Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Assessment of the feasibility of frozen sections for the detection of spread through air spaces (STAS) in pulmonary adenocarcinoma

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Example of artifact.
Fig. 2: Concordant case.
Fig. 3: Discordant case.
Fig. 4: Discordant case.
Fig. 5: Comparison of diagnostic performance.
Fig. 6: Grade versus STAS.
Fig. 7: Recurrence-free survival (RFS, days) in patients who underwent sublobar resection.

References

  1. 1.

    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.

  2. 2.

    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.

    CAS  Article  Google Scholar 

  3. 3.

    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.

    CAS  Article  Google Scholar 

  4. 4.

    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.

    Article  Google Scholar 

  5. 5.

    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.

    Article  Google Scholar 

  6. 6.

    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.

    Article  Google Scholar 

  7. 7.

    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.

    Article  Google Scholar 

  8. 8.

    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.

    Article  Google Scholar 

  9. 9.

    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.

    Article  Google Scholar 

  10. 10.

    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.

    Article  Google Scholar 

  11. 11.

    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.

    Article  Google Scholar 

  12. 12.

    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.

    CAS  Article  Google Scholar 

  13. 13.

    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.

    Article  Google Scholar 

  14. 14.

    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.

    Article  Google Scholar 

  15. 15.

    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.

    Article  Google Scholar 

  16. 16.

    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.

  17. 17.

    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.

    Article  Google Scholar 

  18. 18.

    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.

    Article  Google Scholar 

  19. 19.

    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.

    Article  Google Scholar 

  20. 20.

    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.

  21. 21.

    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.

    Article  Google Scholar 

  22. 22.

    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.

    Article  Google Scholar 

  23. 23.

    Lackey A, Donington JS. Surgical management of lung cancer. Semin Interv Radio. 2013;30:133–40.

    Article  Google Scholar 

  24. 24.

    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.

    Article  Google Scholar 

  25. 25.

    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.

  26. 26.

    Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33:159–74.

    CAS  Article  Google Scholar 

  27. 27.

    Kotrlik JW, Williams HA, Jabor MK. Reporting and interpreting effect size in quantitative agricultural education research. J Agric Educ. 2011;52:132–42.

    Article  Google Scholar 

  28. 28.

    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.

    Article  Google Scholar 

  29. 29.

    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.

    Article  Google Scholar 

Download references

Acknowledgements

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).

Author information

Affiliations

Authors

Contributions

Study concept and design: FZ, NN, ALM. Methodology development: FZ, ALM. Data acquisition, analysis, and interpretation: FZ, JAV, TMSS, MM-K, HP, ALM. Writing: FZ, NN, MM-K, ALM. All authors read and approved the final paper.

Corresponding author

Correspondence to Fang Zhou.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

The study was approved by each respective Institution Review Board and performed according to HIPAA regulations.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Search

Quick links