Benign and Low-Grade Superficial Endothelial Cell Neoplasms in the Molecular Era

Superficial vascular anomalies comprise a spectrum of diseases with a wide range of clinical presentations and courses, characterized by the abnormal development or growth of blood and lymphatic vessels in dermis and subcutis. These vascular anomalies are divided into malformations and neoplasms1. Herein, we focus on vascular neoplasms. They result from the uncontrolled proliferation of endothelial cells that adopt an endothelial progenitor cell phenotype, angioblast-like, due to diverse recurrent genetic alterations2. Contrary to earlier assumptions about neoplastic endothelial progenitor cells, it has been demonstrated that they are undoubtedly different from the bone marrow derived normal endothelial progenitor cells2,3. Neoplastic endothelial progenitor cells are induced pluripotent stem cells with altered genetics, morphology and function3,4. The pathogenic role and signaling triggered by these gene alterations is specific in each subtype of endothelial cell neoplasm5,6, although they share many commonalities. Genetic and epigenetic abnormalities induce cell reprograming with alteration of the transcriptional program landscape, allowing the neoplastic transformation1,7. A cascade of growth factors and cytokines regulates a network of signaling pathways leading to a phenotypic diversity; the resulting variable degrees of differentiation towards mature endothelial or perivascular cells manifests as the richly diverse spectrum observed histologically5,6,8,9,10.

These neoplasms frequently demonstrate significant histologic overlap; a clear separation between entities may not be initially evident, and clinical and radiologic correlation is required1. Nonetheless, the phenotypic heterogeneity and overlapping symptoms among these conditions make their diagnosis difficult. Recently, molecular profiling has identified recurrent genetic alterations in most vascular tumors11,12, including those that arise in superficial locations12. Figure 1 depicts the molecular alterations observed in vascular neoplasms. These molecular signatures have current13 – or potential future2,14 – utility to help identify each neoplasm. Advances in molecular genetics have also given new insights into the pathogenesis of vascular neoplasms15,16, providing potential molecular targets for precision pharmacotherapy17,18. This review discusses the latest developments in molecular pathology of superficial benign and locally aggressive endothelial cell neoplasms.

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