Zhengjie Zhu

Yongxin Guo, Hao Lu, Onur Koyun et al.

Integrating transcriptomics and histopathology can improve cancer risk modelling, yet practical use is constrained by the limited availability of RNA profiling in routine settings. Here we introduce Mixture of Pathway Experts (MoPE), a knowledge-distillation framework that reframes multimodal learning as privileged distillation for histology-only inference. MoPE is motivated by the partial observability between RNA profiles and whole-slide images: histology can capture morphology-linked consequences of certain molecular programmes, but cannot be expected to reconstruct the full transcriptomic state. MoPE encodes RNA-derived pathways and transfers the molecular supervision to pathway-indexed pathology experts through memory-usage alignment. Across diverse public benchmarks and two independent breast cancer cohorts, MoPE consistently improved WSI-only inference performance relative to baseline methods. Pathway-usage analyses and human-audited visual inspection provide bounded inspection of model behaviour and candidate morphology-linked readouts. These results support pathway-structured privileged distillation as a promising route to using molecular information during training while preserving RNA-free inference.

Yi Lin, Zhongchen Zhao, Zhengjie ZHU et al.

Multiple instance learning (MIL) has emerged as a popular method for classifying histopathology whole slide images (WSIs). However, existing approaches typically rely on pre-trained models from large natural image datasets, such as ImageNet, to generate instance features, which can be sub-optimal due to the significant differences between natural images and histopathology images that lead to a domain shift. In this paper, we present a novel, simple yet effective method for learning domain-specific knowledge transformation from pre-trained models to histopathology images. Our approach entails using a prompt component to assist the pre-trained model in discerning differences between the pre-trained dataset and the target histopathology dataset, resulting in improved performance of MIL models. We validate our method on two publicly available datasets, Camelyon16 and TCGA-NSCLC. Extensive experimental results demonstrate the significant performance improvement of our method for different MIL models and backbones. Upon publication of this paper, we will release the source code for our method.

Jiabo Ma, Zhengrui Guo, Fengtao Zhou et al.

Foundation models pretrained on large-scale datasets are revolutionizing the field of computational pathology (CPath). The generalization ability of foundation models is crucial for the success in various downstream clinical tasks. However, current foundation models have only been evaluated on a limited type and number of tasks, leaving their generalization ability and overall performance unclear. To address this gap, we established a most comprehensive benchmark to evaluate the performance of off-the-shelf foundation models across six distinct clinical task types, encompassing a total of 72 specific tasks, including slide-level classification, survival prediction, ROI-tissue classification, ROI retrieval, visual question answering, and report generation. Our findings reveal that existing foundation models excel at certain task types but struggle to effectively handle the full breadth of clinical tasks. To improve the generalization of pathology foundation models, we propose a unified knowledge distillation framework consisting of both expert and self-knowledge distillation, where the former allows the model to learn from the knowledge of multiple expert models, while the latter leverages self-distillation to enable image representation learning via local-global alignment. Based on this framework, we curated a dataset of 96,000 whole slide images (WSIs) and developed a Generalizable Pathology Foundation Model (GPFM). This advanced model was trained on a substantial dataset comprising 190 million images extracted from approximately 72,000 publicly available slides, encompassing 34 major tissue types. Evaluated on the established benchmark, GPFM achieves an impressive average rank of 1.6, with 42 tasks ranked 1st, while the second-best model, UNI, attains an average rank of 3.7, with only 6 tasks ranked 1st.

Yongxin Guo, Hao Lu, Onur C. Koyun et al.

Multimodal learning that integrates genomics and histopathology has shown strong potential in cancer diagnosis, yet its clinical translation is hindered by the limited availability of paired histology-genomics data. Knowledge distillation (KD) offers a practical solution by transferring genomic supervision into histopathology models, enabling accurate inference using histology alone. However, existing KD methods rely on batch-local alignment, which introduces instability due to limited within-batch comparisons and ultimately degrades performance. To address these limitations, we propose Momentum Memory Knowledge Distillation (MoMKD), a cross-modal distillation framework driven by a momentum-updated memory. This memory aggregates genomic and histopathology information across batches, effectively enlarging the supervisory context available to each mini-batch. Furthermore, we decouple the gradients of the genomics and histology branches, preventing genomic signals from dominating histology feature learning during training and eliminating the modality-gap issue at inference time. Extensive experiments on the TCGA-BRCA benchmark (HER2, PR, and ODX classification tasks) and an independent in-house testing dataset demonstrate that MoMKD consistently outperforms state-of-the-art MIL and multimodal KD baselines, delivering strong performance and generalization under histology-only inference. Overall, MoMKD establishes a robust and generalizable knowledge distillation paradigm for computational pathology.

Hao Lu, Onur C. Koyun, Yongxin Guo et al.

