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.

中文翻译：

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P53，生长抑素受体2a和嗜铬粒蛋白A免疫染色可作为高级胃肠道胰腺神经内分泌肿瘤的预后标志物。

背景技术Ki67增殖指数> 20％的高级胃肠道胰腺（GEP）神经内分泌肿瘤（NEN）包括3级高分化肿瘤（NET G3）和低分化（PD）神经内分泌癌（NEC）。p53表达异常是PD肿瘤的特征，而嗜铬粒蛋白A（CgA）和生长抑素受体2a（SSTR-2a）的表达可能是分化良好的肿瘤的特征。这项研究的目的是阐明这三种标记物在163个Ki67指数> 20％的GEP-NEN患者中的表达和预后价值。方法根据Kaplan-Meier法和Cox回归分析临床资料，组织病理学和总生存期。通过免疫组织化学分析肿瘤标本中SSTR-2a，CgA和突触素的表达，并半定量记为阴性（< 5％），异类阳性（5-30％）或强阳性（> 30％）。P53被定义为异类阳性（1-30％）时为正常，而阴性（0％）或强阳性（> 30％）时为异常。结果在多变量分析中，p53异质阳性的患者比强阳性的患者生存率更高（p <0.001）。二等分时，p53异质性阳性与p53阴性和强烈阳性的肿瘤也显示出明显更好的生存率（p = 0.002）。与异质阳性CgA相比，阴性CgA的生存期明显更差（p = 0.02）。在163名患者中，有26％发现了SSTR-2a的强阳性表达。分化良好的形态与SSTR-2a和CgA的强表达以及p53染色呈异质阳性相关，并且在胰腺原发中更为常见。在胰腺原发中，强阳性的SSTR-2a与更长的生存期相关（单因素分析，p = 0.02）。发现p53，SSTR-2a和CgA表达异质的患者Ki67增殖指数明显降低。结论我们的结果表明，p53异常表达是GEP-NEN中一个独立的阴性预后指标，Ki67指数> 20％。p53异种阳性的患者预后最好。SSTR-2a是胰腺NEN的阳性预后指标。在多变量亚分析中，与异质阳性CgA表达相比，CgA阴性与OS差得多。较低的Ki67指数与异质性p53，SSTR-2a和CgA阳性表达显着相关。