Stain normalization reduces color variations caused by variations in staining protocols and imaging conditions, thereby enhancing computer-aided diagnostic system performance. Traditional methods derive mapping relationships from individual or limited reference images through pixel-wise transformation, offering style flexibility but suffering from inaccurate color mapping extraction. While existing deep-learning-based approaches achieve accurate dataset-wide color mapping through complex neural networks, they face challenges including computational inefficiency, artifact generation, and fixed normalization directions requiring model retraining for directional changes. To address these limitations, we propose StainPresetNet - a novel framework that combines structural preservation with dataset-level color mapping while maintaining computational efficiency. Our method implements pixel-wise normalization guided by preset reference images, enabling multi-directional adaptability without retraining. Evaluations on cytopathology and histopathology datasets demonstrate that StainPresetNet achieves superior color mapping accuracy compared to conventional methods, effectively improves classifier generalization in diagnostic tasks, and reduces computational overhead by 90\% versus existing deep learning approaches. The proposed preset-guided mechanism facilitates flexible adjustment of normalization directions through simple reference image replacement, overcoming the directional rigidity of current deep-learning-based solutions.
Baoshun Wang, Weiping Lin, Linwu Wang +3cs.CV cs.AI
Virtual staining aims to computationally generate target-stained histopathological images while reducing the cost and time associated with conventional staining procedures. However, existing methods rely predominantly on strictly paired and accurately registered training data, which are difficult and expensive to obtain in routine practice. To reduce this dependence, we propose a stable semi-supervised virtual staining framework that jointly exploits both limited paired data and abundant unpaired source images. Directly incorporating unpaired images is challenging because their generated results lack corresponding targets for supervision, potentially leading to unrealistic staining, morphological degradation, or even training collapse. To obtain reliable supervision from these images, Hessian-derived morphology preservation extracts structural cues from each source image and constrains the generated output to retain tissue morphology. Histopathological realism constraints further guide the output toward plausible target-stain characteristics, preventing the source-derived structural supervision from degenerating into contour enhancement or simple color transformation. Together, the two components suppress structural and appearance drift, stabilize semi-supervised stain translation, and promote the preservation of diagnostically relevant information. Extensive experiments on H&E-to-IHC translation for Ki67 and HER2, as well as FFPE-to-H&E translation, demonstrate consistent improvements in image quality, morphology preservation, robustness, and downstream diagnostic performance. Code will be available.
Visual classifiers are expected to generalize under data shifts, target shifts, and their combinations, yet most existing methods focus on domain invariance while failing to address intra-image predictive sufficiency. We investigate the structural hypothesis that each image contains a sample-adaptive oracle intra-image predictive subset sufficient for label prediction, while the remaining patches form non-essential complementary context that may correlate with the label. The theoretical analysis shows that restricting prediction to this oracle subset preserves the Bayes risk achievable by the full-patch representation while admitting a complexity bound that tightens with the oracle-subset size. Based on this view, we propose PatchGen, a text-free module that learns a sample-dependent soft predictive-subset mask as a task-driven proxy for the unobserved oracle subset mask. Specifically, histopathology visualizations suggest that PatchGen assigns higher scores to tumor-consistent regions than to some frequently co-occurring inflammatory context. Extensive experiments on natural and histopathological image benchmarks spanning all three shift settings show that PatchGen improves average performance over matched-backbone baselines in most evaluated configurations, enhances generalization to unknown classes, and remains competitive with vision-language methods without text supervision.
Unpaired image-to-image translation must decide, per image, what to change and what to preserve without paired supervision. Many diffusion-based unpaired translators control preservation through a single global noise or guidance value applied across the image, which cannot separate content to keep from appearance to change. We present PRISM, a GAN-free flow-matching framework that replaces this global control with a learned per-feature gate. The gate's spatial prior is derived from each source feature's standardized distance to the target feature distribution, so features far from the target are freed while target-consistent features are preserved. The same gate controls both the initialization, which mixes the real source latent with a task-matched corruption, and the transport timing during Ordinary Differential Equation (ODE) integration. The corruption is matched to the task, content-anchored (AdaIN) for structure-preserving translation and partially anchored for structure-changing translation, and the gate can be overridden locally at inference from text or a detector without retraining, preserving important structures of the original image while still generating realistic results. We evaluate PRISM on five natural and biomedical benchmarks (AFHQ cat->dog, CelebA-HQ appearance translation, day->night relighting, virtual staining, and breast frozen->permanent histopathology). Among the evaluated methods under a shared same-split protocol, PRISM attains the best Inception FID and KID on four benchmarks and a competitive result on the fifth, and on histopathology yields the nuclei-count ratio closest to the ideal, supporting a favorable balance between target realism and structural preservation.
Fuqiang Chen, Yifeng Wang, Hongpeng Wang +1cs.CV eess.IV
A unified multiplex virtual staining model enables scalable and non-destructive multiplex analysis from H&E slides while promoting parameter efficiency, shared pathological knowledge, and consistent cross-biomarker representations. However, in clinical practice, data for new biomarkers are typically acquired sequentially over time. Fine-tuning on such temporally arriving data leads to severe performance degradation on previously learned biomarkers, as sequential optimization disrupts the structured relationships among biomarker representations in the latent space. To address this issue, we propose ContiStain, an IHC multi-domain relational distillation framework for continual virtual staining. We first (i) construct a domain-aware structured feature space using a mixture-of-experts (MoE) feature extractor to reduce representation interference across biomarker domains. Based on this stabilized feature space, we then (ii) propose a relation-preserving distillation strategy that explicitly enforces the consistency of cross-domain token-level cosine similarity matrices between learned biomarker domains during continual adaptation. By maintaining cross-domain structural coherence, ContiStain mitigates forgetting while retaining adaptability to new domains. Experiments on the MIST dataset under a four-domain sequential virtual IHC staining setting show improved stability, reducing FID and ConchFID by 11.1 and 60.9 compared to sequential fine-tuning, enabling scalable and robust multi-domain virtual staining. Code is released at https://github.com/ccitachi/ContiStain.
