Spread through air spaces as a prognostic factor in resected non-small cell lung cancer

Abstract

Aims: To evaluate the prognostic impact of spread through air spaces (STAS) in patients with resected non-small cell lung cancer (NSCLC) and to investigate its association with clinicopathological features and survival outcomes. Methods: A retrospective analysis was conducted on 207 patients with pathological stage IA–IIIA NSCLC who underwent curative-intent surgery between 2018 and 2024. STAS was defined as the presence of micropapillary clusters, solid nests, or single tumor cells within alveolar spaces beyond the main tumor. Patients were categorized as STAS-positive or STAS-negative. Disease free survival (DFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Univariate and multivariate Cox regression models were used to assess prognostic factors. Results: STAS was identified in 57% of patients. STAS positivity was significantly associated with poor differentiation, a higher rate of lymphovascular invasion, and increased use of adjuvant chemotherapy. Median DFS was 29.9 months in STAS-positive patients but was not reached in STAS-negative patients (p<0.001). In multivariable analysis, STAS independently predicted shorter DFS (HR: 2.38; 95% CI: 1.34–4.23; p=0.003). No statistically significant association was found between STAS and OS (p=0.079). Conclusion: STAS is an independent adverse prognostic factor for DFS in resected NSCLC. Its presence should be considered in prognostic evaluation and surgical planning, particularly in patients with early-stage disease.

Keywords

• Non-small cell lung cancer
• STAS
• disease-free survival
• prognostic factors
• surgery

Rezeke edı̇len küçük hücrelı̇ dışı akcı̇ğer kanserı̇nde prognostı̇k bı̇r faktör olarak hava boşluklarına yayılım

Abstract

Amaç: Bu çalışmanın amacı, rezeke edilmiş küçük hücreli dışı akciğer kanseri (KHDAK) hastalarında hava boşlukları yoluyla yayılımın (STAS) prognostik etkisini değerlendirmek ve STAS’ın klinikopatolojik özellikler ile sağkalım sonuçlarıyla ilişkisini araştırmaktır. Yöntemler: 2018–2024 yılları arasında küratif amaçlı cerrahi uygulanan patolojik evre IA–IIIA KHDAK tanılı 207 hastanın verileri retrospektif olarak analiz edildi. STAS, ana tümör sınırları dışında alveoler boşluklarda mikropapiller kümeler, solid adacıklar veya tekil tümör hücrelerinin varlığı olarak tanımlandı. Hastalar STAS-pozitif ve STAS-negatif olarak sınıflandırıldı. Hastalıksız sağkalım (DFS) ve genel sağkalım (OS), Kaplan–Meier yöntemi ile hesaplandı. Prognostik faktörler, univaryant ve multivaryant Cox regresyon analizleri ile değerlendirildi. Bulgular: Hastaların %57’sinde STAS pozitifliği saptandı. STAS pozitifliği; kötü diferansiasyon, artmış lenfovasküler invazyon ve adjuvan kemoterapi kullanım oranı ile anlamlı şekilde ilişkiliydi. STAS pozitif hastalarda medyan DFS 29.9 ay iken, STAS negatif hastalarda medyan DFS’ye ulaşılamadı (p < 0.001). Multivaryant analizde STAS, hastalıksız sağkalım için bağımsız bir kötü prognostik faktör olarak belirlendi (HR: 2.38; %95 GA: 1.34–4.23; p = 0.003). STAS ile genel sağkalım arasında istatistiksel olarak anlamlı bir ilişki saptanmadı (p = 0.079). Sonuç: STAS, rezeke edilmiş KHDAK hastalarında hastalıksız sağkalımı olumsuz yönde etkileyen bağımsız bir prognostik faktördür. Erken evre hastalar başta olmak üzere, STAS varlığı prognostik değerlendirme ve cerrahi planlamada dikkate alınmalıdır.

Keywords

• Küçük hücreli dışı akciğer kanseri
• STAS
• hastalıksız sağkalım
• prognostik faktörler

References

1. Filho AM, Laversanne M, Ferlay J, et al. The GLOBOCAN 2022 cancer estimates: data sources, methods, and a snapshot of the cancer burden worldwide. Int J Cancer. 2025;156(7):1336-1346. doi:10.1002/ijc.35278
2. Institute NC. Cancer stat facts: lung and bronchus cancer. Surveillance, Epidemiology, and End Results (SEER) Program, NCI. 28.06.2025, Accessed 28 June 2025, https://seer.cancer.gov/statfacts/html/lungb.html
3. NCCN. NCCN Clinical Practice Guidelines in Oncology: non-small cell lung cancer (Version 5.2025). National Comprehensive Cancer Network. 28 June 2025, Accessed 28 June 2025, https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
4. Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization Classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol. 2015;10(9):1243-1260. doi:10.1097/jto.0000000000000630
5. Travis WD, Eisele M, Nishimura KK, et al. The International Association for the Study of Lung Cancer (IASLC) staging project for lung cancer: recommendation to introduce spread through air spaces as a histologic descriptor in the ninth edition of the TNM classification of lung cancer. Analysis of 4061 pathologic stage I NSCLC. J Thorac Oncol. 2024;19(7): 1028-1051. doi:10.1016/j.jtho.2024.03.015
6. Chen D, Mao Y, Wen J, et al. Tumor spread through air spaces in non-small cell lung cancer: a systematic review and meta-analysis. Ann Thorac Surg. 2019;108(3):945-954. doi:10.1016/j.athoracsur.2019.02.045
7. Terada Y, Takahashi T, Morita S, et al. Spread through air spaces is an independent predictor of recurrence in stage III (N2) lung adenocarcinoma. Interact Cardiovasc Thorac Surg. 2019;29(3):442-448. doi:10.1093/icvts/ivz116
8. Ren Y, Xie H, Dai C, et al. Prognostic impact of tumor spread through air spaces in sublobar resection for 1A lung adenocarcinoma patients. Ann Surg Oncol. 2019;26(6):1901-1908. doi:10.1245/s10434-019-07296-w

