This work shows promising results using multiple instance learning on salivary gland tumours in classifying cancers on whole slide images. Utilising CTransPath as a patch-level feature extractor and CLAM as a feature aggregator, an F1 score of over 0.88 and AUROC of 0.92 are obtained for detecting cancer in whole slide images.
Multiple instance learning (MIL) has become a standard paradigm for weakly supervised classification of whole slide images (WSI). However, this paradigm relies on the use of a large number of labelled WSIs for training. The lack of training data and the presence of rare diseases present significant challenges for these methods. Prompt tuning combined with the pre-trained Vision-Language models (VLMs) is an effective solution to the Few-shot Weakly Supervised WSI classification (FSWC) tasks. Nevertheless, applying prompt tuning methods designed for natural images to WSIs presents three significant challenges: 1) These methods fail to fully leverage the prior knowledge from the VLM's text modality; 2) They overlook the essential multi-scale and contextual information in WSIs, leading to suboptimal results; and 3) They lack exploration of instance aggregation methods. To address these problems, we propose a Multi-Scale and Context-focused Prompt Tuning (MSCPT) method for FSWC tasks. Specifically, MSCPT employs the frozen large language model to generate pathological visual language prior knowledge at multi-scale, guiding hierarchical prompt tuning. Additionally, we design a graph prompt tuning module to learn essential contextual information within WSI, and finally, a non-parametric cross-guided instance aggregation module has been introduced to get the WSI-level features. Based on two VLMs, extensive experiments and visualizations on three datasets demonstrated the powerful performance of our MSCPT.
Whole slide images (WSIs) are gigapixel-scale digital images of H\&E-stained tissue samples widely used in pathology. The substantial size and complexity of WSIs pose unique analytical challenges. Multiple Instance Learning (MIL) has emerged as a powerful approach for addressing these challenges, particularly in cancer classification and detection. This survey provides a comprehensive overview of the challenges and methodologies associated with applying MIL to WSI analysis, including attention mechanisms, pseudo-labeling, transformers, pooling functions, and graph neural networks. Additionally, it explores the potential of MIL in discovering cancer cell morphology, constructing interpretable machine learning models, and quantifying cancer grading. By summarizing the current challenges, methodologies, and potential applications of MIL in WSI analysis, this survey aims to inform researchers about the state of the field and inspire future research directions.
Whole Slide Image (WSI) classification with multiple instance learning (MIL) in digital pathology faces significant computational challenges. Current methods mostly rely on extensive self-supervised learning (SSL) for satisfactory performance, requiring long training periods and considerable computational resources. At the same time, no pre-training affects performance due to domain shifts from natural images to WSIs. We introduce Snuffy architecture, a novel MIL-pooling method based on sparse transformers that mitigates performance loss with limited pre-training and enables continual few-shot pre-training as a competitive option. Our sparsity pattern is tailored for pathology and is theoretically proven to be a universal approximator with the tightest probabilistic sharp bound on the number of layers for sparse transformers, to date. We demonstrate Snuffy's effectiveness on CAMELYON16 and TCGA Lung cancer datasets, achieving superior WSI and patch-level accuracies. The code is available on https://github.com/jafarinia/snuffy.
Multiple instance learning (MIL) problem is currently solved from either bag-classification or instance-classification perspective, both of which ignore important information contained in some instances and result in limited performance. For example, existing methods often face difficulty in learning hard positive instances. In this paper, we formulate MIL as a semi-supervised instance classification problem, so that all the labeled and unlabeled instances can be fully utilized to train a better classifier. The difficulty in this formulation is that all the labeled instances are negative in MIL, and traditional self-training techniques used in semi-supervised learning tend to degenerate in generating pseudo labels for the unlabeled instances in this scenario. To resolve this problem, we propose a weakly-supervised self-training method, in which we utilize the positive bag labels to construct a global constraint and a local constraint on the pseudo labels to prevent them from degenerating and force the classifier to learn hard positive instances. It is worth noting that easy positive instances are instances are far from the decision boundary in the classification process, while hard positive instances are those close to the decision boundary. Through iterative optimization, the pseudo labels can gradually approach the true labels. Extensive experiments on two MNIST synthetic datasets, five traditional MIL benchmark datasets and two histopathology whole slide image datasets show that our method achieved new SOTA performance on all of them. The code will be publicly available.
