Tumor Islands in Resected Early-stage Lung Adenocarcinomas are Associated With Unique Clinicopathologic and Molecular Characteristics and Worse Prognosis

Abstract

Tumor islands -large collections of tumor cells isolated within alveolar spaces -can be seen in lung adenocarcinomas. Recently we observed by 3D reconstruction that these structures were connected with each other and with the main tumor in different tissue planes, raising the possibility of tumor islands being a means of invasion. However, the clinical and prognostic significance of tumor islands remain unknown. In this study, we compared clinicopathological and molecular characteristics and prognosis of Stage I-II lung adenocarcinomas with tumor islands (n=58) and those without (n=203). Lung adenocarcinomas with tumor islands were more likely to occur in smokers, exhibit higher nuclear grade and a solid or micropapillary pattern of growth, and harbor KRAS mutations. In contrast, lung adenocarcinomas without tumor islands were more likely to present as minimally invasive adenocarcinoma, show a lepidic pattern of growth, and harbor EGFR mutations. Although there was no difference in stage, the prognosis of lung adenocarcinomas with tumor islands was significantly worse than those without. The five-year recurrence-free survival for patients with tumor islands and those without was 44.6% and 74.4%, respectively (log-rank p = 0.010). The survival difference remained significant (p < 0.020) by multivariate analysis, and the presence of tumor islands was associated with almost two-fold increase in the risk of recurrence. Even in the Stage IA cohort, more than half of the patients with tumor islands experienced recurrence within 5 years. Thus, aggressive surveillance and/or further intervention may be indicated for patients whose tumors exhibit tumor islands.

Spread through air spaces (STAS): a comprehensive update

“…Furthermore, Onozato et al described so-called tumor islands and their adverse prognostic impact, a morphological feature closely related to STAS in 2013 (7). In principal, tumor islands can be separated from STAS by specific criteria (8).…”

Taking the measure of lung adenocarcinoma: towards a quantitative approach to tumor spread through air spaces (STAS)

“…The association between these two entities is well documented (6)(7)(8). In fact, one of the morphological subtypes of STAS consists of "small papillary structures without central fibrovascular cores" compatible with the cytoarchitectural features of the micropapillary pattern (7).…”

“…In 2011, the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society (IASLC/ATS/ERS) put forth a new adenocarcinoma classification (1) that recognizes five major histologic patterns (lepidic, acinar, papillary, solid, and micropapillary) with prognostic implications that have been validated extensively (2)(3)(4) and adopted by the World Health Organization (WHO) classification of Tumours of the Lung, Pleura, Thymus and Heart 4th edition 2015 (5). Shortly thereafter, we and a group of researchers from the Memorial Sloan Kettering Cancer Center (MSKCC) independently reported distinct patterns of tumor extension through the air spaces of the lung (6,7), which are now encompassed by the concept of tumor "spread through air spaces" (STAS). STAS is currently considered as a novel pattern of invasion in lung adenocarcinoma by the WHO 2015 classification (5) and recent studies from different countries have corroborated the association between the presence of STAS and adverse pathological features (e.g., lymphovascular invasion, high-grade histologic subtypes), EGFR wild-type, and higher risk of recurrence and death in resected (early-stage and advanced) lung adenocarcinomas ( had high STAS.…”

Spread through air spaces (STAS): prognostic impact of a semi-quantitative assessment

“…Onozato et al described so-called tumor islands and their adverse prognostic impact, a morphological feature closely related to STAS in 2013 (8). 3D reconstructions revealed that tumor islands are connected to the main tumor at different levels (9).…”