Clinical implication of tumor spread through air spaces in stage IA lung adenocarcinoma: prognostic impact and association with the International Association for the Study of Lung Cancer (IASLC) grade

Introduction

Recent advances in the treatment of lung adenocarcinoma (LUAD) have been largely based on the continuous improvements in tumor staging and histological grading. The histological grading systems of LUAD play a crucial role in determining post-operative treatment and prognosis (1). According to the classification of invasive non-mucinous LUAD proposed by the World Health Organization (WHO) in 2015, the architectural subtypes are categorized as low grade (lepidic-predominant), intermediate grade (acinar- and papillary-predominant), and high grade (micropapillary- and solid-predominant) (2). This architectural grading system reflects the correlation between the predominant histological patterns and prognostic differences in patients with LUAD (3). However, recent studies have demonstrated that even a low percentage of high-grade patterns, including cribriform and fused gland patterns, may also be associated with inferior survival outcomes (4,5). As a result, the International Association for the Study of Lung Cancer (IASLC) proposed a new grading system for invasive non-mucinous LUAD in 2020, by upgrading any tumors containing ≥20% high-grade patterns into the poorly differentiated category (6). The prognostic significance of this newly devised grading system has been further validated in other studies, especially those on patients with early-stage LUAD (7,8). Meanwhile, other histopathological characteristics including lymphovascular invasion (LVI), visceral pleural invasion (VPI), and spread through airspaces (STAS) have been shown to be correlated with a higher IASLC grade (9).

STAS was first defined by Kadota et al. in 2015 as tumor cells within air spaces in the lung parenchyma beyond the edge of the main tumor, with the presence of specific morphological patterns (single cells, micropapillary clusters, and solid tumor islands) (10). It has been widely reported that STAS is associated with high-grade histological subtypes in LUAD, including the micropapillary and solid-predominant patterns (11). Other studies have shown that STAS is correlated with VPI, LVI and higher tumor stage, as well as a potential factor contributing to poor prognosis in patients with LUAD (12,13). Other research has identified STAS as an independent risk factor for recurrence-free survival (RFS) and overall survival (OS) in post-operative patients with LUAD; however, the prognostic role of STAS according to different histological subtypes and resection types is yet to be determined (11,14). In stage IA patients with LUAD, adjuvant chemotherapy is not recommended as a routine treatment following curative resection; however, one multicenter study suggested that suitable candidates with STAS could benefit from adjuvant chemotherapy (15). Studying STAS in early-stage LUAD, in particular under the novel IASLC grading system, may shed new light on postoperative treatment options and routine surveillance in patients with stage IA LUAD. To the best of our knowledge, although few studies have reported on the survival outcome of patients with stage I LUAD by incorporating STAS into the IASLC grading system (6,9,12,16), the ability of STAS to further stratify risk within specific IASLC grade categories is unclear, and the association between STAS and the IASLC grading system in pathological T1N0M0 LUAD remains to be determined.

In this study, we analyzed a cohort of patients with surgically resected pathological stage (p-stage) IA LUAD to assess the association of STAS with clinicopathological features including the IASLC grading system. We also assessed the prognostic value of STAS based on the new grading system. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-253/rc).

Methods

Study population

This retrospective study was approved by the Institutional Review Board of Shanghai Chest Hospital (No. IS24157) and was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Individual consent for this retrospective analysis was waived. We reviewed the pathological reports of 1,031 patients with p-stage T1N0M0 LUAD who underwent surgical resection with curative intent between January 2018 and October 2020 at Shanghai Chest Hospital. All included cases underwent R0 resection, and the exclusion criteria were as follows: (I) radiological evidence of synchronous or metachronous nodules; (II) a history of cancer or pre-operative anti-cancer therapies, including chemotherapy, microwave ablation, radiotherapy, etc.; (III) pathological diagnosis of invasive mucinous LUAD or other variants; and (IV) incomplete clinical information or lack of follow-up records. A total of 789 patients with p-stage IA LUAD were included for analysis in this retrospective study (Figure S1).

Data collection, radiological evaluation, and histological analysis

Clinical data, including gender, age at surgery, smoking history, pre-operative carcinoembryonic antigen (CEA) levels, pathological tumor stage [based on the tumor-node-metastasis (TNM) classification 9th edition], and surgical type, were obtained and analyzed. Chest computed tomography (CT) scans were performed for all patients within 1 month before surgery. Records of nodule type for both included non-solid and solid nodules were obtained for each patient. In our study, nodules were categorized as follows: solid nodule, a nodule with completely solid density [absence of ground-glass opacity (GGO) component]; non-solid nodule, a nodule with any GGO component, including those with both GGO and solid components (including predominantly solid) and nodules without any solid component.

