Distribution-based deep multiple instance learning for tumor proportion scoring in NSCLC

In prostate cancer histopathology, the Gleason Score is determined by the most frequent (Primary) and second most frequent (Secondary) Gleason patterns within a whole-slide image. Although these slide-level labels are routinely available in clinical practice, instance-level Gleason annotations are rarely provided, making patch-level learning challenging. We propose a Multiple Instance Learning (MIL) framework that estimates instance-level Gleason patterns from slide-level Primary and Secondary labels. The proposed method formulates instance-level learning according to the clinical definition of the Gleason Score by aggregating instance predictions into class counts and explicitly modeling the Primary pattern, Secondary pattern, and their dominance. Experimental results demonstrate that the proposed formulation enables effective instance-level learning and outperforms existing MIL approaches on the SICAP-MIL dataset.

Zero-shot vision-language models (VLMs) offer a promptable alternative to task-specific training for gross tumor volume (GTV) delineation in non-small-cell lung cancer (NSCLC), but the prompt dimensions that govern their spatial behavior remain poorly understood. We study this question by probing alignment directions in VoxTell on a held-out internal NSCLC tumor dataset through sub-prompt decomposition into diagnosis, demographic, staging, anatomical, generic, and irrelevant controls; attribute-wise perturbation robustness; specificity ladders; and cross-case prompt swaps, while benchmarking against fine-tuned and zero-shot baselines using the Dice Similarity Coefficient (DSC) with Wilcoxon signed-rank tests and Benjamini-Hochberg correction. Alignment analyses revealed that anatomical location is the dominant driver of VoxTell's spatial attention: 63.4 percent of location perturbations caused catastrophic drops, prompt specificity improved from generic to full descriptions except for diagnosis-only prompts, irrelevant prompts correctly yielded zero segmentation, and cross-case prompt swaps confirmed patient-specific conditioning (matched DSC 0.906 vs. mismatched 0.406). Histology and stage substitutions had minimal effect, indicating that the model prioritizes "where to look" over "what to look for." In this context, VoxTell, operating fully zero-shot, achieved a mean DSC of 0.613, statistically indistinguishable from nnUNet (0.690, adjusted p = 0.156) and Ahmed et al. (0.675, adjusted p = 0.679), while significantly outperforming all other zero-shot models. Together, these findings argue that segmentation VLMs should be evaluated not only by Dice, but also by the prompt dimensions to which they align.

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).