Vipoma (Werner-Morrison syndrome).

VIPoma is a non-beta cell tumor of the pancreatic islet cells that secretes vasoactive intestinal peptide (VIP), causing a syndrome of watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome). Diagnosis is by serum VIP levels, and tumor localization is by CT and endoscopic ultrasound. Treatment of VIPoma involves surgical resection.

What causes Vipoma?

Of these tumors, 50-75% are malignant and some can be quite large (7 cm). In about 6%, VIPoma develops as part of multiple endocrine neoplasia.

Vipoma is a tumor of the APUD system that produces excessive amounts of vasoactive intestinal polypeptide. In 90% of cases, the tumor is localized in the pancreas, in 10% it is extrapancreatic (in the sympathetic trunk). In approximately half of the cases, the tumor is malignant.

In 1958, Werner and Morrison described the syndrome of watery diarrhea in a patient with a non-beta-cell tumor of the pancreas. Previously, this disease was a variant of Zollinger-Ellison syndrome, its atypical ulcer-free form with hypokalemia. Further studies showed that the cause of clinical manifestations in these cases is the secretion of vasoactive intestinal peptide (VIP) rather than gastrin, as in patients with ulcerogenic syndrome, hence the name of the tumor - VIPoma. Sometimes this disease is called pancreatic cholera or by the initial letters of the English words: watery diarrhea, hypokalemia, achlorhydria - WDHA syndrome.

More than 70% of VIPomas are malignant, % of which already have liver metastases at the time of diagnosis. In 20% of patients, the symptom complex may be the result of islet apparatus hyperplasia.

Excessive secretion of VIP stimulates pronounced excretion of fluid and electrolytes by the small intestine and pancreas, which do not have time to be absorbed in the large intestine. Clinically, this is expressed by profuse diarrhea - at least 700 ml / day, often exceeding 3-5 liters, which leads to dehydration. The loss of potassium, bicarbonates and magnesium contributes to the development of acidosis, severe weakness and tetanic seizures. Azotemia occurs due to dehydration and hypokalemic nephropathy. Hypo- and achlorhydria are detected in about half of the patients. Among other manifestations of the syndrome, hyperglycemia and hypercalcemia not associated with an increased level of parathyroid hormone should be noted.

VIPoma occurs with periods of remission and exacerbation. VIP levels in the blood exceeding 80 pmol/l should always raise concerns about the tumor nature of the disease.

VIPomas are usually large and therefore easily detected by angiography or computed tomography.

Symptoms of VIPoma

The main symptoms of vipoma include prolonged profuse watery diarrhea (fasting stool volume greater than 750-1000 ml/day, and with food intake greater than 3000 ml/day) and signs of hypokalemia, acidosis, and dehydration. In half of the cases, diarrhea is constant; in the rest, the severity of diarrhea varies over a long period of time. In 33%, diarrhea had lasted less than 1 year before diagnosis, but in 25% of cases it had persisted for more than 5 years before diagnosis. Lethargy, muscle weakness, nausea, vomiting, and abdominal cramping are common. Facial flushing similar to carcinoid syndrome occurs in 20% of patients during attacks of diarrhea.

The main characteristic symptoms of vipoma are:

• massive watery diarrhea; the amount of water lost per day can be about 4-10 liters. At the same time, sodium and potassium are lost along with water. Severe dehydration, weight loss, and hypokalemia develop. Diarrhea is caused by high secretion of sodium and water into the intestinal lumen under the influence of vasoactive intestinal polypeptide;
• abdominal pain of an undefined, diffuse nature;
• inhibition of gastric secretion;
• hot flashes and paroxysmal facial flushing (due to the pronounced vasodilating effect of vasoactive intestinal polypeptide); the symptom is inconstant and is observed in 25-30% of patients;
• tendency to decrease blood pressure; severe arterial hypotension is possible;
• enlargement of the gallbladder and the formation of stones in it (due to the development of severe atony of the gallbladder under the influence of vasoactive intestinal polypeptide);
• convulsive syndrome (due to the loss of a large amount of magnesium during diarrhea);
• impaired glucose tolerance (an intermittent symptom caused by increased breakdown of glycogen and increased secretion of glucagon under the influence of vasoactive intestinal polypeptide).

Diagnosis of VIPoma

Secretory diarrhea is required for diagnosis (stool osmolarity is nearly equal to plasma osmolarity, and twice the sum of stool Na and K concentrations determines stool osmolarity). Other causes of secretory diarrhea, particularly laxative abuse, must be excluded. Serum VIP levels should be measured in such patients (best during the diarrhea). Markedly elevated VIP levels suggest the diagnosis, but moderate elevations may be seen in short bowel syndrome and inflammatory diseases. Patients with elevated VIP levels require investigations (endoscopic ultrasound and octreotide scintigraphy and arteriography) to diagnose tumor location and metastases.

Electrolytes and a complete blood count should be obtained. Hyperglycemia and decreased glucose tolerance occur in less than 50% of patients. Hypercalcemia develops in half of patients.

Diagnostic criteria for vipoma

• diarrhea lasts for at least 3 weeks;
• daily stool volume of at least 700 ml or 700 g;
• fasting for 3 days does not reduce the daily stool volume to less than 0.5 l (during fasting, the loss of water and electrolytes must be replenished by intravenous administration of an isotonic solution of table salt and electrolytes);
• hypo- or achlorhydria of gastric juice;
• high blood levels of vasoactive intestinal polypeptide;
• detection of a pancreatic tumor using computed tomography or magnetic resonance imaging (less often, sonography).

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Screening program for vipoma

1. General blood and urine analysis.
2. Stool analysis: coprocytogram, measurement of stool volume per day.
3. BAC: content of sodium, potassium, chlorine, calcium, magnesium, glucose, total protein and protein fractions, aminotransferases.
4. Study of gastric secretion.
5. Fasting test for 3 days.
6. FEGDS.
7. Ultrasound of abdominal organs.
8. Determination of the content of vasoactive intestinal polypeptide in the blood.
9. Computed tomography or magnetic resonance imaging of the pancreas.

Treatment of vipoma

Fluid and electrolyte replacement is required first. Bicarbonate loss in the stool must be replaced to prevent acidosis. Because significant fecal losses of water and electrolytes occur, rehydration by continuous intravenous infusions may be difficult.

Octreotide usually controls diarrhea, but larger doses may be required. Respondents report positive effects from prolonged-release octreotide, 20-30 mg intramuscularly once a month. Patients taking octreotide should also take pancreatic enzymes, as octreotide suppresses pancreatic enzyme secretion.

Tumor resection is effective in 50% of patients with localized disease. In metastatic disease, resection of all visible tumor may provide temporary symptom relief. A combination of streptozocin and doxorubicin may reduce diarrhea and tumor volume if objective improvement is observed (50-60%). Chemotherapy is ineffective.

Drug and preoperative treatment of VIPoma consists of massive transfusion of fluid and electrolytes, sometimes glucocorticoids are used. Chemotherapy for malignant metastatic VIPoma is carried out using streptozotocin. The latter to some extent causes remission of the process in 50% of patients.

Surgical treatment of vipoma is effective only with radical removal of all functioning tumor tissue, which is not always possible. In the absence of a tumor with obvious clinical and laboratory manifestations of the disease, distal resection of the pancreas is recommended.