IMMUNOHISTOCHEMICAL DETERMINATION OF EXPRESSION OF SOMATOSTATIN RECEPTORS TYPES 1, 2A, 3 AND 5 IN NEUROENDOCRINE TUMORS OF VARIOUS LOCALIZATION AND GRADE

Cover Page

Cite item

Abstract

Background: Prediction of clinical benefits of somatostatin analogues in patients with neuroendocrine tumors (NET) is very important prior to their administration. Data on immunohistochemical assessment of the expression of somatostatin receptors (SSR) of various types, obtained from large samples of NET with various localization, functional activity and degree of malignancy, are scarce; therefore, the study was aimed at assessment of the latter.

Materials and methods: We performed an immunohistochemical study with antibodies to SSR1, 2A, 3 and 5  types on tissue samples obtained during diagnostic and intra-operative biopsies from 399 NETs: 168 from pancreas, 120 from gastrointestinal tract (stomach, 48, from small intestine, 39, 14 of which being from duodenum; appendix, 6, colon and the rectum, 15 and 12, respectively), 84 from lung, 6 from thymus/mediastinum, and 21 from NET metastases of unknown primary localization.

Results: Very high levels expression of receptors SSR2A preferentially binding to somatostatin analogues, which are currently used in clinical practice, were detected in the small intestine NETs (22/25, 88%), appendix (5/6, 83.3%), colon (10/15, 66.7%), thymus (4/6, 66.7%), atypical carcinoids of the lung (10/15, 66.7%), stomach (27/41, 65.8%) and pancreas (105/165, 63.6%). The lowest expression was found in rectal NETs (5/12, 41.7%) and small and large cell neuroendocrine lung carcinomas (20, 11.1%). Among functioning NETs, the highest level of SSR2A was found in gastrinomas (18/19, 94.7%), glucagonomas (15/16, 93.8%), small intestine carcinoids (31/35, 88.6%), and somatostatinomas (2/3, 66.7%). The lowest expression was detected in ACTH secreting tumors with Cushing's syndrome (11/12, 50%), and in insulinomas (34/69, 49.3%). SSR2A expression in functionally inactive pancreatic NETs was significantly higher than in insulinomas (57/82, 34/69 vs 69.5 and 49.3%, respectively). SSR2A expression was associated with the degree of malignancy and is higher in pancreatic NET Grade 2A (Ki67 to 10%), Grade 2B (Ki67 10–19%) and in neuroendocrine carcinomas Grade  3, compared to Grade  1 (16/50 (32%), 37/61 (60.6%), 8/12 (66.7%) and 20/24 (83.3%), respectively). Overexpression of SSR5, which is the second clinically significant receptor, was observed in NETs of the duodenum (7/10, 70%) and appendix (2/5, 60%), and among functionally active NETs in glucagonomas and gastrinomas (12/15, 80%). SSR3 are less common, than SSR2A and 5, and are found most often in the gastric NETs (6/11, 54.5%), insulinomas (16/37, 43.2%), neuroendocrine carcinomas of pancreas Grade  3 (4/9, 44.7%), and typical lung carcinoids (7/16, 41.2%). SSR1 in all tumors are rare, the maximum level of expression was observed in small intestine carcinoids (9/21, 42.9%).

Conclusion: Depending on their localization and grade  of malignancy, neuroendocrine tumors differ in expression of various SSR types. Therefore, determination of the receptor profile of each tumor is necessary before administration of somatostatin analogues.

About the authors

L. E. Gurevich

Moscow Regional Research and Clinical Institute (MONIKI)

Author for correspondence.
Email: larisgur@mail.ru

ScD in Biology, Professor, Leading Research Fellow, Department of Pathological Anatomy,

