Expanding the Morphologic and Molecular Spectrum of Spindle Cell Tumors Associated With TERT Fusions

Abstract

The incidence and impact of telomerase reverse transcriptase (TERT) gene fusions in sarcomas remain poorly defined. To date only two cases have been reported, both displaying spindle cell liposarcoma morphology. In this study, we identified four soft tissue spindle cell neoplasms harboring in-frame TERT fusions using targeted RNA sequencing and provide an in-depth characterization of their histologic spectrum, immunoprofile and genomic landscape. Clinically, there was one female and three males, with a wide age range at diagnosis (47–79 years, mean 60 years). The tumors showed a diverse anatomic location, including lower extremity, trunk and retroperitoneum. Histologically, they exhibited a predominantly monomorphic spindle cell phenotype, in keeping with fibroblastic/myofibroblastic differentiation. Three tumors were low-grade, while one displayed increased cellularity and mitotic activity in keeping with a high-grade lesion. Two tumors showed CD34 positivity, while the other two were characterized by actin positivity, with one showing nuclear β-catenin expression. All cases harbored in-frame TERT fusions, involving three different partners, such as TRIO in two cases, and AHRR and SUGCT in one case each. Two of the three cases tested by targeted NGS panels showed in addition TERT gene amplification and CDKN2A deletion, including the high-grade lesion. To define more broadly the recurrent potential and histotype distribution of TERT fusions we also investigated our sarcoma genomic database for this genetic alteration. Results showed that a small subset of well-defined sarcoma types harbored TERT fusions, typically coexisting with numerous other genomic alterations. Thus, our findings suggest that in-frame TERT fusions may drive the pathogenesis of a group of mostly low-grade unclassified sarcomas with fibroblastic/myofibroblastic differentiation. In contrast, TERT fusions may also be detected in other common sarcoma types co-occurring with numerous genomic alterations, likely representing a secondary driver event.