Sarcoma with BCOR genetic alterations represents a class of sarcomas that includes sarcomas with BCOR internal tandem duplication (BCOR ITD) and BCOR gene fusions involving CCNB3 and other fusion partners; some of the genetic alterations in this class can be found in tumor types outside of undifferentiated small round sarcomas of soft tissues and bone. 

Sarcomas with BCOR genetic alterations are very rare. BCOR::CCNB3-rearranged sarcoma mostly occurs in children (90% of patient are less than 20 years of age), and it shows a striking male predominance, with an approximately 6:1 male-to-female ratio.^1,2 Tumors with BCOR ITD occur in infancy (including primitive myxoid mesenchymal tumor of infancy), and there are reports of congenital cases. ^3,4 Sarcomas with alternative BCOR fusions occur over a wide age range based on limited data that are currently available. ⁵

Patients with sarcomas with BCOR genetic alterations usually present with tumor-associated pain or swelling.⁶ BCOR::CCNB3-rearranged sarcoma most commonly occurs in bone (about 60% of cases), with the remaining tumors occurring over a wide range of soft tissue and, rarely, visceral sites.²Tumors with BCOR ITD occur most commonly in the soft tissue of the trunk, retroperitoneum, and head and neck.⁷

Members of the class of sarcomas with BCOR genetic alterations show morphologic overlap with each other and with Ewing sarcoma. They are composed of primitive round to spindle cells with sheet-like or nested growth, sometimes invested by a capillary network.²Some tumors have prominent spindling and/or myxoid stroma.

Members of the class of sarcomas with BCOR genetic alterations share similar immunophenotypic profiles. Similar to CIC-rearranged sarcoma, sarcomas with BCOR genetic alterations express membranous CD99 in approximately half of cases² Other markers that are positive in most cases include BCOR, cyclin D1, SATB2, and, in BCOR::CCNB3-rearranged sarcomas, CCNB3 (Fig. 1).^1,2,4However, many of these markers are non-specific, such that molecular confirmation of BCOR genetic alterations is desirable.¹

Figure 1. Immunohistochemical findings in sarcomas with BCOR genetic alterations. Nuclear expression of WT-1 is present in most tumors within the broad class of sarcomas with BCOR genetic alterations. Nuclear CCNB3 expression is present in BCOR::CCNB3 sarcomas.

The outcomes in BCOR::CCNB3-rearranged sarcoma have been studied, but outcomes in other types of sarcomas with BCOR genetic alterations are not as well described. The 5-year survival rate for BCOR::CCNB3-rearranged sarcoma (72-80%) is comparable to that of Ewing sarcoma. ² Most BCOR::CCNB3-rearranged sarcomas show significant treatment response to neoadjuvant Ewing sarcoma treatment regimens, although there are reports of tumors that show no response.^2,6 Sarcomas with BCOR ITD appear to be more aggressive, with a median survival of about 2 years and a roughly 33% overall survival at 5 years.⁴ In one small series, about half of patients developed distant metastases and about half developed local recurrence.⁴

• BCOR::CCNB3 gene fusion results from a cryptic paracentric inversion rearrangement on the short arm of chromosome X, resulting in the fusion of two nearby genes BCOR and CCNB3 located 10 Mb apart: inv(X)(p11.4p11.22). This fusion leads to the overexpression of CCNB3. ⁸ Alternative, less common BCOR fusion partners include MAML3, ZC3H7B, and KMT2D. ^2,5

• BCOR rearrangements also have been described in uterine sarcomas (mainly high grade endometrial stromal sarcoma),^9,10 ossifying fibromyxoid tumors,¹¹ and a small subset of acute promyelocytic leukemia.¹²

• BCOR ITD, which occur in exon 15, result in upregulation of BCOR, which has oncogenic properties. ^10,13

• BCOR ITD in exon 15 are prominent in certain childhood malignancies, such as clear cell sarcoma of the kidney,¹³ infantile undifferentiated round cell sarcomas, ⁷ and primitive myxoid mesenchymal tumor of infancy, ¹⁴ as well as in a subset of high grade primitive neuroepithelial tumors of the CNS¹⁵ and high grade endometrial stromal sarcomas.¹⁶