Peter J. Schüffler

Indu Joshi, Priyank Upadhya, Gaurav Kumar Nayak et al.

Federated learning is a promising direction to tackle the privacy issues related to sharing patients' sensitive data. Often, federated systems in the medical image analysis domain assume that the participating local clients are \textit{honest}. Several studies report mechanisms through which a set of malicious clients can be introduced that can poison the federated setup, hampering the performance of the global model. To overcome this, robust aggregation methods have been proposed that defend against those attacks. We observe that most of the state-of-the-art robust aggregation methods are heavily dependent on the distance between the parameters or gradients of malicious clients and benign clients, which makes them prone to local model poisoning attacks when the parameters or gradients of malicious and benign clients are close. Leveraging this, we introduce DISBELIEVE, a local model poisoning attack that creates malicious parameters or gradients such that their distance to benign clients' parameters or gradients is low respectively but at the same time their adverse effect on the global model's performance is high. Experiments on three publicly available medical image datasets demonstrate the efficacy of the proposed DISBELIEVE attack as it significantly lowers the performance of the state-of-the-art \textit{robust aggregation} methods for medical image analysis. Furthermore, compared to state-of-the-art local model poisoning attacks, DISBELIEVE attack is also effective on natural images where we observe a severe drop in classification performance of the global model for multi-class classification on benchmark dataset CIFAR-10.

Glejdis Shkëmbi, Johanna P. Müller, Zhe Li et al.

Breast cancer is a major concern for women's health globally, with axillary lymph node (ALN) metastasis identification being critical for prognosis evaluation and treatment guidance. This paper presents a deep learning (DL) classification pipeline for quantifying clinical information from digital core-needle biopsy (CNB) images, with one step less than existing methods. A publicly available dataset of 1058 patients was used to evaluate the performance of different baseline state-of-the-art (SOTA) DL models in classifying ALN metastatic status based on CNB images. An extensive ablation study of various data augmentation techniques was also conducted. Finally, the manual tumor segmentation and annotation step performed by the pathologists was assessed.

Sameer Ambekar, Reza Nasirigerdeh, Peter J. Schuffler et al.

Model merging under unseen test-time distribution shifts often renders naive strategies, such as mean averaging unreliable. This challenge is especially acute in medical imaging, where models are fine-tuned locally at clinics on private data, producing domain-specific models that differ by scanner, protocol, and population. When deployed at an unseen clinical site, test cases arrive in unlabeled, non-i.i.d. batches, and the model must adapt immediately without labels. In this work, we introduce an entropy-adaptive, fully online model-merging method that yields a batch-specific merged model via only forward passes, effectively leveraging target information. We further demonstrate why mean merging is prone to failure and misaligned under heterogeneous domain shifts. Next, we mitigate encoder classifier mismatch by decoupling the encoder and classification head, merging with separate merging coefficients. We extensively evaluate our method with state-of-the-art baselines using two backbones across nine medical and natural-domain generalization image classification datasets, showing consistent gains across standard evaluation and challenging scenarios. These performance gains are achieved while retaining single-model inference at test-time, thereby demonstrating the effectiveness of our method.

Rajna Fani, Rafi Al Attrach, David Restrepo et al.

Masked autoencoders (MAEs) are increasingly applied to electronic health records (EHR) for learning general-purpose representations that support diverse clinical tasks. However, existing approaches typically rely on uniform random masking, implicitly assuming all features are equally predictable. In reality, laboratory tests exhibit substantial heterogeneity in volatility: some biomarkers (e.g., sodium) remain stable, while others (e.g., lactate) fluctuate considerably and are more difficult to model. Clinically, volatile biomarkers often signal acute pathophysiology and require more sophisticated modeling to capture their complex temporal patterns. We propose a volatility-aware pretraining strategy, Coefficient of Variation Masking (CV-Masking), that adaptively adjusts masking probabilities according to the intrinsic variability of each feature. Combined with a value-only masking objective aligned with clinical workflows, CV-Masking yields systematic improvements over random and variance-based strategies. Experiments on a large panel of laboratory tests show that CV-Masking enhances reconstruction, improves downstream predictive performance, and accelerates convergence, producing more robust and clinically meaningful EHR representations.

