Friedrich Feuerhake

Raphael Schäfer, Till Nicke, Henning Höfener et al.

Foundational models, pretrained on a large scale, have demonstrated substantial success across non-medical domains. However, training these models typically requires large, comprehensive datasets, which contrasts with the smaller and more heterogeneous datasets common in biomedical imaging. Here, we propose a multi-task learning strategy that decouples the number of training tasks from memory requirements. We trained a Universal bioMedical PreTrained model (UMedPT) on a multi-task database including tomographic, microscopic, and X-ray images, with various labelling strategies such as classification, segmentation, and object detection. The UMedPT foundational model outperformed ImageNet pretraining and the previous state-of-the-art models. For tasks related to the pretraining database, it maintained its performance with only 1% of the original training data and without fine-tuning. For out-of-domain tasks it required not more than 50% of the original training data. In an external independent validation imaging features extracted using UMedPT proved to be a new standard for cross-center transferability.

Pratibha Kumari, Daniel Reisenbüchler, Lucas Luttner et al.

In recent years, there has been remarkable progress in the field of digital pathology, driven by the ability to model complex tissue patterns using advanced deep-learning algorithms. However, the robustness of these models is often severely compromised in the presence of data shifts (e.g., different stains, organs, centers, etc.). Alternatively, continual learning (CL) techniques aim to reduce the forgetting of past data when learning new data with distributional shift conditions. Specifically, rehearsal-based CL techniques, which store some past data in a buffer and then replay it with new data, have proven effective in medical image analysis tasks. However, privacy concerns arise as these approaches store past data, prompting the development of our novel Generative Latent Replay-based CL (GLRCL) approach. GLRCL captures the previous distribution through Gaussian Mixture Models instead of storing past samples, which are then utilized to generate features and perform latent replay with new data. We systematically evaluate our proposed framework under different shift conditions in histopathology data, including stain and organ shift. Our approach significantly outperforms popular buffer-free CL approaches and performs similarly to rehearsal-based CL approaches that require large buffers causing serious privacy violations.

Till Nicke, Jan Raphael Schaefer, Henning Hoefener et al.

Due to the increasing workload of pathologists, the need for automation to support diagnostic tasks and quantitative biomarker evaluation is becoming more and more apparent. Foundation models have the potential to improve generalizability within and across centers and serve as starting points for data efficient development of specialized yet robust AI models. However, the training foundation models themselves is usually very expensive in terms of data, computation, and time. This paper proposes a supervised training method that drastically reduces these expenses. The proposed method is based on multi-task learning to train a joint encoder, by combining 16 different classification, segmentation, and detection tasks on a total of 912,000 patches. Since the encoder is capable of capturing the properties of the samples, we term it the Tissue Concepts encoder. To evaluate the performance and generalizability of the Tissue Concepts encoder across centers, classification of whole slide images from four of the most prevalent solid cancers - breast, colon, lung, and prostate - was used. The experiments show that the Tissue Concepts model achieve comparable performance to models trained with self-supervision, while requiring only 6% of the amount of training patches. Furthermore, the Tissue Concepts encoder outperforms an ImageNet pre-trained encoder on both in-domain and out-of-domain data.

Jelica Vasiljević, Friedrich Feuerhake, Cédric Wemmert et al.

Virtual stain transfer is a promising area of research in Computational Pathology, which has a great potential to alleviate important limitations when applying deeplearningbased solutions such as lack of annotations and sensitivity to a domain shift. However, in the literature, the majority of virtual staining approaches are trained for a specific staining or stain combination, and their extension to unseen stainings requires the acquisition of additional data and training. In this paper, we propose HistoStarGAN, a unified framework that performs stain transfer between multiple stainings, stain normalisation and stain invariant segmentation, all in one inference of the model. We demonstrate the generalisation abilities of the proposed solution to perform diverse stain transfer and accurate stain invariant segmentation over numerous unseen stainings, which is the first such demonstration in the field. Moreover, the pre-trained HistoStar-GAN model can serve as a synthetic data generator, which paves the way for the use of fully annotated synthetic image data to improve the training of deep learning-based algorithms. To illustrate the capabilities of our approach, as well as the potential risks in the microscopy domain, inspired by applications in natural images, we generated KidneyArtPathology, a fully annotated artificial image dataset for renal pathology.

