An individual nomogram can reliably predict tumor spread through air spaces in non-small-cell lung cancer

(2022) 22:209 Wang et al. BMC Pulmonary Medicine https://doi.org/10.1186/s12890-022-02002-1 Open Access RESEARCH An individual nomogram can reliably predict tumor spread through air spaces in non‑small‑cell lung cancer Shuai Wang1†, Huankai Shou1†, Haoyu Wen1†, Xingxing Wang2, Haixing Wang2, Chunlai Lu1, Jie Gu1, Fengkai Xu1, Qiaoliang Zhu1, Lin Wang1 and Di Ge1* Abstract Background: Tumor spread through air spaces (STAS) has been shown to adversely affect the prognosis of lung cancer. The correlation between clinicopathological and genetic features and STAS remains unclear. Method: We retrospectively reviewed 3075 NSCLC patients between2017-2019. We evaluated the relationship between STAS and patients’ clinicopathological and molecular features. The chi-square test was performed to compare categorical variables. Univariate analysis and multivariate logistic regression analysis were performed to investigate the association of clinical factors with STAS. A nomogram was formulated to predict the presence of STAS. Results: STAS was identified in 617 of 3075 patients (20.07%). STAS was significantly related to sex (p < 0.001), smoking (p < 0.001), CEA (p < 0.001), differentiation (p < 0.001), histopathological type (p < 0.001), lymphatic vessel invasion (p < 0.001), pleural invasion (p < 0.001), T stage (p < 0.001), N stage (p < 0.001), M stage (p < 0.001), and TNM stage (p < 0.001). STAS was frequently found in tumors with wild-type EGFR (p < 0.001), KRAS mutations (p < 0.001), ALK rearrangements (p < 0.001) or ROS1 rearrangements (p < 0.001). For programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1), STAS was associated with PD-L1 expression level in tumor cells (p < 0.001) or stromal cells (p < 0.001), while PD-1 only in stromal cells (p < 0.001). Multivariable analyses demonstrated significant correlations between STAS and CEA level (p < 0.001), pathological grade (p < 0.001), lymphatic vessel invasion (p < 0.001), pleural invasion (p = 0.001), and TNM stage (p = 0.002). A nomogram was formulated based on the results of the multivariable analysis. Conclusions: Tumor STAS was associated with several invasive clinicopathological features. A nomogram was established to predict the presence of STAS in patients with NSCLC. Keywords: Lung cancer, Spread through air spaces, Predict, Nomogram † Shuai Wang, Huankai Shou and Haoyu Wen have contributed equally to this work *Correspondence: 1 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 20032, China Full list of author information is available at the end of the article Background Currently, lung cancer has the highest mortality among malignant neoplasms in the world, accounting for approximately 1.8 million (18%) cancer-related deaths worldwide in 2020 [1]. Spread through air spaces (STAS) is considered to be a new invasion pattern of lung cancer in addition to blood and lymphatic vessel invasion, pleural invasion and direct invasion [2]. STAS consists of micropapillary clusters, solid nests, or single cells beyond © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wang et al. BMC Pulmonary Medicine (2022) 22:209 the edge of the tumor into air spaces in the surrounding lung parenchyma. [3] Recent studies have shown that STAS is associated with clinicopathologic features and suggests a poor clinical prognosis [4–8]. However, the relationship between STAS and genetic mutations remains unclear. The relationship between STAS and immune checkpoints [programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1)] is still unknown. Therefore, further study is needed to clarify the correlation between molecular features and STAS. Recently, STAS has been reported to be associated with poor prognosis in lobectomy as well as limited resection [10]. Besides, in early-stage adenocarcinoma with STAS, lobectomy was associated with better outcomes than sublobar resection [9]. Hence, it is important to identify STAS preoperatively or intraoperatively to help stratify patients for limited resection rather than lobectomy. However, it is still difficult for pathologists to accurately identify STAS on frozen sections intraoperatively. Walts et al. [11] reported that the sensitivity for STAS detecting was 50%, and the negative predictive value was only 8% on frozen sections. Therefore, we established a nomogram to predict STAS preoperatively based on patients’ clinical and intraoperative pathological features. Methods Patients We reviewed patients with lung cancer in the Department of Thoracic Surgery of Zhongshan Hospital from October 2017 to August 2019. A total of 3397 consecutive patients who underwent surgical resection were studied. The patients enrolled had to meet the following inclusion criteria: (1) Pathological confirmation of primary NSCLC. (2) Sublobectomy, lobectomy or pneumonectomy with lymph node dissection was performed to achieve complete resection. (3) Negative surgical margins. The exclusion criteria were as follows: (1) Patients who underwent a needle biopsy of the tumor site before Page 2 of 10 surgery. (2) Patients who received preoperative neoadjuvant therapy. (3) Patients with a history of previous lung surgery or other malignancies. According to these criteria, we identified a total of 3075 NSCLC cases. The pathologic stage was reclassified according to the 8th edition of the American Joint Committee on Cancer Staging Manual. Pathologic examination All hematoxylin eosin slides were reviewed by at least two experienced pathologists who were blinded to patients’ clinical outcomes. Tumor STAS was defined as tumor cells either in clusters, solid nests or aggregates of single cells beyond the edge of the main tumor into airspaces in the surrounding lung parenchyma and separation from the main tumor [12]. A representative image of STAS is shown in Fig. 1. Immunohistochemistry (IHC) IHC was carried out on formalin-fixed, paraffin-embedded tissue blocks according (...truncated)