Sarcoma With BCOR Genetic Alterations

Sarcoma with BCOR genetic alterations is presumably staged under Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) TNM principles.

Similar to clear cell sarcoma of kidney and high-grade endometrial stromal sarcoma, infantile undifferentiated round cell sarcomas are characterized either by BCOR-ITD or in rare cases by YWHAE-NUTM2B fusions; both genotypes result in oncogenic upregulation of BCOR. BCOR family tumors share a similar gene expression signature, with strong overexpression of HOX family genes. The molecular consequences of the BCOR genetic abnormalities remain largely unknown. BCOR is both an interactor of BCL6 and a repressor of its expression. BCOR was later shown to be part of the non-canonical polycomb repressive complex 1.1 (PRC1.1). In high-grade neuroepithelial tumor with BCOR alteration, BCOR-ITD activates both sonic hedgehog and WNT/β-catenin signaling pathways. Cyclin B3 (CCNB3) expression, which in normal tissues is restricted to testis, was also shown to be sufficient to increase cellular proliferation in ectopic models.

Tumors are typically large (> 5–10 cm), tan-grey, soft to fleshy lesions, with areas of necrosis. Osseous lesions often show cortical destruction and extension into the soft tissues.

BCOR family tumors show substantial morphological overlap. BCOR-CCNB3 sarcomas are typically composed of a uniform proliferation of primitive small round to ovoid cells arranged in solid sheets or a vague nesting pattern, surrounded by a rich capillary network. Other morphological patterns can occur, including less cellular areas of short spindle cells within a myxoid matrix or solid areas of predominantly plump spindle cells arranged in short fascicles, reminiscent of poorly differentiated synovial sarcoma. The nuclei have finely dispersed chromatin and nucleoli are generally inconspicuous. The mitotic activity is variable. Metastatic/recurrent lesions occasionally display pleomorphic nuclei and osteoid deposition. Rare tumors reported in the kidney show substantial overlap with clear cell sarcoma of the kidney. The spectrum of tumors with BCOR-ITD abnormalities shows variable degrees of cellularity, ranging from solid sheets of small primitive cells to hypocellular areas of dispersed spindle cells, within a myxoid matrix and delicate vessels. Immunohistochemically, all tumors with various BCOR gene alterations show strong and diffuse nuclear BCOR positivity and in most cases also express SATB2, TLE1, and cyclin D1. CD99 is positive in approximately 50% of cases. However, BCOR expression is not specific and, for example, is often observed in synovial sarcoma. BCOR-CCNB3 sarcomas also express cyclin B3, which is not seen in other BCOR family tumors.

Not clinically relevant

Emerging data suggest that patients with BCOR-CCNB3 sarcoma show 5-year survival rates similar to those of patients with Ewing sarcoma (72–80%) and show histological response to Ewing sarcoma–based treatment regimens. A substantial proportion of patients present with metastatic disease; the most common metastatic site is the lung, followed by bone, soft tissue, and visceral locations. The outcomes of the other BCOR family tumors are not well defined.

The BCOR gene rearrangements and BCOR-ITD can be detected by various molecular approaches.

Essential: primitive round to spindle cells arranged in nests, sheets, or fascicular growth; variably myxoid stroma with delicate vasculature; immunohistochemical positivity for BCOR, SATB2, and cyclin D1.

Desirable (in selected cases): molecular confirmation of BCOR genetic abnormality (BCOR fusion, BCOR-ITD).