Multiple Instance Learning

Perineural invasion (PNI) is an adverse histopathologic marker in intrahepatic cholangiocarcinoma (ICC), but it is usually confirmed only after resection. Preoperative T2-weighted MRI may provide noninvasive imaging cues predictive of PNI, although labels are available only at the patient level without slice- or voxel-level annotations. We propose Order-Aware Slab Multiple Instance Learning (OAS-MIL), a weakly supervised framework for patient-level PNI prediction. Each tumor-centered MRI crop is represented as an ordered sequence of overlapping 2.5D slabs formed from contiguous axial slices. A shared encoder extracts slab-level features, which are aggregated by a permutation-invariant set-attention branch and a bidirectional sequence-attention branch. Using five-fold label-stratified cross-validation at the patient level, OAS-MIL achieved a mean AUROC of 0.770, outperforming the evaluated volumetric and MIL baselines. These results suggest that axial order provides a useful inductive bias for weakly supervised PNI prediction from MRI.

Label-free virtual staining offers a compelling, non-destructive alternative to standard histopathology; however, its clinical adoption is hindered by the computational bottlenecks inherent to processing gigapixel Whole Slide Images (WSIs). Current deep learning approaches require patch-based inference to avoid memory constraints, which disrupts global tissue continuity and introduces tiling artifacts--displaying visible seams and color shifts. To address this, we introduce the Consistency Memory Bank (COMB), a novel label-free virtual staining framework that enforces spatial and channel consistency across tiles without memory bottlenecks. COMB decouples context storage from computation, utilizing a dynamic retrieval mechanism to fetch feature representations from adjacent tiles. This enables a retrieval-based context integration strategy that adopts local padding to resolve spatial discontinuities and neighbor-aware channel attention to stabilize statistical drift. Further optimized with a sliding window schedule to ensure minimal memory overhead, our method demonstrates superior performance over state-of-the-art baselines, achieving significant improvements in both perceptual fidelity and tiling consistency, while suggesting its downstream utility in tumor segmentation. Code is available at https://github.com/dou0000/COMB.

Multiple Instance Learning (MIL) is widely used for weakly supervised learning, particularly in digital pathology, where fine-grained annotations are costly. Most MIL methods aggregate instance features via attention mechanisms. However, attention weights do not always faithfully reflect instance importance and may focus on spuriously correlated regions. In this work, we propose CAR-MIL, a framework that explicitly guides attention learning through a counterfactual attention regularization objective inspired by counterfactual explanations. Built on a standard attention-based MIL architecture, our approach introduces a lightweight counterfactual attention branch trained to produce an alternative prediction while remaining close to the factual attention distribution. This encourages prediction changes to arise from minimal, structured redistributions of attention, leading to more informative evidence allocation. The resulting factual and counterfactual attention maps capture complementary evidence: the former highlights regions supporting the prediction, while the latter reveals regions whose reweighting would challenge it. We evaluate our method on synthetic MIL benchmarks with instance-level ground truth enabling controlled analysis of attention behavior and on five digital pathology datasets across four tasks. CAR-MIL maintains competitive classification performance, with the largest gains observed on more challenging tasks, while improving attention reliability, demonstrating the benefits of integrating counterfactual explainability reasoning into attention learning. Code is available at: https://github.com/ImaneCR/CAR-MIL/.

Deep learning models for CT scan analysis are often limited by the scarcity of precise pixel-level annotations, which require significant radiologist effort to produce. Training on scan-level labels alone reduces annotation requirements but introduces challenges: low supervision ratios and large input volumes make models prone to overfitting and shortcut learning. In this work, we investigate two complementary methods to address these challenges: multi-instance learning (MIL) and anatomical filtering. MIL divides CT volumes into 2D slice instances, enabling efficient 2D architectures with ImageNet pretraining rather than computationally demanding 3D models. Anatomical filtering uses Compass, our self-supervised body part regression model, to crop scans to pathology-relevant subregions without requiring segmentation masks. We evaluate two MIL frameworks - Attention-based MIL (ABMIL) and FocusMIL - on kidney tumor classification across one internal dataset (TUH) and two external datasets (KiTS23 and TCGA-KiRC). Our best models achieve F1 = 0.83 on the internal test set using only scan-level labels. We further show that anatomical filtering with the Compass model is critical for the out-of-distribution generalization of embedding-based ABMIL, while instance-based FocusMIL demonstrates greater inherent robustness to distribution shift. While evaluated on kidney tumors, we consider this a proof-of-concept for a broader weakly supervised CT classification pipeline applicable to other organs and pathologies.

Functional tissue units (FTUs), including tertiary lymphoid structures (TLSs), blood vessels, and glands, encode localized immune, vascular, and epithelial organization in histopathology. Accurate quantification of these structures is important for studying tissue architecture and disease-associated tissue organization. However, FTUs are frequently sparse, heterogeneous, and surrounded by large amounts of morphologically similar background tissue, making automated segmentation in whole-slide images (WSIs) challenging. We therefore developed FTU-Seek, a pathology foundation model-guided framework that treats morphology-aware negative-patch selection as a key component of sparse FTU segmentation. FTU-Seek uses frozen multi-depth features from the UNI pathology foundation model to train a patch-level classifier that distinguishes FTU-containing from FTU-absent tissue. Target-absent patches are subsequently ranked according to their predicted target-containing probabilities, and the highest-scoring hard negatives are selected through a static Top$K$ strategy to construct compact segmentation training sets. The framework was evaluated using five-fold cross-validation and internal test cohorts across TLS, blood-vessel, and gland segmentation tasks, with an additional independent 30-WSI held-out cohort for TLS. Positive-only, all-tissue, random-negative, and matched random Top$K$ sampling strategies served as comparators. Segmentation-derived phenotypes were further explored in external TCGA cohorts.

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

Accurate bladder tumor segmentation and assessment of mus- cle invasion from T2-weighted MRI are important for treatment plan- ning, but developing robust models across institutions is challenging be- cause patient data cannot be centrally pooled and imaging characteristics vary across scanners and acquisition protocols. We propose a federated multi-task learning framework for joint bladder tumor segmentation and MIBC/NMIBC classification across four clinical centers. The proposed Swin Hybrid model combines a ResNet-34 branch for local texture and boundary information with a Swin-Tiny Transformer for global anatomi- cal context. A segmentation-guided classification mechanism further uses tumor localization information to support MIBC prediction. We also investigate several augmentation strategies under both centralized and federated training to improve robustness to multi-center variability. Ex- periments on the FedBCa dataset show that the Swin Hybrid provides the best overall balance between segmentation and classification among the evaluated architectures. Under federated training, Geo+Elastic aug- mentation achieved a DSC of 0.8100 and a patient-level AUC of 0.8931, yielding the highest combined score of 0.8474. These results demonstrate that joint segmentation and classification can be effectively performed across multiple institutions using federated training without centralizing patient data.

