Causal-Adversarial Probing of Clinical Covariates for Prostate MRI Grading

Non-invasive prediction of Gleason Grade Group (GGG) in prostate cancer using multiparametric MRI (mpMRI) is clinically vital for reducing unnecessary biopsies. Existing GGG prediction methods face two major limitations. First, they often overlook non-image information critical for GGG prediction, including age, prostate-specific antigen (PSA), and expert priors embedded in radiology reports. Second, they tend to oversimplify GGG as flat categorical labels, failing to account for its intrinsic hierarchy of primary and secondary Gleason patterns. To this end, we propose a novel Knowledge-Driven Ordinal-Aware Learning (KOAL) framework with three synergistic modules. Specifically, the Clinical-Context Modulation (CCM) module uses clinical variables (e.g., age and PSA) to dynamically modulate discriminative image representations. The Knowledge-Guided Prototype Alignment (KGPA) module leverages an LLM to extract group-specific expert knowledge from training radiology reports and clinical guidelines, producing offline semantic anchors describing grade-specific radiological findings without requiring patient-specific reports at inference. Through prototype contrastive alignment, patient-specific mpMRI representations are matched with these anchors to promote pathology-aligned representation learning. The Hierarchical Ordinal-aware Constraints (HOC) module decouples primary and secondary Gleason pattern prediction and maps their probabilistic outputs to GGG via a Differentiable Bio-logic Mapping Layer (DBML), ensuring pathological grading consistency. Experiments on public PI-CAI and in-house datasets demonstrate that KOAL outperforms state-of-the-art methods. Code is available at: https://github.com/Gother-GZ/KOAL.

Biochemical recurrence (BCR) after radical prostatectomy is a critical endpoint in prostate cancer, yet risk stratification relies almost entirely on variables dominated by Gleason grade. Whether H&E whole slide images (WSIs) carry prognostic signal beyond grade, and whether multiple instance learning (MIL) can recover it, remains unsettled. A key obstacle is that many pipelines select model checkpoints on the evaluation fold, artificially inflating concordance. We construct a rigorous benchmark on TCGA-PRAD (487 patients, 101 BCR events) using strict out-of-fold scoring over five-fold cross-validation repeated across five seeds. The choice of MIL aggregator (ABMIL, CLAM, TransMIL, PatchGCN) has little effect (C-index 0.61-0.64 with UNI2-h), while the feature extractor is the dominant factor (ResNet50 0.566 versus pathology foundation models up to 0.639). A clinical Cox model on grade, stage, and age reaches 0.687; no imaging-only model significantly outperforms it (p > 0.10). We introduce Grade-Disentangled MIL (GD-MIL), a gated-attention MIL encoder trained with a gradient-reversal grade adversary that encourages the slide representation to be invariant to Gleason grade before late fusion with clinical variables. GD-MIL achieves C-index 0.704, significantly outperforming both the clinical baseline (delta-c = +0.029, p = 0.0005) and the best imaging-only model (delta-c = +0.062, p = 0.039), suggesting H&E morphology contains prognostic information complementary to grade. A median risk split yields log-rank p < 0.0001 separation in BCR-free survival (~20% vs ~70% at five years).

Objectives: To characterize residual false positives in prostate MRI detection, and to evaluate a lightweight post-hoc refinement head for case-level specificity. Materials and Methods: This retrospective study used PI-CAI (5-fold cross-validation) and Prostate158 (n=158; external). A context-aware evidence head and an 89,216-parameter refinement head were trained on a frozen detection backbone; the evidence head was also trained on four further backbones (bare nnU-Net, bare U-Net, bare Mamba, MIGF-Mamba). For each false-positive region, T2-weighted, apparent-diffusion-coefficient, and high-b-value contrast ratios versus peri-lesional rings were compared against ground-truth lesions and contralateral benign regions. Results: False positives were closer to true cancers than to benign tissue in evidence and raw T2-weighted and apparent-diffusion-coefficient contrast, reproducing 35/35 across five architectures (Cohen's d 1.10; FP/benign evidence ratio 2.38x) and 105/105 across modality-perturbation scenarios. On PI-CAI fold-0, refinement raised case-level specificity from 0.469 to 0.549 (+17.2%) at preserved sensitivity (0.943); 5-fold cross-validation showed fold-conditional behavior (9/15 observations positive; range -22% to +28%). On Prostate158, both models saturated (McNemar pooled p=0.69), while the false-positive contrast-matching finding replicated. Conclusion: Residual false positives are contrast-matched to cancer (sharing raw imaging features rather than histologically confirmed mimicry), reproducing across five architectures -- a data-level imaging property, not model-specific artifacts; post-hoc refinement adds practical specificity in-domain but is fold-conditional.