211 Reproducibility study on invasiveness of pulmonary AdC with a modified classification Table 2. The distribution for ranking the pathologists for the frequency of invasive scores in the lowest third, middle and highest third for round 1 and 2 was compared with the region of work and did not reveal a significant difference. Frequency of invasion score Low Middle High Round Region n % n % n % p-value 1 USA 1 25.0% 2 50.0% 1 25.0% 0.84 Europe 11 34.4% 10 31.3% 11 34.4% Japan 2 33.3% 3 50.0% 1 16.7% 2 USA 1 25.0% 2 50.0% 1 25.0% 0.36 Europe 11 34.4% 13 40.6% 8 25.0% Japan 1 16.7% 1 16.7% 4 66.7% The low concordance is also reflected in the low kappa score for most of the patterns, except for solid adenocarcinoma, see Table 1. The measurement of total tumor size has a low coefficient of variation for all 70 cases (mean 6%, range 1-25%, indicating that pathologists can and do measure total tumor size consistently. In contrast, the measurement of invasive size has a 4-7-fold higher coefficient of variation depending on the measure calculated. These invasion and measurement findings are in line with a recent publication from the IASLC pathology panel317. Apparently, the criteria as defined in the WHO classification permit large variations in interpretation, leading to poor reproducibility on a world-wide scale. There is a clear need for more detailed guidance in the assessment of invasion in pulmonary adenocarcinomas. Round 2 A live online tutorial as well as additional literature was provided between the first and second rounds of assessment, which focused on the mechanism of iatrogenic collapse and its recognition and other criteria (see supplementary file and suggested literature on elastin and collapse206 279, as well as a concept version of chapter 14 of this thesis). In the second round the ‘grey zone’ category was added for areas that contained more alveolar filling growth than was consistent with iatrogenic collapsed AIS but not enough to conform to one of the other surrogate markers of invasion. As focal multilayering is one of the effects of tangential cutting, a surrogate marker of invasion should be consistently present in at least three adjacent alveolar spaces to avoid overdiagnosis of invasiveness. Similarly, to the first round, in the 2nd round 45 cases with invasion scored near-unanimously. The second-round summary data of invasion scoring, measurement of total and invasive size and kappa analysis are also shown in Table 1. The distribution of pathologists’ WHO pattern scores across 70 cases is shown for round 2 in Figure 2B. The case-based comparison of invasion scores in 1st and 2nd round is summarized in Table 3. In a total 19 out of 70 cases there was a significant shift towards assessment of 15
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