We propose Set2Seq Transformer, a novel sequential multiple instance architecture, that learns to rank permutation aware set representations of sequences. First, we illustrate that learning temporal position-aware representations of discrete timesteps can greatly improve static visual multiple instance learning methods that do not regard temporality and concentrate almost exclusively on visual content analysis. We further demonstrate the significant advantages of end-to-end sequential multiple instance learning, integrating visual content and temporal information in a multimodal manner. As application we focus on fine art analysis related tasks. To that end, we show that our Set2Seq Transformer can leverage visual set and temporal position-aware representations for modelling visual artists' oeuvres for predicting artistic success. Finally, through extensive quantitative and qualitative evaluation using a novel dataset, WikiArt-Seq2Rank, and a visual learning-to-rank downstream task, we show that our Set2Seq Transformer captures essential temporal information improving the performance of strong static and sequential multiple instance learning methods for predicting artistic success.
Multiple instance learning (MIL) has become a preferred method for gigapixel whole slide image (WSI) classification without requiring patch-level annotations. Current MIL research primarily relies on embedding-based approaches, which extract patch features using a pre-trained feature extractor and aggregate them for slide-level prediction. Despite the critical role of feature extraction, there is limited guidance on selecting optimal feature extractors to maximize WSI performance. This study addresses this gap by systematically evaluating MIL feature extractors across three dimensions: pre-training dataset, backbone model, and pre-training method. Extensive experiments were conducted on two public WSI datasets (TCGA-NSCLC and Camelyon16) using four state-of-the-art (SOTA) MIL models. Our findings reveal that: 1) selecting a robust self-supervised learning (SSL) method has a greater impact on performance than relying solely on an in-domain pre-training dataset; 2) prioritizing Transformer-based backbones with deeper architectures over CNN-based models; and 3) using larger, more diverse pre-training datasets significantly enhances classification outcomes. We hope that these insights can provide practical guidance for optimizing WSI classification and explain the reasons behind the performance advantages of the current SOTA pathology foundation models. Furthermore, this work may inform the development of more effective pathology foundation models. Our code is publicly available at https://github.com/bryanwong17/MIL-Feature-Extractor-Selection
Multiple instance learning (MIL) has emerged as a powerful framework for weakly supervised whole slide image (WSI) classification, enabling slide-level predictions without requiring detailed patch-level annotations. However, a key limitation of MIL lies in the underexplored potential of pre-training the MIL aggregator. Most existing approaches train it from scratch, resulting in performance heavily dependent on the number of labeled WSIs, while overlooking the abundance of unlabeled WSIs available in real-world scenarios. To address this, we propose PreMix, a novel framework that leverages a non-contrastive pre-training method, Barlow Twins, augmented with the Slide Mixing approach to generate additional positive pairs and enhance feature learning, particularly under limited labeled WSI conditions. Fine-tuning with Mixup and Manifold Mixup further enhances robustness by effectively handling the diverse sizes of gigapixel WSIs. Experimental results demonstrate that integrating HIPT into PreMix achieves an average F1 improvement of 4.7% over the baseline HIPT across various WSI training datasets and label sizes. These findings underscore its potential to advance WSI classification with limited labeled data and its applicability to real-world histopathology practices. The code is available at https://anonymous.4open.science/r/PreMix
Multiple Instance Learning (MIL) models have proven effective for cancer prognosis from Whole Slide Images. However, the original MIL formulation incorrectly assumes the patches of the same image to be independent, leading to a loss of spatial context as information flows through the network. Incorporating contextual knowledge into predictions is particularly important given the inclination for cancerous cells to form clusters and the presence of spatial indicators for tumors. State-of-the-art methods often use attention mechanisms eventually combined with graphs to capture spatial knowledge. In this paper, we take a novel and transversal approach, addressing this issue through the lens of regularization. We propose Context-Aware Regularization for Multiple Instance Learning (CARMIL), a versatile regularization scheme designed to seamlessly integrate spatial knowledge into any MIL model. Additionally, we present a new and generic metric to quantify the Context-Awareness of any MIL model when applied to Whole Slide Images, resolving a previously unexplored gap in the field. The efficacy of our framework is evaluated for two survival analysis tasks on glioblastoma (TCGA GBM) and colon cancer data (TCGA COAD).
