Jeroen van der Laak

Yiping Jiao, Jeroen van der Laak, Shadi Albarqouni et al. · eth-zurich

We introduce LYSTO, the Lymphocyte Assessment Hackathon, which was held in conjunction with the MICCAI 2019 Conference in Shenzen (China). The competition required participants to automatically assess the number of lymphocytes, in particular T-cells, in histopathological images of colon, breast, and prostate cancer stained with CD3 and CD8 immunohistochemistry. Differently from other challenges setup in medical image analysis, LYSTO participants were solely given a few hours to address this problem. In this paper, we describe the goal and the multi-phase organization of the hackathon; we describe the proposed methods and the on-site results. Additionally, we present post-competition results where we show how the presented methods perform on an independent set of lung cancer slides, which was not part of the initial competition, as well as a comparison on lymphocyte assessment between presented methods and a panel of pathologists. We show that some of the participants were capable to achieve pathologist-level performance at lymphocyte assessment. After the hackathon, LYSTO was left as a lightweight plug-and-play benchmark dataset on grand-challenge website, together with an automatic evaluation platform. LYSTO has supported a number of research in lymphocyte assessment in oncology. LYSTO will be a long-lasting educational challenge for deep learning and digital pathology, it is available at https://lysto.grand-challenge.org/.

Péter Bándi, Maschenka Balkenhol, Marcory van Dijk et al.

Recently, large, high-quality public datasets have led to the development of convolutional neural networks that can detect lymph node metastases of breast cancer at the level of expert pathologists. Many cancers, regardless of the site of origin, can metastasize to lymph nodes. However, collecting and annotating high-volume, high-quality datasets for every cancer type is challenging. In this paper we investigate how to leverage existing high-quality datasets most efficiently in multi-task settings for closely related tasks. Specifically, we will explore different training and domain adaptation strategies, including prevention of catastrophic forgetting, for colon and head-and-neck cancer metastasis detection in lymph nodes. Our results show state-of-the-art performance on both cancer metastasis detection tasks. Furthermore, we show the effectiveness of repeated adaptation of networks from one cancer type to another to obtain multi-task metastasis detection networks. Last, we show that leveraging existing high-quality datasets can significantly boost performance on new target tasks and that catastrophic forgetting can be effectively mitigated using regularization.

Michelle Stegeman, Lena Philipp, Fennie van der Graaf et al.

Medical foundation models show promise to learn broadly generalizable features from large, diverse datasets. This could be the base for reliable cross-modality generalization and rapid adaptation to new, task-specific goals, with only a few task-specific examples. Yet, evidence for this is limited by the lack of public, standardized, and reproducible evaluation frameworks, as existing public benchmarks are often fragmented across task-, organ-, or modality-specific settings, limiting assessment of cross-task generalization. We introduce UNICORN, a public benchmark designed to systematically evaluate medical foundation models under a unified protocol. To isolate representation quality, we built the benchmark on a novel two-step framework that decouples model inference from task-specific evaluation based on standardized few-shot adaptation. As a central design choice, we constructed indirectly accessible sequestered test sets derived from clinically relevant cohorts, along with standardized evaluation code and a submission interface on an open benchmarking platform. Performance is aggregated into a single UNICORN Score, a new metric that we introduce to support direct comparison of foundation models across diverse medical domains, modalities, and task types. The UNICORN test dataset includes data from more than 2,400 patients, including over 3,700 vision cases and over 2,400 clinical reports collected from 17 institutions across eight countries. The benchmark spans eight anatomical regions and four imaging modalities. Both task-specific and aggregated leaderboards enable accessible, standardized, and reproducible evaluation. By standardizing multi-task, multi-modality assessment, UNICORN establishes a foundation for reproducible benchmarking of medical foundation models. Data, baseline methods, and the evaluation platform are publicly available via unicorn.grand-challenge.org.

Clément Grisi, Khrystyna Faryna, Nefise Uysal et al.

