Pancreatic Neuroendocrine Tumors - NET

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

Indications for Testing

  • Pancreatic mass
  • Presentation of a functional syndrome associated with pancreatic neuroendocrine tumors (PNET)

Laboratory Testing

  • Testing for nonfunctional tumors
    • Chromogranin A – sensitivity 60-100% 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
  • For specific functional syndrome, use clinical presentation to order laboratory testing 
    • Insulinoma – glucose, insulin, c-peptide
    • Gastrinoma (Zollinger-Ellison syndrome) – gastrin, gastrin pH, stimulation testing
      • Patient should be off acid-suppressive medication for at least 7-10 days prior to testing
    • Glucagonoma – glucose, glucagon
    • VIPoma – vasoactive intestinal polypeptide (VIP), electrolytes
    • Somatostatinoma – somatostatin

Genetic testing

  • MEN1 germline testing – consider if at least two 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 CT/MRI/ultrasound
    • Detects tumors >1.5 cm (many PNETs are small)
  • Somatostatin-receptor scintigraphy (not useful in insulinomas)
  • Endoscopic ultrasound (EUS)
  • Bone scan if clinically indicated
  • 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 WHO or 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 necessary
  • Follow-up testing 3-12 months after resection and annually thereafter
    • History and physical exam
    • Tumor markers – based on syndrome
    • Multiphasic CT/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 – 2-5/1,000,000 (NCCN, 2014; ESMO, 2012)
  • Age – onset 40s-60s
    • Significant number of PNET patients are under the age of 35
    • Early age of onset if associated with genetic syndrome
  • Sex – M>F
  • Occurrence – usually sporadic
  • Ethnicity – African Americans have highest incidence

Risk Factors

  • Genetic – may be associated with MEN1, von Hippel-Lindau syndrome, neurofibromatosis type 1 (NF1), or tuberous sclerosis

Pathophysiology

  • Represent ~30% of neuroendocrine gastroenteropancreatic tumors (GEP-NETs)
    • Pan neuroendocrine marker positive, typically
  • 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 (eg, Verner-Morrison syndrome associated with vasoactive intestinal polypeptide [VIP] secretion)
    • Nonfunctional tumors may secrete hormones but patients lack symptoms
      • Includes pancreatic polypeptidoma (PPoma)
  • Frequency of occurrence – nonfunctional > insulinoma > glucagonoma > gastrinoma or somatostatinoma > VIPoma > cholecystokininoma (CCKoma))>other rare PNETs (eg, calcitonoma, CRHoma, GHRHoma, ACTHoma)
    • Up to 70% of PNETs are insulinomas, of which 90% are benign (NCCN, 2014)

Clinical Presentation

  • Tumors are increasingly identified incidentally on imaging or from imaging performed as a result of obstructive symptoms
    • Most tumors are indolent with few symptoms
    • Nonfunctioning tumors tend to be large
      • 70% are >5 cm and of advanced stage at diagnosis
      • 60-80% have liver metastasis
  • Patients may present with symptoms of a hormonal syndrome
    • Syndrome may present in conjunction with tumor discovery (synchronous) or present after diagnosis (metachronous)
      • Metachronous presentation
        • May represent worse prognosis for patient
    • Insulinoma
      • Hypoglycemia, weakness
    • Gastrinoma (Zollinger-Ellison syndrome)
      • Peptic ulcer disease – recurrent, severe
    • Glucagonoma
      • Mild glucose intolerance, necrolytic migratory erythema, hypoaminoacidemia
    • VIPoma  (Verner-Morrison syndrome)
      • Watery diarrhea, hypokalemia, achlorhydria (WDHA syndrome)
    • Somatostatinoma
      • Steatorrhea, cholelithiasis, hyperglycemia, achlorhydria
  • Patients may have heritable disorders as etiology (eg, MEN1) for these tumors

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

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

Limitations

Poor diagnostic tool, but pretreatment values useful in assessing treatment and detecting recurrence

