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Background: Studies to identify preoperative prognostic variables for pancreatic neuroendocrine tumor (PNET) have been inconclusive. Specifically, the prevalence and prognostic significance of radiographic calcifications in these tumors remains unclear., Methods: From 1998 to 2009, a total of 110 patients with well-differentiated PNET underwent surgical resection at our institution. Synchronous liver metastases present in 31 patients (28%) were addressed surgically with curative intent. Patients with high-grade PNET were excluded. The presence of calcifications in the primary tumor on preoperative computed tomography was recorded and correlated with clinicopathologic variables and overall survival., Results: Calcifications were present in 16% of patients and were more common in gastrinomas and glucagonomas (50%), but never encountered in insulinomas. Calcified tumors were larger (median size 4.5 vs. 2.3 cm, P=0.04) and more commonly associated with lymph node metastasis (75 vs. 35%, P=0.01), synchronous liver metastasis (62 vs. 21%, P<0.01), and intermediate tumor grade (80 vs. 31%, P<0.01). On multivariate analysis of factors available preoperatively, calcifications (P=0.01) and size (P<0.01) remained independent predictors of lymph node metastasis. Overall survival after resection was significantly worse in the presence of synchronous liver metastasis (5-year, 64 vs. 86%, P=0.04), but not in the presence of radiographic calcifications., Conclusions: Calcifications on preoperative computed tomography correlate with intermediate grade and lymph node metastasis in well-differentiated PNET. This information is available preoperatively and supports the routine dissection of regional lymph nodes through formal pancreatectomy rather than enucleation in calcified PNET.

Helicobacter pylori (HP) has been associated with neuroendocrine tumors of the stomach and duodenum. Gastric enterochromaffin-like (ECL) cell tumors and duodenal gastrinomas have also been associated with HP gastritis in separate series but have not been reported together. With other possible causes excluded, we present a patient with HP-associated atrophy of the oxyntic mucosa that ultimately resulted in stimulation and reactive hyperplasia of gastrin-producing cells in both the antrum and proximal duodenum, the latter progressing to formation of a gastrin-producing cell nodule (gastrinoma). Both of these sources of gastrin resulted in ECL hyperplasia in the atrophied oxyntic mucosa with progression to microcarcinoids and well-differentiated neuroendocrine tumors, along with hypertrophy of residual proximal gastric parietal cells. As atrophy tends to spread from the antrum proximally, residual oxyntic mucosa was still infected with HP and offers 1 explanation for the apparent paradox of atrophic gastritis with ECL hyperplasia and neoplasia in the distal oxyntic mucosa, with proximal oxyntic mucosa showing mild hypertrophic changes in a background of typical HP gastritis.

Background: Because of the rarity and variety of pancreatic neuroendocrine tumors (PNETs), there have been few reports regarding the indication for lymph node dissection in patients with these tumors. This study aimed to evaluate the risk of lymph node metastasis of PNETs based on the tumor size and hormonal production., Methods: Data for a total of 66 patients who had PNETs resected at our department between 1987 and 2010 were retrospectively studied. The clinicopathological features, including the disease-specific survival rate, were assessed based on the status of lymph node metastasis at the time of initial surgical resection. Then the cut-off point of tumor size to predict lymph node metastasis was estimated., Results: There were 12 patients (18%) with lymph node metastasis. The frequency of lymph node metastasis tended to be higher in gastrinomas than that in other tumors (43 vs. 15%; P = 0.08). The size of PNETs with lymph node metastasis was significantly larger than that of the PNETs without metastasis (P = 0.04). The postoperative survival rate in the PNET patients with lymph node metastasis was significantly lower than that in the patients without metastasis (P < 0.0001). Only 2 (8%) of 26 PNETs with a tumor size of <15 mm had lymph node metastasis, and both of these were gastrinomas. On the other hand, 10 (25%) of the remaining 40 PNETs with a tumor size of ≥15 mm had lymph node metastasis. Notably, there were no PNETs with lymph node metastasis in 22 non-gastrinomas with a tumor size of <15 mm., Conclusions: Non-gastrinomas with a tumor size of ≥15 mm and all gastrinomas would be an indication for pancreatectomy with lymph node dissection.

Background: Gastrin measurements are performed primarily for the diagnosis of gastrin-producing tumors, gastrinomas, which cause the Zollinger-Ellison syndrome (ZES). Gastrin circulates as several bioactive peptides, however, and the peptide pattern in gastrinoma patients often deviates from normal. Therefore, it is necessary to measure all forms of gastrin., Content: Only immunoassays are useful for measurement of gastrin in plasma. The original assays were RIAs developed in research laboratories that used antibodies directed against the C terminus of gastrin peptides. Because the C-terminal tetrapeptide amide sequence constitutes the active site of gastrin peptides, these assays were well suited for gastrinoma diagnosis. More recently, however, most clinical chemistry laboratories have switched to commercial kits. Because of recent cases of kit-measured normogastrinemia in patients with ZES symptoms, the diagnostic sensitivity and analytical specificity of the available kits have been examined. The results show that gastrin kits frequently measure falsely low concentrations because they measure only a single gastrin form. Falsely high concentrations were also encountered, owing to overreactivity with O-sulfated gastrins or plasma proteins. Thus, more than half of the gastrin kits on the market are unsuited for diagnostics., Summary: Gastrinomas are neuroendocrine tumors, some of which become malignant. A delay in diagnosis leads to fulminant ZES, with major, even lethal, complications. Consequently, it is necessary that the diagnostic sensitivity of gastrin kits be adequate. This diagnostic sensitivity requires antibodies that bind the C-terminal epitope of bioactive gastrins without the influence of O-sulfation.

