232 Chapter 15 in the assessment of invasion” in half of the pulmonary adenocarcinomas ≦ 3cm. Awareness is a part of metacognition (understanding of what our unsolved problems are)339 This issue may conceptually be solved by education: further learning may increase the performance and confidence again. Secondly, clinicopathological studies on small pulmonary adenocarcinomas may show high variation in subtyping of adenocarcinomas and invasion assessment (see supplementary Table S3317). Thirdly, biological studies e.g., those which attempt identify genomic or transcriptomic alterations which drive invasiveness may be hampered. The study of Boland and colleagues examines reproducibility with distinction between AIS, minimal invasive and invasive adenocarcinoma312. They report a kappa score of 0.63. They mention that the agreement data are “likely somewhat falsely inflated because the determination was made by 2 academic pulmonary pathologists practicing at the same large-volume practice”. Interestingly, they hint at overdiagnosis: “tumors with disagreement between MIA and IA had survival similar to agreed MIA, and thus, borderline cases can be confidently classified as MIA.” The overdiagnosis of invasive adenocarcinoma is in line with our findings of a major shift towards ‘no invasion’ in the 2nd and 3rd round in discordant cases, all without recurrence. The term biological collapse denotes a structural change, accompanied by an increased density of curled elastin fibers resulting in marked reduction of the alveolar lumen size, and a monolayer of tumor cells or complete disappearance of the epithelium. In morphological terms the underlying pre-existing architecture is recognizable by the elastin skeleton, where disturbance of the elastin homeostasis has led to an increase in elastin206. A possible issue in the structural change of biological collapse is the collagen accumulation between tumor cells and elastin without active fibroblasts. More study on this issue is warranted. For the current study collagen accumulation was not used as a decisive morphological argument for invasion. At the edge of the biological collapsed area, small angular epithelial cells can be observed. Occasionally, in the center the epithelial lining may disappear, a process that is pathophysiological not understood. Whether this regards atrophy or apoptosis or something else is unclear. For diagnostic purposes it is important to realize that, if the pre-existing lumen in biological collapsed areas contains focally multilayered tumor cells, this is likely a sign of more adjacent proliferation than usually seen in AIS [i.e., associated with invasion]. Limitations of the study Several limitations should be mentioned. A) Folding in histological sections may cause larger areas to be out of focus. Few cases were excluded because of the folding. B) Possibly, part of the results was influenced by the fact that we looked at digital slides. Some pathologists lacked experience in reading digital slides. Some of the pathologists have the habit to screen a slide under the microscope in a standard fashion in one direction and move at the one row upwards/ downwards etc. This is not as easy to do on a digital slide. Therefore, we may have missed small foci of invasion in a case
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