Histopathological aspects of resected non-small cell lung cancer, with emphasis on spread through air spaces and collapsed adenocarcinoma in situ
Authors:   , Blaauwgeers Johannes Lucas Gerhardus 
Published: September 2023

This thesis investigates three aspects in lung resections with non-small cell carcinoma that are relevant for diagnosis, prognosis, and staging. Firstly, the pathological response after neoadjuvant therapy. Secondly, research on the so-called "STAS" with the hypothesis that this phenomenon may be an artifact rather than a biological phenomenon. Thirdly, attempts were made to refine diagnostic tools that can help distinguish invasion from non-invasion in non-mucinous adenocarcinoma.
In chapter 2 of part I, the histological changes after neoadjuvant therapy are described in patients with a sulcus superior tumor who underwent chemoradiation followed by surgical resection.
In chapter 3, additional morphological prognostic characteristics of tumors were sought. Importantly, low MIB-1 expression was associated with improved survival and disease-free survival, while negative PD-L1 expression also predicted better survival.
Chapter 4 presents the results of a national study on T3N0 NSCLC, which includes various tumor categories, including those with parietal pleural invasion or a diameter greater than 7 cm. The study in Chapter 4 had two objectives: to assess the validity of the shift from pT3 to pT4 in the Dutch population and to investigate whether the inclusion of additional morphological factors could improve staging accuracy.
Part II focuses on the phenomenon of Spread Through Air Spaces (STAS). This has been described as a new way of metastases since the 2015 WHO classification, but it may be an artifact. Chapter 5 describes various histopathological artifacts related to tissue treatment after removal and upon receipt at the pathology department. Additionally, spreading of tumor tissue by a knife during the cutting of the resection specimen is described as a possible explanation for the presence of loose tumor cells or cell clusters in alveolar spaces away from the tumor's border.
In Chapter 6, a prospective multicenter study is described that suggests that STAS is an inducible phenomenon. In 44 resection specimens, the number of loose tumor cells and/or cell clusters was counted in four sections taken through the tumor without cleaning the preparation knife. The number of loose cells and/or clusters increased from the first section that was cut without going through the tumor to the last section where the knife had been used twice through the tumor. Based on this study, it was concluded that it is highly likely that STAS is an inducible artifact.
Chapter 7 is a critical evaluation of the STAS phenomenon.
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.
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.
Chapter 13 discusses a proof-of-principle study that investigated whether consideration of surgical collapse leads to a more frequent diagnosis of AIS.
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.
Chapter 15 concerns the largest international interobserver study with pathologists ever, in which the presence of iatrogenic and biological collapse in the assessment of invasion of lung adenocarcinoma using elastin and cytokeratin 7 staining to diagnose (collapsed) AIS more reliably and reduce variation between assessors of invasive patterns in small pulmonary adenocarcinomas was investigated.
Chapter 16 provides strong arguments for abandoning the diameter limit of 3 cm for AIS.