Background: Surgery prolongs survival in patients with gastrinomas, but postoperative recurrences are frequent and controversies still exist about the optimal surgical procedures., Aim: The aim of this study is to analyze biological and morphological recurrences and to search for risk factors., Patients and Methods: Between 1990 and 2008, 22 patients (five with multiple endocrine neoplasia type 1) who underwent curative resection for gastrinoma were evaluated every 6 months for biological and morphological recurrences. All patients were disease-free postresection., Results: The median postoperative follow-up was 37 months (range, 7-204 months). A biological recurrence was observed in 59% of cases, after a median time of 16.5 months (range, 7-90 months). A morphological recurrence was reported in 32% of cases, in the liver (86%) or lymph nodes (43%), after a median time of 21 months (range, 8-91 months). The median delay between biological and morphological recurrence was 3 months (range, 0-69 months). At recurrence, all patients were offered a second treatment (surgical resection in 71% of cases). One and 5 year overall survival were 100 and 76%, respectively. One and 5 year biological disease-free survival (DFS) were 76 and 27%, respectively. One and 5 year morphological DFS were 90 and 62%, respectively. Tumor size of at least 20 mm (P=0.008) and pancreatic location (P=0.04) of the primary tumor had significant effect on morphological DFS. Overall survival was significantly lower in patients with primary tumor of at least 20 mm (P=0.01)., Conclusion: (a) Recurrence occurs in nearly two out of three patients operated upon for gastrinoma, most often detected through biological tests; (b) lymph nodes and liver are the most frequent sites of relapse and patients benefit from second treatment; (c) risk factors for recurrences are as follows: size of at least 20 mm; and the pancreatic location of the primary tumor.

Background and Aims: The purpose of this prospective study was to demonstrate the ability to measure pancreatic tumor tissue blood flow (TBF) with a noninvasive method using xenon inhalation computed tomography (xenon-CT) and to correlate TBF with histological features, particularly microvascular density (MVD)., Methods: TBFs of pancreatic tumors in 14 consecutive patients were measured by means of xenon-CT at diagnosis and following therapy. Serial abdominal CT scans were obtained before and after inhalation of nonradioactive xenon gas. TBF was calculated using the Fick principle. Furthermore, intratumoral microvessels were stained with anti-CD34 monoclonal antibodies before being quantified by light microscopy (×200). We evaluated MVD based on CD34 expression and correlated it with TBF., Results: The quantitative TBF of pancreatic tumors measured by xenon CT ranged from 22.3 to 111.4 ml/min/100 g (mean ± SD, 59.6 ± 43.9 ml/min/100 g). High correlation (r = 0.885, P < 0.001) was observed between TBF and intratumoral MVD., Conclusion: Xenon-CT is feasible in patients with pancreatic tumors and is able to accurately estimate MVD noninvasively.

Purpose: The American Joint Committee on Cancer (AJCC) staging manual (seventh edition) has introduced its first TNM staging classification for pancreatic neuroendocrine tumors (NETs) derived from the staging algorithm for exocrine pancreatic adenocarcinomas. This classification has not yet been validated., Methods: Patients with pancreatic NETs treated at the H. Lee Moffitt Cancer Center between 1999 and 2010 were assigned a stage (I to IV) based on the new AJCC classification. Kaplan-Meier analyses for overall survival (OS) were performed based on age, race, histologic grade, incidental diagnosis, and TNM staging (European Neuroendocrine Tumors Society [ENETS] v AJCC) using log-rank tests. Survival time was measured from time of initial diagnosis to date of last contact or date of death. Multivariate modeling was performed using Cox proportional hazards regression. Weighted Cohen's κ coefficient was computed to evaluate the agreement of ENETS and AJCC classifications., Results: We identified 425 patients with pancreatic NETs. On the basis of histopathologic grade, 5-year survival rates for low-, intermediate-, and high-grade tumors were 75%, 62%, and 7%, respectively (P < .001). When using the ENETS classification, 5-year OS rates for stages I, II, III, and IV were 100%, 88%, 85%, and 57%, respectively (P < .001). Subsequently, using the AJCC classification, 5-year OS rates for stages I, II, III, and IV were 92%, 84%, 81%, and 57%, respectively (P < .001). Both the novel AJCC classification and the ENETS classification were highly prognostic for survival., Conclusion: The AJCC TNM classification for pancreatic NETs is prognostic for OS and can be adopted in clinical practice.

Objective: To describe the pathologic consequences of parenteral nutrition (PN) extravasation into the mediastinum of a cat., Case Summary: An 8-year-old domestic short hair cat with persistent vomiting and anorexia was initiated on PN for nutritional support. PN was being administered at a rate of 12.9 mL/h when inadvertent jugular catheter migration resulted in thrombophlebitis and cellulitis and 40-80 mL of PN extravasated into the SC and mediastinal tissues. The cat was euthanized 36 hours after the extravasation of PN due to poor prognosis related to the gastric complications associated with a presumed primary gastrinoma. Grossly there was excessive mediastinal lymphatic drainage and pronounced edema in the cervical SC and mediastinal tissue. Histopathologic examination of the PN-extravasated area revealed a severe mixed inflammatory reaction, represented by a severe neutrophilic and mild histiocytic infiltrate with lymphoplasmacytic perivascular cuffing. No bacterial agents were observed or cultured from this area., Unique Information Provided: This is the first case report of a foreign body-type reaction due to extravasation of PN (extravasation injury) in a cat. Extravasation of PN is not without pathologic consequence, and can result in a severe inflammatory reaction in affected tissues., (© Veterinary Emergency and Critical Care Society 2011.)

