Department of Pathology, Brigham and Women's Hospital, Harvard Medical School.
Department of Pathology, Stanford University School of Medicine, Stanford, CA.
Am J Surg Pathol. 2018 Mar;42(3):335-341. doi: 10.1097/PAS.0000000000000993.
Endometrial stromal sarcomas (ESSs) are mesenchymal uterine tumors characterized by recurrent genetic events, most commonly chromosomal rearrangements, that create oncogenic gene fusions. High-grade endometrial stromal sarcomas (HG-ESSs), as defined in the 2014 World Health Organization Classification, typically contain oncogenic YWHAE-NUTM2 fusions; however, although not well characterized, there are tumors morphologically overlapping with HG-ESS that do not contain the YWHAE-NUTM2 fusions. These fusions are also found in certain pediatric primitive sarcomas, including clear cell sarcoma of the kidney and soft tissue undifferentiated round cell sarcoma of infancy. A subset of these same pediatric sarcomas lack YWHAE-NUTM2 fusions and instead have internal tandem duplications (ITDs) involving exon 15 of BCOR (BCOR ITD). We investigated the presence of BCOR ITD by targeted sequencing in a series of 31 uterine sarcomas, comprising 5 low-grade ESS, 13 uterine sarcomas diagnosed as HG-ESS, and 13 undifferentiated uterine sarcomas. BCOR ITD were present in 1 uterine sarcoma diagnosed as HG-ESS and 2 undifferentiated sarcomas with uniform nuclear features, all of which lacked any of the recurrent chromosome translocations known to occur in ESS. These 3 high-grade sarcomas with BCOR ITD affected young patients (average age, 24) and morphologically were composed of nonpleomorphic spindle cells admixed with epithelioid and round cell areas. Focal myxoid stroma was present in 2 cases. Mitotic activity was brisk, necrosis was present, and there was lymphovascular involvement in all cases. The 3 uterine sarcomas with BCOR ITD exhibited diffuse cyclin D1 immunohistochemical expression and there was diffuse BCOR expression in the 2 cases tested. Long-term follow-up in 2 patients revealed 1 to be tumor-free after 22 years and the other to die of disease after 8 years. In conclusion, BCOR ITD is an oncogenic alternative to YWHAE-NUTM2 fusion in high-grade uterine sarcomas with uniform nuclear features. We propose that neoplasms with the morphology described and BCOR ITD be regarded as a unique subtype of high-grade uterine sarcoma, possibly within the family of endometrial stromal neoplasia.
子宫内膜间质肉瘤（ESS）是一种间叶性子宫肿瘤，其特征为反复发生的遗传事件，最常见的是染色体重排，导致致癌基因融合。根据 2014 年世界卫生组织分类，高级别子宫内膜间质肉瘤（HG-ESS）通常包含致癌性 YWHAE-NUTM2 融合；然而，尽管形态学上与 HG-ESS 重叠的肿瘤并未包含 YWHAE-NUTM2 融合，但这些融合也存在于某些儿科原始肉瘤中，包括肾透明细胞肉瘤和婴儿软组织未分化圆形细胞肉瘤。这些融合也存在于某些儿科肉瘤中，这些肉瘤缺乏 YWHAE-NUTM2 融合，而是具有涉及 BCOR 外显子 15 的内部串联重复（ITD）。我们通过靶向测序在 31 例子宫肉瘤系列中研究了 BCOR ITD 的存在，包括 5 例低级别 ESS、13 例诊断为 HG-ESS 的子宫肉瘤和 13 例未分化的子宫肉瘤。BCOR ITD 存在于 1 例诊断为 HG-ESS 的子宫肉瘤和 2 例具有均匀核特征的未分化肉瘤中，所有这些肉瘤均缺乏 ESS 中已知发生的反复染色体易位。这 3 例具有 BCOR ITD 的高级别肉瘤影响年轻患者（平均年龄 24 岁），形态上由非多形性梭形细胞与上皮样和圆形细胞区混合组成。2 例有局灶性黏液样基质。所有病例均有活跃的有丝分裂、坏死和血管淋巴管侵犯。3 例具有 BCOR ITD 的子宫肉瘤表现出弥漫性 cyclin D1 免疫组化表达，在 2 例检测中均有弥漫性 BCOR 表达。2 例患者的长期随访显示，1 例患者在 22 年后无肿瘤，另 1 例患者在 8 年后死于疾病。总之，BCOR ITD 是具有均匀核特征的高级别子宫肉瘤中 YWHAE-NUTM2 融合的替代性致癌基因。我们建议将具有所述形态和 BCOR ITD 的肿瘤视为高级别子宫肉瘤的一种独特亚型，可能属于子宫内膜间质肿瘤家族。
