Pancreatic Neuroendocrine Tumors - PNETs

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

Indications for Testing

  • Pancreatic mass
  • Presentation of a functional syndrome associated with pancreatic neuroendocrine tumors (PNETs)
    • Insulinoma
      • Hypoglycemia, diaphoresis, nausea
    • Gastrinoma/Zollinger-Ellison syndrome
      • Gastric and peptic ulcers, hypergastrinemia
    • Glucagonoma
      • Glucose intolerance, weight loss and cachexia, rash
    • Vasoactive intestinal polypeptide secreting tumors (VIPoma)
      • Profuse watery diarrhea, dehydration, hypokalemia
    • Somatostatinoma

Laboratory Testing

  • General tumor markers – suggestive of pancreatic tumor (none currently endorsed for diagnosis, though may be suggested for surveillance after resection) (Oberg, 2016)
    • Chromogranin A
      • Not recommended for diagnosis (Strosberg, 2017; Oberg, 2016)
      • Sensitivity – 60-90% in metastatic disease; 50% in early disease
      • General circulating marker for neuroendocrine tumors (NETs)
      • False positives higher in reference ranges <20-fold
    • Neuron specific enolase (NSE)
    • Pancreatic polypeptide
    • Alpha (α) subunit pituitary glycoprotein hormones
  • Specific tumor markers – use clinical presentation to order laboratory testing (see the following topic links for more detail)
    • Insulinoma – glucose, insulin,  proinsulin, c-peptide
    • Gastrinoma (Zollinger-Ellison syndrome) – gastrin, gastrin pH, stimulation testing
    • Glucagonoma – glucose, glucagon
    • VIPoma – vasoactive intestinal polypeptide (VIP), electrolytes
    • Somatostatinoma – somatostatin
    • ​Other rare pancreatic neuroendocrine tumors – see table in Background section
  • Biomarker tests in development (Oberg, 2016)
    • Circulating tumor cells
    • Circulating DNA
    • mRNA

Genetic testing

  • MEN1 germline testing – consider if at least 2 MEN1-associated tumors, family history of multiple tumors, or clustering of PNET tumors in family
  • Other testing based on family history and presentation (eg, von Hippel-Lindau syndrome [VHL], neurofibromatosis type 1)

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
    • Chromogranin A
    • Synaptophysin
    • May also stain for tumor-specific hormones – gastrin, glucagon, insulin, NSE, somatostatin
      • Positive staining not always associated with clinical syndrome (so-called nonfunctioning tumors)
      • Consider staining for somatostatin receptors – SSTR2

Imaging Studies

  • Multiphasic computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound detect tumors >1.5 cm (many PNETs are small)
  • Somatostatin-receptor scintigraphy (not useful in insulinomas)
  • Endoscopic ultrasound
  • Bone scan if clinically indicated
  • Fluorodeoxyglucose-positron emission tomography (FDG-PET) scan for poorly differentiated tumors

Prognosis

  • Prognostic factors include age, depth of invasion, metastatic spread, and proliferative index
  • Malignancy determined by tumor invasion of surrounding structures
    • Duodenum, bile duct, lymph nodes, or peripancreatic fat may be involved
    • Each PNET variant has a different risk of malignant behavior
  • Tumors may be categorized according to the World Health Organization (WHO) or tumor, node, and metastasis (TNM) classification
  • Survival rate is excellent (90-100%) for patients with complete resections but is lower (25-50%) for those with metastatic disease

Differential Diagnosis

Once diagnosis has been established, screening for multiple endocrine neoplasia type 1 (MEN1) syndrome is indicated.

  • Follow-up testing 3-12 months after resection and annually thereafter
    • History and physical exam
    • Hormonal/tumor markers – if functional syndrome present
    • Multiphasic computed tomography (CT) or magnetic resonance imaging (MRI)
    • Chromogranin A – may be useful in monitoring response to therapy

Pancreatic neuroendocrine tumors (PNETs) are rare tumors of pancreatic islet cells. PNETs account for <5% of all pancreatic tumors.

