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

Abstract

Purpose: 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. Experimental Design: LCNEC (n = 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 (n = 242). Results: Commonly altered genes in LCNEC included TP53 (78%), RB1 (38%), STK11 (33%), KEAP1 (31%), and KRAS (22%). Genomic profiles segregated LCNEC into 2 major and 1 minor subsets: SCLC-like (n = 18), characterized by TP53+RB1 co-mutation/loss and other SCLC-type alterations, including MYCL amplification; NSCLC-like (n = 25), characterized by the lack of coaltered TP53+RB1 and nearly universal occurrence of NSCLC-type mutations (STK11, KRAS, and KEAP1); and carcinoid-like (n = 2), characterized by MEN1 mutations and low mutation burden. SCLC-like and NSCLC-like subsets revealed several clinicopathologic differences, including higher proliferative activity in SCLC-like tumors (P < 0.0001) and exclusive adenocarcinoma-type differentiation marker expression in NSCLC-like tumors (P = 0.005). While exhibiting predominant similarity with lung adenocarcinoma, NSCLC-like LCNEC harbored several distinctive genomic alterations, including more frequent mutations in NOTCH family genes (28%), implicated as key regulators of neuroendocrine differentiation. Conclusions: 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. Clin Cancer Res; 22(14); 3618–29. ©2016 AACR.

Ki-67 labeling index of neuroendocrine tumors of the lung has a high level of correspondence between biopsy samples and surgical specimens when strict counting guidelines are applied

“…This molecular, morphological, and clinical heterogeneity of lung NET [20,39,[46][47][48][49][50] is similar to that of G3 GEP NET for which the Ki-67 LI is of equal diagnostic importance [26,[51][52][53][54][55][56]. Of note, LCNECs of the lung show a wide range of histological and molecular features, as some cases are morphologically close to SCCs [13, 14,16,47], while others are closer to conventional non-small cell carcinoma [47,[57][58][59]] and yet others to AC [3,8,47]. As a result, this is the tumor category with the lowest diagnostic reproducibility among lung NETs [18,60,61].We earlier reported values of Ki-67 LI in LCNECs ranging from 26 to 90% or higher [3,30].…”

“…As a result, this is the tumor category with the lowest diagnostic reproducibility among lung NETs [18,60,61].We earlier reported values of Ki-67 LI in LCNECs ranging from 26 to 90% or higher [3,30]. Along with the dilemmas in therapy choice, LCNECs are a waste-basket category with different genotypes and phenotypes (SCC-like LCNECs, NSCLC-like LCNECs, carcinoid-like LCNECs, as recently proposed) putatively reflecting plasticity of a cancer stem cell rather than a single entity with a characteristic profile [47].We contend that integrated classification of lung NET, merging morphology [62] with grading which includes Ki-67 LI [32], might prove to be useful for clinical purposes [33]. In order to assess clinical usefulness, we assessed how on lung NET biopsies and corresponding resection specimens Ki-67 LI might be established and explored potential sources of variability.…”

Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung

“…35). Recently, Rekhtman and colleagues performed next-generation sequencing of 45 LCNEC samples and reported a frequency of RB1 mutation, loss of RB1, and protein loss of RB was 14 (31%), 3 (7%), and 18 (40%), respectively, suggesting that copy number loss and other molecular events, such as epigenomic modulations, might contribute to the functional impairment of RB proteins (36). Therefore, we additionally evaluated RB protein expression and found that protein loss of RB occurred in up to 74% of cases.…”

Clinicopathological Profiling of Lung Carcinoids with a Ki67 Index > 20%

“…These PD-NENs differ in their general genetic profile from carcinoids [1]. Recent genetic studies using next-generation sequencing showed that pulmonary carcinoids are characterized by MEN1 gene alterations, while PD-NENs frequently reveal inactivation of TP53 and/or RB genes [2, 4]. However, it has also been shown that a number of recurrent somatic gene alterations (i.e., RB1, TP53, TERT, SDHA, RICTOR, PIK3CA, and MYC etc.)…”

“…These observations have been differently interpreted. On the one hand, it was suggested that well-differentiated (WD)-NENs of the lung, i.e., carcinoids with a high mitotic activity, might be NECs with carcinoid morphology [6] or NECs with carcinoid-type genetic alterations [4]. On the other hand, it has been suggested that the occurrence of similar genetic alterations in both carcinoids and NECs reflect a transition from WD-NENs to PD-NENs [5].…”