Tumor spread through air spaces (STAS) is a pattern of tumor cell invasion characterized by micropapillary tumor cell clusters or single tumor cells in alveoli, beyond the primary tumor mass.
STAS was initially identified over a decade ago as a novel invasive pattern associated with recurrence and poor outcomes in non-small cell lung cancer (NSCLC). Since then, a mounting body of evidence points to STAS as a clinically meaningful morphologic finding, detectable only via histopathologic analysis and prognostic of worse outcomes.
“The presence of STAS is associated with poor prognosis and a higher local recurrence rate, particularly after limited resection. However, most of the studies [that evaluated this association] were retrospective, and only a few addressed the significance of STAS between lobectomy and limited resection,” Yasushi Yatabe, MD, said.
Dr. Yatabe, chief of diagnostic pathology at the National Cancer Center Hospital in Japan, presented the findings from the phase III non-inferiority, randomized, multicenter JCOG0802/WJOG4607L study during the 2025 World Conference on Lung Cancer (WCLC).
Presidential Symposium 2 with Lectureship Award Presentations
With on-demand access, registered WCLC 2025 attendees can still watch Yasushi Yatabe, MD, and other experts present much-awaited data during the second Presidential Symposia. Learn more
The trial, conducted by the STAS Working Group of the IASLC, sought to evaluate the association between STAS and clinical outcomes in patients with stage IA NSCLC, defined as T1aN0 (≤ 2 cm). It also evaluated whether the association differed by surgical approach (segmentectomy vs. lobectomy). Previous analyses from this study showed that segmentectomy was non-inferior to lobectomy in patients with early-stage NSCLC.
Pathology slides of resection specimens from all patients were collected for central diagnosis and digitized. The slides were then evaluated by 32 pathologists from the IASLC Pathology Committee across 15 countries, with three pathologists reviewing each case for multiple histologic features, including STAS and IASLC histologic grade.
Of the 646 cases reviewed by pathologists, 640 comprised the final pathology study cohort; of these, 322 had undergone lobectomy and 318 had undergone segmentectomy. Overall, STAS was detected in 35.5% of patients.
Analyses of relapse-free survival (RFS) and overall survival (OS) showed worse outcomes for patients with STAS-positive tumors, with significantly shorter RFS (hazard ratio [HR], 2.050; 95% confidence interval [CI], 1.462–2.874; p < 0.001) and OS (HR, 2.340; 95% CI, 1.704–3.212; p < 0.001), compared to those whose tumors were STAS negative.
The association of STAS-positivity with worse outcomes was confirmed in multivariable Cox regression analysis, which showed that STAS-positivity was an adverse prognostic marker for both RFS (HR, 1.880; p < 0.001) and OS (HR, 1.692; p = 0.004).
In analyses of outcomes by surgical approach, STAS-positive tumors had higher frequencies of local recurrences in both the lobectomy and segmentectomy subgroups. Dr. Yatabe noted that STAS-positivity was associated with higher rates of distant recurrence (compared with STAS-negative tumors) only in patients who underwent segmentectomy.
While STAS-positivity was associated with shorter RFS in both the lobectomy and segmentectomy cohorts, the association between STAS-positivity and worse OS was only significant in the lobectomy group.
The researchers also assessed differences in STAS-positivity and clinical outcomes by histologic grade of NSCLC. In the 487 patients with invasive non-mucinous adenocarcinoma, histologic grade 3 was strongly associated with STAS-positivity (p < 0.001) as well as significantly shorter RFS (HR, 2.977; p < 0.001) and OS (HR, 2.797; p < 0.001). In this subset, both STAS-positivity and high-grade histology were negative prognostic indicators for RFS, but only high histologic grade proved an independent prognostic indicator for worse OS.
“These findings confirm the original conclusion of the JCOG0802/WJOG4607L trial—that segmentectomy was non-inferior to lobectomy in patients with stage IA NSCLC—regardless of the presence of STAS. This means that even if STAS is positive in limited resection, conversion to lobectomy may not be required,” Dr. Yatabe said.
Dr. Yatabe added that these findings, regarding the association of poor prognosis with STAS-positivity in stage IA NSCLC, support consideration of adjuvant treatment, rather than conversion from segmentectomy to lobectomy.
Luisella Righi, MD, associate professor at the University of Turin, and study discussant, highlighted unresolved issues with STAS detection, including reproducibility of STAS findings. She concluded with a call for the development of deep learning models that can help pathologists detect and quantify STAS.
