Primary Renal Sarcomas With BCOR-CCNB3 Gene Fusion

Abstract

We report two primary renal sarcomas demonstrating BCOR-CCNB3 gene fusions that have recently been identified in undifferentiated round cell sarcomas of bone and soft tissue. These neoplasms occurred in male children aged 11 and 12, and both were cystic as a result of entrapment and dilatation of native renal tubules. Both cases were composed of variably cellular bland spindle cells with fine chromatin set in myxoid stroma and separated by a branching capillary vasculature. Both neoplasms demonstrated immunoreactivity for BCOR, cyclin D1, TLE1 and SATB2 in the spindle neoplastic cells and negativity in the prominent capillary vasculature. One case was extensively cystic and had hypocellular areas that simulated cystic nephroma; this neoplasm recurred 3 years later as a solid, highly cellular spindle cell sarcoma in the abdominal cavity. The morphology and immunoprofile of these renal neoplasms was compared to a control group of other sarcomas with BCOR genetic abnormalities, including clear cell sarcoma of the kidney (CCSK), infantile undifferentiated round cell sarcomas of soft tissue/primitive myxoid mesenchymal tumor of infancy (URCS/PMMTI), and bone/soft tissue sarcomas with BCOR-CCNB3 gene fusion; along with primary renal synovial sarcoma. Our findings show that the renal sarcomas with BCOR-CCNB3 gene fusion overlap with CCSK. They are in keeping with a “BCOR-alteration family” of renal and extra-renal neoplasms which includes CCSK and URCS/PMMTI (which typically harbor BCOR internal tandem duplication), and BCOR-CCNB3 sarcomas, all of which are primarily driven by BCOR overexpression and have overlapping (but not identical) clinicopathologic features.

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

“…The tumors were initially thought to be Ewing sarcomas because the tumors were seen in bone and soft tissue with an Ewing sarcoma–like morphology . BCOR‐CCNB3 sarcomas are classified as Ewing‐like and have been treated with Ewing sarcoma chemotherapy regimen . However, gene profiling and SNP array analyses show that BCOR‐CCNB3 sarcoma and Ewing sarcoma have different gene expression profiles, but BCOR‐CCNB3 sarcoma shares similar gene expression profiles with BCOR‐ITD–positive CCSK …”

“…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 . Remarkable similarity in clinical presentation and chemotherapy response in both patients makes it imperative that more patients with BCOR‐CCNB3 fusion CCSK should be identified and their clinical features should be defined.…”

“…Clear cell sarcoma of the kidney (CCSK) is the second most common malignant pediatric renal tumor and comprises 2–5% of primary pediatric renal tumors . CCSK is most often seen in children between 2 and 4 years of age with a male predominance . There are two recurrent somatic alterations reported in CCSK: BCOR (encoding the BCL‐6 corepressor) internal tandem duplication (ITD) is seen in approximately 85% of patients with CCSK; the second most common genetic abnormality is YWHAE‐NUTM2B/E gene fusion, which is seen in approximately 12% of patients with CCSK .…”

“…A minority of patients with CCSK do not have BCOR‐ITD or YWHAE‐NUTM2B/E fusion . Other molecular abnormalities have been reported in these patients, including one patient with EGFR (epidermal growth factor receptor) ITD and three patients with BCOR‐CCNB3 (where CCNB3 is cyclin B3) fusion joining 5′ partner BCOR to the 3′ partner CCNB3 (encoding the testis‐specific cyclin B3) that had been originally reported as a recurrent gene fusion in a subset of Ewing‐like undifferentiated soft tissue sarcomas . We report two additional patients with BCOR‐CCNB3 fusion‐positive CCSK who presented with advanced disease and had an excellent response to chemotherapy.…”

“…1,2 CCSK is most often seen in children between 2 and 4 years of age with a male predominance. [1][2][3] There are two recurrent somatic alterations reported in CCSK: BCOR (encoding the BCL-6 corepressor) internal tandem duplication (ITD) is seen in approximately 85% of patients with CCSK; the second most common genetic abnormality is YWHAE-NUTM2B/E gene fusion, which is seen in approximately 12% of patients with CCSK. 2,4,5 A minority of patients with CCSK do not have BCOR-ITD or YWHAE-NUTM2B/E fusion.…”