- Published: October 31, 2021
- Updated: October 31, 2021
- University / College: University of California, Irvine
- Language: English
- Downloads: 28
Gastroenteropancreaticneuroendocrine tumors (GEP-NETs) consist in a heterogeneous group of slow-growingmalignancies that arise from neuroendocrine cells located in the digestivetract. GEP-NETs occur commonly in the small intestine (30.8%), followed by therectum (26.3%), colon (17.6%), pancreas (12.
1%), stomach (8.9%), and appendix (5.7%) 1. Although they havebeen considered rare, in the last decades the incidence has increasedsignificantly: from 1.0 per 100 000 in 1977 to 3.7 per 100 000 in 2007 2. The understanding of the molecular mechanisms is stillcontroversial and remains an opened challenge for scientists. Indeed, despite the wide clinical behaviour, there are limitedtherapeutic choices and the preferred treatment remained relatively unchanged(surgical resection) with poor progress in the setting up of effective andpersonalized adjuvant therapies 3.
The symptomatology may be vagueor not specific also in advanced disease and the tumors may be confused with non-neoplasticdysfunctions. As consequences tumorsare found late, after specific clinical investigation, and often in metastaticstages, determining poor clinicaloutcomes. The absence of a specific and sensitive biomarker it’s anotherlimitation to establish an early and effective biochemical diagnosis 4 5.In tumors with a neuroendocrine differentiation, plasmaor serum chromogranin A (CgA) levels are the most widely accepted biomarker.
Additional markers, with lower diagnostic accuracy than of CgA, include plasma neuron-specific enolase (NSE),pancreatic polypeptide (PP), pancreastatin,human chorionic gonadotropin. Incase of functional tumors, where occur a hormonal hypersecretion syndrome, it’salso possible to use the specific peptides released by neoplastic cells for adiagnostic purpose (e.g. insulin for insulinoma, gastrin for gastrinoma) 6.CgA, the first granin identified, is a hydrophilic,heat-stable, acidic protein.
It’s released in its full length or in fragmentsafter cleavage and secreted first in the tumor environment and then in theblood, where is detected in abnormal amount. In malignant neoplasms as NETs, CgAhas been related to the mass of tumor and patient survival but its diagnosticvalue is still uncertain 7. Sensitivity of the detected levels of CgA is comprisedbetween 60-90% but the specificity is less than 50% due to CgA levels foundedhigh also in a wide range of not malignant systemic diseases, includinghypertension, heart and hepatic failure, renal insufficiency hypertension,rheumatoid arthritis, inflammatory bowel disease and non-neuroendocrine tumors 8. Regulation in processing of CgA in cells is a criticalpoint in maintaining homeostasis under different physiological conditions. TheCgA chain presents multiple cleavage dibasic sites and, duringpost-translational processes, proteolytic cleavage by pro-hormone convertasesis responsible for the maturation of different biologically active peptides:vasostatins 1 and 2, chromofungin, chromacin, pancreastatin, catestatin, WE14,chromostatin, GE25, parastatin, and serpinin 9. Even if the role of each fragments is not fully understoodthe diagnostic value has been investigated: in a recent studies highlevels of PST have also shown a significant diagnostic value as a biomarker byidentifying patients with neuroendocrine tumor where CgA was found to be normal10.
In particular, pancreastatin levels have been shown tobe elevated in serum of patients diagnosed with duodenal NET and with poorprognosis 11. Considering thevariability of the current diagnostic data further studies are required toelaborate an effective strategy in management and in monitoring of GEP-NETs.