Pancreatic Neuroendocrine Tumors - PNETs

Medical Experts

Contributor

Best

Hunter Best, PhD, FACMG

Professor of Pathology (Clinical), University of Utah

Operations Platform Director, NGS, ARUP Laboratories

Contributor

Doyle

Kelly Doyle, PhD, DABCC, FAACC

Associate Professor of Pathology (Clinical), University of Utah

Medical Director, Special Chemistry and Endocrinology, ARUP Laboratories

Contributor

Kroner

Grace M. Kroner, PhD

Clinical Chemistry Fellow at ARUP Laboratories and University of Utah

Contributor

Straseski

Joely A. Straseski, PhD, MS, MT(ASCP), DABCC, FAACC

Professor of Pathology (Clinical), University of Utah

Head of Clinical Operations for Clinical Chemistry, Toxicology, and Biochemical Genetics; Medical Director, Endocrinology; Co-Director, Automated Core Laboratory, ARUP Laboratories

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

How do pancreatic neuroendocrine tumors present clinically?

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:

Which laboratory tests are useful when pancreatic neuroendocrine tumors are suspected?

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.

What is the association between multiple endocrine neoplasia type 1 and pancreatic neuroendocrine tumors?

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. Approximately 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 ARUP Consult Multiple Endocrine Neoplasia topic for more information about indications and laboratory testing for this disease.

Indications for Testing

Laboratory testing for PNETs is appropriate for:

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

Laboratory Testing

Biochemical Testing

Specific Neuroendocrine Tumor Markers

Clinical presentation generally helps to determine which biochemical markers to test when PNETs are 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.

Condition^a	Associated Markers
Insulinoma	Glucose, insulin, proinsulin, C-peptide, β-hydroxybutyric acid
Gastrinoma (Zollinger-Ellison syndrome)	Gastrin,^b gastric pH
Glucagonoma	Glucagon, blood glucose
VIPoma	VIP, electrolytes
Somatostatinoma	Somatostatin
^aOther rare conditions can occur, including PNETs that secrete adrenocorticotropic hormone, calcitonin, renin, erythropoietin, and growth hormone-releasing hormone, among other hormones. ^bPPI treatment can result in increased gastrin concentrations; 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 Sources: NCCN, 2021; Oberg, 2017; Falconi, 2016; Jensen, 2012

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, a secreted protein, may be increased in more than 60% of patients with both functional and nonfunctional PNETs, and concentrations that are double the normal limit suggest a worse prognosis. However, elevated concentrations 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

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 complex.

Other Testing

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), magnetic resonance imaging (MRI), and/or fluorodeoxyglucose-positron emission tomography.

Monitoring

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 12 weeks to 12 months after resection (and sooner if symptoms appear) and every 6-12 months 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 12 weeks to 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 concentrations, as suggested by symptoms. At-risk family members of these patients should undergo monitoring for MEN1 as well.