PMID- 31924180 OWN - NLM STAT- MEDLINE DCOM- 20200610 LR - 20200610 IS - 1471-2407 (Electronic) IS - 1471-2407 (Linking) VI - 20 IP - 1 DP - 2020 Jan 10 TI - P53, Somatostatin receptor 2a and Chromogranin A immunostaining as prognostic markers in high grade gastroenteropancreatic neuroendocrine neoplasms. PG - 27 LID - 10.1186/s12885-019-6498-z [doi] LID - 27 AB - 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. FAU - Nielsen, Kirstine AU - Nielsen K AD - Department of Surgical Gastroenterology C, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. AD - Department of Clinical Endocrinology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. AD - ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. FAU - Binderup, Tina AU - Binderup T AUID- ORCID: 0000-0001-7898-4546 AD - ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. fxw866@ku.dk. AD - Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Department of Biomedical Sciences, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark. fxw866@ku.dk. FAU - Langer, Seppo W AU - Langer SW AD - ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. AD - Department of Oncology,, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. FAU - Kjaer, Andreas AU - Kjaer A AD - ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. AD - Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Department of Biomedical Sciences, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark. FAU - Knigge, Pauline AU - Knigge P AD - Department of Clinical Endocrinology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. AD - ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. AD - Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Department of Biomedical Sciences, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark. FAU - Grondahl, Veronica AU - Grondahl V AD - Department of Surgical Gastroenterology C, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. AD - Department of Clinical Endocrinology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. AD - ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. FAU - Melchior, Linea AU - Melchior L AD - ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. AD - Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. FAU - Federspiel, Birgitte AU - Federspiel B AD - ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. AD - Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. FAU - Knigge, Ulrich AU - Knigge U AD - Department of Surgical Gastroenterology C, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. AD - Department of Clinical Endocrinology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. AD - ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. LA - eng PT - Journal Article DEP - 20200110 PL - England TA - BMC Cancer JT - BMC cancer JID - 100967800 RN - 0 (Biomarkers, Tumor) RN - 0 (Chromogranin A) RN - 0 (Receptors, Somatostatin) RN - 0 (Tumor Suppressor Protein p53) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Biomarkers, Tumor MH - Carcinoma, Neuroendocrine/*diagnosis/etiology/*metabolism/mortality MH - Cell Line, Tumor MH - Chromogranin A/*metabolism MH - Female MH - Follow-Up Studies MH - Gastrointestinal Neoplasms/*diagnosis/etiology/*metabolism/mortality MH - Humans MH - Immunohistochemistry MH - Male MH - Middle Aged MH - Neoplasm Grading MH - Pancreatic Neoplasms/*diagnosis/etiology/*metabolism/mortality MH - Prognosis MH - Proportional Hazards Models MH - Receptors, Somatostatin/*metabolism MH - Tumor Suppressor Protein p53/metabolism MH - Young Adult PMC - PMC6953213 OTO - NOTNLM OT - Chromogranin A OT - Gastroenteropancreatic neuroendocrine neoplasms OT - NEC OT - NET G3 OT - Neuroendocrine carcinomas OT - Prognostication OT - Somatostatin receptor 2a OT - Survival OT - p53 COIS- The authors declare that they have no competing interests. EDAT- 2020/01/12 06:00 MHDA- 2020/06/11 06:00 PMCR- 2020/01/10 CRDT- 2020/01/12 06:00 PHST- 2019/06/21 00:00 [received] PHST- 2019/12/23 00:00 [accepted] PHST- 2020/01/12 06:00 [entrez] PHST- 2020/01/12 06:00 [pubmed] PHST- 2020/06/11 06:00 [medline] PHST- 2020/01/10 00:00 [pmc-release] AID - 10.1186/s12885-019-6498-z [pii] AID - 6498 [pii] AID - 10.1186/s12885-019-6498-z [doi] PST - epublish SO - BMC Cancer. 2020 Jan 10;20(1):27. doi: 10.1186/s12885-019-6498-z.