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

Original Article Page 1 of 8 Integration of clinicopathological and mutational data offers insight into lung cancer with tumor spread through air spaces Yu Tian1#^, Jing Feng2#, Long Jiang1^, Junwei Ning1, Zenan Gu1, Jia Huang1, Qingquan Luo1 1 Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China; 2Statistical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China Contributions: (I) Conception and design: Q Luo, J Huang, Y Tian; (II) Administrative support: J Huang, Q Luo; (III) Provision of study materials or patients: J Huang, J Feng; (IV) Collection and assembly of data: J Feng, L Jiang; (V) Data analysis and interpretation: Y Tian, J Feng; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. # These authors contributed equally to this work. Correspondence to: Qingquan Luo; Jia Huang. Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China. Email: ; . 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. Keywords: Lung cancer; adenocarcinoma (ADC); spread through air space; pathological; genetic Submitted Apr 16, 2021. Accepted for publication Jun 15, 2021. doi: 10.21037/atm-21-2256 View this article at: https://dx.doi.org/10.21037/atm-21-2256 ^ ORCID: Yu Tian, 0000-0002-5252-9374; Long Jiang, 0000-0002-6860-755X. © Annals of Translational Medicine. All rights reserved. Ann Transl Med 2021;9(12):985 | https://dx.doi.org/10.21037/atm-21-2256 Page 2 of 8 Introduction Lung cancer is the leading cause of cancer-related death, and has a complicated prognosis. With the advancement of imaging, pathological, and molecular detection techniques for lung cancer, the identification, diagnosis, and staging of patients is becoming more comprehensive and individualized (1,2). Early and precise discrimination of tumor features have become the key to achieving optimal treatment modality and improved prognosis. Tumor invasion is one of the decisive factors of tumor treatment and prognosis. Compared with other organ cancers, the tumor invasion patterns in lung adenocarcinoma (ADC) are diverse. The common patterns of pulmonary carcinoma invasion are via vascular, lymphatic, or transcoelomic spread. The concept of spread through air spaces (STAS) was included as a unique pattern of invasion in lung ADC in the World Health Organization (WHO) classification in 2015 (3). In other histological types (i.e., besides ADC), STAS has also been described (4). Recent studies regarding STAS have focused on its value in therapeutic decision-making and prognostic assessment. The presence of STAS was validated as a risk factor of pulmonary recurrence in patients undergoing limited reception (5). STAS was also associated with significantly decreased recurrence free survival and overall survival (6). Several studies attempted to identify the predictive factors of STAS, however their conclusions remained controversial (7,8). Therefore, this study aimed to demonstrate the clinicopathological and genetic signatures of STAS in lung cancer and offer a scale for more comprehensive understanding of the disease. Furthermore, we also expected to explore and analyze the critical features influencing the invasiveness of lung cancer STAS. We presented the following article in accordance with the STROBE reporting checklist (available at https://dx.doi.org/10.21037/atm-21-2256). Methods Study cohort and data collection Between February 2015 and February 2020, 939 patients were pathologically validated as STAS-positive. Of these, 10 cases of bilateral surgeries and 28 cases of biopsy or palliative surgeries were excluded. Of the remaining 901 patients, 878 underwent lymph node systematic dissection or sampling and were finally enrolled. Next generation sequencing (NGS) data was obtained in 139 cases. The study was conducted in accordance © Annals of Translational Medicine. All rights reserved. Tian et al. The signature of spread through air space in lung cancer with the Declaration of Helsinki (as revised in 2013). The study was approved by institutional ethics committee of Shanghai Chest Hospital [No.: KS(Y) 21128] and informed consent was taken from all the patients. Data on clinicopathologic variables, including age, gender, smoking status, tumor location, pathologic tumornode-metastasis (TNM) situation, visceral pleural invasion, lymphovascular invasion, histological classification, and subtype, were obtained by reviewing the patients’ medical records. Staging was on the basis of the eighth edition of the American Joint Committee on Cancer Staging Manual. Capture-based targeted DNA sequencing Tested samples were identified and derived from surgical resected tissue by the pathologist before pathological examination, which followed the principle of anonymity and voluntariness. DNA was (...truncated)