Accurate prediction of biochemical recurrence (BCR) after radical prostatectomy is critical for guiding adjuvant treatment and surveillance decisions in prostate cancer. However, existing clinicopathological risk models reduce complex morphology to relatively coarse descriptors, leaving substantial prognostic information embedded in routine histopathology underexplored. We present a deep learning-based biomarker that predicts continuous, patient-specific risk of BCR directly from H&E-stained whole-slide prostatectomy specimens. Trained end-to-end on time-to-event outcomes and evaluated across four independent international cohorts, our model demonstrates robust generalization across institutions and patient populations. When integrated with the CAPRA-S clinical risk score, the deep learning risk score consistently improved discrimination for BCR, increasing concordance indices from 0.725-0.772 to 0.749-0.788 across cohorts. To support clinical interpretability, outcome-grounded analyses revealed subtle histomorphological patterns associated with recurrence risk that are not captured by conventional clinicopathological risk scores. This multicohort study demonstrates that deep learning applied to routine prostate histopathology can deliver reproducible and clinically generalizable biomarkers that augment postoperative risk stratification, with potential to support personalized management of prostate cancer in real-world clinical settings.

Sander Moonemans, Sebastiaan Ram, Frédérique Meeuwsen et al.

Vision-language models (VLMs) have the potential to become co-pilots for pathologists. However, most VLMs either focus on small regions of interest within whole-slide images, provide only static slide-level outputs, or rely on data that is not publicly available, limiting reproducibility. Furthermore, training data containing WSIs paired with detailed clinical reports is scarce, restricting progress toward transparent and generalisable VLMs. We address these limitations with three main contributions. First, we introduce Polysome, a standardised tool for synthetic instruction generation. Second, we apply Polysome to the public HISTAI dataset, generating HISTAI-Instruct, a large whole-slide instruction tuning dataset spanning 24,259 slides and over 1.1 million instruction-response pairs. Finally, we use HISTAI-Instruct to train ANTONI-α, a VLM capable of visual-question answering (VQA). We show that ANTONI-α outperforms MedGemma on WSI-level VQA tasks of tissue identification, neoplasm detection, and differential diagnosis. We also compare the performance of multiple incarnations of ANTONI-α trained with different amounts of data. All methods, data, and code are publicly available.

Nadieh Khalili, Joey Spronck, Francesco Ciompi et al.

Deep learning algorithms, often critiqued for their 'black box' nature, traditionally fall short in providing the necessary transparency for trusted clinical use. This challenge is particularly evident when such models are deployed in local hospitals, encountering out-of-domain distributions due to varying imaging techniques and patient-specific pathologies. Yet, this limitation offers a unique avenue for continual learning. The Uncertainty-Guided Annotation (UGA) framework introduces a human-in-the-loop approach, enabling AI to convey its uncertainties to clinicians, effectively acting as an automated quality control mechanism. UGA eases this interaction by quantifying uncertainty at the pixel level, thereby revealing the model's limitations and opening the door for clinician-guided corrections. We evaluated UGA on the Camelyon dataset for lymph node metastasis segmentation which revealed that UGA improved the Dice coefficient (DC), from 0.66 to 0.76 by adding 5 patches, and further to 0.84 with 10 patches. To foster broader application and community contribution, we have made our code accessible at

Marina D'Amato, Jeroen van der Laak, Francesco Ciompi

Accurate tumor detection in digital pathology whole-slide images (WSIs) is crucial for cancer diagnosis and treatment planning. Multiple Instance Learning (MIL) has emerged as a widely used approach for weakly-supervised tumor detection with large-scale data without the need for manual annotations. However, traditional MIL methods often depend on classification tasks that require tumor-free cases as negative examples, which are challenging to obtain in real-world clinical workflows, especially for surgical resection specimens. We address this limitation by reformulating tumor detection as a regression task, estimating tumor percentages from WSIs, a clinically available target across multiple cancer types. In this paper, we provide an analysis of the proposed weakly-supervised regression framework by applying it to multiple organs, specimen types and clinical scenarios. We characterize the robustness of our framework to tumor percentage as a noisy regression target, and introduce a novel concept of amplification technique to improve tumor detection sensitivity when learning from small tumor regions. Finally, we provide interpretable insights into the model's predictions by analyzing visual attention and logit maps. Our code is available at https://github.com/DIAGNijmegen/tumor-percentage-mil-regression.

