BCOR Internal Tandem Duplication in High-grade Uterine Sarcomas

Area of Science:

• Gynecologic Pathology
• Molecular Pathology
• Oncogenesis

Background:

• Endometrial stromal sarcomas (ESSs) are uterine tumors with recurrent genetic alterations, often forming oncogenic gene fusions.
• High-grade ESS (HG-ESS) typically features YWHAE-NUTM2 fusions, but some morphologically similar tumors lack this fusion.
• Pediatric sarcomas share fusions with HG-ESS, with a subset exhibiting BCOR internal tandem duplications (ITDs) instead.

Purpose of the Study:

• To investigate the presence of BCOR ITDs in uterine sarcomas.
• To characterize the clinicopathologic and molecular features of uterine sarcomas with BCOR ITDs.
• To determine if BCOR ITDs represent an alternative oncogenic driver in high-grade uterine sarcomas.

Main Methods:

• Targeted sequencing was used to detect BCOR ITDs in 31 uterine sarcomas (5 low-grade ESS, 13 HG-ESS, 13 undifferentiated sarcomas).
• Immunohistochemistry for cyclin D1 and BCOR was performed.
• Clinicopathologic data and follow-up information were reviewed.

Main Results:

• BCOR ITDs were identified in 3 high-grade uterine sarcomas (1 HG-ESS, 2 undifferentiated) that lacked known ESS translocations.
• These tumors occurred in young patients (average age 24) and showed specific morphology: nonpleomorphic spindle cells with epithelioid/round areas, brisk mitoses, necrosis, and lymphovascular invasion.
• Immunohistochemistry revealed diffuse cyclin D1 and BCOR expression in these BCOR ITD-positive tumors.

Conclusions:

• BCOR ITD serves as an oncogenic alternative to YWHAE-NUTM2 fusion in specific high-grade uterine sarcomas.
• These findings suggest a distinct subtype of high-grade uterine sarcoma characterized by BCOR ITD, potentially within the endometrial stromal neoplasia family.
• This molecular finding aids in classifying challenging uterine sarcomas with uniform nuclear features.