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-A) and 77 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.

中文翻译：

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55% 的 Ki-67 指数区分两组具有不同预后的支气管肺纯和复合大细胞神经内分泌癌。

背景 关于支气管肺大细胞神经内分泌癌 (BP-LCNEC) 预后因素的信息很少，对联合 LCNEC (Co-LCNEC) 的了解甚至更少。我们研究了综合形态学、免疫组织化学和分子方法是否可用于其预后评估。方法 形态学（包括组合特征）、增殖（有丝分裂计数/Ki-67 指数）、免疫组织化学（napsin A、p40、TTF-1、CD44、OTP、SSTR2A、SSTR5、mASH1、p53、RB1 和 MDM2）和基因组（TP53、RB1、ATM、JAK2、KRAS 和 STK11）结果在来自 5 个意大利中心的 BP-LCNEC 中进行分析，并与总生存率 (OS) 相关。Ki-67 指数表示为热点中阳性细胞的百分比，如 WHO 2019 消化系统肿瘤所示，对于 Co-LCNEC，Ki-67 指数仅在 LCNEC 组件中进行评估。结果 总共 111 个 LCNECs 被区分为 70 个纯 LCNECs、35 个 Co-LCNECs（27 个有腺癌 [ADC] 和 8 个有鳞状细胞癌 [SqCC]）和 6 个只有 Napsin A 免疫反应性的 LCNECs。在所有 LCNEC 中，在神经内分泌组件中评估的 55% 的 Ki-67 指数截止值是 OS 的最强大预测因子（对数秩 p = 0.0001）；34 例 Ki-67 指数 <55% (LCNEC-A)，77 例 Ki-67 指数≥55% (LCNEC-B)。在纯和 Co-LCNEC 之间也观察到 OS 的统计学显着差异（对数秩 p = 0.0001）。在纯 LCNECs-A 和 Co-LCNECs-A 之间发现 OS 的显着差异（p < 0.05），但在纯 LCNECs-B 和 Co-LCNECs-B 之间没有发现显着差异。Co-LCNEC-ADC 和 LCNEC napsin A+ 病例的 OS 比纯 LCNEC 和 Co-LCNEC-SqCC 病例长（对数秩 p = 0.0001）。在多变量分析中，在调整 Ki-67 指数和研究中心后，肿瘤位置、纯特征与组合特征、napsin A（但无单基因突变）与 OS 显着相关（p < 0.05）。结论 在 LCNECs 中 Ki-67 增殖指数和组合特征的形态学特征似乎是预测 BP-LCNECs 临床结果的重要工具。