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VIPoma

VIP-secreting Tumor

VIPoma is a very rare neuroendocrine tumor that predominantly originates in the pancreas. It causes symptoms such as profuse watery diarrhea, hypokalemia and achlorhydria. The diagnosis is made by measuring serum levels of vasoactive intestinal polypeptide (VIP) and through use of various imaging studies. Because of nonspecific symptoms, patients are often diagnosed in advanced stages of the disease. Treatment strategies include surgical excision, chemotherapy, octreotide administration and adjuvant therapy.


Presentation

The hallmark of VIPoma in terms of symptomatology is the presence of prolonged profuse watery diarrhea, usually more than 3000 ml/day. Such profound water loss results in significant hypokalemia, which can have detrimental effects on the cardiac and skeletal system leading to arrhythmias and diffuse muscle weakness. In addition to watery diarrhea and hypokalemia, nausea and vomiting are frequent symptoms, which lead to achlorhydria. These symptoms comprise the WDHA syndrome that describes patients with VIPomas. WDHA syndrome is also known as pancreatic cholera because profuse water loss mimics the syndrome seen in patients with Vibrio cholera infection. Other symptoms that are reported include flushing (which is one of the main features of carcinoid syndrome), weight loss, lethargy, abdominal pain and bloating [12].

Symptoms that appear in patients can be intermittent, which is one of the reasons why establishing the diagnosis may be difficult, although diarrhea is usually a constant finding in these patients.

