Neuroendocrine Pancreatic Neoplasms

Functional Tumors

1. Insulinoma
1. Epidemiology
• most common functional islet cell tumor (1 – 2 per million people)
• more common in women
• most are sporadic; fewer than 5% are associated with MEN-1 syndrome
• 90% are benign


2. Clinical Manifestations
• symptoms are secondary to hypoglycemia
• neuroglycopenic symptoms include lightheadedness, dizziness, seizures, somnolence, and coma
• other symptoms are related to a hypoglycemic-induced sympathetic discharge: palpitations, nervousness, tachycardia, sweating, tremor
• since symptoms occur during fasting, most patients are overweight since they learn to eat to control their symptoms
• Whipple’s triad: 1) hypoglycemic symptoms while fasting, 2) blood glucose < 50 mg/dL while symptomatic, 3) relief of symptoms following glucose administration


3. Diagnosis
• must demonstrate fasting hypoglycemia and inappropriately high levels of insulin
• gold standard test is a 72-hour supervised fast
• blood for glucose, insulin, and C peptide levels is obtained at 6-hour intervals and when the patient becomes symptomatic
• a ratio of plasma insulin to glucose > 0.4 is diagnostic
• factitious administration of insulin must be excluded by measuring proinsulin, C-peptide, and insulin antibody levels
• factitious administration of oral hypoglycemic agents must be excluded by screening for sulfonylureas in the serum
• some non-pancreatic tumors may cause hypoglycemia (hepatocellular carcinoma, adrenocortical cancer, fibrosarcoma) by secreting insulin-like peptides
• medical conditions causing hypoglycemia include hepatic insufficiency, chronic adrenal insufficiency, and hypopituitarism


4. Preoperative Tumor Localization
• can be challenging given the small size of most of the tumors (10 to 15 mm)
• tumors are evenly distributed throughout the pancreas
• modern CT scanners or MRIs identify most lesions
• endoscopic ultrasound will locate most insulinomas not seen on CT or MRI
• octreotide scanning is not indicated because these tumors rarely express somatostatin receptors
• transhepatic portal venous sampling or calcium angiography with venous sampling can be done in difficult cases or for recurrent disease



5. Preoperative Management
• hypoglycemia is managed with frequent small meals
• diazoxide can be used to suppress insulin secretion


6. Operative Management
• most tumors are small, intrapancreatic, and difficult to palpate
• intraoperative ultrasound is an important tool in locating these tumors
• small lesions, not in proximity to the pancreatic duct, may be enucleated
• large or deep lesions will require pancreatic resection
• patients with MEN-1 require resection because they usually have multiple lesions
• in cases of malignant insulinoma, resection of the primary tumor and accessible metastases should be considered to help control hypoglycemia
• blind pancreatic resection is not indicated if the tumor cannot be localized intraoperatively






2. Gastrinoma
1. Epidemiology
• 75% are sporadic, 25% are associated with MEN-1
• 60% are malignant (liver and bone)
• 0.1% of patients with peptic ulcer disease and 2% of patients with recurrent ulcer disease following standard treatment have a gastrinoma
• 70% originate in the duodenum, 20% in the pancreas, and 10% in nearby lymph nodes


2. Clinical Manifestations
1. Peptic Ulcer Disease
• severe, recurrent, and refractory to treatment
• most frequent site is the duodenal bulb (75%), distal duodenum (14%), jejunum (11%)


2. Diarrhea
• occurs in 70% of patients and may be the sole manifestation of the disease in 10%
• results from gastric hypersecretion, damage to proximal intestinal villi resulting in decreased sodium and water absorption, and inactivation of pancreatic lipase
• treated by nasogastric suction or adequate doses of acid inhibitory agents


3. Other Symptoms
• abdominal pain (90%), heartburn (44%), nausea/vomiting, GI bleeding, weight loss


3. Diagnosis
• requires a high index of suspicion
• must demonstrate both a high serum gastrin level and hyperchlorhydria
• differential diagnosis includes pernicious anemia, atrophic gastritis, G-cell hyperplasia, gastric outlet obstruction, retained antrum after a BII antrectomy


1. Fasting Gastrin Level
• > 1000 is virtually diagnostic
• 200 to 1000 is indeterminate
• necessary to stop proton pump inhibitors for 3 days prior to obtaining the fasting gastrin level
• gastric pH should be less than 2


2. Provocative Testing
• secretin stimulation test is helpful in distinguishing between gastrinoma and other causes of ulcerogenic hypergastrinemia (antral G-cell hyperplasia, retained antrum)
• test is performed by administering 2 units per kilogram of secretin and measuring serum gastrin at 0, 2, 5, 10, 15, and 30 minutes
• an increase in serum gastrin of 110 pg/ml over baseline is diagnostic of gastrinoma
• the other causes of hypergastrinemia will not respond to secretin


