Epithelioid hemangioma is a benign vascular neoplasm that contains blood vessels lined by epithelioid endothelial cells with glassy eosinophilic cytoplasm. There are three morphologic subtypes that have somewhat distinct clinical and genetic features: "conventional", "cellular", and so-called "angiolymphoid hyperplasia with eosinophilia".

Epithelioid hemangioma occurs most commonly in young adults, with a wide age range and no sex predilection.¹

Patients most commonly present with a single cutaneous nodule, although up to 20% of patients develop multiple lesions in the same anatomic region.²Epithelioid hemangioma most commonly occurs in the head and heck and extremities.¹ Some epithelioid hemangiomas develop within large vessels. The three morphologic subtypes occur with somewhat different body site predilections. For example, epithelioid hemangioma with angiolymphoid hyperplasia with eosinophilia morphology occurs most commonly in the head and neck,³ and when epithelioid hemangioma occurs in bone or penis it is frequently cellular.^4-6

Epithelioid hemangioma is characterized by epithelioid neoplastic endothelial cells that have glassy eosinophilic cytoplasm and bland to mildly atypical nuclei. In the conventional and angiolymphoid hyperplasia with eosinophilia subtypes, these vessels proliferate in lobules with centrally compressed and peripherally dilated vessels; the angiolymphoid hyperplasia with eosinophilia subtype additionally has a prominent inflammatory infiltrate rich in eosinophils and lymphocytes. In contrast, the cellular subtype contains vessels that are densely compressed, such that the growth can appear sheet-like, mimicking epithelioid angiosarcoma;⁴ however, in contrast, to epithelioid angiosarcoma, there is no significant atypia, and immunohistochemistry can be used to demonstrate orderly architecture and lack of endothelial multilayering.

Neoplastic cells are positive for the usual vascular markers, including CD31, CD34, and ERG. In addition, 54% of tumors have nuclear FOSB expression (Fig. 1), even in the absence of underlying FOS or FOSB gene fusions.⁷ Although early studies showed the cellular variant to be largely negative for FOSB expression,⁸ more recent studies have shown that the cellular variant is often positive.²

Figure 1. FOSB immunohistochemistry in epithelioid hemangioma. Immunohistochemistry demonstrates nuclear FOSB expression in the most cases of epithelioid hemangioma, especially in the cellular variant.

Although epithelioid hemangioma is benign, it recurs locally in up to 30% of patients.⁹ Some local recurrences likely reflect regional multicentric disease. Distant metastases have never been reported.

• Recurrent fusions in FOS or FOSB have been reported in about 50% of epithelioid hemangioma. The most frequent rearrangement is WWTR1::FOS, and other FOS fusion partners have also been reported, including LMNA, MBNL1, VIM and lincRNA. ^1,6,9,10 FOSB fusions include ZFP36::FOSB and, rarely, WWTR1::FOSB.⁶

• FOS rearrangements in epithelioid hemangioma do not generate a chimeric fusion protein; instead, the gene fusions introduce a stop codon in exon 4, leading to expression of a truncated FOS protein that lacks the normal transactivation domain.¹⁰

• While FOS and FOSB fusions are present in conventional and cellular epithelioid hemangioma, they have not been reported in the angiolymphoid hyperplasia with eosinophilia subtype, suggesting that the latter is genetically distinct.⁶