Angiosarcoma

Staging of angiosarcoma is not recommended, because its typically aggressive natural history is not consistent with soft tissue staging systems.

Angiosarcomas are genetically heterogeneous. Most harbor complex karyotypes, without recurrent chromosomal changes. Unlike other sarcomas with complex genomics, angiosarcomas show low levels of alterations in TP53 and PIK3CA/AKT/mTOR pathways. Genes related to angiogenesis and vascular-specific receptor tyrosine kinases (including TIE1, TEK, KDR [VEGFR2], and FLT4 [VEGFR3]) are usually upregulated compared with other sarcomas. A subset of cases, typically in younger patients, are associated with CIC gene abnormalities and inferior disease-free survival. About 40% harbor recurrent somatic mutations involving angiogenic signaling pathways (e.g., in KDR, PTPRB, and PLCG1), and rare mutations occur in RAS genes, PIK3CA, TP53, FLT4, and TIE1.

High-level MYC gene amplifications (at 8q24) occur in almost all postirradiation and chronic lymphedema-associated angiosarcomas, and rarely in primary angiosarcomas; 25% of secondary angiosarcomas are associated with FLT4 (VEGFR3) coamplification at 5q35. PLCG1 and KDR mutations occur in subsets of both primary and secondary angiosarcomas, particularly in breast and bone/visceral sites, regardless of MYC status. KDR and PLCG1 mutations are mutually exclusive, with both genes involved in the angiogenesis signaling pathway. FLT4-amplified angiosarcomas lack PLCG1 or KDR mutations, occur predominantly in MYC-amplified tumors, and are associated with a poor prognosis.

Angiosarcomas are typically hemorrhagic, diffuse or multinodular masses of variable size (1–15 cm in diameter; median: 5 cm). They can be relatively well demarcated or ill-defined. Better-differentiated tumors often have a hemorrhagic, spongy appearance, whereas more poorly differentiated neoplasms are more solid and fleshy, with firm, greyish-white tissue with focal necrosis or areas of hemorrhage with cystic degeneration.

Angiosarcomas typically have ill-defined margins, and they vary in their degree of cytological atypia and architectural differentiation. They range from well-formed, anastomosing vessels to solid sheets of high-grade epithelioid or spindled cells without clear vasoformation. Tumors often show a mixture of these two patterns. Most show high-grade morphology, with anastomosing vascular channels or more-solid areas, variable nuclear atypia, mitotic activity (most prominent in more-solid areas), and coagulative necrosis. Sometimes atypia is mild and focal, with cells resembling normal vascular endothelium. Marked pleomorphism is rare. Vasoformative areas are composed of ramifying channels lined by atypical spindle or epithelioid cells, with variable endothelial multilayering, intraluminal budding, hobnailing, or papillary-like projections. The vascular channels may be poorly formed, with complex dissecting patterns within fibroadipose tissue, or they may be compressed, with only subtle cleft-like spaces. Solid areas typically comprise cellular sheets of spindled to epithelioid cells with abundant eosinophilic to amphophilic cytoplasm, large vesicular nuclei, and prominent nucleoli. There may be associated blood lakes or extensive hemorrhage and organizing hematoma that obscures much of the neoplasm, making recognition difficult. More rarely, tumors appear morphologically low-grade, with well-formed vascular channels lined by minimally atypical spindled cells. Epithelioid angiosarcomas typically have a solid architecture, with diffuse, sheet-like patterns of large, atypical epithelioid or polygonal cells with ovoid vesicular nuclei, prominent large central nucleoli, and abundant cytoplasm. Vasoformation is often focal.
Angiosarcomas typically show membranous CD31 and nuclear ERG positivity, with variable expression of CD34 and factor VIII–related antigen (now rarely used). An outer layer of SMA-positive pericytes is usually absent. Keratin and EMA expression may be seen, particularly in epithelioid subtypes, and this can lead to misdiagnosis as carcinoma. Irradiation- and lymphedema-associated angiosarcomas are frequently strongly positive for MYC.

Not clinically relevant

Angiosarcomas of soft tissue are highly aggressive. More than half of patients die of disease within 1 year, with a local recurrence rate of 20% and distant metastases in approximately half. The most frequent site of distant metastasis is the lungs, followed by the lymph nodes, soft tissues, bone, liver, and other sites (including the brain). Older patient age, retroperitoneal location, and large size are associated with poor outcome. Factors such as epithelioid change, necrosis, and margin status, which have been shown to be prognostically significant for angiosarcomas in general, require specific validation for angiosarcomas of soft tissue. Standard sarcoma grading systems have been applied to angiosarcoma, although the correlation between histological grade and prognosis has been debated, and well-differentiated tumors often behave aggressively.

Demonstration of MYC amplification may be helpful, although only in the setting of irradiation- or lymphedema-associated angiosarcoma.

Essential: vasoformative or sheet-like growth; multilayering of endothelial cells; nuclear atypia, increased mitoses, necrosis; CD31 and ERG expression by immunohistochemistry.