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(ENETS), UK and Ireland Neuroendocrine Tumour Society or principal, components of the soluble core of dense-
(UKINETS) and Associazione Medici Endocrinologi core secretory granules in neuroendocrine cells and are
(AME) for neuroendocrine tumor management guidelines secreted in a physiologically regulated manner. There are
or position statements using PubMed source. We terminated 8 members in granin family and CgA and chromogranin
our search including results on 7th January 2016. From B (CgB) are the most clinically interesting. However,
[8]
the PubMed results, we chose guidelines or position the precise function of individual granins is dependent on
statements published by scientific societies or institutions the presence of other granins and hormones produced by
in USA, Europe and Italy with recognized exper-tise in a specific neuroendocrine cell, the presence of proteolytic
neuroendocrine tumor patient management. We present processing enzyme and their inhibitors and activators, as
suggestions for clinical practice based on this analysis. well as the density and localization of calcium pumps and
exchangers. Tumors of neuroendocrine origin usually
[13]
WHY SHOULD CIRCULATING present with increased plasma levels of serum or plasma
NEUROENDOCRINE BIOMARKERS BE CgA but the sensitivity of CgA measurements in patient
[8]
USED? with NETs is only about 60-90% with a specificity of
less than 50% due to concomitant therapy with proton-
The current view of DNES was descending from Feyrter’s pump inhibitors (PPIs) or intercurring oncological or
1938 initial discovery of neurons and endocrine cells non-oncological diseases. [14,15] However a recent meta-
sharing a common phenotypic program. These cells analysis demonstrated that abnormally high circulating
were characterized by the expression of markers such as CgA levels are a characteristic feature of patients with
neuropeptides, chromogranins, neuropeptide processing NETs and could serve as non-invasive diagnostic markers
enzymes subtilase-like pro-protein convertases (SPC2 of NETs in clinical practice. CgA is considered
[16]
and SPC3) or dense core secretory granules. All of these a pan-neuroendocrine marker and notably highest
[7]
cells can secrete products such as peptides and biogenic concentrations were found in midgut NETs especially with
amines that are tumour specific and may serve as markers liver metastasis. [17-19] Pancreastin is a post-translational
for the diagnosis and follow-up of treatment. In a few processing product of CgA and was proposed as useful
[8]
cases, clinical presentation is related to a single hormonal diagnostic marker because more standardized assays and
secretion as in insulinoma and gastrinoma, carcinoid lower PPIs exposure interferences than CgA are reported.
syndrome or pheochromocytoma but more frequently A predictive and prognostic value was also demonstrated
the diagnosis is incidental or as a result of tumor bulk. because pre- and post-surgical levels might better reflect
[9]
Circulating tumor biomarkers are readily available and neuroendocrine disease burden and outcome. Other
[20]
should be implemented in clinical practice to diagnose monoanalyte general neuroendocrine biomarkers used in
and monitor patients with NETs. In fact, seventeen managing NETs such as CgB, the cytoplasmatic glycolytic
different circulating biomarkers have been identified for enzyme named neuron-specific enolase (NSE), and
gastroenteric neuroendocrine tumors and more than 30 pancreatic polypeptide (PP) have been used with highest
gut peptide hormone genes are known, which express levels in small-cell lung cancer, poorly differentiated
more than 100 bioactive peptides. In 2010 the World tumors and non-functioning pancreatic tumors,
[8]
Health Organization published the new neuroendocrine respectively, with low diagnostic performance. Also for
tumors classification and now there is consensus on CgB and NSE, sensitivity and specificity performances
[10]
routinely chromogranin A (CgA) and synaptophysin were reported inadequate for diagnosis and prognostic
immunohistochemical assessment for neuroendocrine universal use according to the National Institutes of
[12]
diagnosis. On the other hand, the use of a single Health (NIH) biomarker classification system criteria. [21]
[11]
monoanalytical circulating biomarker for neuroendocrine
tumors management - although frequently recommended Gastrin is a diagnostic marker for Zollinger Ellison
- is now controversial but, so far, unavoidable in NET syndrome characterized by recurrent peptic ulcers and
[12]
management while waiting for new promising circulating secretory diarrhea. Gastrin levels higher than 10 fold upper
biomarkers to be validated in the future. limit of normal in the setting of high gastric acid output is
suggestive of gastrinoma. Determination of gastrin levels
WHICH CIRCULATING BIOMARKERS after a secretin test increases sensitivity in case of borderline
HAVE A ROLE IN NEUROENDOCRINE levels. Insulin is a specific marker of insulinoma and
[22]
TUMOR MANAGEMENT? biochemical diagnosis depends on inappropriate insulin
levels during a fasting glucose tolerance test. [23]
The cytoplasm of neuroendocrine cells is occupied by a
large number of secretory granules of varying electron Neuroendocrine tumors may secrete urinary
densities, size and shape, and is the storage site of secretory 5-hydroxyindoleacetic acid (u-5HIAA), a metabolite
products [i.e. serotonin, 5-hydroxytryptamine (5-HT), of 5-HT but also vasoactive intestinal peptide (VIP),
tachykinins and gastrin]. Upon specific stimulation, glucagon and somatostatin with specific syndromes such
granules are translocated to the cell membrane and their as carcinoid syndrome, watery diarrhea, sweet syndrome
content released by exocytosis. Granins are found as major, or association of gallstones, diabetes and steatorrhea. Even
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 31, 2016 ¦ 349