Insulinoma

Diagnosis

Indications for Testing

• Pancreatic tumor with neuroendocrine symptoms; hypoglycemia without other obvious etiology

Criteria for Diagnosis

• Fasting glucose – ≤45 mg/dL
• Serum insulin – >6 µIU/mL and/or proinsulin ≥5 pmol/L when glucose is ≤45 mg/dL
• C-peptide concentration – ≥0.6 ng/mL

Laboratory Testing

• Insulin/proinsulin ratio – initial testing for insulinoma
  • Use in conjunction with glucose and C-peptide testing
  • 72-hour fast with testing may no longer be necessary with advent of insulin and proinsulin ratio
• Fasting glucose – initial testing for insulinoma
  • Determine presence of hypoglycemia
• C-peptide – initial testing for insulinoma
  • High level of C-peptide is diagnostic in conjunction with other findings
• Urine/serum sulfonylurea screen – 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
  • Basic testing for pancreatic neuroendocrine tumors (PNETs) – chromogranin A, synaptophysin, cytokeratin, Ki-67 (Mib-1), neuron specific enolase polyclonal, protein gene product 9.5
  • Tumor-specific confirmation – proinsulin, insulin

Imaging Studies

• Multiphasic CT (sensitivity 30-85%) or 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
• Endoscopic ultrasound
• Venous drainage catheter localization – if tumor not localized by above methods
  • Calcium stimulation with transhepatic venous sampling

Differential Diagnosis

• Diabetes mellitus
• Hypoglycemia from other causes
• Factitious use of sulfonylureas or insulin
• Nesidioblastosis of the pancreas

Clinical Background

Insulinomas are the most common functional pancreatic neuroendocrine tumors and may be associated with multiple endocrine neoplasia type 1 (MEN1) or Wermer syndrome.

Epidemiology

• Incidence – 1-4/1,000,000
• Age – 40s (median onset)
  • Rare in adolescents
• Sex – M<F (minimal)

Risk Factors

• Genetic – ~10% associated with MEN1
  • 5-10% of insulinomas are malignant and tend to be associated with familial disease (MEN1)

Pathophysiology

• Islet cells (type β) can develop into hyperplasia, macroadenomas, microadenomas, or malignant adenocarcinomas (almost always in pancreas)
  • If multiple tumors are present, suspect MEN1
• Excess hormonal secretion of insulin is cause of major symptoms
  • Insulin synthesized as preproinsulin and released as proinsulin
    • With proinsulin release, equal amounts of C-peptide are also released
  • Catecholamine excess also common

Clinical Presentation

• Generally sporadic
• Whipple triad
  • Neurologic signs/symptoms of hypoglycemia (neuroglycopenia) – confusion, headache, sweating, tremor, visual disturbances
  • Blood glucose ≤45 mg/dL
  • Symptom resolution after glucose ingestion (within 5-10 minutes)
• Other manifestations associated with MEN1 tumors may occur
  • Pituitary, pancreatic, and parathyroid tumors

Treatment

• Surgical – depends on extent of disease
  • Enucleation
  • Partial pancreatectomy
  • Resection
• Medical
  • Localized disease – stabilize glucose levels with diet and/or diazoxide
    • Avoid fasting
  • Metastatic disease – everolimus, sunitinib, or cytotoxic chemotherapy
    • Octreotide – use with caution in insulinomas
      • May precipitously worsen hypoglycemia by suppressing insulin counter-regulatory hormones (growth hormone, glucagon, catecholamines)

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: Quantitative Chemiluminescent Immunoassay
Proinsulin 0070112 Method: Quantitative Enzyme-Linked Immunosorbent Assay
Insulin, Fasting 0070063 Method: Quantitative Chemiluminescent Immunoassay