PC-MIL: Decoupling Feature Resolution from Supervision Scale in Whole-Slide Learning

Whole-slide image (WSI) classification in computational pathology is commonly formulated as slide-level Multiple Instance Learning (MIL) with a single global bag representation. However, slide-level MIL is fundamentally underconstrained: optimizing only global labels encourages models to aggregate features without learning anatomically meaningful localization. This creates a mismatch between the scale of supervision and the scale of clinical reasoning. Clinicians assess tumor burden, focal lesions, and architectural patterns within millimeter-scale regions, whereas standard MIL is trained only to predict whether "somewhere in the slide there is cancer." As a result, the model's inductive bias effectively erases anatomical structure. We propose Progressive-Context MIL (PC-MIL), a framework that treats the spatial extent of supervision as a first-class design dimension. Rather than altering magnification, patch size, or introducing pixel-level segmentation, we decouple feature resolution from supervision scale. Using fixed 20x features, we vary MIL bag extent in millimeter units and anchor supervision at a clinically motivated 2mm scale to preserve comparable tumor burden and avoid confounding scale with lesion density. PC-MIL progressively mixes slide- and region-level supervision in controlled proportions, enabling explicit train-context x test-context analysis. On 1,476 prostate WSIs from five public datasets for binary cancer detection, we show that anatomical context is an independent axis of generalization in MIL, orthogonal to feature resolution: modest regional supervision improves cross-context performance, and balanced multi-context training stabilizes accuracy across slide and regional evaluation without sacrificing global performance. These results demonstrate that supervision extent shapes MIL inductive bias and support anatomically grounded WSI generalization.

SIMPLER: H&E-Informed Representation Learning for Structured Illumination Microscopy

Structured Illumination Microscopy (SIM) enables rapid, high-contrast optical sectioning of fresh tissue without staining or physical sectioning, making it promising for intraoperative and point-of-care diagnostics. Recent foundation and large-scale self-supervised models in digital pathology have demonstrated strong performance on section-based modalities such as Hematoxylin and Eosin (H&E) and immunohistochemistry (IHC). However, these approaches are predominantly trained on thin tissue sections and do not explicitly address thick-tissue fluorescence modalities such as SIM. When transferred directly to SIM, performance is constrained by substantial modality shift, and naive fine-tuning often overfits to modality-specific appearance rather than underlying histological structure. We introduce SIMPLER (Structured Illumination Microscopy-Powered Learning for Embedding Representations), a cross-modality self-supervised pretraining framework that leverages H&E as a semantic anchor to learn reusable SIM representations. H&E encodes rich cellular and glandular structure aligned with established clinical annotations, while SIM provides rapid, nondestructive imaging of fresh tissue. During pretraining, SIM and H&E are progressively aligned through adversarial, contrastive, and reconstruction-based objectives, encouraging SIM embeddings to internalize histological structure from H&E without collapsing modality-specific characteristics. A single pretrained SIMPLER encoder transfers across multiple downstream tasks, including multiple instance learning and morphological clustering, consistently outperforming SIM models trained from scratch or H&E-only pretraining. Importantly, joint alignment enhances SIM performance without degrading H&E representations, demonstrating asymmetric enrichment rather