Prognostic Impact of Intra-alveolar Tumor Spread in Pulmonary Adenocarcinoma

Abstract

Tumor spread, in general, is the most important factor determining outcome in almost all malignant tumors. Lung tumors are unique with respect to potential routes for tumor dissemination, as apart from vascular, nodal, and distant spread of tumor cells, tumor spread through air spaces (STAS) might also occur. However, morphologic criteria for STAS and its prognostic impact have not been defined yet. We evaluated a series of 569 resected pulmonary adenocarcinomas (ADCs) for predefined morphologic criteria of limited and extensive STAS and correlated our findings with clinical, morphologic, molecular, and outcome data. Limited (21.6%) or extensive (29%) STAS was present in roughly half of all ADCs. The presence and type of STAS was tightly linked to specific growth patterns (P<0.001). STAS was much more prevalent in high-stage (P<0.001), nodal-positive (P<0.001) ADC with distant metastasis (P=0.010). STAS was associated with lower rates of EGFR (P=0.009) but higher rates of BRAF (P=0.016) mutations. Furthermore, STAS was associated with significantly reduced overall (P=0.020) and disease-free survival (P=0.004), which was growth pattern but not stage independent. We analyzed morphologic characteristics of a yet underestimated type of tumor spread of pulmonary ADC through air spaces. STAS is a novel morphologic prognosticator, which should be further validated and considered for implementation in routine diagnostic evaluation and reporting.

Spread through air spaces (STAS): a comprehensive update

“…In a series of 569 ADC STAS was significantly associated with male sex, lymph node and distant metastasis, tumor stage, and high-grade histological patterns (2). Further correlations were found with KRAS and BRAF mutations (2). Another recent study concerning STAS in a series of 318 stage I ADC confirmed and extended the yet available data.…”

“…In the second validation study, STAS was a significant prognosticator for both overall and disease-free survival even in patients with lobectomy and independent of the extent of STAS. Furthermore, STAS remained a worse prognosticator in multivariate analysis including the predominant pattern but not independent of stage (2). Although the analyzed subgroups were small, this study also demonstrated for the first time that the presence of STAS adds significant prognostic information to the predominant pattern (2), which was further underlined by a subsequent study focusing on the papillary pattern (16).…”

“…The association of STAS to lymphovascular invasion was subsequently validated by others (10). In a series of 569 ADC STAS was significantly associated with male sex, lymph node and distant metastasis, tumor stage, and high-grade histological patterns (2). Further correlations were found with KRAS and BRAF mutations (2).…”

“…The concept of STAS was initially validated by two large contemporaneous publications (1,2). In a series of 411 stage I ADC it was demonstrated that STAS is a phenomenon usually found in the first alveolar layers close to the tumor but occasionally can be found more than 50 alveolar spaces away from the main tumor.…”

“…Following validation in two large independent cohorts from the US and Germany (1,2), the new concept of spread through air spaces (STAS) was introduced for pulmonary adenocarcinomas (ADC) in the 2015 World Health Organization (WHO) classification for lung cancer and subsequently validated and extended by further studies (3). This article will provide a comprehensive overview on recent developments in this field.…”