Successful Treatment of Hypokalemic Rhabdomyolysis Caused by a Pancreatic VIPoma: A Case Report.

BACKGROUND VIPomas are rare neuroendocrine tumors typically located in the pancreas. The majority of cases autonomously secret vasoactive intestinal polypeptide (VIP), which can result in profuse, refractory, watery diarrhea. The fluid and electrolyte imbalance can progress to dehydration and profound hypokalemia, resulting in the watery diarrhea, hypokalemia, achlorhydria (WDHA) syndrome. One previous case of a pancreatic VIPoma progressing to hypokalemic rhabdomyolysis has been described. CASE REPORT A 33-year-old woman presented with 3 months of progressive, refractory diarrhea and weakness. Her serum VIP level was elevated and imaging discovered a mass in the region of the pancreatic tail. Laparoscopic partial pancreatic resection was performed and a 3.7-cm diameter, solitary stage T2 N0 M0, well-differentiated carcinoma was removed. CONCLUSIONS A high index of suspicion is important when diagnosing chronic diarrhea. Minimally invasive surgery is an option in the surgical treatment of pancreatic VIPoma.

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.

Sporadic pancreatic vasoactive intestinal peptide-producing tumor (VIPoma) in a 47-year-old male.

VIPoma is an exceedingly unusual neuroendocrine neoplasm that autonomously secretes vasoactive intestinal polypeptide (VIP). Its reported incidence is approximately 1 per 10 million individuals per year. Herein, we report the case of sporadic pancreatic VIPoma in a 47-year-old male who presented with a six-month history of chronic, plentiful, watery diarrhea. On physical examination, the patient looked sick, lethargic and had signs of dehydration. Laboratory investigations revealed high VIP hormone level (989pg/mL), hypokalemia, hypercalcemia, hyperglycemia, high blood urea nitrogen, high creatinine, and metabolic acidosis on arterial blood gas. Contrast-enhanced computed tomography (CT) scan showed a 3.1×3.3×4.7cm, well-defined, enhancing lesion involving the pancreatic tail with a cystic component. Moreover, a 5.7×6.1×6.8cm metastatic hepatic lesion was identified. The patient underwent distal pancreatectomy with splenectomy, hepatic lesion resection, and lymph node dissection. Histopathological and immunohistochemical examination of the pancreatic and hepatic lesions revealed neuroendocrine tumor (VIPoma). Postoperatively, the patient received radiofrequency ablation for the hepatic lesion. A post-operative six-month follow-up showed significant symptomatic relief, reduced VIP hormone level (71pg/mL) and normalized electrolyte and acid-base profiles. However, a magnetic resonance imaging (MRI) scan showed a small residual metastatic liver lesion which was considered for hepatic artery embolization (HAE). The patient is still alive with a residual hepatic disease at 18months. We also present a brief literature review on VIPoma.

Sunitinib for the treatment of metastatic paraganglioma and vasoactive intestinal polypeptide-producing tumor (VIPoma).

OBJECTIVES: Gastroenteropancreatic neuroendocrine tumors (NETs) are rare tumors of the endocrine and nervous systems. Whereas early surgical resection can significantly reduce tumor mass, there are few data available concerning the control of hormonal secretion and associated symptoms. Studies have shown that the tyrosine kinase inhibitor sunitinib significantly prolongs progression-free survival in patients with pancreatic NETs. Here, we present 2 case reports of sunitinib in patients with different types of NETs. METHODS: The patients were a 12-year-old boy with metastatic vasoactive intestinal polypeptide-producing tumor (VIPoma) and a 70-year-old woman with metastatic paraganglioma/NET. Both were treated in an outpatient clinical setting. Sunitinib was titrated to 37.5 mg on a continuous daily dosing schedule in the patient with VIPoma, and the dose was 50 mg/d (4 weeks on, 2 weeks off) in the patient with the paraganglioma/NET. RESULTS: The patient with the paraganglioma/NET had a confirmed complete radiographic response and the patient with VIPoma had a confirmed partial response (Response Evaluation Criteria in Solid Tumors). In both patients, improvements were observed in biochemical tumor markers, clinical responses, and quality of life. CONCLUSIONS: In these patients, sunitinib reduced biochemical markers and stabilized or reduced tumor bulk and may therefore be a potential therapeutic option for these tumor types.

