| disease | Vasoactive Intestinal Peptide Tumor |
| alias | Pancreatic Cholera, Pancreatic Cholera, WDHH Syndrome, VIPoma, WDHA Syndrome, Verner-Morrison Syndrome |
Vasoactive intestinal peptide tumor (VIPoma) is a benign or malignant tumor of pancreatic islet D1 cells. Due to the excessive secretion of vasoactive intestinal peptide (VIP) by D1 cells, it causes severe watery diarrhea, hypopotassemia, achlorhydria, or hypochlorhydria, hence also referred to as WDHA or WDHH syndrome. This syndrome was first described by Verner and Morrison in 1958, and is therefore also named Verner-Morrison syndrome. Vasoactive intestinal peptide (VIP) was first isolated and purified from bovine small intestine in 1970. Subsequent studies demonstrated that VIP has various physiological functions, including relaxing small intestine smooth muscle, stimulating small intestine secretion, and inhibiting gastric acid secretion. Consequently, Barbezat and Grossman proposed in 1971 that the disease cause of WDHA syndrome was VIP. In 1973, Bloom confirmed elevated VIP levels in the plasma and tumor tissues of WDHA syndrome patients. Due to the cholera-like severe watery diarrhea, the condition is also termed pancreatic cholera or pancreaticogenic cholera. This disease is clinically rare, even among functional endocrine tumors. To date, over 200 cases have been reported abroad, while only 7 cases have been documented domestically. About 11% of patients are under the age of 10, with the majority being middle-aged; the average age of patients with pancreatic tumors is 40. A small number of patients (4%) may have multiple endocrine neoplasia type I, and rare cases exhibit familial inheritance.
bubble_chart Pathological Changes
Vasoactive intestinal peptide tumors (VIPomas) are mostly single, isolated tumors with considerable variation in size, ranging from 1.5 to 10 cm in diameter.
Approximately 84% of these tumors are located in the pancreas, while the remainder include ganglioneuromas, neuroblastomas, and ganglioneuroblastomas. These tumors are distributed along autonomic nerve trunks or may be found in the adrenal glands, all sharing the characteristics of VIPomas and secreting VIP. Among pancreatic VIPomas, 80% are solitary tumors, and 20% are multicentric.Seventy-five percent are located in the body and tail of the pancreas, while 25% are found in the pancreatic head. About 50% of pancreatic VIPomas are malignant, with half of these patients already having metastases to the liver or surrounding lymph nodes at diagnosis; some may also metastasize to the lungs, stomach, or mediastinum. Most neurogenic VIPomas are benign, with only 10% being malignant. Islet cell hyperplasia is also one of the causes of VIPoma syndrome, in which case no tumor is present.
bubble_chart Clinical Manifestations
1. Diarrhea
The most prominent symptom of this disease is profuse secretory diarrhea, with over 70% of patients experiencing daily diarrhea exceeding 3L. The stool is watery and tea-colored in appearance. Diarrhea often occurs suddenly and explosively, but in severe cases, it may persist continuously. In VIPoma patients, diarrhea continues even after 48–72 hours of fasting, making a 72-hour fast useful for differentiating it from diarrhea caused by other conditions. For details, see Table 1.
Table 1 Clinical Manifestations of VIPoma*
| Symptoms and Signs | Incidence Rate (%) |
| Secretory Diarrhea | 100 |
| Weight Loss | 100 |
| Electrolyte Imbalance | 100 |
| Dehydration | 100 |
| Metabolic Acidosis | 100 |
| Hypochlorhydria or Achlorhydria | 75 |
| Abdominal Cramps | 62 |
| Hypophosphatemia | 60 |
| Hypercalcemia | 41 |
| Impaired Glucose Tolerance | 50 |
| Flushing | 20 |
| Hyperglycemia | 18 |
| Kidney Stones | 4 |
*Mozell E, et al. Curr Probl Surg, 1990, 27(6):309
2. Water, Electrolyte, and Acid-Base Imbalances
Due to prolonged and severe diarrhea, accompanied by significant electrolyte loss, patients exhibit varying degrees of dehydration, reduced circulating blood volume, hypokalemia, hypochloremia, metabolic acidosis, and other water, electrolyte, and acid-base imbalances. In severe cases, this may further lead to complications such as arrhythmia, hypokalemic nephropathy, or renal failure, and even death.
3. Hypochlorhydria or Achlorhydria
Three-quarters of patients exhibit reduced gastric acidity or even achlorhydria. The mechanism involves vasoactive intestinal peptide inhibiting pentagastrin-stimulated gastric acid secretion, thereby lowering gastric acid levels, with some patients developing achlorhydria. Gastric mucosal biopsies in these patients reveal normal parietal cell counts, further indicating that the reduction in gastric acid is unrelated to changes in the parietal cells themselves.
