Pancreatic neuroendocrine tumors (PNETs) have long fascinated clinicians and investigators despite their relative rarity. Their clinical presentation varies depending on whether the tumor is functional or not 3 and according to the specific hormonal syndrome produced. VIPoma constitutes a rare functional neuroendocrine neoplasm that most often originates from pancreatic islet cells and presents as a sporadic, solitary neoplasm of the pancreas, as well as ectopically expresses VIP, leading to large-volume diarrhea (90–100%; 100% > 700 mL/day, 70–80% > 3 L/day), electrolyte disturbances (notably hypokalemia, 70–100%), dehydration (45–95%), hyperglycemia (20–50%), hypercalcemia (25–50%), hypochlorhydria (35–76%), and flushing (15–30%) 1,3,4. Large-volume diarrhea often results in dehydration without an osmolar gap because it is secretory in nature 1,3,4. The diagnosis is confirmed by the presence of large volume secretory diarrhea with an increased serum VIP level together with imaging evidence. However, even in the absence of a tumor that can be imaged, an increased serum VIP level in the presence of documented secretory diarrhea is highly suggestive of VIPoma 1,4. VIP, a 28-amino-acid polypeptide whose function is similar to that of pituitary adenylate cyclase activating peptide (PACAP) 5, which is mostly found in neurons of the gastrointestinal tract, is secreted by pancreatic D1 cells and acts as a neurotransmitter or neuromodulator 6, it can influence surrounding cells or neurons in a paracrine manner 7, thereby inhibiting gastric acid secretion. After VIP receptor overexpression, vascular smooth muscle relaxes, including some nonvascular muscle vessels, which can also relax peripheral blood vessels, result in lower blood pressure, flush the face, and manifest as hypercalcemia in some patients. Furthermore, the high expression of VIP receptors can promote the continuous proliferation of tumor cells and provide an impetus for the progression of VIPoma 8. VIP binds to intestinal epithelial receptors, which belong to the family of G protein-coupled receptors that activate cellular adenylate cyclase (CAMP) through the G protein-coupled pathway and increase the expression of CAMP. At the same time, VIP can cause a large amount of water and electrolyte secretion in the intestine (mostly potassium ions), which can explain the clinical symptoms of watery diarrhea and hypokalemia. Additionally, VIP may induce hypokalemia by inducing increased aldosterone 9. Notably, because the secretion of VIP is intermittent, the level of VIP during the intermittent period of diarrhea is usually normal, and false negative results are prone to occur. Therefore, serological determination should be repeated during diagnosis to improve the overall diagnosis rate of the disease. CT and B-ultrasound are the most common imaging examinations. Because VIPoma is a neuroendocrine tumor of the pancreas, it is highly vascular; therefore, plain CT scans and enhanced imaging are extremely sensitive in its diagnosis. For pancreatic tumors with a diameter > 3 cm, its sensitivity can be as high as 92%, but for tumors < 1 cm in size, the sensitivity of CT is less than 10% 10. B-Ultrasound is not sensitive to pancreatic tumors with a diameter of < 2 cm. EUS can detect 91% of CT-negative PNETs, so the sequential detection of CT and EUS can detect most PNETs 11. Furthermore, somatostatin receptor imaging has obvious advantages in the diagnosis of microscopic, occult and metastatic lesions. A total of 80%-90% of vasoactive intestinal peptide tumors express somatostatin receptors, so it is effective for most patients. The detection of poorly differentiated tumors is more likely with the use of 18F-FDG-PET-CT and 68Ga-SSA-PET-CT. The latter two methods are recommended more for the clinical staging of PNET 12. In summary, the diagnostic inclusion criteria of VIPoma are mainly based on the typical symptoms of the disease, high levels of VIP in plasma, imaging examinations and the final pathological diagnosis. In terms of treatment, radical surgical resection is currently the most suitable treatment and the only modality that offers the possibility of cure 13, which was well presented in this case. Additionally, the use of somatostatin and its analogs (SSAs) can significantly improve the clinical symptoms of 80–90% of patients 14, so SSAs have become the first choice for the treatment of VIPoma 15. In addition, the use of new drugs, such as sunitinib and the mTOR inhibitor everolimus, can increase patient progression-free survival and overall survival rates to obviously higher levels than those of the placebo group 16. In the United States, sunitinib has been approved for the treatment of advanced, well-differentiated pancreatic neuroendocrine tumors, including VIPoma 17. Such tyrosine kinase inhibitors can not only control the secretion of VIP but also curb the growth of tumors and provide a new direction for clinical VIPoma treatment 18. Because most VIPoma patients have watery diarrhea and the diarrhea is not improved after fasting, it is accompanied by hypokalemia and low gastric acid symptoms. Therefore, in addition to combining the above symptoms in the diagnosis of the disease, it is still necessary to consider there are other causes of the severe diarrhea symptoms, such as carcinoid syndrome, colitis, short bowel syndrome, bacterial diarrhea (Vibrio cholerae, enterotoxigenic Escherichia coli), etc. 8. Currently, polypeptide receptor radionuclide therapy (PRRT) has become the most effective second-line treatment to control refractory WHDA syndrome, and combined with SSAs, it can prevent symptoms such as diarrhea, flushing, and hormonal crisis after PRRT 13. In addition, because this neuroendocrine tumor tends to be insidious and slow-growing, the prognosis of patients can be predicted by evaluating tumor metastasis, size, depth, and histological grade 19. In this case, the immunohistochemical Ki-67 proliferation index was less than 1%, and the surrounding tissues had no infiltration or metastasis, so the patient was completely cured after surgery with long-term follow-up.
VIPoma is an uncommon neuroendocrine tumor of the pancreas, the clinical symptoms are dominated by WHDA syndrome, and most patients seek medical treatment for recurrent watery diarrhea. Although its concept is clearly defined, it is clinically similar to chronic gastroenteritis, and misdiagnosis is still a phenomenon that cannot be ignored. We reviewed the characteristics of VIPoma disease through a brief analysis of the medical records. On the one hand, this review aims to improve people’s awareness of early diagnosis and treatment, which can significantly improve the prognosis of the disease. On the other hand, it will consolidate doctors’ understanding of the disease, and then doctors will be able to diagnose PNETS early and accurately so that patients have a greater probability of fully recovering.