LEMON: a foundation model for nuclear morphology in Computational Pathology
Authors: Loïc Chadoutaud, Alice Blondel, Hana Feki, Jacqueline Fontugne, Emmanuel Barillot, Thomas Walter
Organizations: Institut Curie, Paris, France · Mines Paris PSL, Centre for Computational Biology · INSERM U1331, Paris, France · Institut Curie, F-75005 Paris · Mines Paris PSL, Centre for Computational Biology (CBIO), F-75006 Paris · INSERM, U1331, F-75005 Paris · Institut Curie, U1353/UMR9029 IRIS, Equipe IMPACT, Paris, France · Department of Pathology, Université Paris-Saclay, UVSQ, Institut Curie, Saint-Cloud, France · Institut Curie, U1353/UMR9029 IRIS, Equipe IMPACT, F-75006 Paris
Computational pathology relies on effective representation learning to support cancer research and precision medicine. Although self-supervised learning has driven major progress at the patch and whole-slide image levels, representation learning at the single-cell level remains comparatively underexplored, despite its importance for characterizing cell types and cellular phenotypes. We introduce LEMON (Learning Embeddings from Morphology Of Nuclei), a self-supervised foundation model for scalable single-cell image representation learning. Trained on millions of cell images from diverse tissues and cancer types, LEMON learns robust and versatile morphological representations that support large-scale single-cell analyses in pathology. We evaluate LEMON on five benchmark datasets across a range of prediction tasks and show that it provides strong performance, highlighting its potential as a new paradigm for cell-level computational pathology. Model weights are available at https://huggingface.co/aliceblondel/LEMON.
Figures & tables
Figure 1: Overview of the LEMON framework.
MIDOG25
NuCLS
PanNuke
HEST-Bowel
HEST-Breast
HEST-Lung
bal acc
bal acc
bal acc
pcc
pcc
pcc
Embeddings
Natural images TL
Imagenet (ResNet-18)
0.577 (0.008)
0.693 (0.005)
0.56 (0.004)
0.114 (0.023)
0.113 (0.023)
0.083 (0.021)
Imagenet (ResNet-50)
0.603 (0.012)
0.711 (0.005)
0.587 (0.005)
0.12 (0.035)
0.124 (0.023)
0.091 (0.013)
Natural images FM
Table 1: Performance of pretraining strategy on downstream tasks. We report balanced accuracy for MIDOG25 (majority), NuCLS (super) and PanNuke (classification) and Pearson Correlation Coefficient for HEST (breast, lung, bowel). Values are mean (s.d.) over folds, best values are highlighted in bold.
Target
MIDOG25 (majority)
Metric
bal acc
f1 (weighted)
Embeddings
UNI-class (ViT-l/16)
0.539 (0.007)
0.834 (0.004)
UNI-center (ViT-l/16)
0.645 (0.019)
0.876 (0.007)
Virchow2-class (ViT-h/14)
0.538 (0.005)
0.833 (0.002)
Virchow2-center (ViT-h/14)
0.673 (0.017)
0.886 (0.006)
Table 2: Evaluation of representations from larger images ( 128×128 pixel crop size) with patch level foundation models on the MIDOG25 dataset
Figure 2: Performance of pretraining strategies versus Floating point operations. Left: mean balanced accuracy across NuCLS (super, main, raw), MIDOG25 and PanNuke for classification. Right: mean Pearson Correlation Coefficient across breast, lung, and bowel datasets for regression. Marker size indicates model parameter count; color indicates pretraining category.
Figure 3: Performance of models vs. training data composition. Mean balanced accuracy (error bars represents standard errors) across MIDOG25 and the three NuCLS classification tasks. Top: Performance by training dataset size; models improve with larger datasets and level off near 1M images. Bottom: With the total number of images held constant, models perform better as diversity increases (more organs of origin and more slides).
LEMON-MoCov3
Volta
H-Optimus-0
(ViT-s/8)
(ResNet-18)
(ViT-g/14)
Embedding Robustness
RMSE (↓)
0.777 (0.150)
0.879 (0.266)
1.311 (0.076)
Cosine Similariy (↑)
0.687 (0.116)
0.579 (0.246)
0.138 (0.099)
Neightborhood Overlap (↑)
0.398 (0.067)
0.297 (0.059)
0.154 (0.014)
Biological tasks
Table 3: Robustness to Macenko stain normalization across 6 TCGA reference images. Embedding robustness metrics measure the shift in embedding space between original and stain-normalized cells. Biological tasks report balanced accuracy on stain-normalized embeddings. Best in bold.
