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

Abstract

Introduction: Tumor invasion in lung adenocarcinoma is defined as infiltration of stroma, blood vessels, or pleura. Based on observation of tumor spread through air spaces (STAS), we considered whether this could represent new patterns of invasion and investigated whether it correlated with locoregional versus distant recurrence according to limited resection versus lobectomy.

Methods: We reviewed resected small (less than or equal to 2 cm) stage I lung adenocarcinomas (n = 411; 1995-2006). Tumor STAS was defined as tumor cells-micropapillary structures, solid nests, or single cells-spreading within air spaces in the lung parenchyma beyond the edge of the main tumor. Competing risks methods were used to estimate risk of disease recurrence and its associations with clinicopathological risk factors.

Results: STAS was observed in 155 cases (38%). In the limited resection group (n = 120), the risk of any recurrence was significantly higher in patients with STAS-positive tumors than that of patients with STAS-negative tumors (5-year cumulative incidence of recurrence, 42.6% versus 10.9%; P < 0.001); the presence of STAS correlated with higher risk of distant (P = 0.035) and locoregional recurrence (P = 0.001). However, in the lobectomy group (n = 291), the presence of STAS was not associated with either any (P = 0.50) or distant recurrence (P = 0.76). In a multivariate analysis, the presence of tumor STAS remained independently associated with the risk of developing recurrence (hazard ratio, 3.08; P = 0.014).

Conclusion: The presence of STAS is a significant risk factor of recurrence in small lung adenocarcinomas treated with limited resection. These findings support our proposal that STAS should formally be recognized as a pattern of invasion in lung adenocarcinoma.

Figure 1. Morphologic features of tumor spread through air spaces (STAS) pattern (original magnification: ×20 in A and D; ×200 in B, C and E; ×400 in F)

(A) Micropapillary pattern STAS (arrows) identified within air spaces in the lung parenchyma beyond the edge (a dotted line) of the main tumor. (B) Micropapillary pattern STAS consisting of papillary structures without central fibrovascular cores. (C) Micropapillary pattern STAS forming ring-like structures within air spaces. (D) Solid pattern STAS identified within air spaces in the lung parenchyma beyond the edge of the main tumor. (E) Solid type STAS consisting of solid collections of tumor cells filling air spaces. (F) Single cell pattern STAS consisting of scattered discohesive single cells (arrows).

Figure 2. Distance of tumor spread through air spaces (STAS) from edge of main tumor

(A) Distance between tumor surface and farthest STAS away from the tumor edge was measured by a ruler with a median of 1.5 mm (range 0.2–8.5 mm), and (B) according to number of alveolar spaces with a median of 7 (range 1–58).

Figure 3. Cumulative incidence of recurrence (CIR) by spread through air spaces (STAS) in the limited resection group

(A) CIR for any recurrence of patients with STAS-positive tumors was significantly higher than for patients with STAS-negative tumors (5-year CIR, 42.6% vs. 10.9%; P<0.001). (B) CIR for distant recurrence of patients with STAS-positive tumors was significantly higher than for patients with STAS-negative tumors (5-year CIR, 20.4% vs. 6.8%; P=0.035). (C) CIR for locoregional recurrence of patients with STAS-positive tumors was significantly higher than for patients with STAS-negative tumors (5-year CIR, 22.2% vs. 4.1%; P=0.001).

Figure 4. Cumulative incidence of recurrence (CIR) by spread through air spaces (STAS) in the lobectomy group

(A) Presence of tumor STAS was not associated with risk of any recurrence compared with absence of STAS (5-year CIR, 12.7% vs. 9.5%; P=0.50). (B) Presence of tumor STAS was not associated with risk of distant recurrence compared with absence of STAS (5-year CIR, 9.6% vs. 7.6%; P=0.76).