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Stain variation is a phenomenon observed when distinct pathology laboratories stain tissue slides that exhibit similar but not identical color appearance. Due to this color shift between laboratories, convolutional neural networks (CNNs) trained with images from one lab often underperform on unseen images from the other lab. Several techniques have been proposed to reduce the generalization error, mainly grouped into two categories: stain color augmentation and stain color normalization. The former simulates a wide variety of realistic stain variations during training, producing stain-invariant CNNs. The latter aims to match training and test color distributions in order to reduce stain variation. For the first time, we compared some of these techniques and quantified their effect on CNN classification performance using a heterogeneous dataset of hematoxylin and eosin histopathology images from 4 organs and 9 pathology laboratories. Additionally, we propose a novel unsupervised method to perform stain color normalization using a neural network. Based on our experimental results, we provide practical guidelines on how to use stain color augmentation and stain color normalization in future computational pathology applications.

The Gleason score is the most important prognostic marker for prostate cancer patients, but it suffers from significant observer variability. Artificial intelligence (AI) systems based on deep learning can achieve pathologist-level performance at Gleason grading. However, the performance of such systems can degrade in the presence of artifacts, foreign tissue, or other anomalies. Pathologists integrating their expertise with feedback from an AI system could result in a synergy that outperforms both the individual pathologist and the system. Despite the hype around AI assistance, existing literature on this topic within the pathology domain is limited. We investigated the value of AI assistance for grading prostate biopsies. A panel of 14 observers graded 160 biopsies with and without AI assistance. Using AI, the agreement of the panel with an expert reference standard increased significantly (quadratically weighted Cohen's kappa, 0.799 vs. 0.872; p = 0.019). On an external validation set of 87 cases, the panel showed a significant increase in agreement with a panel of international experts in prostate pathology (quadratically weighted Cohen's kappa, 0.733 vs. 0.786; p = 0.003). In both experiments, on a grouplevel, AI-assisted pathologists outperformed the unassisted pathologists and the standalone AI system. Our results show the potential of AI systems for Gleason grading, but more importantly, show the benefits of pathologist-AI synergy. Members of the ISUP Pathology Imagebase Expert Panel are listed below Acknowledgements.

Given the importance of gland morphology in grading prostate cancer (PCa), automatically differentiating between epithelium and other tissues is an important prerequisite for the development of automated methods for detecting PCa. We propose a new deep learning method to segment epithelial tissue in digitised hematoxylin and eosin (H&E) stained prostatectomy slides using immunohistochemistry (IHC) as reference standard. We used IHC to create a precise and objective ground truth compared to manual outlining on H&E slides, especially in areas with high-grade PCa. 102 tissue sections were stained with H&E and subsequently restained with P63 and CK8/18 IHC markers to highlight epithelial structures. Afterwards each pair was co-registered. First, we trained a U-Net to segment epithelial structures in IHC using a subset of the IHC slides that were preprocessed with color deconvolution. Second, this network was applied to the remaining slides to create the reference standard used to train a second U-Net on H&E. Our system accurately segmented both intact glands and individual tumour epithelial cells. The generalisation capacity of our system is shown using an independent external dataset from a different centre. We envision this segmentation as the first part of a fully automated prostate cancer grading pipeline.

Artificial intelligence (AI) has shown promise for diagnosing prostate cancer in biopsies. However, results have been limited to individual studies, lacking validation in multinational settings. Competitions have been shown to be accelerators for medical imaging innovations, but their impact is hindered by lack of reproducibility and independent validation. With this in mind, we organized the PANDA challenge—the largest histopathology competition to date, joined by 1,290 developers—to catalyze development of reproducible AI algorithms for Gleason grading using 10,616 digitized prostate biopsies. We validated that a diverse set of submitted algorithms reached pathologist-level performance on independent cross-continental cohorts, fully blinded to the algorithm developers. On United States and European external validation sets, the algorithms achieved agreements of 0.862 (quadratically weighted κ, 95% confidence interval (CI), 0.840–0.884) and 0.868 (95% CI, 0.835–0.900) with expert uropathologists. Successful generalization across different patient populations, laboratories and reference standards, achieved by a variety of algorithmic approaches, warrants evaluating AI-based Gleason grading in prospective clinical trials.

Prostate cancer is the most prevalent cancer among men in Western countries, with 1.1 million new diagnoses every year. The gold standard for the diagnosis of prostate cancer is a pathologists' evaluation of prostate tissue.To potentially assist pathologists deep-learning-based cancer detection systems have been developed. Many of the state-ofthe-art models are patch-based convolutional neural networks, as the use of entire scanned slides is hampered by memory limitations on accelerator cards. Patch-based systems typically require detailed, pixel-level annotations for effective training. However, such annotations are seldom readily available, in contrast to the clinical reports of pathologists, which contain slide-level labels. As such, developing algorithms which do not require manual pixel-wise annotations, but can learn using only the clinical report would be a significant advancement for the field.In this paper, we propose to use a streaming implementation of convolutional layers, to train a modern CNN (ResNet-34) with 21 million parameters end-to-end on 4712 prostate biopsies. The method enables the use of entire biopsy images at highresolution directly by reducing the GPU memory requirements by 2.4 TB. We show that modern CNNs, trained using our streaming approach, can extract meaningful features from highresolution images without additional heuristics, reaching similar performance as state-of-the-art patch-based and multipleinstance learning methods. By circumventing the need for manual annotations, this approach can function as a blueprint for other tasks in histopathological diagnosis.

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Diagnosis and Gleason grading of prostate cancer in biopsies are critical for the clinical management of men with prostate cancer. Despite this, the high grading variability among pathologists leads to the potential for under-and overtreatment. Artificial intelligence (AI) systems have shown promise in assisting pathologists to perform Gleason grading, which could help address this problem. In this mini-review, we highlight studies reporting on the development of AI systems for cancer detection and Gleason grading, and discuss the progress needed for widespread clinical implementation, as well as anticipated future developments. Patient summary: This mini-review summarizes the evidence relating to the validation of artificial intelligence (AI)-assisted cancer detection and Gleason grading of prostate cancer in biopsies, and highlights the remaining steps required prior to its widespread clinical implementation. We found that, although there is strong evidence to show that AI is able to perform Gleason grading on par with experienced uropathologists, more work is needed to ensure the accuracy of results from AI systems in diverse settings across different patient populations, digitization platforms, and pathology laboratories.