Needle in a Haystack: One-Class Representation Learning for Detecting Rare Malignant Cells in Computational Cytology

Weakly supervised whole-slide image (WSI) classification is widely used in computational pathology because slide-level labels are easier to obtain than dense region annotations. Existing multiple instance learning (MIL) methods often aggregate large bags of patch embeddings using mainly visual cues, which can retain many non-informative patches and provide weak alignment between instance features and class-level disease semantics. We propose Concept-Guided Pruning and Representation Learning (CGRL), a simple framework that introduces class-level concept prototypes derived from disease prompts into the MIL pipeline. First, concept-relevance pruning ranks patch instances by their similarity to class concepts and retains the top-K concept-relevant patches for downstream MIL aggregation. Second, concept-guided contrastive representation learning constructs class-wise positive and negative patch sets from the same similarity matrix and optimizes target-class, symmetric auxiliary, and cross-class separation objectives, thereby regularizing the projected concept space. We evaluate CGRL on TCGA-BRCA and TCGA-NSCLC using multiple representative MIL methods. Experimental results show that CGRL improves several model-dataset combinations, with gains depending on the downstream MIL model and dataset. It achieves particularly clear improvements in accuracy and macro-F1 while reducing computational cost through concept-relevance pruning. These findings demonstrate that class-level semantic concepts provide an effective and practical prior for patch selection and representation learning in weakly supervised computational pathology.

Computational cytology on whole-slide images is challenging because malignant cells are rare, heterogeneous, and annotated slides are scarce. Anomaly detection frameworks can be trained on normal slide-negative patches and then applied at test time to flag abnormal patches in held-out slides. Most unsupervised anomaly detection approaches including generative ones (GAN-based and diffusion-based), are tuned to organ-level imaging and require large curated datasets. In cytology the signal is cell-centric: rotating or flipping a single-cell patch does not change its diagnostic class, yet standard diffusion models treat transformed views as distinct inputs, leading to transformation-dependent reconstructions and unstable anomaly scores. We propose a D4-equivariant diffusion framework that enforces rotation and reflection symmetry both architecturally, via a D4-equivariant U-Net, and at inference, via equivariant noise coupling and (optionally) frame averaging. This alignment with biological invariance yields transformation-consistent pseudo-healthy reconstructions and more stable anomaly ranking under symmetry. On two publicly available cytology datasets of bone marrow and peripheral blood smears, our D4-equivariant diffusion models achieve higher AUC and retrieve more abnormal cells in the top K predictions than non-equivariant generative baselines, a deep one-class, and a multiple instance learning based method, while substantially reducing score variance across rotations and flips. Code is available at https://swchmida.github.io/D4diffCyto/.

Weakly-supervised classification of whole-slide images with attention-based multiple instance learning (ABMIL) on top of foundation features now reaches near-saturation on Camelyon16 slide-level performance, but the corresponding attention maps are an imperfect localization signal: in clinical interpretation, a model that classifies correctly without firing on the actual lesion is hard to trust. We address this gap with cellular sheaves, which equip each vertex and edge of a graph with a finite-dimensional vector space and consistent linear maps between them, providing a principled way to detect local disagreement on graph-structured data. We apply cellular sheaves to weakly-supervised tumour localization on whole-slide images, combining a sheaf disagreement field with ABMIL. The natural training objective, encouraging consistency between similar features, produces a disagreement field that tracks tissue-level texture rather than diagnostic content. We propose attention-conditional consistency, which uses the classifier's attention to define which neighbouring patches should agree. Joint training of the classifier and the sheaf under this objective produces a disagreement field with patch-level AUC 0.940 on Camelyon16 and raises the attention head from its ABMIL-alone level of 0.717 to 0.953. Two-stage ablation with the classifier frozen at its ABMIL values reaches only 0.727 on the disagreement field and leaves attention at 0.717, confirming that the gain comes from the projector co-adapting under both objectives, not from the loss change in isolation. The trained model transfers without retraining to annotated slides from Camelyon17, maintaining Delta AUC 0.932 +/- 0.083 and attention AUC 0.955 +/- 0.099. The result is an attention map and a sheaf-disagreement map that fire on the same diagnostic regions, giving clinicians two complementary explanations for each slide-level prediction.