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

Genes Chromosomes Cancer. 2014 Nov;53(11):951-9. doi: 10.1002/gcc.22206. Epub 2014 Jul 18.


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 intraosseous 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 fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction (RT-PCR). These abnormalities were then screened by FISH in 44 EH from different locations with seven 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Child
  • Female
  • Gene Fusion*
  • Hemangioendothelioma, Epithelioid / genetics*
  • Hemangioendothelioma, Epithelioid / pathology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Male
  • Middle Aged
  • Oncogene Proteins, Fusion / genetics*
  • Plasminogen Activator Inhibitor 1 / genetics
  • Proto-Oncogene Proteins c-fos / genetics*
  • Sequence Analysis, RNA
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • Tristetraprolin / genetics*
  • Vascular Neoplasms / genetics*
  • Vascular Neoplasms / pathology


  • FOSB protein, human
  • Intracellular Signaling Peptides and Proteins
  • Oncogene Proteins, Fusion
  • Plasminogen Activator Inhibitor 1
  • Proto-Oncogene Proteins c-fos
  • SERPINE1 protein, human
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • Tristetraprolin
  • WWTR1 protein, human
  • ZFP36 protein, human
  • ZFP36-FOSB fusion protein, human