Integration of clinicopathological and mutational data offers insight into lung cancer with tumor spread through air spaces

Background: Tumor spread through air spaces (STAS) was defined as a unique tumor invasion pattern in adenocarcinoma (ADC) by The World Health Organization Classification of Lung Tumors in 2015. Since then, STAS had been shown to be associated with local recurrence and poor survival results, as the typical signature and potential mechanisms of STAS remained unclear. Our objectives were to comprehensively demonstrate the clinicopathological and genetic signatures in STAS-positive lung cancer patients. Methods: The clinicopathological and gene alteration characteristics of 878 STAS-positive lung cancer patients were presented. Associations between parameters were evaluated using the Chi-square test, Fisher's exact test, and logistic regression. The capture-based targeted next generation sequencing (NGS) with a platform of 68 lung cancer-related genes was conducted in 139 cases, and the mutational spectrum was summarized. Results: STAS was identified in 391 female and 481 male patients, of which ADC accounted for the majority of cases (92.6%). The concomitant solid or micropapillary subtype was observed in 92.12% patients with ADC. Poorly differentiated histological subtypes were more frequent and negatively correlated with tumor size in smaller tumor cases (P=0.036, Pearson's R=-0.075). Furthermore, in the subgroup of nodules within 3 cm, the distribution of the solid and micropapillary subtypes were significantly frequent in lymph node-positive patients (P<0.001). Tumor protein p53 (TP53) alterations were more frequent in smoking patients (27.6%, P=0.007), human epidermal growth factor receptor 2 (HER2) alterations were more common in female (10.8%, P=0.025), while Kirsten rat sarcoma viral oncogene (KRAS) (20.3%, P=0.024) and TP53 (45.9%, P=0.003) were more prevalent in males. Conclusions: Poorly differentiated histological subtypes likely played a crucial role in promoting the invasiveness of STAS, especially in small tumor-size cases. Epidermal growth factor receptor (EGFR), TP53, KARS, anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS1) were the five most frequent alterations in STAS-positive ADC.