ViPoma


Article Author:
Sartaj Sandhu


Article Editor:
Ishwarlal Jialal


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
6/4/2019 2:38:45 PM

Introduction

Vasoactive intestinal peptide tumors (VIPoma) are neuroendocrine tumors secreting vasoactive intestinal peptide (VIP) in an unregulated manner. Werner and Morrison first described them in 1958 as a pancreatic tumor resulting in watery diarrhea and hypokalemia [1]. In 1973, the team of Bloom, Polak, and Pearse confirmed that the mediator was VIP [2]. The VIPoma syndrome is also known as Verner-Morrison syndrome, watery diarrhea, hypokalemia, and hypochlorhydria or achlorhydria (WDHA) syndrome and pancreatic cholera syndrome [3]. This review highlights the clinical presentation, diagnosis, and management.

Etiology

VIP is a neurohormone produced in the central nervous system as well as in the neurons of the gastrointestinal (GI), respiratory, and urogenital tracts. It functions as a vasodilator and regulator of smooth muscle activity, stimulator of water and electrolyte secretion from the intestinal tract, an inhibitor of gastric acid secretion, and promotor of blood flow mainly in the GI tract.

Epidemiology

VIPomas are rare tumors with an incidence of 0.05% to 2.0% and can occur both in children and adults [4]. In adults, they occur most commonly between the ages of 30 to 50 years and are mostly intra-pancreatic (95%). A small proportion of tumors secreting VIP have been reported as colorectal cancer, lung cancer, pheochromocytoma, neurofibroma, and ganglioneuroblastoma. Majority of VIPomas occur as isolated tumors, but in about 5% of patients, they are part of the multiple endocrine neoplasia type 1 (MEN1) syndromes. More than 50% of VIPomas have metastasized by the time of diagnosis [5].

In children, they are typically diagnosed between ages of 2 to 4 years. The majority of VIPomas in children are either ganglioneuromas or ganglioneuroblastomas, arising from the neural crest tissue of the sympathetic ganglia, in the mediastinum or retroperitoneum. They may also arise from the adrenal medulla [6].

Pathophysiology

Excessive secretion of VIP from the tumor has multiple effects on different organ systems, with its primary effects being on the GI system. VIP is a neurotransmitter belonging to the secretin-glucagon family and consists of 28 amino acids. It is a potent stimulator of intestinal cyclic adenosine monophosphate (cAMP) production and inhibitor of gastric acid secretion. It promotes vasodilation, glycogenolysis, lipolysis, and bone resorption. Effects secondary to these actions of VIP include huge secretion of water and electrolytes from the GI epithelial cells, hypokalemia, facial flushing, decreased gastric acidity, elevated blood glucose, and hypercalcemia.

History and Physical

Patients with VIPoma most commonly present with watery diarrhea which is secretory (it persists after a 48 hour fast). Diarrhea may be present for several years before diagnosis. Typically, stool amount exceeds 700 ml per day despite fasting and can exceed over 3000 ml per day in 70% of patients [7] [8]. These stools are odorless and tea colored and result in substantial losses of fluid and electrolytes such as potassium.

Other symptoms include lethargy, nausea, vomiting, muscle weakness, and cramps which occur due to dehydration and hypokalemia. Flushing has been reported in about 8% to 20% of the patients. Tetany has been reported and is due to hypomagnesemia. If severe, the loss of fluid and electrolytes can result in cardiac arrhythmias, myopathy, tetany and hypovolemic shock.

Children with VIPoma may present with failure to thrive in addition to chronic diarrhea.

Evaluation

Laboratory Studies

Diagnosis of VIPoma is made in patients with secretory diarrhea usually greater than 3.0 liters per day with a serum VIP level around 250 to 500 pg/ml (reference range is less than 190 pg/ml). Secretory diarrhea has a low  fecal osmotic gap of less than 50 mOsm/kg. It is important to repeat levels of VIP to confirm diagnosis since levels may not be elevated between episodes of watery diarrhea. It is also imperative to determine VIP levels when the patient is symptomatic, as the VIPoma may only secrete VIP intermittently. Hence, a normal level may be a false negative. Among children suspected with VIPoma, catecholamine levels should also need to be measured. Levels of pancreatic polypeptide are elevated in tumors originating from the pancreas.

