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

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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

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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.

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