Prognostic Significance and Classification Value of Tumor Budding,Single Cell Invasion,and Spread Through Airspaces (STAS) in Lung Squamous Cell Carcinoma
Restricted accessResearch articleFirst published online 2026
Prognostic Significance and Classification Value of Tumor Budding,Single Cell Invasion,and Spread Through Airspaces (STAS) in Lung Squamous Cell Carcinoma
Lung squamous cell carcinomas (LSCC) currently lack a standardized histopathological grading system, unlike their adenocarcinoma counterparts. In this retrospective study, we examined the prognostic significance and classification value of tumor budding (TB), single-cell invasion, tumor budding nest size (TBNS) grading system, and spread through airspaces (STAS).
Methods
About 268 patients who underwent surgical resection for LSCC between November 2011 and December 2021 were evaluated. TB was assessed in hematoxylin and eosin-stained sections at ×200 magnification from the area showing the most prominent budding activity. A 3-tier TBNS grading system was established by combining the number of tumor buds and the size of tumor cell nests. STAS presence was also evaluated.
Results
Our analysis revealed significant associations between high TBNS scores and adverse pathological features, including higher tumor stage, pleural and lymphovascular invasion, increased stromal fibrosis, and lymph node metastasis. Furthermore, survival analysis demonstrated that high TB, single-cell invasion, elevated TBNS scores, and the presence of STAS were all linked to reduced overall and disease-free survival (P < .005).
Conclusion
These findings suggest that TB, TBNS, and STAS are valuable histopathological markers that may offer additional prognostic insight beyond traditional staging parameters. Incorporating a standardized assessment of these features into routine pathology reports could improve prognostic stratification and inform clinical decision-making in patients with LSCC.
BrayFLaversanneMSungH, et al.Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263. doi:10.3322/caac.21834
2.
WHO Classification of Tumours Editorial BoardThoracic Tumors. 5th edn, Vol 5. International Agency for Research on Cancer; 2021.
3.
WarthAMuleyTKossakowskiCA, et al.Prognostic impact of intra-alveolar tumor spread in pulmonary adenocarcinoma. Am J Surg Pathol. 2015;39(6):793-801. doi:10.1097/PAS.0000000000000409
4.
AminMBGreeneFLEdgeSB, et al.The Eighth Edition AJCC Cancer Staging Manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. 2017;67(2):93-99. doi:10.3322/caac.21388
5.
KadotaKNitadoriJWooKM, et al.Comprehensive pathological analyses in lung squamous cell carcinoma: single cell invasion, nuclear diameter, and tumor budding are independent prognostic factors for worse outcomes. J Thorac Oncol. 2014;9(8):1126-1139. doi:10.1097/JTO.0000000000000253
6.
LugliAKirschRAjiokaY, et al.Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol. 2017;30(9):1299-1311. doi:10.1038/modpathol.2017.46
BasileDBroudinCEmileJF, et al.Tumor budding is an independent prognostic factor in stage III colon cancer patients: a post-hoc analysis of the IDEA-France phase III trial (PRODIGEGERCOR). Ann Oncol. 2022;33(6):628-637. doi:10.1016/j.annonc.2022.03.002
9.
UenoHMurphyJJassJRMochizukiHTalbotIC. Tumour ‘budding’ as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology. 2002;40(2):127-132. doi:10.1046/j.1365-2559.2002.01324.x
10.
BadanaleRMohtaVWaghA, et al.Prognostic role of tumor budding and worst pattern of invasion in lymph node metastasis and disease-free survival in oral squamous cell cancer patients: result from Central India's Regional Cancer Centre. Indian J Otolaryngol Head Neck Surg. 2024 Aug;76(4):3261-3270. doi: 10.1007/s12070-024-04661-4.Epub 2024 Apr 12. PMID: 39130226; PMCID: PMC11306858.
11.
LawlorRTVeroneseNNottegarA, et al.Prognostic role of high-grade tumor budding in pancreatic ductal adenocarcinoma: a systematic review and meta-analysis with a focus on epithelial to mesenchymal transition. Cancers (Basel). 2019 Jan 19;11(1):113. doi: 10.3390/cancers11010113.PMID: 30669452; PMCID: PMC6356259.
12.
PunCLuuSSwallowC, et al.Prognostic significance of tumour budding and desmoplastic reaction in intestinal-type gastric adenocarcinoma. Int J Surg Pathol. 2023 Sep;31(6):957-966. doi: 10.1177/10668969221105617.Epub 2022 Jun 20. PMID: 35726174; PMCID: PMC10492422.
13.
ZhangWSongYShiH, et al.Further confirmation of a highly prognostic grading scheme based upon tumour budding and cell cluster size in cervical squamous cell carcinoma. Histopathology. 2025 May;86(6):967-978. doi: 10.1111/his.15404.Epub 2024 Dec 27. PMID: 39727044.
14.
