259 General discussion and future perspectives Biological collapse In the literature the term ‘collapse’ has been used in two ways. ‘Iatrogenic collapse’ for tissue collapse after resection and ‘biological collapse’ as an in vivo phenomenon. In histology of lung tumors two components of a scar are discerned: fibrosis with dense collagen and biological collapse with increase of elastin. The latter is supporting the recognition of the pre-existing pulmonary architecture, and has in 1995 without invasive characteristics been described as Noguchi type B10 or Type II by Goto et al323. Both studies concluded that this so-called ‘biologic collapse’ is probably non-invasive and was associated with a 100% disease free survival. The biologically collapsed alveolar framework has condensed and curled elastic tissue leading to smaller alveolar spaces265. Important to realize is that elastin is produced by mesenchymal cells and not by epithelial cells. Thus, also not by the functionally crippled tumor cells. In a model study, the presence of elastin induced the production of more elastin206. This may explain the elastin increase in biological collapse. Why epithelial cells may sometimes disappear in the center of biological collapse is unclear. Nevertheless, this should not withhold pathologists to add a connotation of ‘no invasion’ (AIS), unless there is adjacent multilayering of tumor cells. Iatrogenic collapse Another form of collapse, called iatrogenic collapse, is, in contrast to biological collapse, an ex vivo phenomenon that affects the appearance of the lung both macroscopically and microscopically. Iatrogenic collapse was initially as described in pneumothorax and atelectasis318. This iatrogenic collapse was for the first time described in 2013 as “surgical atelectasis artifact”: a possible confusing factor in the distinction between in situ carcinoma and papillary adenocarcinoma332. It was later on called iatrogenic collapse, mentioned in the in chapter 5 presented study on the description of all kinds of ex-vivo artifacts in the lung and accepted for the first time in the 2021 WHO classification of lung cancer as “possible source of confusion in the setting of lepidic adenocarcinoma”19 371. Chapter 14 describes that maximal iatrogenic collapse in peripheral lung tissue is dependent of the epithelial lining thickness, being either the normal, near flat pneumocytes, somewhat larger reactive pneumocytes or tumor cells. We demonstrated that 12 alveolar wall cross sections fit in nearly complete iatrogenic collapsed normal lung parenchyma in a length of 200 μm, as opposed to 4-5 alveolar walls lined with tumor cells. The mathematical model provided arguments for folding of alveolar walls during iatrogenic collapse. This drastic change of normal underlying morphology is not present in any other organ of the body, and the reason that traditional 2-dimensional pattern recognition is without adjustments not applicable. In hindsight, awareness of this phenomenon during microscopy is crucial for proper diagnosis. The orientation of collapsed alveolar walls is frequently parallel to the pleural surface. Besides that, tangential cutting of alveolar walls will be slightly misleading as the focal multilayering should be neglected. The folded alveolar walls have a regular 17
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