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  • br Conflict of interest statement br Acknowledgement The res


    Conflict of interest statement
    Acknowledgement The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 278742 (Eurosarc)
    Introduction Pseudomyogenic hemangioendothelioma/epithelioid sarcoma-like hemangioendothelioma (PHE/ES-HE) is a rare soft tissue or bone tumor; the tumor mainly occurs in soft tissue and less often in bone. Children and young adults are often affected with a male preponderance. More than 50% of cases are reported to have multicentric lesions [1], [2], [3], [4]. The tumor belongs to the group of hemangioendotheliomas (HEs) [5] or intermediate rarely metastasizing tumors (IRMTs) [6]. Histologically, the tumor mimics myogenic tumor or epithelioid sarcoma (ES), but endothelial origin was established [1], [3]. To the best of our knowledge, 90 cases have been reported (69 males and 21 females) in English literature; 83 cases were mainly in soft tissue and 7 cases mainly in bone [1], [2], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. Recently one balanced parp-1 of t(7;19)(q22;q13) and one unbalanced translocation of der(7)t(7;19)(q22;q13) were reported in PHE/ES-HE [19]. In addition, one more balanced translocation of t(7;19) was described in PHE/ES-HE [8]. Walther et al. [8] revealed that 8 cases of PHE/ES-HE have t(7;19)(q22;q13) translocation by fluorescence in situ hybridization (FISH) analysis. Moreover, they showed that SERPINE1-FOSB fusion is observed in the above 2 cases of PHE/ES-HE with balanced t(7;19)(q22;q13) by RT-PCR analysis. Here, we report a case of penile PHE/ES-HE with a novel pattern of SERPINE1-FOSB fusion demonstrated by RT-PCR.
    Case report
    Materials and methods
    Discussion PHE/ES-HE is a rare mesenchymal tumor and shows unique characteristic pathological findings including immunohistochemical patterns. As the name implies, differential diagnosis of ES-HE/PHE from ES is particularly difficult. ERG and Fli1, known as endothelial markers, are shown to be expressed in ESs [23], while loss of INI1 is observed in almost all ESs [22]. By combination of various immunohistochemical results and the unique pathological findings, the definite diagnosis of PHE/ES-HE could be made in our case. We also performed fusion gene analysis by RT-PCR using fresh frozen material, indicating that our case of penile PHE/ES-HE had SERPINE1-FOSB fusion. The breakpoint of SERPINE1 exon 1 in our case is similar to, but other parts are different from those in 2 cases reported by Walther et al. [8]. Thus, to our knowledge, SERPINE1-FOSB fusion pattern in the present case is novel. Hornick et al. [3] reported two PHE/ES-HE cases with penile involvement associated with multiple lesions in other sites. As for the penile location, this is the third case of PHE/ES-HE. Two cases with SERPINE1-FOSB fusion reported by Walther et al. [8] include a case with insertion of 61 nucleotides of SERPINE1 intron 1 between SERPINE exon 1 and FOSB exon 2. This fusion results in formation of putative translation start codon within FOSB exon 2. The other reported case with SERPINE1-FOSB fusion has inserted 59 nucleotides of SERPINE1 intron 1 between SERPINE1 exon 1 and FOSB exon 1. In this case, the fusion results in formation of putative translation start codon within FOSB exon 1. In our case, on the other hand, 86 nucleotides of SERPINE1 intron1 were inserted between SERPINE1 exon 1 and the middle portion of FOSB exon 1, and the fusion results in formation of putative translation start codon within SERPINE1 intron 1. To our knowledge, there were no such cases of making translation initiation codons in the fusion junction, especially in introns. Although the whole cDNA sequence of SERPINE1-FOSB fusion gene in our case cannot be elucidated, the predictable coding sequence might be in-frame and 282 nucleotides longer than native FOSB. Probable SERPIN1-FOSB fusion protein (432 amino acids in total) is 94 amino acids longer than the original FOSB protein (338 amino acids). We could not confirm the molecular weight of the fusion protein in our case due to the lack of extra fresh frozen materials. In three cases of PHE/ES-HE with proven SERPINE1-FOSB fusion by RT-PCR (case 1 & 2 in Walther\'s series [8] and ours), FOSB, 3′ partner of the fusion gene, is thought to be exclusively up-regulated under the SERPINE1 promotor. The similar events are observed in aneurysmal bone cyst and nodular fasciitis, in which USP6 is overexpressed by the promotors of the 5′ partners of the fusion genes [24].