Spread through air spaces as an independent prognostic factor in resected lung adenocarcinoma: the role of resection type

Abstract

Background

Spread through air spaces (STAS) has emerged as an independent prognostic factor in lung adenocarcinoma, yet its interaction with resection type remains poorly defined. We aimed to evaluate the prognostic impact of STAS on overall survival (OS) and disease-free survival (DFS) according to resection type in surgically resected lung adenocarcinoma.

Methods

We retrospectively analysed 252 patients who underwent resection for lung adenocarcinoma at a single institution between 2016 and 2023. Patients were stratified into four groups by STAS status and resection type. Overall survival and DFS were estimated using Kaplan-Meier analysis with log-rank testing. Multivariable Cox regression was performed to identify independent prognostic factors.

Results

STAS was present in 148 patients (58.7%). Among the four groups, patients who underwent STAS-positive sublobar resection demonstrated the worst prognosis, with a mortality rate of 50.0%, a median OS of 98 months, and a 5-year OS of 51.3%. STAS-positive lobar resection patients achieved a 5-year OS of 70.1%, comparable to STAS-negative lobar patients (67.8%). On multivariable Cox regression, STAS-positive sublobar resection was an independent predictor of mortality (HR 2.29, 95% CI 1.10–4.75; p = 0.026), as were lymphovascular invasion (HR 2.28; p = 0.001) and visceral pleural invasion (HR 2.14; p = 0.020). No significant difference in DFS was observed across groups (p = 0.963), suggesting that STAS primarily influences prognosis through its impact on overall survival rather than recurrence.

Conclusions

STAS positivity combined with sublobar resection independently predicts poor overall survival in lung adenocarcinoma. STAS status should inform surgical decision-making when sublobar resection is considered.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s12957-026-04490-5.

Background

Lung cancer remains the leading cause of cancer-related mortality worldwide, accounting for approximately 1.8 million deaths annually [1]. Adenocarcinoma has emerged as the most common histological subtype globally, surpassing squamous cell carcinoma in both men and women, a shift attributed in part to changes in tobacco composition and increasing exposure to environmental carcinogens [2].

Surgical resection remains the cornerstone of treatment for early-stage non-small cell lung cancer (NSCLC). Lobectomy with systematic mediastinal lymph node dissection has long been considered the standard of care [3]. However, the landmark randomised trials JCOG0802 and CALGB 140,503 established sublobar resection as a non-inferior alternative to lobectomy for peripheral clinical stage IA NSCLC measuring 2 cm or less, prompting reassessment of surgical approaches in early-stage NSCLC [4, 5]. As sublobar resection becomes increasingly adopted, identifying factors compromising oncological safety is critically important.

Spread through air spaces (STAS), first described by Kadota et al. in 2015 and subsequently incorporated into the 2015 WHO classification of lung tumors, refers to the presence of tumor cells (forming micropapillary structures, solid nests, or isolated single cells) within air spaces in the lung parenchyma beyond the edge of the main tumor [6]. Since its introduction, STAS has been consistently identified as an independent adverse prognostic factor in resected lung adenocarcinoma, associated with higher rates of recurrence and reduced overall survival across multiple institutional series [7, 8].

The prognostic impact of STAS appears to be modulated by the extent of surgical resection. Several studies have demonstrated that STAS-positive tumors undergoing sublobar resection carry a substantially higher risk of locoregional recurrence and worse survival compared with lobectomy, whereas STAS-positive patients treated with lobectomy achieve outcomes comparable to STAS-negative patients [9, 10]. A 2025 systematic review confirmed that lobectomy remains the preferred approach in STAS-positive patients, as sublobar resection significantly increases recurrence risk in this subgroup [11]. This creates a clinical dilemma: while randomised evidence supports the oncological equivalence of sublobar resection in selected patients, emerging pathological data suggest that STAS positivity may define a subset in whom sublobar resection compromises survival. However, most published series have focused on early-stage tumors with limited sample sizes, and the independent prognostic value of STAS in a broader surgical cohort stratified by resection type remains incompletely characterised.

These findings have gained further institutional weight with the IASLC’s recent proposal to formally recognise STAS as a histological descriptor in the 9th edition of the TNM classification of lung cancer [12]. In that analysis, STAS was found to be an independent predictor of poor prognosis, independent of visceral pleural invasion and lymphovascular invasion, supporting its potential role in refining lung cancer staging.

