Relationship of spread through air spaces and specific clinicopathological features or poor prognosis of lung adenocarcinoma: A systemic review and meta-analysis_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

SONG Yijie ^1,2 , CHEN Nan ^1,2 , WANG Zihuai ^1,2 , ZHOU Jian ^1,2 , YANG Zhenyu ^1,2 ,  LIU Lunxu ¹

1. Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, 610041, P.R.China;
2. West China School of Medicine, Sichuan University, Chengdu, 610041, P.R.China;

Corresponding author：

LIU Lunxu, Email: lunxu_liu@aliyun.com

Keywords：

Spreading through air space; lung adenocarcinoma; prognosis

DOI：

10.7507/1007-4848.201904051

Video：

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Objective To assess the specific clinicopathological characteristics as well as prognostic value of prognostic significance of spread through air spaces (STAS) in lung adenocarcinoma.Methods We systematically searched the databases of PubMed, EMbase and Web of Science databases from their date of inception to March 2019. The quality of the included literature was assessed by the Newcastle-Ottawa scale (NOS). The NOS of the study higher than 6 points was considered as high quality. Software of Stata 12.0 was used for meta-analysis.Results Twenty retrospective cohort studies involved with totally 6 225 patients were included. Quality of included studies was high with NOS score equal or higher than 6 points. STAS was associated with male sex, ever smoking history, abnormal carcino-embryonic antigen (CEA) level, air bronchogram negative, anaplasticlymphoma kinase (ALK) arrangement positive, epidermal growth factor receptor (EGFR) mutation positive, advanced pathological tumor stage and more invasive pathological adenocarcinoma subtypes. The presence of STAS indicated significantly poor recurrence free survival (RFS) (HR=1.960, 95%CI 1.718-2.237, P<0.001) as well as poor overall survival (OS) (HR=1.891, 95%CI 1.389-2.574, P<0.001). Further subgroup analyses showed that exhibiting tumor size including diameter less than 2 cm (HR=2.344, 95%CI 1.703-3.225, P<0.001) and diameter over 2 cm (HR=2.571, 95%CI 1.559-4.238, P<0.001), resection type including lobectomy (HR=1.636, 95%CI 1.258-2.127, P<0.001) and sublobar resection (HR=3.549, 95%CI 2.092-6.021, P<0.001) in stageⅠ adenocarcinoma suggested that STAS had a bad effect on RFS.Conclusion Presence of STAS is associated with more aggressive clinicopathological features and independently associated with worse RFS and OS in lung adenocarcinoma. STAS positive has a negative effect on RFS whatever the tumor size (including the diameter<2 cm or >2 cm) and resection types in stageⅠ adenocarcinoma.

Citation： SONG Yijie, CHEN Nan, WANG Zihuai, ZHOU Jian, YANG Zhenyu, LIU Lunxu. Relationship of spread through air spaces and specific clinicopathological features or poor prognosis of lung adenocarcinoma: A systemic review and meta-analysis. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2019, 26(7): 625-632. doi: 10.7507/1007-4848.201904051 Copy