Weight Loss
  • The patient was a 33-year-old Japanese male who was admitted because of persisting watery diarrhea and weight loss.[ncbi.nlm.nih.gov]
  • Other common features include facial flushing (in 20% of cases), weakness, abdominal pain and weight loss.[endocrinesurgeon.co.uk]
  • Symptoms of diabetes can include thirst, passing excessive amounts of urine, weakness, weight loss and hunger. Diabetes can develop in the over 60’s and not necessarily develop into cancer.[raisingawarness.wordpress.com]
  • Symptoms of VIPoma may include any of the following: Abdominal pain and cramping Diarrhea (watery, and often in large amounts) Dehydration Flushing or redness of the face Muscle cramps due to low blood potassium ( hypokalemia ) Nausea Weight loss The[nlm.nih.gov]
  • loss. [1] [2] When a person has a VIPoma and these associated symptoms, it is referred to as VIPoma syndrome, also called WDHA syndrome or Verner-Morrison syndrome. [1] The majority of people with a VIPoma have VIPoma syndrome. [3] VIPomas are usually[rarediseases.info.nih.gov]
Localized Pain
  • No adverse effects were noted except for localized pain at the site of injection.[ncbi.nlm.nih.gov]
Diarrhea
  • Half of the patients have relatively constant diarrhea while the rest have alternating periods of severe and moderate diarrhea. One third have diarrhea 1yr before diagnosis, but in 25%, diarrhea is present for 5 yr or more before diagnosis.[en.wikipedia.org]
  • 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.[ncbi.nlm.nih.gov]
  • Abstract A patient with a vipoma of the pancreas and persistently elevated blood levels of vasoactive intestinal polypeptide (VIP) had watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome).[ncbi.nlm.nih.gov]
  • SMS 201-995 not only controlled the diarrhea without side effects but appeared to have possibly induced a reduction in metastatic tumor size.[ncbi.nlm.nih.gov]
  • Fluids are often given through a vein (intravenous fluids) to replace fluids lost through diarrhea. The next goal is to slow the diarrhea. Medicines can help control diarrhea. One such medicine is octreotide.[nlm.nih.gov]
Nausea
  • Symptoms of VIPoma may include any of the following: Abdominal pain and cramping Diarrhea (watery, and often in large amounts) Dehydration Flushing or redness of the face Muscle cramps due to low blood potassium ( hypokalemia ) Nausea Weight loss The[nlm.nih.gov]
  • Lethargy, muscle weakness, nausea, vomiting and crampy abdominal pain are frequent symptoms. Hypokalemia and impaired glucose tolerance occur in 50% of patients. Achlorhydria is also a feature.[en.wikipedia.org]
  • Hypokalemia has been reported in most patients with VIPoma and can be accompanied by lethargy, nausea, and muscular discomfort.[endocrinediseases.org]
  • Other symptoms of VIPoma include abdominal pain, cramping, nausea, weight loss, and redness of the face. The low levels of potassium in the blood can also cause muscular discomfort and intense fatigue.[wisegeek.com]
  • Symptoms associated with dehydration and hypokalemia include lethargy, nausea, vomiting, muscle weakness, and muscle cramps. Abdominal pain is mild or absent.[cancertherapyadvisor.com]
Abdominal Pain
  • CASE PRESENTATION: A 46 year old women presented with abdominal pain and diarrhea.[ncbi.nlm.nih.gov]
  • Other common features include facial flushing (in 20% of cases), weakness, abdominal pain and weight loss.[endocrinesurgeon.co.uk]
  • Symptoms of VIPoma may include any of the following: Abdominal pain and cramping Diarrhea (watery, and often in large amounts) Dehydration Flushing or redness of the face Muscle cramps due to low blood potassium ( hypokalemia ) Nausea Weight loss The[nlm.nih.gov]
  • Lethargy, muscle weakness, nausea, vomiting and crampy abdominal pain are frequent symptoms. Hypokalemia and impaired glucose tolerance occur in 50% of patients. Achlorhydria is also a feature.[en.wikipedia.org]
  • pain and cramping, severe watery diarrhea, dehydration, flushing of the face, muscle cramps due to low potassium levels ( hypokalemia ), and weight loss. [1] [2] When a person has a VIPoma and these associated symptoms, it is referred to as VIPoma syndrome[rarediseases.info.nih.gov]
Vomiting
  • Lethargy, muscle weakness, nausea, vomiting and crampy abdominal pain are frequent symptoms. Hypokalemia and impaired glucose tolerance occur in 50% of patients. Achlorhydria is also a feature.[en.wikipedia.org]
  • Symptoms associated with dehydration and hypokalemia include lethargy, nausea, vomiting, muscle weakness, and muscle cramps. Abdominal pain is mild or absent.[cancertherapyadvisor.com]
  • […] secretory diarrhea, anorexia (loss of appetite), chronic fatigue , dehydration , diabetes mellitus , erythema , abdominal pain , hepatomegaly (enlargement of liver), generalized muscle weakness , hypercalcemia , muscle cramps, malabsorption, nausea , vomiting[xpertdox.com]
  • Other less common manifestations include nausea, vomiting, weight loss, bloating, indigestion, skin rash and facial flushing, backache and lethargy.[orpha.net]
Chronic Diarrhea
  • […] or chronic diarrhea.[platform.almanhal.com]
  • Arun Phophalia Doctor (MD) Post-Doctoral Degree 19,897 satisfied customers My 80 year old mother has had chronic diarrhea for almost my 80 year old mother has had chronic diarrhea for almost one year.[justanswer.com]
  • Overview of chronic diarrhea caused by functional neuroendocrine neoplasms. Semin Gastrointest Dis. 1999;10:156. [PubMed: 10548409] Soga J, Yakuwa Y. Vipoma/diarrheogenic syndrome: a statistical evaluation of 241 reported cases.[accesssurgery.mhmedical.com]
  • Differential diagnosis Differential diagnoses include all other causes of chronic diarrhea such as malabsorption syndrome, Crohn disease, ulcerative colitis, microscopic colitis (see these terms), and gastrointestinal infections.[orpha.net]
Flushing
  • During attacks of diarrhea, flushing similar to the carcinoid syndrome occur rarely.[en.wikipedia.org]
  • Other common features include facial flushing (in 20% of cases), weakness, abdominal pain and weight loss.[endocrinesurgeon.co.uk]
  • VIP SYndrome (pancreatic cholera syndrome, Verner-Morrison syndrome) watery diarrhea, hypokalemia, and hypochlorhydria or achlorhydria (WDHA) syndrome 20% get facial flushing VIP secreted Lesion characteristics Lesions are solitary They are usually 3cm[gastroenterologybook.com]
  • At diagnosis he had several features which may have expedited the diagnosis including refractory diarrhoea containing undigested foodstuffs, alcohol-related flushing, electrolyte abnormalities and intestinal oedema on imaging.[endocrine-abstracts.org]
  • Symptoms of VIPoma may include any of the following: Abdominal pain and cramping Diarrhea (watery, and often in large amounts) Dehydration Flushing or redness of the face Muscle cramps due to low blood potassium ( hypokalemia ) Nausea Weight loss The[nlm.nih.gov]
Muscle Weakness
  • Abstract 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.[ncbi.nlm.nih.gov]
  • Lethargy, muscle weakness, nausea, vomiting and crampy abdominal pain are frequent symptoms. Hypokalemia and impaired glucose tolerance occur in 50% of patients. Achlorhydria is also a feature.[en.wikipedia.org]
  • Symptoms associated with dehydration and hypokalemia include lethargy, nausea, vomiting, muscle weakness, and muscle cramps. Abdominal pain is mild or absent.[cancertherapyadvisor.com]
  • They include: large amounts of watery diarrhoea – needing to go 20 times a day or more muscle weakness, aching and cramps numbness caused by low levels of potassium in the blood (hypokalaemia) dehydration – causing thirst, dry skin, a dry mouth, tiredness[cancerresearchuk.org]
Lethargy
  • Lethargy, muscle weakness, nausea, vomiting and crampy abdominal pain are frequent symptoms. Hypokalemia and impaired glucose tolerance occur in 50% of patients. Achlorhydria is also a feature.[en.wikipedia.org]
  • Hypokalemia has been reported in most patients with VIPoma and can be accompanied by lethargy, nausea, and muscular discomfort.[endocrinediseases.org]
  • Other symptoms that are reported include flushing (which is one of the main features of carcinoid syndrome), weight loss, lethargy, abdominal pain and bloating.[symptoma.com]
  • Symptoms associated with dehydration and hypokalemia include lethargy, nausea, vomiting, muscle weakness, and muscle cramps. Abdominal pain is mild or absent.[cancertherapyadvisor.com]
Insomnia
  • Personal Health Photo Credit Gracia Lam Insomnia Can Kill You Chronic insomnia is linked to an increased risk of developing hypertension, Type 2 diabetes, heart attack, depression, anxiety and premature death. By JANE E.[health.nytimes.com]

