Although clinical rarity, there has been increasingly reports recently of a unique type of lung cancer characterized by the presence of round or irregular air-containing cavities with cystic walls radiographically (Zhu et al., 2023, Ma et al., 2022, Shen et al., 2021). Terminologically, some entities were used loosely in association with this type of lung cancer (Detterbeck et al., 2023). In this study, we define the term “lung cancer associated with cystic airspaces” (i.e., LCCA) to refer to lung cancer that manifests as solitary cystic airspaces and has thin walls of 4 mm or less along the lesion circumference (Tan et al., 2019, Hansell et al., 2008).

The comprehensive nature of LCCA is still limited, though most previous studies have described the clinicopathological and radiographical features of LCCA. Accumulating evidence suggests that LCCA occurs in approximately 1–4% lung cancer (Shen et al., 2021, Farooqi et al., 2012, Fintelmann et al., 2017)，and they are predominantly (about 90%) adenocarcinomas and more frequently found in men and smokers (Detterbeck et al., 2023). A four-type classification system was proposed to summarize the morphologic patterns of CT observations in 2015 (Mascalchi et al., 2015). Long-term outcomes are not well-defined as regarded to classification or stage. Still, it is reported that LCCA had a worse prognosis than the non-LCCA (Shen et al., 2021, Toyokawa et al., 2018) and the wall thickness is an independent prognostic factor (Watanabe et al., 2016). Moreover, the nodule pattern is associated with poor differentiation, shorter survival and higher programmed cell death-ligand 1 (PD-L1) expression than other subtypes (Ma et al., 2022, Shen et al., 2021, Shen et al., 2019).

As a clinical subtype of NSCLC, the treatment strategies of LCCA follow its therapeutic principles. It is now widely accepted that genome-guided and immune personalized therapeutics of lung cancer, including driver gene mutations and PD-L1 expression (Rizzo, 2022), such as epidermal growth factor receptor tyrosine kinases inhibitor (Zhao et al., 2019) (EGFR-TKI) and immune checkpoint inhibitors (ICIs). Genome-guided individualized treatment has brought great clinical benefits to patients with lung cancer. However, little is known about the genetic landscape of LCCA. The purpose of this study is to investigate the transcriptional profiles of LCCA as compare to non-LCCA or normal lung tissue.