Weakly supervised semantic segmentation enables histopathology tissue segmentation from image-level annotations, avoiding costly pixel-level labeling by expert pathologists. However, CAM-based methods often localize only highly discriminative regions and remain unreliable near tissue interfaces. We propose ProBAG, a stage-1 pseudo-mask generator that combines dataset-specific visual prototypes with pathology-aligned CONCH text prototypes over multi-scale frozen UNI features. ProBAG introduces two complementary mechanisms: class-wise power recalibration that reshapes inter-class competition while preserving the total foreground activation mass at each pixel, and one-step graph diffusion in which feature affinities are penalized by a late-transformer attention-context discrepancy used as a soft structural boundary cue. The resulting stage-1 pseudo-masks require neither CRF nor an external segmentation model; for complete two-stage comparison, they additionally supervise a downstream Phikon-FPN segmenter. Experiments on BCSS-WSSS and LUAD-HistoSeg show consistent gains over recent WSSS approaches, while ablations indicate that pathology-aligned text semantics provide the largest improvement and graph refinement provides a smaller complementary gain. The code is available at: https://github.com/wterrr/WSSS

Spatial transcriptomics can resolve gene expression at single-cell resolution, but it is costly, limited to targeted panels of a few hundred to a few thousand genes, and applicable to only a small number of samples. H&E imaging, by contrast, is cheap and collected routinely at scale. This makes predicting single-cell expression directly from morphology a practical way to bring molecular analysis to large tissue archives. We therefore present VOICE, a multimodal foundation model that predicts single-cell gene expression from H&E images using paired Xenium data. VOICE first aligns cell centered H&E morphology from a pathology foundation model with single-cell expression embeddings from a transcriptome foundation model, trained using contrastive learning over 23 million cells. Next it predicts expression through two branches. One branch directly regresses expression from morphology. The other branch retrieves measured expression from similar reference cells, recovering genes that do not have morphological signal. Because genes vary in morphological predictability, VOICE fuses the two branches with a per-gene weight. After training, VOICE generalizes to heldout patients, slides, and partially overlapping gene panels from Xenium, and it consistently outperforms prior single-cell expression prediction methods on seven metrics.

Relational inductive biases are essential for capturing structural dependencies among data. This study investigates a dual-level relational framework for image classification, bridging the gap between implicit representation learning and explicit structural modelling. We begin by establishing a baseline using an EfficientNetB3 architecture. To move beyond standard convolutional biases, we adopt a patch-based strategy, employing a convolutional masked autoencoder to learn implicit inter-patch relationships through self-supervised reconstruction. We then extend this approach by incorporating explicit relational modelling, organizing the learned embeddings into various graph topologies, including grid-based, random, and k-nearest neighbour structures. Experimental results on the ISIC-2018 and ISIC-2019 skin lesion diagnosis benchmarks show that combining implicit inter-patch modelling with explicit graph-based message passing yields the best performance. On the ISIC-2018 test set, the baseline model achieves a balanced accuracy of 76.17%, which improves to 77.12% with implicit patch-based relational modelling. The fully integrated grid-structured Graph Attention Network further increases performance to 79.27%. Similarly, on ISIC-2019, the implicit approach reaches 59.84% balanced accuracy, while the combination of implicit and explicit modelling yields 60.67%.

The emergence of medical deepfakes, i.e., medical images manipulated by deep generative models, poses a significant threat to clinical workflows. However, existing detectors suffer from two critical limitations: poor generalization to unseen generative architectures for manipulation detection and lack of interpretability. In this context, we present HexMIL (Hierarchical EXplainable Multiple Instance Learning), a mask-free medical deepfake detector that simultaneously addresses both limitations using only binary volume-level supervision. HexMIL decomposes each CT volume into a two-level hierarchy of patches and slices, aggregated via independent Gated Attention modules whose weights are directly combined into a full-resolution 3D attention volume that localizes the manipulated sub-region without any pixel-level annotation. Unlike post-hoc methods such as Grad-CAM, HexMIL's attention weights constitute the exact forward computation driving the classification decision, providing ante-hoc and structurally faithful spatial attribution. We evaluate HexMIL on M3DSynth and CT-GAN datasets under a rigorous cross-generator generalization protocol, training on a single generative architecture and testing on unseen ones. HexMIL outperforms all baselines by $+9.1$ AUC and $+9.4$ F1 in out-of-domain classification, and achieves the best average IoU and Pointing Game score in localization. Project page: opontorno.github.io/hexmil.

Vision Transformers (ViTs) and their hierarchical variants have achieved strong performance in Computational Pathology (CPath). However, most are pre-trained on single-resolution Whole Slide Images (WSIs), limiting their generalization across arbitrary resolutions. Gigapixel WSIs inherently contain diagnostic patterns at multiple scales, including cellular morphologies, tissue architectures, and global context, mirroring how expert pathologists examine WSIs. We introduce Multi-Resolution Pyramid Transformer (MRPT), a model that hierarchically aggregates multi-resolution information from cellular to tissue and WSI levels. MRPT employs a biologically meaningful Consecutive Cross-Resolution Attention (CCRA) mechanism to capture scale-independent interactions and enforces multi-resolution semantic consistency by aligning embeddings across resolutions, yielding robust and generalizable WSI representations. Pre-trained in a multi-resolution self-supervised manner on 624M patches, 2.4M regions, and 36K WSIs, MRPT learns rich coarse-to-fine histopathology features. Extensive experiments on 34 diverse datasets show that MRPT surpasses recent foundation models and Multimodal Large Language Models (MLLMs) in cancer subtype classification, tissue phenotyping, and Visual Question Answering (VQA) for WSI understanding.

Attention-based multiple instance learning (ABMIL) is the predominant approach for slide-level prediction in computational pathology, yet its attention maps provide only local explanations: they indicate where a model focuses but not which histological features drive its predictions or how the model behaves across a patient cohort. We present Semantic Attention Global Explanations (SAGE), a post-hoc framework that extracts global, language-grounded explanations from a frozen ABMIL model. Using a pathology vision-language model, SAGE scores image patches against a dictionary of 25 histological concepts, aggregates these scores according to the model's learned attention, and quantifies how each concept relates to prediction risk across a cohort. Applied to survival prediction using seven TCGA cancer cohorts and three foundation models, SAGE recovered established prognostic features, such as the adverse association of necrosis, while revealing cancer-specific biology, including a favorable angiogenic signature in renal cell carcinoma consistent with known molecular subtypes. Ablation studies demonstrated that these associations depend on the model's learned attention rather than concept prevalence alone, and that the concept dictionary captures much of the prognostic information encoded by the foundation model features. Through semantically-grounded explanations, SAGE provides a scalable, model-agnostic framework for understanding what ABMIL survival models learn, enabling pathologists to interpret model behavior at the cohort level and offering the potential for biomarker identification.