Current histopathology research has primarily focused on using whole-slide images (WSIs) produced by scanners with weakly-supervised multiple instance learning (MIL). However, WSIs are costly, memory-intensive, and require extensive analysis time. As an alternative, microscopy-based analysis offers cost and memory efficiency, though microscopy images face issues with unknown absolute positions and redundant images due to multiple captures from the subjective perspectives of pathologists. To this end, we introduce MicroMIL, a weakly-supervised MIL framework specifically built to address these challenges by dynamically clustering images using deep cluster embedding (DCE) and Gumbel Softmax for representative image extraction. Graph edges are then constructed from the upper triangular similarity matrix, with nodes connected to their most similar neighbors, and a graph neural network (GNN) is utilized to capture local and diverse areas of contextual information. Unlike existing graph-based MIL methods designed for WSIs that require absolute positions, MicroMIL efficiently handles the graph edges without this need. Extensive evaluations on real-world colon cancer (Seegene) and public BreakHis datasets demonstrate that MicroMIL outperforms state-of-the-art (SOTA) methods, offering a robust and efficient solution for patient diagnosis using microscopy images. The code is available at https://anonymous.4open.science/r/MicroMIL-6C7C
Bevacizumab is a widely studied targeted therapeutic drug used in conjunction with standard chemotherapy for the treatment of recurrent ovarian cancer. While its administration has shown to increase the progression-free survival (PFS) in patients with advanced stage ovarian cancer, the lack of identifiable biomarkers for predicting patient response has been a major roadblock in its effective adoption towards personalized medicine. In this work, we leverage the latest histopathology foundation models trained on large-scale whole slide image (WSI) datasets to extract ovarian tumor tissue features for predicting bevacizumab response from WSIs. Our extensive experiments across a combination of different histopathology foundation models and multiple instance learning (MIL) strategies demonstrate capability of these large models in predicting bevacizumab response in ovarian cancer patients with the best models achieving an AUC score of 0.86 and an accuracy score of 72.5%. Furthermore, our survival models are able to stratify high- and low-risk cases with statistical significance (p < 0.05) even among the patients with the aggressive subtype of high-grade serous ovarian carcinoma. This work highlights the utility of histopathology foundation models for the task of ovarian bevacizumab response prediction from WSIs. The high-attention regions of the WSIs highlighted by these models not only aid the model explainability but also serve as promising imaging biomarkers for treatment prognosis.
Multiple Instance Learning (MIL) has garnered widespread attention in the field of Whole Slide Image (WSI) classification as it replaces pixel-level manual annotation with diagnostic reports as labels, significantly reducing labor costs. Recent research has shown that bag-level MIL methods often yield better results because they can consider all patches of the WSI as a whole. However, a drawback of such methods is the incorporation of more redundant patches, leading to interference. To extract patches with high diagnostic value while excluding interfering patches to address this issue, we developed an attention-based feature distillation multi-instance learning (AFD-MIL) approach. This approach proposed the exclusion of redundant patches as a preprocessing operation in weakly supervised learning, directly mitigating interference from extensive noise. It also pioneers the use of attention mechanisms to distill features with high diagnostic value, as opposed to the traditional practice of indiscriminately and forcibly integrating all patches. Additionally, we introduced global loss optimization to finely control the feature distillation module. AFD-MIL is orthogonal to many existing MIL methods, leading to consistent performance improvements. This approach has surpassed the current state-of-the-art method, achieving 91.47% ACC (accuracy) and 94.29% AUC (area under the curve) on the Camelyon16 (Camelyon Challenge 2016, breast cancer), while 93.33% ACC and 98.17% AUC on the TCGA-NSCLC (The Cancer Genome Atlas Program: non-small cell lung cancer). Different feature distillation methods were used for the two datasets, tailored to the specific diseases, thereby improving performance and interpretability.
Multiple Instance Learning (MIL) represents the predominant framework in Whole Slide Image (WSI) classification, covering aspects such as sub-typing, diagnosis, and beyond. Current MIL models predominantly rely on instance-level features derived from pretrained models such as ResNet. These models segment each WSI into independent patches and extract features from these local patches, leading to a significant loss of global spatial context and restricting the model's focus to merely local features. To address this issue, we propose a novel MIL framework, named SAM-MIL, that emphasizes spatial contextual awareness and explicitly incorporates spatial context by extracting comprehensive, image-level information. The Segment Anything Model (SAM) represents a pioneering visual segmentation foundational model that can capture segmentation features without the need for additional fine-tuning, rendering it an outstanding tool for extracting spatial context directly from raw WSIs. Our approach includes the design of group feature extraction based on spatial context and a SAM-Guided Group Masking strategy to mitigate class imbalance issues. We implement a dynamic mask ratio for different segmentation categories and supplement these with representative group features of categories. Moreover, SAM-MIL divides instances to generate additional pseudo-bags, thereby augmenting the training set, and introduces consistency of spatial context across pseudo-bags to further enhance the model's performance. Experimental results on the CAMELYON-16 and TCGA Lung Cancer datasets demonstrate that our proposed SAM-MIL model outperforms existing mainstream methods in WSIs classification. Our open-source implementation code is is available at https://github.com/FangHeng/SAM-MIL.
