VIPoma and PPoma

VIPoma is a form of a functional p-NET that gives rise to clinical symptoms due to secretion of VIP. They account for less than 5% of all p-NETs corresponding to an incidence of 0.01/100,000 yearly. Mostly located intrapancreatic in adults (mainly pancreatic tail). Some rare extra-pancreatic subtypes are present mainly in children. Median age of diagnosis is 54 years and 2–4 years in children, with a slight female predominance. VIPomas tend to grow slow but have a high metastatic potential, the majority occurs as isolated sporadic, non-familial, tumors. However, association with MEN1, VHL, MEN4, neurofibromatosis type 1, tuberous sclerosis, and familial syndromes characterized by mutations in DAXX and ATRX are also seen. VIPomas usually present with watery diarrhea (accounting for dehydration and metabolic acidosis), hypokalemia, achlorhydria, hypomagnesaemia, hypercalcemia, hypophosphatemia, hyperglycemia and hypovolemia, and flushing. This can induce lethargy, muscular weakness, tetany, cardiac conduction disturbances, weight loss, abdominal pain, paralytic ileus, dyspepsia, and gallbladder hypotonia. Children can present with failure to thrive and chronic diarrhea. Diagnosis is based on secretory diarrhea (>700 ml/day) and plasma VIP levels above 200 pg/ml. Contrast-enhanced multiphasic computed tomography, magnetic resonance imaging (MRI), abdominal ultrasound, endoscopic ultrasound (EUS), with fine needle aspiration or preferable core biopsy, and 68-Ga DOTATATE PET can be used for diagnosis. First of all, the life-threatening hydro-electrolytic disorders must be corrected by aggressive replacement of fluids and electrolytes. Glucocorticoids, loperamide, and opiated can also be used for symptom control. Surgery is the golden standard for localized and resectable disease. In advanced setting, surgery can be considered for debulking as well as other liver directed therapies (embolization, transarterial (chemo) embolization (TACE), radiofrequent ablation (RFA), radiolabeled microspheres). Systemic therapy includes short- and long-acting SSA, interferon-α treatment. Molecular-targeted therapy like sunitinib and everolimus could provide clinical benefit. In addition, chemotherapy with streptozotocin and fluorouracil or capetitabine/temozolomide can be used to treat patients as well as peptide receptor radionuclide treatment (PRRT). PPoma are NETs that produce pancreatic polypeptide, which reduces the release of somatostatin. PPoma represents less than 1% of non-functional NET. They are usually incidentally diagnosed between the fifth and sixth decades due to symptoms like liver enlargement, obstruction of the pancreatic duct or jaundice, abdominal pain, palpable mass, diabetes mellitus and weight loss, gastrointestinal bleeding, and watery diarrhea (only in case of very high PP levels). Most are already metastatic when diagnosed. It can be associated with familial MEN1 and VHL syndromes. The finding of high PP levels is not sufficient for PPoma diagnosis as it can be elevated in non-neoplastic patients including patients with chronic pancreatitis, kidney failure, diabetes, hypoglycemia, duodenal ulcers, alcoholism, advanced age, and medication use (erythromycin, cisapride, laxative abuse). The association with highly vascularized tumors on CT scan should increase the suspicion of PPoma. All abovementioned imaging techniques can be used. In MEN1 patients, ultrasound of parathyroid glands should be performed, and bone scintigraphy can be performed in case of suspected bone metastases. Plasma chromogranin, calcium, serum phosphorus, parathyroid hormone, and urinary calcium should be performed at least once at diagnosis. Cytoreductive and liver directed therapy increase survival by 3–4 times. Similar systemic therapy as in VIPoma can be used in advanced PPoma.