectively, which were treated surgically. Also, surgical treatment of pancreatic or duodenal gastrinomas was performed in 54.5% pts, while pts who already had metastases (45%), or developed them during the follow-up period (18%), were treated by somatostatin analogues (63.6%) and chemotherapy (27.3%). Ten out of 11 pts are alive and in a good condition, whereas 1 patient died 2.8 years after diagnosis. Familiar screening revealed parathyroid adenomas in 4 children of our pts, which were treated surgically. CONCLUSIONS: MEN-1 syndrome should always be considered in pts with ZES. A precise preoperative localization of all pancreaticoduodenal lesions, in combination with a surgical exploration and management by experienced surgeons, seems to be curative in pts without distal metastases. Non-surgical treatment with somatostatin analogues and chemotherapy in pts with progressive disease seem to stabilize the disease, although further studies are needed. A close clinical and biochemical follow-up of all pts, as well as their family members, is necessary in order to reveal and treat all MEN-1 related endocrinopathies and especially PETs, in an early stage.     

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.     

Ovarian mucinous cystadenocarcinoma as a cause of Zollinger-Ellison syndrome: report of a case and review of the literature

Gastrin producing ovarian tumor is a rare cause of the Zollinger-Ellison syndrome. We report the case of an ovarian carcinoma showing increased plasma gastrin concentration. A 60-yr-old woman presented with epigastric pain and diarrhea. Physical examination showed a large mass in the lower abdomen. Computed tomography revealed a large multilocular ovarian cyst. Upper gastrointestinal endoscopy examination showed multiple ulcerations of the stomach and duodenum. The plasma gastrin level was 1500 pg/ml. No tumors were found in the pancreas and duodenum, and salpingo-oophorectomy was performed. Histologic examination revealed a mucinous tumor of borderline malignant potential. Immunoperoxidase studies for gastrin showed many gastrin-producing cells within the epithelium of the tumor. There have been 11 cases (including our patient) of gastrin-producing ovarian tumor reported in the literature. We review here the relevant literature. Although ovarian gastrinoma is extremely rare, it should be considered as a possible cause of the Zollinger-Ellison syndrome in women.     

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.     

Canine Zollinger-Ellison syndrome.

The unusual finding of peptic esophagitis and duodenal ulceration in a dog was associated with a malignant pancreatic islet cell tumor producing gastrin and ACTH. The finding of a gastrinoma in a non-human species introduces the potential for developing an animal model for the study of the protean genetic biochemical, physiologic and metabolic aspects of the Zollinger-Ellison syndrome.     

Case of primary hepatic gastrinoma: Diagnostic usefulness of the selective arterial calcium injection test

Gastrinomas mainly occur in the duodenum and pancreas. Primary hepatic gastrinoma is rare and difficult to diagnose because the liver is a frequent site of metastatic gastrinomas. Clinical factors were assessed in a 28‐year‐old man with diarrhea and heartburn who was hospitalized for recurrent duodenal ulcers. Abdominal ultrasound, endoscopic ultrasound and computed tomography (CT) could not detect a tumor in the duodenum or pancreas. His gastrin level was 846 pg/mL and magnetic resonance imaging showed a mass 12 mm in diameter in the right robe of the liver. A selective intra‐arterial calcium injection (SACI) test and 68‐gallium edotreotide positron emission tomography CT (Ga‐DOTATOC PET‐CT) were therefore performed. Calcium gluconate injection into the proper hepatic artery resulted in a marked increase in serum gastrin concentration in the right hepatic vein, with Ga‐DOTATOC PET‐CT showing uptake only by the liver mass. Following a diagnosis of primary hepatic gastrinoma, the tumor was resected. A histopathological examination indicated gastrinoma. Six months postoperatively, he has no symptoms, is not taking proton‐pump inhibitors and his gastrin level remains within the normal range. The SACI test and the clinical course of this patient strongly suggest that the tumor was a primary hepatic gastrinoma. The SACI test is helpful in the diagnosis of primary hepatic gastrinoma.     

