258 Chapter 17 malignant cells. However, directly attaching to STAS the weight of ‘invasion’ is in our opinion an overinterpretation: a bridge to far. “STAS” and prognosis In the literature, it is frequently stated that the presence of STAS is an independent adverse prognosticator. The association with a worse clinical outcome is not debated. But the “independent” character is doubtful, since there are several significant associations with other known pathological features. In this context is useful to know a study of the International Association for the Study of Lung Cancer (IASLC) pathology committee: a series of histologic prognostic indicators, including STAS, were compared aiming for development of a grading system in resected invasive pulmonary adenocarcinoma. Moreira et al. concluded that several histologic parameters such as nuclear grade, mitotic grade and the presence of STAS were associated with recurrence, but in the final proposed grading model, the added prognostic value of STAS was not selected252. In summary, we provide several arguments (in this general discussion and in chapter 11) that “loose tumor cells” or “STAS” is one of the (inducible) artifacts that can occur during tissue handling of lung specimen. The sampling variation encountered and poor reproducibility of “STAS” should be major issues that need to be solved, before considering the incorporation of STAS in future TNM systems. The biological connotation of “spread through air spaces” implies some exclusivity and danger if true. Luckily, lung cancer is not contagious. It also suggests that we as pathologists are able to add the connotation “spread through air”. Peculiarly, morphological identical cells with a not-for-location-fitting alveolar topology are, according to the expert opinion in the WHO interpreted as “artifact”. This statement of STAS being an inducible artifact, may, in combination with tumor cells displaced to other microanatomic locations such as pulmonary artery, bronchial or bronchiolar lumen, also provide an alternative explanation for the counterintuitive molecular based suggestion in the recent TRACER-X study that lung adenocarcinomas do not always follow an evolutionary route toward higher-grade patterns but also from “high grade” to “low grade”373, as during sampling “low grade” tumor cells may be displaced to an area with a “high grade” pattern. Moreover, the biology of STAS is not solved. Is STAS an energy neutral fly? In the pulmonary artery we limit ourselves with the in chapter 10 provided arguments of ‘loose tumor cells’ in pulmonary arteries of resection specimen to the following statement: “do not attach a biologic annotation and interpret this phenomenon as an artifact”. In part III, we aimed to refine diagnostic tools that can aid in better 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 in the associated prognosis.
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