In the context of these developments, the present study aimed to evaluate the prognostic impact of STAS on overall survival and disease-free survival according to resection type in a single-institution cohort of 252 surgically resected lung adenocarcinoma patients, and to identify the clinical and pathological determinants of STAS positivity.

Patients and methods

Study design and patient selection

A retrospective cohort study was conducted at the Department of Thoracic Surgery, Marmara University Pendik Training and Research Hospital. Patients who underwent surgical resection for primary lung adenocarcinoma between January 2016 and December 2023 were screened. Invasive mucinous adenocarcinoma and adenocarcinoma in situ were excluded, as STAS assessment in mucinous subtypes is pathologically unreliable. Patients with M1 disease, R1 resection, incomplete data, synchronous malignancy, neoadjuvant therapy, or 90-day postoperative mortality were also excluded. Extrathoracic metastases were confirmed by PET-CT and multidisciplinary oncology board consensus. Pathological staging was performed according to the 8th edition of the TNM classification. After exclusions, 252 patients were included in the final analysis (Fig. 1): 205 underwent lobar resection and 47 underwent sublobar resection. The study was approved by the institutional ethics committee (approval number 09.2024.1008) and conducted in accordance with the Declaration of Helsinki.

Fig. 1.

Patient inclusion flow diagram. Patients were screened and excluded according to predefined criteria. The final cohort of 252 patients was stratified into four groups based on STAS status and resection type. STAS: spread through air spaces

Surgical technique

All procedures were performed under general anaesthesia with double-lumen endotracheal intubation. The surgical approach was either video-assisted thoracoscopic surgery (VATS) or open thoracotomy based on tumor characteristics and surgeon’s preference. Lobar resections included lobectomy, bilobectomy, and pneumonectomy; extended resections involving chest wall or intrapericardial structures were performed when oncologically indicated. Sublobar resections comprised anatomical segmentectomy and wedge resection. Systematic mediastinal lymph node dissection was performed in all patients. Postoperative care followed the Enhanced Recovery After Thoracic Surgery (ERATS) protocol.

Pathological assessment

All pathological specimens were reviewed by a single dedicated thoracic pathologist. Histological subtypes were classified according to the 2021 WHO classification of thoracic tumors. STAS was defined as tumor cells spreading beyond the edge of the main tumor into adjacent alveolar parenchyma through air spaces, identified on haematoxylin and eosin-stained sections at 200× magnification. Intraoperative frozen section analysis for STAS was not performed in this cohort; STAS status was determined solely on definitive paraffin-embedded sections. Tumor grade, lymphovascular invasion, visceral pleural invasion, and perineural invasion were recorded for all specimens.

Statistical analysis

Descriptive statistics were reported as mean ± standard deviation or median (range) for continuous variables, and as frequency and percentage for categorical variables. Normality was assessed using the Kolmogorov-Smirnov test. Between-group comparisons were performed using the Mann-Whitney U test for continuous variables and the Pearson chi-square or Fisher’s exact test for categorical variables. Overall survival (OS) was defined as the time from surgery to death from any cause, and disease-free survival (DFS) as the time from surgery to recurrence or death. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test. Patients were stratified into four groups according to STAS status and resection type. Univariable and multivariable Cox proportional hazards regression analyses were performed to identify independent prognostic factors; results were reported as hazard ratios (HR) with 95% confidence intervals (CI). Logistic regression was used to identify predictors of STAS positivity. A p-value of less than 0.05 was considered statistically significant. All analyses were performed using SPSS version 27.0 (IBM Corp., Armonk, NY, USA). This study was presented in part at the European Lung Cancer Congress (ELCC) 2026, Copenhagen, Denmark (poster presentation).

To address the imbalance between lobar and sublobar resection groups, propensity score matching (PSM) was performed using 1:1 nearest-neighbour matching with a caliper of 0.22 (0.2 × standard deviation of the logit propensity score). Matching covariates included age, sex, tumor size, tumor grade, visceral pleural invasion, lymphovascular invasion, and STAS status. Covariate balance after matching was assessed using the Mann-Whitney U test for continuous variables and chi-square or Fisher exact test for categorical variables (Supplementary Table 1A). Survival analyses in the matched cohort were performed using the same methods as the primary analysis; results are presented in Supplementary Tables 1B and 1C. Comorbidity burden was assessed across all 252 patients and compared between sublobar and lobar resection groups, and across wedge resection, segmentectomy, and lobar resection subgroups, using chi-square or Fisher exact tests. Comorbidity categories included hypertension, diabetes mellitus, chronic obstructive pulmonary disease or asthma, and cardiovascular disease.

