Multi-class tissue-type classification of colorectal cancer (CRC) histopathologic images is a significant step in the development of downstream machine learning models for diagnosis and treatment planning. However, publicly available CRC datasets used to build tissue classifiers often suffer from insufficient morphologic diversity, class imbalance, and low-quality image tiles, limiting downstream model performance and generalizability. To address this research gap, we introduce STARC-9 (STAnford coloRectal Cancer), a large-scale dataset for multi-class tissue classification. STARC-9 comprises 630,000 histopathologic image tiles uniformly sampled across nine clinically relevant tissue classes (each represented by 70,000 tiles), systematically extracted from hematoxylin & eosin-stained whole-slide images (WSI) from 200 CRC patients at the Stanford University School of Medicine. To construct STARC-9, we propose a novel framework, DeepCluster++, consisting of two primary steps to ensure diversity within each tissue class, followed by pathologist verification. First, an encoder from an autoencoder trained specifically on histopathologic images is used to extract feature vectors from all tiles within a given input WSI. Next, K-means clustering groups morphologically similar tiles, followed by an equal-frequency binning method to sample diverse patterns within each tissue class. Finally, the selected tiles are verified by expert gastrointestinal pathologists to ensure classification accuracy. This semi-automated approach significantly reduces the manual effort required for dataset curation while producing high-quality training examples. To validate the utility of STARC-9, we benchmarked baseline convolutional neural networks, transformers, and pathology-specific foundation models on downstream multi-class CRC tissue classification and segmentation tasks when trained on STARC-9 versus publicly available datasets, demonstrating superior generalizability of models trained on STARC-9. Although we demonstrate the utility of DeepCluster++ on CRC as a pilot use-case, it is a flexible framework that can be used for constructing high-quality datasets from large WSI repositories across a wide range of cancer and non-cancer applications.

Reinforcement fine-tuning (RFT) is essential for enhancing the reasoning and generalization capabilities of large language models, but its success heavily relies on the quality of the training data. While data selection has been extensively studied in supervised learning, its role in reinforcement learning, particularly during the RFT stage, remains largely underexplored. In this work, we introduce RFT-Inf, the first influence estimator designed for data in reinforcement learning. RFT-Inf quantifies the importance of each training example by measuring how its removal affects the final training reward, offering a direct estimate of its contribution to model learning. To ensure scalability, we propose a first-order approximation of the RFT-Inf score by backtracking through the optimization process and applying temporal differentiation to the sample-wise influence term, along with a first-order Taylor approximation to adjacent time steps. This yields a lightweight, gradient-based estimator that evaluates the alignment between an individual sample’s gradient and the average gradient direction of all training samples, where a higher degree of alignment implies greater training utility. Extensive experiments demonstrate that RFT-Inf consistently improves reward performance and accelerates convergence in reinforcement fine-tuning.

Suboptimal generalization of machine learning models on unseen data is a key challenge which hampers the clinical applicability of such models to medical imaging. Although various methods such as domain adaptation and domain generalization have evolved to combat this challenge, learning robust and generalizable representations is core to medical image understanding, and continues to be a problem. Here, we propose STRAP (Style TRansfer Augmentation for histoPathology), a form of data augmentation based on random style transfer from non-medical style sources such as artistic paintings, for learning domain-agnostic visual representations in computational pathology. Style transfer replaces the low-level texture content of an image with the uninformative style of randomly selected style source image, while preserving the original high-level semantic content. This improves robustness to domain shift and can be used as a simple yet powerful tool for learning domain-agnostic representations. We demonstrate that STRAP leads to state-of-the-art performance, particularly in the presence of domain shifts, on two particular classification tasks in computational pathology. Our code is available at https://github.com/rikiyay/style-transfer-for-digital-pathology.