Lung neuroendocrine tumors: a new addition to the evolving list of spread through air spaces

Air-filled spaces are a notable characteristic of the lung. When a cancer develops in the lung, it is often surrounded by air spaces; thus, there is the possibility that cancer cells spread thorough air spaces. In fact, Kodama and colleagues presented a lung cancer case with multifocal “aerogenous” spread in 1980 and ultrastructurally studied the nature of detached fragments (1). Since then, multiple groups have reported the aerogenous spread of lung cancer cells, but it was not until 2012 when systematic pathological and prognostic analyses of the aerogenous spread of lung cancer cells began conducted. Onozato and colleagues found unique island-like structures in two of four lung adenocarcinomas analysed by 3D reconstruction and named them as tumor islands (2,3). “Tumor islands” are detached, large clusters of tumor cells in alveolar spaces separated from the main tumor mass but are connected to the main tumor mass in different tissue levels (2). Subsequently, they showed the association of tumor islands with shorter recurrence-free survival in stage I–II lung adenocarcinomas and hypothesized that tumor islands represent ‘air space invasion” (3). Kadota and colleagues demonstrated that the spread of single tumor cells or micropapillary/solid type tumor cell clusters within air spaces adjacent to the main tumor [i.e., tumor spread through air spaces (STAS)] is a significant risk factor for shorter recurrence-free survival in patients with small lung adenocarcinomas (≤2？cm) treated with sublobar resection (4). Of note, there appear to be mutual morphologic features between the solid type STAS, in particular, large clusters and tumor islands. Based on these results, STAS was recognized as a new form of invasion, “air space invasion,” in the 2015 World Health Organization (WHO) classification and became an exclusion criterion for minimally invasive adenocarcinoma (5). Subsequently, Dai et al. showed no statistical difference in recurrence free survival between patients with stage IA lung adenocarcinoma harboring STAS and those with stage IB suggesting that STAS could be a staging factor (6). In addition, STAS has been seen not only in lung adenocarcinomas but also in squamous cell carcinomas (7-9) and pleomorphic carcinomas (10). Many subsequent studies reported STAS as a predictor of worse patient outcomes, and a systematic review and meta-analysis of 2,897 patients with non-small cell lung carcinoma showed that the presence of STAS was associated with shorter recurrence-free survival [hazard ratio (HR): 1.975; P<0.001] (11). More recently, Eguchi and