Abstract: Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare and distinct subtype of non-small-cell lung carcinoma associated with Epstein–Barr virus (EBV) infection. We systematically reviewed the recent research that expands our knowledge about PLELC, with main focus on its genetic profile, tumor-infiltrating environment, PD-L1 expression, circulating EBV-DNA, clinical utility of 18F-FDG PET/CT, and treatment strategy. A low frequency of typical driver mutations and widespread existence of copy number variations was detected in PLELC. Persistent EBV infection may trigger intense infiltration of lymphocytes, representing enhanced tumor immunity and possibly resulting in a better prognosis. Circulating EBV-DNA in the plasma of patients with PLELC may predict disease progression and response to therapy. PLELC is 18F-FDG avid, and 18F-FDG PET may help refine palliation strategies and subsequently improve the prognosis. Most of the reported patients present at early and resectable stage, and surgical resection with curative intent is the preferred approach. There is currently no consensus on the regimen of chemotherapy for patients with advanced stages. EGFR-targeted therapies seem to have no therapeutic effect, and the clinical impact of PD-1/PD-L1 therapy is uncertain but worthy of further research.


Keywords: pulmonary lymphoepithelioma-like carcinoma, genetic profile, EBV infection, PD-L1 expression, tumor inflammatory microenvironment, treatment strategy


INTRODUCTION

Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare and distinct subtype of non-small-cell lung cancer (NSCLC) associated with Epstein–Barr virus (EBV) that is less reported and not well understood.1 It accounts for ~0.7% of all NSCLC cases and usually affects young, nonsmoking, Asian populations2 and clinical and radiographic manifestations are not pathognomonic.1,3 The tumor has distinct pathologic features which are indistinguishable from those of undifferentiated nasopharyngeal carcinoma and is characterized by poorly differentiated tumor cells with large vesicular nuclei and prominent nucleoli showing syncytial growth patterns along with heavy lymphocytic infiltration.4,5 It has also been reported that PLELC displays nonclassic morphology with little lymphocytic infiltration.6 The tumor is typically positive for CK5/6, EMA, p63 and p40, suggesting squamous cell lineage.7,8 The presence of EBV in the nuclei of tumor cells is essential for the diagnosis, which can be detected by in situ hybridization for EBV-encoded RNA (EBER). The majority of patients with PLELC are detected at early stage and may have better prognosis than other subtypes of NSCLC.2,4

This review is to summarize recent research that expands our knowledge about PLELC, with main focus on its genetic profile, tumor-infiltrating environment, PD-L1 expression, circulating EBV-DNA, clinical utility of 18F-FDG PET/CT, and treatment strategy (see Table 1).


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Table 1

Genetic Profile of PLELC

Several driver mutations have been reported to cause NSCLC.9 Owing to the rarity of PLELC, few previous studies existed investigating its genetic status and association with clinicopathologic characteristics.8,10,11 Epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement have been the first well-characterized genetic alterations with corresponding targeted agents that have greatly changed the treatment paradigm of advanced NSCLC.9 Other oncogenic drivers have emerged as novel molecular targets with potential therapeutic implications such as mutations in the gene Kirsten rat sarcoma viral oncogene homolog (KRAS), BRAF, and ROS1 and MET gene amplification.12 An earlier study on the prevalence of EGFR mutations among different histological types of lung cancer demonstrated a low prevalence (1 of 11) of EGFR mutations in PLELC (see Table 2).13 Chang et al showed p53 and EGFR mutations were uncommon in PLELCs.8 In this study, p53 mutations were identified in only 3 of 46 cases (6.5%) and EGFR mutations were observed in 8 of 46 cases (17.4%) with a majority of exon 21 mutations but without L858R. Notably, EGFR mutations were more commonly found in patients with tumor size ≤3 cm.8 Wang et al found that only 1 of 42 cases was observed to harbor EGFR L858R mutations.14 Chang et al, in another study, found that the overall frequency of EGFR alterations was 12.1%.15 Liang et al analyzed EGFR mutations in exons 18, 19, 20, and 21 in 11 patients with PLELC and found that all were wild type.2 Yeh et al demonstrated that EGFR was wild type in all 18 patients in whose information was available.6 Liu et al showed that none of the 32 patients with PLELC had EGFR mutations in exons 19 and 21.10 Fang et al found that EGFR mutation rate was 1.8% (2 of 113).16 Recently, Hong et al explored the landscape of PLELC and confirmed a low degree of typical driver mutations including EGFR, KRAS, and BRAF.17 Although MET mutations were detected in two PLELC patients, none of them belong to the canonical MET exon 14 skipping mutations.17 ALK gene rearrangement is rarely detected in PLELC as well.6,14-16,18 It was absent in most studies. Only one patient of PLELC with EML4-ALK fusion gene was reported recently.19 There were another two studies examining the prevalence of KRAS in PLELC, which failed to identify any KRAS mutated patients.15,16 In addition, one of these studies revealed that no aberrations in BRAF and ROS1 in PLELC could be detected.15 These results above suggested that typical driver mutations in other subtypes of NSCLC might not play an important role in the carcinogenesis of PLELC and EGFR-targeted therapy is not suitable for patients with advanced PLELC.

Table 2

In addition to a low frequency of typical driver mutations, a high prevalence of copy number variations was noted in PLELC.17,20 Xie et al showed that copy number variations were detected in 52% of the patients.20 Interestingly, epigenetic regulation might participate in the process of carcinogenesis as reflected by Xie’s finding that 78% of the patients had mutations in epigenetic regulators.20 Moreover, the frequent overexpression of APOBEC family genes, which participated in innate immune response against virus infections, and frequent loss of type I IFN genes were seen in PLELC, reflecting the complex host-virus counteraction during the process of EBV-associated carcinogenesis.17

Chromosome 11 changes might be closely related to EBV-associated malignancies.17 Chan et al compared the frequency of chromosome 11 copy number gains in three different types of EBV-associated malignancies and revealed that trisomy or polysomy 11 was detected in 6 of 8 PLELC.21 Microsatellite instability (MSI) and loss of heterozygosity (LOH) represent molecular disorders acquired by the cell during neoplastic transformation and have been reported in several cancer types, including lung cancer.22 Dacic et al found that MSI was detected in 2 of 7 PLELC cases and LOH was identified in 3 of 7 PLELC.23 Relative higher frequency of LOH suggested inactivation of tumor suppresser gene in chromosome 5q23 might play a role in PLELC tumorigenesis.23

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