A high index of suspicion is the most important step towards making a diagnosis of NET, but there are many serum and urine markers that are used to help refine the diagnosis. Hormonally active tumors enable us to measure peptide or amine concentrations as a disease marker supporting a diagnosis, refining the tumor type, and helping predict disease recurrence or progression.
Functional small intestinal tumors that produce carcinoid syndrome usually produce serotonin, which can be measured in the serum, and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in the urine. A plasma test for this marker, 5-HIAA, is also commercially available. False positive 5-HIAA results occur when foods rich in serotonin are eaten (in particular tropical fruits, chocolate and nuts).
These functional small intestinal tumors also produce tachykinins, and recently a neurokinin A (NKA) assay has become available. While highly specific for small intestinal NETs, many patients do not produce the hormone, so a negative result does not exclude the diagnosis.
Other peptides produced by functional pancreatic NETs such as gastrin, glucagon, insulin (and C-peptide) and VIP can be measured and tend to correspond with symptoms and tumor burden for these tumors. For pheochromocytomas, catecholamines are produced, and standard biochemical evaluation includes serum catecholamines and metanephrines, as well as urinary metanephrines and vanillylmandelic acid (VMA).
General tumor markers can be used as a measure of NET tumor activity. These include chromogranin A (CgA), pancreatic polypeptide (PP) and neuron-specific enolase (NSE). NSE is an older marker that has been replaced by CgA, which is the most commonly used marker and corresponds well with tumor burden, but not all NETs secrete CgA. In patients with benign NETs or some Grade 3 (more aggressive) NETs and many neuroendocrine carcinomas (NECs), CgA is not raised. There is significant laboratory variation in the measurement of CgA, so tests from different laboratories may give different results. It is best therefore to use only one laboratory when following a patient’s progression. The greatest weakness for CgA is that it is elevated in other circumstances, by proton pump inhibitors, in autoimmune atrophic gastritis, inflammatory bowel disease, and in renal injury. PP can be produced by pancreatic NETs that may not be overtly hormonal (non-functional tumors). PP may also be raised occasionally in lung or rectal NETs.
Other newer markers include pancreastatin, CgA fragments, chromogranin B, and a multi-array RNA analysis (the NETest). Some of these tests are commercially available and may be suitable markers for some NETs. A potential issue with the biomarkers is lack of sensitivity and specificity. For example, because of the frequency of CgA unrealiability, recent studies support the substitution of the pancreastatin test; pancreastatin, the breakdown product of Chromogranin A, is more sensitive and specific for NETs.