Pancreatic neuroendocrine tumors (PNETs) are rare tumors of pancreatic islet cells that account for approximately 10% of pancreatic tumors by prevalence. Many neuroendocrine tumors arise sporadically, whereas some are associated with genetic syndromes, such as multiple endocrine neoplasia type 1 (MEN1). PNETs can be either functional, demonstrating symptoms associated with the hypersecretion of hormones (eg, insulin, glucagon, gastrin), or nonfunctional. Approximately 22% of patients with PNETs have functional tumors, many of which are insulinomas. Risk for metastases varies by type; most insulinomas follow an indolent course, but other PNET types, such as gastrinomas, demonstrate a higher risk for metastases. Laboratory testing for PNETs involves evaluation of specific biochemical markers, as determined by the clinical presentation. Genetic testing for hereditary syndromes should be considered for all patients with PNETs.
Quick Answers for Clinicians
Pancreatic neuroendocrine tumors (PNETs) can present in a variety of ways. Patients with nonfunctional PNETs (the more common type) may be asymptomatic, even though the tumors may be large and at an advanced stage when detected. Functional PNETs secrete hormones, and this secretion leads to clinical syndromes such as insulinoma, gastrinoma or Zollinger-Ellison syndrome, glucagonoma, somatostatinoma, or vasoactive intestinal polypeptide (VIP)-secreting tumors (referred to as VIPoma). Patients with insulinomas may present with hypoglycemia, those with gastrinoma may have recurring peptic ulcers, patients with glucagonoma or somatostatinoma may present with hyperglycemia or diabetes mellitus, and those with VIPoma may have watery diarrhea or hypokalemia. Refer to these individual ARUP Consult topics for more information about indications and laboratory testing for these conditions:
In cases of suspected pancreatic neuroendocrine tumors (PNETs), the clinical presentation helps to determine which biochemical markers to test. Tested markers may include glucose or insulin (for insulinoma), gastrin or gastric pH (for gastrinoma), and glucose or glucagon (for glucagonoma). In patients without symptoms of hormone hypersecretion, tests for nonspecific markers such as chromogranin A may be useful. See Laboratory Testing.
Multiple endocrine neoplasia type 1 (MEN1) is characterized by pancreatic neuroendocrine tumors (PNETs), in addition to pituitary adenomas and hyperparathyroidism. Patients with MEN1 often have multiple PNETs, and insulinomas and gastrinomas are the most frequently seen PNETs in patients with MEN1. Personal and family history should be investigated in all patients with PNETs to determine whether MEN1 is present. About 50% of patients with MEN1 will be diagnosed with functioning pancreatic neoplasms (although such neoplasms may be benign), and 20-55% of patients with MEN1 will develop nonfunctioning PNETs. Refer to the Multiple Endocrine Neoplasia ARUP Consult topic for more information about indications and laboratory testing for this disease.
Indications for Testing
- Diagnosing patients with a pancreatic mass or signs and symptoms of a functional syndrome associated with PNETs
- Monitoring patients who have undergone resection or are undergoing treatment for a PNET
Specific Neuroendocrine Tumor Markers
Clinical presentation generally helps to determine which biochemical markers to test when a PNET is suspected. The goal of these tests is to detect hypersecretion of markers that correlate with specific conditions. Refer to the individual ARUP Consult topics listed in the “Condition” column of the table below for additional information about testing patients for these conditions.
|Insulinoma||Glucose, insulin, proinsulin, C-peptide, β-hydroxybutyric acid|
|Gastrinoma (Zollinger-Ellison syndrome)||Gastrin,b gastric pH|
|Glucagonoma||Glucagon, blood glucose|
|aOther rare conditions can occur, including PNETs that secrete growth hormone-releasing hormone, adrenocorticotropic hormone, calcitonin, renin, and erythropoietin, among other hormones.
bPPI treatment can result in increased gastrin levels; ideally, testing should be performed after discontinuation of PPIs for 1 week. Some investigators recommend against abrupt discontinuation of PPIs in patients with suspected gastrinoma and recommend dose tapering instead. Secretin stimulation testing may be necessary to diagnose gastrinoma (Zollinger-Ellison syndrome); in patients with a negative secretin stimulation test, calcium stimulation testing may be useful.
