Spread through air spaces (STAS): prognostic impact of a semi-quantitative assessment

Following validation in two large independent cohorts from the US and Germany (1,2), the concept of spread through air spaces (STAS) was introduced for pulmonary adenocarcinomas (ADC) in the 2015 World Health Organization (WHO) Classification for lung cancer and subsequently validated and extended (3). Now, Uruga et al. provided evidence that a semi-quantitative assessment of STAS might provide additional prognostic information (4).

According to the 2015 WHO Classification, STAS is defined as “micropapillary clusters, solid nests, or single cells spreading within air spaces beyond the edge of the main tumor”. Besides the existing criteria for invasion (a histological subtype other than a lepidic pattern; myofibroblastic stroma associated with invasive tumor cells; vascular or pleural invasion), STAS was thereby established as a fourth category which defines invasion for ADC.

Early reports already indicated that erogenous tumor spread and free floating cell clusters from ADC but also metastases from colorectal cancer are unfavorable prognostic features (5-7). Onozato et al. described so-called tumor islands and their adverse prognostic impact, a morphological feature closely related to STAS in 2013 (8). 3D reconstructions revealed that tumor islands are connected to the main tumor at different levels (9). Tumor islands were significantly associated with a worse recurrence-free survival (8).

The concept of STAS was initially validated by two large simultaneous publications (1,2). In a series of 411 stage I ADC it was demonstrated that STAS is a phenomenon usually found in the first alveolar layers close to the tumor but occasionally can be found more than 50 alveolar spaces away from the main tumor. STAS was significantly associated with lymphovascular invasion and high-grade histological pattern (1). The association of STAS to lymphovascular invasion was subsequently validated (10). In a series of 569 ADC STAS was significantly associated with male sex, lymph node and distant metastasis, tumor stage, and high-grade histological patterns (2). Further correlations were found with KRAS and BRAF mutations (2). Another recent study concerning STAS in a series of 318 stage I ADC confirmed and extended the yet available data. The authors found significant associations of STAS with the male sex, the median CEA level, smoking status, median maxSUV, solid nodules on computed tomography, p-stage, EGFR wild-type, lymphovascular invasion, and pleural invasion (11). In the series by Uruga et al. where STAS was semi-quantitatively analyzed in 208 stage I ADC there were statistically significant associations between higher STAS and solid predominant ADC, pleural invasion, lymphatic invasion, vascular invasion, and tumor size ≥10 mm (4). In this study STAS was arbitrarily categorized as low STAS (1–4 single cells or clusters) and high STAS (>5 single cells or cell clusters). About 52.4% of the cases had no STAS, 18.3% low STAS, and 29.3% high STAS. For the assessment all tumor edges were screened and then STAS was analyzed in 1-3 selected fields with most prominent STAS.

By analyzing a series of 445 stage I–III lung squamous cell carcinomas (SCC), Lu et al. demonstrated for the first time that STAS is not limited to ADC but is also a significant prognostic parameter for SCC (12).

Of note, one of the first validation studies on STAS found different survival rates depending on the type of the resection. Whereas STAS was not significantly associated with recurrence in the lobectomy group it was a significant prognosticator for any as well as locoregional recurrence in the limited resection group (1), pointing towards the potential clinicopathological impact of this new feature. In the second validation study, STAS was a significant prognosticator for both overall and disease-free survival even in patients with lobectomy and independent of the extent of STAS. Furthermore, STAS remained a worse prognosticator in multivariate analysis including the predominant pattern but not independent of stage (2). Although the analyzed subgroups were small, this study also demonstrated for the first time that the presence of STAS adds significant prognostic information to the predominant pattern (2), which was further underlined by a subsequent study focusing on the papillary pattern (13). The additive prognostic value of STAS to histological patterns was confirmed by a retrospective study of ADC with a micropapillary component in which the prognostic impact of free tumor cell clusters was analyzed (10). There was a significant association with recurrence-free survival and mortality (10). More interestingly, the authors demonstrate that the presence of a micropapillary component together with STAS results in a shift of the T stage compared to the same tumors without both features being present. In a further validation study STAS was confirmed as an independent prognostic parameter in multivariate analysis for both overall and recurrence-free survival (11). In a series of 544 ADC with a validation cohort of 541 patients, those with ADCs 3 cm or smaller and STAS had worse recurrence-free and overall survival than those without STAS. Comparable survival rates were observed in patients with stage IA with STAS present and those with stage IB ADC. Multivariate analysis revealed STAS to be an independent prognostic factor in ADC 3 cm or smaller. Among patients with ADC larger than 2 to 3 cm, STAS still stratified the prognosis. Moreover, the unfavorable prognosis of patients with ADC larger than 2 to 3 cm with STAS present was similar to that of patients with stage IB ADC (14).