9. Toki MI, Harrington K, Syrigos KN. The role of spread through air spaces (STAS) in lung adenocarcinoma prognosis and therapeutic decision making. Lung Cancer. 2020;146:127-133. doi:10.1016/j.lungcan. 2020.04.026
10. Toyokawa G, Yamada Y, Tagawa T, et al. Significance of spread through air spaces in resected lung adenocarcinomas with lymph node metastasis. Clin Lung Cancer. 2018;19(5):395-400 e1. doi:10.1016/j.cllc. 2018.04.002
11. Lee MA, Kang J, Lee HY, et al. Spread through air spaces (STAS) in invasive mucinous adenocarcinoma of the lung: incidence, prognostic impact, and prediction based on clinicoradiologic factors. Thorac Cancer. 2020;11(11):3145-3154. doi:10.1111/1759-7714.13632
12. Aly RG, Rekhtman N, Li X, et al. Spread through air spaces (STAS) is prognostic in atypical carcinoid, large cell neuroendocrine carcinoma, and small cell carcinoma of the lung. J Thorac Oncol. 2019;14(9):1583-1593. doi:10.1016/j.jtho.2019.05.009
13. Alvarez Moreno JC, Aljamal AA, Bahmad HF, et al. Correlation between spread through air spaces (STAS) and other clinicopathological parameters in lung cancer. Pathol Res Pract. 2021;220:153376. doi:10. 1016/j.prp.2021.153376
14. Liu C, Wang YF, Wang P, et al. Predictive value of multiple imaging predictive models for spread through air spaces of lung adenocarcinoma: a systematic review and network meta analysis. Oncol Lett. 2024;27(3):122. doi:10.3892/ol.2024.14255
15. Eguchi T, Kameda K, Lu S, et al. Lobectomy is associated with better outcomes than sublobar resection in spread through air spaces (STAS)-positive T1 lung adenocarcinoma: a propensity score-matched analysis. J Thorac Oncol. 2019;14(1):87-98. doi:10.1016/j.jtho.2018.09.005
16. Gutierrez-Sainz L, López-Muñoz S, Cruz-Castellanos P, et al. Retrospective analysis of the prognostic implications of tumor spread through air spaces in lung adenocarcinoma patients treated with surgery. ESMO Open. 2022;7(5):100568. doi:10.1016/j.esmoop.2022.100568
17. Lee JS, Kim EK, Kim M, Shim HS. Genetic and clinicopathologic characteristics of lung adenocarcinoma with tumor spread through air spaces. Lung Cancer. 2018;123:121-126. doi:10.1016/j.lungcan.2018.07.020
18. Hu SY, Hsieh MS, Hsu HH, et al. Correlation of tumor spread through air spaces and clinicopathological characteristics in surgically resected lung adenocarcinomas. Lung Cancer. 2018;126:189-193. doi:10.1016/j.lungcan.2018.11.003
19. Xie H, Su H, Zhu E, et al. Morphological subtypes of tumor spread through air spaces in non-small cell lung cancer: prognostic heterogeneity and its underlying mechanism. Front Oncol. 2021;11608353. doi:10.3389/fonc.2021.608353
20. Cao L, Jia M, Sun PL, Gao H. Histopathologic features from preoperative biopsies to predict spread through air spaces in early-stage lung adenocarcinoma: a retrospective study. BMC Cancer. 2021;21(1):913. doi:10.1186/s12885-021-08648-0
21. Chen X, Zhou H, Wu M, et al. Prognostic impact of spread through air spaces in patients with ≤2 cm stage IA lung adenocarcinoma. J Thorac Dis. 2024;16(4):2432-2442. doi:10.21037/jtd-24-444
22. Tian Y, Feng J, Jiang L, et al. Integration of clinicopathological and mutational data offers insight into lung cancer with tumor spread through air spaces. Ann Transl Med. 2021;9(12):985. doi:10.21037/atm-21-2256
23. Ye R, Yu Y, Zhao R, Han Y, Lu S. Comprehensive molecular characterizations of stage I–III lung adenocarcinoma with tumor spread through air spaces. Front Genet. 2023;14:1101443. doi:10.3389/fgene. 2023.1101443
24. Kadota K, Nitadori JI, Sima CS, et al. Tumor spread through air spaces is an important pattern of invasion and impacts the frequency and location of recurrences after limited resection for small stage I lung adenocarcinomas. J Thorac Oncol. 2015;10(5):806-814. doi:10.1097/jto. 0000000000000486
25. Toyokawa G, Yamada Y, Tagawa T, et al. Significance of spread through air spaces in resected pathological stage I lung adenocarcinoma. Ann Thorac Surg. 2018;105(6):1655-1663. doi:10.1016/j.athoracsur.2018.01.037
26. Kagimoto A, Tsutani Y, Kushitani K, et al. Segmentectomy vs lobectomy for clinical stage IA lung adenocarcinoma with spread through air spaces. Ann Thorac Surg. 2021;112(3):935-943. doi:10.1016/j.athoracsur. 2020.09.020
27. Chen D, Wang X, Zhang F, et al. Could tumor spread through air spaces benefit from adjuvant chemotherapy in stage I lung adenocarcinoma? A multi-institutional study. Ther Adv Med Oncol. 2020;12: 1758835920978147. doi:10.1177/1758835920978147