Gastrinoma is a rare malignant neuroendocrine neoplasia that results in autonomous gastrin secretion that stimulates hypersecretion of gastric acid, resulting in severe gastric and proximal small intestinal ulcerations. The principal clinical manifestation of gastrinoma is persistent vomiting. This report describes an uncommon manifestation of pancreatic gastrinoma in a dog.

Pancreatic neuroendocrine tumours (PNET) are rare entities with an annual incidence of < 100,000. About 1 - 2 % of pancreatic neoplasias are neuroendocrine tumours. About one third of these tumours secrete biologically active substances that lead to development of specific clinical syndromes. PNET may occur sporadically or in association with hereditary syndromes, such as multiple endocrine neoplasia type 1 (MEN1). Among the functional PNET, insulinomas and gastrinomas are the most common entities. In contrast, vasoactive intetinale peptide (VIP)-secreting tumours, glucagonomas, serotonin-secreting carcinoid tumors, and tumours with secretion of ectopic hormones, such as calcitonin, are extremely rare. Once diagnosis has been established on the basis of clinical and laboratory findings, localization of the source of pathologic hormone secretion is warranted. Imaging methods frequently used for localization of PNET comprise anatomical imaging modalities, computed tomography, and magnetic resonance imaging, endoscopic ultrasound, selective arterial catheterization with hepatic venous sampling, DTPA-octreotid scintigraphy and DOTA-D-Phe(1)-Tyr(3)-octreotid positron emission tomography. Therapy is based on the specific tumour entity and the extent of the disease. In the majority of patients, even in the case of malignant disease, a surgical approach is warranted, eventually combined with a medical treatment., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Surgery for pancreatic endocrine tumors (PETs) with blood vessel involvement is controversial., Hypothesis: Resection of PETs with major blood vessel involvement can be beneficial., Design: The combined databases of the National Institutes of Health and Stanford University hospitals were queried., Main Outcome Measures: Operation, pathologic condition, complications, and disease-free and overall survival., Results: Of 273 patients with PETs, 46 (17%) had preoperative computed tomography evidence of major vascular involvement. The mean size for the primary PET was 5.0 cm. The involved major vessel was as follows: portal vein (n = 20), superior mesenteric vein or superior mesenteric artery (n = 16), inferior vena cava (n = 4), splenic vein (n = 4), and heart (n = 2). Forty-two of 46 patients had a PET removed: 12 (27%) primary only, 30 (68%) with lymph nodes, and 18 (41%) with liver metastases. PETs were removed by either enucleation (n = 7) or resection (n = 35). Resections included distal or subtotal pancreatectomy in 23, Whipple in 10, and total in 2. Eighteen patients had concomitant liver resection: 10 wedge resection and 8 anatomic resections. Nine patients had vascular reconstruction: each had reconstruction of the superior mesenteric vein and portal vein, and 1 had concomitant reconstruction of the superior mesenteric artery. There were no deaths, but 12 patients had complications. Eighteen patients (41%) were immediately disease free, and 5 recurred with follow-up, leaving 13 (30%) disease-free long term. The 10-year overall survival was 60%. Functional tumors were associated with a better overall survival (P < .001), and liver metastases decreased overall survival (P < .001)., Conclusion: These findings suggest that surgical resection of PETs with vascular abutment/invasion and nodal or distant metastases is indicated.

A 10-year-old child with Zollinger-Ellison syndrome and primary lymph node gastrinoma is reported to emphasize the difficulties encountered in management and the value of long-term follow-up. The gastrinoma was present in a lymph node close to the greater curvature of the stomach. Primary lymph node gastrinomas are relatively rare in children and, to the best of our knowledge, have not previously been reported at this location., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Gastrinomas, a rare group of neuroendocrine tumors, are responsible for severe peptic disease and diarrhea. Although symptomatic control may be achieved with proton-pump inhibitors (PPIs) and somatostatin analogues (SSAs), data are limited regarding the possible antitumor effect of the peptide receptor radioligand therapy (PRRT) with radiolabeled SSAs in gastrinoma patients. The goal of this study was to assess the effect of PRRT on symptoms, gastrin secretion, and tumor load in patients with progressive malignant gastrinomas., Methods: We retrospectively studied 11 patients with metastatic gastrinomas followed for a mean period of 6 years. All patients were symptomatically treated with PPIs, and 9 of 11 patients received monthly injections of SSAs; all patients had an Eastern Cooperative Oncology Group score of 0-1, and received PRRT ((90) Yttrium- or (177) Lutetium-DOTATOC) for progressive disease. Serum gastrin measurements and radiological assessment (using the Response Evaluation Criteria in Solid Tumors criteria) were performed before and every 3-6 months following PRRT., Results: PRRT induced symptomatic improvement in all patients. The mean serum gastrin decreased significantly from 4831 mI/L to 932.6 mI/L (normal, 40-108 mI/L; P < .001). Periodic radiological surveillance showed complete response in 1 (9%) patient, partial tumor response in 5/11 (45%) patients, and tumor stabilization in 5/11 (45%) patients. In 7/11 (64%) patients, the antitumor effect of PRRT persisted after a median period of 14 months. Four of 11 (36%) patients died due to tumor progression (median time to progression, 11 months); in this group, the mean survival time after the last PRRT was 14 ± 6.9 months., Conclusions: PRRT seems to be a promising tool for the management of patients with inoperable or progressive metastatic gastrinomas., (Copyright © 2010 American Cancer Society.)