Electrolyte abnormalities include hypokalemia, hypochlorhydria, hypomagnesemia, hyperglycemia, and hypercalcemia. Hypokalemia and hyperchloremic metabolic acidosis occur due to a large amount of GI loss and bicarbonate wasting. Hypochlorhydria occurs secondary to the direct gastric acid inhibitory effect of VIP. Hypercalcemia may be due to dehydration, coincidental MEN1 syndrome, or secretion by the tumor of a calcitrophic peptide. Hypomagnesemia may occur from profound diarrhea. Hyperglycemia is due to the increased glycogenolytic activity of VIP.

Imaging Studies

Tumor localization is typically started with helical multiphasic contrast-enhanced CT scan. The sensitivity of multiphasic CT scans is significantly high at greater than 80% for detecting intrapancreatic neuroendocrine tumors [9] [10]. Intravenous (IV) contrast further aids with detecting smaller lesions.

MRI is performed in case of indeterminate lesions and may have a better sensitivity to detect liver metastases.

Somatostatin receptor scintigraphy using radiolabeled somatostatin analog octreotide or lanreotide has the advantage of detecting small, occult metastases within and outside of the abdomen.

Other techniques include endoscopic ultrasound, which is helpful in determining the accurate extent of the disease. A biopsy of the pancreatic lesions can also be performed with this technique.

The FDA approves functional PET imaging technique with 68-Ga DOTATATE injection as the radioactive diagnostic agent for detection of somatostatin receptor positive neuroendocrine tumors in both adult and pediatric patients.

Treatment / Management

Initial Management

The management of VIPoma involves medical management and surgery.

  • Initial medical management is aimed mainly at controlling the symptoms and prompt and aggressive replacement of fluids and electrolytes. 
  • Somatostatin analogs like octreotide and lanreotide inhibit secretion of VIP and are used for symptomatic control. Octreotide is usually started at 50 to 100 mcg subcutaneous every 8 hours and titrated for symptom control. A long-acting formulation of octreotide, Sandostatin LAR is initiated at a dose of 20 mg intramuscularly (IM) monthly and titrated as needed for optimal symptom control.
  • Glucocorticoids are used in patients refractory to somatostatin analogs [11].
  • Interferon alpha has also been used in patients in patients not responding to the above medications.
  • Complete surgical resection is the treatment of choice for primary tumors and is usually a distal pancreatectomy. If the tumor cannot be excised completely, surgical debulking may provide palliative benefit [12].

Management of Metastatic/Progressive Disease

Metastases at the time of detection of VIPoma has been noted in as high as 60% of the cases [13]. The metastases most commonly occur in the liver, lymph nodes, bones, and kidney [14].

Surgical resection of the liver is indicated in cases of liver metastases in the absence of diffuse involvement of both the lobes, decreased liver function or extrahepatic metastases.

Radiofrequency ablation and cryoablation have also been the choice of the modality of treatment in cases of small metastases less than 3 cm [15].  Hepatic artery embolization is a palliative treatment measure in patients with unresectable hepatic metastases.

Systemic chemotherapy is a treatment modality used in patients with large, bulky tumors or patients extrahepatic metastases. A combination regimen with streptozocin or temozolomide-based regimen has been tried [16]. The overall response to systemic chemotherapy is not encouraging.

Novel agents like sunitinib, a tyrosine kinase inhibitor, and everolimus, a mTOR inhibitor are approved in the United States for treatment of advanced, well-differentiated, pancreatic neuroendocrine tumors including VIPomas [17] [18].

