311 Summary In Chapter 10, another possible artifact is investigated, namely the presence of individual tumor cells and tumor cell clusters, as well as macrophages in branches of the pulmonary artery in histological sections of lung resection specimens. In a small pilot study of 33 patients, this was observed in 23 patients (70%), with no relationship between this presence and overall survival. This result was confirmed in two validation cohorts (total of 70 patients) from two institutions in Amsterdam and Milan, where the phenomenon was observed in 41 patients (58%), again without a relationship with recurrence-free or overall survival. Particularly noteworthy was that in cases diagnosed as non-invasive, this observation was seen in 8 out of 10 cases. These findings were considered a strong argument that this is also an artifact rather than a biological phenomenon. Chapter 11 contains the most recent arguments together about STAS as an artifact in the CON part of a Pro-Con editorial. In Part III, the focus is on iatrogenic and biological collapse as a possible pitfall in the assessment of invasion in small adenocarcinomas. Chapter 12 describes the importance of elastin in pulmonary pathology and its potential usefulness in recognizing collapsed lung and non-invasive growth along alveolar walls. In particular, emphasis is placed on the presence of elastin in the alveolar septa and its absence in the septa of a true papillary invasive variant in the case of collapse in an in-situ carcinoma. Chapter 13 discusses a proof-of-principle study that investigated whether consideration of surgical collapse leads to a more frequent diagnosis of AIS. In this study, cytokeratin 7 is used as an immunohistochemical marker to better recognize the regular growth pattern of a monolayer of tumor cells in AIS. In the patient group of the pilot study in Chapter 10, a diagnosis of AIS was made in 33 out of 38 patients, including 5 patients whose tumors were previously considered invasive. The revised diagnosis did not affect the 100% 5-year survival rate. Based on this, it was considered plausible that recognition of collapsed AIS, including with the help of a CK7 staining, can lead to better diagnosis of non-invasive patterns. Chapter 14 describes the morphological features of iatrogenic and biological collapsed AIS, where lessons are learned from a mathematical model, and cytokeratin 7 and elastin stains are used to assess invasiveness. Two independent cohorts of resected adenocarcinomas of 3 cm or less were examined to investigate these aspects, and their relationship with disease-free and overall survival was analyzed. In the Amsterdam and Milan cohorts, as also described in Chapter 10, a diagnosis of AIS was made in 10 patients based on proposed criteria, 9 of whom were originally diagnosed as invasive. As in the proof-of-principle study in Chapter 13, these patients had 100% disease-free and overall survival. This chapter also suggests additional morphological criteria with other intra-alveolar growth patterns than the monolayer in AIS, which can be used as surrogate markers for invasion. Chapter 15 concerns the largest international interobserver study with pathologists ever, in which the presence of iatrogenic and biological collapse in the assessment of A
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