257 General discussion and future perspectives that using downforce, also creates an upward force that could explain the presence of tumor cells, but also erythrocyte in other directions than expected. In the CON part of the STAS editorial in chapter 11 most of the alternative explanations for the presence of tumor cells, normal tissue fragments and erythrocytes, distant from the tumor border are presented. The article highlights potential factors such as surgical clamping forces during lobectomy, which could lead to the displacement of lymph fluids, as well as handling of the specimen during pathological examination. The use of a sharp knife for “gentle” cutting may help to reduce mechanical forces, but an underestimated factor is palpation. Last but not least, the pictures taken from a video, kindly provided by Metovic and Papotti (see chapter 11), shows that the fingers of the left hand are strongly compressing the tumor, in order to cut in a stable manner “gentle” with the new sharp knife in the right hand through the tumor. In this context it is not excluded that (the left hand) palpation force is a confounder, and may be an explanation for an essential part of the different outcomes between Metovic’s and our study. A supporting argument is that palpation by the surgeon leads to more circulating tumor cells during resection procedure, as mentioned in chapter 11. Loose tumor cells in pulmonary artery of resection specimen In chapter 10, it was suggested that “loose tumor fragments” could be an artifact, and a new argument to support this claim is that there was a relatively high incidence (almost 60% of 70 cases) of cytokeratin 7 positive tumor cells in small pulmonary artery branches. In addition to tumor cells, intravascular alveolar macrophages were also discovered. Overall, the presence of displaced tumor cells in a non-invasive disease is difficult to explain biologically, but could be attributed to artifacts. Furthermore, none of the potential differential diagnostic diseases were morphologically fitting with our observations. In our opinion, the only realistic explanation for the intravascular tumor cells is an artifact, probably by cutting the knife during macroscopic procedure. In our opinion, the loose tumor cells in the pulmonary artery are considered to be another artificial spread of detached tumor cells. STAS and dissociation In the debate about the interpretation of “loose tumor cells” as “STAS” there is no controversy about the malignant nature of these cells. In the WHO classification STAS is used as a criterion of “invasion”. In our opinion this is an overinterpretation. In breast cancer cytology dissociation is rightfully used as a criterion of malignancy, but not as “invasion”. The modified adhesion molecules in malignant cells may be used for explanation of the reduced adherence between tumor cells. The shear force on the cells during spreading of the tumor cells on the hard blunt glass slide for cytological examination is probably not much different from the shear forces occurring during cutting with a hard blunt steel knife. In breast cancer ductal carcinoma in situ, tumor cells also lead in cytology to dissociation and is rightfully interpreted as characteristic of malignant cells, but not as invasive. In short, the dissociation is a characteristic of 17
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