Daniel Reisenbüchler

Sophia J. Wagner, Daniel Reisenbüchler, Nicholas P. West et al.

Background: Deep learning (DL) can extract predictive and prognostic biomarkers from routine pathology slides in colorectal cancer. For example, a DL test for the diagnosis of microsatellite instability (MSI) in CRC has been approved in 2022. Current approaches rely on convolutional neural networks (CNNs). Transformer networks are outperforming CNNs and are replacing them in many applications, but have not been used for biomarker prediction in cancer at a large scale. In addition, most DL approaches have been trained on small patient cohorts, which limits their clinical utility. Methods: In this study, we developed a new fully transformer-based pipeline for end-to-end biomarker prediction from pathology slides. We combine a pre-trained transformer encoder and a transformer network for patch aggregation, capable of yielding single and multi-target prediction at patient level. We train our pipeline on over 9,000 patients from 10 colorectal cancer cohorts. Results: A fully transformer-based approach massively improves the performance, generalizability, data efficiency, and interpretability as compared with current state-of-the-art algorithms. After training on a large multicenter cohort, we achieve a sensitivity of 0.97 with a negative predictive value of 0.99 for MSI prediction on surgical resection specimens. We demonstrate for the first time that resection specimen-only training reaches clinical-grade performance on endoscopic biopsy tissue, solving a long-standing diagnostic problem. Interpretation: A fully transformer-based end-to-end pipeline trained on thousands of pathology slides yields clinical-grade performance for biomarker prediction on surgical resections and biopsies. Our new methods are freely available under an open source license.

Daniel Reisenbüchler, Sophia J. Wagner, Melanie Boxberg et al.

Classical multiple instance learning (MIL) methods are often based on the identical and independent distributed assumption between instances, hence neglecting the potentially rich contextual information beyond individual entities. On the other hand, Transformers with global self-attention modules have been proposed to model the interdependencies among all instances. However, in this paper we question: Is global relation modeling using self-attention necessary, or can we appropriately restrict self-attention calculations to local regimes in large-scale whole slide images (WSIs)? We propose a general-purpose local attention graph-based Transformer for MIL (LA-MIL), introducing an inductive bias by explicitly contextualizing instances in adaptive local regimes of arbitrary size. Additionally, an efficiently adapted loss function enables our approach to learn expressive WSI embeddings for the joint analysis of multiple biomarkers. We demonstrate that LA-MIL achieves state-of-the-art results in mutation prediction for gastrointestinal cancer, outperforming existing models on important biomarkers such as microsatellite instability for colorectal cancer. Our findings suggest that local self-attention sufficiently models dependencies on par with global modules. Our LA-MIL implementation is available at https://github.com/agentdr1/LA_MIL.

Leiyue Zhao, Tianyu Shi, Daniel Reisenbuchler et al.

Instance-level quantification of kidney functional units is essential for morphometric analysis, yet most publicly available pathology datasets provide only semantic segmentation annotations, where adjacent structures of the same class are merged into single regions. This prevents reliable instance-level analysis and limits downstream quantitative studies. Existing heuristic post-processing methods often yield suboptimal instance separation, particularly in crowded and adherent regions, while deep learning-based instance segmentation approaches typically require intensive instance-level annotations that are costly and labor-intensive to obtain. We propose MORI-Seg, a deep learning framework that enables instance segmentation without requiring instance-level annotations. Instead of heuristic splitting or instance supervision, MORI-Seg learns morphology-aware geometric representations directly from semantic masks by jointly modeling object-centric distance fields and boundary-band representations to encode interior structure and contact interfaces. A class-conditioned feature disentanglement module further promotes intra-instance coherence and inter-instance separation. Under semantic-only supervision, MORI-Seg decomposes connected semantic regions into distinct instance masks in an end-to-end manner. Experiments demonstrate improved instance separation accuracy and more reliable morphometric quantification compared with classical post-processing pipelines and representative semantic-to-instance learning approaches. The official implementation is publicly available at https://github.com/ddrrnn123/MORI-Seg.

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.

Zhenhao Guo, Rachit Saluja, Tianyuan Yao et al.

Fine-grained glomerular subtyping is central to kidney biopsy interpretation, but clinically valuable labels are scarce and difficult to obtain. Existing computational pathology approaches instead tend to evaluate coarse diseased classification under full supervision with image-only models, so it remains unclear how vision-language models (VLMs) should be adapted for clinically meaningful subtyping under data constraints. In this work, we model fine-grained glomerular subtyping as a clinically realistic few-shot problem and systematically evaluate both pathology-specialized and general-purpose vision-language models under this setting. We assess not only classification performance (accuracy, AUC, F1) but also the geometry of the learned representations, examining feature alignment between image and text embeddings and the separability of glomerular subtypes. By jointly analyzing shot count, model architecture and domain knowledge, and adaptation strategy, this study provides guidance for future model selection and training under real clinical data constraints. Our results indicate that pathology-specialized vision-language backbones, when paired with the vanilla fine-tuning, are the most effective starting point. Even with only 4-8 labeled examples per glomeruli subtype, these models begin to capture distinctions and show substantial gains in discrimination and calibration, though additional supervision continues to yield incremental improvements. We also find that the discrimination between positive and negative examples is as important as image-text alignment. Overall, our results show that supervision level and adaptation strategy jointly shape both diagnostic performance and multimodal structure, providing guidance for model selection, adaptation strategies, and annotation investment.

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.

Pratibha Kumari, Daniel Reisenbüchler, Afshin Bozorgpour et al.

Rapid progress in vision-language modeling has enabled pathology report generation from gigapixel whole-slide images, but most approaches assume static training with simultaneous access to all data. In clinical deployment, however, new organs, institutions, and reporting conventions emerge over time, and sequential fine-tuning can cause catastrophic forgetting. We introduce an exemplar-free continual learning framework for WSI-to-report generation that avoids storing raw slides or patch exemplars. The core idea is a compact domain footprint built in a frozen patch-embedding space: a small codebook of representative morphology tokens together with slide-level co-occurrence summaries and lightweight patch-count priors. These footprints support generative replay by synthesizing pseudo-WSI representations that reflect domain-specific morphological mixtures, while a teacher snapshot provides pseudo-reports to supervise the updated model without retaining past data. To address shifting reporting conventions, we distill domain-specific linguistic characteristics into a compact style descriptor and use it to steer generation. At inference, the model identifies the most compatible descriptor directly from the slide signal, enabling domain-agnostic setup without requiring explicit domain identifiers. Evaluated across multiple public continual learning benchmarks, our approach outperforms exemplar-free and limited-buffer rehearsal baselines, highlighting footprint-based generative replay as a practical solution for deployment in evolving clinical settings.

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.