Insulinoma

Diagnosis

Indications for Testing

• Pancreatic tumor
• Blood glucose ≤40 mg/dL without other etiology
• Hypoglycemia symptoms without other etiology
  • Confusion/altered consciousness
  • Sweating/diaphoresis
  • Headache
  • Visual disturbance

Criteria for Diagnosis

• Diagnosis criteria include (North American Neuroendocrine Tumor Society [NANETS], 2010)
  • Blood glucose ≤40 mg/dL
  • Insulin ≥3 µIU/mL
  • C-peptide levels ≥200 pmol/L
  • Proinsulin levels ≥5 pmol/L
  • Beta-hydroxybutyrate levels ≤2.7 mmol/L
  • Absence of sulfonylurea in plasma and urine

Laboratory Testing

• 72-hour observed fast is the gold standard for diagnosis; measure the following:
  • Insulin
  • Glucose
  • Proinsulin
  • C-peptide
  • Beta-hydroxybutyrate
• Low C-peptide in combination with high insulin – suggestive of surreptitious insulin administration
• Serum/urine sulfonylurea – rule out surreptitious drug-induced hypoglycemia

Histology

• Useful immunohistochemistry stains may include synaptophysin and neuron specific enolase (polyclonal)
  • Tumor-specific confirmation – insulin
  • For more information, refer to ARUP's Immunohistochemistry Stain Offerings

Imaging Studies

• Multiphasic computed tomography (CT), magnetic resonance imaging (MRI), or endoscopic ultrasound (EUS) generally can detect most tumors (NCI, 2018)
• Venous drainage catheter localization and calcium stimulation with transhepatic venous sampling are technically challenging and typically not used except in unusual circumstances (NCI, 2018)

Differential Diagnosis

• Hypoglycemia
  • Diabetes mellitus
  • Persistent hyperinsulinemia of infancy (nesidioblastosis of the pancreas)
  • Noninsulinoma pancreatogenous hypoglycemia syndrome
  • Sulfonylurea-induced hypoglycemia
  • Factitious use of sulfonylurea or insulin
  • Insulin autoimmune hypoglycemia
  • Other causes (eg, sepsis)
• Pancreatic mass
  • Other pancreatic neuroendocrine tumor
  • Pancreatic adenocarcinoma

Background

Epidemiology

• Incidence – 1-32/million (European Neuroendocrine Tumor Society [ENETS] consensus, 2016)
• Age
  • Median onset – 40s-50s
  • Rare in adolescents
• Sex – M<F (minimal)

Risk Factors

Genetic – a small percentage are malignant, and these tend to be associated with familial disease (MEN1)

Pathophysiology

• Generally sporadic
  • Majority are benign
  • >99% located in pancreas
• Islet cells (type beta [β]) can develop into hyperplasia, macroadenomas, microadenomas, or malignant adenocarcinomas (almost always pancreatic in location)
  • If multiple tumors are present, suspect MEN1
  • Only 5-8% of insulinomas are associated with MEN1 (NCI, 2018)
• Symptoms are caused by excess secretion of insulin
  • Insulin is synthesized as preproinsulin and released as proinsulin
  • With proinsulin release, equal amounts of C-peptide are also released
• Catecholamine excess is common

Clinical Presentation

• Whipple triad
  • Neurologic signs/symptoms of hypoglycemia (neuroglycopenia) – confusion, headache, sweating, tremor, visual disturbances
  • Blood glucose ≤40 mg/dL
  • Symptom resolution after glucose ingestion (within 5-10 minutes)
• Other manifestations if syndromic tumor is present (MEN1) – pituitary, pancreatic, and parathyroid tumors