The hematoxylin and eosin (H&E) stained tissue slides were reviewed by two pathologists. Histological patterns were assessed, and the percentage of each pattern was recorded in increments of 5% according to the IASLC classification (17). Complex glandular patterns, including cribriform and fused gland patterns were also identified. The newly proposed IASLC grading system was applied to each patient and categorized as follows: (I) grade 1, lepidic predominant tumors, containing no or <20% high-grade patterns (micropapillary, solid, and complex glandular patterns); (II) grade 2, acinar or papillary predominant tumors, with no or <20% high-grade patterns; and (III) grade 3, any tumor containing ≥20% high-grade patterns (6). LVI and STAS were evaluated for each patient, with STAS determination being conducted according to a previous study by Kadota et al. (10).

Patient follow-up

Each patient received regular postoperative follow-up, mainly in the outpatient department, and for patients who were reviewed in local institutions, telephone calls were performed. The follow-up interval was 3 months for the first 3 years, followed by every 6 months thereafter. Physical examination, blood tumor markers, chest CT, and abdominal ultrasound were conducted at each follow-up. Bone scans or brain magnetic resonance imaging (MRI) were performed annually or as required. OS was defined as the time from the day of surgery to the date of death or last follow-up. RFS was calculated as the interval between the date of surgery and the day of first recurrence or last follow-up.

Statistical analysis

Differences in distribution of categorical variables were assessed with the Chi-squared test. Univariable logistic regression was performed to evaluate the association between clinicopathologic features and STAS, and multivariable logistic regression was applied to identify the independent risk factors for STAS. The Kaplan-Meier method and log-rank tests were carried out to compare survival differences. Cox regression was performed to assess independent prognostic factors. A two-sided P value of <0.05 was considered statistically significant. All analyses were conducted using SPSS version 26.0 (IBM Corp., Armonk, NY, USA) and R version 4.4.1 (R Core Team, The R Foundation for Statistical Computing, Vienna, Austria).

Results

Patient characteristics

The detailed baseline characteristics for the 789 patients (n=409 female, n=380 male) with surgically resected p-stage IA LUAD are provided in Table 1. The Chi-squared test was performed to compare the distribution of different clinicopathological characteristics between the 242 patients with STAS (30.7%) and the 547 patients without STAS (69.3%). STAS-positive patients were more likely to have higher T-stage tumors (97/242, 40.1%), compared with those without STAS (144/547, 26.3%). According to the IASLC grading system, 162 (29.6%), 281 (51.4%), and 104 (19.0%) patients were categorized as having grade 1, grade 2, and grade 3 disease in STAS-negative group, respectively. The majority of patients in the STAS-positive group were stratified as grade 3 (55.8%), followed by grade 2 (43.0%) and grade 1 (1.2%). Significant differences between patients with and without STAS were also found for nodule type, type of surgery, LVI, and adjuvant therapy (P<0.001).

Association between STAS and clinicopathologic characteristics

In order to identify the risk factors that could distinguish between those patients with STAS from those without, several clinicopathologic characteristics, including radiological and pathological features, were incorporated in the logistic analysis. Significant differences between STAS-positive and STAS-negative patients were found for nodule type, pathological T stage, IASLC grading system, and LVI according to the univariable analysis (Table 2). The multivariable logistic regression analysis demonstrated that solid nodules [odds ratio (OR) =3.89; 95% confidence interval (CI): 2.69–5.62; P<0.001], IASLC grade 2 (OR =12.41, 95% CI: 3.83–40.23, P<0.001) and grade 3 tumors (OR =27.35, 95% CI: 8.24–90.82, P<0.001), and LVI (OR =3.30; 95% CI: 1.72–6.35; P<0.001) were independent risk factors for the presence of STAS in patients with p-stage IA LUAD.

