Insulinomas are the most common functional pancreatic neuroendocrine tumors (PNETs). They result from growth of islet cells that produce excess insulin. Insulinomas may be associated with multiple endocrine neoplasia type 1 (MEN1) or Wermer syndrome. Only 10% of insulinomas are malignant (National Cancer Institute [NCI], 2018).
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
ARUP Laboratory Tests
Aid in detection of insulinoma
Components include proinsulin and fasting insulin
Quantitative Chemiluminescent Immunoassay/Quantitative Chemiluminescent Immunoassay
Diagnose and manage diabetes mellitus (DM) and other carbohydrate metabolism disorders
Quantitative Enzymatic Assay
Aid in detection of insulinoma
May aid in distinguishing type 1 from type 2 DM in ambiguous cases
Quantitative Chemiluminescent Immunoassay
Preferred test for evaluating if etiology of hypoglycemia is sulfonylurea ingestion
Qualitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Evaluate if etiology of hypoglycemia is from exposure to sulfonylurea hypoglycemic drugs; serum or plasma is preferred specimen (refer to serum or plasma qualitative hypoglycemia panel)
Quantitative Liquid Chromatography-Tandem Mass Spectrometry
Aid in histologic diagnosis of PNETs
Stained and resulted by ARUP
Immunohistochemistry
Aid in histologic diagnosis of PNETs
Stained and returned to client pathologist; consultation available if needed
Immunohistochemistry
Immunohistochemistry
Aid in detection of insulinoma
Quantitative Chemiluminescent Immunoassay
Quantitative Chemiluminescent Immunoassay
Quantitative Chemiluminescent Immunoassay
Aid in the detection of insulinoma
May aid in distinguishing type 1 from type 2 DM in ambiguous cases
Quantitative Chemiluminescent Immunoassay
Quantitative Chemiluminescent Immunoassay
Quantitative Chemiluminescent Immunoassay
Quantitative Chemiluminescent Immunoassay
Quantitative Chemiluminescent Immunoassay
References
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Oberg K, Couvelard A, Delle Fave G, et al. ENETS Consensus Guidelines for standard of care in neuroendocrine tumours: biochemical markers. Neuroendocrinology. 2017;105(3):201-211.
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Perren A, Couvelard A, Scoazec JY, et al. ENETS Consensus Guidelines for the standards of care in neuroendocrine tumors: pathology: diagnosis and prognostic stratification. Neuroendocrinology. 2017;105(3):196-200.
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Vinik AI, Woltering EA, Warner RR , et al. NANETS consensus guidelines for the diagnosis of neuroendocrine tumor. Pancreas. 2010;39(6):713-734.
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NCCN - Neuroendocrine and Adrenal Tumors Version 2.2018
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine and adrenal tumors. Version 2.2018. [Updated: May 2018; Accessed: May 2018]
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Falconi M, Eriksson B, Kaltsas G, et al. ENETS Consensus Guidelines Update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology. 2016;103(2):153-171.
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NCI - Pancreatic Neuroendocrine Tumors
Pancreatic neuroendocrine tumors (islet cell tumors) treatment (PDQ) - health professional version. National Cancer Institute. [Updated: Jan 2020; Accessed: Dec 2021]
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Medical Experts
Johnson-Davis

Straseski

Panel includes glyburide, glimepiride, glipizide, repaglinide, nateglinide, acetohexamide, chlorpropamide, tolazamide, and tolbutamide