A case of vasoactive intestinal peptide-secreting tumor (VIPoma) arising from MEN1 inactivation which recurred 15 years after the initial resection.

Vasoactive intestinal peptide-secreting tumors (VIPomas) are extremely rare functional pancreatic neuroendocrine neoplasms (p-NENs) characterized by watery diarrhea, hypokalemia, and achlorhydria. Here, we report the case of a 51-year-old female patient with VIPoma that recurred after a long-term disease-free interval. This patient had been asymptomatic for approximately 15 years after the initial curative surgery for pancreatic VIPoma, with no metastasis. The patient underwent a second curative surgery for the locally recurrent VIPoma. Whole-exome sequencing of the resected tumor revealed a somatic mutation in MEN1, which is reportedly responsible not only for multiple endocrine neoplasia type 1 (MEN1) syndrome but also sporadic p-NENs. Symptoms were controlled with lanreotide before and after surgery. The patient is alive with no relapse following 14 months after surgery. This case demonstrates the importance of long-term observation of patients with VIPoma.

A clinical analysis on functioning pancreatic neuroendocrine tumors (focusing on VIPomas): a single-center experience.

VIPomas are generally rare functioning pancreatic neuroendocrine tumors (PanNETs) that cause watery diarrhea, hypokalemia, and achlorhydria. Due to their extreme rarity, the clinicopathological features and outcomes of VIPomas have not been well reported. This study aimed to determine the diagnostic and therapeutic characteristics and prognosis of VIPomas and to compare them with other PanNETs at a Japanese reference hospital. Medical records of 293 patients with PanNETs were collected. Patient and tumor characteristics and outcomes were retrospectively reviewed. This cohort had only 1.4% (four patients) of patients with VIPomas, and three of these patients changed from non-functioning (NF-) PanNETs during their disease course. Recurrences of hormonal symptoms were observed in all patients despite the initial controls, and all of them died from their disease, more specifically mainly from hormonal symptoms. Compared to the other PanNETs, VIPomas were all located at the pancreatic tail, were larger, and had a higher Ki-67 index and more metastasis. The median survival time was significantly shorter for patients with VIPoma than for those with NF-PanNET (5.9 vs. 26.7 years, p < 0.0001), insulinoma (21.8 years, p < 0.0001), and gastrinoma (12.3 years, p = 0.0325). This study presents the possibility of shifting from non-symptomatic to symptomatic VIPomas as they grow or of transforming from NF-PanNETs to VIPomas. VIPomas should be considered in patients with relatively large NF-PanNETs, especially those located in the pancreatic tail, when diarrhea is continuously observed. As hormonal symptoms are an important cause of death in VIPomas, long-term symptomatic control, which is relatively difficult, is of great significance.

Life-threating diarrhea and acute renal failure secondary to pancreatic VIPoma treated by surgery.

Pancreatic neuroendocrine tumors represent less than 5% of all pancreatic tumors. They are a heterogeneous group of neoplasms with a diverse behavior and prognosis. Pancreatic vasoactive intestinal polypeptide tumor (VIPoma) is an exceptional tumor within this group due to its low incidence. The presence of pancreatic VIPoma should be clinically suspected in all patients with watery diarrhea, particularly when accompanied by a loss of potassium and bicarbonate and a pancreatic mass on imaging. There are other pathologies with similar symptoms; therefore, a correct differential diagnosis with an adequate treatment is essential for its management. We present the case of a 46-year-old patient who developed a prerenal kidney failure secondary to severe watery diarrhea after a diagnosis of pancreatic VIPoma. Thus, a resection was performed as the patient was rapidly deteriorating and required an intervention.

[VIPoma in retroperitoneum of elderly, cause of chronic diarrhea in uncommon location]. / VIPoma en retroperitoneo de adulto mayor, causa de diarrea crónica en localización infrecuente.

Chronic secretory diarrhea is a frequent entity. Causes are multiple, that is why reaching final diagnosis can result in delay with complications that this causes in the general condition of the patient. We present the case of one older adult with chronic diarrhea, mild hypokalemia and metabolic hyperchloremic acidosis secondary to a VIPoma in retroperitoneum which is an unusual location of this type of tumor that was diagnosed by biopsy guided by tomography.

MSH2 and CXCR4 involvement in malignant VIPoma.

