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.     

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.     

Multiple giant duodenal ulcers associated with duodenal gastrinoma

A 59-year-old Japanese man with a history of chronic hepatitis C and cirrhosis was admitted to hospital because of severe abdominal pain and diarrhea. His discomfort had begun 2 months earlier and was localized to the upper abdomen. Upper gastrointestinal endoscopy showed multiple ulcerative lesions from the duodenal bulb to the descending part of the duodenum, one of which was a giant ulcer that filled half of the intestinal lumen. Despite continuous intravenous lansoprazole therapy, his abdominal symptoms did not improve. Upper gastrointestinal endoscopy was again performed to detect the tumor, but it was difficult to observe the tumor with a conventional endoscope. We then inverted a transnasal endoscope into the duodenum, and this enabled us to detect a 15-mm submucosal tumor in the upper wall of the duodenal bulb. Examination of specimens from endoscopic ultrasonography fine-needle aspiration biopsy of the tumor revealed gastrinoma in the duodenal bulb. We decided to perform an operative resection. The patient’s symptoms resolved after surgery, and he remained asymptomatic at follow-up 18 months later. Therefore, when it is difficult to detect the tumor directly by conventional endoscopy, we recommend that attempts be made to detect the tumor by inverting a transnasal endoscope into the duodenal bulb.     

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.     

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.     

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.     

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)     

Endoscopic Diagnosis and Removal of a Duodenal Wall Gastrinoma

A 54-year-old man presented with unrelenting abdominal pain. An upper gastrointestinal x-ray showed a gastric ulcer. The duodenum showed minimal cap deformity suggestive of antecedent ulcer disease. The upper small intestine was within normal limits. Gastroduodenoscopy revealed a duodenal polyp. Biopsy of the polyp identified the presence of a gastrinoma. Serum gastrin level before endoscopic polypectomy was 489 pg/ml. Endoscopic polypectomy was performed and electron micrographs of the tissue revealed endosecretory granules of the gastrinoma. Complete removal of the gastrinoma was suggested by comparative gastric analyses, by serum gastrin levels of 93, 180, and 167 pg/ml, and by the clinical course.     

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.     

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.     

Progastrin and its glycine-extended posttranslational processing intermediates in human gastrointestinal tissues

We examined the posttranslational modification of gastrin in human gastrointestinal and Zollinger-Ellison tumor tissues using antibodies specific for progastrin and its glycine-extended processing intermediates. Gel filtration of antral and duodenal extracts on Sephadex G-50 revealed multiple molecular forms of immunoreactive glycine-extended processing intermediates corresponding to known molecular forms of gastrin and cholecystokinin. Immunoaffinity chromatography studies of antral mucosal and gastrinoma extracts identified a molecular form of glycine-extended processing intermediates that was characterized by an amino terminus identical to that of gastrin heptadecapeptide. Large differences in the relative contents of precursors and products of gastrin synthesis were found in gastrinoma tissue as compared to gastrointestinal mucosal extracts. These studies suggest the potential importance of glycine-extended peptides as intermediates in the posttranslational processing of gastrin and cholecystokinin in humans and indicate that gastrin processing mechanisms may be altered in Zollinger-Ellison tumors.     

Primary duodenal MALT lymphoma

Primary duodenal MALT lymphoma (MALToma) is a very rare neoplasm arising from the mucosa-associated lymphoid tissue of the duodenum. We report a 55-year-old woman with MALToma located in the descending duodenum and accompanying Helicobacter pylori infection of the stomach. We performed operative resection due to involvement of the papilla of Vater and submucosal tumor infiltration. Despite wide mucosal spreading, postoperative examination revealed only a small amount of MALToma cells infiltrating into the submucosa. No invasion into the adjacent structure or metastasis to regional lymph nodes was confirmed, suggesting the disease could have been controlled by eradication of Helicobacter pylori.     

Multiple somatostatin- and gastrin-containing carcinoids of the duodenum: report of a case treated by pancreas-sparing duodenectomy

A 59-year-old Japanese man was incidentally discovered to have multiple polyps in the duodenum by endoscopy during a health checkup. Laboratory studies showed an elevated level of serum somatostatin. The mutation of the MEN1 gene was not observed. An endoscopic examination revealed multiple polypoid lesions in the bulbus and in the second portion of the duodenum. An upper gastrointestinal series also showed the multiple polypoid lesions in the bulbus, and in the descending and horizontal portions of the duodenum. The biopsy specimen showed small monotonous cells with round nuclei compatible with a carcinoid tumor. The tumor cells were positive for somatostatin and gastrin. Based on the clinical diagnosis of multiple carcinoids of the duodenum, a pancreas-sparing duodenectomy was performed. Macroscopic findings showed about 30 polypoid lesions throughout the duodenum. The biggest one was not over 10 mm in size. A histological examination revealed well-demarcated carcinoid tumors located in the submucosal layer. Immunohistochemically, the tumors were diffusely positive for somatostatin and were scatteringly positive for gastrin. The patient's postoperative course of treatment was uneventful and his postoperative serum somatostatin went down to normal range. The pancreas-sparing duodenectomy is a safe and effective treatment in patients with multiple carcinoids of the duodenum, that are smaller than 1 cm in size.     