61/2 Shchepkina ul., Moscow, 129110

Russian Federation

N. A. Korsakova

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

MD, PhD, Senior Research Fellow, Department of Pathological Anatomy,

61/2 Shchepkina ul., Moscow, 129110

Russian Federation

I. A. Voronkova

Endocrinology Research Center

Email: fake@neicon.ru

MD, PhD, Physician, Laboratory of Pathomorphology,

11 Dmitriya Ul'yanova ul., Moscow, 117036

Russian Federation

V. E. Ashevskaya 

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

MD, Research Fellow, Department of Pathological Anatomy,

61/2 Shchepkina ul., Moscow, 129110

Russian Federation

A. G. Titov

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

MD, PhD, Leading Research Fellow, Department of Thoracic Surgery,

61/2 Shchepkina ul., Moscow, 129110

Russian Federation

L. M. Kogoniya

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

MD, PhD, Professor of Chair of Oncology and Thoracic Surgery, Postgraduate Training Faculty,

61/2 Shchepkina ul., Moscow, 129110

Russian Federation

A. V. Egorov

I.M. Sechenov First Moscow State Medical University

Email: fake@neicon.ru

MD, PhD, Professor, Head of the Department of Surgical Oncology,

8/2 Trubetskaya ul., Moscow, 119991

Russian Federation

T. A. Britvin

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

MD, PhD, Head of the Department of Endocrine Surgery,

61/2 Shchepkina ul., Moscow, 129110

Russian Federation

I. A. Vasil'ev

I.M. Sechenov First Moscow State Medical University

Email: fake@neicon.ru

MD, PhD, Surgeon, Department of Surgery,

8/2 Trubetskaya ul., Moscow, 119991

Russian Federation

References

  1. Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science. 1973;179(4077):1011–4. doi: 10.1126/science.179.4077.1011.
  2. Reubi JC, Kappeler A, Waser B, Laissue JR, Hipkin W, Schonbrunn A. Immunohistochemical localization of somatostatin receptors sst2A in human tumors. Am J Pathol. 1998;153(1):233–45. doi: 10.1016/S0002-9440(10)65564-2.
  3. Susini C, Buscail L. Rationale for the use of somatostatin analogs as antitumor agents. Ann Oncol. 2006;17(12):1733–42. doi: 10.1093/annonc/mdl105.
  4. Guillermet-Guibert J, Lahlou H, Pyronnet S, Bousquet C, Susini C. Somatostatin receptors as tools for diagnosis and therapy: Molecular aspects. Best Pract Res Clin Gastroenterol. 2005;19(4):535–51. doi: 10.1016/j.bpg.2005.03.007.
  5. Strosberg J, Kvols L. Antiproliferative effect of somatostatin analogs in gastroenteropancreatic neuroendocrine tumors. World J Gastroenterol. 2010;16(24):2963–70. doi: 10.3748/WJG.v16.i24.2963.
  6. Gugger M, Waser B, Kappeler A, Schonbrunn A, Reubi JC. Cellular detection of sst2A receptors in human gastrointestinal tissue. Gut. 2004;53(10):1431–6. doi: 10.1136/gut.2004.042002.
  7. Fischer T, Doll C, Jacobs S, Kolodziej A, Stumm R, Schulz S. Reassessment of sst2 somatostatin receptor expression in human normal and neoplastic tissues using the novel rabbit monoclonal antibody UMB-1. J Clin Endocrinol Metab. 2008;93(11):4519–24. doi: 10.1210/jc.2008-1063.
  8. Öberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewsk P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004;15(6):966–73. doi: 10.1093/annonc/mdh216.
  9. Горбунова ВА, Орел НФ, Кузьминов АЕ. Современные направления лечения нейроэндокринных опухолей. Современная онкология. 2010;(1):30–5.