4. Hypophosphatemia and Hypercalcemia
Approximately 60% of patients develop hypophosphatemia, and 50% exhibit hypercalcemia.
The mechanism of calcium and phosphorus metabolism disorders is not yet fully understood. Since hypercalcemia and hypophosphatemia can return to normal after tumor resection, it is speculated to be related to the increased secretion of parathyroid hormone-like substances by the pancreatic islet tumor itself.
5. Impaired Glucose Tolerance and Hyperglycemia
Approximately 50% of patients exhibit impaired glucose tolerance, while slightly fewer, around 18%, develop hyperglycemia. The reason for this is that the molecular structure of vasoactive intestinal peptide (VIP) closely resembles that of glucagon, potentially leading to glucagon-like effects. Alternatively, it may result from the impact of hypokalemia on pancreatic islet function. Glucose tolerance may return to normal after tumor resection.
About 62% of VIPoma patients may experience abdominal cramps; 20% of patients develop paroxysmal skin flushing, often occurring on the face or chest. Bloom reported that 4% of patients develop kidney stones, though the underlying mechanism remains unclear.
The average time from symptom onset to definitive diagnosis is 3 years (ranging from 2 months to 4 years), with some reports indicating delays of up to 15 years. Although malignant VIPomas often metastasize by the time of diagnosis, fatalities due to the disease are relatively rare. Deaths are typically caused by severe diarrhea leading to water and electrolyte imbalances, ultimately resulting in arrhythmias or renal failure.
bubble_chart Auxiliary Examination
1. Laboratory tests
Dehydration, hypokalemia, hypochloremia, metabolic acidosis, hypochlorhydria, hypercalcemia, hypomagnesemia, and decreased glucose tolerance, among others.
2. Serum vasoactive intestinal peptide (VIP) measurement
In normal individuals, fasting serum VIP levels range from 0 to 170 pg/ml, with an average of 62±22 pg/ml. In VIPoma patients, serum VIP levels are significantly elevated, averaging 956±285 pg/ml, with some cases reaching as high as 2400 pg/ml.
3. Localization diagnosis
Due to the rarity of VIPoma itself, systematic research on localization diagnostic methods for this disease is relatively scarce.
⑴ B-ultrasound and CT: These can reveal the location, size, and number of tumors, as well as determine the presence of liver or surrounding lymph node metastases, making them the preferred localization examinations for surgery.
⑵ Selective pancreatic angiography: This can improve the accuracy and diagnostic rate of localization, but false negatives or positives may occur, and it is difficult to distinguish the specific type of islet cell tumor.
⑶ Percutaneous transhepatic portal vein catheterization (PT-PC):
The method is described in the first section of this chapter. By measuring the concentration of vasoactive intestinal peptide in blood samples taken from different parts of the portal vein system, it helps determine the tumor's location.
⑷ Intraoperative B-ultrasound: This aids in detecting small tumors located within the pancreas.
Secretory diarrhea is the most prominent symptom of this disease. The watery diarrhea is voluminous and prolonged, especially when it persists without relief after 72 hours of fasting, which holds diagnostic value. Other symptoms include weight loss, abdominal cramps, and skin flushing. Combined with laboratory tests, serum vasoactive intestinal peptide (VIP) measurement, ultrasound, CT, selective pancreatic angiography, and percutaneous transhepatic portal vein catheterization (PT-PC) for localization, the diagnosis can be readily established. During the localization diagnosis of this disease, attention should be paid to the possibility of ganglioneuroma in pediatric patients. Additionally, special vigilance is required for the adrenal glands to prevent misdiagnosis of fistula disease.
bubble_chart Treatment Measures
1. Surgical Treatment
Surgical removal of the tumor is the preferred method for treating this disease. The specific surgical approach follows these principles:
(1) For small and single tumors, enucleation or partial pancreatectomy is performed.
(2) If the tumor is located in the tail of the pancreas, resection of the pancreatic tail or distal pancreatectomy can often achieve a cure.
(3) If no tumor is found during preoperative or intraoperative examinations, a blind subtotal pancreatectomy may be performed, as 75% of the tumors in this disease are located in the body and tail of the pancreas.
(4) During surgery, careful exploration of the adrenal glands and the sympathetic nerve distribution area from the diaphragm to the bladder should be conducted to determine the presence of ganglioneuromas. Surgical outcomes for ganglioneuromas are generally favorable.
