101 Critical review on STAS The alternative explanation for ‘tumor cell clusters or loose cells’ In vivo spread of tumor cells in oncologic surgery is a well-known phenomenon and therefore the general approach is to avoid cutting through a tumor, as if this occurs, the whole field of operation is then considered to be contaminated. In a model system, the chance of tumor recurrence was instrument dependent154. In medicine, tumor contamination of a biopsy path with subsequent outgrowth of the tumor along that path is seen in different tumor types such as NSCLC155–159, mesotheliomas160, sarcomas161 and is a well-recognized phenomenon of tumor spread by instrumental forces. The need to collect data for an alternative explanation for ‘tumor cell clusters or loose cells’ evolved after the WHO classification suddenly included STAS as a new pattern of invasion in pulmonary adenocarcinomas at the end of 2015. One alternative hypothesis is that tumor cell clusters or loose cells may be derived from the handling procedure of resection specimens secondary to size differences between the thickness of the knife (~ 1 mm) and tumor cells, which are smaller by factor of 50-100. Cutting may disrupt the smaller cells and spread them along the new surface created by the knife. The ‘tumor cell clusters or loose cells’ in this hypothesis are no more than an artifact, similar to the already mentioned floaters, but caught in the many ‘holes’ present in the lung, the alveolar spaces. A recent prospective, multi-institutional study demonstrated the presence of tumor cell clusters or loose cells in 73% of cases examined with scrutiny162. In contrast, most retrospective studies report the presence of STAS as not higher than in 15-51.6% of cases115 117 118 142 143 146 148 133. Importantly, 93% of all tumor cell clusters or loose cells were found in blocks sampled from the downward side, i.e., after cutting through tumor tissue, both in adenocarcinomas and squamous cell carcinomas and only in a small minority of the lung tissue sampled before the knife cut through the tumor. Remarkably, benign cell clusters or loose cells were also found in this study, mainly consisting of small clusters and strips of normal (not malignant) bronchial epithelium. Although in severe asthma the respiratory epithelium may shed163, the cases in this study did not show signs of asthma in the bronchial mucosa. The fact that the low frequency of benign cell clusters or loose cells has not been reported in the studies examining STAS is possibly explained by the mental focus of the researchers on malignant cell clusters, which might lead them to overlook the benign loose clusters. Overall, this prospective study provides a strong rationale that loose benign and malignant cell clusters or loose cells are a reproducible artifact due to mechanical forces caused by specimen handling and gross cut-up in the pathology laboratory162. An argument in favor of STAS reported in this prospective study is that some tumor cell clusters or loose cells were found in areas on the slide that were cut before passing through tumor tissue. However, this theoretically could also be explained by in vivo mechanical forces other than a knife, for instance due to surgical handling, either during a video assisted thoracoscopic surgical (VATS) procedure or after this procedure during manual handling. In this context, STAS may also stand for “Spread Through A Surgeon”, as coined in a recent review150. 7
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