Zeeshan Nisar, Friedrich Feuerhake, Thomas Lampert

A key challenge in segmentation in digital histopathology is inter- and intra-stain variations as it reduces model performance. Labelling each stain is expensive and time-consuming so methods using stain transfer via CycleGAN, have been developed for training multi-stain segmentation models using labels from a single stain. Nevertheless, CycleGAN tends to introduce noise during translation because of the one-to-many nature of some stain pairs, which conflicts with its cycle consistency loss. To address this, we propose the Domain Shift Aware CycleGAN, which reduces the presence of such noise. Furthermore, we evaluate several advances from the field of machine learning aimed at resolving similar problems and compare their effectiveness against DSA-CycleGAN in the context of multi-stain glomeruli segmentation. Experiments demonstrate that DSA-CycleGAN not only improves segmentation performance in glomeruli segmentation but also outperforms other methods in reducing noise. This is particularly evident when translating between biologically distinct stains. The code is publicly available at https://github.com/zeeshannisar/DSA-CycleGAN.

Junzhuo Liu, Xuemei Du, Daniel Reisenbuchler et al.

Automatic integration of whole slide images (WSIs) and gene expression profiles has demonstrated substantial potential in precision clinical diagnosis and cancer progression studies. However, most existing studies focus on individual gene sequences and slide level classification tasks, with limited attention to spatial transcriptomics and patch level applications. To address this limitation, we propose a multimodal network, BioMorphNet, which automatically integrates tissue morphological features and spatial gene expression to support tissue classification and differential gene analysis. For considering morphological features, BioMorphNet constructs a graph to model the relationships between target patches and their neighbors, and adjusts the response strength based on morphological and molecular level similarity, to better characterize the tumor microenvironment. In terms of multimodal interactions, BioMorphNet derives clinical pathway features from spatial transcriptomic data based on a predefined pathway database, serving as a bridge between tissue morphology and gene expression. In addition, a novel learnable pathway module is designed to automatically simulate the biological pathway formation process, providing a complementary representation to existing clinical pathways. Compared with the latest morphology gene multimodal methods, BioMorphNet's average classification metrics improve by 2.67%, 5.48%, and 6.29% for prostate cancer, colorectal cancer, and breast cancer datasets, respectively. BioMorphNet not only classifies tissue categories within WSIs accurately to support tumor localization, but also analyzes differential gene expression between tissue categories based on prediction confidence, contributing to the discovery of potential tumor biomarkers.

Jan-Philipp Redlich, Friedrich Feuerhake, Stefan Nikolin et al.

Glioblastoma, IDH-wildtype (GBM-IDHwt) is the most common malignant brain tumor. Histomorphology is a crucial component of the integrated diagnosis of GBM-IDHwt. Artificial intelligence (AI) methods have shown promise to extract additional prognostic information from histological whole-slide images (WSI) of hematoxylin and eosin-stained glioblastoma tissue. Here, we present an explainable AI-based method to support systematic interpretation of histomorphological features associated with survival. It combines an explainable multiple instance learning (MIL) architecture with a sparse autoencoder (SAE) to relate human-interpretable visual patterns of tissue to survival. The MIL architecture directly identifies prognosis-relevant image tiles and the SAE maps these tiles post-hoc to visual patterns. The MIL method was trained and evaluated using a new real-world dataset that comprised 720 GBM-IDHwt cases from three hospitals and four cancer registries in Germany. The SAE was trained using 1878 WSIs of glioblastoma from five independent public data collections. Despite the many factors influencing survival time, our method showed some ability to discriminate between patients living less than 180 days or more than 360 days solely based on histomorphology (AUC: 0.67; 95% CI: 0.63-0.72). Cox proportional hazards regression confirmed a significant difference in survival time between the predicted groups after adjustment for established prognostic factors (hazard ratio: 1.47; 95% CI: 1.26-1.72). Our method identified multiple interpretable visual patterns associated with survival. Three neuropathologists separately found that 21 of the 24 most strongly associated patterns could be clearly attributed to seven histomorphological categories. Necrosis and hemorrhage appeared to be associated with shorter survival while highly cellular tumor areas were associated with longer survival.

