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
Gabriele Campanella, Matthew Croken, Olga Lukatskaya +4cs.SE cs.CV
Prospective silent trials provide an important bridge between retrospective validation of artificial intelligence (AI) models and their use in clinical care by evaluating model performance and operational reliability on live clinical data without influencing patient management. In computational pathology, conducting silent trials requires integration across laboratory information systems, digital pathology infrastructure, computational resources, and model inference pipelines, and these workflows are often implemented using application-specific software. We developed the Silent Trial Engine for Pathology (STEP), a reusable software platform for orchestrating prospective silent trials of computational pathology AI models across heterogeneous clinical and computational environments. STEP separates common trial orchestration from institution-specific data access and compute infrastructure through modular adapter interfaces. The platform supports scheduled case discovery, per-slide inference submission, deterministic idempotency, failure recovery, result and ancillary-data ingestion, persistent trial and run state, and audit logging, with compute adapters supporting local execution and high-performance computing environments using LSF and Slurm. STEP was deployed at three institutions to support prospective silent evaluation of EAGLE, an AI model for predicting EGFR mutation status from hematoxylin and eosin-stained whole-slide images. By separating trial-level workflow logic from site-specific integrations, STEP enables a common execution framework to operate across heterogeneous pathology environments while maintaining durable and auditable trial state. This approach may reduce duplicated engineering effort and facilitate systematic real-world evaluation of computational pathology AI before interventional clinical deployment.
Accurate diagnosis in Digital Pathology (DP) relies on high-resolution whole-slide images, yet clinical deployment is often limited by hardware costs. Super-Resolution (SR) offers a promising alternative by computationally enhancing low-resolution acquisitions. However, existing SR methods frequently struggle to preserve fine-grained cellular morphology, leading to texture oversmoothing and blurred structural boundaries under complex tissue variability. To address this issue, we propose Morph-ISR, a morphology-aware implicit super-resolution framework for DP that restores diagnostically relevant details with sub-pixel precision. Morph-ISR reformulates SR as a continuous coordinate-based reconstruction problem and integrates an Implicit Position-aware Kernel Generator (IPKG) to adaptively model spatially varying tissue morphology. To further enhance structural fidelity, a Morphological Fidelity Prior (MFP) is introduced, leveraging semantic guidance from a pre-trained cell segmentation network to enforce boundary-preserving and region-aware reconstruction, thereby improving the representation of critical cellular boundaries and nuclear textures. Experiments on TCGA and SurGen datasets show that Morph-ISR achieves the best LPIPS and ST-LPIPS among the evaluated methods, reducing them by up to 38.37% and 39.55%, respectively, over the second-best methods while maintaining strong PSNR and SSIM. These results demonstrate superior preservation of diagnostically relevant cellular boundaries and nuclear textures, while compact parameterization and high throughput support efficient edge deployment. Code and trained models will be released upon publication.
Accurate cell segmentation and classification are foundational to digital pathology, enabling quantitative tissue analysis for diagnosis and treatment planning. Encoder-decoder architectures that fuse multi-scale features through skip connections have become the dominant paradigm for this task, yet standard direct skip connections treat every spatial location equally, which leads to redundant and potentially conflicting information reaching the decoder. To overcome this problem, various gating mechanisms have been introduced, but most of them operate solely on filtering encoder information, neglecting the benefit of global contextual information from the decoder. This study proposes replacing conventional skip connections in a CellViT-based model with a novel Spatial Attention Fusion (SAF) Gating module. Each SAF gate concatenates the encoder skip and upsampled decoder features, compresses them through two pointwise convolutions with an intermediate ReLU, and applies a channel-wise softmax to produce a per-pixel "heatmap of trust" that sums to unity at every spatial location, allowing the network to learn where each source is most trustworthy. The resulting fused features improve the model's ability to detect the minority "Dead" class, which in turn enhances the multi-class panoptic quality (mPQ) on the PanNuke dataset. SAF Gating is compared against six gating alternatives including no gating, attention gates, squeeze-and-excitation, CBAM, cross-attention, and attentional feature fusion on PanNuke and MoNuSeg datasets. SAF Gating achieves the highest mPQ (0.471), a gain driven primarily by a 14.5-point improvement in Dead-class F1 score compared to ungated CellViT baseline.