Zhengyang Xu, Han Li, Jingsong Liu et al.

Recent AI navigation approaches aim to improve Whole-Slide Image (WSI) diagnosis by modeling spatial exploration and selecting diagnostically relevant regions, yet most operate at a single fixed magnification or rely on predefined magnification traversal. In clinical practice, pathologists examine slides across multiple magnifications and selectively inspect only necessary scales, dynamically integrating global and cellular evidence in a sequential manner. This mismatch prevents existing methods from modeling cross-magnification interactions and adaptive magnification selection inherent to real diagnostic workflows. To these, we propose a clinically consistent Multi-Magnification WSI Navigation Agent (MMNavAgent) that explicitly models multi magnification interaction and adaptive magnification selection. Specifically, we introduce a Cross-Magnification navigation Tool (CMT) that aggregates contextual information from adjacent magnifications to enhance discriminative representations along the navigation path. We further introduce a Magnification Selection Tool (MST) that leverages memory-driven reasoning within the agent framework to enable interactive and adaptive magnification selection, mimicking the sequential decision process of pathologists. Extensive experiments on a public dataset demonstrate improved diagnostic performance, with 1.45% gain of AUC and 2.93% gain of BACC over a non-agent baseline. Code will be public upon acceptance.

Alexander Weers, Alexander H. Berger, Laurin Lux et al.

The histopathological analysis of whole-slide images (WSIs) is fundamental to cancer diagnosis but is a time-consuming and expert-driven process. While deep learning methods show promising results, dominant patch-based methods artificially fragment tissue, ignore biological boundaries, and produce black-box predictions. We overcome these limitations with a novel framework that transforms gigapixel WSIs into biologically-informed graph representations and is interpretable by design. Our approach builds graph nodes from tissue regions that respect natural structures, not arbitrary grids. We introduce an adaptive graph coarsening technique, guided by learned embeddings, to efficiently merge homogeneous regions while preserving diagnostically critical details in heterogeneous areas. Each node is enriched with a compact, interpretable feature set capturing clinically-motivated priors. A graph attention network then performs diagnosis on this compact representation. We demonstrate strong performance on challenging cancer staging and survival prediction tasks. Crucially, our resource-efficient model ($>$13x fewer parameters and $>$300x less data) achieves results competitive with a massive foundation model, while offering full interpretability through feature attribution. Our code is publicly available at https://github.com/HistoGraph31/pix2pathology.

Oskar Thaeter, Tanja Niedermair, Johannes Raffler et al.

Accurate annotation of fixation type is a critical step in slide preparation for pathology laboratories. However, this manual process is prone to errors, impacting downstream analyses and diagnostic accuracy. Existing methods for verifying formalin-fixed, paraffin-embedded (FFPE), and frozen section (FS) fixation types typically require full-resolution whole-slide images (WSIs), limiting scalability for high-throughput quality control. We propose a deep-learning model to predict fixation types using low-resolution, pre-scan thumbnail images. The model was trained on WSIs from the TUM Institute of Pathology (n=1,200, Leica GT450DX) and evaluated on a class-balanced subset of The Cancer Genome Atlas dataset (TCGA, n=8,800, Leica AT2), as well as on class-balanced datasets from Augsburg (n=695 [392 FFPE, 303 FS], Philips UFS) and Regensburg (n=202, 3DHISTECH P1000). Our model achieves an AUROC of 0.88 on TCGA, outperforming comparable pre-scan methods by 4.8%. It also achieves AUROCs of 0.72 on Regensburg and Augsburg slides, underscoring challenges related to scanner-induced domain shifts. Furthermore, the model processes each slide in 21 ms, $400\times$ faster than existing high-magnification, full-resolution methods, enabling rapid, high-throughput processing. This approach provides an efficient solution for detecting labelling errors without relying on high-magnification scans, offering a valuable tool for quality control in high-throughput pathology workflows. Future work will improve and evaluate the model's generalisation to additional scanner types. Our findings suggest that this method can increase accuracy and efficiency in digital pathology workflows and may be extended to other low-resolution slide annotations.