Predicting spatial gene expression from histopathology images enables large-scale transcriptomic profiling without the cost of direct measurement. Existing methods decode the target gene set as a flat, unstructured vector, ignoring the inter-gene dependencies arising from shared biological pathways and regulatory programs. Without explicit structural guidance, models must infer these dependencies entirely from limited paired data, constraining prediction quality. We propose MSGR (Multi-Scale Gene Refiner), which bridges this gap by incorporating the Gene Ontology (GO), a curated functional hierarchy of genes, as an explicit structural prior. MSGR organizes target genes into a four-level GO tree. Its GO-guided decoder then progressively refines predictions from coarse functional domains to fine individual genes via residual corrections under scale-weighted supervision. Operating solely on the gene side, the GO-guided decoder serves as a seamless plug-in replacement that consistently improves existing architectures without requiring any image-side modifications. Extensive experiments on nine datasets from the HEST-1k benchmark provide empirical evidence for two central claims: GO-structured decoding consistently outperforms flat decoding, even against a state-of-the-art generative baseline, and the gain is attributable to biological ontology structure rather than hierarchical decomposition per se, as confirmed by a +0.027 margin over a structurally equivalent random hierarchy.

Understanding tissue organisation in multiplexed imaging requires modelling both cellular phenotypes and their spatial context. Existing approaches typically rely on handcrafted features, such as marker intensity statistics or cell-type proportions, which often fail to scale or generalise across cohorts with heterogeneous marker panels. We introduce MUL-T, a lightweight transformer framework that reframes tissue architecture as a masked contextual prediction task over discrete cell tokens. By learning contextualised [CLS] embeddings without task-specific supervision, the model captures higher-order cellular interactions while remaining computationally efficient. We evaluate MUL-T on several clinically relevant downstream tasks, including core-level tumour pattern classification, patient-level grading, PD-L1 positivity prediction, and cross-dataset treatment response prediction. Across tasks, MUL-T consistently outperforms classical feature-based baselines and achieves performance comparable to a foundation ViT model, despite substantially fewer parameters and lower training cost.

EEG-based disease diagnosis requires one prediction per subject, yet common pipelines segment recordings into short instances, inherit the subject label for every instance, and train instance-level classifiers. This assumes that all instances provide equally reliable diagnostic evidence. Multiple instance learning (MIL) avoids inherited labels by treating each subject as a bag. However, EEG datasets contain far fewer subjects than instances, which can limit the quality of the representations learned by end-to-end MIL. We propose BridgeMIL, a two-stage framework that decouples instance representation learning from subject-level supervision. Stage 1 pretrains the encoder without inherited instance labels by aligning temporally nearby windows and independently sampled within-subject sub-bags. Variance and covariance regularization prevent collapse and reduce redundancy without negative pairs. Stage 2 transfers the encoder to an attention-based MIL aggregator, applies supervision only to subject predictions, and limits representation drift through feature retention. Across three EEG disease datasets and five representative backbones, BridgeMIL attains the highest mean accuracy in 14 of 15 dataset-backbone settings and an overall mean accuracy of 76.57%, 4.28 percentage points higher than the strongest baseline. Further analyses reveal substantial variation in inherited-label reliability across instances, greater performance sensitivity to subject scarcity than to instance scarcity, and a more structured representation space with distinct subject-wise clusters and improved separation between diagnostic classes. Together, these findings underscore the importance of aligning supervision with the subject-level prediction objective while learning from abundant EEG instances without assigning disease labels to individual instances.

Glioma grading from tumor contours is often treated as a pixel problem even when the signal of interest is shape. We align closed contours with a functional shape-alignment framework, separate global deformation from residual Fourier shape, and organize these quantities as frequency-ordered tokens. In five-fold patient-disjoint cross-validation on BraTS~2020 tumor contours, with model selection performed using grouped inner validation, a compact multilayer perceptron (MLP) achieves the highest mean balanced accuracy at 71.5%, compared with 65.9% for ResNet-18 and 63.3% for ViT-Tiny. It also gives the highest mean low-grade glioma F1 at 54.9%. Its pooled out-of-fold balanced accuracy is 72.4% (patient-bootstrap 95% CI: 66.4--77.8%). The selected MLPs use 2.9k--117.3k parameters across folds, at least 46 times fewer than the pixel baselines. In a controlled noise-free simulation, shape-based models reach 56.3--71.5% balanced accuracy while the pixel models remain at 50.0--52.5%. This work demonstrates how incorporating a shape-based inductive bias at the representation level can improve interpretability and scalability while enabling substantial dimensionality reduction.

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.

Whole-slide survival models commonly provide risk rankings without calibrated statements about individual event times. We evaluate fixed-cutoff drcosarc, a post-hoc conformal wrapper for discrete-time multiple-instance learning survival heads using frozen UNI2-h representations, in an internal 18-configuration sweep across five TCGA cohorts and an external five-configuration evaluation across three CPTAC cohorts. We distinguish configuration--fold--split summaries of the inverse-probability-of-censoring-weighted (IPCW) estimate and median lower predictive bound (LPB) from a hierarchy-aware patient-ensemble estimand of the mean drcosarc--naive LPB difference. At $α=0.1$, the drcosarc IPCW estimate was nearest 0.90 in KIRC, LUAD, and STAD. Patient-ensemble drcosarc--naive intervals excluded zero in KIRC, KIRP, STAD, UCEC, and CPTAC-CCRCC, but included zero in internal LUAD, CPTAC-LUAD, CPTAC-UCEC, and the internal LUSC extension. In a 20-replicate low-censoring semi-synthetic setting with known event times, drcosarc empirical coverage was 0.9129 [0.9053, 0.9207]. An exploratory analysis supported a head-error-by-censoring interaction within that data-generating process. In a two-cohort ABMIL sensitivity analysis, increasing the hazard grid to $K=16$ raised localized marginal IPCW estimates above the prespecified 0.87 threshold and yielded positive paired LPB differences, although worst-group estimates remained below 0.87. Overall, performance was cohort dependent, and its interpretation changed with the patient-level unit, estimand, and censoring assumptions.

Multiple instance learning (MIL) has become the main paradigm for whole-slide image (WSI) analysis in computational pathology. However, existing MIL aggregators are still typically trained from scratch for each downstream task, relying on limited slide-level labels to learn both aggregation mechanisms and downstream discriminative representations simultaneously. As a result, they often suffer from unstable optimization, overfitting, and limited transferability. Similar to pretrained ResNet and Vision Transformer models in natural image learning, MIL also requires reusable pretrained initialization. However, high-quality slide-level pretraining data remain scarce, and MIL models are usually lightweight and weakly supervised, making large-scale pretraining difficult in practice. To address this challenge, we propose a distillation-based pretraining framework for MIL, which leverages two slide-level foundation models, TITAN and CARE, as teachers to transfer their representational knowledge into a diverse set of MIL architectures. To effectively balance supervision from different teachers, we further introduce an angular dispersion normalized distillation loss. The distilled weights are then used as initialization for downstream adaptation. We conduct systematic evaluations on 15 benchmark datasets under both linear probing and full-parameter fine-tuning, and further validate its advantages in few-shot scenarios. Experimental results show that pretraining generally improves MIL aggregators over from scratch training, especially in linear-probing and few-shot settings, while maintaining the computational efficiency of lightweight MIL models. Code is available at https://github.com/fu0201/MIL_Pretrained.

