VIPoma

Etiology

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

Epidemiology

VIPomas are rare tumors that are detected in 1 in 1,000,000 people per year.[4] In adults, they are most commonly diagnosed between the ages of 30 and 50 and are intrapancreatic in over 95% of cases. A small proportion of tumors secreting VIP have been reported as colorectal cancer, lung cancer, pheochromocytoma, neurofibroma, and ganglioneuroblastoma. Most VIPomas present as isolated, functioning neuroendocrine tumors predominantly located in the pancreatic body and tail. Approximately 5% of cases are associated with multiple endocrine neoplasia type 1 syndrome. Notably, over 50% of VIPomas exhibit metastatic disease at the time of diagnosis.[5]

In children, VIPomas are typically diagnosed between the ages of 2 to 4. Most of these tumors in the pediatric population 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][7] 

Pathophysiology

Excessive secretion of VIP from the tumor has multiple effects on different organ systems, primarily the GI system. VIP is a neurotransmitter belonging to the secretin-glucagon family and mediates its effects by binding to the G-protein-coupled receptors for vasoactive intestinal peptides—VPAC1 and VPAC2—expressed in various tissues throughout the body.[8] Upon binding, VIP activates the adenylate cyclase cyclic adenosine monophosphate (cAMP) signaling pathway, which increases levels of cAMP with subsequent effects of smooth muscle relaxation. This activation also promotes vasodilation and decreases GI motility, stimulating water, electrolyte, and bicarbonate secretion in the intestines, contributing to the hallmark watery diarrhea observed in VIPoma. Additionally, VIP inhibits gastric acid secretion and promotes glycogenolysis, lipolysis, and bone resorption.

Histopathology

The histopathology of VIPomas is consistent with that of other well-differentiated neuroendocrine tumors. VIPomas specifically present as a firm, homogenous, and well-circumscribed lesion. They are characterized by nests or cords of uniform cells with abundant eosinophilic cytoplasm and round-to-oval nuclei containing fine chromatin, often described as "salt-and-pepper." While immunohistochemistry may reveal positivity for chromogranin A and synaptophysin, staining for VIP is specific and confirms the diagnosis.

Despite their generally low mitotic activity and well-differentiated nature, more than half of VIPomas present with metastasis at the time of diagnosis, commonly involving the liver.[9] VIPomas are usually well-differentiated and fall within the category of grade 1 or grade 2 neuroendocrine tumors based on the World Health Organization classification, depending on the mitotic rate and Ki-67 proliferation index.[10]

History and Physical

Patients with VIPoma most commonly present with watery diarrhea, which is secretory and persists after a 48-hour fast. Diarrhea may be present for several years before diagnosis. Typically, stool amount exceeds 700 mL daily despite fasting and can exceed over 3000 mL in 70% of patients.[11][12] These stools are odorless and tea-colored, resulting in substantial fluid and electrolytes such as potassium losses.

The physical examination of patients with VIPoma often reflects the systemic effects of chronic watery diarrhea, dehydration, and electrolyte imbalances. Typical findings include fatigue, lethargy, and signs of malnutrition due to prolonged fluid loss. Vital signs may reveal hypotension and tachycardia indicative of hypovolemia, while dry skin, decreased skin turgor, and dry mucous membranes are consistent with dehydration. Neuromuscular manifestations, such as muscle weakness, cramps, or diminished reflexes, are frequently observed and are attributable to hypokalemia. If severe, the loss of fluid and electrolytes can result in cardiac arrhythmias, myopathy, tetany, and hypovolemic shock.[13]

Abdominal examination is typically unremarkable, although hepatomegaly may be present in cases of metastatic liver involvement. Additional findings may include clinical features of multiple endocrine neoplasia type 1 (MEN1), such as hyperparathyroidism or pituitary adenomas. 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 liters per day, with a serum VIP level of 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. VIP levels must be repeated to confirm diagnosis since levels may not be elevated between episodes of watery diarrhea. VIP levels must also be obtained 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 of having VIPoma, catecholamine levels should also be measured to differentiate from neuroblastoma. 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 tumor secretion of a calcitrophic peptide. Hypomagnesemia may occur from profound diarrhea. Hyperglycemia is due to the increased glycogenolytic activity of VIP.

Imaging Studies

Tumor localization typically starts with a helical multiphasic contrast-enhanced computed tomography (CT) scan. The sensitivity of multiphasic CT scans is significantly high at greater than 80% for detecting intrapancreatic neuroendocrine tumors.[14][15] Intravenous (IV) contrast further aids in detecting smaller lesions.

Magnetic resonance imaging is performed in cases of indeterminate lesions and may be more sensitive to detect liver metastasis. Somatostatin receptor scintigraphy, using the radiolabeled somatostatin analogs octreotide and lanreotide, has the advantage of detecting small, occult metastases within and outside the abdomen. Other techniques include endoscopic ultrasound, which helps determine the accurate extent of the disease and can be used to biopsy the pancreatic lesions. The United States Food and Drug Administration has approved functional positron emission testing imaging technique with 68-Ga DOTATATE injection as the radioactive diagnostic agent for detecting somatostatin receptor-positive neuroendocrine tumors in adult and pediatric patients.