β, beta; NCCN, National Comprehensive Cancer Network; PPI, proton pump inhibitor; VIP, vasoactive intestinal polypeptide
Nonspecific Neuroendocrine Tumor Markers
Although not currently recommended for diagnosis of PNETs, testing for nonspecific tumor markers may be useful for follow-up after tumor resection. These markers include pancreatic polypeptide, alpha (α) subunit of pituitary glycoprotein hormones, and chromogranin A. Chromogranin A is a secreted protein that may be increased in more than 60% of patients with both functional and nonfunctional PNETs, and levels that are double the normal limit suggest a worse prognosis. However, elevated levels of chromogranin A should be interpreted with caution because PPI use, hypertension, chronic gastritis, and renal or liver failure can result in increased chromogranin A concentrations.
Genetic testing should be considered in all patients with PNETs. Beneficial testing might include MEN1 molecular testing to determine whether the patient has MEN1, an inherited syndrome caused by the inactivation or germline mutation of the MEN1 gene and characterized by PNETs, among other features. Genetic testing should be based on family history and clinical presentation. PNETs are occasionally, but less commonly, associated with other genetic disorders such as von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1, and tuberous sclerosis.
Histopathologic testing, including immunohistochemical (IHC) tests, also has a role in a workup for PNETs. Refer to the ARUP Immunohistochemistry Stain Offerings brochure for more information about relevant IHC tests. In addition to IHC testing, a PNET workup may involve imaging studies such as multiphasic computed tomography (CT) or magnetic resonance imaging (MRI), and fluorodeoxyglucose-positron emission tomography.
Approximately 21-42% of patients with PNETs experience disease recurrence, and in some cases, the disease recurs a number of years after initial diagnosis and treatment. Follow-up testing is recommended 3-12 months after resection (and sooner if symptoms appear) and annually thereafter for up to 10 years. Monitoring should include biochemical marker testing, particularly if a functional syndrome was diagnosed. Chromogranin A may be useful to assess treatment response, detect disease progression, and identify disease recurrence. In addition to laboratory testing, history, physical examination, and imaging are recommended as part of monitoring.
In patients with advanced, unresectable, but stable disease with a low tumor burden, watchful waiting may be appropriate; for these patients, biochemical marker testing every 3-12 months is recommended until clinically relevant disease progression is observed.
Once a PNET diagnosis has been established, patients should be monitored for the development of other conditions associated with MEN1. Even if MEN1 molecular testing is negative, patients with clinical suspicion for MEN1 should be periodically evaluated for malignancies associated with MEN1 by testing serum hormone levels, as suggested by symptoms. At-risk family members of these patients should undergo monitoring for MEN1 as well.
ARUP Laboratory Tests
Aid in monitoring patients with PNETs
Results obtained with different assay methods or kits cannot be used interchangeably
Aid in diagnosis and monitoring of PNETs
Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification
Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ) - Health Professional Version. National Cancer Institute. [Updated: Apr 2019; Accessed: Oct 2019]
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine and adrenal tumors. Version 1.2019. [Updated: Jun 2019; Accessed: Mar 2020]
Oberg K, Couvelard A, Delle Fave G, et al. ENETS Consensus Guidelines for Standard of Care in Neuroendocrine Tumours: Biochemical Markers. Neuroendocrinology. 2017.
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): 153-71.
Jensen RT, Cadiot G, Brandi ML, et al. ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes. Neuroendocrinology. 2012; 95 (2): 98-119.
Ramage JK, Ahmed A, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut. 2012;61(1):6-32.