# Cluster-to-Conquer: A Framework for End-to-End Multi-Instance Learning for Whole Slide Image Classification

arXiv: https://arxiv.org/abs/2103.10626 · HTML: https://mlsanity.com/paper/2103.10626/

## Key facts

- Cited by 65 papers in the map (data through 14 Oct 2026).
- Builds on 12 of its 29 references that are in the map.
- First posted on arXiv 19 Mar 2021.

## Builds on (most cited first, 12 of 12)

- [Deep Residual Learning for Image Recognition](https://mlsanity.com/paper/1512.03385/) (2015)
- [Attention-based Deep Multiple Instance Learning](https://mlsanity.com/paper/1802.04712/) (2018)
- [Data Efficient and Weakly Supervised Computational Pathology on Whole Slide Images](https://mlsanity.com/paper/2004.09666/) (2020)
- [Dual-stream Multiple Instance Learning Network for Whole Slide Image Classification with Self-supervised Contrastive Learning](https://mlsanity.com/paper/2011.08939/) (2020)
- [Whole Slide Images based Cancer Survival Prediction using Attention Guided Deep Multiple Instance Learning Networks](https://mlsanity.com/paper/2009.11169/) (2020)
- [Patch-based Convolutional Neural Network for Whole Slide Tissue Image Classification](https://mlsanity.com/paper/1504.07947/) (2015)
- [Deep Learning for Identifying Metastatic Breast Cancer](https://mlsanity.com/paper/1606.05718/) (2016)
- [Neural Image Compression for Gigapixel Histopathology Image Analysis](https://mlsanity.com/paper/1811.02840/) (2018)
- [Semi-Supervised Histology Classification using Deep Multiple Instance Learning and Contrastive Predictive Coding](https://mlsanity.com/paper/1910.10825/) (2019)
- [Deep Weakly-Supervised Learning Methods for Classification and Localization in Histology Images: A Survey](https://mlsanity.com/paper/1909.03354/) (2019)
- [Multi-Instance Multi-Scale CNN for Medical Image Classification](https://mlsanity.com/paper/1907.02413/) (2019)
- [Deep Learning for Visual Recognition of Environmental Enteropathy and Celiac Disease](https://mlsanity.com/paper/1908.03272/) (2019)