We present a frame-independent audio-text system for the 3rd Ambivalence/Hesitancy Video Recognition Challenge at the 11th Affective & Behavior Analysis in-the-Wild (ABAW) Workshop. Videos are divided into overlapping 5-s windows aligned with transcript timestamps. Each window combines prosodic audio descriptors, emotion-oriented RoBERTa embeddings, and 74 psycholinguistic features representing uncertainty, hedging, and attitudinal conflict. Temporal cross-attention fuses audio and text, while the support features condition gated Multiple Instance Learning (MIL) pooling. A five-seed ensemble achieves an average precision of 0.875 and a macro-F1 of 0.722 on the 525-video labeled public-test split. Notably, our submission ranked third overall on the official challenge leaderboard, with a macro-F1 of 0.7455. Source code is available at https://github.com/Liga-de-IA-PUCPR/abaw-11-ah-challenge/.

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.

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.

Self-supervised learning (SSL) has emerged as an effective paradigm for learning transferable representations from large-scale unlabeled whole slide images (WSIs). However, existing SSL methods primarily learn generic visual features and often fail to explicitly capture pathology-specific morphological patterns that are critical for disease characterization. To address this limitation, we propose Tiny Vision Transformer with Pathology-Aware Prototype Distillation (TVT-PAPD). This self-supervised pathology representation learning framework integrates a Tiny Vision Transformer (TVT) with a novel Pathology-Aware Prototype Distillation (PAPD) module. PAPD employs a learnable pathology prototype bank to discover and preserve representative tissue morphology patterns, encouraging semantically similar pathological regions to learn consistent and discriminative representations. The proposed framework enhances pathology-aware feature learning while maintaining computational efficiency with 90M parameters. Experiments on the Cancer Genome Atlas (TCGA) low-grade glioma (LGG)/glioblastoma (GBM) dataset and the Indian Pathology Brain (IPD-Brain) dataset demonstrate that TVT-PAPD achieves weighted F1-scores of 93.02% and 90.23%, respectively, for LGG-GBM classification, while exhibiting strong cross-cohort generalization across independent glioma datasets.

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.

Whole slide images (WSIs) provide rich diagnostic information for computational pathology, but their gigapixel scale, stain variation, scanner differences, tissue artifacts, and limited expert annotation make robust model training challenging. This paper presents a multi-source Masked Autoencoder (MAE) framework, named ProsMAE, for histopathology representation learning. Tiles from Prostate cANcer graDe Assessment (PANDA), CAncer MEtastases in LYmph nOdes challeNge 2017 (CAMELYON17), and BReAst Carcinoma Subtyping (BRACS) are used for ProsMAE pretraining to expose the encoder to diverse tissue morphology and acquisition conditions. The learned encoder is transferred for International Society of Urological Pathology (ISUP) grade classification through ProsCLS, using a frozen encoder and a linear classification head. ProsMAE achieved a higher mean validation quadratic weighted kappa (QWK) than the vanilla MAE frozen linear-probe baseline under the evaluated disjoint PANDA split. Repeated-split evaluation remains necessary to further establish robustness across split compositions.

Bird's-Eye View (BEV) end-to-end instance prediction has emerged as a robust paradigm for autonomous driving perception, effectively mitigating the error propagation inherent in traditional modular pipelines. However, current state-of-the-art approaches rely predominantly on geometric supervision, such as occupancy regression and optical flow, effectively treating scene agents as generic moving obstacles. This absence of explicit semantic awareness imposes limitations on the capacity of the model to solve ambiguities in complex scenarios, particularly those where object-specific behavior is essential for accurate forecasting (e.g. overtaking, intersections). In this paper, we introduce Text-Guided Representation for Instance Prediction (TGRIP), a novel framework that bridges this gap by injecting rich semantic priors into the instance prediction loop. The proposed teacher-student pipeline employs Vision-Language Foundation Models to generate dense, semantic-enhanced BEV maps from multi-camera images. These maps serve as auxiliary supervision during training, guiding the network to learn spatio-temporal representations that are not only geometrically consistent but also semantically discriminative. To the best of our knowledge, this represents the first attempt to unify semantic guidance with the temporal task of future instance prediction. The experimental results demonstrate that TGRIP surpasses existing state-of-the-art models in nuScenes, validating the hypothesis that semantic enrichment is a fundamental element for robust, end-to-end motion prediction. Code is available on https://github.com/miguelag99/TGRIP.

Model merging offers a practical alternative to conventional continual learning by integrating independently fine-tuned models without retaining previous training data. Recent state-of-the-art model merging methods employ test-time adaptation (TTA-guided merging) to address distribution shifts by adjusting merging-related variables using unlabeled target data. However, these methods have primarily been studied in multi-task or single-target settings, and their behavior under sequential continual learning remains insufficiently understood. We present a benchmark study that maps this family of methods to rehearsal-free continual Whole Slide Image classification and evaluates them against traditional continual-learning approaches. Experiments on six TCGA cancer-subtyping cohorts cover CLASS-IL and TASK-IL scenarios, in-domain and out-of-domain evaluation, and different task orders. The results show that adapting model merging at test time can provide strong task-specific performance and improve retention of previously acquired knowledge without storing historical WSIs. Nevertheless, performance remains sensitive to task order and to the interaction between adaptation on the current distribution and accumulated knowledge. This benchmark identifies model merging with test-time adaptation as a promising direction for continual computational pathology and motivates future methods that balance adaptation to domain shift with explicit preservation of historical knowledge.

Survival analysis on Whole Slide Images (WSIs) is important in computational pathology for prognosis estimation and treatment planning. However, existing survival models are typically trained independently for each cancer cohort, making continual adaptation computationally expensive for gigapixel-scale WSIs. In this study, we propose MergeSurv, a merging-based continual learning framework for WSI survival analysis. A pathology vision-language foundation model is independently fine-tuned on each task, and the learned parameters are sequentially merged into a unified model without storing previous training data. We further investigate two inference strategies: One-for-All (OFA) and Voting-Expert Aggregation (VEA). Experiments on four TCGA cohorts demonstrate that MergeSurv outperforms naive fine-tuning as well as representative regularization-based and rehearsal-based continual learning methods, while effectively reducing catastrophic forgetting. The results suggest that model merging is a promising direction for scalable and privacy-preserving continual learning in computational pathology.

A unified multiplex virtual staining model enables scalable and non-destructive multiplex analysis from H&E slides while promoting parameter efficiency, shared pathological knowledge, and consistent cross-biomarker representations. However, in clinical practice, data for new biomarkers are typically acquired sequentially over time. Fine-tuning on such temporally arriving data leads to severe performance degradation on previously learned biomarkers, as sequential optimization disrupts the structured relationships among biomarker representations in the latent space. To address this issue, we propose ContiStain, an IHC multi-domain relational distillation framework for continual virtual staining. We first (i) construct a domain-aware structured feature space using a mixture-of-experts (MoE) feature extractor to reduce representation interference across biomarker domains. Based on this stabilized feature space, we then (ii) propose a relation-preserving distillation strategy that explicitly enforces the consistency of cross-domain token-level cosine similarity matrices between learned biomarker domains during continual adaptation. By maintaining cross-domain structural coherence, ContiStain mitigates forgetting while retaining adaptability to new domains. Experiments on the MIST dataset under a four-domain sequential virtual IHC staining setting show improved stability, reducing FID and ConchFID by 11.1 and 60.9 compared to sequential fine-tuning, enabling scalable and robust multi-domain virtual staining. Code is released at https://github.com/ccitachi/ContiStain.