Differential Diagnosis

Causes of secretory diarrhea in adults of the developed countries include laxative abuse, carcinoid syndrome, microscopic colitis, and bile salt malabsorption due to ileal resection. Though more common in the developing countries, diarrhea due to infection from Vibrio cholera, enterotoxigenic Escherichia coli may also need to be ruled out after careful assessment of the history. Secretory diarrhea may occasionally occur in association with gastrointestinal disorders like Crohn’s disease and the short bowel syndrome. In rare cases, Munchausen syndrome by proxy may also need to be ruled out.

In children, rarely inherited electrolyte transport defects, like congenital chloride diarrhea and congenital sodium diarrhea may cause secretory diarrhea. These present in early infancy.

Prognosis

The median survival of patients with VIPoma is 96 months [19]. It is mostly dependent on tumor grade, stage, and surgical resectability.

As per recent National Comprehensive Cancer Network (NCCN) guidelines, the post-resection follow up includes history and physical examination, multiphasic CT or MRI and serum VIP level in the initial 3 to 12 month period. After 1 year, it is recommended to follow the same measures every 6 to 12 months.

Enhancing Healthcare Team Outcomes

A vipoma is a rare and challenging tumor to diagnose and treat. Successful care will be enhanced by a coordinated intradisciplinary team of an oncology nurse, pharmacist, and oncologist managing the treatment of a patient with this condition. [Level V]


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ViPoma - Questions

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A 62-year-old female complains of up to 10 loose stools each day for 6 weeks. She has lost 10 pounds. The physical exam and serum laboratories are normal. Stool cultures show no enteric pathogens. A 24-hour collection of stool shows 520 g of stool with a calculated stool osmolality of 215 mmol/L and a measured stool osmolality of 205 mmol/L. What is the most likely diagnosis?



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A female patient complains of profuse, watery diarrhea for 2 weeks with or without eating or drinking. She has tried over-the-counter medication without relief. She denies abdominal pain, hematochezia, recent travel, or ingestion of undercooked food. No one else at home or at work has similar symptoms. On exam, the patient's pulse is 100 bpm, temperature 37 degrees C (98.3 F), and blood pressure 110/70 mmHg sitting but drops to 95/50 standing and the pulse rises to 110. Her mucosa is dry and her skin tents. She is sent to the hospital for hydration and further evaluation. Admission labs show a normal complete blood count, Na+=146 mEq/L K+=2.9 mEq/L, Cl- =97 mEq/L, HCO3-=36 mEq/L, BUN=30 mg/dL, and creatinine 1.3 mg/dL. Stool for Clostridium difficile, ova, parasites, and WBCs are all negative. 24-hour stool collection yields 3 liters of tea colored stool with Na+=49 mEq/L, K+=26 mEq/L, and stool osmolality is 168 mOsm/L. Select the diagnostic test of choice.



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Which of the following often develops with vasoactive intestinal peptide-secreting tumors?



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Which of the following is not a feature of VIPoma?



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Which of the following electrolyte disturbances can be seen with VIPoma syndrome?



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A 55-year-old white male presented with lethargy, nausea, vomiting and persistent diarrhea. Further questioning revealed he has persistent diarrhea for over a year with stool quantity frequently over 1000 ml/ day. Blood work showed serum sodium 147 mmol/L (normal 134-144), serum potassium 2.7 mmol/L (normal 3.5 - 5.2 ), serum bicarbonate 17 mmol/l (normal 18-29), fasting glucose 165 mg/dl (normal 65-99), serum calcium 11.3 mg/dl (8.6 -10.2) and serum albumin 4.2 g/dl (3.5-4.7) . He was admitted, fluids and electrolytes were replaced. Which of the following blood test should be drawn next to confirm the suspected diagnosis?



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Which of the following is a true statement about the VIPoma tumor?