Rafi Al Attrach, Rajna Fani, David Restrepo et al.

Tokenization strategies shape how models process electronic health records, yet fair comparisons of their effectiveness remain limited. We present a systematic evaluation of tokenization approaches for clinical time series modeling using transformer-based architectures, revealing task-dependent and sometimes counterintuitive findings about temporal and value feature importance. Through controlled ablations across four clinical prediction tasks on MIMIC-IV, we demonstrate that explicit time encodings provide no consistent statistically significant benefit for the evaluated downstream tasks. Value features show task-dependent importance, affecting mortality prediction but not readmission, suggesting code sequences alone can carry sufficient predictive signal. We further show that frozen pretrained code encoders dramatically outperform their trainable counterparts while requiring dramatically fewer parameters. Larger clinical encoders provide consistent improvements across tasks, benefiting from frozen embeddings that eliminate computational overhead. Our controlled evaluation enables fairer tokenization comparisons and demonstrates that simpler, parameter-efficient approaches can, in many cases, achieve strong performance, though the optimal tokenization strategy remains task-dependent.

Oskar Thaeter, Christian Grashei, Anette Haas et al.

Stains are essential in histopathology to visualize specific tissue characteristics, with Haematoxylin and Eosin (H&E) serving as the clinical standard. However, pathologists frequently utilize a variety of special stains for the diagnosis of specific morphologies. Maintaining accurate metadata for these slides is critical for quality control in clinical archives and for the integrity of computational pathology datasets. In this work, we compare two approaches for automated classification of stains using whole slide images, covering the 14 most commonly used special stains in our institute alongside standard and frozen-section H&E. We evaluate a Multi-Instance Learning (MIL) pipeline and a proposed lightweight thumbnail-based approach. On internal test data, MIL achieved the highest performance (macro F1: 0.941 for 16 classes; 0.969 for 14 merged classes), while the thumbnail approach remained competitive (0.897 and 0.953, respectively). On external TCGA data, the thumbnail model generalized best (weighted F1: 0.843 vs. 0.807 for MIL). The thumbnail approach also increased throughput by two orders of magnitude (5.635 vs. 0.018 slides/s for MIL with all patches). We conclude that thumbnail-based classification provides a scalable and robust solution for routine visual quality control in digital pathology workflows.

Jingsong Liu, Han Li, Chen Yang et al.

Domain shift is a critical problem for pathology AI as pathology data is heavily influenced by center-specific conditions. Current pathology domain adaptation methods focus on image patches rather than WSI, thus failing to capture global WSI features required in typical clinical scenarios. In this work, we address the challenges of slide-level domain shift by proposing a Hierarchical Adaptation framework for Slide-level Domain-shift (HASD). HASD achieves multi-scale feature consistency and computationally efficient slide-level domain adaptation through two key components: (1) a hierarchical adaptation framework that integrates a Domain-level Alignment Solver for feature alignment, a Slide-level Geometric Invariance Regularization to preserve the morphological structure, and a Patch-level Attention Consistency Regularization to maintain local critical diagnostic cues; and (2) a prototype selection mechanism that reduces computational overhead. We validate our method on two slide-level tasks across five datasets, achieving a 4.1\% AUROC improvement in a Breast Cancer HER2 Grading cohort and a 3.9\% C-index gain in a UCEC survival prediction cohort. Our method provides a practical and reliable slide-level domain adaption solution for pathology institutions, minimizing both computational and annotation costs.

Ashkan Shakarami, Azade Farshad, Yousef Yeganeh et al.