Hans Pinckaers, Wouter Bulten, Jeroen van der Laak et al.

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-of-the-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 high-resolution 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 high-resolution images without additional heuristics, reaching similar performance as state-of-the-art patch-based and multiple-instance learning methods. By circumventing the need for manual annotations, this approach can function as a blueprint for other tasks in histopathological diagnosis. The source code to reproduce the streaming models is available at https://github.com/DIAGNijmegen/pathology-streaming-pipeline .

Carlijn Lems, Sander Moonemans, Natálie Klubíčková et al.

Foundation models with visual question answering capabilities for digital pathology are emerging. Such unprecedented technology requires independent benchmarking to assess its potential in assisting pathologists in routine diagnostics. We created DALPHIN, the first multicentric open benchmark for pathology AI copilots, comprising 1236 images from 300 cases, spanning 130 rare to common diagnoses, 6 countries, and 14 subspecialties. The DALPHIN design and dataset are introduced alongside a human performance benchmark of 31 pathologists from 10 countries with varying expertise. We report results for two general-purpose (GPT-5, Gemini 2.5 Pro) and one pathology-specific copilot (PathChat+) for sequential and independent answer generation. We observed no statistically significant difference from expert-level performance in four of six tasks for PathChat, 2/6 tasks for Gemini, and 1/6 tasks for GPT. DALPHIN is publicly released with sequestered, indirectly accessible ground truth to foster robust and enduring benchmarking. Data, methods, and the evaluation platform are accessible through dalphin.grand-challenge.org.

Clément Grisi, Geert Litjens, Jeroen van der Laak

Vision Transformers are at the heart of the current surge of interest in foundation models for histopathology. They process images by breaking them into smaller patches following a regular grid, regardless of their content. Yet, not all parts of an image are equally relevant for its understanding. This is particularly true in computational pathology where background is completely non-informative and may introduce artefacts that could mislead predictions. To address this issue, we propose a novel method that explicitly masks background in Vision Transformers' attention mechanism. This ensures tokens corresponding to background patches do not contribute to the final image representation, thereby improving model robustness and interpretability. We validate our approach using prostate cancer grading from whole-slide images as a case study. Our results demonstrate that it achieves comparable performance with plain self-attention while providing more accurate and clinically meaningful attention heatmaps.

Clément Grisi, Geert Litjens, Jeroen van der Laak

Vision Transformers (ViTs) have ushered in a new era in computer vision, showcasing unparalleled performance in many challenging tasks. However, their practical deployment in computational pathology has largely been constrained by the sheer size of whole slide images (WSIs), which result in lengthy input sequences. Transformers faced a similar limitation when applied to long documents, and Hierarchical Transformers were introduced to circumvent it. Given the analogous challenge with WSIs and their inherent hierarchical structure, Hierarchical Vision Transformers (H-ViTs) emerge as a promising solution in computational pathology. This work delves into the capabilities of H-ViTs, evaluating their efficiency for prostate cancer grading in WSIs. Our results show that they achieve competitive performance against existing state-of-the-art solutions.

Carlijn Lems, Leslie Tessier, John-Melle Bokhorst et al.