  10. Гуревич ЛЕ, Пантелеева ЕИ, Корсакова НА, Казанцева ИА, Егоров АВ, Бритвин ТА, Васильев ИА, Устинова ЕИ. Экспрессия рецепторов к соматостатину 1, 2, 3 и 5 типов в нейроэндокринных опухолях поджелудочной железы. Практическая медицина. 2012;(9):117–9.
  11. Дедов ИИ, Марова ЕИ, Абросимов АЮ, Лапшина АМ, Григорьев АЮ, Аблицов ЮА, Кузнецов НС, Гончаров НП, Арапова СД, Рожинская ЛЯ. Экспрессия рецепторов соматостатина и дофамина в АКТГ-продуцирующих опухолях. Проблемы эндокринологии. 2010;56(1):14–8.
  12. Егоров АВ, Кондрашин СА, Фоминых ЕВ, Мусаев ГХ, Гитель ЕП, Гуревич ЛЕ, Парнова ВА, Васильев ИА, Рабинович ЭЗ, Волков РЮ. Аналоги соматостатина в диагностике и лечении нейроэндокринных опухолей. Анналы хирургической гепатологии. 2009;14(4): 71–8.
  13. Volante M, Brizzi MP, Faggiano A, La Rosa S, Rapa I, Ferrero A, Mansueto G, Righi L, Garancini S, Capella C, De Rosa G, Dogliotti L, Colao A, Papotti M. Somatostatin receptor type 2A immunohistochemistry in neuroendocrine tumors: a proposal of scoring system correlated with somatostatin receptor scintigraphy. Mod Pathol. 2007;20(11):1172–82. doi: 10.1038/modpathol.3800954.
  14. Zamora V, Cabanne A, Salanova R, Bestani C, Domenichini E, Marmissolle F, Giacomi N, O'Connor J, Mendez G, Roca E. Immunohistochemical expression of somatostatin receptors in digestive endocrine tumours. Dig Liver Dis. 2010;24(3):220–5. doi: 10.1016/j.dld.2009.07.018.
  15. Bertherat J, Tenenbaum F, Perlemoine K, Videau C, Albertini JL, Richard B, Dousset B, Bertagna AX, Epelbaum J. Somatostatin Receptos 2 and 5 A are the major somatostatin receptors in insulinomas: an in vivo and in vitro study. J Clin Endocrinol Metab. 2003;88(11):5353–60. doi: 10.1210/jc.2002-021895.
  16. Papotti M, Bongiovanni M, Volante M, Allìa E, Landolfi S, Helboe L, Schindler M, Cole SL, Bussolati G. Expression of somatostatin receptor types 1–5 in 81 cases of gastrointestinal and pancreatic endocrine tumors. A correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis. Virchows Arch. 2002;440(5):461–75. doi: 10.1007/s00428-002-0609-x.
  17. De Sa SV, Correa-Giannella ML, Machado MC, de Souza JJ, Pereira MA, Patzina RA, Siqueira SA, Machado MC, Giannella-Neto D. Somatostatin receptor subtype 5 (SSTR5) mRNA expression is related to histopathological features of cell proliferation in insulinomas. Endocr Relat Cancer. 2006;13(1):69–78. doi: 10.1677/erc.1.00962.
  18. O'Toole D, Saveanu A, Couvelard A, Gunz G, Enjalbert A, Jaquet P, Ruszniewski P, Barlier A. The analysis of quantitative expression of somatostatin and dopamine receptors in gastro-entero-pancreatic tumours opens new therapeutic strategies. Eur J Endocrinol. 2006;(6):849–57. doi: 10.1530/eje.1.02307.
  19. Schmid HA, Lambertini C, van Vugt HH, Barzaghi-Rinaudo P, Schäfer J, Hillenbrand R, Sailer AW, Kaufmann M, Nuciforo P. Monoclonal antibodies against the human somatostatin receptor subtypes 1–5: development and immunohistochemical application in neuroendocrine tumors. Neuroendocrinology. 2012;95(3):232–47. doi: 10.1159/000330616.
  20. Kanakis G, Grimelius L, Spathis A, Tringidou R, Rassidakis GZ, Oberg K, Kaltass G, Tsolakis AV. Expression of somatostatin receptors 1–5 and dopamine receptor 2 in lung carcinoids: implication for a therapeutic role. Neuroendocrinology. 2015;101(3):211–22. doi: 10.1159/000381061.
  21. Righi L, Volante M, Tavaglione V, Billè A, Daniele L, Angusti T, Inzani F, Pelosi G, Rindi G, Papotti M. Somatostatin receptor tissue distrution in lung neuroendocrine tumors: a clinicopathologic and immunohistochemical study of 218 'clinically aggressive' cases. Ann Oncol. 2010;21(3):548–55. doi: 10.1093/annonc/mdp334.
