Comparative Methods Review: Predicting Tumor Mutational Burden from Routine Pathology Slides

Abstract

Sequencing remains the reference standard for tumor mutational burden (TMB) but is costly, slow, and tissue intensive. Routine hematoxylin-and-eosin whole-slide images (WSIs) are inexpensive to digitize, motivating interest in whether AI can estimate TMB to support triage and prioritize sequencing. This review synthesizes more than thirty studies of TMB-from-WSI, standardizing task framing (primarily binary TMB-high versus TMB-low, with occasional regression) and evaluation practice (AUROC/AUPRC, external validation, calibration, and decision-curve analysis). Reported internal performance frequently falls around AUROC 0.70–0.82; independent-site external results are lower, approximately 0.65–0.73, yet directionally supportive. Multimodal fusion of H&E with basic clinical variables and the use of stronger representation self-supervised encoders and pathology foundation models-improve robustness, but performance remains sensitive to label definitions, class prevalence, tumor purity, and site/scanner domain shift. Reporting calibration quality, clinical net benefit, and subgroup analyses is inconsistent across studies. Overall, the current evidence supports TMB-from-WSI as a tool for triage and sequencing prioritization rather than a replacement for sequencing. This review recommends multicenter external validation, a minimal reporting set with a practical “benchmark card,” and post-deployment monitoring of discrimination, calibration, and drift. Foundation and vision–language models with few-shot adapters are promising for cross-site transfer; prospective multicenter evaluations will be pivotal for clinical credibility.