Organizations: Institute for Biomedical Informatics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany · Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany · Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany · Institute of Pathology, University Hospital Cologne, Cologne, Germany · University of Cologne, Cologne, Germany · Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
Abstract
Deep learning-based segmentation of histopathology whole-slide images (WSIs) requires large amounts of pixel-level annotations, which are costly and time-consuming to obtain. Active learning (AL) has been proposed to reduce this effort, but existing methods exhibit three key limitations. Uncertainty estimation is unreliable on partially annotated WSIs, patch-level acquisition is inconsistent with slide-level annotation workflows, and class imbalance in multi-class settings is not explicitly addressed. To address these challenges, we propose SHAL (Slide-level Hybrid Active Learning), a patient-level AL framework for annotation-efficient multi-class histopathology segmentation. SHAL integrates three complementary components: a foreground-aware strategy that suppresses bias from unlabeled background regions, a stage-adaptive mechanism that hybridizes predictive entropy and epistemic uncertainty across learning stages, and a class-aware strategy that prioritizes diagnostically relevant tissue classes. SHAL is evaluated on the TCGA colorectal cancer dataset. It achieves the highest Macro Dice at the full annotation budget (0.846) and reaches Dice greater than or equal to 0.80 using only 26 percent of the budget (50 of 190 slides), whereas competing methods reach this threshold only at 37 percent (70 slides). Across five independent external cohorts, SHAL attains the highest mean external Macro Dice (0.815) and the smallest internal-to-external generalization gap among all methods (0.025 at Round 3 and 0.026 at the full budget). The results indicate that patient-level hybrid uncertainty acquisition reduces annotation cost without sacrificing cross-domain generalization in computational pathology.
Histopathological whole slide images (WSIs) are central to cancer diagnosis, but their gigapixel scale, tissue heterogeneity, weak slide-level supervision, sparse diagnostic regions, and multi-scale evidence make robust automated analysis challenging. Multiple instance learning (MIL) is widely used to aggregate tile-level features into slide-level predictions, yet existing augmentation strategies often perturb tissue regions without preserving diagnostic relevance, slide context, or cross-scale structure. We propose SlideMix, a model-agnostic multimodal augmentation framework for MIL-based WSI analysis. SlideMix uses a retrieval-augmented vision-language model (VLM)-based Visual-Language Adaptive Region selector to identify diagnostically relevant regions and reduce weak-label noise. It then performs In-place Tile Shuffling within meaningful tissue regions to mix feature embeddings while preserving slide-level context. A VLM-based soft-labeling module supervises mixed samples, while a multi-factor, loss-driven online Curriculum-Learning Feedback scheme adaptively controls shuffle granularity, feature similarity, and shuffle ratio to promote cross-scale representation learning. Across 11 WSI datasets comprising 20,523 slides, 8 diagnostic tasks, and 10 WSI backbones, SlideMix improves accuracy and generalization in most settings and compares favorably with established augmentation baselines, providing a simple plug-and-play approach for more robust and scalable digital pathology models. Source code: https://github.com/Xia-Research-Lab/SlideMix
Existing weakly supervised semantic segmentation (WSSS) methods in computational pathology rely on a multi-stage paradigm: class activation map (CAM) generation, offline pseudo-mask refinement, and fully supervised retraining. While established, this decoupled approach presents fundamental limitations. The multi-stage process not only incurs high computational training costs but also suffers from error propagation: local texture biases in shallow CNN layers generate false-positive artifacts that subsequent refinement steps often fail to correct. To address these persistent challenges through a simple yet highly effective approach, we propose the Single-Stage Hierarchical Rectification (SSHR) framework. Rather than passively refining CAMs post-hoc, our method proactively purifies intermediate feature representations during the forward pass. We introduce a Hierarchical Feature Rectification Module (HFRM) that utilizes deep global semantic context to filter out local anomalies in shallow layers. This mechanism generates high-fidelity activation maps directly within a single training loop. Experiments on the LUAD-HistoSeg and BCSS datasets demonstrate that SSHR outperforms state-of-the-art multi-stage methods. Furthermore, SSHR reduces training duration by 2 to 5 times. This efficiency minimizes computational overhead and accelerates clinical translation for large-scale histopathology workflows. The code is available at: https://github.com/trongduc-nguyen/SSHR
In practical settings, medical image segmentation models are often developed with limited annotated data rather than fully labeled datasets. Training frequently begins in ultra-low labeled regimes where only a small number of volumes are annotated. In such scenarios, practitioners must simultaneously decide which cases to annotate and how to best use the remaining unlabeled data. Although active learning (AL) and semi-supervised learning (SSL) both target annotation scarcity, they are typically designed and optimized independently, resulting in objective mismatch and unstable training during early-stage "cold start" conditions. We propose RegAL, a unified active semi-supervised framework governed by a shared topology-aware Pareto optimization that couples sample acquisition with unlabeled data utilization. RegAL evaluates images along three complementary axes, voxel-wise uncertainty, feature diversity, and a novel topological consistency metric, to select anatomically informative edge cases for annotation. On the other hand, the same criteria are used to identify geometrically stable atlas candidates for diffeomorphic registration-guided augmentation to train a self-supervised Mean Teacher segmentation network. Across BraTS 2021, dHCP, and ProstateX, RegAL remains stable with few labeled volumes and consistently outperforms state-of-the-art AL, SSL, and active semi-supervised baselines across Dice and boundary-distance (ASD, HD95) metrics under extreme annotation scarcity.