Dictionary-based Pathology Mining with Hard-instance-assisted Classifier Debiasing for Genetic Biomarker Prediction from WSIs

Molecular biomarker testing in pathology is often costly and tissue-consuming, limiting scalable clinical deployment. Artificial intelligence applied to hematoxylin and eosin (HE)-stained histology could enable rapid biomarker screening, but clinical translation requires models that are both accurate and interpretable. Here we introduce Hireca, a biomarker-focused pathology foundation model pretrained on more than 80,000 whole-slide images spanning 38 organ types from three medical centers, together with CytoMap, an interpretability module that localizes cellular-scale evidence underlying predictions. Across 10 biomarker tasks encompassing morphological, molecular, genetic, and spatial-transcriptomic-proxy readouts, Hireca ranked first in five tasks and outperformed comparable models overall. In evaluation by eight pathologists from two countries, CytoMap was consistently preferred over alternative visualization approaches and revealed error patterns in difficult cases. These results position Hireca and CytoMap as a transparent framework for clinically reviewable biomarker assessment directly from routine HE histology.

Matched multi-omics can improve WSI-based biomarker and prognosis prediction, but most existing pipelines use omics as a paral lel feature stream or textual context rather than as an explicit retrieval constraint. HERO asks whether observed omics can be a testable mor phology hypothesis: a sparse pathway-to-morphology prior maps DNA methylation and miRNA into a K-dimensional intent vector m (K=16), TF-IDF retrieval over structured 10 captions selects endpoint-relevant regions, and a cosine gate c=cos(m,v) triggers deterministic deficit driven repair when c<τc. This closed-loop design bounds VLM calls, reduces reliance on embedding-based semantic matching, and makes every retrieval and verification step lexically auditable. On TCGA-BRCA (930WSIs, patient-level 5-fold CV), HERO sets new state-of-the-art across ER, PR, HER2, subtype, and risk prediction, outperforming both multimodal fusion and VLM-based baselines.

Joint molecular phenotype prediction is complicated by small joint-positive populations and overlapping histological features across alternative molecular states. Existing computational pathology approaches typically predict biomarkers independently or formulate the joint-positive phenotype as a binary endpoint. Independent prediction does not model interactions between biomarker-specific histological representations, whereas binary joint prediction collapses the double-negative and two single-positive configurations into a single negative class. We propose State-Aware Interaction MIL, a weakly supervised method that preserves biomarker-specific histological representations, models their interaction, and supervises the complete four-state molecular configuration. We evaluate the proposed approach for joint BRAF+/MSI+ prediction in colorectal cancer and EGFR+/TP53+ prediction in lung adenocarcinoma using frozen UNI2-h and CONCH pathology foundation-model representations. With UNI2-h, State-Aware Interaction MIL achieved an average precision of 0.5566 in colorectal cancer (joint-positive prevalence 6.8%) compared with 0.5161 for NaiveMTL, and 0.2784 in lung adenocarcinoma (joint-positive prevalence 8.6%) compared with 0.2525 for IndependentPair. With CONCH, State-Aware achieved an average precision of 0.4410 compared with 0.3932 for DirectJoint in colorectal cancer and 0.1659 compared with 0.1226 for DirectJoint in lung adenocarcinoma. These results indicate that pathology foundation-model representations contain predictive information for rare joint molecular phenotypes and that preserving biomarker-specific representations within a structured molecular-state formulation can improve prediction of these phenotypes from histopathology.