Continuous video anomaly detection is dominated by reactive Multiple Instance Learning (MIL) that collapses spatiotemporal features into scalar scores. We introduce PULS (Predictive Unified Latent Space), a continuous semantic world-model pipeline comprising two modules: a 490M-parameter KSD Bridge (Kinematic-to-Semantic Distillation) and a 16.8M-parameter Anticipatory State Predictor (ASP). The KSD Bridge maps V-JEPA 2 physical tensors into the 2048-d Qwen3-VL-Embedding-2B text-aligned hypersphere, trained on a subset of UCF-Crime. This translation alone yields a chunk-level AUROC of 0.8994 for UCF-Crime and 0.8162 for out-of-distribution XD-Violence without MIL or hierarchical fusion. We introduce and validate the Latent Clarity Hypothesis: because JEPA's temporal predictor discards aleatoric pixel noise while preserving kinematics, anticipated future representations are more semantically separable than observed presents. The ASP sharpens these anticipated future latents, achieving 44.5% mean 14-way zero-shot VQA accuracy (exceeding observation baseline by +9.6 pp). Applying the ASP to Observation Tensors collapses accuracy to 7.3% (random chance), proving Anticipation and Observation occupy distinct sub-manifolds. A Triple-Track Lead-Time protocol with an L1-surprise gate yields a peak +8.9 pp anticipatory advantage at T-0.5s (p < 0.001, N = 1,000 permutation), separating physical anticipation from static scene priors. Zero-shot transfer to XD-Violence confirms that Newtonian-invariant kinematic representations generalize out-of-distribution.

Modernizing cancer registries with deep learning is opening new opportunities to automate labor-intensive tasks such as the coding of pathology reports. However, progress is constrained by the scarcity of report-level human-annotated training data. Cancer registries generate substantial volumes of expert-assigned labels as a routine product of their operations, but these exist at the patient level and are not linked to the individual pathology reports that informed them, limiting their direct use for training models. We develop an efficient framework for training deep learning classifiers by leveraging these operationally-generated labels without requiring per-report human annotation, demonstrated for tumor group classification at the BC Cancer Registry. We use Attention-Based Multiple Instance Learning (ABMIL) to recover the lost link between patient-level labels and the reports that informed them, leveraging the attention the model places on each report to distil a large, noisily-labeled corpus into a compact, high-quality per-report training dataset. A classifier fine-tuned on a distilled dataset achieved a macro F1 of 0.83, outperforming established baselines across most tumor groups. By turning routine operational labels into high-quality training data without additional annotation or large-scale computing infrastructure, ABMIL offers a practical and accessible route to automating cancer registry workflows.

Whole slide image (WSI) analysis is central to computational pathology, with multiple instance learning (MIL) emerging as the standard pipeline for slide-level diagnosis. However, conventional approaches formulate WSI diagnosis as a flat classification task over discrete labels, contradicting the inherently hierarchical, coarse-to-fine nature of clinical reasoning. Although recent hierarchical classifiers and vision-language models (VLMs) have sought to address this structural gap, they either fail to capture semantic continuity between related diagnoses or suffer from unconstrained text generation that produces taxonomic hallucinations and parent-child label violations. To address these limitations, we propose TaxoMIL, a taxonomy-constrained framework that reformulates WSI diagnosis as a multi-granularity text generation task. TaxoMIL utilizes a dual-head Transformer decoder to generate coarse- and fine-level diagnostic text, and introduces taxonomy-guided objectives that explicitly structure the label embedding space and strictly ground slide-level visual representations within the clinical taxonomy. Extensive experiments across three diverse WSI datasets demonstrate that TaxoMIL consistently outperforms state-of-the-art MIL classifiers and VLM-based generative methods, yielding accurate and hierarchy-aware diagnostic predictions. The code is released at https://github.com/QuIIL/TaxoMIL

H&E-stained whole-slide images offer cohort-scale availability and rich spatial context but lack molecular specificity, whereas bulk RNA-seq provides transcriptome-wide resolution at high cost with limited archival availability. We show that training a lightweight alignment module atop frozen histopathology and RNA-Seq foundation models enables open-vocabulary molecular prompting -- querying H&E slides with gene-set signatures to predict pathway activity without sequencing or end-to-end retraining. Using contrastive learning on a multi-cancer cohort (N=1,720), we achieve a 25-fold improvement in retrieval over baseline methods. Systematic analysis reveals a graduated predictability spectrum: morphologically grounded programs (cell-cycle programs, immune-related) are most reliably predicted (R^2>0.5), while predicting pathways with no morphological footprint remains challenging as expected. We validate clinical utility on the POSEIDON clinical trial: H&E-predicted squamous cell carcinoma scores recapitulate NSCLC subtype identity and predicted IFN-gamma mirror PD-L1 tumor-cell expression groups. Furthermore, genesets describing immune activation and fibrosis predict known tumor microenvironment archetypes from histology alone. We further validate generalization of our approach across unseen cohorts and demonstrate data-efficient domain adaptation, establishing a slide-native framework for molecular analysis on H&E images.

Pathology foundation models (PFMs) have demonstrated strong potential across clinical and scientific applications, yet their performance is often hindered by batch effects, which are non-biological variations across tissue source institutions (TSIs) that distort learned feature representations and impair generalization. Conventional mitigation strategies, such as stain normalization, offer limited success in addressing these high-dimensional, complex artifacts. We present GLMP (General-purpose LLM-Mediated Pathology model), a novel framework that generates robust numerical embeddings from histology image patches through an intermediate textual representation. By leveraging pretrained general-purpose multimodal large language models (MLLMs) and text encoders, GLMP effectively prioritizes biologically meaningful signals over TSI-specific artifacts, thereby improving cross-institutional generalization. To our knowledge, GLMP is the first pathology model to use text descriptions of histological features as an intermediate representation for generating numerical embeddings from histology images. Our results highlight the untapped potential of broad-domain, non-specialized MLLMs in computational pathology and introduce a new paradigm for building versatile, generalizable, and robust pathology models.

Predicting distant metastasis from the digital H & E slides of the primary tumor is a critical yet challenging task in computational pathology. Multiple Instance Learning (MIL) approaches can attend to subdomains in whole slide images (WSIs) that harbor features of pre-metastatic cancer regions. However, conventional MIL models largely treat tissue patches as unordered bags, discarding the spatial layout that defines how these regions are arranged and interact across the tissue. We propose that metastatic risk is shaped not only by local patch appearance, but also by the geometric organization of patches in the WSI and the interaction between the tissue compartments. To this end, we introduce Distance-aware Tissue Modeling for Multiple Instance Learning (DTMF-MIL), a spatial MIL framework that reinforces feature embeddings with explicit distance priors. By computing signed distance functions (SDFs) to capture regions with similar features, and representing each patch with radial-basis distance responses and local SDF statistics, DTMF-MIL learns positions of patches with respect to regional interiors and boundaries. The interactions between similar patches are contextualized across local tissue neighborhoods and used to guide slide-level attention while pooling patch feature evidence for metastasis prediction. We evaluate DTMF-MIL for prediction of distant prostate cancer metastasis in an internal prostate needle-biopsy cohort (IPC) from a large hospital system and on public TCGA-COAD and TCGA-KIRC datasets across multiple pathology foundation-model backbones. Across most dataset, backbone, and metric combinations, DTMF-MIL achieves the strongest results consistently.