We propose UTS, a unit-based tissue segmentation framework for histopathology that classifies each fixed-size 32 * 32 tile, rather than each pixel, as the segmentation unit. This approach reduces annotation effort and improves computational efficiency without compromising accuracy. To implement this approach, we introduce a Multi-Level Vision Transformer (L-ViT), which benefits the multi-level feature representation to capture both fine-grained morphology and global tissue context. Trained to segment breast tissue into three categories (infiltrating tumor, non-neoplastic stroma, and fat), UTS supports clinically relevant tasks such as tumor-stroma quantification and surgical margin assessment. Evaluated on 386,371 tiles from 459 H&E-stained regions, it outperforms U-Net variants and transformer-based baselines. Code and Dataset will be available at GitHub.

Zhe Li, Sarah Cechnicka, Cheng Ouyang et al.

As deep learning models grow in complexity and the volume of training data increases, reducing storage and computational costs becomes increasingly important. Dataset distillation addresses this challenge by synthesizing a compact set of synthetic data that can effectively replace the original dataset in downstream classification tasks. While existing methods typically rely on mapping data from pixel space to the latent space of a generative model, we propose a novel stochastic approach that models the joint distribution of latent features. This allows our method to better capture spatial structures and produce diverse synthetic samples, which benefits model training. Specifically, we introduce a low-rank multivariate normal distribution parameterized by a lightweight network. This design maintains low computational complexity and is compatible with various matching networks used in dataset distillation. After distillation, synthetic images are generated by feeding the learned latent features into a pretrained generator. These synthetic images are then used to train classification models, and performance is evaluated on real test set. We validate our method on several benchmarks, including ImageNet subsets, CIFAR-10, and the MedMNIST histopathological dataset. Our approach achieves state-of-the-art cross architecture performance across a range of backbone architectures, demonstrating its generality and effectiveness.

Maximilian Fischer, Peter Neher, Peter Schüffler et al.

Digital pathology offers a groundbreaking opportunity to transform clinical practice in histopathological image analysis, yet faces a significant hurdle: the substantial file sizes of pathological Whole Slide Images (WSI). While current digital pathology solutions rely on lossy JPEG compression to address this issue, lossy compression can introduce color and texture disparities, potentially impacting clinical decision-making. While prior research addresses perceptual image quality and downstream performance independently of each other, we jointly evaluate compression schemes for perceptual and downstream task quality on four different datasets. In addition, we collect an initially uncompressed dataset for an unbiased perceptual evaluation of compression schemes. Our results show that deep learning models fine-tuned for perceptual quality outperform conventional compression schemes like JPEG-XL or WebP for further compression of WSI. However, they exhibit a significant bias towards the compression artifacts present in the training data and struggle to generalize across various compression schemes. We introduce a novel evaluation metric based on feature similarity between original files and compressed files that aligns very well with the actual downstream performance on the compressed WSI. Our metric allows for a general and standardized evaluation of lossy compression schemes and mitigates the requirement to independently assess different downstream tasks. Our study provides novel insights for the assessment of lossy compression schemes for WSI and encourages a unified evaluation of lossy compression schemes to accelerate the clinical uptake of digital pathology.

Christian Grashei, Christian Brechenmacher, Rao Muhammad Umer et al.

Pathology foundation models (FMs) have driven significant progress in computational pathology. However, these high-performing models can easily exceed a billion parameters and produce high-dimensional embeddings, thus limiting their applicability for research or clinical use when computing resources are tight. Here, we introduce Pathryoshka, a multi-teacher distillation framework inspired by RADIO distillation and Matryoshka Representation Learning to reduce pathology FM sizes while allowing for adaptable embedding dimensions. We evaluate our framework with a distilled model on ten public pathology benchmarks with varying downstream tasks. Compared to its much larger teachers, Pathryoshka reduces the model size by 86-92% at on-par performance. It outperforms state-of-the-art single-teacher distillation models of comparable size by a median margin of 7.0 in accuracy. By enabling efficient local deployment without sacrificing accuracy or representational richness, Pathryoshka democratizes access to state-of-the-art pathology FMs for the broader research and clinical community.

