Treatment options of metastatic and nonmetastatic VIPoma: a review.

PURPOSE: VIPoma belongs to the group of neuroendocrine neoplasms. These tumours are located mostly in the pancreas and produce high levels of vasoactive intestinal peptide (VIP). In most cases, a metastatic state has already been reached at the initial diagnosis, with high levels of VIP leading to a wide spectrum of presenting symptoms. These symptoms include intense diarrhoea and subsequent hypopotassaemia but also cardiac complications, with life-threatening consequences. Treatment options include symptomatic therapy, systemic chemotherapy and targeted therapy, as well as radiation and surgery. Due to the low incidence of VIPoma, there are no prospective studies or evidence-based therapeutic standards to date. METHODS: To evaluate the possible impact of different therapy strategies, we performed literature research using PubMed. RESULTS: All possible treatment modalities for VIPoma have at least one of two therapy goals: antisecretory effects (symptom control) and antitumoural effects (tumour burden reduction). Symptomatic therapy is the most important in the emergency setting to rehydrate, balance electrolytes and stabilise the patient. Symptomatic therapy is also of great importance perioperatively. Somatostatin analogues play a major role in symptom control, although their efficiency is often limited. Chemotherapy may be effective in reaching stable disease for a certain time period, although its impact on symptom control is limited and often delayed. Among targeted therapy options, the usage of sunitinib appears to be the most effective in terms of symptom control and showing antitumoural effects at the same time. Experience with radiation is still limited; however, local ablative procedures seem to be promising options. Peptide receptor radiotherapy (PRRT) with radiolabelled somatostatin analogues (SSAs, 177Lu-DOTATATE) offers a targeted approach, especially in patients with high somatostatin receptor density. Surgery is the first-line therapy for nonmetastatic VIPoma. Additionally, if the resection of all visible tumour lesions is possible, the surgical approach seems preferable to other strategies in highly symptomatic patients. The role of surgery in very advanced stages where only tumour debulking is possible remains debatable. However, a high rate of immediate symptom control can be achieved by tumour debulking followed by somatostatin therapy, although the impact on survival remains unclear. CONCLUSION: Surgery is the only curative option for nonmetastatic VIPoma. Additionally, surgery should be a first-line therapy option for highly symptomatic patients, especially if the resection of all tumour lesions (primary tumour and metastasis) is achievable. In frail patients, other modalities can be used.

Sunitinib achieved fast and sustained control of VIPoma symptoms.

VIPomas are rare-functioning neuroendocrine tumors (NETs). Overproduction of vasointestinal peptide (VIP) leads to the Verner-Morrison syndrome, whose management is challenging when refractory to somatostatin analogs. Two patients with progressive metastatic pancreatic NETs and refractory VIPoma symptoms were treated with sunitinib. This led to fast and sustained total relief of VIPoma symptoms, enabling earlier discharge from hospital and improvement in their quality of life. In both cases, sunitinib discontinuation led to the quick recurrence of watery diarrhea, which resolved within a few days after reintroducing sunitinib. The anti-secretory effect of sunitinib on VIPoma syndrome was probably not related to any anti-tumor effect. These observations agree with the rare reported cases of anti-secretory effects with targeted therapies. The sunitinib-driven inhibition of multiple-tyrosine kinase receptors might act on secretory pathways and describe sunitinib's ability to improve VIPoma symptoms. Sunitinib could be a therapeutic option to control refractory VIPoma symptoms in patients with NETs.

Octreotide long-acting repeatable use among elderly patients with carcinoid syndrome and survival outcomes: a population-based analysis.