Computer vision models are increasingly capable of classifying ovarian epithelial cancer subtypes, but they differ from pathologists by processing small tissue patches at a single resolution. Multi-resolution graph models leverage the spatial relationships of patches at multiple magnifications, learning the context for each patch. In this study, we conduct the most thorough validation of a graph model for ovarian cancer subtyping to date. Seven models were tuned and trained using five-fold cross-validation on a set of 1864 whole slide images (WSIs) from 434 patients treated at Leeds Teaching Hospitals NHS Trust. The cross-validation models were ensembled and evaluated using a balanced hold-out test set of 100 WSIs from 30 patients, and an external validation set of 80 WSIs from 80 patients in the Transcanadian Study. The best-performing model, a graph model using 10x+20x magnification data, gave balanced accuracies of 73%, 88%, and 99% in cross-validation, hold-out testing, and external validation, respectively. However, this only exceeded the performance of attention-based multiple instance learning in external validation, with a 93% balanced accuracy. Graph models benefitted greatly from using the UNI foundation model rather than an ImageNet-pretrained ResNet50 for feature extraction, with this having a much greater effect on performance than changing the subsequent classification approach. The accuracy of the combined foundation model and multi-resolution graph network offers a step towards the clinical applicability of these models, with a new highest-reported performance for this task, though further validations are still required to ensure the robustness and usability of the models.
Multiple instance learning (MIL) has been successfully applied for whole slide images (WSIs) analysis in computational pathology, enabling a wide range of prediction tasks from tumor subtyping to inferring genetic mutations and multi-omics biomarkers. However, existing MIL methods predominantly focus on single-task learning, resulting in not only overall low efficiency but also the overlook of inter-task relatedness. To address these issues, we proposed an adapted architecture of Multi-gate Mixture-of-experts with Multi-proxy for Multiple instance learning (M4), and applied this framework for simultaneous prediction of multiple genetic mutations from WSIs. The proposed M4 model has two main innovations: (1) utilizing a mixture of experts with multiple gating strategies for multi-genetic mutation prediction on a single pathological slide; (2) constructing multi-proxy expert network and gate network for comprehensive and effective modeling of pathological image information. Our model achieved significant improvements across five tested TCGA datasets in comparison to current state-of-the-art single-task methods. The code is available at:https://github.com/Bigyehahaha/M4.
Due to the lack of fine-grained annotation guidance, current Multiple Instance Learning (MIL) struggles to establish a robust causal relationship between Whole Slide Image (WSI) diagnosis and evidence sub-images, just like fully supervised learning. So many noisy images can undermine the network's prediction. The proposed Causal Inference Multiple Instance Learning (CI-MIL), uses out-of-distribution generalization to reduce the recognition confusion of sub-images by MIL network, without requiring pixelwise annotations. Specifically, feature distillation is introduced to roughly identify the feature representation of lesion patches. Then, in the random Fourier feature space, these features are re-weighted to minimize the cross-correlation, effectively correcting the feature distribution deviation. These processes reduce the uncertainty when tracing the prediction results back to patches. Predicted diagnoses are more direct and reliable because the causal relationship between them and diagnostic evidence images is more clearly recognized by the network. Experimental results demonstrate that CI-MIL outperforms state-of-the-art methods, achieving 92.25% accuracy and 95.28% AUC on the Camelyon16 dataset (breast cancer), while 94.29% accuracy and 98.07% AUC on the TCGA-NSCLC dataset (non-small cell lung cancer). Additionally, CI-MIL exhibits superior interpretability, as its selected regions demonstrate high consistency with ground truth annotations, promising more reliable diagnostic assistance for pathologists.
