Ferrara Miriam Grazia, Stefani Alessio, Simbolo Michele, Pilotto Sara, Martini Maurizio, Lococo Filippo, Vita Emanuele, Chiappetta Marco, Cancellieri Alessandra, D'Argento Ettore, Trisolini Rocco, Rindi Guido, Scarpa Aldo, Margaritora Stefano, Milella Michele, Tortora Giampaolo, Bria Emilio
Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy.
Medical Oncology, Università Cattolica del Sacro Cuore, Roma, Italy.
Front Oncol. 2021 Apr 15;11:650293. doi: 10.3389/fonc.2021.650293. eCollection 2021.
Large-cell neuroendocrine carcinomas of the lung (LCNECs) are rare tumors representing 1-3% of all primary lung cancers. Patients with LCNEC are predominantly male, older, and heavy smokers. Histologically, these tumors are characterized by large cells with abundant cytoplasm, high mitotic rate, and neuroendocrine immunohistochemistry-detected markers (chromogranin-A, synaptophysin, and CD56). In 2015 the World Health Organization classified LCNEC as a distinct subtype of pulmonary large-cell carcinoma and, therefore, as a subtype of non-small cell lung carcinoma (NSCLC). Because of the small-sized tissue samples and the likeness to other neuroendocrine tumors, the histological diagnosis of LCNEC remains difficult. Clinically, the prognosis of metastatic LCNECs is poor, with high rates of recurrence after surgery alone and overall survival of approximately 35% at 5 years, even for patients with early stage disease that is dramatically shorter compared with other NSCLC subtypes. First-line treatment options have been largely discussed but with limited data based on phase II studies with small sample sizes, and there are no second-line well defined treatments. To date, no standard treatment regimen has been developed, and how to treat LCNEC is still on debate. In the immunotherapy and targeted therapy era, in which NSCLC treatment strategies have been radically reshaped, a few data are available regarding these opportunities in LCNEC. Due to lack of knowledge in this field, many efforts have been done for a deeper understanding of the biological and molecular characteristics of LCNEC. Next generation sequencing analyses have identified subtypes of LCNEC that may be relevant for prognosis and response to therapy, but further studies are needed to better define the clinical impact of these results. Moreover, scarce data exist about PD-L1 expression in LCNEC and its predictive value in this histotype with regard to immunotherapy efficacy. In the literature some cases are reported concerning LCNEC metastatic patients carrying driver mutations, especially EGFR alterations, showing targeted therapy efficacy in this setting of disease. Due to the rarity and the challenging understanding of LCNEC, in this review we aim to summarize the management options currently available for treatment of LCNEC.
肺大细胞神经内分泌癌（LCNEC）是罕见肿瘤，占所有原发性肺癌的1%-3%。LCNEC患者多为男性，年龄较大，且吸烟量大。从组织学上看，这些肿瘤的特征是细胞大、细胞质丰富、有丝分裂率高，且具有神经内分泌免疫组化检测标志物（嗜铬粒蛋白A、突触素和CD56）。2015年，世界卫生组织将LCNEC归类为肺大细胞癌的一种独特亚型，因此属于非小细胞肺癌（NSCLC）的一种亚型。由于组织样本小且与其他神经内分泌肿瘤相似，LCNEC的组织学诊断仍然困难。临床上，转移性LCNEC的预后较差，仅手术治疗后的复发率就很高，即使是早期疾病患者，5年总生存率约为35%，与其他NSCLC亚型相比明显更短。一线治疗方案已被广泛讨论，但基于样本量小的II期研究的数据有限，且没有明确的二线治疗方法。迄今为止，尚未制定出标准治疗方案，如何治疗LCNEC仍存在争议。在免疫治疗和靶向治疗时代，NSCLC的治疗策略已发生根本重塑，但关于LCNEC在这些方面的可用数据较少。由于该领域知识匮乏，人们已做出许多努力以更深入了解LCNEC的生物学和分子特征。二代测序分析已确定了LCNEC的亚型，这些亚型可能与预后和治疗反应相关，但需要进一步研究以更好地确定这些结果的临床影响。此外，关于LCNEC中PD-L1表达及其在该组织学类型中对免疫治疗疗效的预测价值的数据也很少。文献中报道了一些LCNEC转移性患者携带驱动基因突变的病例，尤其是EGFR改变，显示在这种疾病情况下靶向治疗有效。由于LCNEC罕见且难以理解，在本综述中，我们旨在总结目前可用于治疗LCNEC的管理方案。
