Spread through air spaces in non-small cell lung cancer

In 2015, a newly defined cancer growth pattern was identified. Classified as spread through air spaces (STAS) by The World Health Organization (WHO), STAS is best understood as a new form of cancer invasion.

STAS is defined as the presence of tumor cells including micropapillary clusters, solid nests or single cells apart from the primary lesion that spread through the air spaces in the surrounding lung parenchyma (1). In April 2019, Chen et al. published the report entitled “Tumor Spread Through Air Spaces in Non-Small Cell Lung Cancer: a systematic review and meta-analysis” in Annals of Thoracic Surgery (2). While an increasing number of studies have tried to reveal the clinical significance of STAS, it remains a controversial topic of study. Therefore, this meta-analysis may serve as important research to clarify the significance of STAS. In this meta-analysis, the investigators systematically reviewed the studies on the correlation between STAS and prognosis in patients with lung cancer and concluded STAS could be a prognostic predictor for patients with resected non-small cell lung cancer (NSCLC). The authors evaluated 14 published studies including 3,754 patients across various histological types and showed that STAS was associated with worse recurrence-free survival (RFS) [hazard ratio (HR) =1.975, 95% confidence interval (CI): 1.691–2.307, P<0.001] and overall survival (HR =1.75, 95% CI: 1.375–2.227, P<0.001). Subgroup analysis of histological subtypes showed that STAS was significantly correlated with worse RFS in adenocarcinoma (HR =2.288, 95% CI: 1.843–2.840, I²=7.80%), squamous cell carcinoma (HR =1.622, 95% CI: 1.279–2.056, I²=0%) and pleomorphic carcinoma (HR =4.76, 95% CI: 1.168–19.398). The results appear to be clinically meaningful and the current meta-analysis is associated with several concerns.

First of all, in the studies conducted so far, the definition and diagnosis of STAS are not consistent. As shown in this meta-analysis, the frequency of STAS considerably varies among the reports, which means the inconsistent evaluation of STAS. Moreover, further classifications of STAS are slightly different depending on the study, even though the precise definition of STAS has been proposed by WHO. The most common method to identify STAS is based on morphologic features, including single cell, small clusters, and tumor cell nests, which is how WHO defines it.

Other classifications focus on the quantity and the distance of STAS from the main tumor, which are not described in the WHO criteria. Several studies defined STAS as the presence of tumor cells whose distance from the edge of primary lesion as in the first alveolar spaces, and others defined as at least a few alveolar spaces (3-6). Warth et al. divided the extent of STAS into two groups according to the distance from the main tumor (7). They defined ‘limited STAS’ as a solid cell nest no more than three alveoli away from the main tumor mass. ‘Extensive STAS’ was defined as a tumor cell nest more than three alveoli away from the tumor edge. Similar categorization of STAS was adopted in a study by Lu and colleagues (5).

Another classification of STAS was focused on its quantity. Uruga et al. performed a quantitative assessment of STAS, dividing the grades of STAS into three levels: no STAS, low STAS (1–4 cells or clusters), and high STAS (>4 cells or clusters) (6). In this study, the grades of STAS were reported to be associated with the clinical significance of STAS, based on clinicopathological features and prognosis. Although further validation of these classifications is required, these results indicate that the extent and quantity of STAS might reflect how the tumor progresses and invades.

