255 General discussion and future perspectives the anatomical tumor location(s), other reproducible parameters could be employed to enhance the most commonly used clinical prognostic system, which has relied so far solely on those anatomical data for staging. To improve the prognostic ability of the coming 9th edition of the TNM classification, the latest data collection could probably include molecular information such as genetic biomarkers, copy number alterations, and protein alterations. Adding highly reproducible histologic parameters, such as the distinction between adenocarcinoma and squamous cell carcinomas is simple and informative. Bertoglio et al. showed that pT1 micropapillary and solid subtypes, considered as high grade patterns252, had a prognosis comparable to pT2a tumors368. However, the reproducibility of pattern recognition is low14. Integration of reproducible parameters with clinical, biological, and anatomical factors may form prognostic groups that will enhance our capacity to refine prognosis and hopefully personalized therapeutic planning. Rami-Porta suggests that in future editions of the TNM classification, the results of liquid biopsy may play a role in complementing it369. The suggestion of adding the letter B for blood was made, to describe the presence of cancer material in the blood and so leading to a TNMB classification370. He further states that other cancer cells should also be included in future editions of the classification369, namely, those of spread through air spaces (STAS), that have been identified in all types of lung cancer and are associated with a worse prognosis. This last statement seems very premature, because there is still debate on the true nature of STAS and the reproducibility of diagnosing STAS is low and sampling variation high. In part II, the focus was on this phenomenon of “STAS”. Since the introduction of spread through air spaces (STAS) as a new invasive pattern in the 2015 WHO classification on non-small cell lung cancer (NSCLC)4, there has been a debate on whether STAS is a true biological phenomenon or mainly an artifact. In chapter 7, a critical review on the subject is presented, arguing that STAS could well be an inducible phenomenon by surgical and pathology handling of the resected specimen. The basis for this point of view is the in chapter 6 presented prospective multi-institutional study, in which we demonstrate that the number of loose tissue fragments and cells increases along the path that the dissection knife takes at gross handling of the resection specimen. “Loose tumor cells” / “STAS” and definition Although the viewpoint that “loose tumor cells” are an artifact is mainly debated by the initiators of the STAS concept in the 2015 edition of the WHO classification4, they already made nuances in the 2021 WHO edition19 371. In this most recent classification, in contrast to the previous version, artifacts as a possible differential diagnosis of STAS is mentioned: “The following features favor artifactual spread of tumor cells over STAS: (1) randomly situated and ragged-edged clusters of tumor cells often at the edge of the tissue section or out of the plane of section of the tissue; (2) lack of continuous spread in airspaces from the tumor edge to the most distant airspace tumor cells; (3) 17
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