Toxicity Assessment in Preclinical Histopathology via Class-Aware Mahalanobis Distance for Known and Novel Anomalies

Safe deployment of AI methods in medicine requires robust guardrails that detect when input data deviate from the training distribution to ensure that models provide predictions only within their scope of expertise and abstain otherwise. Out-of-distribution (OOD) detection can provide such safeguards and is extensively studied in general computer vision. Yet, it remains underdeveloped in computational pathology, where gigapixel whole-slide images (WSIs), subtle differences between disease subtypes, and variability in tissue preparation pose unique challenges for conventional OOD methods. We propose ZIO, a training-free, multimodal OOD detector for pathology WSIs that leverages vision--language pathology foundation models (FMs). ZIO constructs text and visual prototypes of in-distribution classes and integrates their complementary information through a prototype shrinkage mechanism to derive OOD scores. We provide the ZIO formulation for both slide- and patch-level FMs. We evaluate ZIO across diverse clinically relevant domain shifts, including rare diseases and near-OOD settings. Extensive evaluation of over 14,700 WSIs from five independent consortia shows that ZIO consistently outperforms both unimodal prototypes and 40 state-of-the-art OOD methods. These results demonstrate the benefits of multimodal representation for OOD detection and pave the way towards safer AI deployment in clinical practice.

Foreground segmentation is the critical first step of every computational pathology pipeline, yet existing methods rely on hand-tuned heuristics or supervised models that overfit to narrow stain and scanner distributions, failing silently on specialised stains such as Jones silver or Elastica van Gieson. We propose a coarse-to-fine approach that recasts foreground segmentation as a visual perception task and leverages general-purpose vision-language models (VLMs) as zero-annotation oracles. Our key insight is that tissue-versus-background discrimination is a natural-image recognition problem, not a histopathological one, so VLMs trained on internet-scale corpora generalise where domain-specific models cannot. We introduce Leica-75, a benchmark of 75 renal transplant whole-slide images spanning three stain families. On Leica-75, our method achieves the highest segmentation quality on out-of-distribution stains (Dice 0.858 +/- 0.027 on Jones, 0.853 +/- 0.041 on EVG) with 7x lower cross-stain variance than the best supervised baseline, while remaining competitive on in-distribution H&E. Few-shot prompting with automatically curated exemplars (Auto-context) rescues hard cases on Stress-32 (n=32), a curated stress-test subset (Dice 0.470 to 0.819 for the 2B model). VLM-based annotation review matches human expert consensus (kappa=0.989 for blur detection; mean precision/recall grading accuracy 0.708 vs. human 0.646 for segmentation mask review). The resulting pseudo-labels are used to distil lightweight student models that are as performant as the teacher model while running for a fraction of the cost. Our framework provides a principled, scalable solution to a persistent infrastructure bottleneck in digital pathology.

Zero-shot anomaly localisation via vision-language models (VLMs) offers a compelling approach for rare pathology detection, yet its performance is fundamentally limited by the absence of healthy anatomical context. We reformulate zero-shot localisation as a comparative inference problem in which anomalies are identified through structured comparison against reference distributions of normal anatomy. We introduce WALDO, a training-free framework grounded in optimal transport theory that enables comparative reasoning through: (i) entropy-weighted Sliced Wasserstein distances for anatomically-aware reference selection from DINOv2 patch distributions, (ii) Goldilocks zone sampling exploiting the non-monotonic relationship between reference similarity and localisation accuracy, and (iii) self-consistency aggregation via weighted non-maximum suppression. We theoretically analyse the Goldilocks effect through distributional divergence, and show that references with moderate similarity minimize a bias-variance trade-off in comparative visual reasoning. On the NOVA brain MRI benchmark, WALDO with Qwen2.5-VL-72B achieves $43.5_{\pm1.6}\%$ mAP@30 (95% CI: [40.4, 46.7]), representing a 19% relative improvement over zero-shot baselines. Cross-model evaluation shows consistent gains: GPT-4o achieves $32.0_{\pm6.5}\%$ and Qwen3-VL-32B achieves $32.0_{\pm6.6}\%$ mAP@30. Paired McNemar tests confirm statistical significance ($p<0.01$). Source code is available at https://github.com/bkainz/WALDO_MICCAI26_demo .