Aim: To search for the optimal surgery for gastrinoma and duodenopancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1., Methods: Sixteen patients with genetically confirmed multiple endocrine neoplasia type 1 (MEN 1) and Zollinger-Ellison syndrome (ZES) underwent resection of both gastrinomas and duodenopancreatic neuroendocrine tumors (NETs) between 1991 and 2009. For localization of gastrinoma, selective arterial secretagogue injection test (SASI test) with secretin or calcium solution was performed as well as somatostatin receptor scintigraphy (SRS) and other imaging methods such as computed tomography (CT) or magnetic resonance imaging (MRI). The modus of surgery for gastrinoma has been changed over time, searching for the optimal surgery: pancreaticoduodenectomy (PD) was first performed guided by localization with the SAST test, then local resection of duodenal gastrinomas with dissection of regional lymph nodes (LR), and recently pancreas-preserving total duodenectomy (PPTD) has been performed for multiple duodenal gastrinomas., Results: Among various types of preoperative localizing methods for gastrinoma, the SASI test was the most useful method. Imaging methods such as SRS or CT made it essentially impossible to differentiate functioning gastrinoma among various kinds of NETs. However, recent imaging methods including SRS or CT were useful for detecting both distant metastases and ectopic NETs; therefore they are indispensable for staging of NETs. Biochemical cure of gastrinoma was achieved in 14 of 16 patients (87.5%); that is, 100% in 3 patients who underwent PD, 100% in 6 patients who underwent LR (although in 2 patients (33.3%) second LR was performed for recurrence of duodenal gastrinoma), and 71.4% in 7 patients who underwent PPTD. Pancreatic NETs more than 1 cm in diameter were resected either by distal pancreatectomy or enucleations, and no hepatic metastases have developed postoperatively. Pathological study of the resected specimens revealed co-existence of pancreatic gastrinoma with duodenal gastrinoma in 2 of 16 patients (13%), and G cell hyperplasia and/or microgastrinoma in the duodenal Brunner's gland was revealed in all of 7 duodenal specimens after PPTD., Conclusion: Aggressive resection surgery based on accurate localization with the SASI test was useful for biochemical cure of gastrinoma in patients with MEN 1.

Zollinger-Ellison syndrome is characterized by elevated levels of serum gastrin associated with increased gastric acid secretion, gastrointestinal ulcerations and diarrhea. Most gastrinomas (75%) occur sporadically and are located within the gastrinoma triangle. Extraduodenal, extrapancreatic and extranodal gastrinomas have been shown in 5.6% of the patients with Zollinger-Ellison syndrome who underwent surgery. We report a 44-year-old female who had been complaining of nausea and diarrhea for 12 years. Abdominal computed tomography and magnetic resonance imaging detected a homogeneous, regular-shaped 6 x 7 cm solid mass, located between the liver, right kidney and inferior vena cava. Somatostatin receptor positive scanning led us to investigate a neuroendocrine tumor. Serum gastrin level was found very high and the patient underwent surgery. Local excision of the tumor was performed, and an 8x6x5 cm, well-capsulated, solitary mass, originating from the common bile duct was removed. The unique feature of our case is the unusual localization, and although the tumor was very large in size, only capsule invasion was observed with no evidence of distant metastasis.

Background: The peri-pancreatic sporadic gastrinoma represents a paradigm of digestive endocrinology. It was originally an abnormal secretion of gastrin fits the syndrome Zollinger-Ellison., Aim: The objective of our work is to clarify the diagnostic strategy and therapeutic conduct of gastrinoma., Case: We report the case of a patient aged 42 years, hospitalized for bleeding duodenal ulcer, revealed a Zollinger-Ellison syndrome. The different explorations have shown that it was a primitive péripancréatique sporadic gastrinoma. In surgery, we discover a rétropancréatique tumor associated to a stenosis post-bulbar ulcer. It was conducted a enucleation of the tumor with vagotomie troncular and gastroenteroanastomosis. The forecast was favourable with normalization of the values of gastrinémie., Conclusion: The sporadic gastrinoma is rare, its emphasis is increasingly being facilitated by the technology of modern medical imaging, belonging to a polyendocrinopathie must be systematic search. Treatment of pancreatic gastrinoma is multidisciplinary. Surgery is the only cure for this disease.

Neuroendocrine tumor (NET) metastases represent at this moment the only accepted indication of liver transplantation (LT) for liver secondaries. Between 1984-2007, nine (1.1%) of 824 adult LTs were performed because of NET. There were five well differentiated functioning NETs (four carcinoids and one gastrinoma), three well differentiated non functioning NETs and one poorly differentiated NET. Indications for LT were an invalidating unresectable tumor (4x), and/or a diffuse tumor localization (3x) and/or a refractory hormonal syndrome (5x). Median post-LT patient survival is 60.9 months (range 4.8-119). One-, 3- and 5-year actuarial survival rates are 88%, 77% and 33%; 1, 3 and 5 years disease free survival rates are 67%, 33% and 11%. Due to a more rigorous selection procedure, results improved since 2000; three out of five patients are alive disease-free at 78, 84 and 96 months. Review of these series together with a review of the literature reveals that results of LT for this oncological condition can be improved using better selection criteria, adapted immunosuppression and neo- and adjuvant surgical as well as medical treatment. LT should be considered earlier in the therapeutic algorithm of selected NET patients as it is the only therapy that can offer a cure.