Zeeshan Nisar, Friedrich Feuerhake, Thomas Lampert

Semantic segmentation under domain shift remains a fundamental challenge in computer vision, particularly when labelled training data is scarce. This challenge is particularly exemplified in histopathology image analysis, where the same tissue structures must be segmented across images captured under different imaging conditions (stains), each representing a distinct visual domain. Traditional deep learning methods like UNet require extensive labels, which is both costly and time-consuming, particularly when dealing with multiple domains (or stains). To mitigate this, various unsupervised domain adaptation based methods such as UDAGAN have been proposed, which reduce the need for labels by requiring only one (source) stain to be labelled. Nonetheless, obtaining source stain labels can still be challenging. This article shows that through self-supervised pre-training -- including SimCLR, BYOL, and a novel approach, HR-CS-CO -- the performance of these segmentation methods (UNet, and UDAGAN) can be retained even with 95% fewer labels. Notably, with self-supervised pre-training and using only 5% labels, the performance drops are minimal: 5.9% for UNet and 6.2% for UDAGAN, averaged over all stains, compared to their respective fully supervised counterparts (without pre-training, using 100% labels). Furthermore, these findings are shown to generalise beyond their training distribution to public benchmark datasets. Implementations and pre-trained models are publicly available \href{https://github.com/zeeshannisar/resource-effecient-multi-stain-kidney-glomeruli-segmentation.git}{online}.

Niklas Kormann, Masoud Ramuz, Zeeshan Nisar et al.

Graph Neural Networks (GNNs) have recently been found to excel in histopathology. However, an important histopathological task, where GNNs have not been extensively explored, is the classification of glomeruli health as an important indicator in nephropathology. This task presents unique difficulties, particularly for the graph construction, i.e., the identification of nodes, edges, and informative features. In this work, we propose a pipeline composed of different traditional and machine learning-based computer vision techniques to identify nodes, edges, and their corresponding features to form a heterogeneous graph. We then proceed to propose a novel heterogeneous GNN architecture for glomeruli classification, called HIEGNet, that integrates both glomeruli and their surrounding immune cells. Hence, HIEGNet is able to consider the immune environment of each glomerulus in its classification. Our HIEGNet was trained and tested on a dataset of Whole Slide Images from kidney transplant patients. Experimental results demonstrate that HIEGNet outperforms several baseline models and generalises best between patients among all baseline models. Our implementation is publicly available at https://github.com/nklsKrmnn/HIEGNet.git.

Junzhuo Liu, Markus Eckstein, Zhixiang Wang et al.

Spatial transcriptomics is a technology that captures gene expression levels at different spatial locations, widely used in tumor microenvironment analysis and molecular profiling of histopathology, providing valuable insights into resolving gene expression and clinical diagnosis of cancer. Due to the high cost of data acquisition, large-scale spatial transcriptomics data remain challenging to obtain. In this study, we develop a contrastive learning-based deep learning method to predict spatially resolved gene expression from whole-slide images. Evaluation across six different disease datasets demonstrates that, compared to existing studies, our method improves Pearson Correlation Coefficient (PCC) in the prediction of highly expressed genes, highly variable genes, and marker genes by 6.27%, 6.11%, and 11.26% respectively. Further analysis indicates that our method preserves gene-gene correlations and applies to datasets with limited samples. Additionally, our method exhibits potential in cancer tissue localization based on biomarker expression.

Pratibha Kumari, Daniel Reisenbüchler, Afshin Bozorgpour et al.

