13 Introduction and aim of thesis Secondly, we sought to induce the phenomenon of “STAS” by handling the gross specimen, to investigate whether it is plausible that “loose tumor fragments” interpreted as “STAS” is not a biological way of metastasizing, but rather an artifact. We investigate the potential association between possible artifacts such as spreading tumor cells or clusters caused by mechanical knife force or collapse of lung tissue, and classification, staging, or prognosis. Thirdly, we aimed to refine diagnostic tools that can aid in distinction between invasion and non-invasion in non-mucinous pulmonary adenocarcinoma. To achieve this, we examined the impact of iatrogenic collapse on pulmonary adenocarcinomas and its effect on invasion assessment and prognosis. Part I of this study, comprising chapters 2-4, focuses on describing the histopathologic findings in resected specimens of patients with NSCLC, with the aim of refining pTNM staging. In chapter 2, we try to describe the histological changes after neoadjuvant therapy, analyzing a study cohort of 46 patients with sulcus superior tumors who received chemoradiation treatment followed by surgical resection. In chapter 3, we try to identify additional morphologic prognostic characteristics of residual tumors in this patient group, and examined whether proliferation, PDL-1, and nuclear size after chemoradiation in comparison to pretreatment measurements are related to prognosis. The conversion from TNM-7 to TNM-8 harbors a shift of some T-descriptors to another category. Chapter 4 presents the results of a nationwide study on T3N0 NSCLC, initiated in preparation of chapter 16, which encompasses various tumor categories, including those with parietal pleura invasion or a diameter exceeding 7 cm. The aim of the study in chapter 4 was twofold: to assess the validity of this shift in the Dutch population and to investigate whether the inclusion of additional morphologic factors could improve staging accuracy. Part II concerns with the phenomenon of Spread Through Air Spaces (STAS). In the chapters 5 – 11 we focus on this phenomenon, that in the most recent WHO fascicle is classified as a new way of metastases, but is possibly an artifact. Chapter 5 describes in general several histopathologic artifacts related to specimen handling, such as spreading (tumor) tissue through a knife, while cutting the resected specimen. Chapter 6 describes a prospective multicentered study on the investigation of the phenomenon of STAS being an inducible artifact or a new way of metastasizing. Chapter 7 is a critical review on the subject of STAS and in chapter 8 and 9 we comment on this issue, related to a study on neuroendocrine tumors of the lung and to the findings in a comparable study to ours as described in chapter 6. In chapter 10 we examine another possible artifact, namely the presence of individual tumor cells and tumor cell clusters in pulmonary artery branches in histologic sections of pulmonary resection specimen. Chapter 11 summarizes the most recent arguments about STAS as an artifact in the CON part of a Pro-Con editorial. 1
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