Artificial intelligence (AI)-assisted tools were used in the preparation of this manuscript for language editing and data analysis support. All scientific content, interpretations, and conclusions are the sole responsibility of the authors.

Results

A total of 252 patients were included. The median age was 63 years (range 38–86); 174 patients (69.0%) were male and 205 (81.3%) underwent lobar resection. Adjuvant therapy was administered to 122 patients (48.4%). Median follow-up was 44 months (range 4–108). Full baseline characteristics are presented in Table 1. Among patients who underwent sublobar resection, 22 (46.8%) received wedge resection and 25 (53.2%) underwent segmentectomy.

Table 1.

Baseline characteristics by STAS status

Variable	All (n = 252)	STAS(−) (n = 104)	STAS(+) (n = 148)	p
Age, years, median (range)	63 (38–86)	63 (45–86)	63 (38–82)	0.743
Sex
Male	174 (69.0%)	77 (74.0%)	97 (65.5%)
Female	78 (31.0%)	27 (26.0%)	51 (34.5%)	0.194
Tumor size, cm, median (range)	2.2 (0.5–10.0)	2.0 (0.5–10.0)	2.5 (0.5–8.0)	0.081
T descriptor
T1a	21 (8.3%)	14 (13.5%)	7 (4.7%)
T1b	85 (33.7%)	41 (39.4%)	44 (29.7%)
T1c	57 (22.6%)	16 (15.4%)	41 (27.7%)
T2a	40 (15.9%)	16 (15.4%)	24 (16.2%)
T2b	11 (4.4%)	3 (2.9%)	8 (5.4%)
T3	26 (10.3%)	7 (6.7%)	19 (12.8%)
T4	12 (4.8%)	7 (6.7%)	5 (3.4%)	0.014
Tumor grade
Grade 1	30 (11.9%)	20 (19.2%)	10 (6.8%)
Grade 2	97 (38.5%)	41 (39.4%)	56 (37.8%)
Grade 3	124 (49.2%)	42 (40.4%)	82 (55.4%)	0.007
Histological subtype
Acinar	107 (42.5%)	38 (36.5%)	69 (46.6%)
Solid	60 (23.8%)	29 (27.9%)	31 (20.9%)
Papillary	30 (11.9%)	12 (11.5%)	18 (12.2%)
Lepidic	27 (10.7%)	18 (17.3%)	9 (6.1%)
Micropapillary	21 (8.3%)	2 (1.9%)	19 (12.8%)
Othera	7 (2.8%)	5 (4.8%)	2 (1.4%)	0.001*
Pathological stage
Stage I	164 (65.1%)	76 (73.1%)	88 (59.5%)
Stage II	41 (16.3%)	21 (20.2%)	15 (14.4%)
Stage III	46 (18.3%)	13 (12.5%)	33 (22.3%)	0.110
Nodal status
N0	192 (76.2%)	88 (84.6%)	104 (70.3%)
N1	31 (12.3%)	12 (11.5%)	19 (12.8%)
N2: single station	14 (5.6%)	2 (1.9%)	12 (8.1%)
N2: multiple stations	15 (6.0%)	2 (1.9%)	13 (8.8%)	0.013
Pathological features
Visceral pleural invasion	44 (17.5%)	12 (11.5%)	32 (21.6%)	0.056
Lymphovascular invasion	105 (41.7%)	23 (22.1%)	82 (55.4%)	< 0.001
Perineural invasion	10 (4.0%)	2 (1.9%)	8 (5.4%)	0.286
Resection type
Lobar resection	205 (81.3%)	83 (79.8%)	122 (82.4%)
Sublobar resection	47 (18.7%)	21 (20.2%)	26 (17.6%)	0.717
Adjuvant therapy	122 (48.4%)	47 (45.2%)	75 (50.7%)	0.466
Outcomes
Mortality	82 (32.5%)	32 (30.8%)	50 (33.8%)	0.714
Recurrence	78 (31.0%)	33 (31.7%)	45 (30.4%)	0.932
Follow-up, months, median (range)	44 (4–108)	45 (4–107)	42 (4–108)	0.540

