Significance of Chromogranin A and Synaptophysin in Gastroenteropancreatic Neuroendocrine Tumors
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Jan 30, 2024
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Abstract
The two most commonly used immunohistochemical markers for neuroendocrine tumors are chromogranin A and synaptophysin. We had previously studied immunohistochemical staining on pancreatic neuroendocrine tumors: chromogranin A strongly positive tumors including gastrinomas, glucagonomas, pancreatic polypeptidomas were more malignant (>50%) than chromogranin A weakly positive tumors of insulinomas (<10%). With additional 40 cases of gastroenteric neuroendocrine tumors, formerly carcinoid tumors, we investigated chromogranin A and synaptophysin immunostaining: more aggressive neuroendocrine tumors of duodenum, small intestine and ascending colon were strongly positive for chromogranin compared to less aggressive neuroendocrine tumors of sigmoid colon and rectum. Immunohistochemical staining for chromogranin A represents a marker for the secretary granules with a possible marker of prognosis on all gastroenteropancreatic neuroendocrine tumors. Furthermore, serum CgA levels may be used as an indirect, independent diagnostic and prognostic marker for gastroenteropa-ncreatic neuroendocrine tumors in three folds: First to diagnose gastroenteropancreatic neuroendocrine tumors. Secondly, to assess the degree of malignancy by tissue and serum CgA levels and thirdly, evaluate increasing serum CgA levels as a prognostic indicator. Since there is no difference of immunostaining for synaptophysin between more aggressive neuroendocrine tumors and less aggressive tumors, immunostaining for synaptophysin is not a marker for aggressive tumors.
Keywords:
chromogranin A, gastroenteropancreatic neuroendocrine tumors, immunohistochemistry, synaptophysin
Article Details
How to Cite
TOMITA, Tatsuo.
Significance of Chromogranin A and Synaptophysin in Gastroenteropancreatic Neuroendocrine Tumors.
Medical Research Archives, [S.l.], v. 12, n. 1, jan. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4918>. Date accessed: 15 may 2024.
doi: https://doi.org/10.18103/mra.v12i1.4918.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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6. Tomita, T: Significance of chromogranin A and synaptophysin in pancreatic neuroendocrine tumors. Bosn J Basic Med Sci 2020, 20(3):336-346.
7. Yantis, RK, Odze, R, Farraye, F: Solitary versus multiple carcinoid tumors and ileum: An clinical and pathologic review of 68 cases. Am J Surg Pathol 2003, 27(6):811-817.
8. Burke, AP, Thomas, RM, Elsayed, AM, Sobin, LH: Carcinoids of the jejunum and ileum: An immunohistochemical andclinicopathological study of 167 cases. Cancer 1997,79(6 ):934-959.
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11. Capella, C, Solcia, E, Sobin, H, Arnold, R: Endocrine tumors of the colon and rectum. Hamilton, SR, Arltonen, LA, Tumors of Digestive System. World Health Organization Classification of Tumors, IARC Press, Lyon, France, 137-141.
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13. Jansson, L, Barbu, A, Drotte, CJ, Espes, D, Gao, X (2016) Pancreatic islet blood supply and its measurement. Upsala J Med Sci 12;81-95.
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16. Tomita, T., Friesen, S.R., Kimmel, J.R.: Pancreatic polypeptide secreting islet cell tumor. A conclusive follow-up study. Cancer 57(1):129-133, 1986.
17. Robertson, RG, Geiger, WJ, Davis, NB: Carcinoid syndrome. Am Fam Physicians 2006, 74(3):429-434.
18. Janson, ET, Holmberg,L, Strisberg, M, Ericksoson, B, Thoerdorsson, E et al: Carcinoid tumors: Analysis of prognostic factors and survival in 301 patients from a referral center. Ann Oncol 1997, 8(7):685-690.
19. Gut, P, Czabywihtek, A, Fishback, J, Baczyk, M, Ziemnicka, K et al: Chromogranin: A non-specific neuroendocrine marker: Clinical utility and potential diagnostic pitfalls. Arch Med Sci 2016, 121(1):1-9.
20. Tomassetti, P, Migliori, M, Simori, P, Cassadei, R, De Lasio, R et al: Diagnostic values of plasma chromogranin A in neuroendocrine tumours. Eu J Gastroenterol Hepatol 2001, 13 (1 ):55-58.
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25. Ehehalt, F, Saeger, HD, Schwidt, CM, Grutzmann, R: Neuroendocrine tumors of the pancreas. Oncologists 2009,14(5):456-67.