Accurate assessment of tumor proportion score (TPS) in non-small cell lung cancer (NSCLC) is critical for treatment planning and prognosis. Key challenges include the tedious manual work required to annotate each slide, combined with the limited number of experts certified for this task. Multiple instance learning (MIL) has proven to be an effective approach for predicting TPS scores at the slide level; however, existing methods struggle with non-expressive (zero class) images. Our approach involves two models: (1) an embedding-extraction and multiclass-classification network that captures the histopathological features of individual patches, and (2) a MIL model that aggregates these embeddings to predict zero-inflated beta (ZIBeta) parameters representing the overall TPS probability distribution for the entire slide. Using only slide-level TPS scores as labels, we demonstrate how this end-to-end framework can leverage a novel distribution-based architecture to improve prediction accuracy and explainability. ZIBeta modeling significantly outperforms baseline linear and ridge regression while capturing expected accuracy through distribution concentration.

Data scarcity is a major bottleneck in medical Multiple Instance Learning (MIL), especially for rare diseases or expensive modalities. We introduce a statistically grounded patient augmentation approach that generates realistic patients directly in embedding space. Using Gaussian Mixture Models as a probabilistic clustering approach on pooled instance embeddings from all patients, our method learns disease-specific "recipes"-statistical distributions of instances across unsupervised clusters. New patients are then generated by sampling embeddings from clusters based on learned recipes. Unlike existing methods that require examples from all categories, our method can generate patients offline by re-mixing pooled embeddings. Generated patients are further selected based on uncertainty quantification to improve MIL performance. We evaluate our method across three clinically relevant scarcity scenarios: (i) cross-dataset transfer, where an entirely missing "healthy" class is generated using statistics from an external cohort; (ii) low-data regimes, where class sizes are extremely limited; and (iii) small-cohort non-image tasks, including single-cell RNA-seq and flow cytometry. Across all experiments, our method improves performance over baseline, often outperforming other bag-mixing strategies. Notably, in the missing-class scenario, a performance comparable to full-dataset training is achieved, demonstrating its potential for rare disease diagnostic and privacy-preserving patient augmentation. The code is available at https://github.com/marrlab/RECIPE

Automated diagnosis of 3D brain CT scans is essential for critical care, yet it remains challenging due to the heavy reliance on manual annotations and the limited semantic understanding of conventional models. While 2D foundation vision-language models (VLMs) have shown remarkable generalization, effectively transferring their representational power to 3D volumes remains an open problem. In this paper, we propose Brain-Adapter, a novel dual-stream multiple instance learning (MIL) framework that leverages pre-trained 2D biomedical VLMs and raw diagnostic reports for robust scan-level multi-label classification. Specifically, we introduce a Text-Conditioned Attention (TCA) mechanism, utilizing raw diagnostic sentences as semantic queries to dynamically align visual cues with specific disease concepts. Concurrently, a parallel visual MIL stream captures global scan characteristics, supervised by structured labels extracted via a Large Language Model (LLM). To ensure representation coherence, a consistency constraint enforces synergy between the two streams. During inference, an Uncertainty-Aware Refinement (UAR) module dynamically calibrates and fuses these dual-stream predictions to resolve ambiguous cases. Extensive experiments demonstrate that our method significantly outperforms state-of-the-art 3D models and standard MIL approaches. By eliminating the reliance on dense annotations, Brain-Adapter provides a highly scalable and clinically viable solution for 3D acute intracranial pathology analysis.

Preterm birth (PTB) prediction can enable targeted surveillance and timely intervention, yet most ultrasound-based models use a single selected transvaginal ultrasound (TVUS) frame per patient despite routine exams acquiring multiple cervical images. We formulate PTB prediction as a multiple instance learning (MIL) problem, representing each patient as a variable-sized bag of TVUS images with a single outcome label. To move beyond standard MIL aggregators that collapse a bag into a point estimate, we propose a Gaussian Mixture Model (GMM) pooling, which summarizes all images in a bag into a fixed-length representation by modeling their feature distribution. This design captures intra-patient variability. We evaluate the method on a private clinical cohort and on a public lymph node metastasis benchmark. For PTB prediction, GMM pooling improves over the instance-based model PR-AUC from 0.44 to 0.56. On the lymph node benchmark, it achieves state-of-the-art performance with 0.91 F1-score and 0.89 ROC-AUC for classification and 0.18 MAE for regression. The code is publicly available at https://github.com/HussainAlasmawi/GMM_Pooling.

Recent advances in large pre-trained models have led to remarkable progress in instance segmentation on general images. However, industrial scenarios remain challenging. Instance definitions are often application-specific and inconsistent, and the domain gap from general imagery is substantial due to weak textures and limited contextual cues. Consequently, a direct application of existing models is unreliable. We propose Boundary-by-Mask, a few-shot instance segmentation framework that supervises boundaries instead of interior appearance. Given a few RGB images and corresponding instance masks, the method extracts rich visual features using a foundation-model encoder and trains a lightweight Signed Distance Function (SDF) head to predict boundary-aware distance maps. Segmentation masks are obtained through an SDF-to-mask reconstruction process. By explicitly estimating contours, the framework achieves reliable instance separation even on low-texture and color-uniform surfaces. The instance definition is conditioned by the instance mask. Replacing the mask specifies the segmentation target, such as the whole object or a sub-part. A pixel-wise shallow MLP head enables rapid training. Experiments on industrial parts and food items with ambiguous boundaries show strong few-shot generalization, robustness in feature-poor conditions, and precise control over mask-level targets.

Matched multi-omics can improve WSI-based biomarker and prognosis prediction, but most existing pipelines use omics as a paral lel feature stream or textual context rather than as an explicit retrieval constraint. HERO asks whether observed omics can be a testable mor phology hypothesis: a sparse pathway-to-morphology prior maps DNA methylation and miRNA into a K-dimensional intent vector m (K=16), TF-IDF retrieval over structured 10 captions selects endpoint-relevant regions, and a cosine gate c=cos(m,v) triggers deterministic deficit driven repair when c<τc. This closed-loop design bounds VLM calls, reduces reliance on embedding-based semantic matching, and makes every retrieval and verification step lexically auditable. On TCGA-BRCA (930WSIs, patient-level 5-fold CV), HERO sets new state-of-the-art across ER, PR, HER2, subtype, and risk prediction, outperforming both multimodal fusion and VLM-based baselines.

