Data from Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma–like and Non–Small Cell Carcinoma–like Subsets

Abstract

<div>Abstract<p><b>Purpose:</b> Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm, whose biologic relationship to small cell lung carcinoma (SCLC) versus non-SCLC (NSCLC) remains unclear, contributing to uncertainty regarding optimal clinical management. To clarify these relationships, we analyzed genomic alterations in LCNEC compared with other major lung carcinoma types.</p><p><b>Experimental Design:</b> LCNEC (<i>n</i> = 45) tumor/normal pairs underwent targeted next-generation sequencing of 241 cancer genes by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) platform and comprehensive histologic, immunohistochemical, and clinical analysis. Genomic data were compared with MSK-IMPACT analysis of other lung carcinoma histologies (<i>n</i> = 242).</p><p><b>Results:</b> Commonly altered genes in LCNEC included <i>TP53</i> (78%), <i>RB1</i> (38%), <i>STK11</i> (33%), <i>KEAP1</i> (31%), and <i>KRAS</i> (22%). Genomic profiles segregated LCNEC into 2 major and 1 minor subsets: SCLC-like (<i>n</i> = 18), characterized by <i>TP53</i>+<i>RB1</i> co-mutation/loss and other SCLC-type alterations, including <i>MYCL</i> amplification; NSCLC-like (<i>n</i> = 25), characterized by the lack of coaltered <i>TP53</i>+<i>RB1</i> and nearly universal occurrence of NSCLC-type mutations (<i>STK11, KRAS</i>, and <i>KEAP1</i>); and carcinoid-like (<i>n</i> = 2), characterized by <i>MEN1</i> mutations and low mutation burden. SCLC-like and NSCLC-like subsets revealed several clinicopathologic differences, including higher proliferative activity in SCLC-like tumors (<i>P</i> < 0.0001) and exclusive adenocarcinoma-type differentiation marker expression in NSCLC-like tumors (<i>P</i> = 0.005). While exhibiting predominant similarity with lung adenocarcinoma, NSCLC-like LCNEC harbored several distinctive genomic alterations, including more frequent mutations in <i>NOTCH</i> family genes (28%), implicated as key regulators of neuroendocrine differentiation.</p><p><b>Conclusions:</b> LCNEC is a biologically heterogeneous group of tumors, comprising distinct subsets with genomic signatures of SCLC, NSCLC (predominantly adenocarcinoma), and rarely, highly proliferative carcinoids. Recognition of these subsets may inform the classification and management of LCNEC patients. <i>Clin Cancer Res; 22(14); 3618–29. ©2016 AACR</i>.</p></div>