ZFP36‐FOSB fusion defines a subset of epithelioid hemangioma with atypical features

Abstract

Epithelioid hemangioma (EH) is a benign neoplasm with distinctive vasoformative features, which occasionally shows increased cellularity, cytologic atypia, and/or loco-regional aggressive growth, resulting in challenging differential diagnosis from malignant vascular neoplasms. Based on two intra-osseous EH index cases with worrisome histologic features, such as the presence of necrosis, RNA sequencing was applied for possible fusion gene discovery and potential subclassification of a novel atypical EH subset. A ZFP36-FOSB fusion was detected in one case, while a WWTR1-FOSB chimeric transcript in the other, both were further validated by FISH and RT-PCR. These abnormalities were then screened by FISH in 44 EH from different locations with 7 additional EH revealing FOSB gene rearrangements, all except one being fused to ZFP36. Interestingly, 4/6 penile EH studied showed FOSB abnormalities. Although certain atypical histologic features were observed in the FOSB-rearranged EH, including solid growth, increased cellularity, mild to moderate nuclear pleomorphism, and necrosis in 3/9 cases, no overt sarcomatous areas were discerned to objectively separate the lesions from the fusion-negative EH. No patient has developed recurrence to date, but the follow-up was relatively limited and short to draw definitive conclusions regarding behavior. Although FOSB-rearranged EH do not show significant morphologic overlap with SERPINE1-FOSB fusion-positive pseudomyogenic hemangioendothelioma, FOSB oncogenic activation is emerging as an important event in these benign and intermediate groups of vascular tumors.

Frequent FOS Gene Rearrangements in Epithelioid Hemangioma

“…Although our group has recently identified recurrent ZFP36-FOSB fusions in a small subset of EH with atypical features 10 , the underlying genetic alteration responsible for most EHs remains elusive. In this study, we took advantage of an index case with available frozen tissue, which was subjected to RNA sequencing and FusionSeq analysis, to identify novel gene rearrangements.…”

“…Kimura disease), while at the other end of the spectrum (cellular EH) with malignant epithelioid vascular tumors, such as epithelioid hemangioendothelioma (EHE) and epithelioid angiosarcoma (AS). Moreover, the distinction from malignant lesions is further complicated by the aggressive clinical presentation of intra-osseous EH with destructive growth and/or multifocality, or by the presence of atypical histologic features with increased mitotic activity and necrosis 2, 3, 10 .…”

Diagnostically Challenging Epithelioid Vascular Tumors

“…20 The epithelioid hemangiomas with this finding were more common on the penis and had atypical features, including solid growth, less inflammation, and necrosis. Conventional epithelioid hemangiomas were not found to have this cytogenetic abnormality, suggesting that what has been collectively described as epithelioid hemangioma may represent a molecularly diverse group of tumors with morphologic overlap.…”

“…[21][22][23] The vascular component of Kimura disease has relatively flattened, attenuated endothelial cells compared with the plumper, often "tomb-stoning" endothelial cells in epithelioid hemangioma. 20,24 The distinct clinical presentation of Kimura disease, including Asian men with lymphadenopathy, peripheral eosinophilia, increased serum immunoglobulin E (IgE), and possibly proteinuria and nephrotic syndrome, also is useful when clinical information is available.…”

Role of Next-Generation Sequencing as a Diagnostic Tool for the Evaluation of Bone and Soft-Tissue Tumors

“…Huang et al [58] have demonstrated FOS rearrangement in a third of EH, with increased prevalence in intraosseous (59% of intraosseous EH) and cellular EH (70% of all FOS-rearranged EH). In a study by Antonescu et al [59] , FOSB rearrangement was observed in 20% of EH. Morphologically, tumors with FOSB rearrangement contained solid areas, increased cellularity, and nuclear pleomorphism.…”