26. Stabile, BE, Morrow, DJ, Passaro, E Jr: The gastrinoma triangle: Operative implications. Am J Surg 1984,147(1):25-31.
27. Jensen, RT: Gastrinoma (Duodenal and pancreatic) Neuroendocrinol 2006,84(2):173-82.
28. Tomita, T., Friesen, S.R., Kimmel, J.R, Pollock. HG.: Pancreatic polypeptide-secreting islet cell tumors. A study of three cases. Amer. J. Pathol. 113(2):134-142, 1983.
29. Marx, S, Spiegel, AM, Skarulis, MC, Doppman, JL, Collins, FS et al: Multiple endocrine neoplasia type 1: Clinical and genetic topics. Ann Intern Med 1998, 129(6):484-94.
30. Piecha, G, Chudek, J, Wiecek,A: Multiple endocrine neoplasia 1. Eur J Intern Med 2008, 19(2):99-103.
31. Le Bodic, MF, Heymann, MF, Lecomte, M: Immunohistochemical study of 100 pancreatic endocrine tumors in 28 patients with MEN, type 1. Am J Surg Pathol 1996, 20(11):1378-84.
32. Bonfils, S, Landor, JH, Mignon, M, Hervoir, P: Results of surgical management in 92 consecutive patients with Zollinger-Ellison syndrome: a 25-year assessment. Am J Surg 1981,194(6):6926-97.
33. Bonfils, S, Landor, JH, Mignon, M, Hervoir, P: Results of surgical management in 92 consecutive patients with Zollinger-Ellison syndrome: a 25-year assessment. Am J Surg 1981,194(6):6926-97.
34. Malagelada, JR, Edis, AJ, Adson, MA, van Heeden, JA, Go, VL: Medical and surgical options in the management of patients with gastrinoma. Gastroenterol 1983, 84(6):1524-32.
35. Taupenot,L, Haper, KL, O’Connor, DT: The chromogranin-secretogranin family. N Eng J Med 2003, 248(3):1134-49.
36. Tomita, T, Friesen, SR, Kimmel, JR, Doull, V, Pollock, HG: Pancreatic polypeptide in islet cell tumors: Morphologic and functional correlations. Cancer 1985,56(7):1649-1657.
37. Adams, DJ, Arthur, CD, Stowell, HB: Architecture of the synaptophysin/synaptobrevin complex: Structural evidence for an entropic clustering function at the synapse. Science Rep 2015(13659)
38. Han, L, Suda, M, Tsuzuki, K, Wang, R, Ohe, Y et al: A large form of secretogranin III functions as a sorting receptor for chromogranin A aggregates in PC12 cells. Molec Endocrinol 2008, 22(8):1935-49.
39. Matschinsky, FM, Liang, Y, Kesavan, P: Glucokinase as pancreatic β-cell sensor and diabetes. J Clin Invest 1993,92(5):2092-98.
40. Matschinsky, FM: Banting Lecture: A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 1995,45(2):223-41.
41. Nobels, FRE, Kwekkeboom, DJ, Coopmans, W, Schoenmarkfers, CHH, Lindemans, J et al: Chromogranin A as serum marker for neuroendocrine neoplasia: Comparison with neuron-specific enolase and the α-subunit of glycoprotein hormones. J Clin Endocrinol Metab 1997, 82(8):2622-28.
42. Fossmark, R, Jianu, CS, Martinsen, TC, Ovgstad, G, Syversen, U et al: Serum gastrin and chromogranin A levels in patients with fundic gland polyp caused by long-term proton-pump inhibition. Scand J Gastroenerol 20008, 43(1):20-24.
43. Walter, T, Chardon, L, Chopin-Laly, X, Raverot, V, Caffin, AG et al: Is the combination of chromogranin A and pancreatic polypeptide serum determinations of interest in diagnosis and follow-up of gastro-entero-pancreatic neuroendocrine tumors? Eur J Cancer 2012, 48(12):1766-1773.
44. Wang, YH, Yang, Q, Lin, Y, Ling, X, Chen, M, Chen, J: Chromogranin A as a marker for diagnosis, treatment and survival in patients with gastroenteropancratic neuroendocrine neoplasm. Medicine 2014, 93: e247.
45. Ferrari, L, Seregni, E, Lucignani, G, Bajetta, E, Martinetti, A et al: Accuracy and clinical correlates of two different methods for chromogranin assay in neuroendocrine tumours. Int J Biol Markers, 2004, 19(4):295-304.