BACKGROUND: Vasoactive intestinal polypeptide secreting tumors(VIPomas) are rare endocrine tumors of the pancreas with an estimated incidence of 0.1 per million per year. The molecular mechanisms that mediate development of VIPomas are poorly investigated and require definition. METHODS: A genome- and gene expression analysis of specimens of a primary pancreatic VIPoma with hepatic metastases was performed. The primary tumor, the metastases, the corresponding healthy tissue of the liver, and the pancreas were compared with each other using oligonucleotide microarrays and loss of heterozygosity (LOH). RESULTS: The results revealed multiple LOH events and several differentially expressed genes. Our finding of LOH and downregulation was conspicuous in the microarray analysis for the mismatch repair gene MSH2 in the primary pancreatic VIPoma tumor, the hepatic metastasis but not in the corresponding healthy tissue. Further a strong overexpression of the chemokine CXCR4 was detected in the hepatic metastases compared to its pancreatic primary. With a review of the literature we describe the molecular insights of metastatic development in VIPoma. CONCLUSION: In VIPoma, defects in the mismatch repair system especially in MSH2 may contribute to carcinogenesis, and increased CXCR4 may be associated with liver metastasis.

A case of VIPoma.

This case report addresses the management of a pregnant woman in the peripartum period with a VIPoma. This rare and highly malignant neuroendocrine tumour secretes vasoactive intestinal peptide (VIP), a substance that may cause potentially life-threatening disruption to physiology. A 36-year-old woman presented for induction of labour with a three-year history of chronic diarrhoea, hypophosphataemia, palpitations and skin flushing. Raised VIP levels indicated presence of a VIPoma, however despite extensive investigation prior to pregnancy by neuroendocrine specialists, the tumour location remained unidentified. The patient delivered a healthy boy with the aid of forceps in theatre following an epidural top-up. Key features of management were a multidisciplinary approach, avoidance of triggers for VIP secretion, strict management of electrolytes and avoidance of severe changes in sympathetic tone during labour with epidural analgesia.

[A long-term survival case of recurrent pancreatic vipoma with liver metastases treated by a combination of surgical resection and loco-regional therapies].

We report a case of recurrent pancreatic VIPoma with liver and peritoneal metastases who has been surviving over 7 years by a successful treatment with a combination of surgical resection and loco-regional therapies. A 59-year-old female underwent distal pancreatectomy for pancreatic endocrine tumor. Five years after pancreatectomy, she had a recurrence of liver and peritoneal metastases with the symptoms by hypersecretion of VIP, and she underwent hepatectomy and peritoneal tumor resection. Seven months later, multiple liver metastases appeared and were treated with transcatheter arterial chemoembolization (TACE). Additionally radiofrequency ablation( RFA) for remnant viable lesion was performed. Seven years and eight months after primary panceatectomy and two years and six months after resection of the liver and peritoneal recurrences, she is now disease-free with good quality of life. The progression of well-differentiated pancreatic neuroendocrine carcinoma is usually slow. It is potentially useful in controlling of liver metastases to combine the loco-regional therapy like TACE and RFA with surgical resection.

Hypokalemic rhabdomyolysis due to watery diarrhea, hypokalemia, achlorhydria (WDHA) syndrome caused by vipoma.

Mild hypokalemia is common and encountered in a multitude of diseases, but severe hypokalemia leading to rhabdomyolysis is relatively rare. The watery diarrhea, hypokalemia, achlorhydria (WDHA) syndrome caused by vasoactive intestinal polypeptide (VIP)-producing tumors, is an extremely rare cause of hypokalemic rhabdomyolysis and the literature is limited to one case report. We report a second case of an adult who presented with rhabdomyolysis due to severe hypokalemia. Further evaluation revealed that he had a VIP-producing pancreatic neuroendocrine tumor (NET), which was the cause of his hypokalemic rhabdomyolysis. Although rare in occurrence, a high index of suspicion is of paramount importance for establishing the correct diagnosis and treatment.

Clinicopathological data and treatment modalities for pancreatic vipomas: a systematic review.