## Built on by (most cited first, 30 of 65)

- [TransMIL: Transformer based Correlated Multiple Instance Learning for Whole Slide Image Classification](https://mlsanity.com/paper/2106.00908/) (2021)
- [DTFD-MIL: Double-Tier Feature Distillation Multiple Instance Learning for Histopathology Whole Slide Image Classification](https://mlsanity.com/paper/2203.12081/) (2022)
- [Interventional Bag Multi-Instance Learning On Whole-Slide Pathological Images](https://mlsanity.com/paper/2303.06873/) (2023)
- [Multimodal Optimal Transport-based Co-Attention Transformer with Global Structure Consistency for Survival Prediction](https://mlsanity.com/paper/2306.08330/) (2023)
- [Feature Re-Embedding: Towards Foundation Model-Level Performance in Computational Pathology](https://mlsanity.com/paper/2402.17228/) (2024)
- [Dynamic Graph Representation with Knowledge-aware Attention for Histopathology Whole Slide Image Analysis](https://mlsanity.com/paper/2403.07719/) (2024)
- [Advances in Medical Image Analysis with Vision Transformers: A Comprehensive Review](https://mlsanity.com/paper/2301.03505/) (2023)
- [Multiple Instance Learning Framework with Masked Hard Instance Mining for Whole Slide Image Classification](https://mlsanity.com/paper/2307.15254/) (2023)
- [Multiple Instance Learning for Digital Pathology: A Review on the State-of-the-Art, Limitations & Future Potential](https://mlsanity.com/paper/2206.04425/) (2022)
- [Bi-directional Weakly Supervised Knowledge Distillation for Whole Slide Image Classification](https://mlsanity.com/paper/2210.03664/) (2022)
- [DGMIL: Distribution Guided Multiple Instance Learning for Whole Slide Image Classification](https://mlsanity.com/paper/2206.08861/) (2022)
- [Towards Label-efficient Automatic Diagnosis and Analysis: A Comprehensive Survey of Advanced Deep Learning-based Weakly-supervised, Semi-supervised and Self-supervised Techniques in Histopathological Image Analysis](https://mlsanity.com/paper/2208.08789/) (2022)
- [An Aggregation of Aggregation Methods in Computational Pathology](https://mlsanity.com/paper/2211.01256/) (2022)
- [AMIGO: Sparse Multi-Modal Graph Transformer with Shared-Context Processing for Representation Learning of Giga-pixel Images](https://mlsanity.com/paper/2303.00865/) (2023)
- [xMIL: Insightful Explanations for Multiple Instance Learning in Histopathology](https://mlsanity.com/paper/2406.04280/) (2024)
- [CAMIL: Context-Aware Multiple Instance Learning for Cancer Detection and Subtyping in Whole Slide Images](https://mlsanity.com/paper/2305.05314/) (2023)
- [Shapley Values-enabled Progressive Pseudo Bag Augmentation for Whole Slide Image Classification](https://mlsanity.com/paper/2312.05490/) (2023)
- [AEM: Attention Entropy Maximization for Multiple Instance Learning based Whole Slide Image Classification](https://mlsanity.com/paper/2406.15303/) (2024)
- [MixUp-MIL: Novel Data Augmentation for Multiple Instance Learning and a Study on Thyroid Cancer Diagnosis](https://mlsanity.com/paper/2211.05862/) (2022)
- [Nested Multiple Instance Learning with Attention Mechanisms](https://mlsanity.com/paper/2111.00947/) (2021)
- [Detecting Heart Disease from Multi-View Ultrasound Images via Supervised Attention Multiple Instance Learning](https://mlsanity.com/paper/2306.00003/) (2023)
- [Advances in Multiple Instance Learning for Whole Slide Image Analysis: Techniques, Challenges, and Future Directions](https://mlsanity.com/paper/2408.09476/) (2024)
- [HistoTransfer: Understanding Transfer Learning for Histopathology](https://mlsanity.com/paper/2106.07068/) (2021)
- [SLPD: Slide-level Prototypical Distillation for WSIs](https://mlsanity.com/paper/2307.10696/) (2023)
- [MoMA: Momentum Contrastive Learning with Multi-head Attention-based Knowledge Distillation for Histopathology Image Analysis](https://mlsanity.com/paper/2308.16561/) (2023)
- [Nucleus-aware Self-supervised Pretraining Using Unpaired Image-to-image Translation for Histopathology Images](https://mlsanity.com/paper/2309.07394/) (2023)
- [Data efficient deep learning for medical image analysis: A survey](https://mlsanity.com/paper/2310.06557/) (2023)
- [SC-MIL: Sparsely Coded Multiple Instance Learning for Whole Slide Image Classification](https://mlsanity.com/paper/2311.00048/) (2023)
- [SAM-MIL: A Spatial Contextual Aware Multiple Instance Learning Approach for Whole Slide Image Classification](https://mlsanity.com/paper/2407.17689/) (2024)
- [Self-Supervision Enhances Instance-based Multiple Instance Learning Methods in Digital Pathology: A Benchmark Study](https://mlsanity.com/paper/2505.01109/) (2025)

## Abstract (arXiv)

In recent years, the availability of digitized Whole Slide Images (WSIs) has enabled the use of deep learning-based computer vision techniques for automated disease diagnosis. However, WSIs present unique computational and algorithmic challenges. WSIs are gigapixel-sized (~100K pixels), making them infeasible to be used directly for training deep neural networks. Also, often only slide-level labels are available for training as detailed annotations are tedious and can be time-consuming for experts. Approaches using multiple-instance learning (MIL) frameworks have been shown to overcome these challenges. Current state-of-the-art approaches divide the learning framework into two decoupled parts: a convolutional neural network (CNN) for encoding the patches followed by an independent aggregation approach for slide-level prediction. In this approach, the aggregation step has no bearing on the representations learned by the CNN encoder. We have proposed an end-to-end framework that clusters the patches from a WSI into k-groups, samples k' patches from each group for training, and uses an adaptive attention mechanism for slide level prediction; Cluster-to-Conquer (C2C). We have demonstrated that dividing a WSI into clusters can improve the model training by exposing it to diverse discriminative features extracted from the patches. We regularized the clustering mechanism by introducing a KL-divergence loss between the attention weights of patches in a cluster and the uniform distribution. The framework is optimized end-to-end on slide-level cross-entropy, patch-level cross-entropy, and KL-divergence loss (Implementation: https://github.com/YashSharma/C2C).