46. Qiao, XW, Qiu, L, Chen, YJ, Meng, CT, Sun, Z, Bai, CM et al: Chromogranin A is a reliable serum diagnostic biomarker for pancreatic neuroendocrine tumors but not for insulinomas. BMC Endocrine Disorders 2014, 14:64
47. Hijioka, M, Ito, T, Igarashi, H, Fujimori, N, Lee, L et al: Serum chromogranin A is a useful marker of Japanese patients with pancreatic neuroendocrine tumors. Can Sci 2014, 105(11):1464-1471.
48. Nolting, S, Kuttner, A, Lauseker, M, M, Vogeser, M, Haug, A et al: Chromogranin A as serum marker for gastroenteropancreatic neuroendocrine tumors: A single center experience and literature review. Cancers, 2012, 4 (1):141-155.
49. Goto, Y, Silva, MG, Toscani, A, Prabhakaar, BS, Notkins, AL, Lam, MS: A novel human insulinoma-associated cDNA, IA-1 encodes a protein with ‘zink-finger’ DNA-binding motifs. J Biol Chem 1992, 267(21):15252-15257.
50. Gierl, MS, Karoulias, N, Wende, H, Strehle, M, Birchmeier, C: The zin-finger factor Insm 1 (IA-1) is essential for the development of pancreatic β cells and intestinal cells. Genes Develop 2006, 20(17):2465-2478.
51. Mukhopadhyay, S, Dermawan, J, Lanigan, C, Farver, CF: Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms : an immunohistochemical study of 345 cases, including 292 whole-tissue sections. Mod Pathol 2019, 32(1):100-109.
52. Maleki, Z, Nadella, A, Nadella, M, Patel, G, Patel, S et al: INSM1, a novel biomarker for detection of neuroendocrine neoplasms : Cytopathologists’ view. Diagnostics, 2021, 11(12):2172.
53. Juhlin, CC: Second generation neuroendocrine immunohistochemical markers: Reflection from clinical implementation. Biology 2021, 10(9):874.
2. Ehrhart, M, Gruse, D, Bader, MF, Aunis, D, Gratzi, M: Chromogranin A in the pancreatic islets: Cellular and subcellular distribution. J Histochem Cytochem 1986, 34(12):1673-82.
3. Elferink, LA, Scheller, RH: Synaptic vesicle proteins and related exocytosis. Prog Brain Res 1995, 105:79-85.
4. Tomita, T.: New markers for pancreatic islets and islet cell tumors. Pathol Int 2002,52(7):425-432.
5. Kim, JY, Hong, SM: Recent updates on neuroendocrine tumors from the gastrointestinal and pancreaticobiliary tracts. Arch Path Lab Med, 2016, 140 (5):437-448.
6. Tomita, T: Significance of chromogranin A and synaptophysin in pancreatic neuroendocrine tumors. Bosn J Basic Med Sci 2020, 20(3):336-346.
7. Yantis, RK, Odze, R, Farraye, F: Solitary versus multiple carcinoid tumors and ileum: An clinical and pathologic review of 68 cases. Am J Surg Pathol 2003, 27(6):811-817.
8. Burke, AP, Thomas, RM, Elsayed, AM, Sobin, LH: Carcinoids of the jejunum and ileum: An immunohistochemical andclinicopathological study of 167 cases. Cancer 1997,79(6 ):934-959.
9. Modlin, IM, Lye, KD, Kidd, M: A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003, 97(4 ):934-959.
10. Volante, M, Grillo, F, Maletta, F, Mastracci, L et al: Neuroendocrine neoplasms of the appendix, colon and rectum. Pathologica 2021, 113(1);19-27.
11. Capella, C, Solcia, E, Sobin, H, Arnold, R: Endocrine tumors of the colon and rectum. Hamilton, SR, Arltonen, LA, Tumors of Digestive System. World Health Organization Classification of Tumors, IARC Press, Lyon, France, 137-141.
12. Federspiel, BH, Burke, G, Arnold, R, Shekitka, KM: Rectal and colonic carcinoids. A clinicopathological study of 84 cases. Cancer,1990, 65 (1 ):135-140.
13. Jansson, L, Barbu, A, Drotte, CJ, Espes, D, Gao, X (2016) Pancreatic islet blood supply and its measurement. Upsala J Med Sci 12;81-95.
14. Rosai, J: Carcinoid tumors and related endocrine tumors. In: Rosai, J, Ackerman’s Surgical Pathology. 2004, 9th ed, St Louis, Mosby, 730-733.