Gastrinoma is the most frequent functional pancreaticoduodenal endocrine tumor in patients with multiple endocrine neoplasia type 1 (MEN 1). Primary hepatic gastrinomas in MEN 1 are very rare, with no previous reports published in the literature. We reported the case of a 39 yr old female patient with a history of repeated peptic ulcers and a hypoglycemia episode. Abdominal CT indicated a well-defined liver mass and a pancreatic head mass. Somatostatin-receptor scintigraphy with [(111)In] DTPA octreotide demonstrated a strong uptake of the radiotracer in the left lateral segment at the site of the hepatic mass. After operation, immunohistochemical staining was consistent with pancreatic insulinoma and primary hepatic gastrinoma. As the liver is a common site of metastases from gastrinoma, primary liver gastrinoma has not yet been reported with MEN 1. We diagnosed this patient using immunohistochemical studies and treated this patient by hepatic segmentectomy.

Functional neuroendocrine tumors are often low-grade malignant neoplasms that can be cured by surgery if detected early, and such detection may in turn be accelerated by the recognition of neuropeptide hypersecretion syndromes. Uniquely, however, relief of peptic symptoms induced by hypergastrinemia is now available from acid-suppressive drugs such as proton-pump inhibitors (PPIs). Here we describe a clinical case in which time to diagnosis from the onset of peptic symptoms was delayed more than 10 years, in part reflecting symptom masking by continuous prescription of the PPI omeprazole. We propose diagnostic criteria for this under-recognized new clinical syndrome, and recommend that physicians routinely measure serum gastrin levels in persistent cases of PPI-dependent dyspepsia unassociated with H. pylori.

It is clear that a properly performed initial operation is the key to success in the management of a patient with ZES. However, reoperation is frequently a consideration in the management of patients with ZES because high rates of persistent and recurrent disease are manifest even with modern imaging and surgical approaches. In carefully selected patients, reoperation can result in durable biochemical cure and improved survival and should be considered. A thorough knowledge of the natural history of the sporadic form of ZES and ZES in the context of MEN-1, patterns of presentation, and sites of metastases are necessary to achieve the best outcome in patients with this unusual disease.

A patient who was given metoclopramide for vomiting and diarrhoea developed circulatory collapse with his blood pressure dropping to 50/20 mm Hg. A gastrinoma was diagnosed histologically. The extent of the tumour was defined by octreotide scanning and magnetic resonance imaging. Metoclopramide was again given for colicky abdominal pain and the patient developed circulatory collapse a second time. A laparotomy involving extensive resection of the tumour was performed. The MEN1 mutation was not detected in blood or tumour tissue. Follow-up octreotide scanning did not show any residual tumour. Possible causes for the circulatory collapse are discussed. Our case is probably the first patient with gastrinoma to develop circulatory collapse after being given metoclopramide.

Objective: To report 3 cases of primary neuroendocrine tumors (PNT) of the extrahepatic biliary tree (EHBT) in patients with Zollinger-Ellison syndrome (ZES), 2 of whom had multiple endocrine neoplasia type 1 (MEN 1)., Methods: Three new cases of gastrin-producing tumors of the EHBT are presented, and the pertinent literature relating to PNT of the EHBT is reviewed., Results: Eighty-one previous cases of PNT of the EHBT have been reported in the world literature, 7 of which were hormonally active and associated with peptic ulcer disease, diarrhea, or ZES. Three additional patients presented to us with ZES due to PNT of the EHBT. One patient with MEN 1 was treated with a Whipple procedure for a common bile duct gastrinoma. A second patient underwent left hepatectomy with resection of the confluence of the right and left hepatic ducts for a primary left hepatic duct gastrinoma. The second patient with MEN 1 under-went resection of a gastrinoma at the junction of the cystic duct and the common bile duct., Conclusion: Although PNT of the EHBT are uncommon, the association with ZES is even more so. Often, nonfunctioning tumors are diagnosed late in the course of the disease from symptoms related to biliary obstruction. Patients with ZES may be diagnosed earlier because of symptoms resulting from gastrin excess. Surgical resection is the only chance for cure and is often helpful in the palliation of symptoms.

The role of operation in patients with Multiple Endocrine Neoplasia Type 1 (MEN-1) and Zollinger-Ellison Syndrome (ZES) is controversial. Our institutional bias for this disease has, in general, been towards aggressive imaging and operative removal of localized gastrinomas. Few studies have reported long-term outcomes in patients with MEN-1 and ZES. A single institution retrospective review of all patients with MEN-1 and ZES from 1970 to present was performed. Twelve patients were identified (median age = 37 years at diagnosis). The median follow-up was 18 years from diagnosis of ZES. Common symptoms associated with gastrinoma in these patients were diarrhea (n = 6), abdominal pain (n = 4), and nausea/vomiting (n = 4). Most commonly identified sites of gastrinoma were: pancreas (n = 10), duodenum (n = 4), lymph nodes (n = 3), and liver (n = 1). Fifteen celiotomies were performed in total (median = 1; range 0-3). Operative procedures performed included: distal pancreatectomy (n = 4), acid reducing procedure (n = 4), enucleation of pancreatic gastrinoma (n = 3), duodenal resection (n = 3), pancreaticoduodenectomy (n = 1), and other (n = 7). One patient had a transient biochemical cure after operation lasting 3 years. Only one patient in this series had documented liver metastases of gastrinoma and no patients expired of metastatic gastrinoma. There was one postoperative patient death, secondary to respiratory arrest thought to be a result of aspiration or pulmonary embolus. Three patients died of nondisease related causes, and seven patients were alive at the time of last follow-up. Operations rarely result in biochemical cures in patients with MEN-1 and ZES. In our experience, resection of localized gastrinomas often did not require extended surgical resection and were associated with excellent long-term outcomes.