Data are presented as median (range) or n (%). p values by Mann-Whitney U test for continuous variables and chi-square or Fisher exact test for categorical variables

STAS Spread through air spaces, VPI Visceral pleural invasion, LVI Lymphovascular invasion, PNI Perineural invasion

^aOther subtypes were excluded from chi-square analysis due to small cell counts

^*p value calculated for the five major subtypes (n=245)

STAS was identified in 148 patients (58.7%). On logistic regression, lymphovascular invasion (OR 4.02, 95% CI 2.11–7.68; p < 0.001) and tumor grade (OR 2.26, 95% CI 1.32–3.88; p = 0.003) were independent predictors of STAS positivity. Solid subtype was independently associated with a lower likelihood of STAS positivity compared with other subtypes (OR 0.34, 95% CI 0.14–0.79; p = 0.012), despite its aggressive histological features. Although micropapillary subtype showed the strongest positive association with STAS among all subtypes (OR 3.29), this did not reach statistical significance, likely reflecting the limited number of micropapillary cases in this cohort (n = 21). Age, sex, tumor size, visceral pleural invasion, and micropapillary subtype were not independently associated with STAS status (Table 2).

Table 2.

Predictors of STAS positivity: logistic regression

Variable	OR	95% CI	p
Age	0.99	0.95–1.02	0.414
Female sex	1.93	1.00–3.74	0.050
Tumor size	0.88	0.72–1.07	0.203
Tumor grade	2.26	1.32–3.88	0.003
Visceral pleural invasion	2.15	0.79–5.88	0.137
Lymphovascular invasion	4.02	2.11–7.68	< 0.001
Micropapillary subtype	3.29	0.64–16.87	0.154
Solid subtype	0.34	0.14–0.79	0.012

OR odds ratio, CI confidence interval, STAS spread through air spaces, VPI visceral pleural invasion, LVI lymphovascular invasion

Patients were stratified into four groups according to STAS status and resection type (Fig. 1). Overall survival differed significantly across groups (log-rank p = 0.014; Table 3, Fig. 2). The STAS-positive sublobar resection group demonstrated the worst prognosis, with a mortality rate of 50.0%, a median OS of 98 months, and a 5-year OS of 51.3%. In contrast, STAS-positive patients who underwent lobar resection achieved a 5-year OS of 70.1%, comparable to the STAS-negative lobar resection group (67.8%), with median OS not reached in either group. OS differed significantly between STAS-positive lobar and sublobar groups (log-rank p = 0.002). No significant difference in disease-free survival was observed across the four groups (log-rank p = 0.963), suggesting that STAS influences prognosis primarily through overall survival rather than recurrence (Fig. 3).

Table 3.

Survival outcomes by STAS status and resection type

Group	n	Mortality n (%)	Median OS (mo)	1-yr OS (%)	3-yr OS (%)	5-yr OS (%)	Median DFS (mo)	1-yr DFS (%)	3-yr DFS (%)	5-yr DFS (%)
STAS(−) Lobar	83	28 (33.7%)	106	89.1	82.5	67.8	NR	89.9	66.6	61.3
STAS(−) Sublobar	21	4 (19.0%)	NR	95.2	88.4	75.8	NR	92.9	73.8	59.1
STAS(+) Lobar	122	37 (30.3%)	NR	92.6	79.5	70.1	NR	88.0	70.6	62.8
STAS(+) Sublobar	26	13 (50.0%)	98	65.4	57.7	51.3	96	83.5	76.6	76.6

NR not reached, OS overall survival, DFS disease-free survival, mo months, STAS spread through air spaces

Log-rank OS overall p=0.014; DFS overall p=0.963. STAS(+) lobar vs STAS(+) sublobar OS: p=0.002

Fig. 2.

Kaplan-Meier curves for overall survival according to STAS status and resection type. Log-rank p = 0.014. NR: not reached. STAS: spread through air spaces

Fig. 3.