Workup

In order to establish the diagnosis of VIPoma, key steps include detailed patient history, obtaining levels of serum electrolytes and VIP and various imaging techniques to identify the location the tumor.

Patient history may be the key for suspecting VIPoma as a possible etiology for the symptoms. Supporting facts include prolonged diarrhea without an established cause, accompanied by other symptoms that are typical for this tumor. In all patients who suffer from dehydration and severe diarrhea, assessment of serum electrolytes is vital in preventing complications that may be quite severe. Severe dehydration may lead to hypotension, cardiogenic shock and even cardiac arrest, which is why serum potassium, sodium, chloride, bicarbonate and calcium levels should be obtained promptly. Significant hypokalemia and hypochlorhydria may be observed, while hypercalcemia is also a common finding, which presents a significant risk for the cardiac muscle. Additional tests can include evaluation of gastric pH (which will show alkalosis, due to inhibition of gastric acid secretion), while hyperglycemia and anion-gap metabolic acidosis may be reported as well.

Serum VIP levels can confirm the diagnosis of VIPoma. VIP has a very short half-life in the circulation (< 1 min), and its serum levels are usually below 200 pg/ml. Elevated VIP levels together with imaging studies should confirm the diagnosis.

CT and MRI are primary studies of choice for finding the exact location of this tumor, as tumors are up to several centimeters in diameter in a majority of the cases. However, PET scan may be used in patients in whom prior imaging studies have not identified the location of the tumor, while endoscopic ultrasound and scintigraphy using octreotide as contrast have been recommended as well [13]. Imaging studies should also investigate possible metastatic disease, which includes a full body workup with either CT or MRI, with the most common sites being the liver, lungs, lymph nodes proximal to the primary site and kidneys.

