177 Pattern recognition in pulmonary AdC; a modified classification In hematoxylin and eosin (H&E) staining, the condensed elastic tissue may be mistaken for fibrosis, while in elastin staining, the preponderance of elastic over collagen fibers is easily recognizable. This parenchymal collapse is referred to as ‘biological collapse’, as opposed to iatrogenic collapse. In 1995, two Japanese studies showed that nonmucinous adenocarcinomas with tumour cell growth along alveoli and central biological collapse, had a favorable prognosis10, 277. In 2016, the collapse of peripheral lung during surgery was described as having an effect on the pre-existing morphology120. More examples of this iatrogenic collapse involving areas with lepidic growth, consistent with AIS have recently been published279. If the amount of collapse is minimal, with a clear number of airspaces between the alveolar walls, the diagnosis of AIS can be readily made. However, if the collapse is more prominent, overlap may occur with diagnostic criteria for papillary and acinar adenocarcinoma patterns in particular90. Therefore, according to the WHO classification, collapsed AIS may be (over)diagnosed as invasive adenocarcinoma (Figure 1 C-F). The aim of this study is to improve understanding of the complex 3-dimensional morphology of lung adenocarcinoma, especially for non-mucinous AIS in resection specimens, under conditions of iatrogenic and biological collapse. To this end, we first used a mathematical approach to evaluate morphological changes on alveolar walls and tumour cells during iatrogenic collapse. Subsequently, we investigated diagnostic criteria for collapsed AIS using hematoxylin and eosin (H&E), cytokeratin 7 (CK7) and elastin staining and considered more extensive intra-alveolar growth patterns as surrogate markers for invasion. By using the proposed criteria, we investigated whether cases could be reclassified as AIS and whether this was supported by follow-up outcomes. Modifications lead to a proposal for a revised classification of pulmonary adenocarcinoma. Material and methods Patient cohorts Two retrospective cohorts of patients with resected pulmonary adenocarcinoma diagnosed between the 1st January 2011 and the 31st December 2016 were collected in: A) OLVG Hospital, Amsterdam, The Netherlands and B) San Raffaele Scientific Institute, Milan, Italy. The inclusion criteria for the cases were: resection specimen with a primary pulmonary adenocarcinoma of a pathological tumour diameter of 3 cm or less and available follow-up information. Exclusion criteria were the presence of nodal or hematogenous metastases at the time of resection, treatment with neoadjuvant chemo(radio)therapy, multiple nodules in the same or other lobes, previous lung carcinoma, and invasive mucinous adenocarcinoma or other special type patterns (intestinal and fetal adenocarcinoma). Assuming the fraction of cases to be downgraded to AIS to be around 20%320 and a 95% confidence interval between 10-30% the minimum sample size required is 70 14
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