Deep learning has demonstrated remarkable success in high-throughput histopathology image analysis. However, the performance of learning-based models critically depends on the quality and size of annotations by expert pathologists, which is a resource-intensive and time-consuming process. To address the limitations of data scarcity and annotation burden, several methods have been proposed to synthesize paired histopathology data. Nevertheless, these frameworks typically still require annotation data, albeit in reduced quantities, to impose structural constraints during training. In this work, we present CHIS, a plug-in framework that guides the sampling trajectory of a pretrained diffusion model through two key stages: structural initialization at the start and textural modulation during generation. The initial noise state is refined by fusing the phase information from a prior mask with the amplitude of Gaussian noise in the frequency domain, yielding a structurally informed starting point. During the reverse diffusion process, we adaptively modulate both coarse-grained and fine-grained textures at different wavelet decomposition levels. This enables a diffusion model pretrained solely on unlabeled images to generate outputs that align with prior structural masks while preserving the reference tissue style. We conducted extensive experiments demonstrating the superiority of CHIS in generation fidelity and its substantial benefits for downstream segmentation tasks. Code is available at https://github.com/IBIL-Code/CHIS.
Christian Zöllner, Mozzam Motiwala, Aysel Ahadova +4cs.CV cs.AI
Training of neural networks for histopathology classification tasks typically relies on data encoding into latent space, which reduces complexity and improves performance. There are several encoder networks available, either pretrained on general image datasets such as ImageNET, or specifically on histopathological images. Training of encoder networks should be adapted to downstream tasks, allowing encoding of biologic/diagnostic content while rendering networks invariant to label-irrelevant transformations. This paper investigates the effect of classical image transformation on the latent space, using networks provided by Lunit Inc. and Bioptimus, both focusing on pathological images, and by Meta Research Team. We assess variance of embeddings resulting from standard data transformations by comparing original and transformed image embeddings and by contrasting them with random, unrelated embeddings, using image tiles from hematoxylin/eosin-stained sections available in a colorectal tissue dataset and the publicly accessible TCGA dataset. Our findings show that embeddings of original and transformed images are closer to each other than to random embeddings, indicating robustness to transformations. However, they are not fully invariant, revealing that the encoder networks do not completely neutralize transformation effects in latent space, explaining why transformation-mediated augmentation of datasets can improve performance. Significant differences were observed between general and histopathology-specific encoder networks.
Duc T. Nguyen, Hoang-Long Nguyen, Thanh-Ha DO +1cs.CV
Existing weakly supervised semantic segmentation (WSSS) methods in computational pathology rely on a multi-stage paradigm: class activation map (CAM) generation, offline pseudo-mask refinement, and fully supervised retraining. While established, this decoupled approach presents fundamental limitations. The multi-stage process not only incurs high computational training costs but also suffers from error propagation: local texture biases in shallow CNN layers generate false-positive artifacts that subsequent refinement steps often fail to correct. To address these persistent challenges through a simple yet highly effective approach, we propose the Single-Stage Hierarchical Rectification (SSHR) framework. Rather than passively refining CAMs post-hoc, our method proactively purifies intermediate feature representations during the forward pass. We introduce a Hierarchical Feature Rectification Module (HFRM) that utilizes deep global semantic context to filter out local anomalies in shallow layers. This mechanism generates high-fidelity activation maps directly within a single training loop. Experiments on the LUAD-HistoSeg and BCSS datasets demonstrate that SSHR outperforms state-of-the-art multi-stage methods. Furthermore, SSHR reduces training duration by 2 to 5 times. This efficiency minimizes computational overhead and accelerates clinical translation for large-scale histopathology workflows. The code is available at: https://github.com/trongduc-nguyen/SSHR
Won June Cho, Daeky Jeong, Hyeongyeol Lim +1cs.CV cs.AI cs.CE cs.LG
Synthetic histopathology image generation addresses critical challenges in computational pathology, including patient privacy and the growing need for large-scale training data for foundation models. Latent diffusion models have dominated the image generation domain, with recent works emphasizing that the choice of latent space is critical to the quality of generated images. Existing state-of-the-art generative models in histopathology use pretrained Vision Foundation Models (VFMs) as conditioning signals, and we observe that this leads to "conditioning collapse," where the conditioning signal dominates the latent space and lowers the quality and diversity of generated samples. Therefore, we instead use pretrained histopathology VFMs as the latent space itself, leveraging their patch-token features that encode rich semantic information. We empirically show that these features are $\ell_2$-normalized and lie on the unit hypersphere $\mathcal{S}^{d-1}$ with strong angular dominance and intrinsic curvature, making them naturally suited for a Riemannian formulation. We therefore present STREAM, the first framework to apply Riemannian flow matching in the pathology domain. STREAM consists of two stages: 1) a bridge-type stochastic perturbation that establishes per-token rectifiability on $\mathcal{S}^{d-1}$ for training a Diffusion Transformer (DiT) in latent space, and 2) a novel anisotropic decoder that allocates robustness to low-energy directions of the velocity-field Jacobian while preserving fidelity along its high-energy directions. Together, STREAM achieves state-of-the-art reconstruction and generation performance on breast and colorectal cancer datasets. The code will be publicly released upon acceptance.