With the approach by Uruga et al. to semi-quantitatively analyze STAS there was a significant association between high STAS in the tumor periphery and shorter recurrence-free survival in univariate analysis. In multivariate analysis, STAS remained a significant predictor of survival (4). The incidence for recurrence was 2% for no STAS, 5% for low STAS, and 21% for high STAS. This points out that, although the distance of STAS from the main tumor does not seem to be of high prognostic relevance in neither for ADC nor SCC (2,12,14), the quantity of STAS might be an important prognostic parameter. Further studies are needed where STAS is analyzed quantitatively to further narrow in on this and to potentially define clinically meaningful cut-offs.

In SCC the cumulative incidence of any, distant, and locoregional recurrence as well as lung cancer-specific death were significantly higher in patients with STAS compared to those without, and these associations remained significant in multivariate analyses. As demonstrated in ADC (2) the extent of STAS was not relevant for prognosis (12). The prognostic impact of STAS in SCC was most recently confirmed in a series of 2016 cases from Japan (15). Thus, beyond budding and cell nest size which have previously been identified as prognostically relevant morphological parameters in SCC (16-19). STAS seems to be another morphological feature to allow for a better prognostic stratification of SCC and potentially the establishment of a clinically meaningful grading system in the near future.

An interesting point is that there are first data pointing towards that STAS might be a potential candidate to upgrade the T stage in order to improve the accuracy of the prognosis of early stage ADC. Eguchi et al. demonstrated that the 5-year cumulative incidence of recurrence and cumulative incidence of lung cancer–specific death in patients with ADCs 2 cm or smaller was stratified by STAS (20). This is further underlined by a large multinational cohort of >2,000 early stage ADC where STAS together with solid and micropapillary patterns were significant parameters for an optimized patient stratification based on respective nomograms (21).

Up to now all studies on STAS, despite different definitions, demonstrate that this novel morphologic feature is of high prognostic value. Thus, STAS should be included into pathological reports. However, it is still debatable whether STAS is an in vivo effect in any instances or potentially an artifact (22). With respect to a better separation of STAS from artificial floaters it was suggested to consider only tumor cells as STAS if they appear as detached small clusters within air spaces in a continuous manner from the edge of the tumor, and the distribution is consistent with the overall configuration of the circumferential tumor edge. Haphazardly distributed fragments of tumor with sharp jagged edges might be regarded as artifacts (12). Within this context further studies are clearly warranted to better separate floaters from STAS and evaluate the potential prognostic impact of both. Another yet open question is if STAS can be reliably detected in frozen sections, the only option to directly impact the surgical procedure since STAS is not evident in preoperative imaging procedures. Up to now only sparse data are available in this context. Kameda et al. reported that STAS could be identified in frozen sections with a sensitivity, specificity, and accuracy of 71%, 92.4%, and 80%, respectively. Clearly these results have to be validated in subsequent studies (23).

In summary, STAS is associated with multiple pathologic and clinical features of aggressiveness in both SCC and ADC and is an important prognostic feature independent of tumor stage and ADC growth patterns. The data by Uruga et al. (4) indicate that a semi-quantitative assessment of STAS might provide additional prognostic information, which should be validated and extended in subsequent studies.

Acknowledgements

None.

Footnote

Conflicts of Interest: The author has no conflicts of interest to declare.