A nongastrin malignant ampullary tumor causing gastric acid and pepsin hypersecretion. A case report

We report a case of multiple duodenal ulcers with gastric hypersecretion due to a nongastrin secretagogue produced by a malignant tumor of the pancreas in a 78-year-old man. The case resembled a Zollinger-Ellison syndrome (ZES) with high acid output (basal acid output 27, sham meal-stimulated 37, maximum acid output 47 mEq/h), but with fasting gastrin 43 pg/ml, nonresponsive to secretin. As in ZES, pepsin output was comparatively low, and secretion was inhibitable by atropine (50% inhibited by 1 microM). The tumor removed at surgery contained less than 1 ng gastrin per gram, but was many times more potent than pentagastrin in stimulating acid from a lumen-perfused rat stomach. The tumor also contained cholecystokinin (CCK-8 and CCK-33), motilin, insulin, and somatostatin, which were also present in adjacent normal pancreas; in addition, the tumor contained pancreatic polypeptide and pancreatic cancer-associated antigen. This case represents a rare syndrome due to an as yet undefined peptide secreted by a (frequently malignant) pancreatic endocrine tumor and masquerading as ZES. This is the first report of studies of pepsin secretion and of the effect of atropine, suggesting that the physiologic effects of the secretagogue resemble that of gastrin.     

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…     

Hemobilia due to biliary intraepithelial neoplasia associated with Zollinger–Ellison syndrome

A 58-year-old man was transferred to us from his local hospital because of failure to control his gastrointestinal bleeding by endoscopic hemostasis. Abdominal imaging suggested a hypervascular tumor of the pancreatic head (36?mm diameter), and laboratory testing showed an elevated serum gastrin level (17,800?pg/mL). Gastroduodenal endoscopy revealed multiple duodenal ulcers and active bleeding from the ampulla of Vater. The selective arterial secretagogue injection test suggested a gastrinoma in the pancreatic head, but no gastrinoma in the pancreatic tail. The patient was diagnosed with solitary pancreatic head gastrinoma complicated by hemosuccus pancreaticus, and pancreaticoduodenectomy was performed. Intraoperatively, the diagnosis was changed to primary peripancreatic lymph node gastrinoma without pancreatic involvement. The gastrointestinal bleeding stopped postoperatively and serum gastrin levels returned to normal. Histological examination of the surgical specimens revealed a small submucosal gastrinoma in the duodenum (7?mm diameter). The final diagnosis was microgastrinoma of the duodenum with peripancreatic lymph node metastasis. The cause of bleeding from the ampulla of Vater was initially obscure, but eventually a hemorrhagic erosion with moderate atypia was found in the common bile duct, indicating biliary intraepithelial neoplasia (BilIN). This is the first report of hemobilia due to BilIN with gastrinoma.     

Zollinger-Ellison syndrome. Cure by surgical resection of a jejunal gastrinoma containing growth hormone releasing factor

Zollinger-Ellison syndrome developed in a 46-yr-old woman due to a gastrinoma originating in the proximal jejunum. Resection of the tumor and adjacent lymph nodes containing metastatic carcinoma resulted in prompt reversal of all clinical and biochemical abnormalities, and she remains well 42 mo after surgery. To our knowledge, this patient is one of the first well-documented cases of primary jejunal gastrinoma causing the Zollinger-Ellison syndrome. The tumor contained numerous cells positive for gastrin and smaller numbers positive for serotonin, somatostatin, or bovine pancreatic polypeptide, as diagnosed by immunohistochemistry. In addition, a small subset of tumor cells was positive for growth hormone releasing factor. Our case is the first to document the presence of this neuropeptide in an enteric gastrinoma.     