Hypochlorhydria
  • VIPoma an endocrine tumor, usually a type of islet cell tumor, that produces excessive amounts of vasoactive intestinal polypeptide, producing severe diarrhea, hypokalemia, and hypochlorhydria, leading to renal failure that can be fatal.[medical-dictionary.thefreedictionary.com]
  • Found on vipoma An endocrine tumour, usually arising in the pancreas, that produces vasoactive intestinal polypeptide, which is the mediator of a syndrome of watery diarrhoea, hypokalaemia, and hypochlorhydria, leading to renal failure and death. ...[encyclo.co.uk]
  • Clinical syndrome of watery diarrhea, hypokalemia, acidosis, hypochlorhydria, and hypercalcemia. Usually with regional lymph node or liver involvement at diagnosis. Elevated VIP levels are diagnostic of VIPoma.[online.epocrates.com]
  • Vipoma: A tumor that secretes VASOACTIVE INTESTINAL PEPTIDE, a neuropeptide that causes VASODILATION; relaxation of smooth muscles; watery DIARRHEA; HYPOKALEMIA; and HYPOCHLORHYDRIA.[kmle.com]
  • MyAccess include: Remote Access Favorites Save figures into PowerPoint Download tables as PDFs Go to My Dashboard Close • A non-beta islet cell tumor of the pancreas that secretes VIP • VIPomas cause the WDHH syndrome (watery diarrhea, hypokalemia, hypochlorhydria[accesssurgery.mhmedical.com]

Treatment

Once VIPoma is confirmed and staging completed, initial therapy can be started. This includes management of severe water loss and dehydration. Intravenous administration of fluids supplemented with potassium and bicarbonate is pivotal, thereby preventing further deterioration and potential development of acidosis. Additional therapy includes administration of octreotide, which is an analog of somatostatin. Octreotide exerts its effects by reducing the rate of intestinal motility without further reducing gastric acid secretion. It is usually given intramuscularly as one dose of 20-30 mg per month, while 100–300 μg/day is the standard dosing regimen [14], and shows good results in terms of reducing the burden of diarrhea in patients. Additional drugs that have shown benefit in certain studies include prednisone, loperamide, metoclopramide, and interferon.

Once the fluid loss and electrolyte levels have been stabilized, definite treatment measures may be started. Surgical excision is the only form of treatment that may be curable for the patient and is performed even if metastatic disease is noted. Surgery includes removal of all metastases in addition to the primary tumor. Surgical excision provides significant benefit over chemotherapy, which may be useful only as adjuvant therapy. Streptozocin together with doxorubicin is mentioned as the most favorable combination of chemotherapy. Chemoembolization and embolization of metastatic disease leads to significant improvement in survival rates. [15]. As a last resort, liver transplantation has been also been used in the treatment of liver metastases [16].

Prognosis

This tumor is slow growing in nature and between 50-75% of diagnosed tumors are malignant [10]. This tumor has a very good prognosis if diagnosed in its early stages, with 5-year survival rates exceeding 90% when complete surgical excision is achieved [11]. Unfortunately, only a minority of patients are diagnosed in early stages and between 60-80% of patients have evidence of metastatic disease at the time of diagnosis. As it is a slow growing tumor, even patients with metastasis survive long but the treatment in these patients can present significant challenges.

Etiology

VIPoma is a tumor that develops in non-β pancreatic islet cells and it was initially described during the 1950s [4], when its connection to refractory diarrhea and hypokalemia was established. However, the exact cause of this tumor remains unknown.

Epidemiology

According to reported prevalence rates VIPomas occur in approximately 1 in 10,000,000 individuals every year, suggesting that this neuroendocrine tumor is extremely rare [5]. The vast majority of VIPomas arise in the pancreas, with about 80% occurring in the body and tail, while about 20% originate in the head of the pancreas [6]. Other primary sites that have been reported include the lungs, colon, liver, adrenal glands, and ganglia of the sympathetic system [7], while its association with MEN 1 syndrome has also been reported in rare cases.

This neuroendocrine tumor is seen in both adults and children Extrapancreatic location of the tumor is commonly observed in children, with the adrenal glands and sympathetic ganglia being reported as most frequent sites [8]. Gender predilection has not been established.

