175 Pattern recognition in pulmonary AdC; a modified classification Introduction According to the World Health Organization’s 2021 classification of non-mucinous lung adenocarcinoma, the predominant pattern is used to subtype the tumours313 314. Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are associated with a 100% 5-year recurrence free survival (RFS) rate7 315. AIS is defined as growth of a monolayer of tumour cells along pre-existing alveolar structures with focal cell overlap or mild stratification314, i.e. pure lepidic growth without any invasive feature, in tumours that are 30 mm or smaller316. The 8th edition of UICC/AJCC TNM classification system for non-small cell lung cancer (NSCLC) recommends that the size of the primary tumour should be determined by the invasive components only307. It is therefore crucial to differentiate between a lepidic growth pattern, specifically AIS, and other patterns that are deemed “invasive”. However, assessment of invasion has a poor reproducibility14. Moreover, the Pathology Committee of the International Association for the Study of Lung Cancer (IASLC) recently published a proposal for defining morphologic features of invasion in pulmonary non-mucinous adenocarcinoma with lepidic growth, involving also the effects of collapse on morphology317. It appears that, in the past decade, the fog around adequately recognizing invasion patterns implicitly present in the WHO classification of pulmonary adenocarcinomas has not lifted as their recent publication stimulates research on this topic317. Typically, when identifying pre-neoplastic lesions, in situ carcinomas, and invasive patterns, pathologists compare the observed tissue to its normal physiological state as a reference. For example, to recognize mild cervical dysplasia, pathologists compare the abnormal epithelium with the adjacent normal non-keratinized squamous epithelium, or if absent, with their mental visualization of the normal squamous epithelial surface. Unlike the cervix, where tissue structure remains largely unchanged following biopsy or resection, the peripheral pulmonary parenchyma undergoes significant morphological alteration during resection. This alteration in morphology is similar to the impact of compression atelectasis observed in tension pneumothorax318. When the thorax is opened during surgery, the negative pressure in the pleural cavity is reversed, leading to a positive atmospheric pressure. As a consequence, the lung parenchyma deflates, and there is a decrease in vascular blood and lymph flow, which ultimately results in peripheral lung collapse120 (see Supplementary Figure S3 in 317). In addition, when a tissue sample is taken from its natural context, such as during surgical resection, the natural recoil of the elastic fibers changes the shape and length of the alveolar walls308. As a consequence, so called iatrogenic collapse of the lung parenchyma occurs, which is identifiable under microscopy by the close proximity of alveolar septa with little or no air retained between them (Figure 1 A, B). 14
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