Pancreatic polypeptide hyperplasia causing watery diarrhea syndrome: a case report.
Neuroendocrine tumours of the pancreas can secrete numerous peptides, leading to various recognizable clinical syndromes. The secretion of pancreatic polypeptide has been used as a marker for neuroendocrine tumours but is considered to be a biologically inert peptide. A 37-year-old woman had watery diarrhea syndrome from pancreatic polypeptide hyperplasia. Only 2 other reported cases in the literature have described pancreatic polypeptide hyperplasia; however, this is the first reported case in which the patient was successfully treated by surgical resection, with a 2-year follow-up. This report and review of the literature illustrate that pancreatic polypeptide hypersecretion may present as a clinical endocrinopathy. (+info)
Mutations of the DPC4/Smad4 gene in neuroendocrine pancreatic tumors.
Tumors of the endocrine pancreas are extremely rare, and molecular mechanisms leading to their development are not well understood. A candidate tumor suppressor gene, DPC4, located at 18q21, has recently been shown to be inactivated in half of pancreatic adenocarcinoma xenografts. The close anatomical relationship of the exocrine and endocrine pancreas prompted us to determine the role of DPC4 in the tumorigenesis of 25 pancreatic islet cell tumors (11 insulinomas, nine non-functioning endocrine carcinomas, three gastrinomas, two vipomas). A mutation screening of the highly conserved COOH-terminal domain of DPC4 (exons 8-11) was performed by single-strand conformational variant (SSCP) analysis and a PCR-based deletion assay. Five of nine (55%) non-functioning endocrine pancreatic carcinomas revealed either point mutations, small intragenic deletions or homozygous deletion of DPC4 sequences compared to none of the insulinomas, gastrinomas or vipomas. These results suggest that DPC4 is an important target gene promoting tumorigenesis of non-functioning neuroendocrine pancreatic carcinomas. (+info)
Putative tumor suppressor loci at 6q22 and 6q23-q24 are involved in the malignant progression of sporadic endocrine pancreatic tumors.
Our previous comparative genomic hybridization study on sporadic endocrine pancreatic tumors (EPTs) revealed frequent losses on chromosomes 11q, 3p, and 6q. The aim of this study was to evaluate the importance of 6q losses in the oncogenesis of sporadic EPTs and to narrow down the smallest regions of allelic deletion. A multimodal approach combining polymerase chain reaction-based allelotyping, double-target fluorescence in situ hybridization, and comparative genomic hybridization was used in a collection of 109 sporadic EPTs from 93 patients. Nine polymorphic microsatellite markers (6q13 to 6q25-q27) were investigated, demonstrating a loss of heterozygosity (LOH) in 62.2% of the patients. A LOH was significantly more common in tumors >2 cm in diameter than below this threshold as well as in malignant than in benign tumors. We were able to narrow down the smallest regions of allelic deletion at 6q22.1 (D6S262) and 6q23-q24 (D6S310-UTRN) with LOH-frequencies of 50.0% and 41.2 to 56.3%, respectively. Several promising tumor suppressor candidates are located in these regions. Additional fluorescence in situ hybridization analysis on 46 EPTs using three locus-specific probes (6q21, 6q22, and 6q27) as well as a centromere 6-specific probe revealed complete loss of chromosome 6 especially in metastatic disease. We conclude that the two hot spots found on 6q may harbor putative tumor suppressor genes involved not only in the oncogenesis but maybe also in the malignant and metastatic progression of sporadic EPTs. (+info)
Prevalence, characteristics and prognosis of MEN 1-associated glucagonomas, VIPomas, and somatostatinomas: study from the GTE (Groupe des Tumeurs Endocrines) registry.
Few studies have concerned the rare functioning endocrine pancreatic tumors associated with multiple endocrine neoplasia type 1 (MEN 1). When sporadic, these tumors have a poor prognosis. AIM: To analyze the frequency, characteristics and prognosis of MEN 1-associated glucagonomas, VIPomas and somatostatinomas recorded in the GTE (Groupe des Tumeurs Endocrines) registry. METHODS: Records of the patients whose GTE registry codes included glucagonoma, VIPoma or somatostatinoma were reviewed. The diagnosis was confirmed when there were clinical signs of a functioning tumor and/or when blood levels of the peptide were higher than twice the upper limit of normal. RESULTS: Among 580 patients with MEN 1, duodeno-pancreatic involvement was present in 307 (52.9%). Five (1.6%) had a glucagonoma, 3 (0.98%) a VIPoma and 2 (0.65%) a somatostatinoma. A clinical syndrome was present in 1 patient with glucagonoma, in the 3 with VIPomas and in 1 with somatostatinoma. Tumor size was greater than 3 cm more often for these rare tumours (67%) than in patients with other type of duodeno-pancreatic involvement (28%) (P=0.02) and visceral metastases were more frequent (40% vs 15%; P=0.056). Ten-year survival of patients with glucagonomas, VIPomas or somatostatinomas (53.8%; CI95%: 15.5-92.1) was poorer than that of patients with insulinomas (91.4%; CI95%: 83.399.5; P=0.01) or gastrinomas (81.7%; CI95%: 74.9-88.5; P=0.20) and close to that of patients with non-functioning tumors (62.2%, CI95%: 41.0-83.9; NS). CONCLUSION: Glucagonomas, VIPomas and somatostatinomas, especially the functioning type, are very rare in patients with MEN 1. Prognosis is poor, probably because of large tumor size and high rate of metastasis. Survival is similar to that in patients with non-functioning tumors. (+info)
BRAF gene mutations are rare events in gastroenteropancreatic neuroendocrine tumors.