Sex distribution
Age distribution

Pathophysiology

Vasoactive intestinal polypeptide (VIP) contains 28 amino acids and is structurally similar to secretin and glucagon. VIP exerts its functions as a neurotransmitter in various parts of the nervous system, including the CNS and nerves of the respiratory, urogenital and enteric systems. Stimulation of enteric smooth muscles, inhibition of gastric acid secretion, regulation of immune system activation, stimulation of exocrine pancreas and modulation of gastrointestinal blood flow are all recognized functions of VIP. Other functions in which VIP may play a role include maintenance of neuronal integrity, glycogen metabolism, prolactin secretion and regulation of catecholamine release [9].

VIP exerts its effect in the intestinal system through stimulation of cyclic adenosine monophosphate (cAMP), and overstimulation of receptors leads to profuse electrolyte and water secretion into the intestinal lumen, ultimately resulting in severe diarrhea and hypokalemia. Inhibition of gastric acid secretion leads to either hypo or achlorhydria, which can have significant effects on bicarbonate concentrations in the circulation, in addition to bicarbonate loss through diarrhea. These factors are combined to form the typical presentation of Watery Diarrhea, Hypokalemia, and Achlorhydria - WDHA syndrome.

Prevention

Prevention of VIPomas is currently not possible, as the cause of this tumor remains unknown. However, an early diagnosis may be life-saving for many patients, which is why a detailed diagnostic workup should include VIPoma as a possible cause of diarrhea and achlorhydria when all other conditions have been excluded. Regular patient check-ups can reduce the burden of many diseases that are diagnosed in late stages, VIPoma being one of them.

Summary

VIPoma is a rare neuroendocrine neoplasia that secretes excessive amounts of vasoactive intestinal polypeptide (VIP) [1]. This hormone acts as a neurotransmitter both in the central and peripheral nervous systems and performs significant functions in the enteric nerves. VIP is classified into a group of hormones and neuropeptides that share similar structures together with secretin, glucagon, growth hormone releasing factor and several others [2]. Its functions in the gastrointestinal tract include smooth muscle stimulation, gastric acid inhibition, and stimulation of exocrine pancreatic secretion. The majority of VIPomas originate as solitary lesions in the pancreas, most commonly in the head and body, but in rare cases, the adrenal glands, liver, colon, and lungs have been reported as its primary site of occurrence. These tumors may be benign, but the majority of tumors are malignant and a significant number of patients have metastatic disease at the time of their diagnosis. Metastases may be identified often in the liver but can also be found in the proximal lymph nodes, kidneys or lungs, as well other organs [3]. The characteristic syndrome of frequent and profuse watery diarrhea, hypokalemia and achlorhydria (known as WDHA syndrome or pancreatic cholera) can be observed in virtually all patients and manifests as severe dehydration, weakness, and lethargy. Flushing may be present as well. The diagnosis may not be established easily, as symptoms tend to be intermittent. VIPoma can be diagnosed through various imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), because tumors are usually several centimeters in size, while positron emission tomography (PET scan) may be necessary to establish smaller tumors. Serum electrolytes, as well as high levels of VIP in the blood, can confirm that the tumor described through imaging studies is VIPoma. In rare cases, VIPoma can be associated with multiple endocrine neoplasia (MEN) type 1 syndrome, in which hyperparathyroidism and presence of pituitary tumors, most commonly prolactinomas, are present. Initial therapy includes adequate rehydration and correction of serum electrolytes, while a surgical excision is the recommended treatment strategy. Administration of octreotide, a somatostatin analog, chemotherapy and additional drugs including corticosteroids and antimotility agents are part of the adjunctive therapy.