Causal inference using front door intervention and multi-instance learning (MIL) has advanced the analysis of Whole Slide Images (WSI) in digital pathology. These methods adjust feature distributions of subtle evidence sub-images to correctly associate them with WSI-level diagnoses. We propose and prove 2 hypotheses for evaluating such methods: 1) Causal inference MIL introduces an independent classification channel that effectively completes WSI classification; 2) Greater difference between features extracted by the new and baseline channels increases effectiveness in eliminating false correlations. This hypothesis describes the core of causal inference MILs: overlaying parallel, independent channels to eliminate false associations between WSI-level diagnostic and non-diagnostic evidence sub-images by increasing deep feature diversity. Based on these hypotheses, we evaluated several causal inference MILs on breast cancer and non-small cell lung cancer datasets. This hypothesis provides a new theoretical perspective for applying causal inference to WSI analysis.
The rapid growth of digital pathology has created an urgent need for efficient indexing and retrieval of whole slide images (WSIs). This need is intensified by emerging generative AI workflows, particularly retrieval-augmented generation (RAG), which require dependable similarity search to support high-stakes clinical decision-making. Yet the substantial cost of high-performance storage limits the scalability and accessibility of WSI indexing for many healthcare institutions. Consequently, methods that can reduce storage demands while preserving retrieval accuracy have become a critical research priority. We propose ARReST (Antithetical Redundancy Reduction Strategy), a principled oppositional framework that leverages redundancy across dissimilar tissue classes to markedly decrease the number of patches that must be indexed from each WSI. Instead of eliminating only within-class duplicates, ARReST identifies antithetical patches-those whose representations contribute minimally to cross-class discrimination-and prunes them from the searchable archive. This targeted reduction substantially compresses the index without sacrificing morphological diversity or retrieval fidelity. By minimizing superfluous patch representations, ARReST reduces storage footprint, lowers computational overhead, and accelerates similarity search across large pathology repositories. Extensive experiments on TCGA repository (The Cancer Genome Atlas with 21 organs) demonstrate that ARReST achieves significant index compression while maintaining competitive retrieval performance. The observed storage savings of 3% to 60% (14%$\pm$13%) can be reliably achieved without compromising retrieval performance for many organs. The proposed strategy enables scalable, cost-efficient WSI indexing and is well-suited for next-generation retrieval-driven clinical AI systems.
Multiple instance learning (MIL) has become a standard paradigm for whole slide image (WSI) analysis in digital pathology, as it enables slide-level prediction without dense annotations. Existing MIL methods typically rely on exhaustive extraction and encoding of high-resolution patches. However, this practice suffers from two critical limitations in real-world clinical settings: it struggles to capture global visual cues at lower magnifications, and incurs substantial computational overhead due to the massive number of high-resolution patches per slide. To address these limitations, we propose an efficient low-resolution multiple instance learning (LRMIL) framework that transfers high-resolution knowledge to low-resolution representations. LRMIL adopts a two-stage distillation strategy. First, patch-level cross-resolution distillation aligns low-resolution patch embeddings with high-resolution representations. Second, slide-level knowledge distillation trains a low-resolution student MIL model under both slide-level supervision and teacher guidance. At inference time, LRMIL operates exclusively on low-resolution patches, substantially reducing data preprocessing and computational cost. Extensive experiments on multiple WSI benchmarks demonstrate that LRMIL consistently outperforms state-of-the-art MIL methods while achieving more efficient inference. These results highlight LRMIL as a practical and scalable solution for WSI analysis in clinical pathology.
Yanqing Luo, Julius Hense, Niklas Prenißl +4cs.CV cs.LG
Explanations of multiple instance learning (MIL) models are widely used for validation and discovery in digital histopathology. Existing methods primarily rely on heatmaps that highlight influential regions but do not explain how evidence from different tissue regions is combined to produce a prediction. This limits interpretability, especially when decisions depend on interactions between tissue features. We introduce Symbolic explainable MIL (Symb-xMIL), a post-hoc explanation framework that quantifies how a MIL model's behavior aligns with human-readable decision rules, expressed as logical relationships (e.g., AND, OR, NOT) between input features. These alignment scores reveal semantic patterns underlying the model's predictions. We evaluate Symb-xMIL on synthetic and real-world histopathology datasets. On synthetic MIL data, Symb-xMIL reliably recovers ground-truth logical rules. In a clinical tumor detection task, the best-aligned rules uncover heterogeneous decision patterns and expose hidden model errors. On an HPV-prediction task on TCGA-HNSCC, a cohort of head and neck cancer, our framework refines patient survival stratification beyond HPV status with potential clinical relevance. Overall, Symb-xMIL extends MIL explainability beyond visual attribution toward structured, rule-based reasoning, enabling more transparent and semantically grounded interpretation of model predictions.