Antonescu Cristina R, Owosho Adepitan A, Zhang Lei, Chen Sonja, Deniz Kemal, Huryn Joseph M, Kao Yu-Chien, Huang Shih-Chiang, Singer Samuel, Tap William, Schaefer Inga-Marie, Fletcher Christopher D
Departments of *Pathology †Surgery ¶Medicine, Memorial Sloan Kettering Cancer Center, New York, NY ‡Department of Pathology, Erciyes University, Kayseri, Turkey §Department of Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei ∥Department of Anatomical Pathology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan #Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Am J Surg Pathol. 2017 Jul;41(7):941-949. doi: 10.1097/PAS.0000000000000846.
CIC-DUX4 gene fusion, resulting from either a t(4;19) or t(10;19) translocation, is the most common genetic abnormality detected in EWSR1-negative small blue round cell tumors. Following their discovery it was debated if these tumors should be classified as variants of Ewing sarcoma (ie, atypical Ewing sarcoma) or as a stand-alone pathologic entity. As such the WHO classification temporarily grouped the CIC-rearranged tumors under undifferentiated sarcomas with round cell phenotype, until further clinical evidence was available. However, most studies reported so far include small series with limited follow-up information, which preclude a more definitive assessment. The present work investigates the clinicopathologic features of a large cohort of sarcomas with CIC gene rearrangement, to define their clinical presentation, morphologic spectrum, and outcome. Our study further examines the overall survival of the CIC-positive cohort compared with a control group of EWSR1-rearranged Ewing sarcoma matched for age and stage. The study cohort included 115 patients, with a mean age of 32 years and a slight male predominance. Most tumors occurred in the soft tissue (86%), predominantly deep-seated and equally divided among trunk and extremity, followed by visceral locations (12%) and rarely in the bone (3%). Microscopically, most tumors showed round to ovoid cytomorphology but half of the cases showed also focal areas of spindling and epithelioid/rhabdoid phenotype, with frequent myxoid stromal changes. Variable CD99 reactivity was seen in 84% cases, with a diffuse pattern only in 23% of cases, whereas nuclear WT1 was seen in 92%. A CIC-DUX4 fusion was detected in 57% of cases, with either DUX4 on 4q35 (35%) or on 10q26 in 25 (22%) cases. No FOXO4 gene rearrangements were present in 39 cases tested. Clinical follow-up was available in 57 patients, with a 5-year survival of 43%, which was significantly lower than the 77% 5-year survival in the control Ewing sarcoma group (P=0.002). Our findings show that CIC-DUX4 sarcomas occur most commonly in young adults within the somatic soft tissues, having a wide spectrum of morphology including round, epithelioid and spindle cells, and associated with an aggressive clinical course, with an inferior overall survival compared with Ewing sarcoma. The results support the classification of CIC-rearranged tumors as an independent molecular and clinical subset of small blue round cell tumors distinct from Ewing sarcoma.
由t(4;19)或t(10;19)易位导致的CIC-DUX4基因融合，是在EWSR1阴性的小蓝圆细胞肿瘤中检测到的最常见的基因异常。自其被发现后，对于这些肿瘤应被归类为尤因肉瘤的变异型（即非典型尤因肉瘤）还是独立的病理实体存在争议。因此，在有更多临床证据之前，世界卫生组织分类将CIC重排的肿瘤暂时归为具有圆细胞表型的未分化肉瘤。然而，目前报道的大多数研究纳入的病例数较少且随访信息有限，这妨碍了更明确的评估。本研究调查了一大组具有CIC基因重排的肉瘤的临床病理特征，以明确其临床表现、形态学谱和预后。我们的研究进一步比较了CIC阳性队列与年龄和分期相匹配的EWSR1重排的尤因肉瘤对照组的总生存期。研究队列包括115例患者，平均年龄32岁，男性略占优势。大多数肿瘤发生于软组织（86%），主要为深部，在躯干和四肢分布均等，其次为内脏部位（12%），很少发生于骨（3%）。显微镜下，大多数肿瘤表现为圆形至卵圆形细胞形态，但半数病例也显示有局灶性梭形和上皮样/横纹肌样表型区域，伴有频繁的黏液样间质改变。84%的病例可见CD99反应性可变，仅23%的病例呈弥漫性模式，而92%的病例可见核WT1。57%的病例检测到CIC-DUX4融合，其中4q35上有DUX4的占35%，10q26上有DUX4的占22%（25例）。在检测的39例病例中未发现FOXO4基因重排。57例患者有临床随访资料,5年生存率为43%，显著低于对照组尤因肉瘤的5年生存率77%（P = 0.002）。我们的研究结果表明，CIC-DUX4肉瘤最常见于成人躯体软组织内，具有包括圆形、上皮样和梭形细胞在内的广泛形态学谱，且临床过程侵袭性强，与尤因肉瘤相比总生存期较差。这些结果支持将CIC重排的肿瘤归类为不同于尤因肉瘤的小蓝圆细胞肿瘤的一个独立分子和临床亚组。
