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more rarely, tumors can secrete corticotropn releasing carcinoma), parathyroid hormone (ectopic secretion
factor (CRF) and/or adrenocorticotropic hormone (ACTH), of PTH), vasoactive compounds, including biogenic
growth hormone releasing hormone (GHRH), arginine amines (tumor responsible of carcinoid syndrome) and
vasopressine (AVP), parathyroid-hormone related peptide catecholamines (pheochromocytoma). In these cases, a
(PTH-rp) or calcitonin with paraneoplastic Cushing’s range of specific peptide hormones may also be measured
disease, acromegaly, inappropriate antidiuretic hormone and are useful as diagnostic and prognostic biomarkers.
secretion syndrome (SIADH). Both functional and nonfunctional NETs produce CgA but
this marker does not distinguish between functional and
Calcitonin is a peptide hormone that is normally nonfunctional tumors. [2]
secreted by thyroid C cells, but may be rarely produced
ectopically by neuroendocrine tumors especially WHEN SHOULD BIOMARKERS TESTING
pancreatic NETs usually in association with other BE PERFORMED?
ectopically produced peptides and frequently with
AVP [24] along with typical clinical symptoms of diarrhea Nonspecific circulating NET biomarkers do not have a
and electrolyte disturbance. crucial role in NET diagnosis and are not recommended
for population screening in the absence of strong clinical
Secretion of luteinizing hormone releasing hormone or radiological evidence of tumor presence. [5,6]
(LHRH), erythropoietin, cholecystokinin (CCK),
renin and glucagon-like peptide 1 (GLP-1) in NETs CgA is correlated with tumor load and levels tend to be
are presented in only a few case reports or miniseries highest in metastatic cancer, particularly in the liver.
[17]
papers. [25] Diagnosis of these tumor subtypes is Recently however a meta-analysis reported a sensibility
sometimes very difficult and so a multidisciplinary and specificity of 73% and 95% respectively for CgA with
neuroendocrine team trained to suspect the disease based higher diagnostic accuracy. u-5HIAA is mandatory
[16]
on symptoms is very important for early diagnosis. in patients with carcinoid syndrome but not as useful
[6]
For those paraneoplastic syndromes, the circulating in patients with foregut (bronchial, gastric) or hindgut
biomarkers are not the starting point but the conclusion (rectal) NETs or in most patients with pancreatic NETS
of a very difficult pathway from subtle and misleading which do not secrete serotonin. Its value is dependent
[29]
clinical manifestation and biochemical alteration to on tumor load and only very highly levels (> 5,000 µg/L)
diagnosis. For example potassium levels and euvolemic have been demonstrated to have a prognostic role in
hyponatremia are ‘per se’ markers of possible ectopic metastatic disease. [19-30] There is consensus about weak
Cushing disease or SIAD when presenting in a particular diagnostic role for CgA and u-5HIAA in early tumor
clinical context. [26,27] detection for non-functioning tumors. [5,29,31-33]
During the natural course of disease, additional peptides The significance of NSE is limited in guidelines to poorly
could be secreted or co-secreted resulting in different differentiated tumors but recent reports pointed to a
[28]
overlapping clinical manifestations with potential impacts possible prognostic role for this marker on progression-
on morbidity and mortality. These possibilities further free survival, overall survival, as a marker of treatment
complicate the puzzle that is NET patient management. outcome in well differentiated, advanced pancreatic
neuroendocrine tumors (pNET) during everolimus
ARE CIRCULATING BIOMARKERS treatment and more recently as a prognostic marker
[34]
USEFUL IN THE DIFFERENTIATION in gastroenteroNETs. For syndromic patients the
[35]
BETWEEN FUNCTIONAL AND NON- biomarkers should be evaluated according to signs and
FUNCTIONAL TUMOURS? symptoms from the first diagnostic step. [29]

The spectrum of clinical presentation of NETs is highly In 2011, the NET Task Force of the National Cancer
variable. Many are incidental findings, whereas other Institute GI Steering Committee recommended the
patients present with mass effects of the primary tumour inclusion of serial plasma CgA measurements into all
or metastases (usually liver). Most NETs are nonfunctional prospective trials for validation as a prognostic and
or secrete peptides with low biological consequences. potential biomarker predicting response. All guidelines
[32]
Approximately 10-20% of NETs are functional and recommend CgA in all NETs at diagnosis and during
present with an associated endocrine syndrome. They follow up as well as u-5HIAA for carcinoid tumors
include tumors that secrete insulin (insulinoma) and and specific markers according to clinical syndrome in
gastrin (gastrinoma) but more rarely also vasointestinal functioning tumors. [Table 1]
peptide (VIPoma), glucagon (glucagonoma), somatostatin
(somatostatinoma), antidiuretic hormone (tumor DO CIRCULATING BIOMARKERS
responsible of SIAD) adrenocorticotropic hormone CORRELATE WITH TUMOR BURDEN?
(ectopic ACTHoma), growth-hormone releasing hormone
(ectopic GHRHoma), calcitonin (medullary thyroid Although there are no data showing an absolute
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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 31, 2016 ¦