Kaplan-Meier curves for disease-free survival according to STAS status and resection type. Log-rank p = 0.963. NR: not reached. STAS: spread through air spaces

On multivariable Cox regression for overall survival, STAS-positive sublobar resection was an independent predictor of mortality (HR 2.29, 95% CI 1.10–4.75; p = 0.026), alongside lymphovascular invasion (HR 2.28, 95% CI 1.39–3.74; p = 0.001), visceral pleural invasion (HR 2.14, 95% CI 1.13–4.07; p = 0.020), and age (HR 1.05, 95% CI 1.02–1.08; p < 0.001). STAS positivity in the context of lobar resection was not independently associated with mortality (HR 0.69; p = 0.157). For disease-free survival, lymphovascular invasion (HR 2.08; p = 0.005) and perineural invasion (HR 2.32; p = 0.038) were independent predictors of recurrence, while STAS-positive sublobar resection was not independently associated with recurrence risk (HR 1.07; p = 0.892) (Table 4). Comorbidity burden was comparable between sublobar and lobar resection groups across all individual comorbidity categories and overall (all p > 0.05; Supplementary Table 2A). When sublobar resection was stratified into wedge resection and segmentectomy, no significant between-group differences were observed (all p > 0.10; Supplementary Table 2B).

Table 4.

Multivariable Cox regression for OS and DFS

Variable	Overall Survival			Disease-free Survival
	HR	95% CI	p	HR	95% CI	p
Resection group (ref: STAS(−) Lobar)
STAS(−) Sublobar	1.16	0.39–3.47	0.786	1.55	0.57–4.27	0.392
STAS(+) Lobar	0.69	0.42–1.15	0.157	0.69	0.42–1.16	0.264
STAS(+) Sublobar	2.29	1.10–4.75	0.026	0.99	0.39–2.50	0.978
Pathological factors
Lymphovascular invasion	2.28	1.39–3.74	0.001	2.08	1.25–3.45	0.005
Visceral pleural invasion	2.14	1.13–4.07	0.020	1.36	0.74–2.52	0.328
Perineural invasion	0.95	0.29–3.12	0.932	2.32	1.05–5.14	0.038
Tumor grade	1.23	0.86–1.76	0.264	1.42	0.98–2.06	0.066
Age	1.05	1.02–1.08	< 0.001	0.99	0.96–1.02	0.529
Tumor size	0.98	0.84–1.14	0.829	1.12	0.97–1.28	0.124

HR hazard ratio, CI confidence interval, STAS spread through air spaces, VPI visceral pleural invasion, LVI lymphovascular invasion, PNI perineural invasion

Reference group: STAS(−) lobar resection

Discussion

The present study demonstrated that the prognostic impact of STAS in resected lung adenocarcinoma is critically determined by resection type, a relationship that, despite growing evidence, had not been formally characterised in a stratified four-group cohort. Our findings support the position that STAS positivity defines a subset in whom sublobar resection compromises survival: in STAS-positive patients, sublobar resection was independently associated with worse overall survival, while lobectomy effectively neutralised this risk. This finding is clinically significant in the context of the expanding adoption of sublobar resection following JCOG0802 and CALGB 140,503 [4, 5].

Our results show that STAS-positive patients undergoing sublobar resection had a 5-year OS of 51.3%, compared with 70.1% in STAS-positive lobar resection patients. This pattern aligns with data reported by Khalil et al., who demonstrated in 421 resected stage I patients that 5-year OS was 73% in STAS-positive sublobar patients compared with 90% in lobectomy patients regardless of STAS status [10]. Eguchi et al., in a propensity score-matched analysis of STAS-positive T1 adenocarcinoma, similarly found that sublobar resection was independently associated with lung cancer-specific mortality (subhazard ratio 2.63, p = 0.021), while no such association was observed in STAS-negative patients [9]. Importantly, in our cohort STAS-positive lobar resection patients achieved survival comparable to STAS-negative lobar resection patients (5-year OS 70.1% vs. 67.8%), supporting the concept that lobectomy neutralises the adverse prognostic impact of STAS. This reinforces the implication that STAS status should guide the choice between lobar and sublobar resection, as supported by recent meta-analytic evidence [11].