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ViPoma - References

References

Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia., VERNER JV,MORRISON AB,, The American journal of medicine, 1958 Sep     [PubMed]
Vasoactive intestinal peptide and watery-diarrhoea syndrome., Bloom SR,Polak JM,Pearse AG,, Lancet (London, England), 1973 Jul 7     [PubMed]
Vasoactive Intestinal Peptide Tumor (VIPoma), Vinik A,,, 2000     [PubMed]
Ito T,Igarashi H,Jensen RT, Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best practice & research. Clinical gastroenterology. 2012 Dec     [PubMed]
Perry RR,Vinik AI, Clinical review 72: diagnosis and management of functioning islet cell tumors. The Journal of clinical endocrinology and metabolism. 1995 Aug     [PubMed]
Belei OA,Heredea ER,Boeriu E,Marcovici TM,Cerbu S,Mărginean O,Iacob ER,Iacob D,Motoc AGM,Boia ES, Verner-Morrison syndrome. Literature review. Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie. 2017     [PubMed]
Grier JF, WDHA (watery diarrhea, hypokalemia, achlorhydria) syndrome: clinical features, diagnosis, and treatment. Southern medical journal. 1995 Jan     [PubMed]
Mekhjian HS,O'Dorisio TM, VIPoma syndrome. Seminars in oncology. 1987 Sep     [PubMed]
Legmann P,Vignaux O,Dousset B,Baraza AJ,Palazzo L,Dumontier I,Coste J,Louvel A,Roseau G,Couturier D,Bonnin A, Pancreatic tumors: comparison of dual-phase helical CT and endoscopic sonography. AJR. American journal of roentgenology. 1998 May     [PubMed]
Khashab MA,Yong E,Lennon AM,Shin EJ,Amateau S,Hruban RH,Olino K,Giday S,Fishman EK,Wolfgang CL,Edil BH,Makary M,Canto MI, EUS is still superior to multidetector computerized tomography for detection of pancreatic neuroendocrine tumors. Gastrointestinal endoscopy. 2011 Apr     [PubMed]
O'Dorisio TM,Mekhjian HS,Gaginella TS, Medical therapy of VIPomas. Endocrinology and metabolism clinics of North America. 1989 Jun     [PubMed]
Friesen SR, The development of endocrinopathies in the prospective screening of two families with multiple endocrine adenopathy, type I. World journal of surgery. 1979 Nov     [PubMed]
Smith SL,Branton SA,Avino AJ,Martin JK,Klingler PJ,Thompson GB,Grant CS,van Heerden JA, Vasoactive intestinal polypeptide secreting islet cell tumors: a 15-year experience and review of the literature. Surgery. 1998 Dec     [PubMed]
Fernández-Cruz L,Blanco L,Cosa R,Rendón H, Is laparoscopic resection adequate in patients with neuroendocrine pancreatic tumors? World journal of surgery. 2008 May     [PubMed]
Moug SJ,Leen E,Horgan PG,Imrie CW, Radiofrequency ablation has a valuable therapeutic role in metastatic VIPoma. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]. 2006     [PubMed]
Krug S,Boch M,Daniel H,Nimphius W,Müller D,Michl P,Rinke A,Gress TM, Streptozocin-Based Chemotherapy in Patients with Advanced Neuroendocrine Neoplasms--Predictive and Prognostic Markers for Treatment Stratification. PloS one. 2015     [PubMed]
Raymond E,Dahan L,Raoul JL,Bang YJ,Borbath I,Lombard-Bohas C,Valle J,Metrakos P,Smith D,Vinik A,Chen JS,Hörsch D,Hammel P,Wiedenmann B,Van Cutsem E,Patyna S,Lu DR,Blanckmeister C,Chao R,Ruszniewski P, Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. The New England journal of medicine. 2011 Feb 10     [PubMed]
Yao JC,Shah MH,Ito T,Bohas CL,Wolin EM,Van Cutsem E,Hobday TJ,Okusaka T,Capdevila J,de Vries EG,Tomassetti P,Pavel ME,Hoosen S,Haas T,Lincy J,Lebwohl D,Öberg K, Everolimus for advanced pancreatic neuroendocrine tumors. The New England journal of medicine. 2011 Feb 10     [PubMed]
Roland CL,Bian A,Mansour JC,Yopp AC,Balch GC,Sharma R,Xie XJ,Schwarz RE, Survival impact of malignant pancreatic neuroendocrine and islet cell neoplasm phenotypes. Journal of surgical oncology. 2012 May     [PubMed]

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