Pheochromocytoma with histologic transformation to composite type, complicated by watery diarrhea, hypokalemia, and achlorhydria syndrome.

OBJECTIVE: To describe the rare occurrence of histologic transformation of a pheochromocytoma to a composite type of tumor during a long-term follow-up, which was complicated by watery diarrhea, hypokalemia, and achlorhydria syndrome. METHODS: We report the case of a 12-year-old girl who presented with headache, hypertension, and elevated catecholamine levels in the blood and urine. A tumor was found in the right adrenal gland and resected. When she was 15 years of age, multiple metastatic nodules were found in the lung and liver. Intensive chemotherapy was ineffective, and she underwent follow-up with conservative therapy. At 25 years of age, she complained of diarrhea. Laboratory studies revealed hypokalemia and an increase in the level of serum vasoactive intestinal polypeptide (VIP). A year later, she died of extensive metastatic disease. The primary and recurrent tumors at autopsy were histologically examined. RESULTS: The primary tumor was pure pheochromocytoma, and the tumors at autopsy were a composite type of pheochromocytoma and ganglioneuroma. Only a few VIP-positive cells were found in the primary tumor, whereas both pheochromocytoma and ganglioneuroma cells of composite tumors were frequently positive for VIP. CONCLUSION: Our case showed histologic transformation from pheochromocytoma to a composite type of tumor during a 14-year clinical course, which was associated with additional hormone production and a change in symptoms. Careful attention should be paid to the alteration of endocrine symptoms and hormone levels during prolonged follow-up of pheochromocytoma in young patients.

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.

[The VIP-secreting tumor as a differential diagnosis of protracted diarrhea in pediatrics]. / Der VIP-produzierende Tumor in der Pädiatrie als Differenzialdiagnose der protrahierten Diarrhö

BACKGROUND: Vasoactive intestinal peptide (VIP) can be produced by mature neurogenic tumors. Pathologically elevated VIP plasma levels cause secretory diarrhea with excessive loss of water and electrolytes. Despite the clinical severity diagnosis of a VIP-secreting tumor is often delayed and subsequently its extirpation as the mainstay of therapy. PATIENTS: We report on two patients with ganglioneuroblastoma and secretory diarrhea. We contrast the case of a 13-month-old boy with advanced symptoms of secretory diarrhea, high VIP plasma levels, and late diagnosis to the case of a 14-month-old boy with mild secretory diarrhea and normal VIP plasma levels but positive proof of VIP in tumor tissue. Reviewing the literature we found 57 cases of pediatric VIP-secreting tumors. RESULTS: The clinical situation is characterized by the typical symptoms of secretory diarrhea with hypokalemia and metabolic acidosis. Histopathology predominantly reveals ganglioneuroblastoma or ganglioneuroma. The symptoms mostly stop after complete resection of the tumor whereas lack of resection is associated with elevated mortality rates. CONCLUSIONS: In case of prolonged therapy-resistant secretory diarrhea the existence of a VIP-secreting tumor should be considered. Diagnostic work-up should include the assessment of VIP plasma levels, catecholamines in urine, and appropriate imaging techniques in order to rule out or confirm the possibility of a VIP producing tumor.

Circulating ghrelin levels in patients with pancreatic and gastrointestinal neuroendocrine tumors: identification of one pancreatic ghrelinoma.

