Breast Cancer Prognostic Factors in the Digital Era: Comparison of Nottingham Grade using Whole Slide Images and Glass Slides

Abstract

Background: To assess reproducibility and accuracy of overall Nottingham grade and component scores using digital whole slide images (WSIs) compared to glass slides. Methods: Two hundred and eight pathologists were randomized to independently interpret 1 of 4 breast biopsy sets using either glass slides or digital WSI. Each set included 5 or 6 invasive carcinomas (22 total invasive cases). Participants interpreted the same biopsy set approximately 9 months later following a second randomization to WSI or glass slides. Nottingham grade, including component scores, was assessed on each interpretation, providing 2045 independent interpretations of grade. Overall grade and component scores were compared between pathologists (interobserver agreement) and for interpretations by the same pathologist (intraobserver agreement). Grade assessments were compared when the format (WSI vs. glass slides) changed or was the same for the two interpretations. Results: Nottingham grade intraobserver agreement was highest using glass slides for both interpretations (73%, 95% confidence interval [CI]: 68%, 78%) and slightly lower but not statistically different using digital WSI for both interpretations (68%, 95% CI: 61%, 75%; P = 0.22). The agreement was lowest when the format changed between interpretations (63%, 95% CI: 59%, 68%). Interobserver agreement was significantly higher ( P < 0.001) using glass slides versus digital WSI (68%, 95% CI: 66%, 70% versus 60%, 95% CI: 57%, 62%, respectively). Nuclear pleomorphism scores had the lowest inter- and intra-observer agreement. Mitotic scores were higher on glass slides in inter- and intra-observer comparisons. Conclusions: Pathologists’ intraobserver agreement (reproducibility) is similar for Nottingham grade using glass slides or WSI. However, slightly lower agreement between pathologists suggests that verification of grade using digital WSI may be more challenging.

Visual assessment of mitotic figures in breast cancer: a comparative study between light microscopy and whole slide images

“…Although we have demonstrated that interobserver agreement for Nottingham grade using LM is not inferior to that reported using WSI in a previous study, a tendency towards a lower mitotic count in WSI was observed 18,19 …”

“…16,17 Although we have demonstrated that interobserver agreement for Nottingham grade using LM is not inferior to that reported using WSI in a previous study, a tendency towards a lower mitotic count in WSI was observed. 18,19 The guidelines and diagnostic criteria for mitoses that are well established and currently in use are derived from LM practice, and whether they can be applied as such to WSIs or need further adjustments remains to be investigated before using WSI in routine practice. The lack of defined criteria for assessing mitoses digitally may lead to inconsistent reporting, which would have clinical implications.…”

Technical and Diagnostic Issues in Whole Slide Imaging Published Validation Studies

“…However, in most studies, especially the most recent publications, overall diagnostic concordance was above the cutoff of 95% recommended in the CAP guidelines for WSI vali-dation, and discordances with a potential impact on clinical management were often lower than 3% ( 8 , 10 , 21 , 29 – 31 ). Another frequently reported area of discordance, as well source of dissatisfaction among pathologists, when using WSI relates to counting mitoses, such as is required in grading meningiomas ( 32 ) or breast carcinoma ( 33 , 34 ) or when diagnosing malignancy in a melanocytic lesion ( 35 ). Other less frequently reported.…”

Rapid Validation of Whole-Slide Imaging for Primary Histopathology Diagnosis

“…Discrepancies in dysplasia assessment and grading can have 2 broad contributory factors. Davidson et al 33 observed a 27% intraobserver disagreement using glass slides in assigning a Nottingham grade to cases of invasive breast carcinoma. Similar figures have long been obtained in studies examining intraobserver agreement in grading of cervical intraepithelial neoplasia 34 and Gleason grading of prostatic acinar adenocarcinoma.…”