STAS and the IASLC grading system stratified survival outcomes in p-stage IA LUAD

The median follow-up time for the 789 patients was 59 months. According to the survival analyses, significant differences were found for RFS and OS in patients stratified by STAS and the IASLC grading system. STAS-negative patients had superior 5-year RFS (93.4% vs. 82.2%) and OS (95.2% vs. 86.0%) compared with those with STAS (Figure 1A,1B). For patients stratified by the new grading system, grade 3 tumors had the worst survival outcomes (RFS: 84.5% and OS: 87.9%), while grade 1 (RFS: 98.8% and OS: 99.4%) and grade 2 (RFS: 89.6% and OS: 92.2%) had better survival rates (Figure 1C,1D). Using Cox regression analysis and following adjustments for significant variables identified in the univariable analysis, both STAS and IASLC grading system were identified as independent prognostic factors for unfavorable RFS [STAS: hazard ratio (HR) =2.24, 95% CI: 1.34–3.76, P=0.002; grade 2: HR =6.10, 95% CI: 1.45–25.75, P=0.01; grade 3: HR =6.95, 95% CI: 1.56–30.92, P=0.01] and OS (STAS: HR =2.85, 95% CI: 1.58–5.14, P=0.001; grade 2: HR =9.60, 95% CI: 1.29–71.65, P=0.03; grade 3: HR =11.04, 95% CI: 1.42–86.05, P=0.02) in p-stage IA LUAD (Table 3).

Figure 1 RFS and OS in patients with p-stage IA adenocarcinoma stratified by STAS (A,B) and IASLC grade (C,D). IASLC, International Association for the Study of Lung Cancer; OS, overall survival; RFS, recurrence-free survival; STAS, spread through air spaces.

STAS was associated with worse survival in patients with grade 3 tumors but not in patients with grade 2 tumors

We next investigated the prognostic impact of STAS as stratified by the IASLC grading system. As there were only three patients with STAS in the grade 1 group, the analysis was performed in the grade 2 and grade 3 groups. Of the 385 patients with grade 2 LUAD, STAS was significantly associated with OS but not RFS according to the log-rank test (Figure 2A,2B). Compared with grade 2 nodules, grade 3 nodules exhibited significant differences in RFS and OS between those with and without STAS (Figure 2C,2D).

Figure 2 RFS and OS in patients with p-stage IA adenocarcinoma stratified by STAS in the IASLC grade 2 (A,B) and grade 3 (C,D) groups. IASLC, International Association for the Study of Lung Cancer; OS, overall survival; RFS, recurrence-free survival; STAS, spread through air spaces.

Multivariable Cox regression analysis showed that in patients with grade 2 tumors, p-stage T1c tumor (2 cm < tumor ≤3 cm) was an independent prognostic factor for unfavorable RFS (HR =4.30, 95% CI: 1.07–19.08; P=0.045) and OS (HR =4.95, 95% CI: 1.14–21.54; P=0.03) (Table 4). In grade 3 p-stage IA LUAD, STAS was independently associated with unfavorable RFS (HR =2.81, 95% CI: 1.32–5.97; P=0.007) and OS (HR =2.04, 95% CI: 1.40–7.75; P=0.006) after adjustments were made for other significant variables in the univariable analysis. Data for the Cox regression analysis are presented in Tables S1,S2.

Discussion

Our study demonstrated that STAS was independentlyassociated with solid nodule, tumor with higher IASLC grade, and LVI. We found that STAS and IASLC grading were both independent factors for worse RFS and OS in patients with p-stage T1N0M0 LUAD. Furthermore, our study revealed that STAS was an independent prognostic indicator for unfavorable RFS and OS for patients with grade 3 tumors but not those with grade 2. Tumor grade plays a critical role in the treatment of patients with lung cancer, as a number of risk factors may influence the selection of postoperative therapy and follow-up intervals. Emerging evidence demonstrates that the new IASLC grading system can successfully stratify early-stage patients with LUAD in terms of prognosis and identify those patients who may benefit from adjuvant therapies (6-9). In addition to this, STAS, as an aggressive histological feature, is significantly associated with a higher tendency for tumor recurrence and worse survival in those with stage I LUAD, and some STAS-positive patients should be considered for adjuvant therapies (11,15,18). To the best of our knowledge, the association between STAS and the IASLC grading system in patients with p-stage IA LUAD, as well as their prognostic significance, has not been investigated. To address this knowledge gap, we conducted a retrospective study to determine whether IASLC grading is a significant risk factor for the presence of STAS.

