Insulinoma

Insulinoma arises from beta-cells, located in the Langerhans islets (click here to learn more). Beta cells make insulin, and hormone which regulates sugar metabolism. Tumor proliferation causes an inappropriate insulin production, and this results in low blood sugar levels (hypoglycemia). The clinical features of this tumor are related to hypoglycemia, and include weakness, confusion, sweating, rapid heart rate, hunger, and weight gain. When blood sugar gets very low, it can lead to the patient passing out or even going into a coma and having seizures. These symptoms are relieved by food and glucose intake. Insulinoma will typically first present symptoms between the ages of 40 and 50, is more common among women, and tends to be small in size. It is in fact mostly diagnosed at an early stage (<2 cm), because a small but persistent increase in insulin levels is enough to cause symptoms. Insulinomas are far more likely to be benign than malignant. Only 10% are malignant, and only 10% are multiple. Multiple insulinomas are typically seen in young patients with MEN-1 syndrome. Fasting hypoglycemia (<40 mg/dL) associated with an elevated insulin level (in the absence of exogenous administration of insulin) is pathognomonic. Measurement of plasma proinsulin may be helpful for diagnosing insulin-secreting carcinomas. Because insulinomas are typically small, in 20-30% of cases the primary tumor cannot be detected on cross-sectional imaging. When the primary tumor cannot be assessed but the presence of a hormonal syndrome related to insulin hypersecretion has been ascertained, surgical exploration with intra-operative ultrasonography is mandatory. If intraoperative ultrasonography is unable to locate the primary neoplasm, “blind” surgical resection is contraindicated. Curative surgical excision, by laparotomy or laparoscopy, is the treatment of choice. In lesions devoid of malignancy concern, parenchyma-sparing resections, such as middle segment pancreatectomy and enucleation, can be proposed. These operations can be performed by minimally invasive techniques.

Gastrinoma

Gastrinoma arises from specialized cells that make gastrin, a hormone that regulates gastric acid secretion. Tumor proliferation causes an inappropriate production of gastrin, and this results in a condition known as Zollinger-Ellison syndrome. Zollinger-Ellison syndrome is characterized by a triad of signs and symptoms including atypical peptic ulcer disease, gastric hyperacidity and hyper-secretion. Ulcers may start bleeding, leading to anemia and melena (black tarry stools), or may result in gastric/duodenal perforation. Ulcers in patients with gastrinomas can be hard to treat, requiring high doses of anti-ulcer medication to heal. Patients need to stay on these drugs for a long time, because the ulcers tend to come back if treatment is stopped. Other symptoms include diarrhea and weight loss. Gastrinomas are usually located within the gastrinoma triangle, which roughly corresponds to the duodeno-pancreatic area. The tumor is often > 2cm at the time of diagnosis, it is multifocal in 60% of patients, and may be associated with MEN1 syndrome (20-60%). Most patients are male (60%) and the average age at diagnosis is about 60 years. More than half of gastrinomas (60-65%) are malignant, 50% of patients will have metastases at the time of diagnosis. Diagnosis is dependent on elevated serum gastrin and elevated gastric acid levels. Provocative testing with secretin may cause a substantial elevation of serum gastrin. The primary tumor may not be detected on cross-sectional imaging, whereas CT and MRI are very accurate for the detection of liver metastases. The most accurate imaging technique for the localization of gastrinomas is endoscopic ultrasound, that has been shown to be able to detect 50% of duodenal lesions and up to 75-90% of pancreatic lesions. The management of gastrinoma is surgical. The approach to treatment often depends on the results of preoperative localization studies (bearing in mind that gastrinoma may be multifocal), and findings at exploratory laparotomy. Very small lesions (< 1cm) located on the surface of the pancreas can be enucleated. Otherwise, pancreaticoduodenectomy with regional lymphadenectomy is the procedure of choice. When the tumor is located within the duodenal, duodenotomy with exploration of the inner duodenal surface may be required. Intraoperative ultrasound should be always performed to check for multifocality.

VIPoma

Vipoma arises from specialized cells that make vasoactive intestinal peptide (VIP), a hormone that stimulates water and electrolyte secretion from the bowel; dilation of intestinal blood vessels and smooth muscle; and the secretion of bicarbonate from the pancreas while blocking gastric acid secretion. These phenomena result in augmented intestinal motility. Tumor proliferation causes an inappropriate production of VIP, and this results in a condition known as Verner-Morrison syndrome. Verner-Morrison syndrome is characterized by watery diarrhea (with as many as 20 bowel movements per day), hypokaliemia (low potassium levels) and hypo-/achlorydria. Immediate fluid resuscitation is often necessary to correct the electrolyte and fluid problems (dehydration, acidosis) that occur as a result of the syndrome that patients experience. Elevated seri VIP levels are diagnostic. The tumor is often > 3cm at the time of diagnosis, more than half of VIPomas (60-65%) are malignant, and located in the body-tail of the pancreas. The treatment of choice is surgical resection (left pancreatectomy).  Somatostatin analogs are also used to ameliorate the large fluid and electrolyte losses prior to surgery. In the case of locally advanced or metastatic disease, where curative resection is not possible, debulking and removal of gross disease, including metastases, should be considered to alleviate the characteristic manifestations of VIP overproduction. VIPomas are rarely associated with MEN1 syndrome. Occasionally, adrenal tumors and tumors of nerve ganglia, of the retroperitoneum and the lung may cause a Verner-Morrison-like sydrome. 

