Pseudomyogenic hemangioendothelioma of bone with rare WWTR1‐FOSB fusion gene: Case report and literature review

Abstract Pseudomyogenic hemangioendothelioma rarely arises in bone. WWTR1‐FOSB fusion gene is rarely reported in PMHE of bone. Currently, fusion genes can be used as diagnostic markers in PMHE; however, their prognostic and therapeutic significance is unclear.


| INTRODUCTION
Pseudomyogenic hemangioendothelioma (PMHE) is an uncommon vascular neoplasm of intermediate malignant potential that rarely arises in bone. SERPINE1-FOSB fusion gene occurs frequently in PMHE of bone; however, WWTR1-FOSB fusion gene is rarely reported. The prognostic and therapeutic significance of these gene rearrangements is unclear and needs to be investigated further.

| CASE PRESENTATION
A previously healthy 7-year-old girl presented to the clinic with intermittent pain of the right thigh for two-year duration. The pain was more severe at night. It was not associated with fever, weight loss, or other constitutional symptoms. Analgesics were given initially which relieved her symptoms temporarily; however, she started to feel pain at her right knee after an accident of falling. X-ray was performed, which revealed a well-demarcated radiolucent lytic lesion arising from the metaphysis of the right distal femur with cortical thinning. However, no periosteal reaction or soft tissue involvement was identified (   Figure 3A-3C). They also show diffuse and strong nuclear reactivity for FOSB antibody ( Figure 3D), but are negative for CAMTA1 and TFE3. A final diagnosis of pseudomyogenic hemangioendothelioma was rendered. Next-generation sequencing (NGS) was performed to identify possible targeted therapies for the patient's tumor. Genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue by macrodissection technique. A sarcoma-targeted gene fusion panel was used to test for the presence of rearrangements in 138 targeted genes. The tumor was found to carry WWTR1-FOSB fusion gene. Whole-body magnetic resonance imaging (MRI) and positron emission tomography (PET) scan were performed and revealed no evidence of distant metastasis. The patient underwent partial excision of the affected bone cortex with overlying muscle (vastus intermedius), along with extended curettage of the lesion. This was followed by filling of the defect using cancellous bone graft with internal fixation by plates and screws that do not cross the epiphyseal plate to avoid leg length discrepancy and growth retardation. Postoperative X-ray showed satisfactory impaction of the bone graft and plate fixation (Figure 4). The patient was followed up for 6 months after operation, and there was no evidence of local recurrence during that period. She is still now on regular follow-up.