Epidemiology

  • Incidence – 2-5/million (National Comprehensive Cancer Network [NCCN], 2014; European Society for Medical Oncology [ESMO], 2012)
  • Age – onset 40s-60s
    • Significant number of PNET patients are <35 years
    • Early age of onset common if tumor is associated with genetic syndrome
  • Sex – M>F
  • Occurrence – usually sporadic
  • Ethnicity – African Americans have highest incidence

Risk Factors

Genetic – may be associated with multiple endocrine neoplasia type 1 (MEN1), von Hippel-Lindau syndrome, neurofibromatosis type 1, or tuberous sclerosis (~15-25% of cases)

Pathophysiology

  • Represent ~30% of neuroendocrine gastroenteropancreatic tumors – solid or cystic tumors located anywhere within the pancreas
  • Tumors may be nonfunctional (most PNETs) or functional
    • Functional tumors secrete hormones, producing classic clinical syndromes
    • Nonfunctional tumors may secrete hormones but patients lack symptoms
      • Much more common than functional tumors
      • Includes pancreatic polypeptidoma (PPoma)
      • Tend to be large
        • 70% are >5 cm and of advanced stage at diagnosis
        • 60-80% have liver metastasis
    • Up to 70% of PNETs are insulinomas, of which 90% are benign (NCCN, 2014)

Clinical Presentation

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.

Glucose, Plasma or Serum 0020024
Method: Quantitative Enzymatic

Insulin, Fasting 0070063
Method: Quantitative Chemiluminescent Immunoassay

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

Gastrin 0070075
Method: Quantitative Chemiluminescent Immunoassay

Glucagon 0099165
Method: Quantitative Radioimmunoassay

Vasoactive Intestinal Peptide 0099435
Method: Quantitative Radioimmunoassay

Somatostatin Quantitative, Plasma 2010001
Method: Quantitative Extraction/Immunoassay

Multiple Endocrine Neoplasia Type 1 (MEN1) Sequencing and Deletion/Duplication 2005360
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Limitations 

Diagnostic errors can occur due to rare sequence variations

Regulatory region mutations and deep intronic mutations will not be detected

Breakpoints of large deletions/duplications will not be determined

Variations in genes other than MEN1 are not evaluated

Chromogranin A 0080469
Method: Quantitative Enzyme Immunoassay

Limitations 

Results obtained with different assay methods or kits cannot be used interchangeably

Chromogranin A by Immunohistochemistry 2003830
Method: Immunohistochemistry

Synaptophysin by Immunohistochemistry 2004139
Method: Immunohistochemistry

Ki-67 with Interpretation by Immunohistochemistry 2007182
Method: Immunohistochemistry

Guidelines

Anthony LB, Strosberg JR, Klimstra DS, Maples WJ, O'Dorisio TM, Warner RR, Wiseman GA, Benson AB, Pommier RF, North American Neuroendocrine Tumor Society (NANETS). The NANETS consensus guidelines for the diagnosis and management of gastrointestinal neuroendocrine tumors (nets): well-differentiated nets of the distal colon and rectum. Pancreas. 2010; 39(6): 767-74. PubMed

Falconi M, Eriksson B, Kaltsas G, Bartsch DK, Capdevila J, Caplin M, Kos-Kudla B, Kwekkeboom D, Rindi G, Klöppel G, Reed N, Kianmanesh R, Jensen RT, Vienna Consensus Conference participants. ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors. Neuroendocrinology. 2016; 103(2): 153-71. PubMed

Garcia-Carbonero R, Sorbye H, Baudin E, Raymond E, Wiedenmann B, Niederle B, Sedlackova E, Toumpanakis C, Anlauf M, Cwikla JB, Caplin M, O'Toole D, Perren A, Vienna Consensus Conference participants. ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas. Neuroendocrinology. 2016; 103(2): 186-94. PubMed

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

Kulke MH, Anthony LB, Bushnell DL, de Herder WW, Goldsmith SJ, Klimstra DS, Marx SJ, Pasieka JL, Pommier RF, Yao JC, Jensen RT, North American Neuroendocrine Tumor Society (NANETS). NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas. 2010; 39(6): 735-52. 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

Oberg K, Couvelard A, Fave GD, Gross D, Grossman A, Jensen RT, Pape U, Perren A, Rindi G, Ruszniewski P, Scoazec J, Welin S, Wiedenmann B, Ferone D, all other Antibes Consensus Conference participants. ENETS Consensus Guidelines for Standard of Care in Neuroendocrine Tumours: Biochemical Markers. Neuroendocrinology. 2017; 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 Neuroendocrine Tumors (Carcinoid Tumors) of the Small Intestine and Ampulla. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Oct 2013. College of American Pathologists (CAP). Northfield, IL [Revised Oct 2013; Accessed: Jun 2017]

