Insulinoma

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

Epidemiology

Incidence – 1-4/1,000,000
Age – median onset is 40s
- Rare in adolescents
Sex – M<F (minimal)
Occurrence
- Most common functioning pancreatic neuroendocrine tumor
- Second most common functioning pancreatic tumor in MEN1

Risk Factors

Generally sporadic
Genetic – ~10% associated with MEN1

Pathophysiology

5-10% are malignant and tend to be associated with familial disease (MEN1)
Diffuse islet cell hyperplasia, adenomas and carcinomas are typically present
- Islet cell type β
Islet cells can develop into macroadenomas, microadenomas or malignant adenocarcinomas (almost always in pancreas)
- Multiple tumors are infrequently present; if 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 also released
- Catecholamine excess also common

Clinical Presentation

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
- Nesidioblastosis of the pancreas following gastric bypass

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 or 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 Testing

Pancreatic tumor with neuroendocrine symptoms; hypoglycemia without other obvious etiology

Laboratory Testing

Insulin/proinsulin ratio (72-hour fast with testing may no longer be necessary with advent of insulin and proinsulin ratio)
The following results are diagnostic
- Fasting blood 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
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
- Basic for diagnosis – chromogranin A, synaptophysin, cytokeratin, Ki-67 (Mib-1)
- 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

Tests generally appear in the order most useful for common clinical situations

Test name: Proinsulin/Insulin Ratio

ARUP #: 0070256

Methodology: Refer to individual components

Use:

Diagnostic test for insulinoma

Test name: Glucose, Plasma or Serum

ARUP #: 0020024

Methodology: Quantitative Enzymatic

Use:

Diagnostic test for insulinoma

Test name: Insulin, Fasting

ARUP #: 0070063

Methodology: Quantitative Chemiluminescent Immunoassay

Use:

Diagnostic test for insulinoma

Test name: C-Peptide, Serum or Plasma

ARUP #: 0070103

Methodology: Quantitative Chemiluminescent Immunoassay

Use:

Diagnostic test for insulinoma

Test name: Sulfonylurea Hypoglycemics Panel (Qualitative), Serum or Plasma

ARUP #: 2004279

Methodology: High Performance Liquid Chromatography-Tandem Mass Spectrometry

Use:

Rule out drug-induced hypoglycemia

Test name: Sulfonylurea Hypoglycemics Panel (Quantitative), Urine

ARUP #: 0091100

Methodology: Quantitative Liquid Chromatography/Tandem Mass Spectrometry

Use:

Rule out drug-induced hypoglycemia

Test name: Chromogranin A by Immunohistochemistry

ARUP #: 2003830