Diagnostic value of SSTR2A, ATRX, and clusterin immunohistochemical expression in high-grade gastroenteropancreatic neuroendocrine neoplasms.

High-grade gastroenteropancreatic neuroendocrine neoplasms (NENs) are a heterogeneous group of rare tumors, classified into well-differentiated neuroendocrine tumors grade 3 (G3 NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Distinguishing G3 NETs from NECs is challenging. We aimed to summarize the clinicopathologic characteristics of G3 NETs; examine the expression of somatostatin receptor 2A (SSTR2A), clusterin, and ATRX in G3 NETs and NECs; and explore the diagnostic and prognostic value of combining these markers for the differential diagnosis of G3 NETs. Data on 87 patients with high-grade NENs (G3 NETs: 18, NECs: 69) were retrospectively collected and classified according to the 5th edition of the WHO Classification of Digestive System Tumors. Immunohistochemistry was performed for SSTR2A, ATRX, and clusterin. Relationships between protein expression and clinicopathological features were analyzed. The diagnostic significance of combining these markers was assessed using receiver operating characteristic curves. SSTR2A protein expression, loss of ATRX expression, and positivity rate for clusterin were significantly higher in G3 NETs than in NECs [77.8 % (14/18) vs. 42.0 % (29/69), 61.1 % (11/18) vs. 33.3 % (23/69), and 77.8 % (14/18) vs. 30.4 % (21/69), respectively]. ATRX expression loss was significantly more common in large-cell than small-cell NECs. In differentiating G3 NETs from NECs, the area under the curve of the combined diagnosis using SSTR2A, clusterin, and ATRX was significantly higher than the individual values (0.833 vs. 0.679, 0.737, and 0.639, respectively). Combining SSTR2A, clusterin, and ATRX improves diagnostic accuracy. Our immunohistochemical assessment provides diagnostic insights for distinguishing G3 NETs from NECs.