The KAT6B::KANSL1 Fusion Defines a New Uterine Sarcoma with Hybrid Endometrial Stromal Tumor and Smooth Muscle Tumor Features.

Neoplasms harboring a KAT6B/A::KANSL1 fusion were initially reported as benign (leiomyomas) and malignant (leiomyosarcomas, low-grade endometrial stromal sarcomas [LG-ESS]) uterine neoplasms. However, they may represent an emerging entity, characterized by clinical aggressiveness contrasting with a rather reassuring microscopic appearance. Herein, we aimed to confirm that this neoplasm is a distinct clinico-pathological and molecular sarcoma, and identify criteria that should alert pathologists and lead to KAT6B/A::KANSL1 fusion testing in routine practice. We therefore conducted a comprehensive clinical, histopathological, immunohistochemical, and molecular study including array-Comparative Genomic Hybridization (array-CGH), whole RNA-sequencing, unsupervised clustering, and cDNA mutational profile analysis of 16 tumors with KAT6B::KANSL1 fusion from 12 patients. At presentation, patients were peri-menopausal (median 47.5 years), and the primary tumors were located in the uterine corpus (12/12, 100%), with an additional prevesical location in 1/12 (8.3%) case. The relapse rate was 33.3% (3/9). All tumors (16/16, 100%) showed morphological and immunohistochemical features overlapping between leiomyoma and endometrial stromal tumors. A whirling recurrent architecture (resembling fibromyxoid-ESS/fibrosarcoma) was found in 13/16 (81.3%) tumors. All tumors (16/16, 100%) exhibited numerous arterioliform vessels, and 13/16 (81.3%) large hyalinized central vessels and collagen deposits. Estrogen and progesterone receptors were expressed in 16/16 (100%) and 14/16 (87.5%) tumors, respectively. Array-CGH performed on 10 tumors classified these neoplasms as simple genomic sarcomas. Whole RNA-sequencing on 16 samples and clustering analysis on primary tumors found that the KAT6B::KANSL1 fusion always occurred between exons 3 of KAT6B and 11 of KANSL1; no pathogenic variant was identified on cDNA; all neoplasms clustered together, close to LG-ESS; pathway enrichment analysis showed cell-proliferation and immune infiltrate recruitment pathway involvement. These results confirm that the sarcomas harboring a KAT6B/A::KANSL1 fusion represent a distinct clinico-pathological entity, close to LG-ESS but different, with clinical aggressiveness despite a reassuring morphology, for which the KAT6B/A::KANSL1 fusion is the driver molecular alteration.