Pancreatic Neuroendocrine Tumors (PNETs)

  • Diagnosis
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Undiagnosed pancreatic tumor
  • Serum glucose <45 mg/dL without other etiology
  • Hypoglycemia symptoms without other etiology
    • Confusion/altered consciousness
    • Sweating/diaphoresis
    • Headache
    • Visual disturbance

Criteria for Diagnosis

  • Diagnosis is suggested by
    • Insulin >3 µIU/mL when glucose is <40-45 mg/dL
    • Insulin-to-glucose ratio ≥0.3
    • Elevated C-peptide levels
  • Low C-peptide in combination with high insulin – suggestive of surreptitious insulin administration

Laboratory Testing

  • 48- to 72-hour observed fast
    • Insulin levels
    • Proinsulin levels
    • C-peptide levels
    • Glucose concentrations
  • Serum/urine sulfonylurea screen
    • Rule out surreptitious drug-induced hypoglycemia


  • 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 – insulin

Imaging Studies

  • Multiphasic computed tomography (CT), magnetic resonance imaging (MRI), or endoscopic ultrasound (EUS) generally can detect most tumors (National Cancer Institute [NCI], 2015)
  • Venous drainage catheter localization and calcium stimulation with transhepatic venous sampling are technically challenging and typically not used except in unusual circumstances (NCI, 2015)

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

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], 2015).

Pancreatic islet


  • Incidence – 1-3/million (European Neuroendocrine Tumor Society [ENETS] consensus, 2012)
  • 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)


  • Generally sporadic
    • Majority are benign
    • >99% located in pancreas
  • Islet cells (type 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, 2015)
  • 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 ≤45 mg/dL
    • Symptom resolution after glucose ingestion (within 5-10 minutes)
  • Other manifestations if syndromic tumor is present (MEN1) – pituitary, pancreatic, and parathyroid tumors
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.

Proinsulin, Intact/Insulin Ratio 0070256
Method: Quantitative Chemiluminescent Immunoassay/Quantitative Chemiluminescent Immunoassay

Glucose, Plasma or Serum 0020024
Method: Quantitative Enzymatic

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

Hypoglycemia Panel, Sulfonylureas Qualitative, Serum or Plasma 2010292
Method: Qualitative Liquid Chromatography-Tandem Mass Spectrometry

Sulfonylurea Hypoglycemia Panel, Quantitative, Urine 0091100
Method: Quantitative Liquid Chromatography/Tandem Mass Spectrometry

Chromogranin A by Immunohistochemistry 2003830
Method: Immunohistochemistry

Ki-67 with Interpretation by Immunohistochemistry 2007182
Method: Immunohistochemistry

Synaptophysin by Immunohistochemistry 2004139
Method: Immunohistochemistry

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

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

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


Jensen RT, Cadiot G, Brandi ML, de Herder WW, Kaltsas G, Komminoth P, Scoazec J, Salazar R, Sauvanet A, Kianmanesh R, Barcelona Consensus Conference participants. ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes. Neuroendocrinology. 2012; 95(2): 98-119. PubMed

Klöppel G, Couvelard A, Perren A, Komminoth P, McNicol A, Nilsson O, Scarpa A, Scoazec J, Wiedenmann B, Papotti M, Rindi G, Plöckinger U, Mallorca Consensus Conference participants, European Neuroendocrine Tumor Society. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: towards a standardized approach to the diagnosis of gastroenteropancreatic neuroendocrine tumors and their prognostic stratification. Neuroendocrinology. 2009; 90(2): 162-6. PubMed

NCCN Clinical Practice Guidelines in Oncology, Neuroendocrine Tumors. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Aug 2017]

O'Toole D, Grossman A, Gross D, Fave GD, Barkmanova J, O'Connor J, Pape U, Plöckinger U, Mallorca Consensus Conference participants, European Neuroendocrine Tumor Society. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: biochemical markers. Neuroendocrinology. 2009; 90(2): 194-202. PubMed

Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ) – Health Professional Version. National Cancer Institute. [Updated Apr 2015; Accessed: Aug 2017]

Protocol for the Examination of Specimens from Patients with Tumors of the Endocrine Pancreas. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Jan 2016. College of American Pathologists (CAP). Northfield, IL [Revised Aug 2016; Accessed: Jun 2017]

Vinik AI, Woltering EA, Warner RR, Caplin M, O'Dorisio TM, Wiseman GA, Coppola D, Go VL, North American Neuroendocrine Tumor Society (NANETS). NANETS consensus guidelines for the diagnosis of neuroendocrine tumor. Pancreas. 2010; 39(6): 713-34. PubMed

Öberg K, Knigge U, Kwekkeboom D, Perren A, ESMO Guidelines Working Group. Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012; 23 Suppl 7: vii124-30. PubMed

General References

Desai KK, Khan MS, Toumpanakis C, Caplin ME. Management of gastroentero-pancreatic neuroendocrine tumors (GEP-NETs). Minerva Gastroenterol Dietol. 2009; 55(4): 425-43. PubMed

Mathur A, Gorden P, Libutti SK. Insulinoma. Surg Clin North Am. 2009; 89(5): 1105-21. PubMed

Morgan KA, Adams DB. Solid tumors of the body and tail of the pancreas. Surg Clin North Am. 2010; 90(2): 287-307. PubMed

Oberg K. Pancreatic endocrine tumors. Semin Oncol. 2010; 37(6): 594-618. PubMed

Vaidakis D, Karoubalis J, Pappa T, Piaditis G, Zografos GN. Pancreatic insulinoma: current issues and trends. Hepatobiliary Pancreat Dis Int. 2010; 9(3): 234-41. PubMed

Medical Reviewers

Content Reviewed: 
August 2017

Last Update: September 2017