Ghrelin is a novel gastrointestinal hormone involved in several metabolic functions. Although the expression of ghrelin has been demonstrated in most gastrointestinal carcinoids and pancreatic tumors, the circulating levels of this peptide have been marginally assessed in patients with these disorders. We measured plasma ghrelin levels in 16 patients with gastrointestinal carcinoid (10 with midgut and 6 with gastric carcinoid), 24 patients with pancreatic tumor (8 with gastrinoma, 2 with insulinoma, 2 with vipoma, 1 with glucagonoma, and 11 with nonfunctioning tumor), and 35 healthy controls. Plasma ghrelin levels recorded in patients with gastroenteropancreatic tumors were similar to controls (mean +/- SE, 182.7 +/- 66.5 pM in patients vs. 329 +/- 32 pM in controls, P = not significant), and no significant difference between gastrointestinal and pancreatic, functioning and nonfunctioning, and metastatic and nonmetastatic tumors was observed. One patient with metastatic nonfunctioning pancreatic tumor had circulating ghrelin levels of 12,000 pM that were slightly reduced during chemotherapy and interferon therapy. Immunohistochemistry performed on peritoneal lesions showed an intense, focal cytoplasmic positivity for ghrelin. Despite the 50-fold increase in ghrelin concentrations, the patient had normal serum GH and IGF-I levels. In conclusion, the study showed that carcinoids and pancreatic tumors rarely cause ghrelin hypersecretion. However, in this series, 1 pancreatic ghrelinoma not associated with clinical features of acromegaly was identified.

[Primary hepatic vipoma]. / Vipome hépatique primitif.

Vipoma is a rare neuroendocrine tumor most frequently localized in the pancreas. When it is extrapancreatic, it is most often neurogenic. We report a case of primary extrapancreatic vipoma that is non neurogenic localized in the right liver in a patient with severe diarrhea and hypokaliema. Computed tomography, magnetic resonance imaging, intraoperative tomography and surgical exploration did not show any other extrahepatic primary lesion. The diagnosis was performed by immunochemistry, tumorous cells were positives with anti-VIP antibody. Forty two months after right hepatectomy, the patient was asymptomatic.

Life threatening diarrhoea ultimately cured by surgery.

A 30-year-old previously healthy woman was diagnosed as having a vasoactive intestinal polypeptide (VIP)-producing tumour of the pancreas. Her medical history was typical for neuroendocrine gastrointestinal tumours, presenting initially with non-specific symptoms but eventually she developed life-threatening manifestations requiring intensive care due to severe dehydration. She immediately recovered following surgical resection. The patient had elevated serum concentrations of VIP as well as pancreastatin, and post-operatively elevated concentrations of three growth factors, IGF-I, EGF and TGF-alpha, were seen. The importance of the alterations in plasma concentrations of the different peptides for her symptomatology are discussed.

WDHA (watery diarrhea, hypokalemia, achlorhydria) syndrome: clinical features, diagnosis, and treatment.

WDHA (watery diarrhea, hypokalemia, and achlorhydria) syndrome is an unusual paraneoplastic condition caused by excess vasoactive intestinal polypeptide (VIP) secreted by certain tumors. The onset of the syndrome is insidious, and diagnosis is usually delayed by months to years. Morbidity and mortality from untreated WDHA syndrome are related to long-standing dehydration and electrolyte and acid-base disturbances resulting in chronic renal failure. Diagnosis requires documentation of large volumes of secretory diarrhea, elevated serum VIP levels, and localization of the VIP-secreting tumor. Treatment includes correction of volume, electrolyte, and metabolic abnormalities, pharmacotherapy to decrease gastrointestinal secretion and increase absorption, and ultimately surgical resection or debulking of the vipoma.

Diagnostic value of fasting plasma peptide concentrations in patients with chronic diarrhea.

