Spread through air spaces (STAS) is reportedly associated with worse prognosis in sublobar resections of lung adenocarcinoma. Recently, it was proposed that STAS detected on frozen sections can be an indication for lobectomy instead of sublobar resection. We undertook this study to evaluate the reliability of STAS assessment on frozen sections compared to permanent sections, as well as the associations among STAS, tumor grade, and recurrence-free survival (RFS) after sublobar resection. A total of 163 stage I lung adenocarcinoma resections with frozen sections were identified retrospectively. For each case, and for frozen and permanent sections separately, the presence or absence of STAS, as well as the tumor grade, were recorded. Compared to permanent sections, STAS detection on frozen sections had low sensitivity (55%), low positive predictive value (48%), and fair agreement (K = 0.34), whereas there was higher specificity (80%) and negative predictive value (85%). Accuracy was 74%. Tumor grade assessment on frozen sections showed higher sensitivity (77%), positive predictive value (90%), agreement (K = 0.72), specificity (94%), and accuracy (87%), and the same negative predictive value (85%). High-grade histology on frozen sections was associated with shorter RFS (p = 0.02), whereas STAS on frozen sections was not (p = 0.47). Our results suggest that the intraoperative detection of STAS has low sensitivity and positive predictive value. False-positive results may lead to overtreatment of patients with lung cancer. The determination of tumor grade on frozen sections offers better sensitivity and specificity, plus it is associated with RFS, whereas STAS on frozen sections is not. Further study is needed to explore the utility of assessing tumor grade on frozen sections.
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Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG (eds). WHO classification of tumours of the lung, pleura, thymus and heart. 4th ed, Vol. 7. Lyon, France: International Agency for Research on Cancer (IARC); 2015.
Mino-Kenudson M. Significance of tumor spread through air spaces (STAS) in lung cancer from the pathologist perspective. Transl Lung Cancer Res. 2020;9:847–59.
Kadota K, Nitadori JI, Sima CS, Ujiie H, Rizk NP, Jones DR, 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;10:806–14.
Kadota K, Kushida Y, Kagawa S, Ishikawa R, Ibuki E, Inoue K, et al. Limited resection is associated with a higher risk of locoregional recurrence than lobectomy in stage I lung adenocarcinoma with tumor spread through air spaces. Am J Surg Pathol. 2019;43:1033–41.
Dai C, Xie H, Su H, She Y, Zhu E, Fan Z, 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;12:1052–60.
Uruga H, Fujii T, Fujimori S, Kohno T, Kishi K. Semiquantitative assessment of tumor spread through air spaces (STAS) in early-stage lung adenocarcinomas. J Thorac Oncol. 2017;12:1046–51.
Eguchi T, Kameda K, Lu S, Bott MJ, Tan KS, Montecalvo J, 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;14:87–98.
Onozato ML, Kovach AE, Yeap BY, Morales-Oyarvide V, Klepeis VE, Tammireddy S, 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;37:287–94.
Toyokawa G, Yamada Y, Tagawa T, Oda Y. Significance of spread through air spaces in early-stage lung adenocarcinomas undergoing limited resection. Thorac Cancer. 2018;9:1255–61.
Lee JS, Kim EK, Kim M, Shim HS. Genetic and clinicopathologic characteristics of lung adenocarcinoma with tumor spread through air spaces. Lung Cancer. 2018;123:121–6.
Masai K, Sakurai H, Sukeda A, Suzuki S, Asakura K, Nakagawa K, et al. Prognostic impact of margin distance and tumor spread through air spaces in limited resection for primary lung cancer. J Thorac Oncol. 2017;12:1788–97.
Qiu X, Chen D, Liu Y, Duan S, Zhang F, Zhang Y, et al. Relationship between stromal cells and tumor spread through air spaces in lung adenocarcinoma. Thorac Cancer. 2019;10:256–67.
Ren Y, Xie H, Dai C, She Y, Su H, Xie D, et al. Prognostic impact of tumor spread through air spaces in sublobar resection for 1A lung adenocarcinoma patients. Ann Surg Oncol. 2019;26:1901–8.
Yang L, Yang Y, Ma P, Zheng B, Liu W, Zhang Z, 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;10:5308–17.