Automated semantic segmentation of whole-slide images (WSIs) stained with hematoxylin and eosin (H&E) is essential for large-scale artificial intelligence-based biomarker analysis in breast cancer. However, existing public datasets for breast cancer segmentation lack the morphological diversity needed to support model generalizability and robust biomarker validation across heterogeneous patient cohorts. We introduce BrEast cancEr hisTopathoLogy sEgmentation (BEETLE), a dataset for multiclass semantic segmentation of H&E-stained breast cancer WSIs. It consists of 587 biopsies and resections from three collaborating clinical centers and two public datasets, digitized using seven scanners, and covers all molecular subtypes and histological grades. Using diverse annotation strategies, we collected annotations across four classes - invasive epithelium, non-invasive epithelium, necrosis, and other - with particular focus on morphologies underrepresented in existing datasets, such as ductal carcinoma in situ and dispersed lobular tumor cells. The dataset's diversity and relevance to the rapidly growing field of automated biomarker quantification in breast cancer ensure its high potential for reuse. Finally, we provide a well-curated, multicentric external evaluation set to enable standardized benchmarking of breast cancer segmentation models.

Artur Jurgas, Marek Wodzinski, Marina D'Amato et al.

The problem of artifacts in whole slide image acquisition, prevalent in both clinical workflows and research-oriented settings, necessitates human intervention and re-scanning. Overcoming this challenge requires developing quality control algorithms, that are hindered by the limited availability of relevant annotated data in histopathology. The manual annotation of ground-truth for artifact detection methods is expensive and time-consuming. This work addresses the issue by proposing a method dedicated to augmenting whole slide images with artifacts. The tool seamlessly generates and blends artifacts from an external library to a given histopathology dataset. The augmented datasets are then utilized to train artifact classification methods. The evaluation shows their usefulness in classification of the artifacts, where they show an improvement from 0.10 to 0.01 AUROC depending on the artifact type. The framework, model, weights, and ground-truth annotations are freely released to facilitate open science and reproducible research.

John-Melle Bokhorst, Iris D. Nagtegaal, Filippo Fraggetta et al.

Artificial Intelligence (AI) can potentially support histopathologists in the diagnosis of a broad spectrum of cancer types. In colorectal cancer (CRC), AI can alleviate the laborious task of characterization and reporting on resected biopsies, including polyps, the numbers of which are increasing as a result of CRC population screening programs, ongoing in many countries all around the globe. Here, we present an approach to address two major challenges in automated assessment of CRC histopathology whole-slide images. First, we present an AI-based method to segment multiple tissue compartments in the H\&E-stained whole-slide image, which provides a different, more perceptible picture of tissue morphology and composition. We test and compare a panel of state-of-the-art loss functions available for segmentation models, and provide indications about their use in histopathology image segmentation, based on the analysis of a) a multi-centric cohort of CRC cases from five medical centers in the Netherlands and Germany, and b) two publicly available datasets on segmentation in CRC. Second, we use the best performing AI model as the basis for a computer-aided diagnosis system (CAD) that classifies colon biopsies into four main categories that are relevant pathologically. We report the performance of this system on an independent cohort of more than 1,000 patients. The results show the potential of such an AI-based system to assist pathologists in diagnosis of CRC in the context of population screening. We have made the segmentation model available for research use on https://grand-challenge.org/algorithms/colon-tissue-segmentation/.

Johannes Lotz, Nick Weiss, Jeroen van der Laak et al.