The absence of a significant difference in disease-free survival across the four groups (log-rank p = 0.963) suggests that STAS contributes to prognosis primarily through overall survival rather than through recurrence frequency. Liu et al. reported that among 5,947 patients the survival impact of resection type was more pronounced for OS than for DFS in STAS-positive patients [13]. However, given the limited sample size of our cohort, this finding warrants confirmation in larger series. The numerically higher 5-year DFS in the STAS-positive sublobar group (76.6%) warrants cautious interpretation given the small sample size and high censoring rate. Furthermore, overall comorbidity prevalence was significantly higher in STAS-positive patients compared with STAS-negative patients (83.2% vs. 67.9%; p = 0.007; Supplementary Table 2), which may contribute to the observed OS difference through competing non-cancer mortality. Whether the observed OS difference is driven by cancer-specific mortality, competing non-cancer mortality, or both cannot be determined from the available data, and we acknowledge this as an important limitation.

Lymphovascular invasion emerged as the strongest independent predictor of STAS positivity in logistic regression (OR 4.02) and independently predicted both OS and DFS in multivariable Cox analysis. This is consistent with prior reports of a shared biological substrate between STAS and LVI [9], and with the recent demonstration by Chen et al. that STAS combined with LVI constitutes the highest-risk prognostic subgroup in stage I NSCLC, with conventional adjuvant chemotherapy offering limited benefit in this population [14]. Visceral pleural invasion was likewise independently associated with OS, and perineural invasion with DFS. These findings support the view that STAS, LVI, and VPI are complementary histological descriptors, a position endorsed by the IASLC in recommending STAS as a descriptor in the 9th TNM edition [12].

The association between histological subtype and STAS positivity in our cohort was consistent with published literature, with micropapillary pattern showing the strongest numerical association (OR 3.29) and lepidic pattern demonstrating the lowest STAS prevalence (33.3%), in keeping with its predominantly non-invasive growth pattern. Across the entire sublobar cohort (wedge n = 22, segmentectomy n = 25), no statistically significant differences were identified in visceral pleural invasion (9.1% vs. 4.0%, p = 0.909), lymphovascular invasion (45.5% vs. 32.0%, p = 0.518), overall survival (5-year OS 52.1% vs. 73.8%, log-rank p = 0.173), or disease-free survival (5-year DFS 56.3% vs. 78.6%, log-rank p = 0.367). Within the STAS-positive sublobar group, 14 patients (53.8%) underwent wedge resection and 12 patients (46.2%) underwent anatomical segmentectomy. Wedge resection patients had a numerically shorter median overall survival compared with those who underwent segmentectomy (22.5 vs. 29.5 months); however, this difference did not reach statistical significance (log-rank p = 0.764), likely reflecting the limited sample size of each subgroup. Visceral pleural invasion and lymphovascular invasion rates were comparable between wedge resection and segmentectomy patients (VPI: 14.3% vs. 8.3%, p = 1.000; LVI: 64.3% vs. 58.3%, p = 1.000), indicating that the two subgroups were pathologically similar at baseline. While these findings are insufficient to draw definitive conclusions, the numerical trend favouring segmentectomy is biologically plausible: anatomical segmentectomy provides wider surgical margins and includes segmental lymph node dissection compared with wedge resection, potentially better addressing the aerogenous spread pattern characteristic of STAS-positive tumors. Whether segmentectomy may partially mitigate the survival disadvantage associated with sublobar resection in STAS-positive patients warrants investigation in larger prospective series. Although micropapillary subtype showed the strongest numerical association with STAS (OR 3.29), this did not reach statistical significance, likely due to the limited number of micropapillary cases in our cohort (n = 21). Larger series have consistently identified micropapillary pattern as the subtype most associated with STAS positivity [15]. Notably, the independent prognostic role of STAS has been confirmed across different surgical contexts, including patients with multiple primary lung cancers, in whom STAS positivity was associated with a recurrence rate of 34% compared with 0% in STAS-negative patients [16]. Female sex demonstrated a borderline association with STAS positivity on multivariable logistic regression (OR 1.93, p = 0.050). Given the borderline p-value and the absence of consistent evidence in the published literature identifying female sex as an independent determinant of STAS positivity, this finding should be considered hypothesis-generating and warrants confirmation in larger series.

From a practical surgical perspective, the potential role of intraoperative STAS assessment warrants consideration. If frozen section diagnosis of STAS were reliably achievable, it could enable real-time surgical decision-making, allowing conversion from a planned sublobar resection to lobectomy when STAS positivity is identified intraoperatively. However, frozen section assessment of STAS remains technically challenging and is not yet standardised across institutions, being subject to sampling error and interobserver variability. In our cohort, intraoperative frozen section analysis for STAS was not performed. Prospective studies incorporating intraoperative STAS assessment are needed to determine whether this approach may improve surgical decision-making in real time.