Patient Information

VIPoma is a tumor that predominantly originates in the pancreas and is malignant in most cases. This tumor is very rare and is reported to occur in approximately 1 in 10 million individuals. Although it is often diagnosed when metastases have developed, as it is slow growing, patients continue to live relatively long. It can develop both in adults and in children and the cause remains unknown. The name stems from the fact that cells that undergo malignant transformation secrete vasoactive intestinal polypeptide (VIP), which exerts numerous functions in the body. VIP acts as a neurotransmitter in the nervous system of various organs, including the gastrointestinal system, where most of the symptoms occur. VIP stimulates contraction of smooth muscles in the gut and stimulates the movement of fluids and electrolytes into the intestinal lumen, thus leading to often profuse diarrhea and severe dehydration. A specific term is used for the constellation of symptoms that occur in this condition: the WDHA syndrome (Watery Diarrhea, Hypokalemia, and Achlorhydria). Diarrhea is the main symptom in patients with VIPomas and is usually profuse and causes significant fluid and potassium loss. VIP also inhibits production of gastric acid, which results in reduced acidity of the stomach, thus impairing its normal function. Additional symptoms include nausea, vomiting, abdominal pain, bloating, weakness, and lethargy. Symptoms may be intermittent, which provides a significant challenge in establishing the diagnosis. VIPoma can be diagnosed by obtaining serum levels of VIP, while its location may be identified using various imaging procedures, such as computed tomography (CT scan) and magnetic resonance imaging (MRI) because tumors are usually up to several centimeters in length. Smaller tumors can be identified using positron emission tomography (PET scan). Correction of dehydration and improving levels of potassium and chloride through intravenous fluid administration is very important in managing patients once the diagnosis is made, while administration of various drugs have shown some efficacy in reducing the burden of diarrhea. In most cases, octreotide is the drug of choice, while corticosteroids may provide additional benefit. Definite treatment measures depend on the staging of the tumor, but surgical removal is recommended in all patients, even in those with metastases because it is the only therapeutic strategy that has shown curative effects. Chemotherapy has inferior results compared to surgery and can be used as adjuvant therapy. This tumor can present significant challenges in diagnosis and therapy, but early identification is the key to preventing complications and prolonging the life of the patient.

References

Article

  1. Batcher E, Madaj P, Gianoukakis AG. Pancreatic neuroendocrine tumors. Endocr Res. 2011;36(1):35-43.
  2. Delgado M, Ganea D. Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions. Amino acids. 2013;45(1):10.1007/s00726-011-1184-1188.
  3. Ayub A, Zafar M, Abdulkareem A, et al. Primary hepatic vipoma. Am J Gastroenterol. 1993;88(6):958-961.
  4. Verner JV, Morrison AB. Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med. 1958;25:374–380.
  5. Friesen SR. Update on the diagnosis and treatment of rare neuroendocrine tumors. Surg Clin North Am 1987;67:379.
  6. Perry RR, Vinik AI. Clinical review 72: diagnosis and management of functioning islet cell tumors. J Clin Endocrinol Metab 1995;80:2273.
  7. Ectors N. Pancreatic endocrine tumors: diagnostic pitfalls. Hepatogastroenterology 1999;46:679.
  8. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill;2012.
  9. Harmar AJ, Fahrenkrug J, Gozes I, et al. Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR Review 1. Br J Pharmacol. 2012;166(1):4-17.
  10. Porter RS, Kaplan JL. Merck Manual of Diagnosis and Therapy. 19th Edition. Merck Sharp & Dohme Corp. Whitehouse Station, N.J. 2011;
  11. Oberg K. Chemotherapy and biotherapy in the treatment of neuroendocrine tumors. Ann Oncol. 2001;12(2):S111-S114.
  12. Peng SY, Li JT, Liu YB, Fang HQ, Wu YL, Peng CH, et al. Diagnosis and treatment of VIPoma in China: (case report and 31 cases review) diagnosis and treatment of VIPoma. Pancreas. 2004;28(1):93-97.
  13. Ghaferi AA, Chojnacki KA, Long WD, et al. Pancreatic VIPomas: subject review and one institutional experience. J Gastointest Surg. 2008;12:382-393. .
  14. Nguyen HN, Backes B, Lammert F, et al. Long-term survival after diagnosis of hepatic metastatic VIPoma: report of two cases with disparate courses and review of therapeutic options. Dig Dis Sci. 1999;44:1148-1155.
  15. Ho AS, Picus J, Darcy MD, et al. Long-term outcome after chemoembolization and embolization of hepatic metastatic lesions from neuroendocrine tumors. AJR Am J Roentgenol. 2007;188:1201-1207.
  16. Johnston PC, Ardill JE, Johnston BT, et al. Vasoactive intestinal polypeptide secreting pancreatic tumour with hepatic metastases: long term survival after orthotopic liver transplantation. Ir J Med Sci. 2010;179:439-441.

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Last updated: 2017-08-09 18:22