1.	Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2.	Meza R, Meernik C, Jeon J, et al. Lung cancer incidence trends by gender, race and histology in the United States, 1973-2010. PLoS One, 2015, 10(3): e0121323.
3.	Aberle DR, Berg CD, Black WC, et al. The National Lung Screening Trial: overview and study design. Radiology, 2011, 258(1): 243-253.
4.	Jin X, Zhao SH, Gao J, et al. CT characteristics and pathological implications of early stage (T1N0M0) lung adenocarcinoma with pure ground-glass opacity. Eur Radiol, 2015, 25(9): 2532-2540.
5.	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.
6.	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.
7.	Morimoto J, Nakajima T, Suzuki H, et al. Impact of free tumor clusters on prognosis after resection of pulmonary adenocarcinoma. J Thorac Cardiovasc Surg, 2016, 152(1): 64-72.e61.
8.	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(3): 567-572.
9.	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.
10.	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.
11.	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.
12.	Makinen JM, Laitakari K, Johnson S, et al. Histological features of malignancy correlate with growth patterns and patient outcome in lung adenocarcinoma. Histopathology, 2017, 71(3): 425-436.
13.	Kadota K, Kushida Y, Katsuki N, 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.
14.	孙平丽, 刘京男, 曹岚清, 等. 气腔内播散与肺腺癌患者临床病理学特征及预后之间的相关性分析. 中华病理学杂志, 2017, 46(5): 303-308.
15.	Masai K, Sakurai H, Sukeda A, et al. Prognostic impact of margin distance and tumor spread through air spaces in limited resection for primary lung cancer. J Thorac Oncol, 2017, 12(12): 1788-1797.
16.	Travis WD, Brambilla E, Burke AP, et al. Introduction to The 2015 World Health Organization classification of tumors of the lung, pleura, thymus, and heart. J Thorac Oncol, 2015, 10(9): 1240-1242.
17.	Ren Y, Xie H, Dai C, et al. Prognostic impact of tumor spread through air spaces in sublobar resection for Ⅰa lung adenocarcinoma patients. Ann Surg Oncol, 2019, 26(6): 1901-1908.
18.	Liu H, Yin Q, Yang G et al. Prognostic impact of tumor spread through air spaces in non-small cell lung cancers: a meta-analysis including 3564 patients. Pathol Oncol Res, 2019.doi: 10.1007/s12253-019-00616-1. [Epub ahead of print].
19.	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(8): 395-400.e391.
20.	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(9): 1655-1663.
21.	Kang YK, Song YS, Cho S, et al. Prognostic stratification model for patients with stage Ⅰ non-small cell lung cancer adenocarcinoma treated with surgical resection without adjuvant therapies using metabolic features measured on F-18 FDG PET and postoperative pathologic factors. Lung Cancer, 2018, 119(10): 1-6.
22.	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(11): 189-193.
23.	Kim SK, Kim TJ, Chung MJ, et al. Lung adenocarcinoma: CT features associated with spread through air spaces. Radiology, 2018, 289(12): 831-840.
24.	Liu Y, Chen D, Qiu X, et al. Relationship between MTA1 and spread through air space and their joint influence on prognosis of patients with stage Ⅰ-Ⅲ lung adenocarcinoma. Lung Cancer, 2018, 124(13): 211-218.
25.	Toyokawa G, Yamada Y, Tagawa T, et al. Computed tomography features of resected lung adenocarcinomas with spread through air spaces. J Thorac Cardiovasc Surg, 2018, 156(14): 1670-1676.e1674.
26.	Toyokawa G, Yamada Y, Tagawa T, et al. Significance of spread through air spaces in early-stage lung adenocarcinomas undergoing limited resection. Thorac Cancer, 2018, 9(15): 1255-1261.
27.	Bains S, Eguchi T, Warth A, et al. Procedure-specific risk prediction for recurrence in patients undergoing lobectomy or sublobar resection for small (≤2 cm) lung adenocarcinoma: an international cohort analysis. J Thorac Oncol, 2019, 14(16): 72-86.
28.	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(17): 5308-5317.
29.	Lee JS, Kim EK, Kim M, et al. Genetic and clinicopathologic characteristics of lung adenocarcinoma with tumor spread through air spaces. Lung Cancer, 2018, 123(18): 121-126.
30.	Hara K, Mizuguchi S, Okada S, et al. Intensity of SLX predicts distance of tumor spread through alveolar spaces in stage Ⅰ lung adenocarcinoma. Thorac Cancer, 2019, 10(20): 832-838.

