MUL-T: Decoding Spatial Cellular Architecture in Multiplexed Tissue Images
Authors: Farzaneh Seyedshahi, Kai Rakovic, Adalberto Claudio Quiros, John LeQuesne, Ke Yuan
Organizations: Cancer Research UK Scotland Institute, Glasgow, UK · University of Glasgow, Glasgow, UK
Abstract
Understanding tissue organisation in multiplexed imaging requires modelling both cellular phenotypes and their spatial context. Existing approaches typically rely on handcrafted features, such as marker intensity statistics or cell-type proportions, which often fail to scale or generalise across cohorts with heterogeneous marker panels. We introduce MUL-T, a lightweight transformer framework that reframes tissue architecture as a masked contextual prediction task over discrete cell tokens. By learning contextualised [CLS] embeddings without task-specific supervision, the model captures higher-order cellular interactions while remaining computationally efficient. We evaluate MUL-T on several clinically relevant downstream tasks, including core-level tumour pattern classification, patient-level grading, PD-L1 positivity prediction, and cross-dataset treatment response prediction. Across tasks, MUL-T consistently outperforms classical feature-based baselines and achieves performance comparable to a foundation ViT model, despite substantially fewer parameters and lower training cost.
Predicting distant metastasis from the digital H & E slides of the primary tumor is a critical yet challenging task in computational pathology. Multiple Instance Learning (MIL) approaches can attend to subdomains in whole slide images (WSIs) that harbor features of pre-metastatic cancer regions. However, conventional MIL models largely treat tissue patches as unordered bags, discarding the spatial layout that defines how these regions are arranged and interact across the tissue. We propose that metastatic risk is shaped not only by local patch appearance, but also by the geometric organization of patches in the WSI and the interaction between the tissue compartments. To this end, we introduce Distance-aware Tissue Modeling for Multiple Instance Learning (DTMF-MIL), a spatial MIL framework that reinforces feature embeddings with explicit distance priors. By computing signed distance functions (SDFs) to capture regions with similar features, and representing each patch with radial-basis distance responses and local SDF statistics, DTMF-MIL learns positions of patches with respect to regional interiors and boundaries. The interactions between similar patches are contextualized across local tissue neighborhoods and used to guide slide-level attention while pooling patch feature evidence for metastasis prediction. We evaluate DTMF-MIL for prediction of distant prostate cancer metastasis in an internal prostate needle-biopsy cohort (IPC) from a large hospital system and on public TCGA-COAD and TCGA-KIRC datasets across multiple pathology foundation-model backbones. Across most dataset, backbone, and metric combinations, DTMF-MIL achieves the strongest results consistently.
Sandesh Pokhrel, Hamid Manoochehri, Beatrice S Knudsen +1
Vision Transformers (ViTs) and their hierarchical variants have achieved strong performance in Computational Pathology (CPath). However, most are pre-trained on single-resolution Whole Slide Images (WSIs), limiting their generalization across arbitrary resolutions. Gigapixel WSIs inherently contain diagnostic patterns at multiple scales, including cellular morphologies, tissue architectures, and global context, mirroring how expert pathologists examine WSIs. We introduce Multi-Resolution Pyramid Transformer (MRPT), a model that hierarchically aggregates multi-resolution information from cellular to tissue and WSI levels. MRPT employs a biologically meaningful Consecutive Cross-Resolution Attention (CCRA) mechanism to capture scale-independent interactions and enforces multi-resolution semantic consistency by aligning embeddings across resolutions, yielding robust and generalizable WSI representations. Pre-trained in a multi-resolution self-supervised manner on 624M patches, 2.4M regions, and 36K WSIs, MRPT learns rich coarse-to-fine histopathology features. Extensive experiments on 34 diverse datasets show that MRPT surpasses recent foundation models and Multimodal Large Language Models (MLLMs) in cancer subtype classification, tissue phenotyping, and Visual Question Answering (VQA) for WSI understanding.
Basit Alawode, Moshira Ali Abdalla, Dwarikanath Mahapatra +2
Dense prediction is a fundamental requirement for many medical vision tasks such as medical image restoration, registration, and segmentation. The most popular vision model, Convolutional Neural Networks (CNNs), has reached bottlenecks due to the intrinsic locality of convolution operations. Recently, transformers have been widely adopted for dense prediction for their capability to capture long-range visual dependence. However, due to the high computational complexity and large memory consumption of self-attention operations, transformers are usually used at downsampled feature resolutions. Such usage cannot effectively leverage the tissue-level textural information available only at the full image resolution. This textural information is crucial for medical dense prediction as it can differentiate the subtle human anatomy in medical images. In this study, we hypothesize that Multi-layer Perceptrons (MLPs) are superior alternatives to transformers in medical dense prediction where tissue-level details dominate the performance, as MLPs enable long-range dependence at the full image resolution. To validate our hypothesis, we develop a full-resolution hierarchical MLP framework that uses MLPs beginning from the full image resolution. We evaluate this framework with various MLP blocks on a wide range of medical dense prediction tasks including restoration, registration, and segmentation. Extensive experiments on six public well-benchmarked datasets show that, by simply using MLPs at full resolution, our framework outperforms its CNN and transformer counterparts and achieves state-of-the-art performance on various medical dense prediction tasks.