Current cervical cytopathology whole slide image (WSI) screening primarily relies on detection-based approaches, which are limited in performance due to the expense and time-consuming annotation process. Multiple Instance Learning (MIL), a weakly supervised approach that relies solely on bag-level labels, can effectively alleviate these challenges. Nonetheless, MIL commonly employs frozen pretrained models or self-supervised learning for feature extraction, which suffers from low efficacy or inefficiency. In this paper, we propose an efficient framework for cervical cytopathology WSI classification using only WSI-level labels through unsupervised and weakly supervised learning. Given the sparse and dispersed nature of abnormal cells within cytopathological WSIs, we propose a strategy that leverages the pretrained foundation model to filter the top$k$ high-risk patches. Subsequently, we suggest parameter-efficient fine-tuning (PEFT) of a large foundation model using contrastive learning on the filtered patches to enhance its representation ability for task-specific signals. By training only the added linear adapters, we enhance the learning of patch-level features with substantially reduced time and memory consumption. Experiments conducted on the CSD and FNAC 2019 datasets demonstrate that the proposed method enhances the performance of various MIL methods and achieves state-of-the-art (SOTA) performance. The code and trained models are publicly available at https://github.com/CVIU-CSU/TCT-InfoNCE.
Multiple instance learning (MIL) has been extensively applied to whole slide histopathology image (WSI) analysis. The existing aggregation strategy in MIL, which primarily relies on the first-order distance (e.g., mean difference) between instances, fails to accurately approximate the true feature distribution of each instance, leading to biased slide-level representations. Moreover, the scarcity of WSI observations easily leads to model overfitting, resulting in unstable testing performance and limited generalizability. To tackle these challenges, we propose a new Bayesian nonparametric framework for multiple instance learning, which adopts a cascade of Dirichlet processes (cDP) to incorporate the instance-to-bag characteristic of the WSIs. We perform feature aggregation based on the latent clusters formed by the Dirichlet process, which incorporates the covariances of the patch features and forms more representative clusters. We then perform bag-level prediction with another Dirichlet process model on the bags, which imposes a natural regularization on learning to prevent overfitting and enhance generalizability. Moreover, as a Bayesian nonparametric method, the cDP model can accurately generate posterior uncertainty, which allows for the detection of outlier samples and tumor localization. Extensive experiments on five WSI benchmarks validate the superior performance of our method, as well as its generalizability and ability to estimate uncertainties. Codes are available at https://github.com/HKU-MedAI/cDPMIL.
Segmenting tumors in histological images is vital for cancer diagnosis. While fully supervised models excel with pixel-level annotations, creating such annotations is labor-intensive and costly. Accurate histopathology image segmentation under weakly-supervised conditions with coarse-grained image labels is still a challenging problem. Although multiple instance learning (MIL) has shown promise in segmentation tasks, surprisingly, no previous pseudo-supervision methods have used MIL-based outputs as pseudo-masks for training. We suspect this stems from concerns over noises in MIL results affecting pseudo supervision quality. To explore the potential of leveraging MIL-based segmentation for pseudo supervision, we propose a novel distillation framework for histopathology image segmentation. This framework introduces a iterative fusion-knowledge distillation strategy, enabling the student model to learn directly from the teacher's comprehensive outcomes. Through dynamic role reversal between the fixed teacher and learnable student models and the incorporation of weighted cross-entropy loss for model optimization, our approach prevents performance deterioration and noise amplification during knowledge distillation. Experimental results on public histopathology datasets, Camelyon16 and Digestpath2019, demonstrate that our approach not only complements various MIL-based segmentation methods but also significantly enhances their performance. Additionally, our method achieves new SOTA in the field.
Slide-level classification for whole-slide images (WSIs) has been widely recognized as a crucial problem in digital and computational pathology. Current approaches commonly consider WSIs as a bag of cropped patches and process them via multiple instance learning due to the large number of patches, which cannot fully explore the relationship among patches; in other words, the global information cannot be fully incorporated into decision making. Herein, we propose an efficient and effective slide-level classification model, named as FALFormer, that can process a WSI as a whole so as to fully exploit the relationship among the entire patches and to improve the classification performance. FALFormer is built based upon Transformers and self-attention mechanism. To lessen the computational burden of the original self-attention mechanism and to process the entire patches together in a WSI, FALFormer employs Nystr\"om self-attention which approximates the computation by using a smaller number of tokens or landmarks. For effective learning, FALFormer introduces feature-aware landmarks to enhance the representation power of the landmarks and the quality of the approximation. We systematically evaluate the performance of FALFormer using two public datasets, including CAMELYON16 and TCGA-BRCA. The experimental results demonstrate that FALFormer achieves superior performance on both datasets, outperforming the state-of-the-art methods for the slide-level classification. This suggests that FALFormer can facilitate an accurate and precise analysis of WSIs, potentially leading to improved diagnosis and prognosis on WSIs.