An interpretable cell-centric representation of pancreatic ductal adenocarcinoma matches multiple-instance learning for clinical outcomes and leads to novel pathologist-driven histological biomarkers

Current state of the art computational pathology foundation models attain satisfying accuracy most general pathology tasks including detection of pancreatic ductal adenocarcinoma (PDAC) but fail to provide sufficient explainability, operating as "black boxes". Some interpretability effort has been made, with models providing attention maps that project back on the slide the models high attended areas that pushed for the given prediction result, without further naming or reasoning explanation which can limit pathologists trust toward the prediction. We developed C3PRO, a cell-centric framework attempting to provide deeper understanding and explainability, by using embeddings extracted using a pathology foundation model, from cell centered tiles containing both the cell and its close neighborhood, which were then clustered into recurrent morphological phenotypes. A spatial graph was additionally constructed on top of the back-projected vocabulary to account for recurrent motifs. The evaluation of the model performance involved a cohort of 809 patients (825 diagnostic biopsies) using nested cross validation. C3PRO was benchmarked against four different multiple instance learning frameworks and achieved on-par performance for diagnostic (0.958 AUC), survival (0.617) and resectability (0.696) prediction, while providing additional insights compared to the strongest baseline models. Each clustered phenotype was probed and extracted as a representative tile mosaic and annotated by two expert pathologists, constituting a phenotype vocabulary available for statistical analysis. These phenotypes were scored by pathologists with physical brightfield microscopy and replicated the independent statistical significance impact on overall survival prediction from diagnostic biopsies.