To evaluate the utility of screening for multiple gastrointestinal peptides in the evaluation of patients with chronic diarrhea, we studied 193 patients referred for evaluation of chronic diarrhea and eight patients with known peptide-secreting tumors as a reference group. Fasting plasma samples were assayed for motilin, neurotensin, pancreatic polypeptide, somatostatin, substance P, vasoactive intestinal polypeptide, gastrin-releasing peptide, and calcitonin during a protocol evaluation for causes of chronic diarrhea. Although none of the referred patients were found to have tumors, abnormal levels of one or more peptides were found in 86 of 193 patients (45%). Abnormal plasma peptide levels were sometimes as high in these patients as in patients with known peptide-secreting tumors and would have led to mistaken diagnoses of tumors much more often than they would have led to correct diagnoses. The positive predictive value of elevation of any assayed peptide was < 2% at realistic prevalence rates for peptide-secreting tumors; the negative predictive value of a series of normal results was > 99%, but much of this was due to the rarity of these tumors. Patients with chronic diarrhea should not be screened routinely with a panel of plasma peptide assays in an effort to detect tumors; instead, peptide levels should be ordered selectively. Elevated fasting concentrations of the plasma peptides measured in this study are most likely epiphenomena due to diarrhea and should not be the sole basis for invasive diagnostic or surgical management of these patients.

[Diagnosis of Verner-Morrison syndrome (VDHA) and its treatment with sandostatin an streptozocitin]. / Verner-Morrison (WDHA) szindróma diagnózisa és kezelése Sandostatin és streptozotocin adagolással.

A case report is presented of a man with Verner-Morrison syndrome of extreme severity, caused by an unresectable pancreatic VIPoma. The pathological role of vasoactive intestinal polypeptide (VIP) is discussed in the pathogenesis of Watery Diarrhoea, Hypokalaemia, Achlorhydria (WDHA) syndrome. The authors describe the typical symptoms of the syndrome and provide a diagnostic and therapeutic strategy. Plasma level of VIP was determined by the authors' own VIP RIA method. Administration of a long acting somatostatin analogue, octreotide (Sandostatin, Sandoz) at a dose of 100 micrograms daily, decreased the plasma level of VIP from about 55 to 38 fmol/ml, which was associated with complete regression of the diarrhoea. Due to the 'escape phenomenon' the dose of Sandostatin was gradually increased and finally completed with streptozotocin (Zanosar, Upjohn) administration, which was repeated every 8 weeks. The combination of Sandostatin and streptozotocin resulted in complete regression of diarrhoea and substantial diminution of the tumour mass. The patient displayed a weight gain and returned to normal life.

Calcitonin, as SMS 201-995, ameliorates the VIPoma syndrome.

A 72-year-old woman was referred to our hospital for diarrhea, abdominal and back pain, weight loss, low serum potassium level. Pathological findings and high circulating Vasoactive Intestinal Peptide (VIP) levels allowed us to diagnose "VIPoma syndrome". The patient underwent a treatment with SMS 201-995 with improvement of symptomatology and reduction of circulating VIP levels. After a wash-out period the patient was treated with salmon calcitonin with a net improvement of diarrhea, normalization of potassium serum level and reduction of VIP level. The symptomatology recurred after calcitonin withdrawal. These data confirm the effectiveness of SMS 201-995 in the VIPoma syndrome and suggest that calcitonin may ameliorate symptomatology and reduce circulating VIP level in patients with VIPoma tumor.

[Use of octreotide in the treatment of digestive endocrine tumors. A French multicenter study]. / Utilisation de l'octréotide dans les tumeurs endocrines digestives. Etude française multicentrique.

Morbidity and mortality in endocrine gastro-enteropancreatic (GEP) tumours are mainly related to the clinical consequences of tumoral peptide hypersecretion. Surgical resection at an early stage is the only curative treatment. However, most tumours are detected only when the hypersecretory state reflects the presence of metastases; surgery and chemotherapy then give only palliative results counterbalanced by serious side-effects. Somatostatin inhibits most endocrine secretions of the GEP tract and thus can alleviate invalidating symptoms. Its use is limited by its short half-life (2 min), the necessity of i.v. infusion and the possibility of a rebound phenomenon. Octreotide, a synthetic somatostatin analogue with a long duration of action, is administered subcutaneously and allows ambulatory treatment. In our series of 78 patients we observed about 80 percent of excellent or good clinical results, enabling the patients to resume normal life. Only minor and transient side-effects were noted. The overall tolerance of the drug was considered excellent or good. Prolonged administration of octreotide is a safe and effective symptomatic treatment in patients without any restriction of anti-tumoral procedures. Furthermore, it prevents the severe carcinoid crises that occur during surgery or embolization in patients with carcinoid syndromes.

