Cancer diagnosis, prognosis, and therapy response predictions from tissue specimens highly depend on the phenotype and topological distribution of constituting histological entities. Thus, adequate tissue representations for encoding histological entities is imperative for computer aided cancer patient care. To this end, several approaches have leveraged cell-graphs that encode cell morphology and organization to denote the tissue information. These allow for utilizing machine learning to map tissue representations to tissue functionality to help quantify their relationship. Though cellular information is crucial, it is incomplete alone to comprehensively characterize complex tissue structure. We herein treat the tissue as a hierarchical composition of multiple types of histological entities from fine to coarse level, capturing multivariate tissue information at multiple levels. We propose a novel multi-level hierarchical entity-graph representation of tissue specimens to model hierarchical compositions that encode histological entities as well as their intra- and inter-entity level interactions. Subsequently, a graph neural network is proposed to operate on the hierarchical entity-graph representation to map the tissue structure to tissue functionality. Specifically, for input histology images we utilize well-defined cells and tissue regions to build HierArchical Cell-to-Tissue (HACT) graph representations, and devise HACT-Net, a graph neural network, to classify such HACT representations. As part of this work, we introduce the BReAst Carcinoma Subtyping (BRACS) dataset, a large cohort of H&E stained breast tumor images, to evaluate our proposed methodology against pathologists and state-of-the-art approaches. Through comparative assessment and ablation studies, our method is demonstrated to yield superior classification results compared to alternative methods as well as pathologists.

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