Chronic Lymphocytic Leukemia Progression Diagnosis with Intrinsic Cellular Patterns via Unsupervised Clustering

Identifying the progression of chronic lymphocytic leukemia (CLL) to accelerated CLL (aCLL) or transformation to diffuse large B-cell lymphoma (Richter transformation; RT) has significant clinical implications as it prompts a major change in patient management. However, the differentiation between these disease phases may be challenging in routine practice. Unsupervised learning has gained increased attention because of its substantial potential in data intrinsic pattern discovery. Here, we demonstrate that cellular feature engineering, identifying cellular phenotypes via unsupervised clustering, provides the most robust analytic performance in analyzing digitized pathology slides (accuracy = 0.925, AUC = 0.978) when compared to alternative approaches, such as mixed features, supervised features, unsupervised/mixed/supervised feature fusion and selection, as well as patch-based convolutional neural network (CNN) feature extraction. We further validate the reproducibility and robustness of unsupervised feature extraction via stability and repeated splitting analysis, supporting its utility as a diagnostic aid in identifying CLL patients with histologic evidence of disease progression. The outcome of this study serves as proof of principle using an unsupervised machine learning scheme to enhance the diagnostic accuracy of the heterogeneous histology patterns that pathologists might not easily see.