Advances In Research Of Spreading Through Air Spaces And The Effects On The Prognosis Of Lung Cancer

Figures & data

Figure 1 The potential mechanism of STAS.

Abbreviations: GFs, growth factors; MMPs, matrix metalloproteinases; CAFs, cancer-associated fibroblasts; TAMs, tumor-associated macrophages.

Table 1 The Studies On Stage I Lung Cancer Corrected With STAS Are Shown As Reported In The Published Studies

Study	Entity	Stage I (Number)	Results
Onozato et al.^Citation13 2013	ADC	IA (151) IB (66)	The presence of tumor islands was significantly associated with poor outcomes in the Stage IA cohort
Kadota et al.^Citation10 2015	ADC	I (411)	The presence of STAS correlated with higher risk of distant and locoregional recurrence
Shiono et al.^Citation27 2016	ADC	I (318)	STAS was closely related to poor prognosis and recurrence in stage I ADCs
Lu et al.^Citation21 2017	SCC	I (249)	In stage I SCC, patients with STAS had higher incidence of locoregional recurrence and lung cancer-specific death compared to those without STAS
Uruga et al.^Citation42 2017	ADC	I (208)	One-third of resected small adenocarcinomas had high STAS. Higher STAS was predictive of worse RFS
Dai et al^Citation16 2017	ADC	IA (383) IB (161)	Multivariate analysis revealed STAS to be an independent prognostic factor in stage I ADCs
Yanagawa et al^Citation22 2018	SCC	I (220)	STAS was associated with recurrence and worse survival in stage I SCC, but not in stage II and III SCC
Yang et al^Citation19 2018	ADC	I (242)	STAS was a significantly worse predictor for Stage I patients with lung ADC >2 cm who underwent radical lobectomy
Shiono et al.^Citation18 2018	NSCLC	IA (514)	STAS is a prognostic factor of poor outcomes for sublobar resection in patients with lung cancer
Toyokawa et al.^Citation17 2018	ADC	I (276)	Patients with STAS had significantly shorter RFS and OS than patients without STAS, STAS-positivity remained an independent prognostic factor for both RFS and OS

Abbreviations: ADC, adenocarcinoma; SCC, squamous cell carcinoma; STAS, spread through air spaces; NSCLC, nonsmall cell lung carcinoma; RFS, recurrence-free survival; OS, overall survival.

Table 2 The Relationship Between STAS And Lung Cancer-Related Molecules Are Shown As Reported In The Published Studies

Study	Entity	Molecular	Results
Warth et al.^Citation5 2015	ADC	EGFR BRAF	STAS was associated with lower rates of EGFR but higher rates of BRAF mutations, and not associated with KRASmutations
Jin et al.^Citation26 2015	ADC	ROS1	STAS was associated with poor DFS in ROS1-rearranged ADCs
Shiono et al.^Citation27 2016	ADC	EGFR	Wild-type EGFR was significantly related to STAS
Toyokawa et al.^Citation17 2018	ADC	EGFR PD-L1	STAS was not significantly associated with EGFRmutations or PD-L1 expression
Lee et al.^Citation28 2018	ADC	EGFR ALK	STAS was frequently observed in tumors with wild-type EGFR and ALK rearrangement, and they found no association with KRASmutation
Kim et al.^Citation29 2018	ADC	EGFR ALK	STAS was associated with a lower incidence of EGFR mutation (P = 0.02) and a higher incidence of ALK rearrangement (P = 0.003)

Abbreviations: ADC, adenocarcinoma; EGFR, epidermal growth factor receptor; ROS1, c-ros oncogene 1; ALK, anaplastic lymphoma kinase; STAS, spread through air spaces; DFS, disease-free survival.

Onozato ML, Kovach AE, Yeap BY, et al. Tumor islands in resected early-stage lung adenocarcinomas are associated with unique clinicopathologic and molecular characteristics and worse prognosis. Am J Surg Pathol. 2013;37(2 ):287–294. doi:10.1097/PAS.0b013e31826885fb23095504

 PubMed Web of Science ®Google Scholar

Kadota K, Nitadori J, 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 ):806–814.25629637

 PubMed Web of Science ®Google Scholar

Shiono S, Yanagawa N. Spread through air spaces is a predictive factor of recurrence and a prognostic factor in stage I lung adenocarcinoma. Interact Cardiovasc Thorac Surg. 2016;23(4 ):567–572. doi:10.1093/icvts/ivw21127354463

 PubMed Web of Science ®Google Scholar

Lu S, Tan KS, Kadota K, 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.2016.09.12927693541

 PubMed Web of Science ®Google Scholar

Uruga H, Fujii T, Fujimori S, et al. 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.2017.03.01928363628

 PubMed Web of Science ®Google Scholar

Dai C, Xie H, Su H, et al. Tumor spread through air spaces affects the recurrence and overall survival in patients with lung adenocarcinoma >2 to 3 cm. J Thorac Oncol. 2017;12(7 ):1052–1060. doi:10.1016/j.jtho.2017.03.02028389373

 PubMed Web of Science ®Google Scholar

Yanagawa N, Shiono S, Endo M, et al. Tumor spread through air spaces is a useful predictor of recurrence and prognosis in stage I lung squamous cell carcinoma, but not in stage II and III. Lung Cancer. 2018;120:14–21. doi:10.1016/j.lungcan.2018.03.01829748009

 PubMed Web of Science ®Google Scholar

Yang L, Yang Y, Ma P, et al. Spread through air spaces predicts a worse survival in patients with stage I adenocarcinomas >2 cm after radical lobectomy. J Thorac Dis. 2018;10(9 ):5308–5317. doi:10.21037/jtd.2018.09.2230416778

 PubMed Web of Science ®Google Scholar

Shiono S, Endo M, Suzuki K, et al. Spread through air spaces is a prognostic factor in sublobar resection of non-small cell lung cancer. Ann Thorac Surg. 2018;106(2 ):354–360. doi:10.1016/j.athoracsur.2018.02.07629625101

 PubMed Web of Science ®Google Scholar

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.2018.01.03729453963

 PubMed Web of Science ®Google Scholar

Warth A, Muley T, Kossakowski CA, 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.000000000000040925723114

 PubMed Web of Science ®Google Scholar

Jin Y, Sun PL, Park SY, et al. Frequent aerogenous spread with decreased E-cadherin expression of ROS1-rearranged lung cancer predicts poor disease-free survival. Lung Cancer. 2015;89(3 ):343–349. doi:10.1016/j.lungcan.2015.06.01226149475

 PubMed Web of Science ®Google Scholar

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.2018.07.02030089582

 PubMed Web of Science ®Google Scholar

Kim SK, Kim TJ, Chung MJ, et al. Lung adenocarcinoma: CT features associated with spread through air spaces. Radiology. 2018;289(3 ):831–840. doi:10.1148/radiol.201818043130179108

 PubMed Web of Science ®Google Scholar