小细胞肺癌（SCLC）分子亚型的临床特征和患者结局。
Clinical characteristics and patient outcomes of molecular subtypes of small cell lung cancer (SCLC).
机构信息
Department of Radiation Oncology, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China.
Graduate School, Ningxia Medical University, Yinchuan, 750004, Ningxia, China.
出版信息
World J Surg Oncol. 2022 Feb 27;20(1):54. doi: 10.1186/s12957-022-02528-y.
BACKGROUND
Recent studies have shown that according to the expression levels of achaete-scute homolog 1 (ASCL1), neurogenic differentiation factor 1 (NEUROD1), and POU class 2 homeobox 3 (POU2F3), small cell lung cancer (SCLC) can be divided into four subtypes: SCLC-A (ASCL1-dominant), SCLC-N (NEUROD1-dominant), SCLC-P (POU2F3-dominant), and SCLC-I (triple negative or SCLC-inflamed). However, there are limited data on the clinical characteristics and prognosis of molecular subtypes of SCLC.
METHODS
Immunohistochemistry (IHC) was used to detect the expression levels of ASCL1, NEUROD1, and POU2F3 in 53 patient samples of resectable SCLC. The subtype was defined by the differential expression of the transcription factors for ASCL1, NEUROD1, and POU2F3 or the low expression of all three factors with an inflamed gene signature (SCLC-A, SCLC-N, SCLC-P, and SCLC-I, respectively). The clinicopathological characteristics, immunological features (programmed death ligand 1 [PD-L1] expression and CD8+ tumor infiltrating lymphocyte [TIL] density), and patient outcomes of the four subtypes of SCLC were analyzed.
RESULTS
Positive ASCL1, NEUROD1, and POU2F3 staining was detected in 43 (79.2%), 27 (51.0%), and 17 (32.1%) SCLC specimens by IHC. According to the results of IHC analysis, SCLC was divided into four subtypes: SCLC-A (39.6%), SCLC-N (28.3%), SCLC-P (17.0%), and SCLC-I (15.1%). The 5-year overall survival (OS) rates of these four subtypes were 61.9%, 69.3%, 41.7%, and 85.7%, respectively (P=0.251). There were significant differences in smoking status among different subtypes of SCLC (P= 0.031). However, we did not confirm the correlation between subtypes of SCLC and other clinicopathological factors or immune profiles. Cox multivariate analysis showed that N stage (P=0.025), CD8+ TILs (P=0.024), Ki-67 level (P=0.040), and SCLC-P (P=0.023) were independent prognostic factors for resectable SCLC.
CONCLUSIONS
Our IHC-based study validated the proposed classification of SCLC using the expression patterns of key transcriptional regulatory factors. We found that SCLC-P was associated with smokers and was one of the poor prognostic factors of limited-stage SCLC. In addition, no correlation was found between PD-L1 expression or CD8+ TIL density and SCLC subtypes.
背景
最近的研究表明，根据 AchAte-Scute 同源物 1（ASCL1）、神经分化因子 1（NEUROD1）和 POU 类 2 同源框 3（POU2F3）的表达水平，小细胞肺癌（SCLC）可分为四个亚型：SCLC-A（ASCL1 占主导）、SCLC-N（NEUROD1 占主导）、SCLC-P（POU2F3 占主导）和 SCLC-I（三阴性或 SCLC 炎症型）。然而，关于 SCLC 分子亚型的临床特征和预后的数据有限。
方法
采用免疫组织化学（IHC）检测 53 例可切除 SCLC 患者样本中 ASCL1、NEUROD1 和 POU2F3 的表达水平。通过 ASCL1、NEUROD1 和 POU2F3 的转录因子差异表达或三个因子的低表达伴有炎症基因特征（分别为 SCLC-A、SCLC-N、SCLC-P 和 SCLC-I）来定义亚型。分析了四种 SCLC 亚型的临床病理特征、免疫特征（程序性死亡配体 1 [PD-L1]表达和 CD8+肿瘤浸润淋巴细胞 [TIL]密度）和患者结局。
结果
通过 IHC 检测到 43 例（79.2%）、27 例（51.0%）和 17 例（32.1%）SCLC 标本中存在阳性 ASCL1、NEUROD1 和 POU2F3 染色。根据 IHC 分析结果，SCLC 分为四个亚型：SCLC-A（39.6%）、SCLC-N（28.3%）、SCLC-P（17.0%）和 SCLC-I（15.1%）。这四种亚型的 5 年总生存率（OS）分别为 61.9%、69.3%、41.7%和 85.7%（P=0.251）。不同亚型的 SCLC 在吸烟状态方面存在显著差异（P=0.031）。然而，我们并未证实 SCLC 亚型与其他临床病理因素或免疫特征之间存在相关性。Cox 多因素分析显示，N 期（P=0.025）、CD8+TILs（P=0.024）、Ki-67 水平（P=0.040）和 SCLC-P（P=0.023）是可切除 SCLC 的独立预后因素。
结论
我们的基于 IHC 的研究使用关键转录调节因子的表达模式验证了 SCLC 的提出分类。我们发现 SCLC-P 与吸烟者有关，是局限期 SCLC 的不良预后因素之一。此外，PD-L1 表达或 CD8+TIL 密度与 SCLC 亚型之间没有相关性。
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