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Table 1: Comparative practical clinical suggestion for circulating NET biomarkers use in functioning and non-
functioning tumors from NCCN 2.2015, NANETS 2010-2013, ESMO 2012, ENETS 2009-2015-2016, UKINETS
2012 guidelines and AME posizione statement 2014
Plasma gastrin, Others
insulin,
(plasma
Source of Cromogranin A NSE u-5HIAA glucagon, calcitonin, GHRH,
indications somatostatin, IGF1, ACTH,
VIP, PP PTH-rp)*
YES* for diagnosis
NCCN YES for NENs diagnosis YES for diagnosis and FU YES* for diagnosis
2. 2015 [32] and FU and FU YES PP in pNEN and FU
for diagnosis and FU
YES GEP-NENs
diagnosis and FU YES diagnosis SUGGESTED** SUGGESTED**
(only if + at diagnosis Useful in THY-
NANENS and not resected) BRO diagnosis and FU mid-gut for diagnosis and FU for diagnosis and FU
2010-2013 [29,37-40] NENs (only if significant (only if significant
SUGGESTED and FU YES* others NENs before) before)
THY-BRO NENs
diagnosis and FU

YES GEP NEN diagnosis YES* for diagnosis
ESMO and FU YES in SI-NEN and FU YES* in THY-BRO
2012 [41-42] YES THY-BRO diagnosis YES in THY-BRO YES* in NF-pNEN USEFUL (ACTH-GHRH-
and FU THY-BRO PP IGF1)
YES GEP-NEN diagnosis
and FU
ENETS USEFUL in NEC Useful in NEC YES in SI-NEN YES* for diagnosis YES* for diagnosis
2015-2016 [11,22,25,31,43,44] diagnosis and FU diagnosis and FU YES* in THY-BRO and FU and FU
YES THY-BRO diagnosis
and FU
YES* for diagnosis
YES in SI, digiunal,
UKINETS YES for NENs diagnosis colon, appendiceal and FU YES* for diagnosis
2012 [33] and FU NF-pNEN USEFUL and FU
NENs
PP
YES for GEP-NEN YES* diagnosis YES*
AME diagnosis and follow only YES for FU NOT PP YES*
2014 [5] after diagnosis or strong if significant before in pratical clinical use
clinical suspicion
NCCN: National Comprehensive Cancer Network; NANETS: North American Neuroendocrine Tumor; ESMO: European Society
of Medical Oncology; ENETS: European Neuroendocrine Tumor Society; UKI NETS: UK and Ireland Neuroendocrine Tumour
Society; NSE: plasmatic neuron-specific enolase; u-5HIAA: urinary 5-Hydroxy-indolacetic acid; NENs: neuroendocrine tumors;
VIP: vasoactive ntestinal peptide; PP: pancreatic polypeptide; GHRH: growth hormone releasing hormone; IGF1: insulin like growth
factor 1; ACTH: adrenocorticotropin; PTH-rp: parathyroid-hormone like hormone; YES: recommended; FU: follow up; YES*:
recommended when clinically indicated; THY-BRO: neuroendocrine thymic and bronchial tumors; GEP-NEN: neuroendocrine
gastroenteric tumors; SUGGESTED**: suggested a large panel of markers at diagnosis or key point individually tailored; NEC:
neuroendocrine carcinoma; SI-NEN: small intestine neuroendocrine tumors; NF-pNENs: non functioning pancreatic neuroendocrine
tumors; NOT: recommend against

relationship between biomarker level and the degree (when assessed as < 25%, 25-50%, > 50%) and correlates
of disease burden, higher levels are frequent in patients with survival. In addition, CgA levels are reduced after
with metastasis, particularly in the liver. In other words, hepatic resection or transplantation. In a retrospective
circulating biomarkers may reflect the tumor burden. study, a CgA decrease of 80% or more was predictive of
Circulating markers are useful for monitoring specific complete symptom resolution and disease stabilization.
tumors by providing a surrogate endpoint: CgA for By contrast, reduction of urinary 5-hydroxyindoleacetic
the majority of cases, pancreastatin for hepatic tumor acid concentrations of 80% or more (or normalization)
load, and neurokinin A for serotonin-secreting tumors was predictive of symptomatic relief but not of disease
of the small bowel. In particular, circulating CgA is stabilization. [45]
[33]
higher in patients with large metastases compared with
localized disease or even limited hepatic involvement Despite the fact that gastrinomas show high circulating
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 31, 2016 ¦ 351