Promising immunohistochemical and circulating markers of insulinoma

Insulinoma is the most common functioning pancreatic neuroendocrine tumor. The review examines the currently used immunohistochemical and circulating markers for its diagnosis, and discusses the sensitivity and specificity of these parameters. At the same time, the relevance of searching for new biochemical indicators of the presence of insulinoma and its characteristics, as well as studying the mechanisms of tumor growth and hormonal hypersecretion is emphasized. One of the primary methods for solving these problems is immunohistochemical testing with the determination of circulating markers. The results of recent studies of alternative secretory products, in particular, cocaine - and amphetamine - regulated transcript (CART), chromogranin B, and neuroendocrine secretory protein 55 (NESP55) are presented. In addition, the question of expression of various receptors in the insulinoma tissue is considered, including in the context of determining molecular targets for its visualization or radiotherapy. In particular, the expression of receptors for glucagon-like peptide 1 in the tumor tissue is characterized. The possible role of melatonin receptors MT1 (MTNR1a) and MT2 (MTNR1b) in the pathogenesis of insulinoma is clarified. The article also discusses the possible use of tumor protein D52 (TPD52) as a new predictive biomarker for the differential diagnosis of benign and malignant insulinoma.

1. Giovanella LC. Chromogranin A. A circulating neuroendocrine marker biology, pathology, assay technology and clinical applications. France: CIS bio international; 2005.

2. Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3(10):1335–1342. Doi: 10.1001/jamaoncol.2017.0589.

3. Ramachandran R, Bech P, Murphy KG, et al. Comparison of the utility of cocaine- and amphetamine-regulated transcript (CART), chromogranin A, and chromogranin B in neuroendocrine tumor diagnosis and assessment of disease progression. J Clin Endocrinol Metab. 2016;100(4):1520–1528. Doi: 10.1210/jc.2014-3640.

4. Maxwell JE, Dorisio TMO, Howe JR. Biochemical diagnosis and preoperative imaging of gastroenteropancreatic neuroendocrine tumors. Surg Oncol Clin N Am. 2016;25(1):171–194. Doi: 10.1016/j.soc.2015.08.008.

5. Mckenna LR, Edil BH. Update on pancreatic neuroendocrine tumors. Gland Surg. 2014;3(4):258–275. Doi: 10.3978/j.issn.2227-684X.2014.06.03.

6. Falconi M, Eriksson B, Kaltsas G, et al. ENETS Consensus Guidelines Update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology. 2016;103(2):153–171. Doi: 10.1159/000443171.

7. Tümör N, Genel B, Bakış B, et al. An overview of neuroendocrine tumour markers. Turkish journal of endocrinology and metabolism. 2014;18(4):132–136. Doi: 10.4274/tjem.2422.

8. Kyriakopoulos G, Mavroeidi V, Chatzellis E, et al. Histopathological, immunohistochemical, genetic and molecular markers of neuroendocrine neoplasms. Ann Transl Med. 2018;6(12):252. Doi: 10.21037/atm.2018.06.27.

9. Ángel J, Pérez D, Freixes MC. Chromogranin A and neuroendocrine tumors. Endocrinol Nutr. 2013;60(7):386–395. Doi: 10.1016/j.endonu.2012.10.003.

10. Qiao X, Qiu L, Chen Y, et al. Chromogranin A is a reliable serum diagnostic biomarker for pancreatic neuroendocrine tumors but not for insulinomas. BMC Endocr Disord. 2014;14:64. Doi: 10.1186/1472-6823-14-64.

11. Oberg K. Circulating biomarkers in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer. 2011;18 Suppl 1:S17–S25. Doi: 10.1530/ERC-10-0280.

12. Bech PR, Martin NM, Ramachandran R, Bloom SR. The biochemical utility of chromogranin A, chromogranin B and cocaine- and amphetamine-regulated transcript for neuroendocrine neoplasia. Ann Clin Biochem. 2013;51(Pt 1):8–21. Doi: 10.1177/0004563213489670.

13. Ardill JES, O’Dorisio TM. Circulaing biomarkers in neuroendocrine tumors of the enteropancreatic tract: application to diagnosis, monitoring disease, and as prognostic indicators. Endocrinol Metab Clin N Am. 2010;39(4):777–790. Doi: 10.1016/j.ecl.2010.09.001.

14. Bech P, Winstanley V, Murphy KG, et al. Elevated cocaine- and amphetamine-regulated transcript immunoreactivity in the circulation of patients with neuroendocrine malignancy. J Clin Endocrinol Metab. 2008;93(4):1246–1253. Doi: 10.1210/jc.2007-1946.