15. Goto, Y, De Silva, MG, Toscani, A, Prabhakar, BS, Notkins, AL, Lan, MS: A novel human insulinoma-associated DNA, IA-1, encodes a protein with ‘zink finger’ cDNA-binding motifs. J Biol Chem 1992, 267 (21):15252-15257.
16. Tomita, T., Friesen, S.R., Kimmel, J.R.: Pancreatic polypeptide secreting islet cell tumor. A conclusive follow-up study. Cancer 57(1):129-133, 1986.
17. Robertson, RG, Geiger, WJ, Davis, NB: Carcinoid syndrome. Am Fam Physicians 2006, 74(3):429-434.
18. Janson, ET, Holmberg,L, Strisberg, M, Ericksoson, B, Thoerdorsson, E et al: Carcinoid tumors: Analysis of prognostic factors and survival in 301 patients from a referral center. Ann Oncol 1997, 8(7):685-690.
19. Gut, P, Czabywihtek, A, Fishback, J, Baczyk, M, Ziemnicka, K et al: Chromogranin: A non-specific neuroendocrine marker: Clinical utility and potential diagnostic pitfalls. Arch Med Sci 2016, 121(1):1-9.
20. Tomassetti, P, Migliori, M, Simori, P, Cassadei, R, De Lasio, R et al: Diagnostic values of plasma chromogranin A in neuroendocrine tumours. Eu J Gastroenterol Hepatol 2001, 13 (1 ):55-58.
21. Korse, CM, Nonfrer, NM, Aaronson, NK, Hart, AA, Taal, BG: Chromogranin as an alternative to 5-hydroxyindoacetic acid in the evaluation of symptoms during treatment of patients with neuroendocrine tumors. Neuroendocrinol 2009, 89(3 ):296-301.
22. Frankel, WL: Update on pancreatic endocrine tumors. Arch Pathol Lab Med 2006,130(7):963-66.
23. Klimstra, DS: Non-ductal neoplasms of the pancreas. Mod Pathol 2007,20: s94-s112.
24. Ito, T, Igarashi, H, Jensen, RT: Pancreatic neuroendocrine tumors: Clinical features, diagnosis and medical treatment: Advances. Best Prac Res Clin Gastroenterol. 2012,26(6):737-53.
25. Ehehalt, F, Saeger, HD, Schwidt, CM, Grutzmann, R: Neuroendocrine tumors of the pancreas. Oncologists 2009,14(5):456-67.
26. Stabile, BE, Morrow, DJ, Passaro, E Jr: The gastrinoma triangle: Operative implications. Am J Surg 1984,147(1):25-31.
27. Jensen, RT: Gastrinoma (Duodenal and pancreatic) Neuroendocrinol 2006,84(2):173-82.
28. Tomita, T., Friesen, S.R., Kimmel, J.R, Pollock. HG.: Pancreatic polypeptide-secreting islet cell tumors. A study of three cases. Amer. J. Pathol. 113(2):134-142, 1983.
29. Marx, S, Spiegel, AM, Skarulis, MC, Doppman, JL, Collins, FS et al: Multiple endocrine neoplasia type 1: Clinical and genetic topics. Ann Intern Med 1998, 129(6):484-94.
30. Piecha, G, Chudek, J, Wiecek,A: Multiple endocrine neoplasia 1. Eur J Intern Med 2008, 19(2):99-103.
31. Le Bodic, MF, Heymann, MF, Lecomte, M: Immunohistochemical study of 100 pancreatic endocrine tumors in 28 patients with MEN, type 1. Am J Surg Pathol 1996, 20(11):1378-84.
32. Bonfils, S, Landor, JH, Mignon, M, Hervoir, P: Results of surgical management in 92 consecutive patients with Zollinger-Ellison syndrome: a 25-year assessment. Am J Surg 1981,194(6):6926-97.
33. Bonfils, S, Landor, JH, Mignon, M, Hervoir, P: Results of surgical management in 92 consecutive patients with Zollinger-Ellison syndrome: a 25-year assessment. Am J Surg 1981,194(6):6926-97.
34. Malagelada, JR, Edis, AJ, Adson, MA, van Heeden, JA, Go, VL: Medical and surgical options in the management of patients with gastrinoma. Gastroenterol 1983, 84(6):1524-32.