We present a rare case of renal gastrinoma. To the best of our knowledge, only one case of renal gastrinoma has been reported in the literature so far. An African American male was diagnosed with Zollinger Ellison syndrome at the age of 15 years, when he underwent surgery for peritonitis secondary to duodenal ulcer perforation. Further evaluation was deferred and proton pump inhibitors were prescribed. Later evaluation showed a left renal mass. Serum gastrin levels were 4,307 pg/ml. A CAT scan of the abdomen showed 4- x 4-cm heterogeneous solid mass in the interpolar region of the left kidney with central hypodensity. Somatostatin scintigraphy confirmed a receptor-positive mass in the same location. Nephrectomy was done and the tumor was diagnosed on histopathological examination as a gastrinoma. At 6-month follow-up, gastrin levels were 72 pg/ml. After a follow-up of 6 years, the patient has no recurrent symptoms.

Preoperative assessment and localization is crucial in the management and outcome of patients with duodenal gastrinoma. Localization can be challenging because of small size and variable location. We describe our experience of managing 1 such patient by localizing the lesion during the preoperative period. Side-viewing endoscopy, endoscopic ultrasound, and somatostatin receptor scintigraphy determined the exact location of the tumor, which was confirmed during surgery on palpation, endoscopic transillumination, and duodenotomy. Antrectomy was performed, and the patient was asymptomatic after 8 months of follow-up and did not require antisecretory medications. His serum gastrin levels returned to normal during the postoperative period.

Pancreatic gastrinoma is a rare non-beta islet cell tumor. Approximately 60% of gastrinomas are malignant; despite the fact that they are usually slow growing, liver metastases have a major impact on prognosis. Most authors have advocated aggressive surgical management as being the only potentially curative therapy to improve survival as well as to provide outstanding relief from symptoms. We present a case of a 57-year-old man referred to our hospital with a diagnosis of liver metastases from pancreatic gastrinoma, with suspected involvement of the inferior vena cava (IVC). At the age of 37 years, he was diagnosed in his local hospital as having a pancreatic gastrinoma, with liver metastases, and he underwent distal pancreatectomy, splenectomy and enucleation of liver metastases. A liver tumor recurred twice, 7 and 9 years after the first surgery, for which double liver resections were performed: the first time he underwent enucleation of multiple liver metastases in segments II, III, IV, V, VI, VII and VIII, with resection of the right hepatic vein and partially resection of the diaphragm; the second time he underwent enucleation of multiple liver metastases in segments II, III, IV, and V. In our hospital, 8 years after the last surgery, the patient underwent right extended trisectionectomy, resection of segment I, combined resection of the IVC, and partial removal of the diaphragm. To the best of our knowledge, from a review of the literature, this is the first case to achieve successful long-term survival through aggressive surgical management of this type of metastatic endocrine tumor. The patient described here is still alive, free of disease and leading a normal life, 20 years after the initial diagnosis and 3 years after the last surgery.

Background: Gastrinomas are the most frequent hormonally-active neuroendocrine tu-mours in patients with multiple endocrine neoplasia type 1 (MEN1)., Case Report: We report on the diagnostic difficulties in a 62-year-old female patient with MEN1 and lymph node gastrinoma. At six and twelve months after resection of a lymph node gastrinoma, no signs of recurrence were observed. Basal and peak gastrin levels during secretin stimulation test were normalized. Extensive explorations, including gastrointesinal endoscopy, endoscopic ultrasonography, and Ga-68-DOTATOC-PET/CT, did not reveal a primary duodenal or pancreatic tumour., Conclusion: Localization of gastrinomas in patients with MEN1 is challenging due to their small size, frequent duodenal location, and multiplicity. Therefore, while some studies support the existence of primary lymph node gastrinoma in patients with sporadic disease, this diagnosis should not be made in MEN1 patients. In both cases, however, extensive follow-ups are required.

Peptic ulcer due to Zollinger-Ellison syndrome is a rare entity. In this case report a 55-year-old man had a medical history of esophageal reflux, vomiting, and diarrhea for 10 years. Despite continuous medication with a proton pump inhibitor, no complete recovery from symptoms was achieved. A diagnosis of gastrinoma was at first not considered. After discontinuation of the proton pump inhibitor for only a few days, the strong stimulation of the gastrinoma led to fulminant hydrochloric acid burn of the distal esophagus with iatrogenic or spontaneous perforation at the esophagogastral junction. We describe the operative treatment as a two-stage reconstruction with colon interposition and resection of the primary tumor in the duodenum.

Background: Collision tumors of the stomach are exceedingly rare, with only six previous reported instance in which adenocarcinoma of the stomach were found in association with carcinoid tumor. Only in one case the adenocarcinoma was associated with a gastrinoma., Aim: we report the second case of Collision tumor between adenocarcinoma and gastrinoma., Observation: A 55 years old man was admitted in our department for an exploration of gastric pain with rapid weight loss. Physical examination showed an epigastric mass. Upper endoscopy showed in the fundic region of the stomach an exophytic process wildly ulcerative in his center associated with the presence of a multiple polypoid tumors. The pathologic examination of the biopsy specimen of the process revealed an adenocarcinoma and of the polypoid tumors showed a carcinoid type tumor. There was no merged appearance between both tumors suggesting collision tumor. The biopsies of the non tumoral gastric mucosa were normal. The Zollinger Ellison syndrome was then suspected. The serum gastrin level showed a rate raised at 8676pg/ml. The diagnosis of collision type tumors between adenocarcinoma and gastrinoma was retained. The assessment of extension revealed the presence of hepatic and ganglion nodes. The patient was treated by chemotherapy but he died three months after initiation of chemotherapy because of tumoral progression., Conclusion: Through this observation and with a review of literature, the coexistence of adenocarcinoma and carcinoid tumor of the stomach is discussed.

