Insulinoma

Diagnosis

Indications for Testing

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

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
Test Name and Number Recommended Use Limitations Follow Up
Proinsulin, Intact/Insulin Ratio 0070256
Method: Quantitative Chemiluminescent Immunoassay/Quantitative Chemiluminescent Immunoassay

One of three initial diagnostic tests for insulinoma

Includes proinsulin and fasting insulin

   
Glucose, Plasma or Serum 0020024
Method: Quantitative Enzymatic

One of three initial diagnostic tests for insulinoma

   
C-Peptide, Serum or Plasma 0070103
Method: Quantitative Chemiluminescent Immunoassay

One of three initial diagnostic tests for insulinoma

   
Sulfonylurea Hypoglycemics Panel (Qualitative), Serum or Plasma 2004279
Method: High Performance Liquid Chromatography-Tandem Mass Spectrometry

Rule out sulfonylurea-induced hypoglycemia

   
Sulfonylurea Hypoglycemics Panel (Quantitative), Urine 0091100
Method: Quantitative Liquid Chromatography/Tandem Mass Spectrometry

Rule out sulfonylurea-induced hypoglycemia

   
Chromogranin A by Immunohistochemistry 2003830
Method: Immunohistochemistry

Aid in histologic diagnosis of PNETs

Stained and returned to client pathologist; consultation available if needed

   
Ki-67 with Interpretation by Immunohistochemistry 2007182
Method: Immunohistochemistry

Aid in histologic diagnosis of PNETs

Stained and resulted by ARUP

   
Synaptophysin by Immunohistochemistry 2004139
Method: Immunohistochemistry

Aid in histologic diagnosis of PNETs

Stained and returned to client pathologist; consultation available if needed

   
Neuron Specific Enolase, Polyclonal (NSE P) by Immunohistochemistry 2004052
Method: Immunohistochemistry

Aid in histologic diagnosis of PNETs

Stained and returned to client pathologist; consultation available if needed

   
Protein Gene Product (PGP) 9.5 by Immunohistochemistry 2004091
Method: Immunohistochemistry

Aid in histologic diagnosis of PNETs

Stained and returned to client pathologist; consultation available if needed

   
Pan Cytokeratin (AE1,3) by Immunohistochemistry 2003433
Method: Immunohistochemistry

Aid in histologic diagnosis of PNETs

Stained and returned to client pathologist; consultation available if needed

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Insulin, Random 0070107
Method: Quantitative Chemiluminescent Immunoassay
Proinsulin, Intact 0070112
Method: Quantitative Chemiluminescent Immunoassay
Insulin, Fasting 0070063
Method: Quantitative Chemiluminescent Immunoassay