BACKGROUND: Octreotide long-acting repeatable (LAR) is indicated for the treatment of carcinoid syndrome and diarrhea related to VIPoma, and may delay tumor growth in patients with neuroendocrine tumors (NETs). To the authors' knowledge, the pattern of octreotide LAR use in clinical practice and its impact on survival outcomes has not been well documented. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, the authors identified patients with NET aged ≥ 65 years who were diagnosed between July 1999 and December 2007. Patients with US Food and Drug Administration-approved indications for octreotide LAR were identified from Medicare claims. Multivariate logistic regression was performed to ascertain factors associated with octreotide LAR use, whereas the Cox proportional hazards model was used to evaluate the impact of octreotide LAR on survival. RESULTS: Among those with Food and Drug Administration-approved indications, 245 of 4848 patients with distant-stage disease (51%) and 81 of 807 patients with local/regional disease (10%) initiated treatment with octreotide LAR within 6 months of diagnosis. Multivariate logistic regression indicated that among those with distant-stage disease, older age (≥ 80 years vs 65-69 years) (odds ratio [OR], 0.43; 95% confidence interval [95% CI], 0.23-0.81), female sex (OR, 0.62; 95% CI, 0.40-0.97), and living in the South (vs Northeast) (OR, 0.36; 95% CI, 0.18-0.72) were associated with a lower likelihood of using octreotide LAR. The multivariate proportional hazards model showed that octreotide LAR provided a significant 5-year survival benefit for patients with distant-stage disease (hazards ratio, 0.61; P ≤ .001), whereas this survival benefit was not shown for the patients with local/regional stage (hazards ratio, 0.88; P = .563). CONCLUSIONS: The results of this retrospective study suggest a possible survival benefit for the use of octreotide LAR in elderly patients with distant-stage NET with carcinoid syndrome. The results of the current study also suggest that octreotide LAR is underused in this population despite recommended guidelines.

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.

[Verner-Morrison syndrome: a case study]. / Verner-Morrison-szindróma egy esete.

Verner and Morrison described a syndrome of watery diarrhea, hypokalemia, and achlorhydria (WDHA) in 1958. VIPomas producing high amounts of vasoactive intestinal peptide (VIP) commonly originate from the pancreas. Typical symptoms play a momentous role in the diagnosis of VIPoma. Diarrhea may persist for years before the diagnosis. Morbidity from untreated WDHA syndrome is associated with long-standing dehydration and with electrolyte and acid-base metabolism disorders, which may cause chronic renal failure. Assessment of specific marker (VIP) offers high sensitivity in establishing the diagnosis. Imaging modalities include endoscopic ultrasonography, computed tomography and magnetic resonance imaging, and particularly, scintigraphy with somatostatin analogues. Treatment options include resection of the tumor, chemotherapy or the reduction of symptoms with somatostatin analogues. Early diagnosis and management may affect survival of patients favorably. VIPoma cases may be associated with multiple endocrine neoplasia type 1.

Amelioration of symptoms and reduction of VIP levels after hepatic artery chemoembolization in a patient with sandostatin resistant VIPoma.

Vasoactive intestinal polypeptide secreting islet cell tumors (VIPomas) are neuroendocrine tumors that secrete excessive amounts of vasoactive intestinal polypeptide (VIP) that cause distinct syndromes characterized by large-volume diarrhea, hypokalemia, and dehydration. The annual incidence of these tumors is estimated to be about one per 10,000,000 individuals in the general population. We report a successful treatment of VIPoma with hepatic chemoembolization of a metastatic hepatic lesion evidenced by a reduction of VIP levels and resolutions of symptoms in a patient with pancreatic VIPoma unresponsive to increased doses of an octreotide analog.

VIPoma with expression of both VIP and VPAC1 receptors in a patient with WDHA syndrome.

We report a case of VIPoma in a 72-year-old female patient who presented with excessive diarrhea, severe hypokalemia, and acidemia. She had been referred to our hospital three times because of severe diarrhea. No primary tumor site was found by conventional techniques, including contrast-enhanced CT and MRI, angiography, endoscopy, and positron emission tomography (PET), but a tumor was subsequently found in the head of the pancreas by octreotide scanning. Her diarrhea diminished dramatically after octreotide treatment, while her diarrhea has ceased without the therapy of octreotide at the first admission in the course of 2 years of her disease. Immunohistochemial analysis of the excised tumor tissue revealed the expression of both vasoactive intestinal peptide (VIP) and VIP and pituitary adenylate cyclase-activating peptide 1 (VPAC1) receptors. This is the first case report of a VIPoma that immunostains for VIP and VPAC1 receptors and indicates that abundant VIP produced by VIPoma might inhibit its growth and reduce VIP secretion via the VPAC1 receptor in vivo.

The surgical and systemic management of neuroendocrine tumors of the pancreas.