Introduction: Pancreatic neuroendocrine tumours (PNT) are infrequent epithelial neoplasms associated with a better outcome than pancreatic adenocarcinoma., Materials and Methods: We analysed our 22 years of experience in managing PNT. Forty-nine patients (27 women and 22 men) with a mean age of 49 years were studied. There were 28 insulinomas, eight glucagonomas, three gastrinomas, one VIPoma and one carcinoid. Eight patients presented with nonfunctional tumours. Enucleation was performed in 20 patients, distal pancreatectomy in 16, middle pancreatic resection in four, cephalic pancreatoduodenectomy in two and total pancreatoduodenectomy in one. In six patients, the tumour was not resected., Results: Postoperative complication rate was 22%: six pancreatic fistulas, three intra-abdominal collections, one remnant pancreatitis and one pancreatic pseudocyst. There was no mortality. 39 cases showed benign histologic features and ten malignant ones. Symptomatic palliation was achieved in 94% of the cases. Five patients presented recurrences: three liver metastases and two pancreatic recurrences. Actuarial mean survival was 163 months and was longer in insulinomas, in those tumours completely resected and in tumours with benign histological features., Conclusion: Conservative surgery of the pancreas is preferred, but aggressive surgery is indicated when the primary tumour can be controlled. Despite of minimising pancreatic resection, there is a high complication rate, mainly pancreatic fistulas, though they can often be conservatively managed. Insulinomas are the PNT with better outcome; those completely resected also associate a better prognosis.

Background: To investigate the appearance of multiple primary malignancies in patients with sporadic neuroendocrine pancreatic tumors (NEPTs)., Methods: One hundred forty-five patients with NEPTs were treated at the Department of Surgery, Philipps-University Marburg. Multiple primary malignancies included tumors that were not considered to be a metastasis, invasion, or recurrence of NEPTs. Data on sex, age at diagnosis of cancer, follow-up time after diagnosis, and death rate were collected., Results: Of 115 patients with sporadic NEPTs, 15 (13.0%) patients were identified with at least one malignant tumor, other than a NEPT. The median age at diagnosis of the associated tumor(s) was 57 years (range, 10-72 years). Two of the 15 patients had insulinomas, 5 had gastrinomas and 8 had non-functioning NEPTs, respectively. The risk of developing multiple cancers was the highest for patients with gastrinoma (21.7%), followed by patients with non-functioning NFPTs (20.5%)., Conclusions: In patients with NEPTs multiple primary malignancies are found more frequently than in the general population. The etiology of the increased risk of other primaries is not clearly defined, but it may be the result of accumulated growth stimulation by the secreted hormones or a genetic alteration that leads to tumorogenesis in these patients.

Objective: To present a case of a young woman with Cushing syndrome caused by ectopic production of adrenocorticotropic hormone from a metastatic pancreatic gastrin-secreting endocrine carcinoma, who had a good response to combination peptide receptor radionuclide therapy., Methods: We review the history, physical examination, laboratory investigations, and radiographic findings in this unusual patient. Moreover, the multimodal interventions are described and discussed., Results: In a 38-year-old woman with typical signs of cortisol excess, laboratory studies revealed diabetes mellitus, hypokalemia, and high levels of adrenocorticotropic hormone, plasma cortisol, and urinary cortisol. Abdominal computed tomography showed a 4-cm pancreatic mass and multiple metastatic lesions in the liver, and ectopic Cushing syndrome was diagnosed. Treatment consisted of surgical debulking of the tumor, ketoconazole, somatostatin analogues, chemoembolization of the liver metastatic lesions, and peptide receptor radionuclide therapy with the radiolabeled somatostatin analogues 90Y-DOTATOC ([90Y-DOTA0, Tyr3]-octreotide) and 177Lu-DOTATATE ([177Lu-DOTA0, Tyr3]-octreotate). The 5 1/2-year follow-up showed positive results, which included complete regression of all clinical and hormonal evidence of the tumor and substantial decrease in the size and number of hepatic metastatic lesions. The patient achieved and still maintains an optimal quality of life., Conclusion: To the best of our knowledge, this is the first report of a multidisciplinary approach including peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE, which proved to be effective in improving clinical outcome in a case of metastatic endocrine carcinoma of the pancreas in conjunction with ectopic Cushing syndrome. In this unusual case, the patient has one of the longest durations of survival in this setting described in the literature.

