Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Department of Pathology, University of Miami, Miami, Florida, USA.
Genes Chromosomes Cancer. 2021 Sep;60(9):616-622. doi: 10.1002/gcc.22970. Epub 2021 May 18.
Undifferentiated sarcomas remain difficult to classify. Despite the remarkable advances in sarcoma classification made by the increased application of RNA sequencing in clinical practice, the unexpected result of a novel gene fusion raises further questions regarding the tumor histogenesis and subclassification. In this study, we present two high grade sarcomas with epithelioid phenotype occurring in the deep-soft tissues (shoulder, thigh) of young adults which based on the non-specific pathologic findings were deemed unclassified and subjected to targeted RNA sequencing for further diagnostic interpretation. The results showed an identical EWSR1 exon 7-SSX1 exon 5 fusion. The breakpoints in both genes represent similar hot spots as seen in Ewing sarcoma and synovial sarcoma, generating a fusion transcript predicted to be in frame, and to retain the same protein domains within the fusion oncoprotein. These results were further confirmed by FISH analysis for both break-apart and fusion come-together assays in both genes. Both tumors showed a round to epithelioid morphology associated with extensive stromal hyalinization and necrosis. One case showed scattered psammomatous calcifications. The tumors shared a similar immunoprofile, including reactivity for EMA, CK, TLE1, BCOR, and CD99, while negative for S100, SOX10, CD34, SMA, and desmin. Both cases showed MUC4 positivity (one diffuse, one patchy), while one case showed patchy ALK positivity. One patient developed lymph node metastases, while the other showed no evidence of disease at 6-month follow-up. Neither case fit in any known pathologic categories. Larger series are needed to interrogate if the presence of EWSR1-SSX1 fusion defines a novel pathologic entity of a sarcoma with epithelioid cytomorphology, sclerotic stroma, and epithelial differentiation immunohistochemically.
未分化肉瘤的分类仍然具有挑战性。尽管 RNA 测序在临床实践中的广泛应用使得肉瘤分类取得了显著进展，但新基因融合的意外结果进一步引发了关于肿瘤发生和亚分类的问题。在这项研究中，我们报告了两例发生于年轻成年人深部软组织（肩部、大腿）的具有上皮样表型的高级别肉瘤，根据非特异性病理发现，这些肿瘤被认为无法分类，并进行了靶向 RNA 测序以进行进一步的诊断解读。结果显示存在相同的 EWSR1 外显子 7-SSX1 外显子 5 融合。这两个基因的断点与尤因肉瘤和滑膜肉瘤中看到的相似热点相同，产生融合转录本，被预测为框架内，并保留融合癌蛋白内的相同蛋白结构域。这些结果通过 FISH 分析在两个基因中均进行了分离和融合检测得到进一步证实。两个肿瘤均表现为圆形至上皮样形态，伴有广泛的间质玻璃样变和坏死。一个病例显示散在的砂粒体样钙化。肿瘤具有相似的免疫表型，包括对 EMA、CK、TLE1、BCOR 和 CD99 的反应性，而对 S100、SOX10、CD34、SMA 和结蛋白的反应性为阴性。两个病例均显示 MUC4 阳性（一个弥漫性，一个斑片状），一个病例显示斑片状 ALK 阳性。一名患者发生淋巴结转移，另一名患者在 6 个月随访时无疾病证据。两种情况均不符合任何已知的病理类别。需要进行更大的系列研究，以探讨 EWSR1-SSX1 融合的存在是否定义了一种具有上皮样细胞形态、硬化性基质和上皮分化免疫组化特征的新型肉瘤的病理实体。