Neuroendocrine tumors of the pancreas comprise a class of rare tumors that can be associated with symptoms of hormone overproduction. Five distinct clinical endocrinopathies are associated with neuroendocrine tumors; however, most of these tumors remain asymptomatic and follow an indolent course. Complete surgical resection offers the only hope for cure, but understanding the basic biology of the tumors has advanced the medical management in metastatic disease. Surgical resection of hepatic metastases offers survival advantage and should be performed when feasible. Although hepatic artery embolization is currently the preferred mode of nonsurgical palliation for pain and hormonal symptoms, other modalities may play a role in metastatic disease.

Characterization of an outbreak of astroviral diarrhea in a group of cheetahs (Acinonyx jubatus).

A Mamastrovirus was identified in an outbreak of diarrhea in cheetahs (Acinonyx jubatus). Five young adult and two adult cheetahs presented with lethargy, anorexia, watery diarrhea and regurgitation over an 11-day period. Fecal samples were submitted for electron microscopy and culture. Electron microscopy results revealed particles morphologically consistent with an astrovirus, and no other viral pathogens or significant bacterial pathogens were identified. The astrovirus was confirmed and sequenced using consensus astroviral PCR, resulting in a 367 base pair partial RNA-dependent-RNA polymerase (RdRp) product and a 628 base pair partial capsid product. Bayesian and maximum likelihood phylogenetic analyses were performed on both the RdRp and the capsid protein segments. All animals were monitored and treated with bismuth subsalicylate tablets (524mg PO BID for 5 days), and recovered without additional intervention. This is the first report we are aware of documenting an astrovirus outbreak in cheetah.

Diagnosis and treatment of VIPoma in a female patient.

We report a case of VIPoma in an 83-year-old female patient, who presented with frequent and excessive diarrhoea, muscle weakness, and severe hypokalaemia. Abdominal computed tomography (CT) revealed a 4x6 cm mass in the body of the pancreas. Laboratory analysis showed elevated levels of both vasoactive intestinal polypeptide (VIP; 153 pmol/l) and pancreatic polypeptide (161 pmol/l). In view of the patient's age, physical condition, and tumour size, surgical resection was not performed. The patient was treated with a long-acting octreotide, after which her symptoms diminished. After 24 months of follow-up, the patient remained in good physical condition without any further serious gastrointestinal symptoms. The VIPoma syndrome is caused by a neuroendocrine tumour, usually located in the pancreas, which secretes VIP, causing severe diarrhoea, dehydration and hypokalaemia. Treatment options include resection of the tumour, chemotherapy or the reduction of symptoms with somatostatin analogues. We provide an overview of the incidence, pathophysiology, diagnosis, treatment strategies, and prognosis of this rare syndrome.

Large cell carcinoma with calcitonin and vasoactive intestinal polypeptide-associated Verner-Morrison syndrome.

Verner-Morrison syndrome, characterized by diarrhea, hypokalemia, and hypochlorhydria, is caused most commonly by vasoactive intestinal polypeptide-secreting islet cell tumors of the pancreas. Verner-Morrison syndrome has not been described as a paraneoplastic syndrome in non-small cell lung cancer. We describe a 38-year-old man with metastatic non-small cell lung cancer of large cell carcinoma with neuroendocrine differentiation who presented with bone metastasis and intractable secretory diarrhea that was unresponsive to pharmacological treatment, including octreotide. Laboratory evaluation indicated elevated serum calcitonin and vasoactive intestinal polypeptide levels. Chemotherapy resulted in a transient response in the patient's diarrhea and neuroendocrine markers. The patient did not respond to further therapy and died 5 months after onset of back pain. To our knowledge, this is the first published case of large cell carcinoma with neuroendocrine differentiation associated with treatment-responsive paraneoplastic Verner-Morrison syndrome.

Rapid and sustained relief from the symptoms of carcinoid syndrome: results from an open 6-month study of the 28-day prolonged-release formulation of lanreotide.

