Abstract
INTRODUCTION: Tumor spread through air spaces (STAS) has prognostic significance in lung adenocarcinoma and squamous cell carcinoma. We sought to investigate the prognostic importance of STAS in lung neuroendocrine tumors (NETs). METHODS: All tumor slides from patients with resected pathologic stage I to III lung NETs (N = 487) (299 with typical carcinoid [TC], 38 with atypical carcinoid [AC], 93 with large cell neuroendocrine carcinoma [LCNEC], and 57 with SCLC) treated between 1992 and 2012 were evaluated for presence of STAS. Cumulative incidence of recurrence (CIR) and lung cancer-specific cumulative incidence of death (LC-CID) were analyzed by using a competing-risks approach. RESULTS: STAS was identified in 26% of NETs (16% of TCs, 37% of ACs, 43% of LCNECs, and 46% of SCLCs). STAS was associated with distant metastasis, as well as with higher CIR and LC-CID in the overall cohort and in the AC, LCNEC, and SCLC cohorts (owing to a small number of recurrences and deaths [<5], prognostic analysis was not performed in the TC cohort). In multivariable analysis stratified by stage, STAS was significantly associated with higher CIR (subhazard ratio = 2.85, 95% confidence interval: 1.73-4.68, p < 0.001) and LC-CID (subhazard ratio = 2.72, 95% confidence interval: 1.57-4.70, p < 0.001), independent of histologic subtype. STAS was independently associated with CIR and LC-CID in the LCNEC cohort and LC-CID in the SCLC cohort. CONCLUSIONS: In patients with lung NETs, STAS is associated with early distant metastasis and worse LC-CID. In patients with LCNEC or SCLC, STAS is an independent poor prognostic factor.