Vector Quantization (VQ) underpins many modern generative frameworks such as VQ-VAE, VQ-GAN, and latent diffusion models. Yet, it suffers from the persistent problem of codebook collapse, where a large fraction of code vectors remains unused during training. This work provides a new theoretical explanation by identifying the nonstationary nature of encoder updates as the fundamental cause of this phenomenon. We show that as the encoder drifts, unselected code vectors fail to receive updates and gradually become inactive. To address this, we propose two new methods: Non-Stationary Vector Quantization (NSVQ), which propagates encoder drift to non-selected codes through a kernel-based rule, and Transformer-based Vector Quantization (TransVQ), which employs a lightweight mapping to adaptively transform the entire codebook while preserving convergence to the k-means solution. Experiments on the CelebA-HQ dataset demonstrate that both methods achieve near-complete codebook utilization and superior reconstruction quality compared to baseline VQ variants, providing a principled and scalable foundation for future VQ-based generative models. The code is available at: https://github.com/CAIR- LAB- WFUSM/NSVQ-TransVQ.git

Hao Lu, Onur C. Koyun, Yongxin Guo et al.

Vector-quantized autoencoders deliver high-fidelity latents but suffer inherent flaws: the quantizer is non-differentiable, requires straight-through hacks, and is prone to collapse. We address these issues at the root by replacing VQ with a simple, principled, and fully differentiable alternative: an online PCA bottleneck trained via Oja's rule. The resulting model, PCA-VAE, learns an orthogonal, variance-ordered latent basis without codebooks, commitment losses, or lookup noise. Despite its simplicity, PCA-VAE exceeds VQ-GAN and SimVQ in reconstruction quality on CelebAHQ while using 10-100x fewer latent bits. It also produces naturally interpretable dimensions (e.g., pose, lighting, gender cues) without adversarial regularization or disentanglement objectives. These results suggest that PCA is a viable replacement for VQ: mathematically grounded, stable, bit-efficient, and semantically structured, offering a new direction for generative models beyond vector quantization.

Hongyi Wang, Zhengjie Zhu, Jiabo Ma et al.

The rapid digitization of histopathology slides has opened up new possibilities for computational tools in clinical and research workflows. Among these, content-based slide retrieval stands out, enabling pathologists to identify morphologically and semantically similar cases, thereby supporting precise diagnoses, enhancing consistency across observers, and assisting example-based education. However, effective retrieval of whole slide images (WSIs) remains challenging due to their gigapixel scale and the difficulty of capturing subtle semantic differences amid abundant irrelevant content. To overcome these challenges, we present PathSearch, a retrieval framework that unifies fine-grained attentive mosaic representations with global-wise slide embeddings aligned through vision-language contrastive learning. Trained on a corpus of 6,926 slide-report pairs, PathSearch captures both fine-grained morphological cues and high-level semantic patterns to enable accurate and flexible retrieval. The framework supports two key functionalities: (1) mosaic-based image-to-image retrieval, ensuring accurate and efficient slide research; and (2) multi-modal retrieval, where text queries can directly retrieve relevant slides. PathSearch was rigorously evaluated on four public pathology datasets and three in-house cohorts, covering tasks including anatomical site retrieval, tumor subtyping, tumor vs. non-tumor discrimination, and grading across diverse organs such as breast, lung, kidney, liver, and stomach. External results show that PathSearch outperforms traditional image-to-image retrieval frameworks. A multi-center reader study further demonstrates that PathSearch improves diagnostic accuracy, boosts confidence, and enhances inter-observer agreement among pathologists in real clinical scenarios. These results establish PathSearch as a scalable and generalizable retrieval solution for digital pathology.

Yi Lin, Zhengjie Zhu, Kwang-Ting Cheng et al.

Multiple instance learning (MIL) has emerged as a popular method for classifying histopathology whole slide images (WSIs). Existing approaches typically rely on frozen pre-trained models to extract instance features, neglecting the substantial domain shift between pre-training natural and histopathological images. To address this issue, we propose PAMT, a novel Prompt-guided Adaptive Model Transformation framework that enhances MIL classification performance by seamlessly adapting pre-trained models to the specific characteristics of histopathology data. To capture the intricate histopathology distribution, we introduce Representative Patch Sampling (RPS) and Prototypical Visual Prompt (PVP) to reform the input data, building a compact while informative representation. Furthermore, to narrow the domain gap, we introduce Adaptive Model Transformation (AMT) that integrates adapter blocks within the feature extraction pipeline, enabling the pre-trained models to learn domain-specific features. We rigorously evaluate our approach on two publicly available datasets, Camelyon16 and TCGA-NSCLC, showcasing substantial improvements across various MIL models. Our findings affirm the potential of PAMT to set a new benchmark in WSI classification, underscoring the value of a targeted reprogramming approach.