15. Jensen PB, Kristensen P, Clausen JT, et al. The hypothalamic satiety peptide CART is expressed in anorectic and non-anorectic pancreatic islet tumors and in the normal islet of Langerhans. FEBS Lett. 1999;447(2–3):139–143. Doi: 10.1016/s0014-5793(99)00291-4.

16. Sathanoori R, Erlinge D, Wierup N. Cocaine- and amphetamine-regulated transcript (CART) protects beta cells against glucotoxicity and increases cell. J Biol Chem. 2013;288(5):3208–3218. Doi: 10.1074/jbc.M112.437145.

17. Wierup N, Sundler F. CART is a novel islet regulatory peptide. Peptides. 2006;27(8):2031–2036. Doi: 10.1016/j.peptides.2006.02.011.

18. Bargsten G. Cytological and immunocytochemical characterization of the insulin secreting insulinoma cell line RINm5F. Arch Histol Cytol. 2004;67(1):79–94. Doi: 10.1679/aohc.67.79.

19. Stridsberg M, Oberg K, Li Q, et al. Measurements of chromogranin A, chromogranin B (secretogranin I), chromogranin C (secretogranin II) and pancreastatin in plasma and urine from patients with carcinoid tumours and endocrine pancreatic tumours. J Endocrinol. 1995;144(1):49–59. Doi: 10.1677/joe.0.1440049.

20. Jakobsen AM, Ahlman H, Ko L. NESP55, a novel chromogranin-like peptide, is expressed in endocrine tumours of the pancreas and adrenal medulla but not in ileal carcinoids. Br J Cancer. 2003;88(11):1746–1754. Doi: 10.1038/sj.bjc.6600924.

21. Korner M. Specific biology of neuroendocrine tumors: peptide receptors as molecular targets. Best Pract Res Clin Endocrinol Metab. 2016;30(1):19–31. Doi: 10.1016/j.beem.2016.01.001.

22. Waser B, Blank A, Karamitopoulou E, et al. Glucagon-like-peptide-1 receptor expression in normal and diseased human thyroid and pancreas. Mod Pathol. 2015;28(3):391–402. Doi: 10.1038/modpathol.2014.113.

23. Luo Y, Pan Q, Yao S, et al. Glucagon-like peptide-1 receptor PET/CT with 68ga-nota-exendin-4 for detecting localized insulinoma: a prospective cohort study. J Nucl Med. 2016;57(5):715–720. Doi: 10.2967/jnumed.115.167445.

24. Wild D, Christ E, Caplin ME, et al. Glucagon-like peptide-1 versus somatostatin receptor targeting reveals 2 distinct forms of malignant insulinomas. J Nucl Med. 2011;52(7):1073–1078. Doi: 10.2967/jnumed.110.085142.

25. Peschke E, Mühlbauer E. New evidence for a role of melatonin in glucose regulation. Best Pract Res Clin Endocrinol Metab. 2016;24(5):829–841. Doi: 10.1016/j.beem.2010.09.001.

26. Peschke E, Bähr I, Mühlbauer E. Melatonin and pancreatic islets: interrelationships between melatonin, insulin and glucagon. Int J Mol Sci. 2013;14(4):6981–7015. Doi: 10.3390/ijms14046981.

27. Mühlbauer E, Albrecht E, Bazwinsky-Wutschke I, Peschke E. Melatonin influences insulin secretion primarily via MT(1) receptors in rat insulinoma cells (INS-1) and mouse pancreatic islets. J Pineal Res. 2012;52(4):446–459. Doi: 10.1111/j.1600-079X.2012.00959.x.

28. Li Y, Wu H, Liu N, et al. Melatonin exerts an inhibitory effect on insulin gene transcription via MTNR1B and the downstream Raf-1/ERK signaling pathway. Int J Mol Med. 2018;41(2):955–961. Doi: 10.3892/ijmm.2017.3305.

29. Alkatout I, Friemel J, Sitek B, et al. Novel prognostic markers revealed by a proteomic approach separating benign from malignant insulinomas. Mod Pathol. 2015;28(1):69–79. Doi: 10.1038/modpathol.2014.82.

30. Baudin E, Caron P, Lombard-Bohas C, et al. Malignant insulinoma: recommendations for characterisation and treatment. Ann Endocrinol (Paris). 2013;74(5–6):523–533. Doi: 10.1016/j.ando.2013.07.001.