JesinghausMStrehlJBoxbergM, et al.Introducing a novel highly prognostic grading scheme based on tumour budding and cell nest size for squamous cell carcinoma of the uterine cervix. J Pathol Clin Res. 2018;4(2):93-102. doi:10.1002/cjp2.95
15.
WeichertWKossakowskiCHarmsA, et al.Proposal of a prognostically relevant grading scheme for pulmonary squamous cell carcinoma. Eur Respir J. 2016;47(3):938-946. doi:10.1183/13993003.00937-2015
16.
KadotaKMiyaiYKatsukiN, et al.A grading system combining tumor budding and nuclear diameter predicts prognosis in resected lung squamous cell carcinoma. Am J Surg Pathol. 2017;41(6):750-760. doi:10.1097/PAS.0000000000000826
17.
TravisWDBrambillaENicholsonAG, 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
18.
KadotaKNitadoriJISimaCS, 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
19.
KimuraTNakamuraHOmuraA, et al.Novel imprint cytological classification is correlated with tumor spread through air spaces in lung adenocarcinoma. Lung Cancer. 2020;148(10):62–68. doi:10.1016/j.lungcan.2020.08.005
20.
TravisWDEiseleMNishimuraKK, 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
21.
DagherSSulaimanABayle-BleuezS, et al.Spread through air spaces (STAS) is an independent prognostic factor in resected lung squamous cell carcinoma. Cancers (Basel). 2022;14(9):2281. Published 2022 May 3. doi:10.3390/cancers14092281
22.
KadotaKKushidaYKatsukiN, et al.Tumor spread through air spaces is an independent predictor of recurrence-free survival in patients with resected lung squamous cell carcinoma. Am J Surg Pathol. 2017;41(8):1077-1086. doi:10.1097/PAS.0000000000000872
23.
LuSTanKSKadotaK, et al.Spread through air spaces (STAS) is an independent predictor of recurrence and lung cancer-specific death in squamous cell carcinoma. J Thorac Oncol. 2017;12(2):223-234. doi:10.1016/j.jtho.2016.09.129
24.
TravisWDBrambillaENoguchiM, et al.International association for the study of lung cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma. J Thorac Oncol. 2011;6(2):244-285. doi:10.1097/JTO.0b013e318206a221
25.
Zombori-TóthNHegedűsFAlmásiS, et al.Proposal of a grading system for squamous cell carcinoma of the lung - the prognostic importance of tumour budding, single cell invasion, and nuclear diameter. Virchows Arch. 2023;483(3):393-404. doi:10.1007/s00428-023-03612-8
26.
StögbauerFLautiziMKriegsmannM, et al.Tumour cell budding and spread through air spaces in squamous cell carcinoma of the lung - determination and validation of optimal prognostic cut-offs. Lung Cancer. 2022;169(7):1–12. doi:10.1016/j.lungcan.2022.04.012
27.
TairaTIshiiGNagaiK, et al.Characterization of the immunophenotype of the tumor budding and its prognostic implications in squamous cell carcinoma of the lung. Lung Cancer. 2012;76(3):423-430. doi:10.1016/j.lungcan.2011.11.010
28.
MasudaRKijimaHImamuraN, et al.Tumor budding is a significant indicator of a poor prognosis in lung squamous cell carcinoma patients. Mol Med Rep. 2012;6(5):937-943. doi:10.3892/mmr.2012.1048
29.
GürelDUlukuşÇKaraçamV, et al.The prognostic value of morphologic findings for lung squamous cell carcinoma patients. Pathol Res Pract. 2016;212(1):1-9. doi:10.1016/j.prp.2015.10.006
30.
NicotraSMelanLPezzutoF, et al.Significance of spread through air spaces and vascular invasion in early-stage adenocarcinoma survival: a comprehensive clinicopathologic study of 427 patients for precision management. Am J Surg Pathol. 2024;48(5):605-614. doi:10.1097/PAS.0000000000002199
31.
KutlayCGülhanSŞEAcarLNAslanMTanrıkuluFB. Impact of spread through air spaces (STAS) and lymphovascular invasion (LVI) on prognosis in NSCLC: a comprehensive pathological evaluation. Updates Surg. 2025;77(4):1205–1213. doi:10.1007/s13304-025-02170-9
32.
LuSTanKSKadotaK, et al.Spread through air spaces (STAS) is an independent predictor of recurrence and lung cancer-specific death in squamous cell carcinoma. J Thorac Oncol. 2017;12(2):223-234. doi:10.1016/j.jtho.2016.09.129
33.
UrugaHFujiiTFujimoriSKohnoTKishiK. Semiquantitative assessment of tumor spread through air spaces (STAS) in early-stage lung adenocarcinomas. J Thorac Oncol. 2017;12(7):1046-1051. doi:10.1016/j.jtho.2017.03.019
34.
EguchiTKamedaKLuS, 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