Protocol for the Examination of Specimens from Patients with Neuroendocrine Tumors (Carcinoid Tumors) of the Stomach. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Oct 2013. College of American Pathologists (CAP). Northfield, IL [Revised Jun 2014; Accessed: Jun 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]

Ramage JK, Ahmed A, Ardill J, Bax N, Breen DJ, Caplin ME, Corrie P, Davar J, Davies AH, Lewington V, Meyer T, Newell-Price J, Poston G, Reed N, Rockall A, Steward W, Thakker RV, Toubanakis C, Valle J, Verbeke C, Grossman AB, UK and Ireland Neuroendocrine Tumour Society. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut. 2012; 61(1): 6-32. PubMed

Strosberg JR, Halfdanarson TR, Bellizzi AM, Chan JA, Dillon JS, Heaney AP, Kunz PL, O'Dorisio TM, Salem R, Segelov E, Howe JR, Pommier RF, Brendtro K, Bashir MA, Singh S, Soulen MC, Tang L, Zacks JS, Yao JC, Bergsland EK. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Midgut Neuroendocrine Tumors. Pancreas. 2017; 46(6): 707-714. PubMed

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

Ardill JE, O'Dorisio TM. Circulating biomarkers in neuroendocrine tumors of the enteropancreatic tract: application to diagnosis, monitoring disease, and as prognostic indicators. Endocrinol Metab Clin North Am. 2010; 39(4): 777-90. PubMed

Capelli P, Martignoni G, Pedica F, Falconi M, Antonello D, Malpeli G, Scarpa A. Endocrine neoplasms of the pancreas: pathologic and genetic features. Arch Pathol Lab Med. 2009; 133(3): 350-64. PubMed

de Mestier L, Hentic O, Cros J, Walter T, Roquin G, Brixi H, Lombard-Bohas C, Hammel P, le Diebold M, Couvelard A, Ruszniewski P, Cadiot G. Metachronous hormonal syndromes in patients with pancreatic neuroendocrine tumors: a case-series study. Ann Intern Med. 2015; 162(10): 682-9. PubMed

Hörsch D, Bert T, Schrader J, Hommann M, Kaemmerer D, Petrovitch A, Zaknun J, Baum RP. Pancreatic neuroendocrine neoplasms. Minerva Gastroenterol Dietol. 2012; 58(4): 401-26. PubMed

Milan SA, Yeo CJ. Neuroendocrine tumors of the pancreas. Curr Opin Oncol. 2012; 24(1): 46-55. PubMed

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

Ro C, Chai W, Yu VE, Yu R. Pancreatic neuroendocrine tumors: biology, diagnosis,and treatment. Chin J Cancer. 2013; 32(6): 312-24. PubMed

Starker LF, Carling T. Molecular genetics of gastroenteropancreatic neuroendocrine tumors. Curr Opin Oncol. 2009; 21(1): 29-33. PubMed

Verbeek WH, Korse CM, Tesselaar ME. GEP-NETs UPDATE: Secreting gastro-enteropancreatic neuroendocrine tumours and biomarkers. Eur J Endocrinol. 2016; 174(1): R1-7. PubMed

Vinik AI, Silva MP, Woltering EA, Woltering G, Go VL, Warner R, Caplin M. Biochemical testing for neuroendocrine tumors. Pancreas. 2009; 38(8): 876-89. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Pacak K, Jochmanova I, Prodanov T, Yang C, Merino MJ, Fojo T, Prchal JT, Tischler AS, Lechan RM, Zhuang Z. New syndrome of paraganglioma and somatostatinoma associated with polycythemia. J Clin Oncol. 2013; 31(13): 1690-8. PubMed

Yang C, Sun MG, Matro J, Huynh TT, Rahimpour S, Prchal JT, Lechan R, Lonser R, Pacak K, Zhuang Z. Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas. Blood. 2013; 121(13): 2563-6. PubMed

Medical Reviewers

Content Reviewed: 
August 2017

Last Update: September 2017