Insulinoma

Diagnostic Algorithm

Clinical Background

Insulinomas are functional pancreatic neuroendocrine neoplasms which may be associated with multiple endocrine neoplasia type 1 (MEN 1) or Wermer syndrome.

Epidemiology

• Incidence – 1-4/1,000,000
• Age – median onset is 40s
• Sex – M<F (minimal)
• Occurrence
  • Most common functioning pancreatic neuroendocrine tumor
  • Second most common functioning pancreatic tumor in MEN 1

Risk Factors

• Generally sporadic
• Genetic – around 10% associated with MEN 1

Pathophysiology

• 5-10% are malignant and tend to be associated with familial disease
• Diffuse islet cell hyperplasia, adenomas and carcinomas are typically present
• Islet cells can develop into macroadenomas, microadenomas or malignant adenocarcinomas
  • Frequently multiple tumors are present
• Excess hormonal secretion of insulin is cause of symptoms

Clinical Presentation

• Whipple triad
  • Signs/symptoms of hypoglycemia – confusion, headache, sweating, tremor, visual disturbances
  • Blood glucose ≤45 mg/dL
  • Symptom resolution after glucose ingestion (within minutes)
  • Other manifestations associated with MEN 1 tumors may occur
    • Pituitary, pancreatic and parathyroid tumors

Treatment

• Surgical
  • Depends on extent of disease
    • Enucleation
    • Partial pancreatectomy
    • Resection
• Medical
  • Diazoxide
  • Avoid fasting

Diagnosis

• Indications for testing – pancreatic tumor with neuroendocrine symptoms; hypoglycemia without other obvious etiology
• Laboratory testing
  • Fasting blood glucose ≤45 mg/dL; serum insulin >6 µIU/mL and/or proinsulin levels ≥5 pmol/L when glucose is ≤45 mg/dL; C-peptide levels ≥0.6 ng/mL
  • Urine/serum sulfonylurea screen to rule out drug-induced hypoglycemia
• Histology
  • Nested or trabecular arrangement of small- to medium-sized cells
    • Finely granular eosinophilic cytoplasm
    • Central round to oval nuclei
    • Stippled chromatin (“salt and pepper”)
  • Immunohistochemistry – chromogranin, synaptophysin, insulin
• Imaging studies
  • CT – sensitivity 30-85%
  • MRI – sensitivity 85-95%
  • Tumors <2 cm difficult to detect by CT or MRI
    • Low density of somatostatin receptor subtypes in insulinomas makes somatostatin receptor scintigraphy less sensitive

Differential Diagnosis

• Diabetes mellitus
• Hypoglycemia from other causes
• Factitious use of sulfonylureas or insulin
• Nesidioblastoses

Pharmacogenetics and Therapeutic Drug Monitoring

Screening

Monitoring

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Insulin, Random 0070107 Method: Chemiluminescent Immunoassay

General References