Yi E, Bae MK, Cho S, Chung JH, Jheon S, Kim K. Pathological prognostic factors of recurrence in early stage lung adenocarcinoma. ANZ J Surg. 2018;88:327–31.
Villalba JA, Shih AR, Sayo TMS, Kunitoki K, Hung YP, Ly A, et al. Accuracy and reproducibility of intra-operative assessment on tumor spread through air spaces (STAS) in stage 1 lung adenocarcinomas. J Thorac Oncol. 2021;16:619–29. https://doi.org/10.1016/j.jtho.2020.12.005.
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;23:567–72.
Morimoto J, Nakajima T, Suzuki H, Nagato K, Iwata T, Yoshida S, et al. Impact of free tumor clusters on prognosis after resection of pulmonary adenocarcinoma. J Thorac Cardiovasc Surg. 2016;152:64–72.e61.
Blaauwgeers H, Flieder D, Warth A, Harms A, Monkhorst K, Witte B, et al. A prospective study of loose tissue fragments in non-small cell lung cancer resection specimens: an alternative view to “spread through air spaces”. Am J Surg Pathol. 2017;41:1226–30.
Moreira AL, Ocampo PS, Xia Y, Zhong H, Russell PA, Minami Y, et al. A Grading system for invasive pulmonary adenocarcinoma: a proposal from the IASLC pathology committee. J Thorac Oncol. 2020;15:1599–610. https://doi.org/10.1016/j.jtho.2020.06.001.
Takahashi Y, Kuroda H, Oya Y, Matsutani N, Matsushita H, Kawamura M. Challenges for real-time intraoperative diagnosis of high risk histology in lung adenocarcinoma: a necessity for sublobar resection. Thorac Cancer. 2019;10:1663–8.
Shapiro M, Weiser TS, Wisnivesky JP, Chin C, Arustamyan M, Swanson SJ. Thoracoscopic segmentectomy compares favorably with thoracoscopic lobectomy for patients with small stage I lung cancer. J Thorac Cardiovasc Surg. 2009;137:1388–93.
Lackey A, Donington JS. Surgical management of lung cancer. Semin Interv Radio. 2013;30:133–40.
Shiono S, Endo M, Suzuki K, Yarimizu K, Hayasaka K, Yanagawa N. Spread through air spaces is a prognostic factor in sublobar resection of non-small cell lung cancer. Ann Thorac Surg. 2018;106:354–60.
Walts AE, Marchevsky AM. Current evidence does not warrant frozen section evaluation for the presence of tumor spread through alveolar spaces. Arch Pathol Lab Med. 2018;142:59–63.
Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33:159–74.
Kotrlik JW, Williams HA, Jabor MK. Reporting and interpreting effect size in quantitative agricultural education research. J Agric Educ. 2011;52:132–42.
Blaauwgeers H, Russell PA, Jones KD, Radonic T, Thunnissen E. Pulmonary loose tumor tissue fragments and spread through air spaces (STAS): invasive pattern or artifact? A critical review. Lung Cancer. 2018;123:107–11.
Fitzgibbons PL, Bradley LA, Fatheree LA, Alsabeh R, Fulton RS, Goldsmith JD, et al. Principles of analytic validation of immunohistochemical assays: guideline from the College of American Pathologists Pathology and Laboratory Quality Center. Arch Pathol Lab Med. 2014;138:1432–43.
The authors would like to thank Benjamin A. Levinson, PhD (Department of Population Health, Division of Biostatistics, NYU Langone Health) for his statistical advice; the Center for Biospecimen Research and Development (CBRD) for logistical support; and NIH NCI Cancer Center support grant P30 CA016087-39 (ALM). MM-K is partially supported by the National Institutes of Health (R01CA240317).
The authors declare no competing interests.
The study was approved by each respective Institution Review Board and performed according to HIPAA regulations.
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Zhou, F., Villalba, J.A., Sayo, T.M.S. et al. Assessment of the feasibility of frozen sections for the detection of spread through air spaces (STAS) in pulmonary adenocarcinoma. Mod Pathol (2021). https://doi.org/10.1038/s41379-021-00875-x