97 Critical review on STAS Introduction The concept of tumor cell clusters or loose cells as a pattern of invasion in lung carcinoma has recently been proposed and is included in the 2015 WHO fascicle on the classification of lung tumors, so-called ‘spread through air spaces” or STAS4. This inclusion is controversial, as there are significant data to support that this histologic finding represents an artifact of tissue handling and processing rather than a pattern of invasion. An extraneous tissue contaminant on a histologic slide is a very well-known phenomenon for pathologists and is called a floater. This can be a source of potential diagnostic error and occurs in approximately 1.2% of prepared slides102. Since at least half of these contaminants are not derived from the same patient sample103, many of them are recognized as artifacts on morphological grounds alone. Moreover, in patients’ samples many of these contaminants are easily recognized as irrelevant, most likely produced by the biopsy procedure passing through other tissues, for instance when fragments of colonic mucosa are seen in prostate biopsies or fragments of skin are present in breast biopsies. In addition, many of these aberrant tissue fragments lie on top of the tissue to be examined, above the tissue plane of the slide, and therefore are also easily recognizable as an artifact. “Displacement of tumor cell clusters or loose cells” in organs other than the lung have been described in the colon135, uterus136,137, and thyroid138. In these cases, the tumor is occasionally displaced into vascular structures during biopsy procedures, surgical manipulation, or pathologic gross processing. We question the validity of the inclusion of the presence of tumor cell clusters or loose cells as an invasive pattern in lung cancer. In this review, we will submit the data on tumor cell clusters or loose cells in the lung and will examine whether this histologic finding should be considered an invasive pattern, a useful prognostic artifact, or simply an artifact. The road of tumor cell clusters or loose cells to STAS Loose tumor cell clusters or loose cells in the lung have been recognized by pathologists for a long time and have been interpreted by many as an artifact. The first study adding importance to the phenomenon of ‘tumor cell clusters or loose cells’ was that by Onozato and colleagues115 in 2013, adding a prognostic relevance to loose fragments. Prior to this however, in the 1990’s the concept of aerogenic spread of what was previously called bronchioloalveolar carcinoma already existed139. While this concept uses the term ‘aerogenic spread’, an alternative explanation, in which field cancerization may be a major factor, is not excluded140. In a preparatory meeting in which issues relating to the prospective 2015 WHO classification of lung tumors were being discussed, eight of the 16 pathologists (50%) were in favor of STAS as a pattern of tumor invasion in lung adenocarcinoma, while the other half reflected that it was most likely an artifact. However, the majority of the other 7
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