Smith Steven Christopher, Buehler Darya, Choi Eun-Young Karen, McHugh Jonathan B, Rubin Brian P, Billings Steven D, Balzer Bonnie, Thomas Dafydd G, Lucas David R, Goldblum John R, Patel Rajiv M
1] Department of Pathology, University of Michigan Health System, Ann Arbor, MI, USA [2] Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Pathology and Laboratory Medicine, University of Wisconsin Hospital, Madison, WI, USA.
Mod Pathol. 2015 Jan;28(1):57-68. doi: 10.1038/modpathol.2014.83. Epub 2014 Jun 20.
Recent molecular advances have identified a novel, clinically aggressive subgroup of undifferentiated round cell sarcomas defined molecularly by oncogenic fusion of the gene, CIC, and either DUX4 or its paralog, DUX4L, herein termed CIC-DUX sarcomas. Morphologically, CIC-DUX sarcomas are round cell sarcomas with high-grade nuclear features, including vesicular chromatin and nucleoli, patchy clear cell foci, myxoid change, and necrosis. Here, we studied a cohort of 10 cases, including 6 newly identified cases, 2 with paired metastases. Given our prior observation of trisomy 8 in these tumors, we assayed for amplification and expression of MYC (c-Myc) and representative downstream targets. Trisomy 8 was detected in 5/7 testable cases, with further amplification of MYC locus in 6/7 testable cases and immunohistochemical expression of MYC in 10/10. The canonical MYC transcriptional target, p21, but not MTDH, was differentially expressed compared with Ewing sarcomas. Given prior observation of induction of ETS-family transcription factors by the fusion oncoprotein, we assayed and identified highly prevalent positivity for ERG (9/10) and FLI1 (8/8). These findings are cautionary regarding use of these immunostains in prospective case workup, whereas the prevalent MYC amplification may represent a therapeutically targetable oncogenic pathway in CIC-DUX sarcomas.
最近的分子研究进展已经确定了一种新型的、具有临床侵袭性的未分化圆形细胞肉瘤亚组，其分子定义为基因CIC与DUX4或其旁系同源基因DUX4L发生致癌性融合，在此称为CIC-DUX肉瘤。形态学上，CIC-DUX肉瘤是具有高级别核特征的圆形细胞肉瘤，包括泡状染色质和核仁、散在的透明细胞灶、黏液样改变和坏死。在此，我们研究了一组10例病例，包括6例新确诊病例，其中2例伴有配对转移灶。鉴于我们之前在这些肿瘤中观察到8号染色体三体，我们检测了MYC（c-Myc）及其代表性下游靶点的扩增和表达情况。在7例可检测的病例中，5例检测到8号染色体三体，7例可检测病例中有6例存在MYC基因座的进一步扩增，10例病例中有10例MYC免疫组化表达阳性。与尤因肉瘤相比，经典的MYC转录靶点p21而非MTDH存在差异表达。鉴于之前观察到融合癌蛋白可诱导ETS家族转录因子，我们检测并确定ERG（9/10）和FLI1（8/8）高度普遍阳性。这些发现警示了在预期病例检查中使用这些免疫染色的情况，而普遍存在的MYC扩增可能代表了CIC-DUX肉瘤中一个可靶向治疗的致癌途径。
