Neuroendocrine tumors (NETs) are neoplasms arising from a group of neurosecretory cells found in different organs of the body including the lungs, pancreas, and the gastrointestinal tract. These tumors can be benign or malignant. Different tumor types exist depending on tumor location and hormone produced. The WHO 2010 classification of neuroendocrine neoplasm defined low to intermediate grade tumors (grade 1-2) and well to moderately differentiated neuroendocrine neoplasms as neuroendocrine tumors (NET), while Neuroendocrine carcinomas (NEC) are used to describe high-grade (grade 3), moderately to poorly differentiated neuroendocrine neoplasms. These definitions were chosen as they are widely accepted, and indicate clinical prognosis. Tumors arising from organs which exhibit hypersecretion of its native hormone are referred to as entopic. Of these tumors, Carcinoid is the most frequently encountered condition, and has been identified throughout the gastrointestinal tract including the esophagus, stomach, liver, pancreas, small intestines, colon, rectum, and the appendix. In the pancreas, the commonly recognized tumors under this category include the insulinomas, gastrinomas, pancreatic glucagonomas, and somatostatinomas. Important to consider is that there are non-functioning neuroendocrine neoplasms that occur more frequently than these hormonal hypersecreting tumors.
Ectopic neuroendocrine tumors are those that are located in areas which do not normally produce the involved hormones. Examples of such are those associated with Bronchogenic malignancies producing excessive secretion of the ACTH prohormone leading to Cushing’s syndrome, and the hypersecretion of Vasoactive intestinal peptides (VIP) by the pancreas (normally secreted by the intestinal mucosal cells).
Some of these tumors may occur in combination, and are commonly found in recognized inherited conditions such as the Multiple Endocrine Neoplasia (MEN) syndromes.
II. Diagnostic Approach.
A. What is the differential diagnosis for this problem?
Endocrine tumors are either functional or non-functional. Functional tumors present with clinical symptoms relating to hormonal hypersecretion while non-functional tumors are usually clinically asymptomatic until they cause significant mass effect.
As endocrine tumors are not common, clinical suspicion for such should be raised if the more common clinical differentials are unlikely. In hypoglycemic patients, it is reasonable to rule out medications (insulin, sulfonylurea use), ethanol, factitious, and adrenal insufficiency as possible causes before raising clinical suspicion for insulinomas.
Although most of these tumors occur sporadically, it is important to recognize that some may be associated with familial syndromes such as in MEN syndrome.
B. Describe a diagnostic approach/method to the patient with this problem.
Depending on the hormone involved, clinical presentation of functional endocrine tumors are highly variable. After effectively ruling out common differentials for each common presenting symptom, clinical suspicion for further investigating the presence of endocrine tumors should be initiated.
1. Historical information important in the diagnosis of this problem.
It is important to recognize the common presenting symptom for the more commonly recognized neuroendocrine tumors:
Insulinoma: This is a neuroendocrine tumor of the pancreas that can secrete insulin and result in hypoglycemia. Patients typically present with varying neuroglycopenic symptoms (confusion, behavioral changes, blurred vision, seizures) with or without sympathoadrenal manifestations such as palpitations, diaphoresis, and tremulousness. These manifest in the setting of episodic hypoglycemia due to insulin hypersecretion.
Gastrinoma/Zollinger-Ellison Syndrome (ZES): This neuroendocrine tumor secretes gastrin and thus causes gastric acid hypersecretion. Symptoms relating to peptic ulcers are commonly encountered and may be accompanied by diarrhea.
Glucagonomas: Also a neuroendocrine tumor of the pancreas that secretes excessive amounts of glucagon. Patients are typically diabetics presenting with weight loss, weakness and a skin rash called necrolytic migratory erythema.
VIPomas: These are characterized by hypersecretion of vasoactive intestinal peptides (VIP) and cause the Verner-Morrison syndrome or the pancreatic cholera syndrome of severe watery diarrhea, hypokalemia and achlorhydria.
Somatostatinoma: Excessive somatostatin production by this neuroendocrine tumor causes mild diabetes (due to inhibition of insulin), steatorrhea (decreased secretion of pancreatic enzyme), and gallstones (inhibits cholecystokinin that decreases gallbladder contractility).
Carcinoid: Primarily secretes serotonin but may also produce bradykinin, prostaglandin and hydroxytrptophan, and histamine. The 2 most common clinical presentations include flushing, and diarrhea. Flushing is typically characterized as sudden onset of a deep red or violaceous erythema of the face and neck associated with a sensation of warmth or sometimes facial edema. Flushing can be precipitated by alcohol, stress, exercise, certain food (e.g. cheese), etc.
