263 General discussion and future perspectives Tangential cutting The extent of stratification needs to be analyzed to avoid inclusion of folds and tangential cutting as features of multilayering. Extensive multilayering is a characteristic of micropapillary pattern. As in AIS the histological section is a cross section of a threedimensional lesion deformed by iatrogenic collapse, a monolayer may focally show cellular crowding that impresses as multilayering. This pseudostratification is frequently visible close to the top and bottom (angles) of the folds. In essence tangential cutting is present in focal area of the collapsed alveolar space, and not in the whole alveolar space. This focal multilayering should not be interpreted to be beyond a monolayer. Minimum involvement For a criterion to be associated with invasion, the underlying collapsed histology is used: i.e. the underlying functional histology of an acinus. A minimum of a few adjacent alveoli must contain the criterion throughout. This minimum approach is in line with the approach taken in other organs like breast diagnosis for lobular carcinoma in situ, whereby more than 50% of the acini in a terminal duct lobular unit must be filled and expanded by the neoplastic cells to qualify as lobular carcinoma in situ333. Awareness that a focal artificial stratification in this context is not a sign of a highly proliferative tumor and raising the bar for invasion to more than one alveolar space completely filled with stratified cells may avoid overdiagnosis of iatrogenic collapsed AIS as invasive adenocarcinoma. Regular pattern CK7 The regular pattern of iatrogenic collapsed AIS is easily observed in the CK7 staining. The CK7 positive borders respect the underlying architecture of secondary lobular septa, bronchovascular bundles with surrounding stroma and visceral pleura. In collapsed AIS CK7 positive pneumocytes type II may also be clearly visible. The difference with tumor cells is easily observed in the accompanying H&E. These CK7 positive cells should not be interpreted as collapsed AIS or part of lepidic adenocarcinoma. In search of a regular pattern the pathologist should not be immediately happy and diagnose collapsed AIS, as the catch to be missed is the presence of focal invasion. Any irregular area in the CK7 pattern the corresponding area in elastin and H&E stainings should be scrutinized for focal invasion. Elastin The original philosophy of WHO classifications that all diagnosis be made on H&E stain because of the worldwide applicability, has been abandoned: for the diagnosis of ‘large cell neuroendocrine carcinoma’ a positive neuroendocrine immunohistochemical marker is obligatory. The current study uses in the 2nd round morphological criteria derived in three different stains: beside the H&E also an elastin and a cytokeratin 7 stain. This provides crucial additional morphological information, allowing separation 17
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