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

Attention-based Multiple Instance Learning aggregators in medical imaging are prone to attention concentration, producing overconfident and unstable predictions. We introduce QG-MIL, a gated transformer aggregator that addresses this through four synergistic architectural components: RMSNorm-based pre-normalization, per-head QK normalization, fine-grained attention output gating, and SwiGLU-style feed-forward modules. Together, these design choices stabilize training and distribute attention more uniformly across instances without auxiliary losses, masking, or multi-stage regularization. We evaluate QG-MIL across six benchmarks spanning whole-slide pathology and cell-level hematology, covering two fundamentally different MIL scales. The best-performing QG-MIL variants outperform leading baselines on all six benchmarks, with an average improvement of +6.1 mean macro F1 points. Attention overlays and attention mass analysis confirm more distributed instance weighting. Ablation studies show that while individual components can match the full model on specific datasets, the QG-MIL design provides the most consistent cross-domain performance and tightest variance when compared to selected baselines. We release a configurable implementation to support reproducibility at: https://github.com/unica-visual-intelligence-lab/QG-MIL

Multiple Instance Learning (MIL) is a standard paradigm for Whole-Slide Image (WSI) analysis and has achieved strong results in computational pathology. However, most MIL pipelines assume a single "gold" label per slide, which conflicts with clinical practice where substantial inter-pathologist variability is common. Existing multi-annotator learning and label-refinement methods typically estimate global annotator reliability or rely on single-instance assumptions, making them poorly suited to MIL and to localized diagnostic contexts where experts disagree. We propose RaLMPH (Reliability-aware Learning for Multi-Pathologist Harmonization), a MIL-based label reconciliation framework for WSIs annotated by multiple pathologists. RaLMPH introduces a reliability field that jointly models (i) local neighborhood structure in WSI feature space and (ii) expert uncertainty (entropy), enabling per-sample identification of trustworthy reference neighborhoods. Leveraging this field, RaLMPH performs sample-wise local annotator ranking to select reliable opinions per slide and applies an adaptive gating mechanism to fuse labels conditioned on local reliability. Experiments on a clinical WSI dataset with labels from six pathologists, as well as controlled simulated benchmarks, show that RaLMPH consistently outperforms existing approaches. Further analyses clarify how our reliability-aware mechanism improves label reconciliation and downstream MIL performance.

Modern image classifiers widely adopt global average pooling (GAP) followed by a linear classification head. This linearity ensures that the image-level logits equal the average of logits obtained by applying the classification head pointwise to the feature grid prior to GAP. Consequently, standard classifiers may inherently retain spatial class evidence that remains recoverable even when the image-level prediction is incorrect. This structure naturally suggests a multiple-instance learning (MIL) interpretation, where an image is viewed as a bag of spatial instances. Within this formulation, we demonstrate that standard classifiers trained with a single label per image can still learn the intended classification task in multi-object scenes. We further exploit this property to decompose image-level logits into a prediction grid, providing a post-hoc diagnostic to extract spatial class evidence that GAP otherwise obscures. Our systematic evaluation reveals that off-the-shelf models consistently recover the ground-truth class within foreground regions. The MIL interpretation further suggests that common classifier failures reflect known limitations of mean aggregation.

Existing computational pathology methods predominantly operate within whole-slide image (WSI)-level multiple instance learning (MIL) paradigms, while patient-level modeling remains underexplored. In routine pathological practice, however, pathologists derive diagnostic and prognostic conclusions by integrating evidence across multiple WSIs rather than relying on any single slide. This discrepancy creates a fundamental misalignment when patient-level supervision is directly imposed on conventional MIL frameworks, often leading to unstable optimization and degraded predictive reliability. To address this issue, we propose Anchor-Guided Evidence MIL (AGE-MIL), a weakly supervised framework for patient-level prediction. AGE-MIL constructs a patient-level anchor from slide representations to capture global pathological context and guide the retrieval and integration of diagnostically relevant local patches, enabling robust patient-level modeling. Patient-level risk is further modeled as an evidence accumulation process, promoting stable optimization under weak supervision. AGE-MIL is evaluated on six clinically relevant patient-level prediction tasks from two independent cohorts. Experimental results show that the proposed framework consistently outperforms eight state-of-the-art MIL methods. Code is available at https://github.com/wodeniua/AGE-MIL.

Foundation Models (FMs) have recently redefined the state-of-the-art in histopathology by providing robust representations for whole-slide image (WSI) analysis. However, selecting the optimal foundation model (FM) for a specific clinical cohort currently requires multiple preprocessing steps, followed by computationally expensive feature extraction and the training of a Multiple Instance Learning (MIL) aggregator for every model. In this work, we investigate whether efficient tile-level linear probing can serve as a reliable proxy for slide-level performance, reducing the need to run full slide-level pipelines for every candidate encoder. We benchmark 19 state-of-the-art FMs on 42 slide-level and 16 tile-level tasks, comparing tile probing metrics against slide-level outcomes using ABMIL and Mean Pooling aggregations. We observe a high correlation between tile and slide performance across varying task difficulties, indicating that encoder representation quality is the primary determinant of WSI success. Sensitivity analyses show that transferability is stable across models and is more influenced by cohort sizes and numbers of tiles per slide than by average task difficulty. We also measure the agreement in best performing models between tile and slide-level tasks, showing tile benchmarks reliably shortlist strong candidates. Overall, our study indicates that tile-level benchmarking provides an efficient and practical first step for narrowing down candidate models, while slide-level evaluation remains essential for final validation on clinical tasks.

Reliable evaluation of instance segmentation models requires metrics that accurately and consistently reflect segmentation quality. However, the metrics most widely used in biological imaging carry fundamental mathematical weaknesses: hard Intersection-over-Union (IoU) thresholds that produce discontinuous, low sensitivity scoring; per-object normalization that distorts scores under object size variation; and greedy or one-to-many matching procedures that yield non-optimal, order-dependent correspondences. Together, these properties produce unintuitive and unreliable model rankings under common failure modes such as split cells, merged cells, and cell boundary imprecision. We propose Maximum Matching Accuracy (MMA), a threshold-free continuous metric that finds a globally optimal one-to-one matching between predicted and ground truth objects and aggregates total overlap using per-pixel normalization. We evaluate MMA against AP@50, PQ, SEG, and AJI across three experiments: synthetic failure cases, progressive corruption tests, and a model ranking comparison. MMA produces scores that are more stable, more sensitive, and more interpretable than existing alternatives, providing a principled foundation for fair instance segmentation benchmarking in biological cell imaging.

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).

Cell detection in histopathology images strongly depends on surrounding tissue context, where visually similar cells may belong to different classes under different microenvironments. Recent tissue-aware methods incorporate contextual priors, but often rely on static fusion strategies that may propagate noisy information. In this work, we propose DualGate-Net, a prior-aware dual-encoder framework that combines a ConvNeXtV2-based local encoder and a SegFormer-based global encoder through a learnable prior-gated fusion mechanism. The proposed module adaptively regulates the influence of tissue priors across spatial locations, while an auxiliary foreground reconstruction branch preserves high-frequency cellular structures during training. In addition, auxiliary cellness-guided cues are incorporated to further improve localization robustness. Experiments on the OCELOT benchmark demonstrate consistent improvements, achieving macro F1-scores of 0.7722 on the validation set and 0.7345 on the test set, highlighting the effectiveness of adaptive prior integration for robust histopathology cell detection.