PURPOSE: Vasoactive intestinal peptide (VIP) secreting tumor (VIPoma) constitutes a rare functional neuroendocrine tumor that most often originates from pancreatic islet cells and presents as a sporadic, solitary neoplasm of the pancreas. The purpose of this study was to systematically review the literature of pancreatic VIPomas and report clinicopathologic data and treatment modalities for this rare entity. METHODS: A systematic literature search was performed. The reviewed clinical series and case reports were included if they reported surgical treatment and also analyzed oncological outcomes on individual patients. Data extraction was performed using a standard registry pro-forma. RESULTS: The search resulted in 53 case reports and 2 case series including 65 patients in total. Median age reported was 54 years. The predominant pancreatic location was the pancreatic tail. The most common clinical symptom was watery diarrhea. Serum VIP levels were remarkably elevated in all patients. Distal pancreatectomy with or without splenectomy was the most commonly applied surgical procedure. Overall survival associated with pancreatic VIPoma was 67.7%, recurrence rate 40.4% and relevant median disease-free interval was 16 months. CONCLUSIONS: VIPomas are functional tumors that secrete excessive amounts of VIP. Clinically, production of VIP causes refractory watery diarrhea, hypokalemia and achlorydria. As far as diagnosis is concerned, elevated VIP plasma levels are required. Moreover, the majority of VIPomas are malignant or have already metastasized on diagnosis. Despite recent research on the therapeutic strategies against pancreatic VIPoma, surgical resection appears as the only potentially curative approach.

Diagnostic and Management Challenges in Vasoactive Intestinal Peptide Secreting Tumors: A Series of 15 Patients.

OBJECTIVES: Vasoactive intestinal peptide-secreting tumors (VIPomas) are rare functioning neuroendocrine tumors often characterized by a difficult-to-control secretory syndrome and high potential to develop metastases. We hereby present the characteristics of 15 cases of VIPomas and provide a recent literature review. METHODS: This was a retrospective data analysis of 15 patients with VIPoma from 3 different centers and literature research through PubMed database during the last 10 years. RESULTS: Fifteen patients with VIPomas (9 with hepatic metastases at diagnosis) with watery diarrhea and raised VIP levels were studied. Ten patients (67%) had grade 2 tumors, 6 of 15 had localized disease and underwent potentially curative surgery, whereas the remaining 9 received multiple systemic therapies; 3 patients died during follow-up. The median overall survival was 71 months (range, 41-154 months). Patients who were treated with curative surgery (n = 7) had longer median overall survival compared with patients who were treated with other therapeutic modalities (44 vs 33 months). CONCLUSIONS: The management of VIPomas is challenging requiring the application of multiple treatment modalities. Patients who underwent surgical treatment with curative intent appear to have higher survival rate. Central registration and larger prospective studies are required to evaluate the effect of currently employed therapies in these patients.

Pancreatic VIPomas: subject review and one institutional experience.

VIPomas are rare pancreatic endocrine tumors associated with a well-defined clinical syndrome characterized by watery diarrhea, hypokalemia, and metabolic acidosis. The objective of this study was to review a single institution's experience with VIPomas, as well as to review the English literature. A retrospective review of the Johns Hopkins pancreatic database revealed four cases of VIPoma, with three patients being male. All patients presented with watery diarrhea, hypokalemia, hypercalcemia, and acidosis. All patients had no family history of multiple endocrine neoplasia. Computed tomography revealed the primary pancreatic tumor in all patients, with three tumors located in the tail of the pancreas. One tumor involved the entire pancreas. Computed tomography and/or octreotide radionuclide scans identified hepatic metastasis in three patients. Mean serum vasoactive intestinal polypeptide levels were 683 pg/ml (range 293 to 1,500 pg/ml). All patients underwent resection of the pancreatic primary tumor. Two patients also had simultaneous liver resections. All patients had evidence of malignancy as defined by the presence of metastatic lymph nodes and/or hepatic metastases. Two patients had complete resolution of symptoms after surgical resection. One patient required radioablation of liver metastases and adjuvant octreotide therapy for control of symptoms. One patient died of progressive metastatic disease 96 months after surgery, whereas the other three remain alive. Extended, meaningful survival can be achieved for VIPoma patients, combining an aggressive surgical approach with additional strategies for treatment of unresected disease.

Multi-visceral resection of pancreatic VIPoma in a patient with sinistral portal hypertension.