In 20% of cases gastrin may only be 5-20% above reference range

Patient should be fasting

Patients should be off protein pump inhibitor (PPI) and H2-receptor blockers for 5-7 days

Glucagon 0099165
Method: Quantitative Radioimmunoassay

Vasoactive Intestinal Peptide 0099435
Method: Quantitative Radioimmunoassay

Limitations

Patients frequently present with VIP ≤20-50% over reference range

Somatostatin Quantitative, Plasma 2010001
Method: Quantitative Extraction/Immunoassay

Limitations

May be elevated in atrophic gastritis

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, deep intronic mutations, breakpoints of large deletions/duplications, and mutations in genes other than MEN1 are not evaluated

Chromogranin A 0080469
Method: Quantitative Enzyme Immunoassay

Limitations

May be elevated due to PPI therapy or impaired renal function

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

Additional Tests Available

Electrolyte Panel 0020410
Method: Quantitative Ion-Selective Electrode/Enzymatic

Comments

General test for PNET

Nonspecific test for VIPoma and Zollinger-Ellison syndrome (ZES)

Proinsulin, Intact 0070112
Method: Quantitative Chemiluminescent Immunoassay

Comments

Aids in the diagnosis of insulinoma

Helps rule out insulin abuse

Pancreatic Polypeptide 0099436
Method: Quantitative Radioimmunoassay

Comments

Elevated in 50% of nonfunctional (ie, nonsyndromic) PNETs; 80% specificity

Gastrin by Immunohistochemistry 2003896
Method: Immunohistochemistry

Comments

IHC levels do not correlate with serum levels

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

Comments

Identifies tissue of neuronal and neuroectodermal origin

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

Calcium, Ionized, Serum 0020135
Method: Ion-Selective Electrode/pH Electrode

Parathyroid Hormone, Intact with Calcium 0070172
Method: Quantitative Electrochemiluminescent Immunoassay

Prolactin 0070115
Method: Quantitative Chemiluminescent Immunoassay

Multiple Endocrine Neoplasia Type 1 (MEN1) Sequencing 2005359
Method: Polymerase Chain Reaction/Sequencing

Comments

Acceptable initial test, but does not detect deletions/duplications

Clinical sensitivity – 90%

Multiple Endocrine Neoplasia Type 1 (MEN1) Deletion/Duplication 2005346
Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification

Comments

Use if no mutations detected by sequencing

Clinical sensitivity – 4%

Guidelines

Anthony L, Strosberg J, Klimstra D, Maples W, O'Dorisio T, Warner R, Wiseman G, Benson A, Pommier R, 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

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: Sep 2015]

O'Toole D, Grossman A, Gross D, Fave G, 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

Protocol for the Examination of Specimens from Patients with Carcinoma of the Endocrine Pancreas. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: June 2012. College of American Pathologists (CAP). Northfield, IL [Accessed: Nov 2015]

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: June 2012. College of American Pathologists (CAP). Northfield, IL [Accessed: Sep 2015]

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: February 2010. College of American Pathologists (CAP). Northfield, IL [Accessed: Nov 2015]

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

Vinik A, Woltering E, Warner R, Caplin M, O'Dorisio T, Wiseman G, Coppola D, Go V, 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 J, O'Dorisio T. 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 R. Pancreatic neuroendocrine neoplasms. Minerva Gastroenterol Dietol. 2012; 58(4): 401-26. PubMed

Milan S, Yeo C. 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 V, Yu R. Pancreatic neuroendocrine tumors: biology, diagnosis,and treatment. Chin J Cancer. 2013; 32(6): 312-24. PubMed

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

Vinik A, Silva M, Woltering E, Woltering G, Go V, 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 M, Fojo T, Prchal J, Tischler A, Lechan R, Zhuang Z. New syndrome of paraganglioma and somatostatinoma associated with polycythemia. J Clin Oncol. 2013; 31(13): 1690-8. PubMed

Yang C, Sun M, Matro J, Huynh T, Rahimpour S, Prchal J, 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

Last Update: February 2016