Figure 4: Alignment between morphological embeddings and marker-gene expression in a bowel Xenium tissue section (HEST id: TENX147). Left: t-SNE projection of LEMON morphological embeddings. Right: normalized expression maps for marker genes, showing their spatial distribution within the morphology-derived manifold.
Appendix figures & tables13 assets
Supplementary material from the paper’s appendix.
Appendix
Table S1: NuCLS dataset with different annotation levels
Class
Number of images
NMF
10191
AMF
1748
Appendix
Table S2: MIDOG25 dataset.
Class
Number of images
NMF
7955
AMF
1160
Appendix
Table S3: MIDOG25 dataset with 128×128 crop images
Class
Number of images
0
39222
1
26108
2
17258
3
13457
4
1582
Appendix
Table S4: PanNuke dataset.
MIDOG25
NuCLS
HEST-Bowel
HEST-Breast
HEST-Lung
bal acc
bal acc
pcc
pcc
pcc
Model
DINOv2-Baseline (vits8)
0.678 (0.011)
0.681 (0.002)
0.117 (0.014)
0.119 (0.023)
0.106 (0.015)
DINOv2-No local-to-global (vits8)
0.673 (0.012)
0.703 (0.003)
0.131 (0.016)
0.129 (0.021)
0.110 (0.018)
DINOv2-No local-to-global + KDE (vits8)
0.67 (0.011)
0.767 (0.007)
0.142 (0.024)
0.143 (0.024)
0.147 (0.02)
MoCov3 (vits8)
0.741 (0.02)
0.779 (0.005)
0.16 (0.027)
0.156 (0.021)
0.128 (0.028)
Appendix
Table S5: Effect of architectural and framework adaptations on downstream tasks. We report balanced accuracy for NuCLS (super) and MIDOG25 (majority) and PCC for HEST datasets. Values are mean (s.d.), best values are highlighted in bold.
Figure S1: Examples of nuclei images with different augmentation strategies with three random augmentations from either the MoCo v3 augmentation or ours
MIDOG25
NuCLS
HEST-Bowel
HEST-Breast
HEST-Lung
bal acc
bal acc
pcc
pcc
pcc
Augmentations
a0 (MoCo)
0.682 (0.013)
0.771 (0.003)
0.154 (0.03)
0.148 (0.023)
0.116 (0.027)
a1
0.715 (0.021)
0.784 (0.003)
0.161 (0.028)
0.155 (0.025)
0.133 (0.032)
a1+gray
0.746 (0.015)
0.779 (0.005)
0.16 (0.027)
0.156 (0.021)
0.128 (0.028)
a1+gmm1
0.736 (0.018)
0.768 (0.005)
0.164 (0.019)
0.162 (0.021)
0.126 (0.029)
Appendix
Table S6: Effect of augmentation policy on downstream tasks. We report balanced accuracy for NuCLS (supervised) and MIDOG25 (majority), and Pearson Correlation Coefficient for HEST (breast, lung, bowel). Values are mean (s.d.) over folds, best values are highlighted in bold.
Figure S2: Visualization of Macenko stain augmentation. The first panel shows a subset of original MIDOG25 cell images, while the remaining panels display the same images after Macenko augmentation using six different reference stains.
Figure S3: Benchmark of performances under different Macenko staining augmentations. Balanced accuracy of three models (H-optimus-0, LEMON, and Volta) on the NuCLS (left) and MIDOG25 (right) datasets. For each dataset, results are shown for the original images, six Macenko-stained augmentation conditions, as well as the mean across these six augmentations.
Figure S4: Morphological map of learned cell representations. A t-distributed Stochastic Neighbor Embedding projection of 100,000 cells randomly sampled from a breast cancer whole-slide image (TCGA) is shown. A regular grid of cell images visualizes the embedding space, revealing a smooth continuum of latent morphologies. Five representative regions were annotated by an expert pathologist, corresponding to distinct cellular phenotypes: (1) epithelial cells, (2) neoplastic epithelial cells with large, irregular nuclei, (3) small lymphocytes, (4) plasma cells, and (5) fibroblasts.