(5) Radical resection should also be attempted for metastatic tumors. Even debulking surgery can alleviate clinical symptoms. Nagorney reported that reoperation for recurrent VIPoma resulted in sustained remission.
(6) For extensive non-B-cell hyperplasia of the pancreas, partial pancreatectomy of the tail may be performed first. If symptoms improve postoperatively, a total pancreatectomy can be performed in a second surgery, with an 80% cure rate.
2. Drug Therapy
(1) Drug therapy is crucial for stabilizing the condition before surgery, correcting metabolic disturbances, and treating advanced-stage patients who are no longer candidates for surgery. The first step is aggressive fluid replacement to correct dehydration, electrolyte imbalances, and acid-base disorders. Oral glucose and electrolyte solutions are preferable to intravenous fluids, as they promote jejunal absorption of water and electrolytes, reducing fluid loss in feces.
(2) To control diarrhea, prednisone tablets can be used at a dose of 60–80 mg daily. Indomethacin, as a prostaglandin inhibitor, can reduce diarrhea volume at a dose of 25 mg orally every 8 hours. Lithium carbonate, 300 mg twice daily, can also reduce diarrhea but does not lower VIP levels; its mechanism involves inhibiting cyclic adenosine monophosphate (cAMP).
(3) The most effective drug for treating this condition is octreotide acetate, which reduces circulating VIP levels, decreases diarrhea, corrects electrolyte and acid-base imbalances, and addresses VIP-induced hypercalcemia. Its reported efficacy is 70%. It also inhibits tumor secretion of other polypeptides that may cause clinical symptoms. Octreotide acetate is the first-line treatment for advanced-stage VIPoma patients. However, some patients may not respond to drug therapy.
(3) Chemotherapy
Chemotherapy is effective for metastatic tumors and may control symptoms in patients unresponsive to drug therapy. Streptozotocin can be administered intravenously at a dose of 20–30 mg/kg weekly for 8–10 doses or directly into the peritoneal cavity as a stirred pulse at 5–10 mg/kg body weight. Its reported efficacy is 50%, and it may also shrink tumors. Combining it with 5-FU can enhance its therapeutic effect. Intraperitoneal stirred pulse injection reduces the dose, improves efficacy, and minimizes renal toxicity.
Interferon therapy can reduce diarrhea volume, lower plasma VIP levels, and even shrink tumors, though reported outcomes vary.
Hypophosphatemia, hypercalcemia, hyperglycemia, kidney stones, etc.
1. Severe watery diarrhea should be differentiated from diarrhea caused by various other reasons, mainly including: ① Infectious diarrhea: Diarrhea caused by bacterial infection has a more acute onset compared to secretory diarrhea in patients with vasoactive intestinal peptide tumor diseases. Pathogenic bacteria can be detected through stool microscopy or culture, whereas no pathogenic bacteria are found in the stool of VIPoma patients. ② Cholera or paracolera: Cholera has a more acute onset and often rapidly worsens without treatment. Vibrio cholerae or paracolera can be cultured from the stool, whereas patients with vasoactive intestinal peptide tumor diseases may have a disease course lasting months or years, with no such bacteria found in stool cultures. ③ Osmotic diarrhea: This type of diarrhea may be caused by malabsorption of food or excessive osmotic load in the intestines, such as lactose intolerance. Differentiation from vasoactive intestinal peptide tumor can be achieved through a fasting test. After 48–72 hours of fasting, symptoms of osmotic diarrhea disappear, whereas secretory diarrhea persists. ④ Other functional endocrine tumors may also cause diarrhea, but each has its own unique clinical manifestations for differentiation.
2. Differentiation between vasoactive intestinal peptide tumor and gastrinoma: Patients with gastrin tumor diseases exhibit increased gastric acid, ulcer diathesis, and low potassium content in stool, which can distinguish them from vasoactive intestinal peptide tumor. Moreover, diarrhea in gastrin tumor patients can often be alleviated by gastrointestinal decompression, whereas diarrhea in vasoactive intestinal peptide tumor patients remains unchanged despite decompression.
3. Differentiation between vasoactive intestinal peptide tumor and somatostatinoma: The latter primarily presents with steatorrhea, which is distinctly different from the watery diarrhea of the former.
4. Differentiation between vasoactive intestinal peptide tumor and carcinoid: Carcinoid patients also exhibit symptoms such as diarrhea and skin flushing, but their blood levels of serotonin and bradykinin are elevated, and urinary 5-hydroxyindoleacetic acid (5-HIAA) levels are increased, which can help differentiate them from vasoactive intestinal peptide tumor patients.
