99 Critical review on STAS Table 1. The definitions of STAS and distance from the main tumor are shown as reported in the published studies. (continued) Study / year Criteria of STAS Defined distance from main tumor Uruga et al. 2017142 Clusters of micropapillary or solid nest, single cells Even in the first alveolar layer from the tumor edge Masai et al. 2017141 Single cell, small cluster, or large cluster Not reported The prognostic argument in favor of STAS The claimed relevance of STAS seems to be supported by the presence of tumor cell clusters or loose cells, which, irrespective of their numbers, were frequently significantly associated with adverse clinicopathological features. The published studies and the types of clinicopathologic factors associated with STAS are summarized in Table 2. The presence of STAS has been found to be associated with lymphovascular-, vascular- and pleural invasion as well as with criteria for higher histological grade tumors, such as solid and micropapillary adenocarcinomas. A few studies also mention the association between the presence of KRAS mutations and the absence of EGFR mutations in STAS-positive tumors. The presence of STAS has also been found to be significantly associated with poorer overall survival (OS) and/or disease-free survival (DFS), in some studies also in multi-variate analysis142 133. A more recent study has also confirmed that the presence of STAS is a significant risk factor for local recurrence in early-stage NSCLC in patients who undergo limited resections141. Furthermore, another recent study reported that a semi-quantitative assessment of STAS provided additional prognostic information, with shorter recurrence-free survival seen in tumors with “high STAS” on univariate analysis142. In the same study, STAS retained its significance as a predictor of survival on multivariate analysis. But could there be an alternative explanation for the observation of loose tumor cells and tissue fragments in NSCLC with a worse prognosis? 7
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