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.

Multiple Instance Learning (MIL) addresses problems where supervision is available at the level of bags of instances and has been successfully applied in fields ranging from computational pathology to satellite imagery. Nevertheless, existing algorithms struggle in the low-label regime that characterizes many real-world applications. Flexible models overfit and rigid ones fail to adapt to the task at hand. We show that pretraining an in-context learner with a Perceiver-style architecture on synthetic data yields a model that can solve new tasks from a handful of labeled bags. At inference time, classification happens in a single forward pass and requires no gradient updates. We propose and investigate different synthetic data generators for bag-structured data and find that they capture complementary inductive biases. A model pretrained on a mixture of these generators inherits their per-task strengths and achieves the best average performance across twelve MIL benchmarks, outperforming supervised baselines that require task-specific training.

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.

Whether attention maps from pathology foundation models capture genuine biology remains unknown, yet this question is critical for clinical trust and regulatory approval. We propose a spatial transcriptomics-based framework for orthogonal, hypothesis-free evaluation of attention and apply it to five pathology foundation models (CONCH v1.5, UNI v2, Virchow2, GigaPath, H-Optimus-1) and a ResNet50 baseline. Using attention-based multiple instance learning, we train single-task and multi-task models to predict five molecular alterations in glioblastoma on the CPTAC cohort, validate on an independent TCGA cohort, and evaluate biological coherence of attention maps against 87 transcriptional signatures using co-registered Visium spatial transcriptomics data from 18 samples. Internally, no single encoder dominates across all tasks, and external validation inverts internal performance rankings. Attention maps show a five-fold enrichment gradient from pathways (Cohen's d=0.329) to individual genes (d=0.055), indicating that attention captures emergent multi-gene transcriptional programs rather than individual molecular events. Spatially smooth attention maps do not imply biological coherence, and different encoders attend to distinct biological compartments. Our framework provides objective, quantitative assessment of what foundation models learn from histopathology, moving the field beyond qualitative saliency map review.

We show every multi-group learner in the transductive setting may incur a multiplicative penalty in its error rate on some group relative to the error rate achievable in the single-group setting, and the penalty can increasing linearly with the number of groups, up to roughly the square-root of the sample size. This stands in stark contrast to optimal multi-group learners in an analogous (group-realizable) statistical setting, where the penalty is always at most logarithmic in the sample size and independent of the number of groups.

Integrating transcriptomics and histopathology can improve cancer risk modelling, yet practical use is constrained by the limited availability of RNA profiling in routine settings. Here we introduce Mixture of Pathway Experts (MoPE), a knowledge-distillation framework that reframes multimodal learning as privileged distillation for histology-only inference. MoPE is motivated by the partial observability between RNA profiles and whole-slide images: histology can capture morphology-linked consequences of certain molecular programmes, but cannot be expected to reconstruct the full transcriptomic state. MoPE encodes RNA-derived pathways and transfers the molecular supervision to pathway-indexed pathology experts through memory-usage alignment. Across diverse public benchmarks and two independent breast cancer cohorts, MoPE consistently improved WSI-only inference performance relative to baseline methods. Pathway-usage analyses and human-audited visual inspection provide bounded inspection of model behaviour and candidate morphology-linked readouts. These results support pathway-structured privileged distillation as a promising route to using molecular information during training while preserving RNA-free inference.

The Panoptic Quality (PQ) metric is the standard for jointly evaluating instance and semantic segmentation. However, its original definition relies on a One-to-One matching between predicted and ground truth segments, which is only straightforward when the IoU threshold exceeds 0.5. Below 0.5, multiple matching strategies emerge in a poorly explored problem space. We systematically elucidate this space by recasting segment matching as a constrained bipartite assignment problem. Independently bounding the prediction- and ground-truth-side degrees yields four matching strategies: One-to-One, Many-to-One, One-to-Many, and Many-to-Many. We show that the first three are well-defined within the PQ framework, while Many-to-Many falls outside it. These strategies become relevant when instances are fragmented, adjacent objects are difficult to delineate, or annotations are noisy. Central to our framework is a vertex-based accounting of TP, FN, and FP, anchored to ground truth and predicted segments rather than to matching edges. We further show that the framework extends naturally to part-aware panoptic segmentation, and we explore part-aware evaluation on biomedical data. Across configurable case studies we report how different combinations of thresholds and matching strategies behave in practice. We release a unified open-source package built on Panoptica. It exposes Voronoi-based region-wise analysis, part-aware evaluation, and Area Under Threshold Curve computations as configurable options.

Cell instance segmentation models trained on cell-specific datasets suffer severe performance drops on out-of-distribution cell types, while interactive foundation models overcome this through per-instance prompting at a cost that is prohibitively expensive for histopathology images containing hundreds to thousands of densely packed instances. We introduce \textbf{Group Prompting}, a new paradigm that shifts interactive segmentation from per-instance $O(N)$ to per-type $O(T)$, where a single click per cell type suffices to segment all instances of that type. Our key observation is that the frozen image encoder of the Segment Anything Model (SAM) already clusters same-type cells in its feature space before any prompt is given, and that this clustering holds across staining modalities without any training. Exploiting this property, we propose \textbf{Chain-of-Prompts (CoP)}, a training-free framework that recursively expands a single user click by (1) identifying reliable same-type locations through non-parametric gating of multi-scale encoder features, and (2) selecting the most spatially distant reliable point as the next prompt to maximize coverage. On eleven benchmarks, CoP generalizes to both unseen cell types and unseen imaging modalities without any adaptation: with one click per type it retains over 90% of per-instance performance on three cell-type-annotated datasets while surpassing fully-supervised methods, and with one click per image it retains over 95% on eight datasets spanning both H&E and non-H&E imaging. Project Page: https://shjo-april.github.io/Chain-of-Prompts/

Instance-level quantification of kidney functional units is essential for morphometric analysis, yet most publicly available pathology datasets provide only semantic segmentation annotations, where adjacent structures of the same class are merged into single regions. This prevents reliable instance-level analysis and limits downstream quantitative studies. Existing heuristic post-processing methods often yield suboptimal instance separation, particularly in crowded and adherent regions, while deep learning-based instance segmentation approaches typically require intensive instance-level annotations that are costly and labor-intensive to obtain. We propose MORI-Seg, a deep learning framework that enables instance segmentation without requiring instance-level annotations. Instead of heuristic splitting or instance supervision, MORI-Seg learns morphology-aware geometric representations directly from semantic masks by jointly modeling object-centric distance fields and boundary-band representations to encode interior structure and contact interfaces. A class-conditioned feature disentanglement module further promotes intra-instance coherence and inter-instance separation. Under semantic-only supervision, MORI-Seg decomposes connected semantic regions into distinct instance masks in an end-to-end manner. Experiments demonstrate improved instance separation accuracy and more reliable morphometric quantification compared with classical post-processing pipelines and representative semantic-to-instance learning approaches. The official implementation is publicly available at https://github.com/ddrrnn123/MORI-Seg.