有KAT6B/A::KANSL1融合的肿瘤最初报告为良性(平滑肌瘤)和恶性(平滑肌肉瘤,低度子宫内膜间质肉瘤[LG-ESS])子宫肿瘤。然而,他们可能代表一个新兴的实体,其特征是临床侵略性与相当令人放心的微观外观形成对比。在这里,我们的目的是确认这种肿瘤是一种独特的临床病理和分子肉瘤,并确定应提醒病理学家并在常规实践中导致KAT6B/A::KANSL1融合测试的标准。因此,我们进行了全面的临床,组织病理学,免疫组织化学,和分子研究,包括阵列-比较基因组杂交(阵列-CGH),全RNA测序,无监督聚类,和来自12例患者的16例KAT6B::KANSL1融合肿瘤的cDNA突变谱分析。在介绍时,患者围绝经期(中位数47.5年),原发肿瘤位于子宫体(12/12,100%),在1/12(8.3%)病例中有额外的膀胱前位置。复发率为33.3%(3/9)。所有肿瘤(16/16,100%)均显示在平滑肌瘤和子宫内膜间质肿瘤之间重叠的形态学和免疫组织化学特征。在13/16(81.3%)肿瘤中发现了旋转的复发性结构(类似于纤维粘液样ESS/纤维肉瘤)。所有肿瘤(16/16,100%)均表现出大量的小动脉样血管,和13/16(81.3%)大的透明中央血管和胶原沉积。雌激素和孕激素受体在16/16(100%)和14/16(87.5%)肿瘤中表达,分别。对10种肿瘤进行的Array-CGH将这些肿瘤分类为简单基因组肉瘤。对16个样品的全RNA测序和对原发性肿瘤的聚类分析发现,KAT6B::KANSL1融合始终发生在KAT6B的外显子3和KANSL1的11之间;在cDNA上未发现致病性变异;所有肿瘤聚集在一起,接近LG-ESS;途径富集分析显示细胞增殖和免疫浸润招募途径参与。这些结果证实,带有KAT6B/A::KANSL1融合的肉瘤代表了一种独特的临床病理实体,接近LG-ESS但不同,尽管形态令人放心,但具有临床攻击性,其中KAT6B/A::KANSL1融合是驱动分子改变。
Neoplasms harboring a KAT6B/A::KANSL1 fusion were initially reported as benign (leiomyomas) and malignant (leiomyosarcomas, low-grade endometrial stromal sarcomas [LG-ESSs]) uterine neoplasms. However, they may represent an emerging entity characterized by clinical aggressiveness contrasting with a rather reassuring microscopic appearance. Here, we aimed to confirm that this neoplasm is a distinct clinicopathologic and molecular sarcoma and identify criteria that should alert pathologists and lead to KAT6B/A::KANSL1 fusion testing in routine practice. Therefore, we conducted a comprehensive clinical, histopathologic, immunohistochemical, and molecular study, including array comparative genomic hybridization, whole RNA-sequencing, unsupervised clustering, and cDNA mutational profile analyses 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 (8.3%) of 12 cases. The relapse rate was 33.3% (3/9). All tumors (16/16, 100%) showed morphologic and immunohistochemical features overlapping between leiomyoma and endometrial stromal tumors. A whirling recurrent architecture (resembling fibromyxoid-ESS/fibrosarcoma) was found in 13 (81.3%) of 16 tumors. All tumors (16/16, 100%) exhibited numerous arterioliform vessels, and 13 (81.3%) of 18 had large hyalinized central vessels and collagen deposits. Estrogen and progesterone receptors were expressed in 16 (100%) of 16 and 14 (87.5%) of 16 tumors, respectively. Array comparative genomic hybridization 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, and 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 clinicopathologic entity, close to LG-ESS but different, with clinical aggressiveness despite a reassuring morphology, for which the KAT6B/A::KANSL1 fusion is the molecular driver alteration.