Bladder cancer (BC) diagnosis and prediction of prognosis are hindered by subjective pathological evaluation, which may cause misdiagnosis and under-/over-treatment. Computational pathology (CPATH) can identify clinical outcome predictors, offering an objective approach to improve prognosis. However, a systematic review of CPATH in BC literature is lacking. Therefore, we present a comprehensive overview of studies that used CPATH in BC, analyzing 33 out of 2285 identified studies. Most studies analyzed regions of interest to distinguish normal versus tumor tissue and identify tumor grade/stage and tissue types (e.g., urothelium, stroma, and muscle). The cell’s nuclear area, shape irregularity, and roundness were the most promising markers to predict recurrence and survival based on selected regions of interest, with >80% accuracy. CPATH identified molecular subtypes by detecting features, e.g., papillary structures, hyperchromatic, and pleomorphic nuclei. Combining clinicopathological and image-derived features improved recurrence and survival prediction. However, due to the lack of outcome interpretability and independent test datasets, robustness and clinical applicability could not be ensured. The current literature demonstrates that CPATH holds the potential to improve BC diagnosis and prediction of prognosis. However, more robust, interpretable, accurate models and larger datasets—representative of clinical scenarios—are needed to address artificial intelligence’s reliability, robustness, and black box challenge.

The most prevalent form of bladder cancer is urothelial carcinoma, characterized by a high recurrence rate and substantial lifetime treatment costs for patients. Grading is a prime factor for patient risk stratification, although it suffers from inconsistencies and variations among pathologists. Moreover, absence of annotations in medical imaging renders it difficult to train deep learning models. To address these challenges, we introduce a pipeline designed for bladder cancer grading using histological slides. First, it extracts urothelium tissue tiles at different magnification levels, employing a convolutional neural network for processing for feature extraction. Then, it engages in the slide-level prediction process. It employs a nested multiple-instance learning approach with attention to predict the grade. To distinguish different levels of malignancy within specific regions of the slide, we include the origins of the tiles in our analysis. The attention scores at region level are shown to correlate with verified high-grade regions, giving some explainability to the model. Clinical evaluations demonstrate that our model consistently outperforms previous state-of-the-art methods, achieving an F1 score of 0.85.

We present a pioneering investigation into the application of deep learning techniques to analyze histopathological images for addressing the substantial challenge of automated prognostic prediction. Prognostic prediction poses a unique challenge as the ground truth labels are inherently weak, and the model must anticipate future events that are not directly observable in the image. To address this challenge, we propose a novel three-part framework comprising of a convolutional network based tissue segmentation algorithm for region of interest delineation, a contrastive learning module for feature extraction, and a nested multiple instance learning classification module. Our study explores the significance of various regions of interest within the histopathological slides and exploits diverse learning methods in real-world clinical scenarios. The pipeline is initially validated on artificially generated data and a simpler diagnostic task. Transitioning to prognostic prediction, tasks become more challenging. Employing bladder cancer as use case, our best models yield an AUC of 0.721 and 0.678 for recurrence and treatment outcome prediction respectively for a private data cohort. Altogether, this research serves as an initial investigation on the shortcomings of histopathological image analysis for treatment outcome prediction.

Strongly supervised learning requires detailed knowledge of truth labels at instance levels, and in many machine learning applications this is a major drawback. Multiple instance learning (MIL) is a popular weakly supervised learning method where truth labels are not available at instance level, but only at bag-of-instances level. However, sometimes the nature of the problem requires a more complex description, where a nested architecture of bag-of-bags at different levels can capture underlying relationships, like similar instances grouped together. Predicting the latent labels of instances or inner-bags might be as important as predicting the final bag-of-bags label but is lost in a straightforward nested setting. We propose a Nested Multiple Instance with Attention (NMIA) model architecture combining the concept of nesting with attention mechanisms. We show that NMIA performs as conventional MIL in simple scenarios and can grasp a complex scenario providing insights to the latent labels at different levels.