Undifferentiated round cell sarcoma with BCOR internal tandem duplications (ITD) or YWHAE fusions: a clinicopathologic and molecular study

Abstract

Until recently, undifferentiated round cell sarcomas (URCS) in infants have been considered a wastebasket diagnosis, composed of various pathologic entities and lacking consistent genetic alterations. The recent identification of recurrent BCOR internal tandem duplications (ITD) and less common alternative YWHAE-NUTM2B/E fusions in half of infantile URCS and the majority of so-called primitive myxoid mesenchymal tumors of infancy (PMMTI) suggests a common pathogenesis with clear cell sarcoma of the kidney which also harbors the same genetic alterations. These tumors also share a similar morphology and immunoprofile, including positivity for BCOR, cyclin D1 and SATB2. In this study we investigate the largest cohort to date of genetically confirmed URCS and PMMTI with BCOR ITD or YWHAE fusions to better define their morphologic spectrum and clinical behavior. Twenty-eight cases harbored BCOR ITD and 5 YWHAE fusions, occurring in 29 infants and 4 children, 19 males and 14 females. Microscopically, 20 were classified as URCSs and 13 as PMMTI. Follow-up was available in 25 patients, with 14 (56%) succumbing to their diseases at a mean duration of 18-months follow-up (range: 2–62). Six patients remained with no evidence of disease at a mean follow-up of 63 months (range: 4–192), 4 patients were still alive with disease (mean follow-up: 46 months, range: 4–120), and 1 died of other causes. Local recurrence and distant metastasis were each observed in 11/25 (44%) of the patients. The overall survival was 42% at 3 years and 34% at 5 years (median survival: 26 months). There was no statistically significant survival difference between cases diagnosed as URCS and PMMTI and between those with BCOR ITD and YWHAE fusions.

Intra‐ and extra‐cranial BCOR‐ITD tumours are separate entities within the BCOR‐rearranged family

“…The family of BCOR ‐ITD tumours offers a heterogeneous set of presentations, reflecting the variety of locations. The main features in common are the median age at diagnosis as previously reported in CCSK (2.0 years over 33 cases [1(p),2,3]), URCS (0.8 year over 28 cases [ 12 ]), and CNS BCOR ‐ITD (3.5 years over 49 cases [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 26 , 36 , 37 , 38 ]); the local presentation; and the poor prognosis.…”

“…Five cases of URCS were reported previously in the study by Watson et al , although without clinical, radiological, and histopathological details [27]. Another case of URCS (P16) and one case of CNS BCOR ‐ITD (P23) were also previously reported (in Refs [12] and [16], respectively).…”

“…BCOR ‐internal tandem duplication (ITD) tumours are a heterogeneous group of neoplasms comprising sarcomas and neuroepithelial tumours of the brain. Sarcomas are described in the kidney as clear cell sarcomas of the kidney (CCSK) [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ], in the endometrium as high‐grade endometrial stromal sarcomas (HG‐ESS) [ 9 , 10 , 11 ], and in the bone [ 12 , 13 ] and soft tissue as undifferentiated round cell sarcoma (URCS), but also including primitive myxoid mesenchymal tumour of infancy (PMMTI) [ 12 , 14 , 15 ]. In the central nervous system (CNS), tumours with BCOR ‐ITD alteration were first identified by DNA methylation analyses and termed high‐grade neuroepithelial tumours BCOR (HGNET‐ BCOR ) [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ].…”

BCOR-CCNB3 Sarcoma with Prominent Rhabdoid Cells Mimicking Rhabdomyoblasts: Expanding the Morphologic spectrum of BCOR-CCNB3 Sarcoma

“…BCOR-ITD occurs predominantly in infants and BCS occurs predominantly in teenage male patients, while sarcomas with alternative BCOR gene rearrangements are seen in a wider age range. 2,12,16 All these sarcomas share overlapping morphologic features and immunohistochemical profile.…”

DNA methylation profiling as a model for discovery and precision diagnostics in neuro-oncology

“…While specific among CNS tumors, the exon 15 ITD in BCOR that defines this tumor type is also present in clear cell sarcoma of the kidney 71 and undifferentiated round cell sarcoma/primitive myxoid mesenchymal tumor of infancy. 72 , 73 The methylation profile of CNS-BCOR-ITD is distinct 29 and the diagnosis can be reliably made with methylation array profiling. 27 Interestingly, genetic alterations other than BCOR ITD may also occur in tumors related to this methylation class.…”