Target
NuCLS (super)
Metric
auc
aupr
bal acc
f1 (macro)
f1 (weighted)
Embeddings
Imagenet (ResNet-18)
0.876 (0.003)
0.757 (0.005)
0.693 (0.005)
0.698 (0.006)
0.74 (0.005)
Imagenet (ResNet-50)
0.891 (0.004)
0.777 (0.006)
0.711 (0.005)
0.717 (0.005)
0.756 (0.004)
DINOv2 (ViT-s/14)
0.905 (0.001)
0.794 (0.002)
0.732 (0.003)
0.738 (0.004)
0.775 (0.004)
DINOv2 (ViT-b/14)
0.903 (0.003)
0.792 (0.006)
0.732 (0.003)
0.738 (0.004)
0.775 (0.003)
Appendix
Table S7: Evaluation on the NuCLS dataset - task super
Recent advances in pathology foundation models have substantially improved patch and slide level representation learning from whole-slide images (WSIs).However, cell-level representations learning remain underexplored, limiting cell resolved interpretability, biological discovery, and clinical translation. We propose CellDETR, a detection-guided framework built on Deformable DETR for scalable cell representation learning from WSIs. By introducing location feature decoupling and box-constrained attention mechanism, CellDETR enables automated extraction of cell-level embeddings, and outperform existing state-of-the-art methods in supervised cell classification on PanNuke data. In addition, by incorporating contrastive learning design, we build a CellDETR-based pretraining model for scalable cell representation learning from unlabeled WSIs, which improves downstream cell classification performance. Furthermore, we show that after pretraining with Xenium spatial transcriptomics-derived cell annotations, CellDETR achieves accurate cross-dataset cell classification, demonstrating the transferability and biological relevance of the learned cell embeddings. Together, CellDETR provides a scalable route toward general cell-level representation learning framework for interpretable computational patholog
Shikang Zhang, Guojun Li, Yicong Mao +1
Zhejiang University of Technology · Tianjin University · Hangzhou Institute of Medicine, Chinese Academy of Sciences
Pathology foundation models (PFMs) are increasingly used as general-purpose backbones, yet existing benchmarks cannot systematically diagnose their whole-slide cellular representation capabilities, including the decodability of cell-type information and the transferability of such information across tissue sections, datasets, and anatomical organs. We introduce CellPath-Bench, a cellular-resolution benchmark that evaluates frozen PFMs themselves. Following quality control of 52 candidate Xenium datasets, we construct a panel of 25 spatially aligned H&E--Xenium tissue sections spanning 11 organs and 7,079,283 cells, harmonized into fine- and coarse-grained taxonomies. CellPath-Bench samples frozen WSI feature maps at registered nuclear coordinates and evaluates them using standardized multiclass linear probes. Cell Representation Advantage (CRA) measures the within-section advantage of nucleus-anchored representations over patch-level mean pooling, while Cell Representation Transferability (CRT) characterizes the generalization of cell-type decodability across tissue sections, datasets, and organs. We benchmark 30 pathology-specific and general-purpose foundation models through 304,920 runs across spatial readouts, magnifications, taxonomic granularities, and evaluation protocols. The results reveal substantial model-dependent differences in cell-type decodability and its cross-domain generalization, yielding distinct multidimensional capability profiles. CellPath-Bench provides a standardized framework for auditing cellular information in frozen PFM representations.
Bokai Zhao, Yiyang Zhang, Hanqing Chao +6
School of Artificial Intelligence, University of Chinese Academy of Sciences. · Brainnetome Center, Institute of Automation, Chinese Academy of Sciences. · DAMO Academy, Alibaba Group. +1
Computational pathology needs whole-slide image (WSI) foundation models that transfer across diverse clinical tasks, yet current approaches remain largely slide-centric, often depend on private data and expensive paired-report supervision, and do not explicitly model relationships among multiple slides from the same patient. We present MOOZY, a patient-first pathology foundation model in which the patient case, not the individual slide, is the core unit of representation. MOOZY explicitly models dependencies across all slides from the same patient via a case transformer during pretraining, combining multi-stage self-supervision with scaled low-cost task supervision. In Stage 1, we pretrain a vision-only slide encoder on 77,134 public slide feature grids using masked self-distillation. In Stage 2, we align these representations with clinical semantics using a case transformer and multi-task supervision over 333 tasks from 56 public datasets, including 205 classification and 128 survival tasks across four endpoints. Across sixteen held-out tasks, MOOZY improves macro weighted F1, balanced accuracy, and macro weighted ROC-AUC relative to PRISM by +4.19%, +7.93%, and +6.95%, respectively. MOOZY is also parameter efficient with 85.77M parameters, 14× smaller than GigaPath. These results suggest that patient-level pretraining yields transferable embeddings, providing a path toward scalable patient-first histopathology foundation models.
Yousef Kotp, Vincent Quoc-Huy Trinh, Christopher Pal +1
CSSE, Concordia University, Montréal, Canada · Mila – Québec AI Institute, Montréal, Canada · CHUM, Université de Montréal, Montréal, Canada +4