Maximilian Fischer, Peter Neher, Tassilo Wald et al.

Processing histopathological Whole Slide Images (WSI) leads to massive storage requirements for clinics worldwide. Even after lossy image compression during image acquisition, additional lossy compression is frequently possible without substantially affecting the performance of deep learning-based (DL) downstream tasks. In this paper, we show that the commonly used JPEG algorithm is not best suited for further compression and we propose Stain Quantized Latent Compression (SQLC ), a novel DL based histopathology data compression approach. SQLC compresses staining and RGB channels before passing it through a compression autoencoder (CAE ) in order to obtain quantized latent representations for maximizing the compression. We show that our approach yields superior performance in a classification downstream task, compared to traditional approaches like JPEG, while image quality metrics like the Multi-Scale Structural Similarity Index (MS-SSIM) is largely preserved. Our method is online available.

Zhang Li, Jiehua Zhang, Tao Tan et al.

Accurate segmentation of lung cancer in pathology slides is a critical step in improving patient care. We proposed the ACDC@LungHP (Automatic Cancer Detection and Classification in Whole-slide Lung Histopathology) challenge for evaluating different computer-aided diagnosis (CADs) methods on the automatic diagnosis of lung cancer. The ACDC@LungHP 2019 focused on segmentation (pixel-wise detection) of cancer tissue in whole slide imaging (WSI), using an annotated dataset of 150 training images and 50 test images from 200 patients. This paper reviews this challenge and summarizes the top 10 submitted methods for lung cancer segmentation. All methods were evaluated using the false positive rate, false negative rate, and DICE coefficient (DC). The DC ranged from 0.7354$\pm$0.1149 to 0.8372$\pm$0.0858. The DC of the best method was close to the inter-observer agreement (0.8398$\pm$0.0890). All methods were based on deep learning and categorized into two groups: multi-model method and single model method. In general, multi-model methods were significantly better ($\textit{p}$<$0.01$) than single model methods, with mean DC of 0.7966 and 0.7544, respectively. Deep learning based methods could potentially help pathologists find suspicious regions for further analysis of lung cancer in WSI.

Peter J. Schüffler, Judy Sarungbam, Hassan Muhammad et al.

Accurate subtyping of renal cell carcinoma (RCC) is of crucial importance for understanding disease progression and for making informed treatment decisions. New discoveries of significant alterations to mitochondria between subtypes make immunohistochemical (IHC) staining based image classification an imperative. Until now, accurate quantification and subtyping was made impossible by huge IHC variations, the absence of cell membrane staining for cytoplasm segmentation as well as the complete lack of systems for robust and reproducible image based classification. In this paper we present a comprehensive classification framework to overcome these challenges for tissue microarrays (TMA) of RCCs. We compare and evaluate models based on domain specific hand-crafted "flat"-features versus "deep" feature representations from various layers of a pre-trained convolutional neural network (CNN). The best model reaches a cross-validation accuracy of 89%, which demonstrates for the first time, that robust mitochondria-based subtyping of renal cancer is feasible

Stefan Bauer, Nicolas Carion, Peter Schüffler et al.

Accurate and robust cell nuclei classification is the cornerstone for a wider range of tasks in digital and Computational Pathology. However, most machine learning systems require extensive labeling from expert pathologists for each individual problem at hand, with no or limited abilities for knowledge transfer between datasets and organ sites. In this paper we implement and evaluate a variety of deep neural network models and model ensembles for nuclei classification in renal cell cancer (RCC) and prostate cancer (PCa). We propose a convolutional neural network system based on residual learning which significantly improves over the state-of-the-art in cell nuclei classification. Finally, we show that the combination of tissue types during training increases not only classification accuracy but also overall survival analysis.