Cause-specific mortality data were not available in our retrospective dataset, precluding formal cancer-specific survival or competing risk analysis. Limitations of this study include the retrospective single-institution design, the relatively small size of the STAS-positive sublobar group (n = 26), and our cohort predating the widespread adoption of JCOG0802 and CALGB 140,503 recommendations; The sublobar resection cohort is relatively small (n = 47), reflecting the institutional practice pattern during the study period, in which sublobar resection was performed predominantly for functional rather than oncological indications, predating the widespread adoption of guideline-recommended oncological sublobar resection following the JCOG0802 and CALGB 140,503 trials. Pulmonary function variables including FEV1 and DLCO, as well as ECOG performance status, were not systematically recorded in our institutional database during the study period and could not be retrospectively retrieved; this precluded their inclusion in the multivariable models and represents an additional limitation of the present study. STAS assessment was performed by a single thoracic pathologist with extensive experience in this field; interobserver agreement data could not be obtained retrospectively. Restriction to adenocarcinoma reflects the unreliability of STAS assessment in invasive mucinous subtypes, and our findings should be evaluated in other histological subtypes in dedicated studies. None of the patients in the STAS-positive sublobar resection group received adjuvant therapy, precluding any assessment of its potential benefit in this high-risk subgroup; whether adjuvant treatment may improve outcomes in STAS-positive patients undergoing sublobar resection remains an important question for future investigation [14]. Accordingly, prospective multicentre studies with pre-planned STAS assessment in oncological sublobar resection candidates are needed to validate these findings and to determine the potential role of adjuvant therapy in this high-risk subgroup. The small number of patients remaining at risk beyond 60 months, particularly in the sublobar resection subgroups (STAS-positive sublobar: n = 6 at 60 months; STAS-negative sublobar: n = 6 at 60 months), limits the precision of 5-year survival estimates in these groups.

Conclusion

In this single-institution cohort of 252 surgically resected lung adenocarcinoma patients, STAS positivity combined with sublobar resection was independently associated with significantly worse overall survival, while STAS-positive patients undergoing lobar resection achieved outcomes comparable to STAS-negative patients. These findings demonstrate that the prognostic impact of STAS is determined by the extent of surgical resection, supporting incorporation of STAS status into surgical decision-making when sublobar resection is considered. Lymphovascular invasion and visceral pleural invasion were identified as independent predictors of overall survival alongside STAS-positive sublobar resection, reinforcing the complementary prognostic value of these pathological descriptors. The absence of a significant difference in disease-free survival across groups suggests that STAS influences prognosis predominantly through overall survival rather than recurrence. Prospective multicentre studies with larger sublobar cohorts are needed to validate these findings and to determine whether adjuvant therapy may mitigate the survival disadvantage associated with STAS-positive sublobar resection.

Abbreviations

CI

Confidence interval

CT

Computed tomography

DFS

Disease-free survival

ERATS

Enhanced Recovery After Thoracic Surgery

HR

Hazard ratio

IASLC

International Association for the Study of Lung Cancer

LVI

Lymphovascular invasion

NSCLC

Non-small cell lung cancer

NR

Not reached

OR

Odds ratio

OS

Overall survival

PET

Positron emission tomography

PNI

Perineural invasion

STAS

Spread through air spaces

TNM

Tumor-node-metastasis

VATS

Video-assisted thoracoscopic surgery

VPI

Visceral pleural invasion

WHO

World Health Organization

Authors’ contributions

R.E. conceived and designed the study, collected and analysed the data, and wrote the main manuscript text. E.B. performed all pathological assessments. K.B. supervised the study and provided critical revision of the manuscript. All authors reviewed and approved the final manuscript.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This study was approved by the Marmara University Faculty of Medicine Non-Drug and Non-Medical Device Research Ethics Committee (approval number 09.2024.1008, date 04.10.2024). This study was conducted in accordance with the Declaration of Helsinki. Although retrospective in design, written informed consent for participation in research was obtained from all patients as part of routine clinical practice at our institution.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.