What are Neuroendocrine Tumor (NET) markers?

From the Guidelines

Chromogranin A (CgA) is the most reliable general marker for neuroendocrine tumors (NETs), and it should be used as the primary marker for diagnosis and monitoring, as stated in the 2012 guidelines for the management of gastroenteropancreatic neuroendocrine tumors 1.

Importance of NET Markers

NET markers are crucial for the diagnosis, treatment, and monitoring of neuroendocrine tumors. These markers help assess the efficacy of treatment and changing prognosis, and they can indicate residual disease in patients who have undergone surgery.

• The measurement of secretory products of NETs is helpful in three respects: to assist with initial diagnosis, to assess the efficacy of treatment, and to assess changing prognosis.
• CgA is usually found in high concentrations regardless of whether the tumor is accompanied by hormone-related clinical features, making it a useful general marker.

Specific Markers

In addition to CgA, other specific markers can be used to diagnose and monitor NETs, including:

• 5-hydroxyindoleacetic acid (5-HIAA) for carcinoid tumors
• Gastrin for gastrinomas
• Insulin for insulinomas
• Pancreatic polypeptide (PP) as a useful additional or alternative general marker in some circumstances
• These markers should be used in conjunction with CgA to provide a comprehensive assessment of the patient's condition.

Clinical Considerations

When using NET markers, it is essential to consider the potential for false positives due to certain medications or foods, and proper patient preparation before testing is crucial.

• Proton pump inhibitors (PPIs) and H2 antagonists can raise circulating CgA and gastrin levels, and should be withdrawn before testing.
• Dietary restrictions and drug interference problems associated with the measurement of serotonin and 5-HIAA should be considered, and the laboratory should be contacted to ensure that inappropriate foods and drugs are excluded for 3 days before and during the urine collection.
• A secretin test may be performed to confirm the diagnosis of gastrinoma, and fasting calcium, parathyroid hormone, and prolactin measurements should be made to consider MEN1 syndrome.

From the Research

NET Markers

• Neuroendocrine tumors (NETs) are associated with elevated levels of certain biomarkers, including:
  • 5-hydroxyindoleacetic acid (5-HIAA) 2, 3, 4
  • Chromogranin A (CgA) 2, 3, 4, 5
• These biomarkers can be used to monitor disease progression and response to treatment in patients with NETs 2, 3, 4
• CgA is considered a valuable marker of NETs, despite its non-specificity and potential for false results 5
• Elevated levels of 5-HIAA and CgA have been associated with improved clinical outcomes, including longer progression-free survival (PFS) and improved symptom control 2, 3

Clinical Utility of NET Markers

• Monitoring 5-HIAA and CgA levels can be useful in the management of patients with nonfunctional neuroendocrine tumors 3
• CgA has been shown to be the most sensitive marker for detecting patients with disseminated disease, while 5-HIAA is the most sensitive marker for identifying syndromic patients 4
• Changes in CgA levels have been associated with progressive disease and stable disease in patients with NETs 4

Potential Diagnostic Pitfalls

• CgA is not specific to NETs and can be elevated in other pathological processes, leading to potential diagnostic difficulties 5
• The molecular structure of CgA is susceptible to proteolytic activity, resulting in the formation of biologically active peptides that can affect its concentration 5