Interobserver agreement in dysplasia grading of intraductal papillary mucinous neoplasms: performance of Kyoto guidelines and optimization of endomicroscopy biomarkers through pathology reclassification

Abstract

Background and aims: Interobserver agreement (IOA) among pancreaticobiliary (PB) pathologists in evaluating high-grade dysplasia and/or invasive carcinoma (HGD-IC) of intraductal papillary mucinous neoplasms (IPMNs) remains understudied. EUS-guided needle-based confocal endomicroscopy (nCLE) can evaluate papillary architecture in branch duct IPMNs. We assessed IOA among PB pathologists in classifying dysplasia in resected IPMNs and compared the performance of the Kyoto guidelines' high-risk stigmata (HRS) and presurgical EUS-nCLE against reclassified pathology.

Methods: Participants in prospective clinical trials (2015-2023) with resected IPMNs were included. Blinded PB pathologists independently reviewed histopathology, achieving a consensus diagnosis. The accuracies of cyst fluid next-generation sequencing analysis, EUS-nCLE, and Kyoto HRS in predicting HGD-IC were compared with the reclassified pathology.

Results: Among 64 participants, 25 (39%) exhibited HGD-IC (17 HGD, 8 invasive carcinoma). Disagreements occurred in 14% of cases with substantial IOA (κ = 0.70; 95% confidence interval, 0.53-0.88) between 2 PB pathologists for differentiating HGD-IC versus low-grade dysplasia (LGD). To detect HGD-IC, the sensitivity, specificity, and accuracy of Kyoto HRS and EUS-nCLE were 52%, 95%, 78% and 68%, 87%, 80%, respectively. Integrating nCLE with Kyoto HRS improved sensitivity to 80%, with specificity and accuracy at 82% and 81%, respectively. The sensitivity, specificity, and accuracy of next-generation sequencing (n = 47) to detect HGD-IC were 6.3%, 100%, and 68%, respectively. A unique subset of IPMNs were identified in all (n = 8, P = .01) cases where presurgical EUS-nCLE underestimated dysplasia revealing a distinct micropapillary architecture on postsurgical histopathology.

Conclusions: Despite substantial IOA among experienced PB pathologists, a second pathologist's review may be warranted for dysplasia classification in IPMNs under certain circumstances. Incorporating an imaging biomarker such as EUS-nCLE with Kyoto HRS improves sensitivity for HGD-IC without sacrificing accuracy.