References

1. 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;10:806-14. [Crossref] [PubMed]
2. Warth A, Muley T, Kossakowski CA, et al. Prognostic Impact of Intra-alveolar Tumor Spread in Pulmonary Adenocarcinoma. Am J Surg Pathol 2015;39:793-801. [Crossref] [PubMed]
3. Warth A, Beasley MB, Mino-Kenudson M. Breaking New Ground: The Evolving Concept of Spread through Air Spaces (STAS). J Thorac Oncol 2017;12:176-8. [Crossref] [PubMed]
4. 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;12:1046-51. [Crossref] [PubMed]
5. Clayton F. Bronchioloalveolar carcinomas. Cell types, patterns of growth, and prognostic corre-lates. Cancer 1986;57:1555-64. [Crossref] [PubMed]
6. Shiono S, Ishii G, Nagai K, et al. Predictive factors for local recurrence of resected colorectal lung metastases. Ann Thorac Surg 2005;80:1040-5. [Crossref] [PubMed]
7. Shiono S, Ishii G, Nagai K, et al. Histopathologic prognostic factors in resected colorectal lung metastases. Ann Thorac Surg 2005;79:278-82; discussion 283. [Crossref] [PubMed]
8. Onozato ML, Kovach AE, Yeap BY, et al. Tumor islands in resected early-stage lung adenocarci-nomas are associated with unique clinicopathologic and molecular characteristics and worse prognosis. Am J Surg Pathol 2013;37:287-94. [Crossref] [PubMed]
9. Onozato ML, Klepeis VE, Yagi Y, et al. A role of three-dimensional (3D)-reconstruction in the classification of lung adenocarcinoma. Anal Cell Pathol (Amst) 2012;35:79-84. [Crossref] [PubMed]
10. Morimoto J, Nakajima T, Suzuki H, et al. Impact of free tumor clusters on prognosis after resec-tion of pulmonary adenocarcinoma. J Thorac Cardiovasc Surg 2016;152:64-72.e1. [Crossref] [PubMed]
11. 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. [Crossref] [PubMed]
12. 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;12:223-234. [Crossref] [PubMed]
13. Warth A, Muley T, Harms A, et al. Clinical Relevance of Different Papillary Growth Patterns of Pulmonary Adenocarcinoma. Am J Surg Pathol 2016;40:818-26. [Crossref] [PubMed]
14. 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. [Epub ahead of print]. [Crossref] [PubMed]
15. Kadota K, Kushida Y, Katsuki N, et al. Tumor Spread Through Air Spaces Is an Independent Pre-dictor of Recurrence-free Survival in Patients With Resected Lung Squamous Cell Carcinoma. Am J Surg Pathol 2017. [Epub ahead of print]. [Crossref]
16. Weichert W, Kossakowski C, Harms A, et al. Proposal of a prognostically relevant grading scheme for pulmonary squamous cell carcinoma. Eur Respir J 2016;47:938-46. [Crossref] [PubMed]
17. Zhao Y, Shen H, Qiu C, et al. Invasion Types Are Associated With Poor Prognosis in Lung Squa-mous Carcinoma Patients. Medicine (Baltimore) 2015;94:e1634. [Crossref] [PubMed]
18. Kadota K, Nitadori J, Woo KM, 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;9:1126-39. [Crossref] [PubMed]
19. Masuda R, Kijima H, Imamura N, et al. Tumor budding is a significant indicator of a poor prog-nosis in lung squamous cell carcinoma patients. Mol Med Rep 2012;6:937-43. [PubMed]
20. Eguchi T, Kameda K, Lu S, et al. OA07.06 In Early-Stage Lung Adenocarcinomas, Survival by Tu-mor Size (T) is Further Stratified by Tumor Spread through Air Spaces. J Thoracic Oncol 2017;12:S270-1. [Crossref]
21. Bains S, Eguchi T, Warth A, et al. PUB016 A multi-national cohort validation of proce-dure-specific nomograms to predict recurrence for small lung adenocarcinomas. J Thoracic Oncol 2017;12:S1455-6. [Crossref]
22. Warth A. Spread Through Air Spaces (STAS): A Comprehensive Update. Translational Lung Cancer Research 2017. [Epub ahead of print].
23. Kameda K, Lu S, Eguchi T, et al. MA12.05 Can Tumor Spread through Air Spaces (STAS) in Lung Adenocarcinomas Be Predicted Pre- and Intraoperatively? J Thoracic Oncol 2017;12:S411-2. [Crossref]