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2. Meza R, Meernik C, Jeon J, et al. Lung cancer incidence trends by gender, race and histology in the United States, 1973-2010. PLoS One, 2015, 10(3): e0121323.
3. Aberle DR, Berg CD, Black WC, et al. The National Lung Screening Trial: overview and study design. Radiology, 2011, 258(1): 243-253.
4. Jin X, Zhao SH, Gao J, et al. CT characteristics and pathological implications of early stage (T1N0M0) lung adenocarcinoma with pure ground-glass opacity. Eur Radiol, 2015, 25(9): 2532-2540.
5. 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.
6. 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.
7. Morimoto J, Nakajima T, Suzuki H, et al. Impact of free tumor clusters on prognosis after resection of pulmonary adenocarcinoma. J Thorac Cardiovasc Surg, 2016, 152(1): 64-72.e61.
8. 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(3): 567-572.
9. 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.
10. 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.
11. 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.
12. Makinen JM, Laitakari K, Johnson S, et al. Histological features of malignancy correlate with growth patterns and patient outcome in lung adenocarcinoma. Histopathology, 2017, 71(3): 425-436.
13. Kadota K, Kushida Y, Katsuki N, 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.
14. 孙平丽, 刘京男, 曹岚清, 等. 气腔内播散与肺腺癌患者临床病理学特征及预后之间的相关性分析. 中华病理学杂志, 2017, 46(5): 303-308.
15. Masai K, Sakurai H, Sukeda A, et al. Prognostic impact of margin distance and tumor spread through air spaces in limited resection for primary lung cancer. J Thorac Oncol, 2017, 12(12): 1788-1797.
16. Travis WD, Brambilla E, Burke AP, et al. Introduction to The 2015 World Health Organization classification of tumors of the lung, pleura, thymus, and heart. J Thorac Oncol, 2015, 10(9): 1240-1242.
17. Ren Y, Xie H, Dai C, et al. Prognostic impact of tumor spread through air spaces in sublobar resection for Ⅰa lung adenocarcinoma patients. Ann Surg Oncol, 2019, 26(6): 1901-1908.
18. Liu H, Yin Q, Yang G et al. Prognostic impact of tumor spread through air spaces in non-small cell lung cancers: a meta-analysis including 3564 patients. Pathol Oncol Res, 2019.doi: 10.1007/s12253-019-00616-1. [Epub ahead of print].
19. 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(8): 395-400.e391.
20. 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(9): 1655-1663.
21. Kang YK, Song YS, Cho S, et al. Prognostic stratification model for patients with stage Ⅰ non-small cell lung cancer adenocarcinoma treated with surgical resection without adjuvant therapies using metabolic features measured on F-18 FDG PET and postoperative pathologic factors. Lung Cancer, 2018, 119(10): 1-6.
22. 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(11): 189-193.
23. Kim SK, Kim TJ, Chung MJ, et al. Lung adenocarcinoma: CT features associated with spread through air spaces. Radiology, 2018, 289(12): 831-840.
24. Liu Y, Chen D, Qiu X, et al. Relationship between MTA1 and spread through air space and their joint influence on prognosis of patients with stage Ⅰ-Ⅲ lung adenocarcinoma. Lung Cancer, 2018, 124(13): 211-218.
25. Toyokawa G, Yamada Y, Tagawa T, et al. Computed tomography features of resected lung adenocarcinomas with spread through air spaces. J Thorac Cardiovasc Surg, 2018, 156(14): 1670-1676.e1674.
26. Toyokawa G, Yamada Y, Tagawa T, et al. Significance of spread through air spaces in early-stage lung adenocarcinomas undergoing limited resection. Thorac Cancer, 2018, 9(15): 1255-1261.
27. Bains S, Eguchi T, Warth A, et al. Procedure-specific risk prediction for recurrence in patients undergoing lobectomy or sublobar resection for small (≤2 cm) lung adenocarcinoma: an international cohort analysis. J Thorac Oncol, 2019, 14(16): 72-86.
28. 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(17): 5308-5317.
29. Lee JS, Kim EK, Kim M, et al. Genetic and clinicopathologic characteristics of lung adenocarcinoma with tumor spread through air spaces. Lung Cancer, 2018, 123(18): 121-126.
30. Hara K, Mizuguchi S, Okada S, et al. Intensity of SLX predicts distance of tumor spread through alveolar spaces in stage Ⅰ lung adenocarcinoma. Thorac Cancer, 2019, 10(20): 832-838.

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