Cutaneous Angiosarcoma: Clinicopathologic Spectrum, Immunohistochemical Features, and Diagnostic Pearls

Background Cutaneous angiosarcoma (cutaneous AS) is a rare, aggressive endothelial malignancy characterized by rapid growth, early metastasis, and poor prognosis. Accurate diagnosis remains challenging due to variable clinical presentations, a broad histologic spectrum, and overlap with benign vascular proliferations. Objective To provide a comprehensive review of cutaneous AS, emphasizing clinical contexts, histopathologic subtypes, immunohistochemical features, molecular alterations, and key diagnostic distinctions from histologic mimics. Methods A literature review of recent clinicopathologic, immunohistochemical, and genomic studies was performed to synthesize current diagnostic and molecular insights into primary and secondary cutaneous AS. Findings Primary cutaneous AS most often arises on sun-damaged skin of older adults, whereas secondary cutaneous AS develops after radiation exposure or chronic lymphedema. Cutaneous AS exhibits diverse morphologies ranging from well-differentiated vasoformative to solid or epithelioid patterns. Immunohistochemistry supports endothelial lineage (CD31, ERG, FLI1) and excludes morphologic mimics, although keratin expression represents a diagnostic pitfall. MYC amplification, detected by FISH or IHC, is a hallmark of secondary cutaneous AS and distinguishes it from benign atypical vascular lesions. Next-generation sequencing (NGS) further identifies MYC / FLT4 co-amplification, UV mutational signatures, and DNA damage response pathway alterations, providing both diagnostic and therapeutic implications. Conclusions Diagnosis of cutaneous AS requires integration of clinical context, histopathology, and ancillary testing. MYC testing is critical for differentiating secondary cutaneous AS from post-radiation atypical vascular lesions, while NGS expands the molecular understanding of cutaneous AS. Early biopsy, adequate tissue sampling, and judicious use of IHC, FISH, and NGS improve diagnostic precision and may guide targeted or immune-based therapies.