35. Taupenot,L, Haper, KL, O’Connor, DT: The chromogranin-secretogranin family. N Eng J Med 2003, 248(3):1134-49.
36. Tomita, T, Friesen, SR, Kimmel, JR, Doull, V, Pollock, HG: Pancreatic polypeptide in islet cell tumors: Morphologic and functional correlations. Cancer 1985,56(7):1649-1657.
37. Adams, DJ, Arthur, CD, Stowell, HB: Architecture of the synaptophysin/synaptobrevin complex: Structural evidence for an entropic clustering function at the synapse. Science Rep 2015(13659)
38. Han, L, Suda, M, Tsuzuki, K, Wang, R, Ohe, Y et al: A large form of secretogranin III functions as a sorting receptor for chromogranin A aggregates in PC12 cells. Molec Endocrinol 2008, 22(8):1935-49.
39. Matschinsky, FM, Liang, Y, Kesavan, P: Glucokinase as pancreatic β-cell sensor and diabetes. J Clin Invest 1993,92(5):2092-98.
40. Matschinsky, FM: Banting Lecture: A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 1995,45(2):223-41.
41. Nobels, FRE, Kwekkeboom, DJ, Coopmans, W, Schoenmarkfers, CHH, Lindemans, J et al: Chromogranin A as serum marker for neuroendocrine neoplasia: Comparison with neuron-specific enolase and the α-subunit of glycoprotein hormones. J Clin Endocrinol Metab 1997, 82(8):2622-28.
42. Fossmark, R, Jianu, CS, Martinsen, TC, Ovgstad, G, Syversen, U et al: Serum gastrin and chromogranin A levels in patients with fundic gland polyp caused by long-term proton-pump inhibition. Scand J Gastroenerol 20008, 43(1):20-24.
43. Walter, T, Chardon, L, Chopin-Laly, X, Raverot, V, Caffin, AG et al: Is the combination of chromogranin A and pancreatic polypeptide serum determinations of interest in diagnosis and follow-up of gastro-entero-pancreatic neuroendocrine tumors? Eur J Cancer 2012, 48(12):1766-1773.
44. Wang, YH, Yang, Q, Lin, Y, Ling, X, Chen, M, Chen, J: Chromogranin A as a marker for diagnosis, treatment and survival in patients with gastroenteropancratic neuroendocrine neoplasm. Medicine 2014, 93: e247.
45. Ferrari, L, Seregni, E, Lucignani, G, Bajetta, E, Martinetti, A et al: Accuracy and clinical correlates of two different methods for chromogranin assay in neuroendocrine tumours. Int J Biol Markers, 2004, 19(4):295-304.
46. Qiao, XW, Qiu, L, Chen, YJ, Meng, CT, Sun, Z, Bai, CM et al: Chromogranin A is a reliable serum diagnostic biomarker for pancreatic neuroendocrine tumors but not for insulinomas. BMC Endocrine Disorders 2014, 14:64
47. Hijioka, M, Ito, T, Igarashi, H, Fujimori, N, Lee, L et al: Serum chromogranin A is a useful marker of Japanese patients with pancreatic neuroendocrine tumors. Can Sci 2014, 105(11):1464-1471.
48. Nolting, S, Kuttner, A, Lauseker, M, M, Vogeser, M, Haug, A et al: Chromogranin A as serum marker for gastroenteropancreatic neuroendocrine tumors: A single center experience and literature review. Cancers, 2012, 4 (1):141-155.
49. Goto, Y, Silva, MG, Toscani, A, Prabhakaar, BS, Notkins, AL, Lam, MS: A novel human insulinoma-associated cDNA, IA-1 encodes a protein with ‘zink-finger’ DNA-binding motifs. J Biol Chem 1992, 267(21):15252-15257.
50. Gierl, MS, Karoulias, N, Wende, H, Strehle, M, Birchmeier, C: The zin-finger factor Insm 1 (IA-1) is essential for the development of pancreatic β cells and intestinal cells. Genes Develop 2006, 20(17):2465-2478.
51. Mukhopadhyay, S, Dermawan, J, Lanigan, C, Farver, CF: Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms : an immunohistochemical study of 345 cases, including 292 whole-tissue sections. Mod Pathol 2019, 32(1):100-109.
52. Maleki, Z, Nadella, A, Nadella, M, Patel, G, Patel, S et al: INSM1, a novel biomarker for detection of neuroendocrine neoplasms : Cytopathologists’ view. Diagnostics, 2021, 11(12):2172.
53. Juhlin, CC: Second generation neuroendocrine immunohistochemical markers: Reflection from clinical implementation. Biology 2021, 10(9):874.