BCOR-CCNB3 Fusion Positive Sarcomas

Abstract

BCOR-CCNB3 sarcoma (BCS) is a recently defined genetic entity among undifferentiated round cell sarcomas, which was initially classified as and treated similarly to the Ewing sarcoma (ES) family of tumors. In contrast to ES, BCS shows consistent BCOR overexpression, and preliminary evidence suggests that these tumors share morphologic features with other tumors harboring BCOR genetic alterations, including BCOR internal tandem duplication (ITD) and BCOR-MAML3. To further investigate the pathologic features, clinical behavior, and their relationship to other round cell sarcomas, we collected 36 molecularly confirmed BCSs for a detailed histologic and immunohistochemical analysis. Four of the cases were also analyzed by RNA sequencing (RNAseq). An additional case with BCOR overexpression but negative CCNB3 abnormality showed a novel KMT2D-BCOR fusion by targeted RNAseq. The patients ranged in age from 2 to 44 years old (mean and median, 15), with striking male predominance (M:F=31:5). The tumor locations were slightly more common in bone (n=20) than soft tissue (n=14), with rare visceral (kidney, n=2) involvement. Histologically, BCS showed a spectrum of round to spindle cells with variable cellularity, monomorphic nuclei and fine chromatin pattern, delicate capillary network, and varying amounts of myxoid or collagenous stroma. The morphologic features and immunoprofile showed considerable overlap with other round cell sarcomas with BCOR oncogenic upregulation, that is, BCOR-MAML3 and BCOR ITD. Follow-up available in 22 patients showed a 5-year overall survival of 72%, which was relatively similar to ES (79%, P=0.738) and significantly better than CIC-DUX4 sarcomas (43%, P=0.005) control groups. Local recurrences occurred in 6 patients and distant metastases (lung, soft tissue/bone, pancreas) in 4. Seven of 9 cases treated with an ES chemotherapy regimen with evaluable histologic response showed >60% necrosis in posttherapy resections. Unsupervised clustering by RNAseq data revealed that tumors with BCOR genetic alterations, including BCOR-CCNB3, BCOR-MAML3, and BCOR ITD, formed a tight genomic group distinct from ES and CIC-rearranged sarcomas.

BCOR‐CCNB3 fusion‐positive clear cell sarcoma of the kidney

“…The unique features of our two cases include that both patients presented with a large renal mass with tumor thrombus extending from IVC to right atrium and that there was no viable tumor after neoadjuvant chemotherapy. To date, both patients are without evidence of disease despite presenting with advanced disease; however, long‐term follow‐up is needed given CCSK is associated with late recurrence …”

“…However, each BCOR gene abnormality has a distinct clinical presentation. BCOR‐CCNB3 fusion is seen mostly in males with a predilection for older children and adolescents . Furthermore, the tumors are seen mostly in bone and soft tissue .…”

“…Furthermore, the tumors are seen mostly in bone and soft tissue . BCOR‐ITD and YWHAE‐NUTM2 is seen in younger children (<4 years of age) . In infants, BCOR‐ITD tumors often present as locally aggressive tumors in the paraspinal region and are histologically referred to as primitive myxoid mesenchymal tumor of infancy.…”

“…This needs to be confirmed in a larger series. On the other hand, the majority of BCOR‐CCNB3 sarcomas receive Ewing sarcoma–based therapy with a 5‐year survival rate of 72% . Given BCOR‐CCNB3 sarcomas share similar transcriptomic profiles with BCOR‐ITD–positive CCSK and patients with CCSK demonstrated improved outcome with doxorubicin‐based chemotherapy, we may consider treating BCOR‐CCNB3 sarcomas with CCSK‐based therapy .…”

“…To date, both patients are without evidence of disease despite presenting with advanced disease; however, long-term follow-up is needed given CCSK is associated with late recurrence. 7 BCOR-CCNB3 is a fusion between BCOR and CCNB3 due to paracentric inversion on chromosome X. 8,9 BCOR-CCNB3 was first reported in sarcomas.…”