Frequent FOS Gene Rearrangements in Epithelioid Hemangioma

Abstract

Epithelioid hemangioma (EH) is a unique benign vasoformative tumor composed of epithelioid endothelial cells. Although a small subset of EHs with atypical features harbor ZFP36-FOSB fusions, no additional genetic abnormalities have been found to date in the remaining cases. Based on a novel FOS-LMNA gene fusion identified by RNA sequencing in an index case of a skeletal EH with typical morphology, we sought to investigate the prevalence of FOS rearrangement in a large cohort of EHs. Thus 57 additional EH cases lacking FOSB rearrangements were studied for FOS gene abnormalities by FISH and results were correlated with morphologic appearance and clinical presentation. The EHs were subclassified as typical (n=25), cellular (n=21) and ALHE (angiolymphoid hyperplasia with eosinophilia)(n=12) variants. The ALHE was defined as an EH with a vascular ‘blow-out’ pattern associated with a variable degree of inflammation. There were 17 (29%) cases bearing FOS gene rearrangements among 58 cases tested, including 12 males and 5 females, with a mean age of 42 years. Most FOS-rearranged EHs occurred in the bone (10) and soft tissue (6), while only one case was cutaneous. The predominant anatomic site was the extremity (12), followed by trunk (3), head and neck (1), and penis (1). The incidence of FOS rearrangement was significantly higher in bone (59%, p = 0.006) and lower in head and neck (5%, p = 0.009). Twelve of the FOS rearranged cases were cellular EH (p = 0.001) associated with moderate mitotic activity (2-5/10 HPF) and milder inflammatory background. All 12 ALHE cases lacked FOS gene abnormalities, suggesting different pathogenesis. In conclusion, FOS rearrangement was present in a third of EHs across different locations and histologic variants; however, it was more prevalent in cellular EH and intra-osseous lesions, compared to those in skin, soft tissue and head and neck. This genetic abnormality can be useful in challenging cases, to distinguish cellular EHs from malignant epithelioid vascular tumors. These results also suggest that dysregulation of the FOS family of transcription factors through chromosomal translocation is as a key event in the tumorigenesis of EH except for the ALHE variant.

FOSB immunoreactivity in endothelia of epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia)

“…The expression of FOS gene is significantly increased in EH compared to a group of other vascular and perivascular tumors (EHE, AS and glomus tumors). 19 Some EH (20%) harbor ZFP36-FOSB fusions, 18 especially penile EH (two-thirds), but also bone and soft tissue EH. In a series of EH lacking FOSB rearrangements, FOS gene rearrangements were identified in one-third of cases, 19 with a higher prevalence among the cellular variant (57%), intra-osseous location (59%), lesions with mild inflammatory reaction (44%), and lesions with elevated mitotic activity (2-5/10 HPF, 60%).…”

“…A neoplastic origin is further supported by the recently reported recurrent cytogenetic abnormalities involving FOS gene. 18,19 The Fos gene family consists of 4 members: Our aim is to characterize the staining pattern by FOSB immunohistochemistry in EH with ALHE morphology (EH-AHLE) and to evaluate its diagnostic value to differentiate EH-ALHE from its histological mimickers.…”

Molecular Pathogenesis and Diagnostic, Prognostic and Predictive Molecular Markers in Sarcoma

“…1 Transcriptome sequencing of epithelioid hemangioma revealed a recurrent translocation breakpoint involving the FOS gene fused to different partners. 9,10 The break was observed in exon 4 of the FOS gene and the fusion event led to the introduction of a STOP codon, truncating the FOS protein and resulting in loss of the Trans-Activation Domain. 9 Atypical variants of epithelioid hemangioma were shown to harbor ZFP36-FOSB fusions.…”

“…11 The distinction between epithelioid hemangioma and angiosarcoma can be challenging, and detection of FOS rearrangements may assist in the differential diagnosis. 9,10,12 Treatment with curettage or marginal en bloc excision is usually sufficient for epithelioid hemangioma, while patients with angiosarcoma need more aggressive treatment. 13 …”

Angiolymphoid hyperplasia with eosinophilia and Kimura disease overlap, with evidence of diffuse visceral involvement

“…25 Importantly, FOSB gene fusions have only been documented in pure epithelioid hemangiomas. 26,27 Despite an obvious histological overlap between this entity and ALHE, it is possible that these entities are eti- or YAP1-TFE3 fusion. [28][29][30] Both KD and ALHE are marked by a chronic clinical course that persists for years.…”