A Challenging Case of an Intraosseous Composite Hemangioendothelioma of the Occipital Bone With YAP1::FOXR1 Fusion

We were very intrigued by the recent article by Linos et al. [1], which describes a unique case of a composite hemangioendothelioma (CHE) characterized by a novel YAP1::FOXR1 fusion and neuroendocrine differentiation. Recently, we encountered a case of a 41-year-old male who presented with a painless swelling at the back of his head since 6 months. Radiologic evaluation (CT, PET/CT, and MRI) revealed a 2.0 cm osteolytic intraosseous lesion in the occipital skull bone. The lesion showed cortical disruption with an accompanying soft tissue component in the left occipital region. An open biopsy of the lesion was performed. Histologically, this intra-osseous lesion showed an infiltrative and destructive growth pattern with a striking combination of morphologies. The bulk of the tumor resembled retiform hemangioendothelioma with elongated, branching vascular channels surrounded by myoid-appearing spindled cells. The vascular channels were lined by monotonous hobnailed endothelial cells with high nuclear to cytoplasmic ratios, hyperchromatic nuclei, and low mitotic activity (Figure 1A,B). No high-grade cytonuclear atypia or multilayering of endothelial cells was observed. In some areas, an admixture of smaller and noticeably dilated vascular channels were observed, showing a more ‘hemangioma-like’ appearance (Figure 1C). The retiform hemangioendothelioma-like areas were juxtaposed to solid regions composed of a sheet-like proliferation of uniform, large epithelioid cells with well-defined cell borders, containing individual intracytoplasmic vacuoles. Although these features resembled epithelioid hemangioendothelioma, they lacked the distinctive myxohyaline matrix typically seen in true epithelioid hemangioendothelioma (Figure 1D–F). Necrosis and areas of conventional angiosarcoma were absent. Immunohistochemically, the tumor cells were diffusely positive for CD31, CD34, and ERG. They were negative for D2-40, CAMTA1, TFE3, Fosb, cMyc, CK AE1/3, S100, SOX10, CD56, synaptophysin, and chromogranin A. SMA was positive, highlighting the surrounding pericytes. Additional targeted RNA sequencing analysis (Archer FusionPlex Expanded Sarcoma panel, IDT) identified an in-frame YAP1 (exon 6)::FOXR1 (exon 1) gene rearrangement (Figure 2). Based on the “composite” morphology together with the immunohistochemical profile and molecular findings (YAP1::FOXR1 fusion), the diagnosis of a CHE was made. Additionally, CT-scans of the chest and abdomen, as well as a bone scan, showed no evidence of distant metastasis. To our knowledge, this report represents the second case of a CHE with an YAP1::FOXR1 fusion [1], and the first reported CHE case (with this confirmed underlying molecular gene fusion) occurring in bone. It is noteworthy that the involved exons in the in-frame YAP1::FOXR1 fusion were not entirely identical to those reported by Linos et al. [1]; specifically, our case involved exon 6 instead of exon 4 of YAP1, along with an unaligned sequence of 21 bp between the two fusion gene partners but still resulting in an in-frame fusion transcript. Primary CHE in the bone is extremely rare with only four cases reported in literature to date, none of which include molecular characterization [2-4]. Interestingly, based on the original description and the available H&E images in the article of Linos et al. [1], our case showed a more “complex” mixture of morphologies with more pronounced cellular epithelioid solid tumor areas and hemangioma-like structures, next to the classical areas with retiform hemangioendothelioma-like morphology. Notably, our case didn't show expression for synaptophysin or other neuroendocrine markers, in contrast to the reported patchy synaptophysin expression in the case of Linos et al. [1]. Expression of some neuroendocrine markers (particularly synaptophysin) is a rare and usually focal phenomenon in CHE. In addition to the reported neuroendocrine “differentiation” in individual CHE cases with EPC1::PHC2 [2], ARID1B::MAML2 [1], and YAP1::FOXR1 fusions [1], neuroendocrine “differentiation” seems to be particularly associated with an underlying PTBP1::MAML2 fusion [2, 5, 6]. To conclude, CHE remains a highly heterogeneous clinicopathologic and molecular entity. Further in-depth studies involving a larger number of cases are needed to better understand the characteristics and prognosis, specifically regarding this rare molecular CHE subtype with a YAP1::FOXR1 fusion. Fleur Cordier performed the writing of the paper. Liesbeth Ferdinande, Siebe Loontiens, Joni Van der Meulen and Jo Van Dorpe performed the review of the paper. David Creytens performed the study concept, design and writing of the paper. All authors read and approved the final paper. This study was performed in accordance with the Declaration of Helsinki and with the Code of Conduct of the Federation of Medical Scientific Societies in Belgium. The authors declare no conflicts of interest. The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.