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...
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doaj-c384757899ea4148bfbfb4d4284db0732021-01-10T13:00:10ZengBMCBMC Cancer1471-24072020-01-0120111410.1186/s12885-019-6498-zP53, Somatostatin receptor 2a and Chromogranin A immunostaining as prognostic markers in high grade gastroenteropancreatic neuroendocrine neoplasmsKirstine Nielsen0Tina Binderup1Seppo W. Langer2Andreas Kjaer3Pauline Knigge4Veronica Grøndahl5Linea Melchior6Birgitte Federspiel7Ulrich Knigge8Department of Surgical Gastroenterology C, Copenhagen University Hospital, RigshospitaletENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, RigshospitaletENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, RigshospitaletENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, RigshospitaletDepartment of Clinical Endocrinology, Copenhagen University Hospital, RigshospitaletDepartment of Surgical Gastroenterology C, Copenhagen University Hospital, RigshospitaletENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, RigshospitaletENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, RigshospitaletDepartment of Surgical Gastroenterology C, Copenhagen University Hospital, RigshospitaletAbstract 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 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%. 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. Conclusion 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.https://doi.org/10.1186/s12885-019-6498-zGastroenteropancreatic neuroendocrine neoplasmsp53Somatostatin receptor 2aChromogranin ANeuroendocrine carcinomasNEC |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kirstine Nielsen Tina Binderup Seppo W. Langer Andreas Kjaer Pauline Knigge Veronica Grøndahl Linea Melchior Birgitte Federspiel Ulrich Knigge |
spellingShingle |
Kirstine Nielsen Tina Binderup Seppo W. Langer Andreas Kjaer Pauline Knigge Veronica Grøndahl Linea Melchior Birgitte Federspiel Ulrich Knigge P53, Somatostatin receptor 2a and Chromogranin A immunostaining as prognostic markers in high grade gastroenteropancreatic neuroendocrine neoplasms BMC Cancer Gastroenteropancreatic neuroendocrine neoplasms p53 Somatostatin receptor 2a Chromogranin A Neuroendocrine carcinomas NEC |
author_facet |
Kirstine Nielsen Tina Binderup Seppo W. Langer Andreas Kjaer Pauline Knigge Veronica Grøndahl Linea Melchior Birgitte Federspiel Ulrich Knigge |
author_sort |
Kirstine Nielsen |
title |
P53, Somatostatin receptor 2a and Chromogranin A immunostaining as prognostic markers in high grade gastroenteropancreatic neuroendocrine neoplasms |
title_short |
P53, Somatostatin receptor 2a and Chromogranin A immunostaining as prognostic markers in high grade gastroenteropancreatic neuroendocrine neoplasms |
title_full |
P53, Somatostatin receptor 2a and Chromogranin A immunostaining as prognostic markers in high grade gastroenteropancreatic neuroendocrine neoplasms |
title_fullStr |
P53, Somatostatin receptor 2a and Chromogranin A immunostaining as prognostic markers in high grade gastroenteropancreatic neuroendocrine neoplasms |
title_full_unstemmed |
P53, Somatostatin receptor 2a and Chromogranin A immunostaining as prognostic markers in high grade gastroenteropancreatic neuroendocrine neoplasms |
title_sort |
p53, somatostatin receptor 2a and chromogranin a immunostaining as prognostic markers in high grade gastroenteropancreatic neuroendocrine neoplasms |
publisher |
BMC |
series |
BMC Cancer |
issn |
1471-2407 |
publishDate |
2020-01-01 |
description |
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 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%. 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. Conclusion 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. |
topic |
Gastroenteropancreatic neuroendocrine neoplasms p53 Somatostatin receptor 2a Chromogranin A Neuroendocrine carcinomas NEC |
url |
https://doi.org/10.1186/s12885-019-6498-z |
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