3. Ruling Out MEN 1
• serum calcium, parathyroid hormone, prolactin, and fasting insulin levels should be measured


4. Tumor Localization
• since the tumors are small, accurate preoperative localization is mandatory
• CT scan is usually the first test performed – it provides information about the primary tumor as well as detects hepatic metastases
• octreotide scintigraphy or PET CT is the most accurate method in localizing the primary tumor (85%)
• endoscopic ultrasound and angiography may be used if the CT scan and octreotide scintigraphy are negative



5. Management
1. Medical Therapy
• goal is to control gastric acid hypersecretion
• proton pump inhibitors are the drugs of choice
• may be used as primary therapy in patients with metastatic disease
• also, since patients with MEN-1 have multiple tumors, they rarely benefit from surgery and should be treated medically
• formerly, total gastrectomy was the only way to control the ulcer disease


2. Surgical Therapy
1. Abdominal Exploration
• liver is palpated, and a general exploration performed
• lesser sac is opened, and the pancreas palpated from head to tail
• Kocher maneuver is performed
• peripancreatic nodes are excised and sent for frozen section
• intraoperative ultrasound is an important adjunct for examining the pancreas
• a longitudinal duodenotomy should be performed and the duodenum bimanually palpated
• most gastrinomas (80%) are found within the gastrinoma triangle, which is defined by the junction of the cystic and common bile ducts, the junction of the 2nd and 3rd portions of the duodenum, and the junction of the neck and body of the pancreas
• if the tumor is found, it may be treated with enucleation if small or pancreatic resection (Whipple) if large



2. Negative Exploration
• may occur in ~ 33% of cases
• surgeon should strongly consider performing an ulcer operation (parietal cell vagotomy)
• total gastrectomy should be considered only if the patient has failed previous medical or surgical ulcer therapy


3. MEN 1
• hyperparathyroidism should be addressed first, since eliminating hypercalcemia reduces basal gastric acid secretion
• most patients have multiple duodenal tumors and metastatic lymph nodes
• surgery is not curative and should be reserved for larger tumors


6. Management of Metastatic Disease
• primary cause of death now from gastrinoma is metastatic disease
• long-term survival with liver metastases is possible
• patients with limited liver metastases can be considered for resection, as long as the primary tumor is controlled and there is no extrahepatic disease
• hepatic artery embolization, TACE, RFA may all be considered for patients who are not resectable
• octreotide is of limited value in metastatic disease


3. VIPoma
1. Clinical Manifestations
• profuse watery diarrhea that causes hypokalemia, achlorhydria, and hypovolemia (WDHA)
• patients have 5 to 10 liters of stool per day
• diarrhea is secretory in nature: it persists during fasting and does not respond to antidiarrheal agents
• severe metabolic acidosis results from loss of bicarbonate in the stool
• 50% are malignant
• 95% are sporadic; 5% associated with MEN 1


2. Diagnosis
• fasting levels of VIP > 500 pg/ml is diagnostic
• tumors are usually > 3 cm in size and easily identified on CT scan
• 75% are located in the body and tail



3. Management
• definitive treatment is surgical excision of the tumor
• fluid and electrolyte losses must be replaced before surgery, and octreotide is used to control the diarrhea


4. Glucagonoma
1. Clinical Manifestations
• mild diabetes and a severe migratory, necrolytic dermatitis are the main symptoms
• additional symptoms include stomatitis, hypoaminoacidemia, and anemia
• increased incidence of venous thrombosis and pulmonary emboli
• majority are malignant and have metastasized by the time of diagnosis (60%)



2. Diagnosis
• made by documenting an elevated fasting glucagon level >1000 pg/mL
• CT scan will identify the mass and assess for resectability and metastatic disease



3. Management
• dermatitis responds to zinc supplements
• hyperalimentation may be required in patients with profound hypoaminoacidemia
• octreotide has been reported to return serum glucagon and amino acid levels to normal, clear the dermatitis, and promote weight gain
• patients should receive early and aggressive DVT prophylaxis
• most tumors are found in the tail of the pancreas and tend to be large
• distal pancreatectomy is the procedure of choice


5. Somatostatinoma
1. Clinical Manifestations
• extremely rare tumor
• characterized by diabetes, gallstones, and steatorrhea
• 90% are malignant
• 60% are found in the pancreatic head
• duodenum and small bowel are other possible locations
• diagnosis is made by documenting an elevated somatostatin level
• resection for cure is usually not possible, although safe debulking is indicated to help manage symptoms