261 General discussion and future perspectives Collapse and diagnosis The application of pattern recognition is the heart of pathology and is applied in all organs of the body. Pathologists are masters in pattern recognition. The word collapse is mentioned in the 5th edition of the WHO classification of Thoracic Tumors19, but a distinction between iatrogenic and biological collapse is not made. The notion of iatrogenic collapse as a morphological artifact is not mentioned, but possible confusion of collapsed lepidic adenocarcinoma and AIS with acinar or papillary invasive patterns is recognized. More importantly, an explanation how to recognize collapsed AIS and how to differentiate it from invasive adenocarcinoma is lacking. The description of the papillary and acinar patterns in the WHO classification of pulmonary adenocarcinoma with by definition associated invasion overlaps with iatrogenic collapsed AIS. Not surprisingly, different pathologists may diagnose iatrogenic collapsed AIS, as lepidic adenocarcinoma, papillary90, acinar adenocarcinoma or minimal invasive adenocarcinoma to the same case. Differentiation between lepidic and invasive patterns is crucial for a practical reason: for invasive size measurement according to the 8th Edition TNM UICC/AJCC of 201719 for non-small cell lung cancer all invasive patterns should be incorporated, except the lepidic pattern380. The categorization of non-mucinous adenocarcinoma subtypes and identification of invasive patterns are both prone to differences in interpretation among different observers. The clinical consequences are large as patients with some invasive subtypes have a worse prognosis368, while in situ carcinomas have a survival rate of 100% and patients with AIS do not require any further treatment following resection, because they are cured. In 2012 a reproducibility study showed that one group of pathologists consistently judged a subset of adenocarcinomas to be invasive, while another group of pathologists consistently judged the same subset to be non-invasive14. This clearly points toward a necessity for calibration or re-evaluation of the diagnostic criteria. Thus far, this calibration did not evolve. Recently, Yambayev and colleagues performed a local study with 2 pathologists in the same pulmonary adenocarcinoma domain, defining low malignant potential (LMP) subgroup with a better prognosis336. Their proposed criteria for LMP adenocarcinoma among non-mucinous adenocarcinoma were: a total size of ≤3 cm, exhibiting ≥15% lepidic growth, and lacking predominant high-grade patterns (≥10% cribriform, ≥5% micro- papillary, ≥5% solid), >1 mitosis per 2mm2, angiolymphatic or visceral pleural invasion, spread through air spaces or necrosis336. They largely followed the managerial process of the current WHO classification19 and selected for low proliferative tumors, but did no attempt to distinguish morphological invasion or not. In our study, a seemingly micropapillary pattern less than three adjacent alveoli is in our study not sufficient for assigning the micropapillary pattern and is not associated with a recurrence. It is likely that cases in our studies may represent the same subgroup as in the study of Yambayev and colleagues. For example, in their figure 1D, which was diagnosed as acinar predominant adenocarcinoma, we would diagnosis this as collapsed AIS, unless 17
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