MEN syndrome: In MEN type 1, tumors involve the parathyroid, anterior pituitary and the pancreatic islet cells with varying clinical presentation relating to different hormonal hypersecretion. MEN 2A is composed of medullary carcinoma of the thyroid, adrenal pheochromocytoma, and secondary parathyroid hyperplasia. MEN 2 B include medullary carcinoma of the thyroid, pheochromocytoma, and mucosal neuromas and intestinal ganglioneuromas.
2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.
No specific or diagnostic physical finding exist in patients presenting with endocrine tumors. However, in patients with suspected glucagonomas, the presence of pruritic and painful erythematous plaques or papules in the face, perineum, and legs should raise the suspicion for necrolytic migratory erythema.
3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.
Demonstration of elevated hormonal levels characteristic of each endocrine tumor supports the diagnosis and is typically followed by varying imaging studies for tumor localization.
C. Criteria for Diagnosing Each Diagnosis in the Method Above.
Insulinoma: Important to obtain biochemical evidence of elevated serum insulin levels during spontaneous, or induced hypoglycemic episodes. Serum levels of glucose, proinsulin, insulin and c-peptide levels are measured every 4-8 hours during a supervised 72-hour fast, or until symptoms occur, or glucose are persistently below <2.2 mmoL/L (40 mg/dL). Demonstration of hypoglycemia, elevated insulin, proinsulin, and C peptide coupled with a negative sulfonylurea screen are diagnostic for insulinoma.
Once biochemical evidence is achieved, imaging techniques are utilized to localize the tumor. Modality of choice will depend on facility availability and local radiologic experience. Commonly used are multi-detector computed tomography (CT – imaging modality of choice), magnetic resonance imaging (MRI), endoscopic ultrasound, transabdominal ultrasound, PET scan using 18F-DOPA, and 111-In-pentetreotide imaging. If these non-invasive tests are negative and suspicion for insulinoma remains high, percutaneous transhepatic portal venous sampling (PTPVS), arterial stimulation with venous sampling (ASVS), intraoperative palpation, and ultrasound may be helpful.
Gastrinoma/Zollinger-Ellison Syndrome (ZES): demonstration of an elevated fasting gastrin level with a low gastric pH (<2.5) is highly suggestive of gastrinoma especially with gastrin levels >1000 pg/mL. Basal acid output determination, and calcium provocative test are also helpful. Localization of the tumor is achieved by employing endoscopic ultrasounds, conventional cross-sectional imaging, and somatostatin-receptor scintigraphy.
Glucagonomas: Elevated serum glucagon levels especially if greater than 1000 pg/mL is diagnostic (normal is <150 pg/mL). Findings of hyperglycemia, and a normocytic, normochromic anemia is also common. Though certain conditions can physiologically raise serum glucagon levels such as trauma, pancreatitis, prolonged fasting, sepsis, pancreatitis, levels are typically <500 pg/mL. Commonly utilized imaging studies include CT scans (modality of choice), endoscopic ultrasound, and somatostatin-receptor scintigraphy.
VIPomas are typically diagnosed by demonstration of secretory diarrhea unresponsive to fasting coupled with elevated fasting serum VIP levels greater than 75 pg/mL. Levels exceeding 200 pg/mL is typically diagnostic. A stool volume of <700 mL/d potentially can exclude the diagnosis. Imaging studies for tumor localization are the same as in the other endocrine tumors listed above.
Somatostatinoma: excessive fasting serum somatostatin levels of greater than 100 pg/mL is diagnostic of the disease. Most cases are found by accident during cholecystectomy, or endoscopy. The presence of psammoma bodies in a duodenal tumor is also suspicious for somatostatinomas. Tumor localization is achieved by utilization of standard imaging modalities commonly used for the other endocrine tumors above.
Carcinoid: Elevated levels of 24-hour urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) typically above 100 mg/day is suggestive of carcinoid. Whole blood serotonin levels are helpful if the 24 hour urinary test is equivocal. Localization of the tumor typically involves use of abdominal CT scan, MRI, Abdominal ultrasound with power Doppler imaging, PET-CT or PET-MRI or somatostatin-receptor scintigraphy.
D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.
It is important to recognize that although somatostatin-receptor scintigraphy is useful in the work-up of most endocrine tumors, it is less useful in tumor localization of insulinomas given its low density of somatostatin receptors.
III. Management while the Diagnostic Process is Proceeding.
A. Management of Clinical Problem Endocrine Tumors.
Treatment of pancreatic neuroendocrine tumors can be directed to: (1) control the hormone-excess state (e.g. Hypoglycemia in insulinoma or gastric acid hypersecretion in gastrinomas), and (2) to address the tumor itself (since >50% of the tumors could be malignant, except for insulinomas in which 5-15% are malignant).
