102 Chapter 7 Moreover, the biological implication of the term ‘spread through air spaces’ has no comparable accepted biological connotation, except with micro-organisms such as viruses and bacteria. However, micro-organisms or cells growing along alveolar walls with all cellular nutrition available from the underlying capillaries is not the same as growing into the air. A distance of more than 100 microns from a capillary, leads to cellular apoptosis, of which high grade ductal carcinoma in the breast is a clear example. The implication in STAS that tumor cells can live on air alone is biologically not plausible. Moreover, pathologists are aware that when a bronchial biopsy is taken from the lung and it is not immediately fixed, the cells may appear dried out under the microscope e.g., after placing the biopsy on a piece of gauze during transport to the laboratory rather than into formalin. This has been compared to the difference between raisins and grapes. Peculiarly, in the published photomicrographs of examples of STAS the tumor cells appear viable and not dried out. This is another argument that the presence of loose tissue fragments is a phenomenon associated with the moment of resection, and not present for days. In addition, lung cancer is not a contagious disease, i.e., it is not distributed to other human beings by air spreading. In a recent review of STAS, the authors acknowledge that whilst ‘invasion of air’ by a tumor is an unconventional concept, the presence of tumor cells and tumor cell clusters floating in pools of mucin in cases of mucinous and colloid adenocarcinomas, such as in lung and colon, is “internationally accepted” as evidence of tumor invasion despite the lack of stromal invasion148. However, in morphological terms tumor cells and tumor cell clusters do not invade pre-existing mucin but produce the mucin themselves. Furthermore, these mucin pools are also present within the confines of the tumor, sometimes at the tumor’s edge, but still recognized to be within the microscopic boundaries of the tumor. Similarly, in the colorectum, mucin pools are not normally present in the bowel wall but develop in mucinous adenocarcinomas due to secretion of mucin by tumor cells within the bowel wall and not by air movements within the bowel wall. Therefore, we look upon this comparison as an argument for STAS as a fallacy. Overall, there are no accepted similar morphological criteria in other situations that would not require stromal, vascular or pleural invasion as evidence of invasion, so the concept of air invasion is unprecedented. Mimickers of ‘tumor cell clusters or loose cells’ Yet other explanations of 2-dimensional representations of tumor cell clusters or loose cells are i) poor fixation and ii) collapse of certain adenocarcinoma subtypes. In pulmonary specimens subjected to a delay in fixation resulting in poor fixation, the bronchial epithelium frequently detaches from the underlying basement membrane and can be displaced by handling, with displacement occurring into the adjacent alveolar spaces. This phenomenon is well known, especially in autopsy specimens, but may also occur in lobectomy and pneumonectomy specimens. One would expect this phenomenon to be more pronounced in freshly cut specimen, compared to properly formalin fixed ones. This is indeed found in the above mentioned prospective study162.
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