Alì Greta, Di Stefano Iosè, Poma Anello Marcello, Ricci Stefano, Proietti Agnese, Davini Federico, Lucchi Marco, Melfi Franca, Fontanini Gabriella
Unit of Pathological Anatomy, University Hospital of Pisa, Pisa, Italy.
Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy.
Front Oncol. 2021 Sep 9;11:729765. doi: 10.3389/fonc.2021.729765. eCollection 2021.
Delta-like protein 3 (DLL3) is a protein of the Notch pathway, and it is a potential therapeutic target for high-grade lung neuroendocrine tumors (NETs), i.e., small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC). However, DLL3 prevalence in lung NETs and its association with clinicopathological characteristics and prognosis remained unclear. We analyzed the immunohistochemical expression of DLL3 and its prognostic role in a consecutive series of 155 surgically resected lung NETs, including typical carcinoid (TC), atypical carcinoid (AC), LCNEC, and SCLC patients. The DLL3 expression was categorized as high (>50% positive tumor cells) or low (<50%). In addition, tumors were categorized by H-score (i.e., percentage of positive cells by staining intensity, ≥150 <150). DLL3 staining was positive in 99/155 (64%) samples, and high DLL3 expression was frequently observed in high-grade tumors. In detail, 46.9% and 75% of SCLC and 48.8% and 53.7% of LCNEC specimens showed a high DLL3 expression by using H-score and percentage of positive tumor cells, respectively. Regarding low-grade NETs, only 4.9% and 12.2% TCs and 19.5% and 24.4% ACs had high DLL3 expression considering H-score and percentage of positive tumor cells, respectively. High DLL3 expression was associated with advanced American Joint Committee on Cancer (AJCC) stage, peripheral location, and chromogranin A expression in high-grade tumors (p < 0.05). In low-grade NETs, high DLL3 expression was associated with female sex, peripheral location, a higher number of mitoses, higher Ki-67 index, presence of necrosis, and pleural infiltration (p < 0.05). No association was observed between high DLL3 expression and overall survival (OS) and disease-free survival (DFS) in high-grade NETs, whereas high DLL3 expression was associated with lower DFS in ACs (p = 0.01). In conclusion, our study demonstrated a high prevalence of DLL3 expression in high-grade lung NET patients and its association with aggressive clinicopathological features. These findings confirm that DLL3 could represent a useful biomarker for target therapy in high-grade tumors. Our results also suggest that the DLL3 expression could identify a subset of AC tumors with more aggressive behavior, thus providing the basis for new therapeutic options in this group of patients.
Delta样蛋白3（DLL3）是Notch信号通路中的一种蛋白，是高级别肺神经内分泌肿瘤（NETs），即小细胞肺癌（SCLC）和大细胞神经内分泌癌（LCNEC）的潜在治疗靶点。然而，DLL3在肺NETs中的患病率及其与临床病理特征和预后的关系仍不清楚。我们分析了155例接受手术切除的肺NETs患者（包括典型类癌（TC）、非典型类癌（AC）、LCNEC和SCLC患者）中DLL3的免疫组化表达及其预后作用。DLL3表达分为高表达（>50%阳性肿瘤细胞）或低表达（<50%）。此外，肿瘤通过H评分进行分类（即染色强度阳性细胞的百分比，≥150或<150）。155个样本中有99个（64%）DLL3染色呈阳性，高级别肿瘤中经常观察到高DLL3表达。具体而言，分别使用H评分和阳性肿瘤细胞百分比时，46.9%和75%的SCLC以及48.8%和53.7%的LCNEC标本显示高DLL3表达。对于低级别NETs，分别考虑H评分和阳性肿瘤细胞百分比时，只有4.9%和12.2%的TC以及19.5%和24.4%的AC有高DLL3表达。高DLL3表达与高级别肿瘤中美国癌症联合委员会（AJCC）晚期、外周位置和嗜铬粒蛋白A表达相关（p<0.05）。在低级别NETs中，高DLL3表达与女性、外周位置、较高的有丝分裂数、较高的Ki-67指数、坏死的存在和胸膜浸润相关（p<0.05）。在高级别NETs中，未观察到高DLL3表达与总生存期（OS）和无病生存期（DFS）之间的关联，而在AC中，高DLL3表达与较低的DFS相关（p = 0.01）。总之，我们的研究表明高级别肺NET患者中DLL3表达普遍存在，且与侵袭性临床病理特征相关。这些发现证实DLL3可能是高级别肿瘤靶向治疗的有用生物标志物。我们的结果还表明，DLL3表达可以识别出具有更侵袭性行为的AC肿瘤亚组，从而为这组患者的新治疗选择提供依据。