Secretin provocation in normal and duodenal ulcer subjects

The secretin provocation test for gastrinoma is based on the premise that secretin decreases or has no effect on serum gastrin in normal and duodenal ulcer subjects while inducing a paradoxical rise in gastrinoma. We reexamined the serum gastrin response to pharmacologic amounts of secretin in normal volunteers (N = 17) and unoperated duodenal ulcer patients (N = 10). GIH secretin caused significant early gastrin rises from baseline in both groups (P less than 0.05). The gastrin response curves after secretin were not significantly different between normal and ulcer subjects. Similar gastrin rises were seen when synthetic secretin was administered to normal subjects (N = 6). In normal volunteers, intravenous bolus saline (N = 10) or amino acid (L-cysteine, N = 8) caused no change in serum gastrin from baseline. The gastrin response curves to GIH secretin and saline were significantly different (P less than 0.05). Our findings suggest that the gastrin rise in gastrinoma patients after secretin is an exaggeration of the normal response and not paradoxical.     

Endoscopic ultrasonography in patients with gastrinomas

Placing the endoscopic ultrasound transducer in the descending duodenum, the duodenal bulb and the stomach, all the pancreas can be imaged. Endoscopic ultrasonography is a sophisticated imaging technique able to accurately diagnose and localize primary endocrine tumours of the pancreas (mostly insulinoma and gastrinoma) which may not be detectable with other imaging modalities. Furthermore, endoscopic ultrasonography-guided fine needle aspiration allows cytology and/or biopsy specimens to be obtained, that are crucial for clinicians in decision making. In the case of extrapancreatic endocrine tumours, which are often localized in the second and third part of the duodenum, endoscopic ultrasonography may have difficulty in localizing small and flat lesions. In this case, the initial step would be identification of duodenal nodules by duodenoscopy and thereafter, a catheter echoprobe can be inserted to identify the extent of submucosal lesion. Then gastroduodenal nodules found by endoscopy and confirmed by endoscopic ultrasonography can be removed endoscopically using the technique of mucosectomy. In the case of large pancreatic lesions, endoscopic tattoo with dye-India ink or methylene blue may become helpful for the surgeon to perform local resection via duodenostomy.     

Primary peripancreatic lymph node gastrinoma in a woman with MEN1

A 39-year-old woman was admitted to hospital due to perforated relapsing duodenal ulcer. Clinical, laboratory, and surgical examinations revealed a peripancreatic lymph node gastrinoma as the cause of Zollinger-Ellison syndrome. Further examinations established multiple endocrine neoplasia type 1 (MEN1) with a germline mutation at codon 1153 (T->A) in exon 7, causing an amino-acid change, from isoleucine to asparagine (Ile348Asn), in the MEN1 gene. The following findings strongly supported a diagnosis of primary lymph node gastrinoma: a rapid fall of the serum gastrin level after operation, the continuous normalization of the serum gastrin level before and after secretin stimulation, the lack of any symptoms, and the absence of another tumor for 13 years after surgical resection of the tumor-bearing lymph node. A review of similar cases in the world literature reveals that not all gastrinomas in lymph nodes are the result of metastastic spread. A long-term symptom-free follow-up after the excision of a lymphnode gastrinoma is the only reliable criterion for the diagnosis of a primary lymph node tumor. To our knowledge, this is the only well-documented case of a primary lymph node gastrinoma in a patient with MEN1. Our case supports the idea that any gastrinoma in patients with MEN1 should be surgically resected for cure if possible.     

Primary lymph node gastrinoma in jejunal mesentery.

Primary gastrinomas have been reported in lymph nodes within the gastrinoma triangle. We report a 56-year-old woman with possible primary lymph node gastrinoma in the jejunal mesentery. Six months after excision of the tumor, she is asymptomatic and serum gastrin level is normal.     

Heterotopic pancreas in the stomach which caused obstructive stenosis in the duodenum

The patient, a 43-year-old Japanese man suffering from duodenal ulcer and reflux esophagitis, was admitted to our hospital because of submucosal tumor in the antrum and obstructive stenosis of duodenum. Several imaging tests could not rule out the possibility of malignant disease. Therefore, the patient was surgically treated. Pathohistological examination of resected tissue demonstrated Heinrich type I heterotopic pancreas in the gastric lesion and submucosal abscess in the duodenal lesion with stenosis. In this case, it was considered that the heterotopic pancreas caused chronic inflammation to form the gastric tumor, and submucosal abscess leading to the severe duodenal stenosis.     

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 gastrointestinal stromal tumor of the duodenum with a huge abscess

A 36-year-old man admitted for upper abdominal pain and fever. Enhanced abdominal computed tomography showed a cystic tumor with an air fluid level, measuring 140mm in size, along the side of the first and second portions of the duodenum. The common bile duct, portal vein, and proper hepatic artery were displaced by the tumor. Upper gastrointestinal endoscopy showed duodenal ulcer, but fistula was not confirmed. Combining all imaging and clinical findings, it was clinically diagnosed as duodenal submucosal tumor with abscess, and elective surgery was performed. There was a huge mass in the Morrison pouch, with severe adhesion to the second portion of the duodenum, gall bladder, common bile duct, and transverse colon. Subtotal stomach-preserving pancreaticoduodenectomy with transverse colectomy was performed. A fistula from the second portion of the duodenum to the tumor was confirmed on the resected specimen. Histological examination showed gastrointestinal stromal tumor originating in the duodenum.