A multicenter analysis of genomic profiles and PD-L1 expression of primary lymphoepithelioma-like carcinoma of the lung

Zhanhong Xie,Xinqing Lin,Shiyue Li,Laiyu Liu,Shuyin Chen,Hao Liu,Han Han-Zhang,Nanshan Zhong,Bing Li,Xiaohong Xie,Jiexia Zhang,Ming Liu,Chengzhi Zhou,Ming Ouyang,Hua Zhang,Analyn Lizaso,Yingying Gu,Weineng Feng,Yinyin Qin

doi:10.1038/s41379-019-0391-9

Abstract

To understand the molecular mechanism of tumorigenesis of pulmonary lymphoepithelioma-like carcinoma and explore potential therapeutic strategies, we investigated the genomic profiles and PD-L1 expression of 29 Chinese pulmonary lymphoepithelioma-like carcinoma patients at various stages. We performed capture-based targeted sequencing on tissue samples collected from 27 patients with sufficient samples using a panel consisting of 520 cancer-related genes, spanning 1.64 Mb of the human genome. We identified 184 somatic mutations in 109 genes from 26 patients. One patient had no mutations detected by this panel. Copy number variations were detected in 52% (14/27) of the patients, with a majority having advanced-stage disease (10/14). Except for the detection of ERBB2 amplification and KRAS mutation in two patients, no other classic lung cancer driver mutations were detected. Interestingly, 78% (21/27) of the patients had mutations in epigenetic regulators. Of the 184 mutations identified, 51 occurred in 29 epigenetics-related genes. Furthermore, we performed PD-L1 immunohistochemistry staining using the Dako 22C3 assay and demonstrated that 69% (20/29) of the cohort had positive PD-L1 expression, of which three patients received and benefited from a PD-1 inhibitor. In conclusion, we elucidated a distinct genomic landscape associated with pulmonary lymphoepithelioma-like carcinoma with no classic lung cancer driver mutation but an enrichment of mutations in epigenetic regulators. The detection of high PD-L1 expression and lack of any canonical druggable driver mutations raises the potential of checkpoint immunotherapy for pulmonary lymphoepithelioma-like carcinoma.

Highlights

A majority of lymphoepithelial carcinoma originates from the nasopharynx, but some will involve the lung, salivary glands, stomach, urinary tract, and rarely ovaries [1, 2]
Numerous studies have examined the involvement of classic lung cancer oncogenic pathways in the development of pulmonary lymphoepithelioma-like carcinoma, including EGFR [4, 6, 7, 15, 23, 24], KRAS, BRAF, ALK, and ROS1 [23] and discovered that these pathways are not major oncogenic drivers of pulmonary lymphoepithelioma-like carcinoma
Despite the EGFR mutation rate of 12.1% (8/66) reported by Chang et al, only one patient was detected with a sensitizing EGFR mutation—an EGFR exon 19 deletion; all the other 11 EGFR mutations detected in 7 pulmonary lymphoepithelioma-like carcinoma patients located in exons 18–21 are uncommon mutations with no evidence of therapeutic response to EGFR inhibitors [4, 23, 24]

Summary

Introduction

A majority of lymphoepithelial carcinoma originates from the nasopharynx, but some will involve the lung, salivary glands, stomach, urinary tract, and rarely ovaries [1, 2]. Pulmonary lymphoepithelioma-like carcinoma is a rare and distinct subtype of non-small-cell lung cancer with an incidence of ~0.7% of all non-small cell lung cancer cases. Pulmonary lymphoepithelioma-like carcinoma tends to affect young, non-smoking patients of Asian ethnicity [3,4,5,6,7,8,9]. It was previously classified as a variant of large cell carcinoma [10] but has recently been reclassified under other and unclassified carcinomas in the 2015 World Health Organization (WHO) classification of lung tumors [11]. Non-classic histologic morphologies have been observed for pulmonary lymphoepithelioma-like carcinoma including

Methods

Results

Conclusion