Purpose: In digital histopathology, virtual multi-staining is important for diagnosis and biomarker research. Additionally, it provides accurate ground-truth for various deep-learning tasks. Virtual multi-staining can be obtained using different stains for consecutive sections or by re-staining the same section. Both approaches require image registration to compensate tissue deformations, but little attention has been devoted to comparing their accuracy. Approach: We compare variational image registration of consecutive and re-stained sections and analyze the effect of the image resolution which influences accuracy and required computational resources. We present a new hybrid dataset of re-stained and consecutive sections (HyReCo, 81 slide pairs, approx. 3000 landmarks) that we made publicly available and compare its image registration results to the automatic non-rigid histological image registration (ANHIR) challenge data (230 consecutive slide pairs). Results: We obtain a median landmark error after registration of 7.1 μm (HyReCo) and 16.0 μm (ANHIR) between consecutive sections. Between re-stained sections, the median registration error is 2.3 μm and 0.9 μm in the two subsets of the HyReCo dataset. We observe that deformable registration leads to lower landmark errors than affine registration in both cases, though the effect is smaller in re-stained sections. Conclusion: Deformable registration of consecutive and re-stained sections is a valuable tool for the joint analysis of different stains. Significance: While the registration of re-stained sections allows nucleus-level alignment which allows for a direct analysis of interacting biomarkers, consecutive sections only allow the transfer of region-level annotations. The latter can be achieved at low computational cost using coarser image resolutions.

Caner Mercan, Maschenka Balkenhol, Roberto Salgado et al.

Nuclear pleomorphism, defined herein as the extent of abnormalities in the overall appearance of tumor nuclei, is one of the components of the three-tiered breast cancer grading. Given that nuclear pleomorphism reflects a continuous spectrum of variation, we trained a deep neural network on a large variety of tumor regions from the collective knowledge of several pathologists, without constraining the network to the traditional three-category classification. We also motivate an additional approach in which we discuss the additional benefit of normal epithelium as baseline, following the routine clinical practice where pathologists are trained to score nuclear pleomorphism in tumor, having the normal breast epithelium for comparison. In multiple experiments, our fully-automated approach could achieve top pathologist-level performance in select regions of interest as well as at whole slide images, compared to ten and four pathologists, respectively.

Mart van Rijthoven, Maschenka Balkenhol, Karina Siliņa et al.

We propose HookNet, a semantic segmentation model for histopathology whole-slide images, which combines context and details via multiple branches of encoder-decoder convolutional neural networks. Concentricpatches at multiple resolutions with different fields of view are used to feed different branches of HookNet, and intermediate representations are combined via a hooking mechanism. We describe a framework to design and train HookNet for achieving high-resolution semantic segmentation and introduce constraints to guarantee pixel-wise alignment in feature maps during hooking. We show the advantages of using HookNet in two histopathology image segmentation tasks where tissue type prediction accuracy strongly depends on contextual information, namely (1) multi-class tissue segmentation in breast cancer and, (2) segmentation of tertiary lymphoid structures and germinal centers in lung cancer. Weshow the superiority of HookNet when compared with single-resolution U-Net models working at different resolutions as well as with a recently published multi-resolution model for histopathology image segmentation

David Tellez, Diederik Hoppener, Cornelis Verhoef et al.

We focus on the problem of training convolutional neural networks on gigapixel histopathology images to predict image-level targets. For this purpose, we extend Neural Image Compression (NIC), an image compression framework that reduces the dimensionality of these images using an encoder network trained unsupervisedly. We propose to train this encoder using supervised multitask learning (MTL) instead. We applied the proposed MTL NIC to two histopathology datasets and three tasks. First, we obtained state-of-the-art results in the Tumor Proliferation Assessment Challenge of 2016 (TUPAC16). Second, we successfully classified histopathological growth patterns in images with colorectal liver metastasis (CLM). Third, we predicted patient risk of death by learning directly from overall survival in the same CLM data. Our experimental results suggest that the representations learned by the MTL objective are: (1) highly specific, due to the supervised training signal, and (2) transferable, since the same features perform well across different tasks. Additionally, we trained multiple encoders with different training objectives, e.g. unsupervised and variants of MTL, and observed a positive correlation between the number of tasks in MTL and the system performance on the TUPAC16 dataset.

Wouter Bulten, Maschenka Balkenhol, Jean-Joël Awoumou Belinga et al.