In this retrospective study, STAS was observed in 30.7% (242/789) of patients, which is slightly lower than the 37.4% incidence reported in a previous meta-analysis (19). Chen et al. have attested to the correlation between STAS prevalence and higher tumor stage (14); however, in our study regarding the association between STAS and the IASLC grading system, we focused specifically on p-stage IA LUAD, which may have resulted in a lower incidence of STAS. Other clinicopathological features have been studied in terms of their relationship with STAS, including solid nodules, LVI, VPI, and a micropapillary-predominant pattern (11,13,14,19). Gao et al. reported that a solid lesion was an independent risk factor for STAS (20), and we confirmed this observation in our study. Our data also showed that the newly proposed IASLC grading system was a significant independent factor associated with the presence of STAS. In 2020, Moreira et al. established a novel grading system to stratify the prognoses of patients with invasive non-mucinous adenocarcinoma based on the presence of high-grade patterns (6). This grading system reconsidered the impact of those more invasive patterns, namely micropapillary, solid, and complex glandular patterns, even if they were not predominant in one sample. Several studies have validated this newly proposed system in patients with lung cancer and demonstrated its superiority over other grading systems (8,9,12). Studies have confirmed that non-lepidic predominant patterns are associated with STAS-positive LUAD (21,22), while others have reported an association with only micropapillary- and solid-predominant LUAD (11,14). We hypothesized that this discrepancy could be attributed to the fact that the impact of high-grade patterns is diminished in lepidic-, acinar- and papillary-predominant tumors. In our study, IASLC grade was an independent factor associated with the presence of STAS, which may suggest that it is worth evaluating the proportion of high-grade patterns as risk factors of STAS.

It is widely accepted that STAS is an aggressive feature that is associated with worse survival outcomes in patients with LUAD who have undergone surgery (10,11,13,15,19,21). In this study, we confirmed STAS as an independent prognostic factor for RFS and OS in patients with p-stage IA LUAD. However, due to the different tumor stages in the included cohort, the prognostic impact of STAS across different subgroups could not be ascertained. Kadota et al. identified an association between STAS and recurrence in patients with stage I LUAD who had undergone limited resection but not lobectomy (10). Ren et al. reported similar results for those with p-stage IA LUAD, and further demonstrated that T1c stage was associated with an increased risk for STAS (21). Dai et al. reported that STAS could more precisely stratify the prognosis of patients with T1c LUAD (11). Concerning the subgroups categorized by histological subtypes, Chen et al. found that STAS was an unfavorable prognostic factor for RFS and OS in patients with stage N0 acinar- and papillary-predominant LUAD but not those with micropapillary or solid-predominant tumors (14). Considering that the IASLC grading system was originally established for stage I LUAD when combined with p-stage and histological subtype, we speculated that applying the IASLC system to investigate the prognostic impact of STAS, an unfavorable pathological and prognostic factor, may be meaningful. According to the multivariable analysis, stage T1c tumor (2 to 3 cm) was an independent prognostic factor for RFS and OS in patients with grade 2 LUAD, while STAS was a risk factor in patients with grade 3 LUAD. Subgroup analyses showed that STAS demonstrated grade-dependent prognostic effects. STAS had greatest discriminatory power in grade 3 tumors, suggesting that possible reconsideration in postoperative treatment is required when STAS is present. According to our findings, the IASLC grading system plays an important role in addressing baseline histological subtypes in the evaluation of STAS. Our results also provide a novel perspective for understanding the prognostic impact of STAS in specific subgroups.

However, some limitations in this study should be acknowledged. First, certain selection biases arose due to the retrospective, single-center study design. Second, a relatively small number of the included patients restricted the completion of subgroup analyses, especially for grade 1 tumors and limited resections, including wedge resection and segmentectomy. Therefore, our findings warrant validation in a larger sample cohort in multicenter studies. Third, data of biomarker mutations were not examined, and thus further studies investigating the association between STAS and molecular alterations are required. In addition, due to the small number of patients with p-stage IA LUAD, another important feature, VPI, was not extensively analyzed, thereby additional studies in this population to address this issue are needed. Meanwhile, we did not evaluate the extent of STAS or its distance from the primary tumor, which may represent important prognostic variables worthy of future investigation. Finally, while our study identified a significant link between STAS, RFS and OS in grade 3 LUAD, future prospective studies are required to confirm whether these patients will benefit from adjuvant systemic therapies.

Conclusions

Solid nodules, IASLC grade, and LVI were independent factors associated with the presence of STAS. Both STAS and the IASLC grading system were significant prognostic factors for RFS and OS in patients with p-stage IA LUAD. Among those with IASLC grade 2 tumors, T1c tumor was independently associated with unfavorable RFS and OS. Meanwhile, STAS was significantly associated with RFS and OS in patients with IASLC grade 3 early-stage LUAD. These findings suggest that STAS and IASLC grade can be used to identify a subset of early-stage LUAD patients who may benefit from adjuvant therapy.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-253/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-253/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-253/prf

Funding: This work was supported by the National Natural Science Foundation of China (No. 82102965).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-253/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by institutional Review Board of Shanghai Chest Hospital (No. IS24157) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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