The BRAF gene, one of the human isoforms of RAF, is activated by ras, leading to cooperative effects in cells responsive to growth factor signals. We studied the frequency of BRAF and k-ras-2 mutations in primary neuroendocrine gastroenteropancreatic (GEP) tumors. Mutation analysis of the BRAF and k-ras-2 genes was performed in 40 primary neuroendocrine tumors of the GEP system. The expression of extracellular signaling-related kinase (ERK) 1/2, an important downstream point of convergence in the ras-RAF-mitogen-activated protein-ERK pathway was analyzed immunohistochemically. We detected one 1796 T-->A BRAF mutation that led to a substitution of valine by glutamic acid at position 599 (V599E) in 40 primary neuroendocrine GEP tumors (3%). We failed to detect specific mutation of the k-ras-2 gene. We identified constitutively activated ERK in almost all neuroendocrine tumor tissues tested irrespective of BRAF mutation or localization or functional activity. These results suggest that BRAF mutations do not have a role in tumorigenesis of neuroendocrine tumors. Nevertheless, activation of the RAF/mitogen-activated protein kinase pathway might have a causative role in the development of neuroendocrine tumors, independent of BRAF or k-ras-2 mutation. (+info)
Outcome of duodenopancreatic resections in patients with multiple endocrine neoplasia type 1.
OBJECTIVE: To evaluate the outcome of an aggressive surgical approach for duodenopancreatic neuroendocrine tumors (PETs) associated with multiple endocrine neoplasia type 1 (MEN1). SUMMARY BACKGROUND DATA: The management of PETs is still controversial in the setting of the autosomal dominant inherited MEN1 syndrome. METHODS: MEN1 patients that had either biochemical evidence of functioning PETs or visualized nonfunctioning PETs larger than 1 cm in size on imaging were operated. Since 1997, patients were followed annually by biochemical testing and imaging studies. RESULTS: Twenty-six genetically confirmed MEN1 patients underwent duodenopancreatic resection for functioning (n = 17) or nonfunctioning (n = 9) PETs. Ten (38%) patients had malignant PETs as characterized by the presence of lymph node (10 patients) and/or distant metastases (2 patients). The surgical approach was selected based on the type, location, and size of PETs. Four Zollinger-Ellison syndrome (ZES) patients required pylorus preserving pancreaticoduodenectomy (PPPD) as initial or redo procedure, 20 patients underwent other duodenopancreatic resections, and 2 patients had simple enucleations of PETs. After median 83 months (range, 5-241 months), 24 patients were alive and 2 patients died of an unrelated cause. All patients with insulinoma or vipoma and 7 of 11 patients with ZES were biochemically cured, including the ZES patients who underwent PPPD. However, 19 of 26 (73%) patients developed new small PETs (<1 cm) in the pancreatic remnant, but no patient had yet detectable metastases on imaging. CONCLUSIONS: Early and aggressive surgery of PETs in MEN1 patients prevents the development of liver metastases, which are the most life-threatening determinant. PPPD might be the procedure of choice for MEN1-ZES, which has to be proven in large scale studies. (+info)
Watery diarrhea, hypokalemia and achlorhydria syndrome due to an adrenal pheochromocytoma.
Watery diarrhea, hypokalemia and achlorhydria (WDHA) syndrome caused by vasoactive intestinal polypeptide (VIP) -producing tumor only rarely occurs in patients with nonpancreatic disease. A 49-year-old woman was referred for evaluation of a right adrenal tumor incidentally diagnosed by abdominal ultrasound during the investigation of chronic watery diarrhea. Laboratory findings showed hypokalemia and excessive production of VIP and catecholamines. After surgical resection of the tumor, diarrhea subsided and both electrolytes and affected hormone levels normalized. Immunohistochemical examination confirmed a diagnosis of pheochromocytoma, which contained VIP-positive ganglion-like cells. We herein present the clinical and histogenetic implications of this rare clinical entity, with literature review. (+info)
Population-based study of islet cell carcinoma.
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. (+info)