The BCOR gene located at Xp11.4 encoded the ubiquitously expressed BCOR protein that interacts with BCL6 to enhance BCL6-mediated transcriptional repression [2, 4, 12]. Physiologically, BCOR plays an important role in pluripotency by regulating differentiation and cell fate determination . In bone and soft tissue sarcomas, BCOR gene mutated mainly through internal tandem duplications (ITD) and gene fusion, among which the BCOR-CCNB3 is the most common fusion. CCNB3 is a member of the cyclin B family and is mainly expressed in the germ cells of testis . In addition to CCNB3, BCOR has been reported to be fused with ZC3H7B, CIITA, MAML3 and KMT2D . However, no fusion gene other than BCOR-CCNB3 has been reported in BCOR-CCNB3 sarcoma so far. The BCOR-CCNB3 sarcoma with RNF213-SLC26A11 gene fusion is the first discovered case, which is featured by the changes in morphology and immunophenotype after neoadjuvant chemotherapy.
The BCOR-CCNB3 sarcoma is more common in men, mainly in older children and adolescents, more in bone than in soft tissue [4–6]. The core biopsy of the BCOR-CCNB3 sarcoma with RNF213-SLC26A11 gene fusion is similar to regular BCOR-CCNB3 sarcomas in terms of histology. Regular BCOR-CCNB3 sarcoma is often composed of round or oval cells in different proportions, distributing in solid sheets, with less cytoplasm, fine chromatin, indistinct nucleoli, and rich capillary network . Other morphological features in this tumor include myxoid spindle cell component, solid areas of high cellularity alternating with less cellular areas, hemangiopericytoma-like pattern, whorls-like arrangement, trabeculae or cord formation, heterologous cartilaginous differentiation, and fascicular architecture reminiscent of infantile fibrosarcoma [6, 7, 14–17]. BCOR-CCNB3 sarcomas treated with neoadjuvant chemotherapy are usually similar to the untreated samples in morphology, but they may display hypocellular loose fibrous tissue, a highly myxoid and sclerotic stroma, coagulative tumor necrosis and elongated bland-appearing nuclei without mitotic activity. Sometimes there are spindle cells with slit-like spaces and extravasated erythrocytes, foci of extramedullary haematopoiesis, pleomorphic tumor cells with multi-nucleated cells. Epithelioid cells appear in small clusters or cords, with focally prominent nucleoli [1, 5–8, 18]. However, we observed previously undescribed morphological changes in the BCOR-CCNB3 sarcoma with RNF213-SLC26A11 gene fusion after neoadjuvant chemotherapy. Most noticeably, two new types of cells, the small round cells similar to classic ES and the larger myoid cells resembling smooth muscle cells or myoepithelioma cells, present in the resected tumor tissue but not the biopsy. The myoid cells showed SMA staining, indicating myogenic differentiation. In addition, we observed a large number of arterioles with thickened or even occluded walls in this tumor, which has never been reported in BCOR-CCNB3 sarcomas. Our discovery extends the morphological spectrum of BCOR-CCNB3 sarcomas after chemotherapy.
So far,there has been no commonly accepted immunohistochemical markers for BCOR-CCNB3 sarcomas. The diffuse positive expression of CCNB3 can help diagnosis, but the focal or weakly positive staining of CCNB3 occurs in solitary fibrous tumor (SFT), rhabdomyosarcoma, ES and fibrosarcoma . Likewise, although BCOR is expressed in almost all the BCOR-CCNB3 sarcomas , its specificity is doubtful. In addition to sarcoma with BCOR ITDs, BCOR also expresses in SFT, synovial sarcoma, ES, malignant lymphoma and small cell carcinoma . Even with the co-staining of CCNB3 and BCOR, the diagnosis could not exclude the possibility of SFT and ES. Androgen (AR) expression has been detected in various benign and malignant soft tissue tumors, including juvenile nasopharyngeal angiofibroma , undifferentiated pleomorphic sarcoma, fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma, myxoid liposarcoma, and angiosarcoma . We reported for the first time that AR is expressed in BCOR-CCNB3 sarcomas. The expression of AR in sarcoma often indicates potential progression , but it may also be a therapeutic target. The immunohistochemical phenotypes of BCOR-CCNB3 sarcomas often change after neoadjuvant chemotherapy. For example, CCNB3 and SATB2 often have weakened expression or no expression [6–8, 15, 18]. In this case, the expression of BCOR, bcl2, CyclinD1, TLE1, AR and Ki67 all decreased after chemotherapy. Interestingly, these markers were preserved in myoid cells completely or partially. Meanwhile, while SMA, SATB1 and CD117 expression were detected in resected tumor tissues but not in biopsy specimens, the restricted expression of SMA and SATB1 in myoid cells indicated the differentiation of the tumor in response to chemotherapy. However, so far there is no clue for the origin of the small round cells.
The RNF213 gene locates on chromosome 17q25.3, coding for a ring finger protein with ubiquitin ligase and ATPase activities, which plays an important role in angiogenesis and inflammatory responses of endothelial cells. RNF213 is a susceptibility gene for moyamoya and it functions to maintain blood flow in the case of hypotension in the brain. It is also a genetic risk factor for pulmonary hypertension and systemic vascular disease . RNF213 mutations have been found in many cancers and sarcomas , while RNF213 gene translocation occurs in anaplastic large cell lymphoma and inflammatory myofibroblastic tumor . As a member of the SLC26 family, SLC26A11 is mainly involved in anion transportation and acts on homeostasis and intracellular electrolyte balance . The role of SLC26A11 in disease is unclear. Currently, RNF213-SLC26A11 gene fusion has only been reported in chronic myeloid leukemia  and glioma , which is related to tumor progression. The expression of RNF213-SLC26A11 fusion protein has not been reported previously, and its function in BCOR-CCNB3 sarcomas is unknown. Because RNF213 is involved in angiogenesis and vascular-related lesions, and the BCOR-CCNB3 sarcoma with RNF213-SLC26A11 gene fusion has the thickening of the arterial wall which has not been described for BCOR-CCNB3 sarcomas after neoadjuvant chemotherapy, we speculate that RNF213-SLC26A11 gene fusion may participate in the vascular change of the tumor.
BCOR-CCNB3 sarcomas are relatively rare tumors with no standard therapeutic schedule, but neoadjuvant chemotherapy can effectively improve overall survival (OS) and disease-free interval (DFI) of patients . The commonly used ES chemotherapy regimens extend the OS to 75% in 5 years [4, 16]. Some authors believe that the use of clear cell sarcoma of the kidney (CCSK)-based therapy regimens (which emphasize Doxorubicin and do not include ifosfamide) can benefit patients while reducing the toxicity of drugs from ES chemotherapy regimens (which include both doxorubicin and ifosfamide) . In this case, the neoadjuvant chemotherapy with oxaliplatin, pirarubicin and ifosfamide was also effective, resulting in no recurrence or metastasis of the tumor half a year post surgery. Therefore, accumulating cases with different regimens may help to evaluate the chemotherapy protocol of BCOR-CCNB3 sarcomas.