Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis
Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis
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DOI：
10.1159/000508376
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发表时间：
2021-05-01
影响因子：
4.1
通讯作者：
Capella, Carlo
中科院分区：
文献类型：
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作者：
Milione, Massimo;Maisonneuve, Patrick;Capella, Carlo
背景资料：关于支气管肺大细胞神经内分泌癌（BP-LCNECs）的预后因素的信息很少，关于联合LCNECs（Co-LCNECs）的信息更少。我们研究了是否可以使用一个综合的形态学，免疫组化和分子方法来评估其预后。研究方法：对来自5个意大利中心的BP-LCNEC的形态学（包括联合特征）、增殖性（有丝分裂计数/Ki-67指数）、免疫组织化学（napsin A、p40、TTF-1、CD 44、OTP、SSTR 2A、SSTR 5、mASH 1、p53、RB 1和MDM 2）和基因组（TP 53、RB 1、ATM、JAK 2、KRAS和STK 11）结果进行了分析，并与总生存期（OS）相关。Ki-67指数表示为WHO 2019消化系统肿瘤中指示的热点中阳性细胞的百分比，对于Co-LCNEC，仅在LCNEC组分中评价Ki-67指数。结果如下：共111个LCNEC被区分为70个纯LCNEC、35个Co-LCNEC（27个腺癌[ADC]和8个鳞状细胞癌[SqCC]）和6个仅具有napsin A免疫反应性的LCNEC。在所有LCNEC中，神经内分泌成分中评估的Ki-67指数临界值为55%是OS的最有力预测因子（对数秩p = 0.0001）; 34例病例的Ki-67指数= 55%（LCNEC-B）。在纯LCNEC和Co-LCNEC之间也观察到OS的统计学显著差异（对数秩p = 0.0001）。在纯LCNECs-A和Co-LCNECs-A之间发现OS的显著差异（p < 0.05），但在纯LCNECs-B和Co-LCNECs-B之间没有。Co-LCNEC-ADC和LCNEC napsin A+病例的OS长于纯LCNEC和Co-LCNEC-SqCC病例（对数秩p = 0.0001）。在多变量分析中，校正Ki-67指数和研究中心后，肿瘤位置、单纯与联合特征和napsin A（但无单基因突变）与OS显著相关（p < 0.05）。结论：Ki-67增殖指数和LCNECs联合特征的形态学特征似乎是预测BP-LCNECs临床结局的重要工具。
Background: Little information is available concerning prognostic factors for bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical, and molecular approach could be used for their prognostic evaluation. Methods: Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, and MDM2), and genomic (TP53, RB1, ATM, JAK2, KRAS, and STK11) findings were analyzed in BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). The Ki-67 index was expressed as the percentage of positive cells in hot spots as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNECs, the Ki-67 index was evaluated only in the LCNEC component. Results: A total of 111 LCNECs were distinguished into 70 pure LCNECs, 35 Co-LCNECs (27 with adenocarcinoma [ADC] and 8 with squamous cell carcinoma [SqCC]), and 6 LCNECs with only napsin A immunoreactivity. The Ki-67 index cutoff at 55% evaluated in the neuroendocrine component was the most powerful predictor of OS (log-rank p = 0.0001) in all LCNECs; 34 cases had a Ki-67 index = 55% (LCNEC-B). Statistically significant differences in OS (log-rank p = 0.0001) were also observed between pure and Co-LCNECs. A significant difference in OS was found between pure LCNECs-A and Co-LCNECs-A (p < 0.05) but not between pure LCNECs-B and Co-LCNECs-B. Co-LCNEC-ADC and LCNEC napsin A+ cases had longer OS than pure LCNEC and Co-LCNEC-SqCC cases (log-rank p = 0.0001). On multivariable analysis, tumor location, pure versus combined features, and napsin A, but no single gene mutation, were significantly associated with OS after adjustment for Ki-67 index and study center (p < 0.05). Conclusions: The Ki-67 proliferation index and the morphological characterization of combined features in LCNECs seem to be important tools for predicting clinical outcome in BP-LCNECs.