  22. Kaemmerer D, Specht E, Sanger J, Witz RM, Sayeg M, Schulz S, Lupp A. Somatostatin receptors in bronchpulmonary neuroendocrine neoplasms: new diagnostic, prognostic, and therapeutic markers. J Clin Endocrinol Metab. 2015;100(3):831–40. doi: 10.1210/jc.2014-2699.
  23. Tsuta K, Wistuba II, Moran CA. Differential expression of somatostatin receptors 1–5 in neuroendocrine carcinoma of the lung. Pathol Res Pract. 2012;208(8):470–4. doi: 10.1016/j.prp.2012.05.014.
  24. Hofland LJ, Liu Q, Van Koetsveld PM, Zuijderwijk J, Van der Ham F, De Krijger RR, Schonbrunn A, Lamberts SW. Immunohistochemical detection of somatostatin receptor subtypes sst1 and sst2A in human somatostatin receptor positive tumors. J Clin Endocrinol Metab. 1999;84(2):775–80. doi: 10.1210/jcem.84.2.5497.
  25. Kulaksiz H, Eissele R, Rössler D, Schulz S, Höllt V, Cetin Y, Arnold R. Identification of somatostatin receptor subtypes 1, 2A, 3,and 5 in neuroendocrine tumours with subtype specific antibodies. Gut. 2002;50(1):52–60. doi: 10.1136/gut.50.1.52.
  26. Janson ET, Stridsberg M, Gobl A, Westlin JE, Oberg K. Determination of somatostatin receptor subtype 2 in carcinoid tumors by immunohistochemical investigation with somatostatin receptor subtype 2 antibodies. Cancer Res. 1998;58(11):2375–8.
  27. Korner M, Waser B, Schonbrunn A, Perren A, Reubi JC. Somatostatin receptor subtype 2A immunohistochemistry using a new monoclonal antibody selects tumors suitable for in vivo somatostatin receptor targeting. Am J Surg Pathol. 2012;36(2):242–52. doi: 10.1097/PAS.0b013e31823d07f3.
  28. Reubi JC, Waser B, Cescato R, Gloor B, Stettler C, Chest E. Internalized somatostatin receptor subtype 2 in neuroendocrine tumors of octreotide-treated patients. J Clin Endocrinol Metab. 2010;95(5):2343–50. doi: 10.1210/jc.2009-2487.
  29. Ferone D, Saveanu A, Culler MD, Arvigo M, Rebora A, Gatto F, Minuto F, Jaquet P. Novel chimeric somatostatin analogs: facts and perspectives. Eur J Endocrinol. 2007;156 Suppl 1:S23–8. doi: 10.1530/eje.1.02356.
  30. Hofland LJ, van der Hoek J, Feelders R, van Aken MO, van Koetsveld PM, Waaijers M, Sprij-Mooij D, Bruns C, Weckbecker G, de Herder WW, Beckers A, Lamberts SW. The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5. Eur J Endocrinol. 2005;152(4):645–54. doi: 10.1530/eje.1.01876.
  31. Ono K, Suzuki T, Miki Y, Taniyama Y, Nakamura Y, Noda Y, Watanabe M, Sasano H. Somatostatin receptor subtypes in human non-functioning neuroendocrine tumors and effects of somatostatin analogue SOM230 on cell proliferation in cell line NCI-H727. Anticancer Res. 2007;27(4B):2231–9.
  32. Modlin IM, Pavel M, Kidd M, Gustafsson BI. Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther. 2010;31(2):169–88. doi: 10.1111/j.1365-2036.2009.04174.x.
  33. Mundschenk J, Unger N, Schulz S, Hollt V, Schulz S, Steinke R, Lehnert H. Somatostatin receptor subtypes in human pheochromocytoma: subcellular expression pattern and functional relevance for octreotide scintigraphy. J Clin Endocrinol Metab. 2003;88(11):5150–7. doi: 10.1210/jc.2003-030262.

Supplementary files

There are no supplementary files to display.


Copyright (c) 2016 Gurevich L.E., Korsakova N.A., Voronkova I.A., Ashevskaya  V.E., Titov A.G., Kogoniya L.M., Egorov A.V., Britvin T.A., Vasil'ev I.A.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies