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

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.