Glucagonoma

Glucagonoma arises from specialized cells that make glucagon, a pancreatic hormone that increases glucose levels in the blood. Its effect is opposite that of insulin. Tumor proliferation causes excess glucagon, that can raise blood sugar, leading to diabetes. Patients also have problems with diarrhea, weight loss, and malnutrition (micronutrients deficiency). The nutrition problems can lead to symptoms like glossitis (irritation of the tongue), angular chielitis (irritation at the corners of the mouth), and anemia. The most distinctive feature of glucagonoma is a rash called necrolytic migratory erythema. It is a red rash with swelling and blisters and it often travels place to place on the skin. These tumors tend to be large and easily visible on CT scan, and are mostly located in the pancreatic head and neck. About 75% of glucagonomas are malignant, and develop lymph node and liver metastasis. The mainstay of therapy is surgical resection, and extended survival is possible even when the disease is metastatic. Resection of metastases is also a consideration when feasible. Chemotherapy or octreotide are used in advanced disease to relieve symptoms.

Somatostatinoma

Somatostatinoma arises from specialized cells that make somatostatin, a gastro-entero-pancreatic hormone which inhibits the production of different other hormones including insulin, glucagon, gastrin, and growth hormone. Furthermore, somatostatin inhibits the secretion of pancreatic enzymes, bile excretion from the gallbladder, amino acid absorption, and gastric acid secretion. Somatostatin inhibits intestinal motility and slows down the intestinal transit time. Somatostatinomas form in the pancreatic head, in the periampullary duodenum, in the ampulla of Vater, and in the small bowel. Duodenal somatostatinomas are associated with Von Recklinghausen’s syndrome. Somatostatinomas can be also associated with MEN1 syndrome. They often present with diarrhea, steatorrhea, diabetes, and/or gallstones. Decreased pancreatic secretion of enzymes and bicarbonate accounts for the diarrhea and steatorrhea. Somatostatin-mediated inhibition of cholecystokinin leads to gallstone formation. Somatostatin also inhibits insulin, producing hyperglycemia. Since symptoms of a somatostatinoma tend to be mild, these tumors tend to be diagnosed at an advanced stage. CT scan, MRI, and endoscopic ultrasound can usually help localize and stage the tumor. Most of these tumors are malignant and have metastases at diagnosis (70%). Complete excision is the therapy of choice, if technically possible. However, metastases often preclude curative resection, and palliative debulking can be considered to relieve symptoms. Chemotherapy is poorly effective. 

Very rare functional neuroendocrine pancreatic neoplasms include corticotropinoma, ACTHoma, GRFoma. They lack a specific hormone syndrome, and are extremely challenging to diagnose. Complete surgical excision is the only curative option when technically possible, and debulking or somatostatin analogues are used for palliation of hormone syndromes.

Functional syndromes with unknown primary neoplasm 

Although spatial resolution of cross-sectional imaging modalities has substantially improved, insulinoma and gastrinoma remain undetected in 10-20% of cases, despite the presence of a well-defined hormone syndrome. In such a situation, surgical exploration is the only chance to identify the primary tumor. After laparotomy, a careful inspection of the liver, stomach, and mesentery should be carried out. The duodeno-pancreatic area has to be well exposed and mobilized from the retroperitoneum. Intra-operative ultrasound is very helpful to localize pancreatic lesions, with an accuracy up to 90-95%. Furthermore, intra-operative ultrasound is helpful to assess the relationship between the primary neoplasm and the main pancreatic duct. This allows the surgeon to choose between a parenchyma-sparing operation (enucleation or middle segment pancreatectomy) and a formal resection (pancreaticoduodenectomy or left pancreatectomy with regional lymph node dissection). Unfortunately, intra-operative ultrasound is less accurate to locate duodenal gastrinomas (30%). When the tumor is located within the duodenal wall, duodenotomy with exploration of the inner duodenal surface is be required. If the primary neoplasm remains undetected, blind resection is contraindicated. The patient should be rather enrolled in a strict clinical and radiologic surveillance protocol, and the hormone syndrome should be controlled by medical therapy. If the primary tumor is found and resection is undertaken, the specimen must be analyzed by the Pathologist to confirm the presence of the neoplasm.