98 Chapter 7 experts present (e.g. pulmonologists, oncologists, radiologists, surgeons) supported the proposal as a histologic pattern of tumor invasion, although they considered that it was not sufficiently mature to enter into the WHO classification. Nevertheless, in the final version of the 2015 WHO classification of Lung Tumors, STAS has been described as a new form of invasion in the lung, namely invasion through alveolar spaces, with the concept said to be validated by two large cohorts117,118. The first cohort consisted of a series of 411 Stage I adenocarcinomas in which tumor cell clusters or loose cells, called STAS, were seen usually in the first alveolar layers close to the tumor border, but also in a few dozen alveolar spaces further away. This phenomenon was associated with lymphovascular invasion and high-grade histological pattern. However, it was not significantly associated with local recurrence in the lobectomy group but was a prognosticator for any recurrence in the limited resection group117. In the second cohort which comprised a series of 569 Stages I-IV adenocarcinomas, STAS was associated with lymph node and distant metastasis as well as with tumor stage and high-grade histological pattern. These authors were not able to examine the effect of STAS on recurrence in patients with limited resection, as there were too few cases of sublobar resections included in their series118. Since then several other studies134,141–146 and various editorials147–149 and reviews150–152 have supported the concept of STAS in pulmonary adenocarcinomas and more recently also in squamous cell carcinoma133,153. In the 2015 WHO Classification of Lung Tumors fascicle, STAS is defined as “spread of micropapillary clusters, solid nests, or single cancer cells into air spaces in the lung parenchyma beyond the edge of the main tumor”4. The exact distance from the main tumor is not defined. In the different studies investigating STAS, the distance from the main tumor varies, as do the criteria used to define STAS (see Table 1). Table 1. The definitions of STAS and distance from the main tumor are shown as reported in the published studies. Study / year Criteria of STAS Defined distance from main tumor Onozato et al. 2013115 Isolated, large collections of tumor cells; no micropapillary configurations At least a few alveolar spaces Kadota et al. 2015117 Micropapillary clusters, solid nests, single cells Even in the first alveolar layer from the tumor edge Warth et al. 2015118 Small cell nest (> 5 tumor cells) Cell nests < 3 alveoli away (limited STAS) > 3 alveoli away (extensive STAS) Morimoto et al. 2016134 A group of more than 3 small clusters containing<20 nonintegrated micropapillary tumor cells > 3mm apart from the main tumor Shiono and Yanagawa. 2016144 Tumor cell cluster lying freely within alveolar spaces At least 0.5 mm from the main tumor Dai et al. 2017143 2015 WHO definition At least a few alveolar spaces Lu et al. 2017133 Tumor cell nests Even in the first alveolar layer from the tumor edge
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