An unusual cause of hypokalemic paralysisCP Lakshmi1, R Vijayahari2, SK Kamalanathan3, GN Rajesh4, SK Verma4
1 Department of Medical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
2 Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
3 Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
4 Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.109501
Source of Support: None, Conflict of Interest: None
Vasoactive intestinal polypeptide (VIP) secreting tumors (VIPomas) are rare tumors of the islet cells of pancreas, with an estimated annual incidence of 1 per 10,000,000 individuals in the general population.  It classically presents with severe watery diarrhea with hypokalemia and hypochlorhydria. More than two-thirds of these tumors are malignant, with evidence of lymph nodal or liver metastasis at presentation.  and more than 90% arise from pancreas. The management is usually surgical.  We present in this paper, a case of VIPoma which presented with acute flaccid paralysis, highlighting the fact that VIPoma should also be included in the differential diagnosis of a case of hypokalemic paralysis.
A 39-year-old female, a known diabetic, presented to the emergency department with acute flaccid bilateral lower limb weakness. She was found to have a serum potassium level of 2 meq/L (3.5-5 meq/L) and improved with intravenous potassium supplementation. She gave a history of recurrent episodes of severe watery diarrhea since the past 2 years. Diarrhea was large volume, with no blood or mucus, with mild crampy periumbilical pain during episodes. Each episode lasted a roughly a week and episodes recurred monthly. She remained fully asymptomatic between episodes. She gave a history of diabetes mellitus since 2 years and was on insulin. She had no clinical and biochemical features suggestive of multiple endocrine neoplasia (MEN) syndrome and an ultrasound abdomen showed a small mass lesion in head of pancreas.
In view of typical episodic diarrhea with hypokalemia and a pancreatic mass, a potential diagnosis of VIPoma was reached. A contrast enhanced computed tomogram (CECT) abdomen showed a 3-cm-mass lesion in uncinate process of pancreas, with no significant enhancement in early arterial phase, appearing isodense to pancreatic parenchyma in portal phase [Figure 1]a and b.
She was taken up for Whipple's pancreatico-duodenectomy, where a well-circumscribed tumor measuring 3.2 × 3 × 2 cm was observed in uncinate process [Figure 1]c. Cut surface of the tumor was homogeneously gray brown with no evidence of hemorrhage or necrosis [Figure 1]d. Microscopic sections showed an encapsulated tumor comprising of small round tumor cells arranged in trabecular and acinar pattern [Figure 2]a. Nuclei had stippled chromatin pattern [Figure 2]b and there was no evidence of mitosis or necrosis. Immunohistochemistry for chromogranin, synaptophysin, and neuron-specific enolase were positive in 40%, 20%, and 10% tumor cells, respectively. Subsequently, immunohistochemistry performed with antibodies for VIP showed strong cytoplasmic expression in 70% of the tumor cells [Figure 2]c and d. The patient had an uneventful post-operative course and is now asymptomatic, and free of diarrhea at 8 months of follow-up.
VIPomas are rare islet cell tumors of pancreas that secrete VIP, a structural homolog of secretin. Elevated serum VIP levels cause increased intestinal secretion of Na + , K + , HCO3− , and Cl− , as well as bone resorption, vasodilation, and inhibition of gastric acid secretion.  These effects lead to a well-defined clinical syndrome, characterized by watery diarrhea, hypokalemia, and hypochlorhydria. This syndrome is commonly known as Watery diarrhea hypokalemia achlorhydria (WDHA) syndrome, other acronyms being pancreatic cholera syndrome, endocrine cholera, and the Verner-Morrison syndrome. In 1968, Verner and Morrison described this clinical syndrome in two male patients, who had pancreatic tumors at autopsy which were considered to be responsible for their clinical manifestations. 
VIPomas are most commonly found in the pancreas, other sites being colon, bronchus, adrenals, liver, and sympathetic ganglia. In pancreas, about 72% are located in the tail of pancreas with the rest being observed on the head of pancreas. The mean tumor size as described in various case series is about 5 cm, with the majority having evidence of locoregional spread or liver metastasis. In a review of 35 cases, 59% had evidence of metastasis at presentation. 
The diagnosis is usually suspected when a cross-sectional imaging, either computed tomography (CT) or magnetic resonance imaging (MRI) shows a pancreatic mass lesion in a patient with typical clinical features. The CT scan is quite sensitive in making a diagnosis as majority of VIPomas are more than 3 cm in size at presentation. Somatostatin receptor positivity is seen in 80-90% of VIPomas, making somatostatin receptor scintigraphy, an useful adjunct in the diagnosis. A serum radioimmunoassay for VIP aids diagnosis, especially at the time of a diarrheal episode. In a review of 35 cases, the serum VIP values ranged from 100 to 7200 pg/ml (mean 1209 pg/ml, median 632 pg/ml).  In our patient, the estimation was not done for want of funds, and also due to the fact that she did not have a diarrheal episode during stay in our hospital. Moreover, a low or normal value of VIP in non-diarrheal state does not rule out VIPoma.
Histologically, the cellular patterns of VIPomas can be either solid, acinar, or trabecular with scant mitoses.  Malignancy is confirmed by the evidence of disease in lymph nodes or distant sites such as liver. Immunohistochemical staining showing positivity for VIP usually confirms the diagnosis, as in our patient.
Aggressive surgical intervention is the main-stay of treatment in most cases, procedures described being distal pancreatectomy, pancreatico-duodenectomy, splenectomy, hemi-gastrectomy, liver resection, and tumor enucleation.  In patients with advanced disease, palliative treatment with octreotide shows improvement in clinical features. Other palliative therapeutic modalities include hepatic artery embolization, radiofrequency ablation, hepatic transplantation, and radioactive octreotide.  With such multimodality management, the largest case series on VIPomas reports a 5-year actuarial survival rate of 69%. 
Literature on VIPoma is limited to case reports and small case series from major pancreatobiliary centers from across the globe. ,,, There has only been one pediatric case of VIPoma reported from India so far.  We now probably report the first adult case of VIPoma from India. Our patient presented with all typical clinical features of this syndrome and the diagnosis was conclusively proven on immunohistochemistry. We would like to highlight that VIPoma should also be kept in mind during the workup of unexplained episodic diarrheas, especially those with severe hypokalemia.
[Figure 1], [Figure 2]