Genomic characterization and histologic analysis of uterine leiomyosarcoma arising from leiomyoma with bizarre nuclei

Abstract Leiomyoma with bizarre nuclei (LM‐BN) is a rare variant of leiomyoma with a benign clinical course. In contrast, leiomyosarcoma (LMS) is a high‐grade, malignant neoplasm characterized by high recurrence rates and poor survival. While LM‐BN and LMS show distinct morphologies, they share similar immunoprofiles and molecular alterations, with both considered ‘genomically unstable’. Rare cases of LM‐BN associated with LMS have been reported; however, the histogenesis and molecular relationship between these two tumors remains unclear. In this study, we assessed 11 cases of LMS arising in conjunction with LM‐BN confirmed by histology and immunohistochemistry (IHC), further analyzed by clinical, histologic, and molecular characteristics of these distinct components. LM‐BN and LMS had similar p16 and p53 IHC patterns, but LMS had a higher Ki‐67 index and lower estrogen and progesterone eceptor expression. Digital image analysis based on cytologic features revealed spatial relationships between LMS and LM‐BN. Genomic copy number alterations (CNAs) demonstrated the same clonal origin of LMS arising from existing LM‐BN through conserved CNAs. LMS harbored highly complex CNAs and more frequent losses of the TP53 , RB1 , and PTEN genomic regions than LM‐BN ( p = 0.0031), with CDKN2A/B deletion identified in LMS only. Mutational profiling revealed many shared oncogenic alterations in both LM‐BN and LMS; however, additional mutations were present within LMS, indicative of tumor progression through progressive genomic instability. Analysis of spatial transcriptomes defined uniquely expressed gene signatures that matched the geographic distribution of LM‐BN, LMS, and other cell types. Our findings indicate for the first time that a subset of LMS arises from an existing LM‐BN, and highly complex genomic alterations could be potential high risks associated with disease progression in LM‐BN. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.