127 Significance of loose tumor cells in pulmonary arteries for disease recurrence188. While the concept of venous drainage from a pulmonary carcinoma is plausible, involvement of arterial tumor cells in this context is not. The morphological and clinical diagnostic aspects discussed above support the idea that our findings are different from clinical entities described so far, except for the report by Pechet and colleagues189, who described arterial invasion in stage I NSCLC. Pechet and colleagues defined the presence of tumor within the lumen of a muscular vessel with a clearly defined internal or external elastic lamina in at least two anatomically distinct vessels as a positive score for arterial invasion. They found that patients without arterial invasion had significantly better survival than those with arterial invasion (73% versus 38%, P < .001). However, their study did not include histopathological images for comparison. In our study, we specifically searched for tumor cells using CK7 immunohistochemical staining in at least one pulmonary artery, while Pechet’s study required at least two vessels (i.e., 39 of the 100 [39%] of the patients). Complete data on recurrence in their study was available for 64 patients, of which 16 had arterial invasion. Remarkably, 6 of the 16 were alive at 5 years (2 with and 4 without recurrence). Although the selection criteria and follow-up in Pechet’s study were different from ours, this does not exclude the possibility of an iatrogenic artifact in their study. Several findings from our study are remarkable. One is the high incidence of intratumorally intravascular tumor cells compared to previous literature (25-50%)190,191. Another is that we only found intra-arterial vascular tumor cells and no intravenous or lymphovascular invasive tumor cells. A third notable finding is that we also found intra-arterial tumor cells in 3 of the 33 cases in the pilot study and also in 8 of the 10 cases in the validation cohorts that were classified as adenocarcinoma in situ (AIS) and also on revision showed no other criteria of invasiveness. This supports the idea that at least some of the intravascular tumor cells we found were not a true representation of vascular invasion, but most likely an artifact. We believe that isolated tumor cells in pulmonary arteries with adjacent abundant tumor cells are easily overlooked in routine H&E staining, but are more clearly recognized in CK7 immunohistochemical staining. This raised the question of whether our observation is a clinically relevant reality or an artifact. Based on the following arguments, we strongly favor the idea that our findings are the result of an iatrogenic artifact during gross handling rather than a clinically relevant reality: (1) the lack of morphological similarities with known clinical entities; (2) the lack of clinical signs of metastases in our patients (also in the 5 year follow-up period); (3) the association with a counterintuitive, better prognosis for patients with intra-arterial tumor cells than those without; (4) the presence of occasional ‘alveolar macrophages’ in the lumen of pulmonary arteries adjacent to tumor cells; (5) the detection in resections specimen and (7) its presence in cases of adenocarcinoma in situ. Moreover, for loose tumor cells in alveolar spaces criteria have been mentioned that might be associated with artifacts such as jagged edges 117. These characteristics were not present in the tumor cells located in the pulmonary artery. Of note, rounded 10
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