Considering the progression style of STAS, it seems that there are many trans-airway metastasis and stump recurrences; however, most of the reported studies have not adequately discussed whether the presence of STAS influenced the recurrent pattern. Furthermore, as described in this meta-analysis study, STAS is associated with poor prognosis in patients who performed limited resection, although it remains controversial whether as is in patients who undergo lobectomy. Our previous report showed that STAS also negatively impacted on the RFS in patients with lobectomy (8). Warth et al. found that STAS is a novel prognosticator in 569 resected pulmonary adenocarcinomas patients, of whom 83% underwent lobectomy (7). In a recent report by Eguchi et al., the presence of STAS in T1 lung adenocarcinoma is associated with higher recurrence and cancer-specific death in patients with sublobar resection than in those who underwent lobectomy (9). Furthermore, the most common recurrence pattern in patients with STAS who performed sublobar resection was locoregional recurrence, regardless of margin-to-tumor ratio. Shiono et al. reported that STAS-positive patients with sublobar resection developed pulmonary metastases more frequently than patients with STAS-negative treated with lobectomy (10). Taken together, these findings suggest that STAS might be associated with locoregional and trans-airway metastasis. Therefore, limited resection should be avoided for patients with STAS. However, predicting the STAS status before surgery was difficult. Our previous study evaluating the association of STAS with computed tomography (CT) findings showed that the presence of notch and the absence of ground grass opacity were independently associated with STAS, and it might be helpful to identify the presence of STAS using CT images before surgery (11). Furthermore, it is unclear whether the prognostic significance of STAS varies by tumor size or stage. Dai et al. reported the prognostic significance of STAS only in patients with small size tumors (12). By contrast, we demonstrated that STAS was an independent prognostic factor of RFS in completely resected adenocarcinomas with lymph node metastasis (13). The significance of STAS in therapeutic strategies, including surgical procedure and adjuvant therapy, needs to be examined in future investigations.

The clinical significance of STAS has been reported in many studies, but a sufficient biological explanation of STAS has not been adequately identified. STAS was shown to be frequently found in tumors with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, epidermal growth factor receptor (EGFR) wild-type and anaplastic lymphoma kinase (ALK) fusions (3,14,15). Several attempts have been made to examine the biological significance of STAS in terms of cell adhesion, epithelial-mesenchymal transition (EMT), and tumor stromal cells. Liu et al. reported that metastasis-associated protein 1 (MTA1), which is involved in several signal transduction pathways and associated with invasive and metastatic phenotypes, was more frequently expressed in STAS-positive patients (16). MTA1 also represses E-cadherin and induces EMT, possibly resulting in the tumor invasion and metastasis (17). Recently, Hara et al. reported SLX, a cell adhesion protein in the selectin family, had no relation with the presence of STAS (18). Qiu et al. evaluated the relationship between STAS and stromal cells, and the presence of STAS was reported to be associated with a high frequency of α-SMA-positive cancer associated fibroblasts and CD204-positive tumor associated macrophages (19).

However, these results are not sufficient to explain the in vivo effect of STAS and therefore, some reports suggest that STAS might be no more than “loose tumor fragments” or artifacts caused by spreading through a knife surface (STAKS) (20). Before the concept of STAS was defined by WHO in 2015, Onozato et al. used a three-dimensional reconstruction model to demonstrate that tumor islands isolated within alveolar spaces, whose morphological feature is similar to STAS, were connected with the primary tumor at different levels. These features could not be recognized by routine observation of histology slides (21). Blaauwgeers et al. explained STAS as an artifact derived from the handling procedure. In a prospective multicenter study, they showed that the number of free tumor cells within air spaces is increased cut-by-cut and concluded that 93% of the STAS could be explained by mechanical forces associated with tissue handling (22). However, if STAS is just an artifact, it is difficult to explain the clinical significance as shown in this meta-analysis. Further studies are warranted to optimally distinguish between STAS and STAKS and to clarify the biological significance of STAS.

STAS is a new concept that is still controversial and it is crucial to establish an accurate definition. As mentioned above, the criteria of STAS, including tumor cell numbers and the distance from the tumor edge, is not clearly described in the WHO definition. Therefore, it is necessary to globally establish the evaluation criteria of STAS.

In conclusion, this meta-analysis showed that STAS could be a prognosticator in NSCLC patients, although it remains unclear whether STAS is induced by an in vivo effect or just artifacts of cutting through a tumor with a knife. Future prospective studies are necessary to elucidate the true significance of STAS in regards to surgical handling, pathological preparation for slides, and coming to a consensus on how STAS is evaluated.

Acknowledgments

We would like to thank Ms. Rachel Sharpton for her editing work on the manuscript.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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