Fig. 2: PICTURE successfully distinguishes glioblastoma from primary central nervous system lymphoma (PCNSL) across diverse tissue types and clinical sites.

The red line indicates the estimated AUROC of PICTURE; the shaded region shows the 95% confidence interval derived from 1000 bootstrap samples. P-values were calculated using one-sided bootstrap hypothesis tests. A, B We developed PICTURE using digital pathology slides from the Mayo Clinic and evaluated its performance on the held-out FFPE test set, PICTURE achieved AUROCs comparable to all foundation models. To assess generalizability, we validated PICTURE on four independent cohorts. Sample counts per site are shown. C–F PICTURE demonstrated consistently high performance on FFPE samples from independent cohorts: at UPenn, it achieved an AUROC of 0.996, outperforming UNI (0.976, P < 0.001) and performing comparably to Virchow2 (0.995, P = 0.243); at BWH, it reached 0.987, significantly higher than UNI (0.977, P = 0.025) and Virchow2 (0.975, P = 0.014); in Vienna, it attained 0.992, outperforming UNI (0.966, P < 0.001) and Virchow2 (0.964, P < 0.001); and at TVGH, it achieved 0.992, exceeding CONCH (0.982, P = 0.001) and Virchow2 (0.980, P < 0.001). G–J PICTURE enabled real-time intraoperative diagnostic support using frozen section slides. At UPenn, it reached 0.958, significantly outperforming the Swin Transformer (0.898, P < 0.001) and showing modest improvement over CONCH (0.946, P = 0.067). At BWH, both PICTURE and CONCH achieved 0.987 (P = 0.505), outperforming CHIEF (0.971, P < 0.001). In Vienna, PICTURE reached 0.988, surpassing UNI (0.966, P < 0.001) and Virchow (0.940, P < 0.001). At TVGH, PICTURE attained 0.924, performing comparably to CONCH (0.919, P = 0.427) and better than CTransPath (0.896, P = 0.672). Asterisks indicate significantly better performance by PICTURE (*P < 0.05; **P < 0.01; ***P < 0.001). Tissue slide illustrations in (A) were created in BioRender. Zhao, J. (2025) https://BioRender.com/j32r478.