While the Gleason score is the most important prognostic marker for prostate cancer patients, it suffers from significant observer variability. Artificial Intelligence (AI) systems, based on deep learning, have proven to 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 fourteen observers graded 160 biopsies with and without AI assistance. Using AI, the agreement of the panel with an expert reference standard significantly increased (quadratically weighted Cohen's kappa, 0.799 vs 0.872; p=0.018). Our results show the added value of AI systems for Gleason grading, but more importantly, show the benefits of pathologist-AI synergy.

Wouter Bulten, Hans Pinckaers, Hester van Boven et al.

The Gleason score is the most important prognostic marker for prostate cancer patients but suffers from significant inter-observer variability. We developed a fully automated deep learning system to grade prostate biopsies. The system was developed using 5834 biopsies from 1243 patients. A semi-automatic labeling technique was used to circumvent the need for full manual annotation by pathologists. The developed system achieved a high agreement with the reference standard. In a separate observer experiment, the deep learning system outperformed 10 out of 15 pathologists. The system has the potential to improve prostate cancer prognostics by acting as a first or second reader.

David Tellez, Geert Litjens, Peter Bandi et al.

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.

David Tellez, Geert Litjens, Jeroen van der Laak et al.

We propose Neural Image Compression (NIC), a two-step method to build convolutional neural networks for gigapixel image analysis solely using weak image-level labels. First, gigapixel images are compressed using a neural network trained in an unsupervised fashion, retaining high-level information while suppressing pixel-level noise. Second, a convolutional neural network (CNN) is trained on these compressed image representations to predict image-level labels, avoiding the need for fine-grained manual annotations. We compared several encoding strategies, namely reconstruction error minimization, contrastive training and adversarial feature learning, and evaluated NIC on a synthetic task and two public histopathology datasets. We found that NIC can exploit visual cues associated with image-level labels successfully, integrating both global and local visual information. Furthermore, we visualized the regions of the input gigapixel images where the CNN attended to, and confirmed that they overlapped with annotations from human experts.

David Tellez, Maschenka Balkenhol, Irene Otte-Holler et al.

Manual counting of mitotic tumor cells in tissue sections constitutes one of the strongest prognostic markers for breast cancer. This procedure, however, is time-consuming and error-prone. We developed a method to automatically detect mitotic figures in breast cancer tissue sections based on convolutional neural networks (CNNs). Application of CNNs to hematoxylin and eosin (H&E) stained histological tissue sections is hampered by: (1) noisy and expensive reference standards established by pathologists, (2) lack of generalization due to staining variation across laboratories, and (3) high computational requirements needed to process gigapixel whole-slide images (WSIs). In this paper, we present a method to train and evaluate CNNs to specifically solve these issues in the context of mitosis detection in breast cancer WSIs. First, by combining image analysis of mitotic activity in phosphohistone-H3 (PHH3) restained slides and registration, we built a reference standard for mitosis detection in entire H&E WSIs requiring minimal manual annotation effort. Second, we designed a data augmentation strategy that creates diverse and realistic H&E stain variations by modifying the hematoxylin and eosin color channels directly. Using it during training combined with network ensembling resulted in a stain invariant mitosis detector. Third, we applied knowledge distillation to reduce the computational requirements of the mitosis detection ensemble with a negligible loss of performance. The system was trained in a single-center cohort and evaluated in an independent multicenter cohort from The Cancer Genome Atlas on the three tasks of the Tumor Proliferation Assessment Challenge (TUPAC). We obtained a performance within the top-3 best methods for most of the tasks of the challenge.

Wouter Bulten, Péter Bándi, Jeffrey Hoven et al.

