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

Abstract

Background: 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 somatostatinreceptor 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%. Method: 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%). Results: In multivariate analysis, better survival was observed among patients with heterogeneously positive p53 compared to strongly positive (p < 0.001). When dichotomised, tumours with a heterogeneously positive p53 vs. negative and strongly positive p53 also showed a significantly better survival (p = 0.002). Survival was significantly worse for negative CgA compared to heterogeneously positive CgA (p = 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, p = 0.02). A significantly lower Ki67 proliferation index was found in patients with a heterogeneously positive p53, a positive SSTR-2a and CgA expression.

64Cu-DOTATATE PET/CT and Prediction of Overall and Progression-Free Survival in Patients with Neuroendocrine Neoplasms

“…In well differentiated tumors, the density of SSTR may be greater compared to poorly differentiated NEN, and SSTR density has been associated with survival (25,31,32). However, a large dataset from 163 patients with NEN Ki-67 > 20%, shows that strong SSTR2a expression is present in a great proportion of patients, especially in pancreatic NEC and SSTR2a density was not prognostic (33). Hence, the notion that SSTR is a trait restricted to low grade NET, and thus an indicator of differentiation, may not hold true.…”

Versatile Functions of Somatostatin and Somatostatin Receptors in the Gastrointestinal System

“…SSTR expression is a biomarker of NEN biology and immunohistochemical staining SST, while SSTR and CGA are candidates for prognostic information and risk-stratification in clinic. SSTR2a was a positive prognostic marker for pancreatic NEN (79,85). Monitoring of treatment of SST analogues and changedcirculating CGA levels can predict disease recurrence, outcome, and efficacy (29).…”

Molecular drivers and cells of origin in pancreatic ductal adenocarcinoma and pancreatic neuroendocrine carcinoma

“…In PanNET, chromogranin A (CgA) and Synaptophysin (Syn) are the most sensitive biomarkers, and staining is generally found to be diffuse and strong; however, CgA and Syn are less sensitive in the diagnosis of PanNEC compared with PanNETs [67]. Well-differentiated morphology and lower Ki67 proliferation index were found to be correlated with the strong expression of SSTR2A and CgA, and highly positive SSTR2A was associated with longer survival in PanNETs [68]. There is overlap in serum biomarkers between PanNEC and PDAC.…”