Epithelioid Haemangioma of Bone

Not clinically relevant

Epithelioid haemangioma of bone is characterized by fusion genes involving the FOS gene at 14q24.3 in 59–71% of the cases. Fusion partners for FOS are variable and include MBNL1, VIM, lincRNA (RP11-326N17.1), and LMNA. Alternatively, the FOSB gene in 19q13.32 is fused to ZFP36 or (rarely) WWTR1. Dysregulation of the FOS family of transcription factors through chromosomal translocation is the key event in the majority of epithelioid haemangiomas of bone. The FOS family includes FOS, FOSB, FOSL1, and FOSL2, which encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. In this way, the FOS proteins regulate cell proliferation, differentiation, and survival. In the FOS fusions, the various fusion partners are at the C-terminal end of the protein and cause loss of the transactivating domain. The C-terminal part is essential for fast, ubiquitin-independent FOS degradation via the 20S proteasome. Loss of the C-terminal part prevents the normal rapid degradation of FOS, and the resulting prolonged FOS activation accounts for the abnormal vessel growth in epithelioid haemangioma. The FOSB fusions occur at the N-terminal part of the protein and are most likely activating promoter-swap events causing upregulation of FOSB.

The lesions range in size from several millimeters to 15 cm; most are < 7 cm and are well defined, nodular, soft, solid, red, and hemorrhagic. They may expand the bone, erode the cortex, and extend into the soft tissue.

The tumors have a lobular architecture, replace the marrow cavity, and often infiltrate pre-existing bony trabeculae. The centers of the lobules are the most cellular and contain epithelioid cells that form vascular lumina or grow in solid sheets. The periphery of the lobules may contain many small arteriole-like vessels lined by flat endothelial cells. In some tumors, solid cellular sheet-like areas predominate, whereas in others they account for a small portion of the neoplasm. The large and polyhedral epithelioid cells have oval or kidney-shaped nuclei, which tend to be hyperlobated or cleaved, with fine chromatin. The cytoplasm is abundant and deeply eosinophilic, occasionally containing one or a few clear vacuoles, which may contain intact or fragmented erythrocytes. Vacuolated cells may aggregate such that neighboring vacuoles coalesce to form vascular lumina. Most tumors contain many well-formed vessels lined by the epithelioid cells that sometimes protrude into lumina in a tombstone-like fashion. Mitoses are relatively infrequent and are not atypical. Small foci of necrosis may be present. The stroma consists of loose connective tissue and may contain a prominent inflammatory infiltrate rich in eosinophils (angiolymphoid hyperplasia with eosinophilia–like), which may even mimic osteomyelitis. Foci of intralesional hemorrhage are present in some tumors, especially those involving the short tubular bones of the extremities. These areas may also contain cytologically banal, sometimes mitotically active spindle cells that are arranged in fascicles. Infrequent findings include scattered intratumoral osteoclast-type giant cells, reactive bone formation that compartmentalizes the tumor into small nodules, and a large dilated vessel lined by epithelioid endothelial cells located within the center of the tumor. A subset of cases, referred to as atypical epithelioid haemangiomas, display more solid growth, increased cellularity, nuclear pleomorphism, and necrosis. These cases more often harbor FOSB fusions.

Not clinically relevant

Epithelioid haemangioma is a locally aggressive lesion, and treatment usually consists of curettage and less frequently marginal en bloc excision. Radiation has been used for tumors in inaccessible locations. The prognosis is very good, and in the largest reported series the local recurrence rate is about 10%; regional lymph nodes can be involved and it is unclear whether this represents multicentric disease or metastatic deposits. Clinicopathological features that are predictive of local recurrence or lymph node involvement have not been reported.

Rearrangement of FOS or FOSB can be detected in the majority of cases.

Essential: primarily located in bone; large epithelioid endothelial cells with densely eosinophilic cytoplasm.

Desirable: lobular architecture with distinct vasoformation.