P53, Somatostatin receptor 2a and Chromogranin A immunostaining as prognostic markers in high grade gastroenteropancreatic neuroendocrine neoplasms

<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>High grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) with a Ki67 proliferation index > 20%, include well-differentiated tumours grade 3 (NET G3) and poorly differentiated (PD) neuroendocrine carcinomas (NEC). Abnormal p53-expression is a feature of PD tumours, while expression of chromogranin A (CgA) and somatostatin-receptor 2a (SSTR-2a) may be a feature of well-differentiated tumours. The aim of this study was to elucidate the expression and prognostic value of these three markers in 163 GEP-NEN patients with a Ki67-index > 20%.</jats:p> </jats:sec><jats:sec> <jats:title>Method</jats:title> <jats:p>Clinical data, histopathology and overall survival were analysed according to Kaplan-Meier’s method and Cox regression. The expression of SSTR-2a, CgA and synaptophysin was analysed in tumour specimens by immunohistochemistry, and semi-quantitatively scored as negative (< 5%), heterogeneously positive (5–30%) or strongly positive (> 30%). P53 was defined as normal when scored as heterogeneously positive (1–30%), and abnormal when negative (0%) or strongly positive (> 30%).</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>In multivariate analysis, better survival was observed among patients with heterogeneously positive p53 compared to strongly positive (<jats:italic>p</jats:italic> < 0.001). When dichotomised, tumours with a heterogeneously positive p53 vs. negative and strongly positive p53 also showed a significantly better survival (<jats:italic>p</jats:italic> = 0.002).</jats:p> <jats:p>Survival was significantly worse for negative CgA compared to heterogeneously positive CgA (<jats:italic>p</jats:italic> = 0.02). Strongly positive SSTR-2a expression was found in 26% of the 163 included patients. Well-differentiated morphology correlated with strong expression of SSTR-2a and CgA, and heterogeneously positive p53-staining, and was more frequent in pancreatic primaries. In pancreatic primaries, strongly positive SSTR-2a was associated with longer survival (univariate analysis, <jats:italic>p</jats:italic> = 0.02). A significantly lower Ki67 proliferation index was found in patients with a heterogeneously positive p53, a positive SSTR-2a and CgA expression.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusion</jats:title> <jats:p>Our results suggest that abnormal p53-expression is an independent negative prognostic marker in GEP-NEN with a Ki67-index > 20%. Patients with heterogeneously positive p53 had the best prognosis. SSTR-2a was a positive prognostic marker in pancreatic NEN. Negative CgA was associated with a significantly worse OS compared to heterogeneously positive CgA-expression in a multivariate sub-analysis. Lower Ki67 index correlated significantly with heterogeneously positive p53, positive SSTR-2a and CgA expression.</jats:p> </jats:sec>