Pancreatic Vasoactive Intestinal Peptide Polypeptide-secreting Tumor With a Good Prognosis: a Case Report and Review of the Literature

Background: Pancreatic vasoactive intestinal polypeptide secreting tumor is a rare pancreatic endocrine tumor, which has high rate of misdiagnosis because of its rarity. We are always seeking for some novel treatment methods, constantly summarizing experience and lessons, and improving the diagnosis. Case presentation: Here we report the case, a 48-year-old female patient was admitted to the hospital for 2 years with recurrent diarrhea. The computerized tomography scan of the upper abdomen demonstrated a 27 mm×31 mm space-occupying lesion in the tail of the pancreas. Electrolyte results suggest hypokalemia and elevated serum vasoactive intestinal peptide levels. After evaluating the condition, consider surgical removal of the pancreatic tail and active symptomatic treatment. Postoperative pathological biopsy was diagnosed as pancreatic neuroendocrine tumor, serum potassium recovered, serum VIP value decreased, and diarrhea stopped. After 8 years of follow-up, all indicators were normal and the prognosis was good. Conclusions: We hope to draw the attention of clinicians from this situation in order to increase the correct rate of disease diagnosis and improve the prognosis.

a 27 mm×31 mm space-occupying lesion in the tail of the pancreas. Electrolyte results suggest hypokalemia and elevated serum vasoactive intestinal peptide levels. After evaluating the condition, consider surgical removal of the pancreatic tail and active symptomatic treatment. Postoperative pathological biopsy was diagnosed as pancreatic neuroendocrine tumor, serum potassium recovered, serum VIP value decreased, and diarrhea stopped. After 8 years of follow-up, all indicators were normal and the prognosis was good.
Conclusions: We hope to draw the attention of clinicians from this situation in order to increase the correct rate of disease diagnosis and improve the prognosis.

Background
Vasoactive intestinal polypeptide-secreting tumor (VIPoma) is a neuroendocrine tumor that autonomously secretes vasoactive intestinal peptide (VIP) to induce a series of clinical features, including watery diarrhea, hypokalemia and achlorhydria, with an incidence of approximately one in ten million 1 .
VIPoma originates from pancreatic endocrine cells, 80% of which are more common in the pancreas, especially in the tail. Approximately 20% of VIPoma occur outside the pancreas, such as the intestine, esophagus and sympathetic ganglia. Most of them have metastasized at the time of diagnosis and have a poor prognosis 2 . However, here, we report a retrospective case over 8 years in which a VIPoma patient was completely cured by surgery with a good prognosis and summarized the characteristics of VIPoma and effective therapy to improve clinicians' understanding of the disease.

Case Presentation
A 48-year-old female patient was admitted to our hospital in 2013 for "repeated diarrhea for 1 year". The patient developed watery diarrhea, yellow and loose stools, 3 to 4 times every day, with little volume, no abdominal pain and bloating, but intermittent attacks for 2 years. She was diagnosed with "chronic gastroenteritis" in many hospitals and improved after treatment with symptomatic supportive treatment.
During the period, her condition was intermittent, and the frequency of diarrhea became 10 times every day with large-volume diarrhea (over 1 L/day), without mucus, pus and blood in the stool, accompanied by nausea, vomiting, acid re ux, no hematemesis, and melena. She was admitted with "chronic colitis" to our hospital and had lost 5 kg in weight since the onset of the disease. Extensive serological examination showed that blood serum potassium was low at 2.34 mmol/L, but serum VIP was high at 260.6 pg/ml ( Fig. 1). Hormone levels, including glucagon and insulin, and tumor indicators such as CA19-9 and CA125 were normal (Table 1). Upper abdominal computerized tomography (CT) and enhanced CT showed that a mass of 27 mm×31 mm was detected in the tail of the pancreas adjacent to the spleen and stomach, but no clear evidence of local in ltration (Fig. 2) and no obvious mucosal lesions were found by gastroscopy or colonoscopy. Endoscopic ultrasonography (EUS) showed that a circular hypoechoic area of 2.55 cm×3.32 cm was visible in the tail of the pancreas with clear boundaries, and no abnormalities of the head and body of the pancreas or pancreatic duct were observed. The distribution of blood vessels was clear, and a stripe blood ow signal was detected in the low echo area (Fig. 3). Based on the clinical symptoms as well as CT and EUS images, pancreatic vasoactive intestinal peptide tumor was highly suspected. Therefore, the somatostatin analog octreotide 0.1 mg was injected subcutaneously every 12 hours for diagnostic treatment, resulting in diarrhea that was immediately and signi cantly reduced.
However, watery diarrhea recurred after octreotide was stopped. At the beginning of 2013, pancreatic tail resection and splenectomy were performed, and a pancreatic lesion 5 cm in diameter was detected on the tail of the pancreas without adherence to the surrounding tissues, as well as no lymph node metastasis. The nal pathological diagnosis showed well-differentiated endocrine pancreatic tumors approximately 2 cm in size. Immunohistochemistry (IHC) staining indicated that CK8, CD56, Syn, CgA and VIP were positive, and Ki67(+) < 1% (Fig. 4). This patient was followed up for 8 years, and she had no diarrhea or other special discomfort and no recurrence, even without any somatostatin analog treatment. The VIP value decreased from 260.6 pg/ml before treatment to 131.7 pg/mL after the operation and was kept at stable and normal levels (36.625 pg/mL) for 8 years. The serum potassium level was increased from 2.34 mmol/L before the operation to 3.67 mmol/L after treatment and remained stable at normal levels for 8 years. Upper abdominal CT showed that the tail of the pancreas was absent, but no obvious abnormality and no metastasis were observed 8 years after the operation.  1,3,4 . The diagnosis is con rmed 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 in uence 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, ush 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 nal 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 signi cantly improve the clinical symptoms of 80-90% of patients 14 , so SSAs have become the rst 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, ushing, 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 in ltration 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 de ned, 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 signi cantly 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.

Consent for publication
Written consent and publicly issued consent have been obtained from the patient in this case.

Availability of data and materials
All information about the patient come from Department of Gastroenterology, A liated Hospital of Zunyi Medical University. The data generated or analyzed during this study are included in this published article. Figure 1 Blood examination of this case. Serum VIP (A) and potassium (B) before and after operation, as well as 8 years followed up.

Figure 2
Images of upper abdominal CT. An uneven density mass of about 27 mm × 31 mm is seen in the back of the pancreas tail, which is unevenly enhanced on enhanced scanning in 2013 before operation (A-C). The tail of the pancreas was absence, the pancreatic duct was not dilated and no other metastasis was observed in the year of 2020. Hemangiomas in the lateral segment of the left liver with multiple small cysts were still observed after 8 years later (D-F).

Figure 3
Images of EUS. EUS showed that a 2.6 cm × 3.3 cm circular hypoechoic area was detected in the tail of the pancreas, with clear boundaries and uniform internal echo. There was no abnormality in the head and body of the pancreas, and the pancreatic duct was not dilated. The distribution of blood vessels was clear, and there were spots of blood in the CDFI (Color Doppler Flow Imaging) hypoechoic area stream signal.