Spread Through Air Spaces (STAS) Is Prognostic in Atypical Carcinoid, Large Cell Neuroendocrine Carcinoma, and Small Cell Carcinoma of the Lung

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.

Keywords: Competing-risks analysis; Lung cancer–specific death; Lung neuroendocrine tumor; Recurrence; Spread through air spaces.

Figure 1:

Artifacts: A) More than four air spaces away from the tumor edge are clusters of tumor cells with ragged edges. These tumor clusters are isolated distantly away from the tumor edge lacking spread in air spaces continuously from the tumor edge. B) Higher power shows this tumor cluster has jagged edges suggesting an artifact from a knife cut. C) These tumor cells are situated on the edge of the tissue and were located far away from the border of the tumor. D) Along the edge of the tumor clusters is a sharp flat edge that indicates a knife cut and the tumor cells appear compressed against the tissue rather than being contained within the tissue.

Figure 1:

Artifacts: A) More than four air spaces away from the tumor edge are clusters of tumor cells with ragged edges. These tumor clusters are isolated distantly away from the tumor edge lacking spread in air spaces continuously from the tumor edge. B) Higher power shows this tumor cluster has jagged edges suggesting an artifact from a knife cut. C) These tumor cells are situated on the edge of the tissue and were located far away from the border of the tumor. D) Along the edge of the tumor clusters is a sharp flat edge that indicates a knife cut and the tumor cells appear compressed against the tissue rather than being contained within the tissue.

Figure 1:

Artifacts: A) More than four air spaces away from the tumor edge are clusters of tumor cells with ragged edges. These tumor clusters are isolated distantly away from the tumor edge lacking spread in air spaces continuously from the tumor edge. B) Higher power shows this tumor cluster has jagged edges suggesting an artifact from a knife cut. C) These tumor cells are situated on the edge of the tissue and were located far away from the border of the tumor. D) Along the edge of the tumor clusters is a sharp flat edge that indicates a knife cut and the tumor cells appear compressed against the tissue rather than being contained within the tissue.

Figure 1:

Artifacts: A) More than four air spaces away from the tumor edge are clusters of tumor cells with ragged edges. These tumor clusters are isolated distantly away from the tumor edge lacking spread in air spaces continuously from the tumor edge. B) Higher power shows this tumor cluster has jagged edges suggesting an artifact from a knife cut. C) These tumor cells are situated on the edge of the tissue and were located far away from the border of the tumor. D) Along the edge of the tumor clusters is a sharp flat edge that indicates a knife cut and the tumor cells appear compressed against the tissue rather than being contained within the tissue.

Figure 2.

Representative images of spread through air spaces (STAS) (red circles) in atypical carcinoid (A), large cell neuroendocrine carcinoma (B), and small cell lung carcinoma (C). STAS is identified as solid nests in the air spaces in the lung parenchyma beyond the edge of the main tumor (black line) (original magnification, x100)

Figure 3.

Cumulative incidence of recurrence (CIR) and lung cancer–specific cumulative incidence of death (LC-CID) curves for patients with and without spread through air spaces (STAS) in the overall cohort (A and E) and the atypical carcinoid (AC; B and F), large cell neuroendocrine carcinoma (LCNEC; C and G), and small cell lung carcinoma (SCLC; D and H) cohorts.