# MorphGen: Morphology-Guided Representation Learning for Robust Single-Domain Generalization in Histopathological Cancer Classification

arXiv: https://arxiv.org/abs/2509.00311 · HTML: https://mlsanity.com/paper/2509.00311/

## Key facts

- Cited by 2 papers in the map (data through 14 Oct 2026).
- Builds on 54 of its 115 references that are in the map.
- First posted on arXiv 30 Aug 2025.

## Builds on (most cited first, 30 of 54)

- [Towards Deep Learning Models Resistant to Adversarial Attacks](https://mlsanity.com/paper/1706.06083/) (2017)
- [SGDR: Stochastic Gradient Descent with Warm Restarts](https://mlsanity.com/paper/1608.03983/) (2016)
- [Benchmarking Neural Network Robustness to Common Corruptions and Perturbations](https://mlsanity.com/paper/1903.12261/) (2019)
- [Supervised Contrastive Learning](https://mlsanity.com/paper/2004.11362/) (2020)
- [Perceptual Losses for Real-Time Style Transfer and Super-Resolution](https://mlsanity.com/paper/1603.08155/) (2016)
- [Model soups: averaging weights of multiple fine-tuned models improves accuracy without increasing inference time](https://mlsanity.com/paper/2203.05482/) (2022)
- [Averaging Weights Leads to Wider Optima and Better Generalization](https://mlsanity.com/paper/1803.05407/) (2018)
- [In Search of Lost Domain Generalization](https://mlsanity.com/paper/2007.01434/) (2020)
- [Domain Generalization: A Survey](https://mlsanity.com/paper/2103.02503/) (2021)
- [Generalizing to Unseen Domains via Adversarial Data Augmentation](https://mlsanity.com/paper/1805.12018/) (2018)
- [SWAD: Domain Generalization by Seeking Flat Minima](https://mlsanity.com/paper/2102.08604/) (2021)
- [Self-Challenging Improves Cross-Domain Generalization](https://mlsanity.com/paper/2007.02454/) (2020)
- [HoVer-Net: Simultaneous Segmentation and Classification of Nuclei in Multi-Tissue Histology Images](https://mlsanity.com/paper/1812.06499/) (2018)
- [Wasserstein Auto-Encoders](https://mlsanity.com/paper/1711.01558/) (2017)
- [The many Shapley values for model explanation](https://mlsanity.com/paper/1908.08474/) (2019)
- [Keystroke Dynamics as Part of Lifelogging](https://mlsanity.com/paper/2010.10144/) (2020)
- [Learning to Learn Single Domain Generalization](https://mlsanity.com/paper/2003.13216/) (2020)
- [Gland Segmentation in Colon Histology Images: The GlaS Challenge Contest](https://mlsanity.com/paper/1603.00275/) (2016)
- [Cell Detection with Star-convex Polygons](https://mlsanity.com/paper/1806.03535/) (2018)
- [ZipIt! Merging Models from Different Tasks without Training](https://mlsanity.com/paper/2305.03053/) (2023)
- [Quantifying the effects of data augmentation and stain color normalization in convolutional neural networks for computational pathology](https://mlsanity.com/paper/1902.06543/) (2019)
- [Learning to Diversify for Single Domain Generalization](https://mlsanity.com/paper/2108.11726/) (2021)
- [Diverse Weight Averaging for Out-of-Distribution Generalization](https://mlsanity.com/paper/2205.09739/) (2022)
- [Ensemble of Averages: Improving Model Selection and Boosting Performance in Domain Generalization](https://mlsanity.com/paper/2110.10832/) (2021)
- [CellViT: Vision Transformers for Precise Cell Segmentation and Classification](https://mlsanity.com/paper/2306.15350/) (2023)
- [Sharpness-Aware Gradient Matching for Domain Generalization](https://mlsanity.com/paper/2303.10353/) (2023)
- [Progressive Domain Expansion Network for Single Domain Generalization](https://mlsanity.com/paper/2103.16050/) (2021)
- [CLIPood: Generalizing CLIP to Out-of-Distributions](https://mlsanity.com/paper/2302.00864/) (2023)
- [Lizard: A Large-Scale Dataset for Colonic Nuclear Instance Segmentation and Classification](https://mlsanity.com/paper/2108.11195/) (2021)
- [MILD-Net: Minimal Information Loss Dilated Network for Gland Instance Segmentation in Colon Histology Images](https://mlsanity.com/paper/1806.01963/) (2018)

## Built on by (most cited first, 2 of 2)

- [Weakly Supervised Teacher-Student Framework with Progressive Pseudo-mask Refinement for Gland Segmentation](https://mlsanity.com/paper/2603.08605/) (2026)
- [Morphology-aware deep learning predicts colorectal cancer survival from whole-slide images](https://mlsanity.com/paper/2610.17603/) (2026)

## Abstract (arXiv)

Domain generalization in computational histopathology is hindered by heterogeneity in whole slide images (WSIs), caused by variations in tissue preparation, staining, and imaging conditions across institutions. Unlike machine learning systems, pathologists rely on domain-invariant morphological cues such as nuclear atypia (enlargement, irregular contours, hyperchromasia, chromatin texture, spatial disorganization), structural atypia (abnormal architecture and gland formation), and overall morphological atypia that remain diagnostic across diverse settings. Motivated by this, we hypothesize that explicitly modeling biologically robust nuclear morphology and spatial organization will enable the learning of cancer representations that are resilient to domain shifts. We propose MorphGen (Morphology-Guided Generalization), a method that integrates histopathology images, augmentations, and nuclear segmentation masks within a supervised contrastive learning framework. By aligning latent representations of images and nuclear masks, MorphGen prioritizes diagnostic features such as nuclear and morphological atypia and spatial organization over staining artifacts and domain-specific features. To further enhance out-of-distribution robustness, we incorporate stochastic weight averaging (SWA), steering optimization toward flatter minima. Attention map analyses revealed that MorphGen primarily relies on nuclear morphology, cellular composition, and spatial cell organization within tumors or normal regions for final classification. Finally, we demonstrate resilience of the learned representations to image corruptions (such as staining artifacts) and adversarial attacks, showcasing not only OOD generalization but also addressing critical vulnerabilities in current deep learning systems for digital pathology. Code, datasets, and trained models are available at: https://github.com/hikmatkhan/MorphGen