Gastric secretion and hormonal interactions in multiple endocrine neoplasia type I

Results of preparathyroidectomy and postparathyroidectomy studies in a patient with multiple endocrine neoplasia type I and gastrinoma suggest that hyperparathyroidism unmasks occult gastrinoma and related secretory abnormalities. Three of four diagnostic findings were later obscured by parathyroidectomy and normalization of serum calcium concentration. Basal acid output, basal acid output/maximal acid output ratio, and serum gastrin concentration were decreased from values consistent with gastrinoma to normal. The secretin stimulation test, though still positive, was attenuated. These observations suggest that in multiple endocrine neoplasia type I, normal values for serum gastrin concentration, gastric secretion, and secretin stimulation may not exclude gastrinoma. The investigations clarify the interpretation of a voluminous but confusing literature on the interrelationship between hyperparathyroidism and altered gastric function in the presence or absence of Zollinger-Ellison syndrome.     

Selective intraarterial methylene blue for pancreatic and duodenal endocrine tumors

Pancreatic and duodenal endocrine tumors can be difficult to localize intraoperatively. Three patients are described in whom selective intraarterial injection of methylene blue was used to correctly identify the position of an endocrine tumor. These patients had a duodenal gastrinoma, a pancreatic polypeptide-producing pancreatic islet cell tumor, and a duodenal somatostatinoma, respectively. Selective arterial secretin injection with hepatic vein gastrin measurement and selective arterial calcium injection with hepatic vein pancreatic polypeptide measurement were used to preoperatively identify the feeding artery. The duodenal somatostatinoma was identified by endoscopy. A catheter placed in the feeding artery just prior to surgery was used for injection of the methylene blue. The combination of selective arterial stimulation and selective arterial methylene blue injection is a promising method for helping surgeons localize elusive endocrine tumors in the duodenum and pancreas.     

Multiple carcinoids in the duodenum, pancreas and stomach accompanied with type A gastritis： A case report

We report a case of multiple duodenal, pancreatic, and gastric carcinoids. A 67-year old woman was admitted to our hospital for treatment of a duodenal carcinoid. Laboratory tests revealed that the patient was associated with macrocytic anemia and hypergastrinemia, and type A gastritis was shown by gastrofiberscopy. During surgery, another tumor was incidentally found in the head of the pancreas. The tumors in the duodenum and pancreas were completely excised by pancreatoduodenectomy and immunohistologically diagnosed as gastrin-and serotonin-producing carcinoids, respectively. Pathological examination revealed that in addition to the grossly found carcinoids, there were subclinical carcinoids, one of which was an endocrine cell micronest, located in the stomach and duodenum. The tumors in the duodenum, pancreas, and stomach showed different characteristics from one another morphologically and immunochemically. Although no definitive evidence has been obtained, some sort of genetic anomaly may have been involved in this case, and hypergastrinemia due to duodenal gastrinoma may induce multiple gastric carcinoids.     

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.     

Comparison of the functional and morphological changes in the pancreatic remnant between pylorus-preserving pancreatoduodenectomy and pancreatoduodenectomy

BACKGROUND/AIMS: Pylorus-preserving pancreatoduodenectomy preserves the secretion of gastrointestinal hormones from the distal stomach and duodenum, whereas after pancreatoduodenectomy they are no longer secreted. It has been suggested that some gastrointestinal hormones exert a trophic effect on the pancreas, although this effect has not been documented in man. It was postulated that the ablation of gastrointestinal hormones, such as gastrin by pancreatoduodenectomy is an important cause of postoperative pancreatic atrophy and, since pylorus-preserving pancreatoduodenectomy preserves the secretion of these hormones, it would be more effective than pancreatoduodenectomy for the maintenance of postoperative pancreatic function. METHODOLOGY: We measured postoperative pancreatic function, parenchymal thickness of pancreas and the release of gastrin in patients who underwent pancreatoduodenectomy or pylorus-preserving pancreatoduodenectomy who had survived > 1 year without tumor recurrence. RESULTS: After pylorus-preserving pancreatoduodenectomy, exocrine pancreatic function, parenchymal thickness of pancreas and gastrin release were significantly greater than after pancreatoduodenectomy. CONCLUSIONS: We concluded that postoperative atrophy of the distal pancreas after pancreatoduodenectomy occurs, in part because of resections of the duodenum and distal stomach, which is the source of trophic stimuli, gastrin.