In the present study, the patient characteristics, survival and prognosis of resected stage I-IIIA LELC were retrospectively investigated. Our data demonstrated that LELC was more prevalent in younger patients and nonsmokers, with no obvious gender predisposition. In addition, LELC is a poorly differentiated disease that lacks typical driver gene mutations and is positive for IHC indicators of squamous cell lineage. In further analyses, LELC had a better survival outcome than other common lung cancers both before and after PSM. Finally, multivariate analyses revealed that both early N stage and preoperative albumin level ≥ 35 were prognostic factors favoring OS and DFS.
In previous study, several clinical series suggested that LELC is often identified in younger nonsmokers [4, 12, 21], and there was no sexual predilection [4, 21, 22], which was akin to our findings. The abovementioned result suggested that unlike SCC, smoking might not be the main etiology of LELC [7, 12]. Most tumors in our cohort were peripheral and had irregular morphology, echoing previous reports [23, 24], but conflicting with Qin et al.’s study .
In our study, almost all the cases were diagnosed as poorly differentiated disease, which was in accordance with previous findings that LELC is characterized by poorly differentiated tumor cells with prominent nucleoli and large vesicular nuclei [24, 25]. IHC data showed that our results were similar to those of Jiang et al, where the authors investigated 43 resected LELC patients and concluded that the tumor is typically positive for CK, CK5/6 and P63, which suggests squamous cell lineage, but is negative for TTF-1 and CK7 . Similar scenarios were also seen in Qin et al’s study  and Liang et al’s study . Owing to the similar morphology and IHC indicators, LELC is often misdiagnosed as SCC . Previous reports demonstrated that the presence of EBV in the nuclei of LELC tumor cells is critical for diagnosis. This can be confirmed by EBER in situ hybridization testing [8, 28]. In our research, EBER was positive in 99.3% of all the tested patients. From our perspective, if the patient originated from an area with a prevalence of EBV infection and presented with a peripheral lung mass, EBER testing was preferred in the pretreatment examination.
In our study, molecular testing revealed that LELC lacked target agent-sensitive mutations (EGFR and ALK). In the study by Hong et al, the authors explored the genetic landscape of LELC and demonstrated a low percentage of typical driver mutations, such as EGFR, BRAF and KRAS . The same scenarios were also observed in Wang et al’s study  and Chang et al’s study . The results above indicated that typical driver gene mutations, the main etiology of other common NSCLCs, might not play a critical role in the carcinogenesis of LELC . Furthermore, EGFR or ALK-targeted agents might not be suitable in the neoadjuvant or adjuvant therapy of advanced LELC.
Our data demonstrated that the OS of LELC was better than those of ADC and SCC both before and after PSM. Consistent with our results, He et al. assessed 62 LELC patients and suggested that LELC patients enjoy a higher level of survival when compared with ADC, SCC and large cell lung cancer . However, their conclusions might be impaired by the relatively small cohort size. In line with our findings, Chen et al. also reviewed 42 LELCs and 132 SCCs and concluded that LELC patients present longer progression-free survival than SCC patients. Nevertheless, OS, the gold standard of evaluating the efficacy of treatment modality, was lacking in their research. In the study by Zhou et al. the authors compared the OS of LELC with ADC, SCC and neuroendocrine tumors . Their data suggested that the OS of LELC is superior to those of SCC and neuroendocrine tumors but comparable to that of ADC , which was contradicted with ours. However, the PSM method was not used in their research, which may confer bias. One plausible explanation for the results observed in our study is that compared with other common NSCLCs, LELC was dominant in younger and nonsmoker patients. Smoking leads to more preoperative complications such as hypertension , coronary heart disease  and respiratory diseases , which might reduce life expectancy.
The multivariate analysis revealed that N stage and preoperative albumin level were correlated with both OS and DFS in our study. It is evidenced that nodal stage is an important influencing factor for LELC patient survival [8, 12, 14]. For albumin level, Liang et al investigated the outcomes of 52 resected LELCs and demonstrated that the serum albumin level was an independent prognostic factor , which was similar to our findings. Surprisingly, T stage and tumor grade, two important prognosis predictors in other NSCLCs, were not correlated with OS and DFS in our study, suggesting that the natural course and biology of LELC might be different from those of other common NSCLCs.
To the best of our knowledge, this study represents the first comprehensive and concurrent analysis of resected stage I-IIIA LELC. In addition, the virtues of this study were that it included the largest cohort size and had a long-term follow-up. Additionally, the evaluation of a wide range of clinicopathological variables allowed us to better understand the demographic trends and prognosis of the disease.
However, our study also had some limitations. First, in the era of precision therapy, molecular indicators such as PD-1, PD-L1, KRAS and BRAF were not involved in our study. Second, despite the significant advantages provided by a larger case number than has ever been reported before, the cohort size was still limited. Finally, the retrospective nature may have contributed to selection bias. Further efforts on prospective data collection and incorporation of the abovementioned factors are warranted.