247 Arguments for pulmonary AIS larger than 7 cm Discussion This study provides arguments that non-mucinous adenocarcinomas in situ with a size > 7cm exist. In two patients the entire resected lobe was histologically examined, revealing tumors both with diameters of 16 cm, without histological criteria of invasion. Three additional cases from a nationwide T3N0 cohort with tumor sizes exceeding 7 cm, yet displaying an AIS-pattern on histological analysis are also described, including extensive follow-up data, supporting the non-invasive nature of the initially resected tumors. The prevalence of AIS in this pT3N0 cohort would be 3 in 112 (2.6%). In all three cases, no evidence of invasive growth was observed in the available retrospective material. Although the follow-up showed in 2 cases similar radiologic disease in other lobes, interpreted as another primary. Although we had for most cases no histological prove, the clinical most likely explanation was that none of the AIS patients had recurrences from or died of their initial disease. Our findings are in line with the study of Inafuku and colleagues, who found 277 cases that showed a non-invasive pattern consistent with AIS344 in 2115 resection specimen. Twenty-two of these (7.9%) had a diameter larger than 3 cm, with a mean of 40,1 mm ± 6,9 mm. Boland et al investigated the interobserver variation between 2 pathologists with respect to AIS and minimal invasive adenocarcinoma (MIA) in 296 resection specimens. They agreed on 1 case of AIS, that had a diameter of 3,5 cm (0.3%)312. Although not purely lepidic, Strand et al found in 5 of 131 resection specimens an adenocarcinoma with more than 95% lepidic pattern, a tumor diameter larger than 3 cm, in 1 of them larger than 5 cm345. These non-invasive tumor sizes are however well below the tumor sizes up to 16 cm that we now present, which to the best of our knowledge has not been reported before. In our study, all five cases of AIS were characterized by tumors with just areas of lepidic growth. However, during gross examination, it was challenging to identify specific tumor nodules as there was no clear demarcation and palpation did not provide any support due to the lack of firm consistency (Figure 1). After a follow-up period of 10 years, one patient (patient 4) is still alive, but suffering from the same type of noninvasive disease in their other lung. Patient 1 died due to a COVID19 infection, patient 3 due to presumed metastatic breast cancer, and the fifth patient died from lung cancer in different lobes. This patient exhibited similar manifestations as the primary tumor, with progressive consolidation patterns in other parts of the lung, which were also believed to be non-invasive based on radiological findings of diffuse ground-glass, similar to patient 4. Despite dying from respiratory insufficiency, there were no clear signs of invasive cancer, though no biopsies were performed. It is possible that extensive AIS deposits throughout large areas of the lung led to reduced ventilation and respiratory insufficiency. However, no pulmonary function tests were conducted to support this hypothesis of impaired diffusion capacity. 16
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