Endothelial cell malignancies are rare in the Western world and range from intermediate grade hemangioendothelioma to Kaposi sarcoma to aggressive high-grade angiosarcoma that metastasize early and have a high rate of mortality. These malignancies are associated with dysregulation of normal endothelial cell signaling pathways, including the vascular endothelial growth factor, angiopoietin, and Notch pathways. Discoveries over the past two decades related to mechanisms of angiogenesis have led to the development of many drugs that intuitively would be promising therapeutic candidates for these endothelial-derived tumors. However, clinical efficacy of such drugs has been limited. New insights into the mechanisms that lead to dysregulated angiogenesis such as mutation or amplification in known angiogenesis related genes, viral infection, and chromosomal translocations have improved our understanding of the pathogenesis of endothelial malignancies and how they evade anti-angiogenesis drugs. In this review, we describe the major molecular alterations in endothelial cell malignancies and consider emerging opportunities for improving therapeutic efficacy against these rare but deadly tumors.
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