Akhoundova Dilara, Haberecker Martina, Fritsch Ralph, Höller Sylvia, Kiessling Michael K, Rechsteiner Markus, Rüschoff Jan H, Curioni-Fontecedro Alessandra
Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland.
Department of Medical Oncology, Inselspital, University Hospital of Bern, Bern, Switzerland.
Front Oncol. 2022 Jun 7;12:911294. doi: 10.3389/fonc.2022.911294. eCollection 2022.
() rearrangements are known oncogenic drivers in non-small cell lung cancer (NSCLC). Few case reports described the occurrence of such rearrangements in large cell neuroendocrine carcinomas (LCNECs) of the lung without information on clinical responses to ALK tyrosine kinase inhibitors (TKIs) in these cases. Currently, neuroendocrine tumors of the lungs are not screened for rearrangements.
To illustrate the clinical impact of molecular characterization in LCNECs, we report the disease course in three patients with -rearranged metastatic LCNEC from our clinical routine, as well as their treatment response to ALK TKIs (index cases). To gain insight into the prevalence of rearrangements in neuroendocrine tumors of the lung, we analyzed a retrospective cohort of 436 tumor biopsies including LCNEC (n = 61), small cell lung cancer (SCLC) (n = 206), typical (n = 91) and atypical (n = 69) carcinoids, and mixed histology (n = 9) for the presence of rearrangements using a sequential diagnostic algorithm. ALK immunohistochemistry (IHC) was evaluable in 362 cases; fluorescence hybridization (FISH) was evaluable in 28 out of the 35 IHC-positive cases, followed by next-generation sequencing (NGS) that was available in 12 cases.
Within the retrospective cohort, ALK IHC was positive in 35 out of 362 (9.7%) evaluable samples. FISH was positive in 3 out of the 28 (10.7%) evaluable cases: 2 with atypical carcinoids and 1 with LCNEC. Additionally, the 3 index cases showed positive ALK IHC, which was confirmed by NGS. Within the retrospective cohort, NGS confirmed the presence of an genomic rearrangement in one FISH-positive atypical carcinoid where material was sufficient for sequencing. Two out of three patients with metastatic -rearranged LCNEC received up-front treatment with the ALK TKI alectinib and showed rapid tumor response at all metastatic sites, including multiple brain metastases.
rearrangements represent rare but targetable oncogenic driver alterations in LCNEC. Contrarily to NSCLC, the detection of rearrangements in neuroendocrine tumors of the lung is challenging, since ALK IHC can lead to false-positive results and therefore needs confirmation by FISH or NGS. Up-front comprehensive molecular profiling with NGS should be performed in metastatic LCNEC in order not to miss actionable genomic alterations.
（）重排在非小细胞肺癌（NSCLC）中是已知的致癌驱动因素。少数病例报告描述了这种重排在肺大细胞神经内分泌癌（LCNEC）中的发生情况，但未提及这些病例对ALK酪氨酸激酶抑制剂（TKIs）的临床反应。目前，肺部神经内分泌肿瘤未进行（）重排筛查。
为了阐明分子特征在LCNEC中的临床影响，我们报告了3例来自我们临床常规的发生（）重排的转移性LCNEC患者的病程，以及他们对ALK TKIs的治疗反应（索引病例）。为了深入了解肺部神经内分泌肿瘤中（）重排的患病率，我们分析了一个回顾性队列，包括436例肿瘤活检样本，其中有LCNEC（n = 61）、小细胞肺癌（SCLC）（n = 206）、典型类癌（n = 91）、非典型类癌（n = 69）和混合组织学类型（n = 9），使用序贯诊断算法检测（）重排的存在情况。362例病例可进行ALK免疫组化（IHC）评估；35例IHC阳性病例中有28例可进行荧光原位杂交（FISH）评估，其中12例可进行二代测序（NGS）。
在回顾性队列中，362例可评估样本中有35例（9.7%）ALK IHC呈阳性。28例可评估病例中有3例（10.7%）FISH呈阳性：2例为非典型类癌，1例为LCNEC。此外，3例索引病例的ALK IHC呈阳性，经NGS确认。在回顾性队列中，NGS在1例FISH阳性且有足够测序材料的非典型类癌中确认存在（）基因组重排。3例发生（）重排的转移性LCNEC患者中有2例接受了ALK TKI阿来替尼的一线治疗，所有转移部位包括多个脑转移灶均显示出快速的肿瘤反应。
（）重排在LCNEC中是罕见但可靶向的致癌驱动因素改变。与NSCLC不同，肺部神经内分泌肿瘤中（）重排的检测具有挑战性，因为ALK IHC可能导致假阳性结果，因此需要通过FISH或NGS进行确认。对于转移性LCNEC应进行NGS的一线全面分子谱分析，以免遗漏可操作的基因组改变。