CONTROLLING HORMONE EXCESS
Though surgery offers the highest chance of cure, there are supportive measures that a clinician can utilize:
To control acid hypersecretion in Zollinger-Ellison Syndrome or Gastrinoma, the use of proton pump inhibitors (1st choice) or Histamine H2-receptor antagonists are recommended.
Management of hypoglycemia among patients with insulinoma before surgery or for those who are non-surgical candidates include small frequent meals, and use of diazoxide. Verapamil and diphenylhydantoin are also available agents that can help control hypoglycemia in these cases.
Management of electrolyte and fluid derangement from severe diarrhea and hypokalemia in patients with VIPoma should be prioritized. Most patients will require 5L/d of fluid and >350 mEq of potassium.
Symptoms associated with Glucagonomas, Carcinoids, Somatostatinomas and VIPomas can be improved with the use of somatostatin analogs such as octreotide.
Interferon alpha either alone or combined with hepatic artery embolization or hepatic artery embolization alone, or combined with chemotherapy can be effective in controlling symptoms of carcinoid syndrome.
TREATMENT OF THE ACTUAL TUMOR
Grades 1-2 NETs grow slowly and thus regardless of the primary tumor, a watch and wait approach with patient follow-up for 3-6 months can be considered before treatment. Medical treatment options are good for grade 1-2 primary NETs of the pancreas. Standard chemotherapy options apply for most NECs. A medical approach to treatment for symptom control or for progressive disease is applicable for those with distant metastasis if curative surgery or ablation procedures are no longer possible.
Surgical tumor resection remains the treatment of choice for neuroendocrine tumors. MEN Type 1 with associated insulinomas often requires a more aggressive surgical approach given presence of multiple pancreatic tumors. The most important prognostic factor for survival is the presence of liver metastases. 5 year survival rate for some NETs with liver metastases tend to be significantly low. Poorly differentiated NETs also have a poor survival rate of 0-15%. Treatment for advanced metastatic disease remains a challenge but the availability of several modalities can be effective. Examples include: cytoreductive surgery or RFA, chemotherapy, somatostatin analogues, interferon alpha, hepatic embolization alone, or with chemotherapy, molecular targeted therapy, radiotherapy, peptide radioreceptor therapy, and liver transplantation.
B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.
Proton pump inhibitors can suppress gastric acid secretion sufficient to cause hypergastrinemia. Thus, it is important to cautiously taper or discontinue this a week before gastrin determination when working up a patient for gastrinoma.
Aggressive prophylactic anticoagulation for patients with glucagonoma is highly suggested due to an increased risk of venous thromboembolism.
IV. What's the evidence?
Davies, K, Conlon, K. “Neuroendocrine Tumors of the Pancreas”. Current Gastroenterology Reports. vol. 11. 2009. pp. 119-127.
Fitgerald, PA, McPhee, SJ, Papadakis, MA. “Pancreatic and Duodenal Neuroendocrine Tumors”. Current Medical Diagnosis and Treatment. 2007. pp. 1202-1203.
Gill, GV, Rauf, O, MacFarlane, IA. “Diazoxide treatment for insulinoma: a national UK survey”. Postgrad Med J. vol. 73. 1997 Oct. pp. 640-1.
Jensen, RT., Kasper, D, Fauci, A, Hauser, S, Longo, D, Jameson, J, Loscalzo, J.. “Endocrine Tumors of the Gastrointestinal Tract and Pancreas”. Harrison's Principles of Internal Medicine. 2015.
Klimstra, DS, Modlin, IR, Coppola, D, Lloyd, RV, Suster, S. “The Pathologic Classification of Neuroendocrine Tumors: A Review of Nomenclature, Grading, and Staging Systems”. Pancreas. vol. 39. August 2010. pp. 707-712.
Rindi, G, Widenmann, B.. “Neuroendocrine neoplasms of the Gut and pancreas: new insights”. Nature Reviews Endocrinology. vol. 8. January 2012. pp. 54-64.
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- Neuroendocrine Tumors
- I. Problem/Condition.
- II. Diagnostic Approach.
- A. What is the differential diagnosis for this problem?
- B. Describe a diagnostic approach/method to the patient with this problem.
- 1. Historical information important in the diagnosis of this problem.
- 2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.
- 3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.
- C. Criteria for Diagnosing Each Diagnosis in the Method Above.
- D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.
- III. Management while the Diagnostic Process is Proceeding.
- A. Management of Clinical Problem Endocrine Tumors.
- B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.