7B2, a possible marker for nonfunctioning pancreatic islet cell tumor.

Plasma 7B2 was measured in 13 patients with pancreatic islet cell tumors, 11 with pancreatic adenocarcinoma and 31 normal subjects as a control. The mean (+/- SD) concentrations of plasma 7B2 in the normal subjects and the patients with pancreatic islet cell tumors were 67 +/- 10 and 1041 +/- 1786 pmol/l, respectively, and the value in the patients with pancreatic islet cell tumors was significantly higher than that in the normal subjects (p less than 0.01). Elevation of plasma 7B2 over the normal range, defined as less than the mean + 3SD value of those in the normal subjects, was found in 10 of 13 patients with pancreatic islet cell tumors including 4 with nonfunctioning tumor. Plasma 7B2 dropped into the normal range postoperatively in 3 patients with nonfunctioning tumor. Plasma 7B2 concentrations in the patients with pancreatic adenocarcinoma remained in the normal range. These results raise a possibility that 7B2 is a useful marker for pancreatic islet cell tumors, in particular nonfunctioning tumor.

PreproVIP-derived peptides in tissue and plasma from patients with VIP-producing tumours.

To elucidate the biosynthetic processing of the precursor for vasoactive intestinal peptide (prepro-VIP) in tumours producing VIP we have used newly developed radioimmunoassays directed against the five functional domains of the VIP precursor molecule: preproVIP 22-79, peptide histidine methionine (PHM), preproVIP 111-122, VIP and preproVIP 156-170 in combination with HPLC to identify and quantify the peptides in tumour specimen and plasma from patients with the watery diarrhoea syndrome. Elevated quantities of all the five peptides were found in the 13 tumours (nine neurogenic tumours, one pheochromocytoma, three pancreatic carcinomas) examined. The preproVIP derived peptides were expressed in non-equimolar amounts and the relative proportion of the various peptides differed markedly from tumour to tumour. The pheochromocytoma was the only tumour type which contained large amounts of preproVIP 156-170 in comparison with the other peptides. A proportion of the VIP precursor which varied from 7% to 73% followed a pathway in which the dibasic conversion site after PHM was uncleaved as evidenced by the presence of PHV, a C-terminally extended form of PHM. It was also found that unlike normal tissue a fraction of the C-terminal VIP precursor peptide, preproVIP 156-170, was having its C-terminal lysine residue removed during processing. The findings indicate that various post-translational processing pathways of preproVIP exist. All the peptide sequences produced in the tumour tissue were secreted as evidenced by their presence in plasma in elevated concentrations. The plasma levels of preproVIP 22-79, preproVIP 111-122 and PHV exceeded those of the remaining preproVIP-derived peptides suggesting that determination of these peptides in patients with VIP-secreting tumours may be better markers than VIP.

Characterization of an alpha-amidating activity in a human pancreatic tumour secreting vasoactive intestinal peptide (VIP).

A case of watery diarrhoea hypokalaemia achlorhydria (WDHA) syndrome due to a pancreatic tumour and identified by VIP plasma level, VIP immunocytochemistry, and ultrastructural analysis of tumour sections, is reported. Since VIP is the mediator of the syndrome and is biologically active under its amidated form, the enzymatic alpha-amidating activity was investigated and characterized in tumour extract; using the synthetic substrate D-Tyr-Val-Gly, the enzyme displayed an optimal activity at pH 7.0, under aerobic conditions and with 35 microM CuSO4 and 3 mM ascorbate as co-factors. The Kmax and Vmax values of the enzymatic activity were 133.7 microM and 26.9 pmol/h/micrograms protein respectively. Its molecular weight, determined by molecular sieving, was close to 36 kDa. Other tumours of the human endocrine pancreas were also investigated for the enzymatic activity. The clinical interest of studying the regulation of the alpha-amidating activity in such tumours is discussed.