128 Chapter 10 clusters / isolated tumor cells can also be an artifact as well. A possible explanation may be that during cutting of the resection specimen a knife is used. The width of the knife is around 10-15 times bigger than that of tumor cells120, inducing a tremendous force with mechanical displacement of tumor cells at the cutting edge. Apparently, the ‘empty’ arterial vascular lumen forms a niche that is fillable, probably due to the still flexible structure of the pulmonary arterial wall compared to veins and lymph vessels. The example of a peripheral pulmonary tissue fragment in the lumen of a pulmonary artery strongly supports this explanation (see Figure 5, B through D, in Thunnissen et al120). We do not have the intention to call isolated tumor cells in pulmonary arteries of resection specimen ‘spread through vascular space’, but rather ‘spread through a knife surface’ as described in a study as 1 of the 4 ex-vivo artifacts in pulmonary resection specimen120. The possibility of artifacts has been described in several organs as well, such as in thyroid resections, in which the artifactual displacement of adenoma and non-malignant epithelial cells has been reported192. But also in resection specimen for prostate cancer it could be a pitfall 193. In colon cancer, extramural venous invasion was associated with a worse prognosis194,195, in contrast to the presence of intramural venous invasion that revealed a similar prognosis when compared to no venous invasion194. In laparoscopic abdominal hysterectomy specimens, vascular pseudo-invasion of malignant and benign cells was reported136,137. In one of these studies a suggestion was made that pathologists may be generating postoperative pseudo-invasion by mechanically transporting tumor into vascular spaces during the grossing process136. Recently Metovic and colleagues196, published an interesting article stating that “STAS is without any doubt, no artifact that can be induced by gross specimen handling.” The authors are to be complimented with the careful designed methodology. Nevertheless the effect of cutting (including the manual pressure) combined with the tendency of dissociation of tumor cells, remains open for discussion197. In short, there are no defined morphological criteria to distinguish true invasive tumor cells or small clusters from mechanically dragged tumor particles. Taking the morphological, clinical, and literature information, including from other organs, into account, we interpret the presence of tumor cells floating in the arterial lumen detached from the vessel wall and without associated thrombus in resection specimens of primary pulmonary adenocarcinomas in the presented cases as an artifact, although true vascular invasion may occur. The study’s limitations include its retrospective design and the use of available tumor blocks, which may not have included the entire tumor for histopathologic examination, even for small tumors. Additionally, because all cases had a low stage and non-mucinous adenocarcinomas, resection alone may lead to a cure. The study did not conduct multivariate analysis to account for potential clinical confounders, which requires at least 20 events for RFS and OS. However, our study did not fulfill the minimum requirements with only 14 RFS events and 18 OS events. Further larger prospective studies examining also higher stages are warranted.
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