A Molecular Study of Epithelioid Angiosarcoma: Malignant Transformation of Epithelioid Hemangioma Is a Rare Event

Context.— Initially, epithelioid endothelial tumors were thought to represent a clinicopathologic continuum, from benign epithelioid hemangioma (EH) to epithelioid hemangioendothelioma (EHE) and malignant epithelioid angiosarcoma (EAS). However, recurrent FOS (FBJ murine osteosarcoma viral oncogene homolog) and FOSB (FosB proto-oncogene, AP-1 transcription factor subunit) fusions and RAS and MAP2K (mitogen-activated protein kinase kinase) alterations have been identified in EH, and CAMTA1 (calmodulin-binding transcription activator 1) or TFE3 (transcription factor binding to IGHM enhancer 3) fusions in EHE, establishing that these represent distinct entities. The genetic landscape of EAS is incompletely understood. Objective.— To characterize the genomic landscape of EAS and its relationship, if any, to EH and EHE. Design.— Targeted next-generation sequencing was performed on 15 EASs to identify pathogenic genomic alterations. Clinical and pathologic findings were tabulated. Results.— A case demonstrating both EH and EAS morphology showed identical FOSB fusions in both components, while the latter also harbored TERT (telomerase reverse transcriptase) and CDKN2A/B (cyclin-dependent kinase inhibitor 2A/2B) alterations. No other EAS harbored variants characteristic of EH or EHE. Pathogenic alterations in the RTK-RAS-MAPK and PTEN-PI3K pathways were identified in 4 of 15 cases (27%) and 3 of 15 cases (20%), respectively. Large-scale chromosomal gains or losses were present in 9 of 15 cases (60%). An EAS in the parotid showed ultraviolet radiation–induced hypermutation. Despite aggressive clinical behavior, 3 of 15 cases (20%) showed no pathogenic alterations. Conclusions.— The presence of a FOSB fusion in a single case demonstrates that EH occasionally undergoes malignant transformation and displays morphology and clinical behavior indistinguishable from that of EAS. Most EAS cases appear to arise de novo, with many pathogenic variants shared with conventional angiosarcoma.