Keogh Anna, Finn Stephen, Radonic Teodora
Department of Histopathology, St. James's Hospital, D08 NHY1 Dublin, Ireland.
Department of Histopathology and Morbid Anatomy, Trinity Translational Medicine Institute, Trinity College Dublin, D08 HD53 Dublin, Ireland.
Cancers (Basel). 2022 Aug 3;14(15):3772. doi: 10.3390/cancers14153772.
Small cell lung cancer (SCLC) is a high-grade neuroendocrine malignancy with an aggressive behavior and dismal prognosis. 5-year overall survival remains a disappointing 7%. Genomically, SCLCs are homogeneous compared to non-small cell lung cancers and are characterized almost always by functional inactivation of RB1 and TP53 with no actionable mutations. Additionally, SCLCs histologically appear uniform. Thus, SCLCs are currently managed as a single disease with platinum-based chemotherapy remaining the cornerstone of treatment. Recent studies have identified expression of dominant transcriptional signatures which may permit classification of SCLCs into four biologically distinct subtypes, namely, SCLC-A, SCLC-N, SCLC-P, and SCLC-I. These groups are readily detectable by immunohistochemistry and also have potential predictive utility for emerging therapies, including PARPi, immune checkpoint inhibitors, and DLL3 targeted therapies. In contrast with their histology, studies have identified that SCLCs display both inter- and intra-tumoral heterogeneity. Identification of subpopulations of cells with high expression of PLCG2 has been linked with risk of metastasis. SCLCs also display subtype switching under therapy pressure which may contribute furthermore to metastatic ability and chemoresistance. In this review, we summarize the recent developments in the understanding of the biology of SCLCs, and discuss the potential diagnostic, prognostic, and treatment opportunities the four proposed subtypes may present for the future. We also discuss the emerging evidence of tumor heterogeneity and plasticity in SCLCs which have been implicated in metastasis and acquired therapeutic resistance seen in these aggressive tumors.
小细胞肺癌（SCLC）是一种高级别神经内分泌恶性肿瘤，行为侵袭性强，预后不佳。5年总生存率仍低至令人失望的7%。在基因组方面，与非小细胞肺癌相比，SCLC具有同质性，几乎总是以RB1和TP53功能失活且无可操作的突变为特征。此外，SCLC在组织学上表现较为一致。因此，目前SCLC被作为单一疾病进行管理，铂类化疗仍然是治疗的基石。最近的研究已经确定了显性转录特征的表达，这可能使SCLC分为四种生物学上不同的亚型，即SCLC-A、SCLC-N、SCLC-P和SCLC-I。这些组通过免疫组织化学很容易检测到，并且对包括PARPi、免疫检查点抑制剂和DLL3靶向治疗在内的新兴疗法也具有潜在的预测效用。与它们的组织学情况相反，研究发现SCLC表现出肿瘤间和肿瘤内的异质性。已发现具有高表达PLCG2的细胞亚群与转移风险有关。SCLC在治疗压力下也会发生亚型转换，这可能进一步导致转移能力和化疗耐药性。在这篇综述中，我们总结了对SCLC生物学认识的最新进展，并讨论了这四种提出的亚型未来可能带来的潜在诊断、预后和治疗机会。我们还讨论了SCLC中肿瘤异质性和可塑性的新证据，这些证据与这些侵袭性肿瘤中出现的转移和获得性治疗耐药性有关。