Background: We examine the epidemiology, natural history, and prognostic factors that affect the duration of survival for islet cell carcinoma by using population-based registries., Methods: The Surveillance, Epidemiology, and End Results (SEER) Program database (1973-2003 release, April 2006) was used to identify cases of islet cell carcinoma by histology codes and tumor site., Results: A total of 1310 (619 women and 691 men) cases with a median age of 59 years were identified. The annual age-adjusted incidence in the periods covered by SEER 9 (1973-1991), SEER 13 (1992-1999), and SEER 17 (2000-2003) were .16, .14, and .12 per 100,000, respectively. The estimated 28-year limited duration prevalence on January 1, 2003, in the United States was 2705 cases. Classified by SEER stage, localized, regional, and distant stages corresponded to 14%, 23%, and 54% of cases. The median survival was 38 months. By stage, median survival for patients with localized, regional, and distant disease were 124 (95% CI, 80-168) months, 70 (95% CI, 54-86) months, and 23 (95% CI, 20-26) months, respectively. By multivariate Cox proportional modeling, stage (P < .001), primary tumor location (P = .04), and age at diagnosis (P < .001) were found to be significant predictors of survival., Conclusions: Islet cell carcinomas account for approximately 1.3% of cancers arising in the pancreas. Most patients have advanced disease at the time of diagnosis. Despite the disease's reputation of being indolent, survival of patients with advanced disease remains only 2 years. Development of novel therapeutic approaches is needed.

Objectives: Immunocytochemical staining for lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) is able to recognize lymphatic vessel endothelium and pancreatic endocrine cells (PETs). Pancreatic endocrine tumors were studied for LYVE-1 immunocytochemical staining compared with normal pancreatic islets to detect possible presence of LYVE-1 in PETs., Methods: Twenty-five cases of primary and metastatic PETs were immunocytochemically stained for LYVE-1, including insulinomas, glucagonomas, somatostatinoma, pancreatic polypeptidomas, gastrinomas, and nonfunctioning tumors. With routinely formalin-fixed and paraffin-embedded tissues, LYVE-1 immunostaining was performed with polyclonal goat antihuman LYVE-1., Results: All normal pancreatic islet cells were positive for LYVE-1, whereas 2 cases of 25 PETs, 1 each of gastrinoma and nonfunctioning tumor, were positive for LYVE-1, retaining immunocytochemical reactivity of islet cells., Conclusions: Normal pancreatic islets were positive for LYVE-1, whereas only 2 of 25 PETs were positive, suggesting that most PETs lost LYVE-1 or contained below detectable levels of LYVE-1. The presence of LYVE-1 in pancreatic islets and in some PETs may suggest structure-function relationship of LYVE-1/lymphatic vessel in hormone synthesis and secretion.

The clinical behavior of endocrine pancreatic tumors (EPTs) is difficult to predict in the absence of metastases or invasion to adjacent organs. Several markers have been indicated as potential predictors of metastatic disease, such as tumor size > or =2 cm, Ki67 proliferative index > or =2%, cytokeratin (CK) 19 status, and recently in insulinomas, chromosomal instability (CIN). The goal of this study was to evaluate the value of these markers, and in particular of the CIN, to predict tumor recurrence or progression and tumor-specific death, using a series of 47 insulinomas and 24 non-insulinoma EPTs. From these EPT cases, a genomic profile has been generated and follow-up data have been obtained. The proliferative index has been determined in 68 tumors and a CK19 expression pattern in 50 tumors. Results are statistically analyzed using Kaplan-Meier plots and the log-rank statistic. General CIN, as well as specific chromosomal alterations such as 3p and 6q loss and 12q gain, turned out to be the most powerful indicators for poor tumor-free survival (P< or =0.0004) and tumor-specific death (P< or =0.0113) in insulinomas. The CIN, chromosome 7q gain, and a proliferative index > or =2% were reliable in predicting a poor tumor-free survival in non-insulinoma EPTs (P< or =0.0181, whereas CK19 expression was the most optimal predictor of tumor-specific death in these tumors. In conclusion, DNA copy number status is the most sensitive and efficient marker of adverse clinical outcome in insulinomas and of potential interest in non-insulinoma EPTs. As a consequence, this marker should be considered as a prognosticator to improve clinical diagnosis, most practically as a simple multi-target test.

Background: Zollinger Ellison syndrome (ZES), an ulcerative disease of the upper gastrointestinal tract that involves the production of high levels of gastrin and gastric acid, is a rare, symptomatic, endocrine neoplastic disease., Case: We report a rare case of gastrinoma that was first diagnosed during pregnancy in which the primary tumor was located in the liver. The ZES was well controlled with Zoton (Lansoprazole) following surgery. The patient had an uneventful pregnancy and delivery without significant complications., Conclusions: The present case suggests that treatment with Zoton for ZES during pregnancy is safe and effective.

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.

Cross sectional imaging in the assessment of gastrinomas has three major applications: Tumor localization (sporadic gastrinoma, MEN I) in patients undergoing primary or secondary surgery. Staging of metastasized tumors, especially assessment of lymph nodes and liver metastases, possibly including a risk analysis prior to liver resection. Post-surgery follow-up and monitoring of bio- or chemotherapy. Detection of primary tumors is strongly correlated with their size. However, the sensitivity of surgical assessment of the mostly small tumors by experienced surgeons is much higher than that of any imaging modality. Of all imaging modalities, endoultrasonography (EUS) followed by Somatostatin receptor scintigraphy (SRS) is the most sensitive modality for the assessment of pancreatic tumors in asymptomatic patients suffering from a MEN-I syndrome. Scintigraphy has the highest sensitivity in tumors of symptomatic patients and in the assessment of metastases. CT and MRI are only second line diagnostic modalities. Their sensitivity is largely dependent on the selection of patients. As a potential application, 3D reconstruction of nearly isotropic CT data sets for the risk assessment prior to liver resection is currently developing. Due to the absent radiation exposure, MRI is increasingly utilized to monitor the response of metastases under systemic therapy, e.g. in clinical trials.