BACKGROUND: VIPomas are rare neuroendocrine tumors poorly described in the literature. Aggressive resection of patients with advanced VIPoma neuroendocrine tumors has rarely been reported. CASE PRESENTATION: A 46 year old women presented with abdominal pain and diarrhea. A three-dimensional (3-D) pancreas protocol computed tomography scan revealed an 18 x 12 cm pancreatic VIPoma abutting the liver, stomach, spleen, left adrenal, colon that also invaded the distal duodenum - proximal jejunum at the ligament of Treitz in association with sinistral portal hypertension. Following preoperative proximal splenic artery embolization, the patient with underwent successful en bloc resection of the locally advanced VIPoma in conjunction with a diaphragmatic resection, total gastrectomy, splenectomy, left adrenalectomy, as well as small and large bowel resection. The estimated blood loss was 500 ml. All margins were negative (R0 resection). The patient is alive and disease-free. CONCLUSION: This case illustrates the role of aggressive resection of pancreatic neuroendocrine tumors and highlights several key technical points that allowed for successful resection.

[Verner-Morrison syndrome revealing a ganglioneuroblastoma in an adult]. / Syndrome de Verner-Morrison révélant un ganglioneuroblastome chez un adulte.

Most vasoactive intestinal peptide (VIP)-producing tumours are from epithelial origin. Tumours derived from the sympathetic nervous system can produce VIP as well. We report here the case of a Verner-Morrison syndrome in a 40-year-old woman revealing a metastatic ganglioneuroblastoma. The diarrhea resolved after the resection of primary tumour and liver metastases. Neuroblastic tumours occur extremely rarely in adults. Thus, the management of these tumours is poorly defined in adults.

Pancreatic neuroendocrine tumours.

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.

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.

Clinico-pathological features of cystic pancreatic endocrine neoplasms and a comparison with their solid counterparts.

AIM: Pancreatic endocrine neoplasms (PENs) may occasionally manifest as cystic lesions of the pancreas. The aim of this study is to report our experience with cystic PENs and to compare their clinico-pathological features with their solid counterparts. MATERIALS AND METHODS: From 1990 to 2004, 38 patients with PENs were reviewed. Six of these tumours appeared on radiological imaging as a cystic lesion of the pancreas. RESULTS: Of the 38 patients with a PEN, 21 of the patients were female and with a median age of 54.5 (range, 33-83) years. Sixteen patients had functional endocrine tumours of which insulinoma was the most common. The six patients with cystic PEN had a median age of 55.5 (range, 41-70) years and half were female. Cystic PENs were significantly larger [48 (range, 25-170) mm vs 19 (range, 3-120) mm, P = 0.013] and were less likely to be benign (0 vs 50%, P = 0.017) compared to their solid counterparts. There was no difference between cystic and solid PENs in terms of age, sex, presence of symptoms, proportion of functioning tumours and location of tumours within the pancreas. CONCLUSION: Cystic PENs share many clinico-pathological features with solid PENs. These differ only in the cystic appearance and tend to be of a larger size. Hence, these findings suggest that cystic and solid PENs are unlikely to be distinct pathological entities but are likely to be morphological variants of the same entity.

Ventricular fibrillation resulting from electrolyte imbalance reveals vipoma in MEN1 syndrome.

Sporadic VIPoma is an exceedingly rare tumor with an annual incidence of 1:10 million people worldwide, yet it is described in approximately 5 % of MEN1 patients. The majority of VIPomas are malignant and radical surgery is the best therapeutic option. A 58-year-old man presented with cardiocirculatory arrest due to ventricular fibrillation. The patient had a 3-month history of epigastric pain with diarrhea. After reanimation, laboratory data revealed severe hypokalemia and hypercalcemia. Further investigations showed hyperparathyroidism, left adrenal adenoma and pituitary microprolactinoma and genetic diagnosis of MEN1 syndrome was made. Abdominal computed tomography revealed a 45 × 30 mm mass of the pancreatic head and two hepatic lesions, which proved to be neuroendocrine after 68 Ga PET and needle biopsy. Vasoactive intestinal peptide (VIP) serum level had increased. Subsequently the patient underwent pylorus-preserving pancreaticoduodenectomy and hepatic resection. Intraoperative VIP returned to normal values. Histopathology confirmed a pancreatic VIPoma metastatic to the liver. The postoperative course was unremarkable and the patient is well with no evidence of disease at a 48 months follow-up. Even in case of anusual presentation, when two or more main clinical findings of MEN1 related tumors are present, unrespectively to the presence of MEN1 mutation, MEN1 syndrome should be suspected. Surgery in MEN1 pancreatic neuroendocrine tumors is indicated both to treat symptoms and to avoid oncological progression even in advanced cases.