2021 NPA-03

This case was originally published in 2021. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A 13-year-old girl presented to the emergency department after three weeks of worsening back pain, resulting in refusal to walk or bear weight on either leg. Associated symptoms of bilateral leg weakness and anorexia were noted. A lumbar x-ray did not demonstrate specific pathology, so an MRI of the spine was performed, revealing an extramedullary mass at the L2-L3 level, involving the neural foramen and compressing the spinal cord (Image A). The patient underwent laminectomy and resection of the lesion.

Tissue Site
Spine, extradural L2 level

The whole slide image provided is an H&E-stained section from L2 extradural tumor resection.

This high-grade spindle cell sarcoma arose in the neural foramen, an unusual location raising a differential diagnosis including nerve sheath tumor (often NF1-associated), metastatic lesion, or sarcoma. Histologic analysis revealed a tumor with a primitive appearance and spindle cell morphology. The tumor lacked expression of GFAP, synaptophysin, OLIG2, and EMA, indicating it did not derive from the CNS or meninges. A nerve sheath tumor was considered unlikely after the tumor demonstrated no immunoreactivity for SOX10 or S100 (Image E) and expression of H3K27me3 was retained; the latter marker typically shows loss of expression in malignant peripheral nerve sheath tumor. Tissue from the resection was submitted for sequencing studies, which revealed a BCOR-CCNB3 fusion. BCOR-CCNB3 fusions are detectable by FISH or RNA sequencing, and tumors harboring this fusion may demonstrate a primitive round cell appearance (Image B) or spindle cell morphology (Image C and Image D). Case series of these tumors indicate that a rich capillary network is a common feature, as is the presence of myxoid stroma (Image D). BCOR-CCNB3 fusion-positive sarcomas typically demonstrate diffuse strong nuclear positivity for BCOR (Image H) and TLE1 (Image G). CD99 is positive in a subset of cases, to a variable extent; only patchy weak expression was seen in this case (Image F). NTRK3 has been shown to be differentially expressed in these tumors, so Pan-TRK IHC is likely unhelpful in this setting.

Clinically, BCOR-CCNB3 fusion-positive sarcomas have been reported throughout the body and typically occur in older children and adolescents. These tumors have been considered part of the heterogeneous group of “Ewing-like tumors,” based on their morphologic similarity to Ewing sarcoma. Although the total number of known cases is very small, early studies suggest that the prognosis for these tumors is better than for CIC-rearranged sarcomas and possibly Ewing sarcomas. Currently, treatment recommendations for these rare tumors follow those of Ewing sarcoma and include chemotherapy with or without radiation therapy.

BCOR-rearranged sarcomas include those with BCOR-CCNB3, BCOR-MAML3, and ZC3H7B-BCOR fusions, and those with BCOR internal tandem duplication (ITD). BCOR exon 15 ITDs are the defining alterations of primitive myxoid mesenchymal tumor of infancy and clear cell sarcoma of the kidney. Also of note, a subset of rare primary brain tumors arising in children harbor BCOR exon 15 ITD; these tumors commonly have high-grade histologic features and demonstrate strong immunoreactivity for BCOR.

Although this case represented a primary sarcoma, the presence of an extradural mass should raise a differential diagnosis including metastatic disease. In the pediatric setting extradural metastatic lesions may arise from neuroblastoma, Wilms tumor, or sarcoma (eg, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma). Many of these tumors have overlapping histologic features, with a small round blue cell appearance being common. Provision of tissue for appropriate molecular studies at the time of intraoperative diagnosis is of particular importance in this setting, since many of these entities will be defined by, or patients clinically stratified by, molecular and cytogenetic features. Another key consideration in the pediatric setting should be leukemia/lymphoma, which may rarely present as an epidural mass causing spinal cord compression. Again, routing of fresh tissue for appropriate ancillary studies (flow cytometry, cytogenetics, or other molecular studies) is advisable at the time of intraoperative consultation.

“Undifferentiated/unclassified sarcoma” is a category of exclusion to be used after extensive evaluation by routine histopathologic, IHC, and molecular means. The increasingly common incorporation of molecular studies has allowed for certain tumors previously considered undifferentiated/unclassified to be specified and studied separately, including the BCOR-altered sarcomas.

• The differential diagnosis for a spinal cord extradural mass includes both metastatic lesions and primary mesenchymal tumors.
• Pediatric solid tumors frequently have a small round blue cell appearance, and it may not be possible to definitively diagnose them at the time of intraoperative consultation.
• Common extradural metastatic lesions in the pediatric population include neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, and Wilms tumor. Acute leukemia/lymphoma can also rarely present as an extradural mass.
• Next-generation sequencing is an essential tool in the workup of sarcomas and can identify characteristic alterations such as BCOR fusions.
• BCOR-rearranged sarcomas include those with BCOR fusions and those with BCOR ITD. Strong immunoreactivity for BCOR is a feature of these tumors.
• The intraoperative pathologist should consider tissue requirements for downstream ancillary testing and triage tissue appropriately for cytogenetics or molecular studies.

1. Kao YC, Owosho AA, Sung YS, et al. BCOR-CCNB3 fusion positive sarcomas: A clinicopathologic and molecular analysis of 36 cases with comparison to morphologic spectrum and clinical behavior of other round cell sarcomas. Am J Surg Pathol. 2018;42(5):604-15.
2. Machado I, Yoshida A, López-Guerrero JA, et al. Immunohistochemical analysis of NKX2.2, ETV4, and BCOR in a large series of genetically confirmed Ewing sarcoma family of tumors. Pathol Res Pract. 2017;213(9):1048-53.
3. Pierron G, Tirode F, Lucchesi C, et al. A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat Genet. 2012;44(4):461-6.