Vasoactive intestinal peptide-oma causing refractory diarrhea in a young woman

Abstract

Vasoactive intestinal peptide (VIP)–secreting neuroendocrine tumors are an exceptionally rare cause of chronic diarrhea. We describe a 36-year-old woman presenting with a 2-year history of severe diarrhea and electrolyte derangements ultimately diagnosed with VIPoma.

Diarrhea is commonly encountered in both the hospital and clinic setting. While acute diarrhea often does not require extensive diagnostic or therapeutic consideration because it is self-limited, cases of chronic diarrhea, defined as lasting >4 weeks, have an extensive differential diagnosis and typically require a thoughtful assessment.

CASE DESCRIPTION

A 36-year-old white woman presented to the hospital with recurrent episodes of persistent diarrhea and dehydration of 2 years duration. Her diarrhea was watery and voluminous, exceeded 2 to 3 L per day, and persisted despite fasting. There was an associated 30-pound weight loss and mild, generalized abdominal pain. The diarrhea was refractory to multiple therapies including loperamide, colestipol, tincture of opium, and elimination diets. Colonoscopy with biopsy demonstrated increased intraepithelial lymphocytes suggestive of lymphocytic colitis. Trials of budesonide and cholestyramine were attempted but unsuccessful. A cholecystectomy was also performed.

On examination, she was thin, ill-appearing, and showed signs of volume depletion. Her body mass index was 21 kg/m². The serum potassium was 2.5 mEq/L and bicarbonate was 12 mEq/L with a normal anion gap. A 24-hr stool collection (Table 1) revealed secretory diarrhea with low osmotic gap and without steatorrhea, inflammatory markers, blood, or osmotic laxatives. A thorough infectious workup and celiac serologies were negative. Endoscopy with duodenal biopsies showed only attenuated villi. Flexible sigmoidoscopy demonstrated no pertinent gross findings, and biopsies were without evidence of inflammatory or microscopic colitis.

Table 1.

Chemical analysis of 24-hour stool collection

Test	Value
Weight (g/day)	2793
Sodium (mEq/L)	84
Potassium (mEq/L)	42
Chloride (mEq/L)	43
Osmotic gap (mOsm/kg)	38
Fecal pH	8.0
Fat output (g/day)	3.4

An abdominal computed tomography (CT) scan revealed a 3.9 × 3.5 cm solid mass arising from the pancreatic tail (Figure 1a). Octreoscan confirmed high levels of uptake (Figure 1b) without metastatic disease. An endoscopic ultrasound with fine needle aspiration revealed the mass to be a highly differentiated neuroendocrine tumor (NET). Serum vasoactive intestinal peptide (VIP) was 1295 pg/mL (normal <75 pg/mL). Serum levels of gastrin, 5-hydroxyindoleacetic acid, chromogranin, and calcitonin were within normal limits. A diagnosis of pancreatic NET was made, specifically a VIPoma. Management included aggressive intravenous fluid resuscitation, electrolyte repletion, and subcutaneous octreotide. The patient underwent a laparoscopic distal pancreatectomy with splenectomy (Figure 1c), with near immediate resolution of her diarrhea. Pathology confirmed a well-differentiated NET with a Ki-67 index of 8% and low mitotic rate without nodal involvement (Figure 1d). The patient had no evidence of disease recurrence 11 months postoperatively.

Figure 1.

(a) Abdominal CT with contrast showing pancreatic mass. (b) Octreotide scan with tracer uptake in location of the mass. (c) Laparoscopic resection of tumor. (d) Hematoxylin-eosin staining of mass showing cells in nests and clusters with salt and pepper chromatin and a high nucleus-to-cytoplasm ratio.

DISCUSSION

VIPomas are a rare cause of chronic diarrhea (1 in 10,000,000 annually). They commonly occur as solitary lesions in the tail of the pancreas and are malignant in up to 90% of cases. ¹ The typical age at presentation is 30 to 50 years. ¹ VIPomas’ median survival (8 years) is significantly lower than that of other NETs. ^{2 , 3} Five-year survival is 60% and 94% in patients with and without metastatic disease, respectively. ⁴ Compared to other NETs, VIPomas are rarely associated with multiple endocrine neoplasia type 1. ⁵

Although it mainly functions as a neurotransmitter, VIP is also produced by pancreatic islet cells. VIP binds to G protein–coupled receptors on enteric smooth muscle and enterocytes, resulting in cyclic adenosine monophosphate–mediated stimulation of chloride secretion with simultaneous inhibition of sodium chloride absorption. ⁶ This results in large-volume secretory diarrhea, vasodilation, smooth muscle relaxation, and excess biliopancreatic secretion. The diarrhea of VIPoma is typically >3 L per day but can exceed 8 L. ¹ This leads to marked hypokalemia and metabolic acidosis, thus earning the title “watery diarrhea with hypokalemia and achlorhydria” syndrome, also known as WDHA or Verner-Morrison syndrome. Diarrheal volumes <700 cc per day exclude this syndrome.

Patients with these findings should undergo abdominal imaging with attention paid to the pancreas. VIPomas are bulky, with size >2 cm at the time of diagnosis, and are easily seen on CT. ⁷ Conventional workup also involves the use of octreotide scintigraphy (Octreoscan), which may have limited sensitivity. ^{8 , 9} Primary and metastatic disease may be better identified using positron emission tomography with gallium-labeled octreopeptides (68 Ga-DOTATATE). ¹⁰ Delays in diagnosis frequently occur, and over half of patients have metastatic disease at the time of diagnosis. ^{1 , 4 , 11}

Treatment begins with intravenous fluid resuscitation and electrolyte repletion. Additionally, octreotide therapy can resolve diarrhea as quickly as 3 d and may also have antineoplastic activity. ^12–14 Surgical resection improves disease-free survival in primary and metastatic disease. ^{11 , 15} For unresectable disease, cytoreductive surgery may be offered for symptom palliation along with biologics or chemotherapy. ^15–17

In conclusion, VIPoma is a rare cause of chronic severe diarrhea and presents with a classic triad of persistent secretory diarrhea, hypokalemia, and achlorhydria. Patients presenting with this syndrome should receive appropriate pancreatic imaging. Treatment with somatostatin analogues is key to improving symptom burden and may have antitumor effects. Patients should also be considered for surgical resection, which may be curative and prolong survival.