Prostate cancer (PCa) is graded by pathologists by examining the architectural pattern of cancerous epithelial tissue on hematoxylin and eosin (H&E) stained slides. Given the importance of gland morphology, automatically differentiating between glandular epithelial tissue and other tissues is an important prerequisite for the development of automated methods for detecting PCa. We propose a new method, using deep learning, for automatically segmenting epithelial tissue in digitized prostatectomy slides. We employed immunohistochemistry (IHC) to render the ground truth less subjective and more precise compared to manual outlining on H&E slides, especially in areas with high-grade and poorly differentiated PCa. Our dataset consisted of 102 tissue blocks, including both low and high grade PCa. From each block a single new section was cut, stained with H&E, scanned, restained using P63 and CK8/18 to highlight the epithelial structure, and scanned again. The H&E slides were co-registered to the IHC slides. On a subset of the IHC slides we applied color deconvolution, corrected stain errors manually, and trained a U-Net to perform segmentation of epithelial structures. Whole-slide segmentation masks generated by the IHC U-Net were used to train a second U-Net on H&E. Our system makes precise cell-level segmentations and segments both intact glands as well as individual (tumor) epithelial cells. We achieved an F1-score of 0.895 on a hold-out test set and 0.827 on an external reference set from a different center. We envision this segmentation as being the first part of a fully automated prostate cancer detection and grading pipeline.

Babak Ehteshami Bejnordi, Guido Zuidhof, Maschenka Balkenhol et al.

Automated classification of histopathological whole-slide images (WSI) of breast tissue requires analysis at very high resolutions with a large contextual area. In this paper, we present context-aware stacked convolutional neural networks (CNN) for classification of breast WSIs into normal/benign, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC). We first train a CNN using high pixel resolution patches to capture cellular level information. The feature responses generated by this model are then fed as input to a second CNN, stacked on top of the first. Training of this stacked architecture with large input patches enables learning of fine-grained (cellular) details and global interdependence of tissue structures. Our system is trained and evaluated on a dataset containing 221 WSIs of H&E stained breast tissue specimens. The system achieves an AUC of 0.962 for the binary classification of non-malignant and malignant slides and obtains a three class accuracy of 81.3% for classification of WSIs into normal/benign, DCIS, and IDC, demonstrating its potentials for routine diagnostics.

Péter Bándi, Rob van de Loo, Milad Intezar et al.

Tissue segmentation is an important pre-requisite for efficient and accurate diagnostics in digital pathology. However, it is well known that whole-slide scanners can fail in detecting all tissue regions, for example due to the tissue type, or due to weak staining because their tissue detection algorithms are not robust enough. In this paper, we introduce two different convolutional neural network architectures for whole slide image segmentation to accurately identify the tissue sections. We also compare the algorithms to a published traditional method. We collected 54 whole slide images with differing stains and tissue types from three laboratories to validate our algorithms. We show that while the two methods do not differ significantly they outperform their traditional counterpart (Jaccard index of 0.937 and 0.929 vs. 0.870, p < 0.01).

Francesco Ciompi, Oscar Geessink, Babak Ehteshami Bejnordi et al.

The development of reliable imaging biomarkers for the analysis of colorectal cancer (CRC) in hematoxylin and eosin (H&E) stained histopathology images requires an accurate and reproducible classification of the main tissue components in the image. In this paper, we propose a system for CRC tissue classification based on convolutional networks (ConvNets). We investigate the importance of stain normalization in tissue classification of CRC tissue samples in H&E-stained images. Furthermore, we report the performance of ConvNets on a cohort of rectal cancer samples and on an independent publicly available dataset of colorectal H&E images.

Babak Ehteshami Bejnordi, Jimmy Linz, Ben Glass et al.

Diagnosis of breast carcinomas has so far been limited to the morphological interpretation of epithelial cells and the assessment of epithelial tissue architecture. Consequently, most of the automated systems have focused on characterizing the epithelial regions of the breast to detect cancer. In this paper, we propose a system for classification of hematoxylin and eosin (H&E) stained breast specimens based on convolutional neural networks that primarily targets the assessment of tumor-associated stroma to diagnose breast cancer patients. We evaluate the performance of our proposed system using a large cohort containing 646 breast tissue biopsies. Our evaluations show that the proposed system achieves an area under ROC of 0.92, demonstrating the discriminative power of previously neglected tumor-associated stroma as a diagnostic biomarker.