Abstract
Pulmonary lymphoepithelioma-like carcinoma (LELC) is a subtype of non-small cell lung cancer (NSCLC) characterized by marked lymphocytic infiltration and association with Epstein–Barr virus (EBV). The molecular basis underlying the disease remains unclear. We sought to study the molecular landscape by multiple approaches including whole genomic sequencing, capture-based targeted sequencing, fluorescent in situ hybridization and immunohistochemistry. Tumor cells from 57 EBV-positive pulmonary LELCs were isolated by careful microdissection prior to genomic sequencing. Integrated analysis revealed a distinct genomic landscape of low TP53 mutation rate (11%), low incidence of known drivers in the RTK/RAS/RAF (11%) and PI3K/AKT/mTOR pathways (7%), but enriched for loss-of-function mutations in multiple negative regulators of the NF-κB pathway. High level programmed cell death ligand-1 (PD-L1) expression was shown with 47% and 79% of the cases showing positive PD-L1 immunoreactivity at ≥50% and ≥1% tumor proportion score, respectively. Subsets of the patients with actionable fibroblast growth factor receptor 3 (FGFR3) aberrations (4%) and mismatch repair deficiency (4%) were potentially eligible for precision medicine. Pulmonary LELC showed a distinct genomic landscape, different from major NSCLC subtypes but resembled that of EBV-associated nasopharyngeal carcinoma. Our work facilitated the understanding of molecular basis underlying pulmonary LELC to explore potential therapeutic options.
Highlights
Lung cancer is the leading cause of cancer-related death worldwide, causing an estimated1.8 million deaths in 2018 [1]
First described in 1987, lymphoepithelioma-like carcinoma (LELC) has a distinct morphological feature of undifferentiated carcinoma with a typical syncytial growth pattern, large vesicular nuclei with prominent nucleoli, and heavy infiltration of lymphocytes [3]. It is characterized by Epstein–Barr virus (EBV) infection, and morphologically resembles nasopharyngeal carcinoma (NPC), an epithelial malignancy with EBV
Pulmonary LELC is a subtype of non-small cell lung cancer (NSCLC) that is characterized by EBV infection and heavy lymphocytic infiltrate
Summary
Lung cancer is the leading cause of cancer-related death worldwide, causing an estimated1.8 million deaths in 2018 [1]. Cancers 2020, 12, 2065 of non-small cell lung cancer (NSCLC), accounting for 0.9% of lung cancer. First described in 1987, LELC has a distinct morphological feature of undifferentiated carcinoma with a typical syncytial growth pattern, large vesicular nuclei with prominent nucleoli, and heavy infiltration of lymphocytes [3]. It is characterized by Epstein–Barr virus (EBV) infection, and morphologically resembles nasopharyngeal carcinoma (NPC), an epithelial malignancy with EBV infection. Pulmonary LELC shows favorable outcomes in comparison with other non-LELC NSCLC subtypes [4]
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