267 General discussion and future perspectives Grey zone As the aim of chapter 13 was to separate patients with definite AIS from clear invasive adenocarcinomas, we defined the AIS as a monolayer and included the tangential cutting effect. However, between the minimum criteria for clear invasive adenocarcinomas and the in this way defined AIS, some adenocarcinomas fall in between. This was called the grey zone. In a recent pathology panel a slightly different approach was followed and the “in between” zone was called “extensive epithelial proliferation”317. In the chapters 13 and 14 studies it turned out that “grey” zone was scored in a minority of the cases by some pathologists. In none of the cases the score was 100% grey zone. In contrast, the diagnosis of AIS was favored by the majority of the pathologists in more than 10 cases. Thus, from the two factors described in the IASLC pathology panel paper the recognition of collapsed AIS is more important than the extensive epithelial proliferation or grey zone. The question whether the ‘grey zone ‘category will be associated with a 100% 5 years disease free survival or not, is a matter of future studies. Application of the revised criteria according to the WHO classification has a poor kappa score, also reflected in high variation in ‘consensus percentage’, and high average uncertainty score for the invasion decision. With the revised classification an essential increase in kappa score is possible. for the application of invasiveness in pulmonary adenocarcinomas, established by pathologists covering three major regions in the world. The one-hour training for the revised classification between 1st and 2nd reading focused on recognition of iatrogenic collapsed AIS. In hindsight it is questionable if the content was broad enough. Probably more training including awareness of biological collapse, and emphasis on searching for focal irregularities in the CK7 will lead to a higher agreement than 0.45 obtained in the 2nd round as the kappa score of the ‘coached’ 3rd round was 0.62. It is likely that the revised diagnostic approach leads to i) a higher fraction of AIS in resected pulmonary adenocarcinomas; ii) in lepidic adenocarcinomas larger noninvasive areas; iii) reduction of number of papillary carcinomas; iv) association of true papillary carcinoma with a worse prognosis; v) reduction of the number of acinar adenocarcinomas and vi) modification of the prognostic associations for papillary and acinar subtypes. The prevalence of AIS in our cohorts was high with 10 out of 70 resections (14.2%). This is higher than previously reported incidences of AIS in NSCLC (5-8%)381 and in the same range as the 16% reported in the adenocarcinoma with low malignant potential study336, but also as in other series of AIS7. History of WHO classification with a hindsight view In the 1999 WHO classification the papillary pattern was defined by expert opinion as papillae with secondary and tertiary papillary structures that replace the underlying architecture32. Although this terminology looks like the terminology used in the original manuscript describing papillary carcinoma11, the actual morphologic connotation of “fibroplasia of the papillary fronds or scarring of the supporting stroma (“stromal 17
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