| DISCUSSION
PMHE is a rare vascular tumor with distinct clinical, pathologic, and molecular features. In 2003, the tumor was recognized as a distinctive entity under the name of "epithelioid sarcoma-like hemangioendothelioma" by Billing et al, due to combined features of morphological similarity with epithelioid sarcoma and immunoreactivity for vascular immunohistochemical markers. 1 The term "pseudomyogenic hemangioendothelioma" was first proposed by Hornick and Fletcher in 2011, when they published a study of 50 cases of this tumor with extensive analysis of the clinicopathological and immunophenotypic features. 4 The term was then adopted by the current World Health Organization (WHO) classification of tumors of soft tissue and bone in 2013. 2 PMHE usually affects young adult males with a predilection for the lower limb. Multifocal presentation is not uncommon. However, in our case the tumor was unifocal. Morphologically, PMHE is an infiltrative neoplasm formed by sheets and loose fascicles of plump spindle and epithelioid cells having abundant bright eosinophilic cytoplasm. The tumor cells usually exhibit mild nuclear pleomorphism with vesicular nuclei and prominent nucleoli. Some cells have rhabdomyoblast-like appearance with dense eosinophilic cytoplasm and peripherally located nuclei. Occasionally, prominent stromal neutrophils are present in the stroma.
PMHE is a locally aggressive tumor with high risk for local recurrence following surgical excision; however, it is a rarely metastasizing neoplasm. [1][2][3][4] It is essential to differentiate this tumor from other epithelioid soft tissue neoplasms including epithelioid hemangioma (EH), epithelioid hemangioendothelioma (EHE), epithelioid sarcoma (ES), and epithelioid angiosarcoma (EAS). Unlike PMHE, EH is characterized by well-defined proliferation of vascular spaces lined by bland epithelioid endothelial cells with hobnailing into the lumen. The stroma usually contains varying numbers of eosinophils. Although the tumor cells in EH can show nuclear reactivity for FOSB antibody, cytokeratin AE1/AE3 is usually negative or shows patchy weak positivity. There is a considerable overlap between PMHE F I G U R E 1 Plain X-ray shows a well-demarcated radiolucent lytic lesion in the metaphysis of the distal femur (blue arrow). There is no soft tissue involvement | 1497 MURSHED Et al. and the spindle cell variant of EH of bone. 18,19 Both tumors share similar clinical presentation, morphology, and immunophenotype, which make the distinction between them difficult and challenging. Both tumors commonly present as multifocal lesions, have prominent spindle cell component, and demonstrate immunoreactivity for cytokeratin and FOSB. 19 Currently, the main distinguishing feature is the ability to demonstrate vasoformative areas lined by "tombstone"-like cuboidal endothelial cells, a finding that is compatible with spindle cell EH. We were not able to demonstrate vasoformative areas in our case.
The distinction between PMHE and EHE can be very challenging. EHE is composed of tumor cells that have characteristic intracytoplasmic lumina containing red blood cells, embedded in myxohyaline stroma. EHE is characterized by recurrent t(1;3)(p36.3;q25) translocation, resulting in WWTR1-CAMTA1 fusion gene, and another subset of cases harbor YAP1-TFE3 fusion gene. 13,20,21 Therefore, the tumor cells in EHE demonstrate diffuse nuclear expression for CAMTA1 and less commonly TFE3 by immunohistochemistry. 21 Unlike PMHE, FOSB is negative in EHE. ES lacks the fascicular growth pattern. The tumor cells in ES are immunoreactive for CD34 and epithelial membrane antigen (EMA), but negative for FOSB. The most essential feature is loss of INI-1 nuclear expression in ES, which is intact in PMHE. The tumor cells in EAS are arranged in freely anastomosing vascular channels lined by markedly atypical tumor cells with frequent mitotic figures including atypical forms. FOSB is negative in EAS. 22 PMHE has distinct molecular prolife. The balanced translocation t(7;19)(q22;q13) producing fusion of SERPINE1 and FOSB genes is well documented. 10,12,13,23 This translocation, which has not been detected in any other bone or soft tissue tumor, results in fusion of SERPINE1 and FOSB genes, which leads to strong expression of FOSB. This gene product can be detected by immunohistochemistry. In 2018, Agaram et al and Zhu et al reported some cases of PMHE with recurrent ACTB-FOSB gene fusions. 24,25 Recently, Panagopoulos et al reported a case of a 33-year-old woman with multifocal PMHE involving the sacrum and spine with novel WWTR1-FOSB fusion gene, which was the first case of primary PMHE of bone carrying this fusion gene. 17 In our case, the tumor was unifocal and harbors similar fusion gene detected by NGS, which revealed a fusion between WWTR1 F I G U R E 2 A, Photomicrograph shows sheets and fascicles of spindle tumor cells (hematoxylin and eosin stain, x100); B, mixture of plump spindle and epithelioid tumor cells (H&E stain, x200); C, the tumor with adjacent reactive woven bone (H&E stain, ×200); D, some areas show scattered osteoclast-type multinucleated giant cells (H&E stain, ×200); and E, elongated tumor cells with dense eosinophilic cytoplasm (blue arrows) and prominent stromal neutrophils (H&E stain, ×400) It is essential to mention that WWTR1-FOSB fusion is not specific for PMHE. In a study performed by Huang et al, FOS gene rearrangement was found to be present in a third of epithelioid hemangioma (EH) cases across different locations and histologic variants with more prevalence in cellular EH and intraosseous lesions. 20,26 The fusion genes detected in EH in that study include ZFP36-FOSB and WWTR1-FOSB.
In summary, we are presenting the second case of primary PMHE of bone with WWTR1-FOSB fusion gene. Several fusion genes have been detected in PMHE. All these fusion genes lead eventually to upregulation of FOSB transcription factor, which makes it a useful immunohistochemical diagnostic marker for PMHE. The relationship between the various gene rearrangements occurring in PMHE and the clinicopathological features as well as the biological behavior of the tumor is still unclear, and further research should be pursued.