This 6-month, open, non-controlled, multicenter, dose-titration study evaluated the efficacy and safety of 28-day prolonged-release (PR) lanreotide in the treatment of carcinoid syndrome. Eligible patients had a carcinoid tumor with > or =3 stools/day and/or > or =1 moderate/severe flushing episodes/day. Six treatments of 28-day PR lanreotide were administered by deep subcutaneous injection. The dose for the first two injections was 90 mg. Subsequent doses could be titrated (60, 90, 120 mg) according to symptom response. Seventy-one patients were treated. Flushing decreased from a mean of 3.0 at baseline to 2.3 on day 1, and 2.0 on day 2, with a daily mean of 2.1 for the first week post-treatment (p < 0.05). Diarrhea decreased from a mean of 5.0 at baseline to 4.3 on day 1 (p < 0.05), and 4.5 on day 2, with a daily mean of 4.4 for the first week post-treatment (p < 0.001). Symptom frequency decreased further after the second and third injections, and reached a plateau after the fourth injection. By month 6, flushing and diarrhea had significantly decreased from baseline by a mean of 1.3 and 1.1 episodes/day, respectively (both p < or = 0.001); 65% of patients with flushing as the target symptom and 18% of diarrhea-target patients achieved > or =50% reduction from baseline. Median urinary 5-hydroxyindoleacetic acid and chromogranin A levels decreased by 24 and 38%, respectively. Treatment was well tolerated. 28-day PR lanreotide was effective in reducing the symptoms and biochemical markers associated with carcinoid syndrome.

[W.D.H.A. Syndrome due to occult neuroendocrine malignancy with concomitant liver metastases]. / Okkulte, maligne neuroendokrine Neoplasie mit Lebermetastasen als Ursache eines WDHA-Syndroms.

In June 1999, a 62-year-old man is hospitalised to evaluate the sonographic suspicion of liver metastases. The biopsy of the liver shows a malignant neuroendocrine tumour. Further diagnostic investigation including gastroscopy, colonoscopy, enteroclysis, thoracal and abdominal CT and somatostatin-receptor-scintigraphy does not localise the primary tumour. In the absence of clinical symptoms a wait and see procedure with clinical and imaging controls at regular intervals is arranged. Beginning in spring of 2001--nearly two years after the initial diagnosis--the patient suffers from progredient diarrhoea and weight loss leading to hospitalisation in September 2001. The existence of secretory diarrhoea, hypokalaemia and hypercalcaemia arouses suspicion of vipoma. This is proven by a remarkably elevated plasma concentration of vasoactive intestinal peptide (VIP). Once more, an accurate investigation is started but no primary tumour can be discovered despite extensive liver metastases. A vipoma is a rare differential diagnosis of secretory diarrhoea. This case report describes the remarkable constellation of liver metastases of a malignant neuroendocrine neoplasm without a primary tumour and the clinical presentation of a W.D.H.A. syndrome (watery diarrhoea, hypokalaemia and hypo- or achlorhydria). Despite extensive disease, therapy with octreotide and prednisolone provides a good clinical response.

Expression of somatostatin receptor and effects of somatostatin analog on pancreatic endocrine tumors.

PURPOSE: Somatostatin analogs have been administered to patients with pancreatic endocrine tumors in an attempt to inhibit hormone hypersecretion and prevent tumor growth. It is speculated that their efficacy is correlated with the expression of specific subtypes of somatostatin receptors. The aim of this study was to immunohistochemically evaluate the expression of somatostatin receptor subtypes in human pancreatic endocrine tumors, and to determine whether the expression of these subtypes is correlated with the effectiveness of the somatostatin analogs. METHODS: Somatostatin receptor subtypes 1, 2, and 3 (sst 1, 2, and 3) were immunohistochemically investigated in seven pancreatic endocrine tumors: four insulinomas, one VIPoma, and two nonfunctioning tumors associated with multiple endocrine neoplasia type I, using paraffin sections. Three of the four patients with insulinoma were given an octreotide injection. RESULTS: Cells were homogeneously stained in the tumor region. More than 85% of the specimens expressed sst 1, 2, and 3. There was no difference among the immunohistochemical stainings of somatostatin receptor subtypes according to most tumor characteristics; however, the expression of sst 2 was extremely positive, and the expression of sst 3 was moderately positive in the specimen from a patient in whom the octreotide injection had proven very effective. CONCLUSION: These findings indicate that the efficacy of octreotide may be correlated with the density of sst 2 and 3 in an immunohistological study using paraffin sections.