Whole slide image (WSI) classification has emerged as a powerful tool in computational pathology, but remains constrained by domain shifts, e.g., due to different organs, diseases, or institution-specific variations. To address this challenge, we propose an Attention-based Generative Latent Replay Continual Learning framework (AGLR-CL), in a multiple instance learning (MIL) setup for domain incremental WSI classification. Our method employs Gaussian Mixture Models (GMMs) to synthesize WSI representations and patch count distributions, preserving knowledge of past domains without explicitly storing original data. A novel attention-based filtering step focuses on the most salient patch embeddings, ensuring high-quality synthetic samples. This privacy-aware strategy obviates the need for replay buffers and outperforms other buffer-free counterparts while matching the performance of buffer-based solutions. We validate AGLR-CL on clinically relevant biomarker detection and molecular status prediction across multiple public datasets with diverse centers, organs, and patient cohorts. Experimental results confirm its ability to retain prior knowledge and adapt to new domains, offering an effective, privacy-preserving avenue for domain incremental continual learning in WSI classification.

Daniel Reisenbüchler, Lucas Luttner, Nadine S. Schaadt et al.

In computational pathology, deep learning (DL) models for tasks such as segmentation or tissue classification are known to suffer from domain shifts due to different staining techniques. Stain adaptation aims to reduce the generalization error between different stains by training a model on source stains that generalizes to target stains. Despite the abundance of target stain data, a key challenge is the lack of annotations. To address this, we propose a joint training between artificially labeled and unlabeled data including all available stained images called Unsupervised Latent Stain Adaptation (ULSA). Our method uses stain translation to enrich labeled source images with synthetic target images in order to increase the supervised signals. Moreover, we leverage unlabeled target stain images using stain-invariant feature consistency learning. With ULSA we present a semi-supervised strategy for efficient stain adaptation without access to annotated target stain data. Remarkably, ULSA is task agnostic in patch-level analysis for whole slide images (WSIs). Through extensive evaluation on external datasets, we demonstrate that ULSA achieves state-of-the-art (SOTA) performance in kidney tissue segmentation and breast cancer classification across a spectrum of staining variations. Our findings suggest that ULSA is an important framework for stain adaptation in computational pathology.

Jan-Philipp Redlich, Friedrich Feuerhake, Joachim Weis et al.

In recent years, the diagnosis of gliomas has become increasingly complex. Analysis of glioma histopathology images using artificial intelligence (AI) offers new opportunities to support diagnosis and outcome prediction. To give an overview of the current state of research, this review examines 83 publicly available research studies that have proposed AI-based methods for whole-slide histopathology images of human gliomas, covering the diagnostic tasks of subtyping (23/83), grading (27/83), molecular marker prediction (20/83), and survival prediction (29/83). All studies were reviewed with regard to methodological aspects as well as clinical applicability. It was found that the focus of current research is the assessment of hematoxylin and eosin-stained tissue sections of adult-type diffuse gliomas. The majority of studies (52/83) are based on the publicly available glioblastoma and low-grade glioma datasets from The Cancer Genome Atlas (TCGA) and only a few studies employed other datasets in isolation (16/83) or in addition to the TCGA datasets (15/83). Current approaches mostly rely on convolutional neural networks (63/83) for analyzing tissue at 20x magnification (35/83). A new field of research is the integration of clinical data, omics data, or magnetic resonance imaging (29/83). So far, AI-based methods have achieved promising results, but are not yet used in real clinical settings. Future work should focus on the independent validation of methods on larger, multi-site datasets with high-quality and up-to-date clinical and molecular pathology annotations to demonstrate routine applicability.

Jelica Vasiljević, Friedrich Feuerhake, Cédric Wemmert et al.

It has been shown that unpaired image-to-image translation methods constrained by cycle-consistency hide the information necessary for accurate input reconstruction as imperceptible noise. We demonstrate that, when applied to histopathology data, this hidden noise appears to be related to stain specific features and show that this is the case with two immunohistochemical stainings during translation to Periodic acid- Schiff (PAS), a histochemical staining method commonly applied in renal pathology. Moreover, by perturbing this hidden information, the translation models produce different, plausible outputs. We demonstrate that this property can be used as an augmentation method which, in a case of supervised glomeruli segmentation, leads to improved performance.