Treatment / Management

Initial Management

The management of VIPoma involves medical management and surgery, outlined below: 

• Initial medical management is aimed mainly at controlling the symptoms by promptly and aggressively replacing fluids and electrolytes.[16]
• Somatostatin analogs like octreotide and lanreotide inhibit the secretion of VIP and are used for symptomatic control. Octreotide is usually started at 50 to 100 mcg subcutaneously every 8 hours and titrated for symptom control. A long-acting formulation of octreotide is initiated at a dose of 20 mg intramuscularly monthly and titrated as needed for optimal symptom control.
• Glucocorticoids are used in patients refractory to somatostatin analogs.[17]
• Interferon-alpha has also been used in patients not responding to the above medications.
• Complete surgical resection is considered the only definitive treatment of choice for nonmetastatic primary tumors and is usually a distal pancreatectomy. If the tumor cannot be excised completely, surgical debulking may provide palliative benefit.[18]

Management of Metastatic/Progressive Disease

Metastases at the time of detection of VIPoma have been noted in over 50% of cases.[19] The metastases most commonly occur in the liver, lymph nodes, bones, and kidney.[20] For metastatic VIPoma, surgical resection is generally not indicated and is typically contraindicated for locally advanced pancreatic neuroendocrine tumors when achieving a macroscopic radical resection is not feasible.[21][22] However, in cases of limited liver metastases, surgical resection may be considered in the absence of diffuse involvement of both liver lobes, decreased liver function, or extrahepatic metastases. Liver transplantation is a potential treatment option for metastatic VIPoma in highly selected patients with isolated, unresectable liver metastases with no extrahepatic disease.[23] Still, strict eligibility criteria and the risk of recurrence limit its use. (B2)

Radiofrequency ablation and cryoablation have also been the choice of the modality of treatment in cases of small metastases less than 3 cm. Hepatic artery embolization is a palliative treatment in patients with unresectable hepatic metastases.[24] Systemic chemotherapy can be used for poorly differentiated, extrahepatic metastatic, or aggressive disease. Therapy options typically include a combination regimen with streptozocin or temozolomide-based therapy.[25] However, evidence of the overall use of chemotherapy and response in VIPoma is limited. Novel agents like sunitinib, a tyrosine kinase inhibitor, and everolimus, an mammalian target of rapamycin inhibitor, are approved in the United States to treat advanced, well-differentiated pancreatic neuroendocrine tumors, including VIPomas.[26][27](A1)

Differential Diagnosis

Secretory diarrhea in adults in developed countries can be caused by laxative abuse, carcinoid syndrome, microscopic colitis, and bile salt malabsorption due to ileal resection. Though more common in developing countries, diarrhea caused by infection with Vibrio cholera and enterotoxigenic Escherichia coli may also need to be ruled out after careful history assessment. Secretory diarrhea may occasionally occur associated with GI disorders like Crohn disease and short bowel syndrome. Rarely inherited electrolyte transport defects, such as such as congenital chloride and sodium diarrhea, may cause secretory diarrhea in children in children. These are present in early infancy. Munchausen syndrome by proxy may also need to be ruled out in rare cases.

Staging

Like other neuroendocrine tumors, VIPoma is based on the tumor-node-metastasis (TNM) staging system developed by the American Joint Committee on Cancer and the European Neuroendocrine Tumor Society. This system considers tumor size, local invasion, lymph node involvement, and distant metastasis. Since more than 50% of VIPomas have metastasized at the time of diagnosis, most patients present with advanced disease (stage IV).

Staging Criteria:

• Primary tumor:
  • T1: Tumor ≤2 cm, confined to the pancreas
  • T2: Tumor >2 cm but ≤4 cm, confined to the pancreas
  • T3: Tumor >4 cm or invading adjacent structures (excluding major vessels)
  • T4: Tumor invades adjacent organs or large vessels
• Regional lymph nodes:
  • N0: No regional lymph node involvement
  • N1: Regional lymph node metastasis present
• Distant metastasis:
  • M0: No distant metastasis
  • M1: Distant metastasis present (commonly the liver, but may also include bones or lungs)

Stages:

• Stage I: T1, N0, M0
• Stage II: T2 or T3, N0, M0
• Stage III: Any T, N1, M0
• Stage IV: Any T, any N, M1

Prognosis

The median survival of patients with VIPoma is 8 years. Survival is dependent primarily on tumor grade, stage, and surgical resectability. As per recent National Comprehensive Cancer Network guidelines, the postresection follow-up includes history and physical examination, multiphasic CT or magnetic resonance imaging, and serum VIP level in the initial 3 to 12 months. After 1 year, it is recommended to follow the same measures every 6 to 12 months.[3]

Complications

VIPoma complications can be categorized by risks associated with the primary tumor, risk of metastasis, and risks from treatment. VIPomas can lead to significant complications, primarily due to excessive VIP secretion from the primary tumor, causing severe dehydration, hypokalemia, metabolic acidosis, renal dysfunction, and malnutrition. Metastatic disease can lead to organ dysfunction along with an increased risk of thromboembolic events. Treatment for VIPoma also includes complications inherent to surgical and medical management of the disease process.