Expanding the clinicopathologic and molecular spectrum of BCOR‐associated sarcomas in adults

Abstract

Aims BCOR gene alteration is a genetic signature of rare subsets of sarcomas. Most BCOR‐associated sarcomas thus far reported are in the pediatric population, except for uterine sarcomas. We studied seven cases of BCOR‐associated non‐uterine sarcomas in adult patients. Methods and results The patients were four men and three women ranging from 26 to 71 years in age. Three tumors, two of which primarily affected the kidney, showed BCOR‐CCNB3. One tumor with a ZC3H7B‐BCOR occurred in the chest wall, and a tumor with a novel CIITA‐BCOR was found in the sinonasal tract. Two tumors in the lung and breast harbored exon 15 internal tandem duplications of BCOR, a highly unexpected observation in this age group. All seven sarcomas consisted of dense proliferations of uniform round to spindle cells with fine chromatin within vascular stroma. BCOR‐CCNB3 sarcomas showed swirling fascicular growth. The tumor with the ZC3H7B‐BCOR fusion showed a multinodular growth of spindle cells, and the tumors with the CIITA‐BCOR fusion showed palisading of oval cells. Both tumors with BCOR internal tandem duplication demonstrated nested to palisading growth of round cells within sclerotic non‐myxoid stroma. All seven sarcomas diffusely expressed BCOR and SATB2 immunohistochemically, with all three BCOR‐CCNB3 sarcomas being immunopositive for CCNB3. BCOR alterations were confirmed by RNA sequencing, polymerase chain reaction, Sanger sequencing, and/or fluorescence in situ hybridization. Conclusions This study expands the clinicopathologic and molecular spectrum of BCOR‐associated sarcomas, and emphasizes the importance of being aware of this entity in the differential diagnosis of adult non‐uterine sarcomas.

NTRK3 overexpression in undifferentiated sarcomas with YWHAE and BCOR genetic alterations

“…[ 2 ] Significant up-regulation of NTRK3 was also recently documented in a small subset of BCOR -associated sarcomas in adults harboring BCOR - CCNB3 , ZC3H7B - BCOR , CIITA - BCOR , and BCOR ITD. [ 8 ] In keeping with this finding, an earlier molecular study using Affymetrix U133A data showed high NTRK3 expression in CCSK, the renal counterpart of BCOR family tumors. [ 15 ] More recent investigations exploring the specificity and sensitivity of pan-Trk immunostaining across various tumor types have also included a few BCOR -associated sarcomas.…”

“…Intriguingly, up-regulated NTRK3 mRNA expression was demonstrated in all of the 4 tumors with KMT2D - BCOR (n=2), BCOR - CHD9 (n=1), or CIITA - BCOR (n=1) fusions. [ 2 , 8 ] Three of the cases tested in this study were all positive for pan-Trk, including the BCOR - CHD9 case with negative BCOR staining, suggesting that NTRK3 expression is not affected by different exon composition of BCOR fusions. Of note, in all tumors reported to date with KMT2D - BCOR , BCOR - CHD9 , or CIITA - BCOR fusions, reciprocal fusion transcripts have been identified.…”

“…In contrast to BCOR - CCNB3 positive tumors, which occur mostly in male children and have a consistent transcript ( BCOR exon 15 fused to CCNB3 exon 5) resulting in BCOR overexpression, other less frequent fusion variants, such as ZC3H7B - BCOR , KMT2D - BCOR , BCOR - CHD9, and the recently reported CIITA-BCOR, occur more commonly in middle-aged adult patients of both genders and show variable BCOR breakpoints. [ 3 , 8 ] Regardless of the canonical or alternative BCOR fusions, tumors typically display a similar morphologic spectrum of primitive round to spindle cell phenotype. However, unlike in BCOR - CCNB3 and BCOR ITD positive tumors, the C-terminal PUFD domain is not consistently retained in the fusion oncoprotein of these uncommon BCOR alternative fusions ( Fig.…”

“…In addition to this genetic variability, there is also a significant clinical heterogeneity. Tumors with BCOR ITD and YWHAE gene rearrangements generally have overlapping clinicopathologic presentations: in children, they may represent one of the following entities: undifferentiated round cell sarcoma in infants, primitive myxoid mesenchymal tumor of infancy (PMMTI), clear cell sarcoma of the kidney (CCSK), central nervous system high-grade neuroepithelial tumor[ 1 , 4 , 5 ]; in adults the diagnosis varies from uterine high grade endometrial stromal sarcomas to other rare visceral round cell sarcomas[ 6 - 8 ]. A similar scenario of genetic promiscuity is seen with BCOR fusions: tumors may represent bone or soft tissue high grade undifferentiated sarcomas, ossifying fibromyxoid tumors, or high grade endometrial stromal sarcomas[ 2 , 3 , 9 , 10 ].…”

Small Round Cell Tumors of Soft Tissue and Bone

“…18 Additional gene fusions involving BCOR have also been subsequently found, including BCOR-ITD (internal tandem duplication), BCOR-MAML3, ZC3H7B-BCOR, BCOR-KMT2D, and CIITA-BCOR. [19][20][21][22] BCOR-CCNB3 sarcomas more frequently arise in bone than soft tissue, have a striking predilection for children and young adults (.90% younger than 20 years), and are male predominant. BCOR-ITD tumors occur preferentially in the somatic soft tissue of the trunk, abdomen, and head and neck, sparing the extremities.…”