Jelica Vasiljević, Friedrich Feuerhake, Cédric Wemmert et al.

The application of supervised deep learning methods in digital pathology is limited due to their sensitivity to domain shift. Digital Pathology is an area prone to high variability due to many sources, including the common practice of evaluating several consecutive tissue sections stained with different staining protocols. Obtaining labels for each stain is very expensive and time consuming as it requires a high level of domain knowledge. In this article, we propose an unsupervised augmentation approach based on adversarial image-to-image translation, which facilitates the training of stain invariant supervised convolutional neural networks. By training the network on one commonly used staining modality and applying it to images that include corresponding, but differently stained, tissue structures, the presented method demonstrates significant improvements over other approaches. These benefits are illustrated in the problem of glomeruli segmentation in seven different staining modalities (PAS, Jones H&E, CD68, Sirius Red, CD34, H&E and CD3) and analysis of the learned representations demonstrate their stain invariance.

Odyssee Merveille, Thomas Lampert, Jessica Schmitz et al.

Objective: This article presents an automatic image processing framework to extract quantitative high-level information describing the micro-environment of glomeruli in consecutive whole slide images (WSIs) processed with different staining modalities of patients with chronic kidney rejection after kidney transplantation. Methods: This four-step framework consists of: 1) approximate rigid registration, 2) cell and anatomical structure segmentation 3) fusion of information from different stainings using a newly developed registration algorithm 4) feature extraction. Results: Each step of the framework is validated independently both quantitatively and qualitatively by pathologists. An illustration of the different types of features that can be extracted is presented. Conclusion: The proposed generic framework allows for the analysis of the micro-environment surrounding large structures that can be segmented (either manually or automatically). It is independent of the segmentation approach and is therefore applicable to a variety of biomedical research questions. Significance: Chronic tissue remodelling processes after kidney transplantation can result in interstitial fibrosis and tubular atrophy (IFTA) and glomerulosclerosis. This pipeline provides tools to quantitatively analyse, in the same spatial context, information from different consecutive WSIs and help researchers understand the complex underlying mechanisms leading to IFTA and glomerulosclerosis.

Thomas Lampert, Odyssée Merveille, Jessica Schmitz et al.

An important part of Digital Pathology is the analysis of multiple digitised whole slide images from differently stained tissue sections. It is common practice to mount consecutive sections containing corresponding microscopic structures on glass slides, and to stain them differently to highlight specific tissue components. These multiple staining modalities result in very different images but include a significant amount of consistent image information. Deep learning approaches have recently been proposed to analyse these images in order to automatically identify objects of interest for pathologists. These supervised approaches require a vast amount of annotations, which are difficult and expensive to acquire---a problem that is multiplied with multiple stainings. This article presents several training strategies that make progress towards stain invariant networks. By training the network on one commonly used staining modality and applying it to images that include corresponding but differently stained tissue structures, the presented unsupervised strategies demonstrate significant improvements over standard training strategies.

Daniel Bug, Steffen Schneider, Anne Grote et al.

While human observers are able to cope with variations in color and appearance of histological stains, digital pathology algorithms commonly require a well-normalized setting to achieve peak performance, especially when a limited amount of labeled data is available. This work provides a fully automated, end-to-end learning-based setup for normalizing histological stains, which considers the texture context of the tissue. We introduce Feature Aware Normalization, which extends the framework of batch normalization in combination with gating elements from Long Short-Term Memory units for normalization among different spatial regions of interest. By incorporating a pretrained deep neural network as a feature extractor steering a pixelwise processing pipeline, we achieve excellent normalization results and ensure a consistent representation of color and texture. The evaluation comprises a comparison of color histogram deviations, structural similarity and measures the color volume obtained by the different methods.