Clinicopathologic Diversity of Undifferentiated Sarcoma With BCOR-CCNB3 Fusion

Abstract

Undifferentiated sarcoma harboring the BCOR-CCNB3 fusion is characterized by its predilection to affect skeletons of adolescent males, cellular small round/spindle cell morphology, and CCNB3 immunoreactivity. We analyzed 11 cases of BCOR-CCNB3 sarcoma, 10 of which were identified in a reverse transcription-polymerase chain reaction-based screen of 85 patient samples recorded in our database as unclassified small round or spindle cell sarcomas. BCOR rearrangements were confirmed by fluorescence in situ hybridization in 8 tumors. All patients were males aged between 6 and 31 years. In addition to 5 tumors in soft tissue and 4 in the axial or appendicular skeletons, which are typical locations, a tumor was located in the paranasal sinus and another in the lung. Microscopically, the tumors comprised proliferating atypical spindle and/or small round cells with diverse morphologic features such as small concentric whorls, myxoid stroma, a hemangiopericytomatous appearance, and/or hyalinized collagen resembling a solitary fibrous tumor, and angiomatous or slit-like spaces containing extravasated erythrocytes. Tumor cells were immunoreactive to CCNB3 (9/11), BCOR (10/10), TLE1 (6/10), bcl-2 (9/11), CD99 (8/10), CD56 (8/10), c-kit (4/10), and cyclin D1 (10/10). In an immunohistochemical analysis of an additional 412 small round or spindle cell tumors, CCNB3 was detected in 6 (1.5%) and BCOR in 18 (4.4%). Our analysis highlights the varying clinicopathologic features of this tumor, which partially overlap with other small round or spindle cell tumors, including solitary fibrous tumor and vascular tumors. Because CCNB3 and BCOR immunohistochemistry lacks adequate sensitivity and specificity, a molecular genetic approach remains essential for diagnosis.

BCOR Involvement in Cancer

“…Conversely, low-grade ESS is often characterized by the involvement of BCOR as a fusion gene with ZC3H7B . The absence of substantial histological differences between ITD–BCOR-positive CCSK and those carrying YWHAE–NUTM2, together with the simultaneous presence of BCOR molecular anomalies and YWHAE–NUTM2 fusion in the ESS, as well as the evidence that various BCOR aberrations (such as ITD, ZC3H7B–BCOR and BCOR–CCNB3) lead to the overexpression of BCOR and of cyclin D1 [34–36,40,41,43,44,52,69,70,128,140] are all elements that reinforce the hypothesis that these alterations activate a common pathogenetic pathway, or at least a partially shared one.…”

Sustained Complete Response to Palbociclib in a Refractory Pediatric Sarcoma With BCOR-CCNB3 Fusion and Germline CDKN2B Variant

“…In the several case series describing BCS, the median age of diagnosis is in the teenage years, with the youngest patient recorded at age 2. 5 - 8 , 11 Again, because of the age of presentation, one could be concerned about an inherited cancer syndrome. Alfaro-Cervello et al 12 published a case report of a congenital undifferentiated sarcoma with BCOR - CCNB3 fusion possibly similar to our patient case.…”

A Case Series of BCOR Sarcomas With a New Splice Variant of BCOR/CCNB3 Fusion Gene

“…BCOR sarcomas define a new category of sarcomas characterized by BCOR genetic alterations. Internal tandem duplication of the BCOR gene and formation of the fusion genes BCOR/CCNB3 or BCOR/MAML3 are the genetic alterations identified with diagnostic meaning (2,3,5,6,9,11,14,24).…”