Digital Staging of Hepatic Hemangiomas Reveals Spatial Heterogeneity in Endothelial Cell Composition and Vascular Senescence

Abstract

Hepatic hemangioma (HH) is the most common benign primary liver tumor; however, despite its high prevalence, a stage-specific classification of this tumor is currently missing. For a spatial stage-specific classification, a tissue microarray (TMA) consisting of 98 HHs and 80 hemangioma margins and 78 distant liver tissues was digitally analyzed for the expression of 16 functional and vascular niche-specific markers. For cross-correlation of histopathology and functional characteristics, computed tomography/MRI imaging data of 28 patients were analyzed. Functional and morphological analyses revealed a high level of intra- and interpatient heterogeneity, and morphological heterogeneity was observed with regard to cellularity, vascular diameter, and endothelial cell subtype composition. While regressed hemangiomas were characterized by low blood vessel density, low beta-catenin levels, and a microvascular phenotype, non-regressed HHs showed a pronounced cellular and architectural heterogeneity. Functionally, cellular senescence–associated p16 expression identified an HH subgroup with high vascular density and increased lymphatic endothelial cell content. Histological HH regions may be grouped into spatially defined morphological compartments that may reflect the current region-specific disease stage. The stage-specific classification of HHs with signs of regression and vascular senescence may allow a better disease course–based and cell state–based subtyping of these benign vascular lesions.