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Recurrent BRAF Gene Fusions in a Subset of Pediatric Spindle Cell Sarcomas Expanding the Genetic Spectrum of Tumors With Overlapping Features With Infantile Fibrosarcoma

发布日期:2018/9/16 16:21:10 文章来源: 作者: 点击次数:1738

 

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Am J Surg Pathol 2018;42:28–38

Recurrent BRAF Gene Fusions in a Subset of Pediatric Spindle Cell Sarcomas Expanding the Genetic Spectrum of Tumors With Overlapping Features With Infantile Fibrosarcoma

(Expanding the Genetic Spectrum of Tumors With Overlapping Features With Infantile Fibrosarcoma)

Yu-Chien Kao, MD,*† Christopher D.M. Fletcher, MD, FRCPath,‡ Rita Alaggio, MD,§

Leonard Wexler, MD, Lei Zhang, MD,* Yun-Shao Sung, MSc,* Dicle Orhan, MD,¶

Wei-Chin Chang, MD,#**†† David Swanson, BSc,‡‡ Brendan C. Dickson, MD,‡‡

and Cristina R. Antonescu, MD

Abstract: Infantile fibrosarcomas (IFS) represent a distinct group of soft tissue tumors occurring in patients under 2 years of age and most commonly involving the extremities. Most IFS show recurrent ETV6-NTRK3 gene fusions, sensitivity to chemotherapy, and an overall favorable clinical outcome. However, outside these well-defined pathologic features, no studies have investigated IFS lacking ETV6-NTRK3 fusions, or tumors with the morphology resembling IFS in older children. This study was triggered by the identification of a novel SEPT7-BRAF fusion in an unclassified retroperitoneal spindle cell sarcoma in a 16-year-old female by targeted RNA sequencing. Fluorescence in situ hybridization screening of 9 additional tumors with similar phenotype and lacking ETV6-NTRK3 identified 4 additional cases with BRAF gene rearrangements in the pelvic cavity (n = 2), paraspinal region (n = 1), and thigh (n = 1) of young children (0 to 3 y old). Histologically, 4 cases including the index case shared a fascicular growth of packed monomorphic spindle cells, with uniform nuclei and fine chromatin, and a dilated branching vasculature; while the remaining case was composed of compact cellular sheets of short spindle to ovoid cells. In addition, a minor small blue round cell component was present in 1 case. Mitotic activity ranged from 1 to 9/10 high power fields. Immunohistochemical stains were nonspecific, with only focal smooth muscle actin staining demonstrated in 3 cases tested. Of the remaining 5 BRAF negative cases, further RNA sequencing identified 1 case with EML4-NTRK3 in an 1-year-old boy with a foot IFS, and a second case with TPM3-NTRK1 fusion in a 7-week-old infant with a retroperitoneal lesion. Our findings of recurrent BRAF gene rearrangements in tumors showing morphologic overlap with IFS expand the genetic spectrum of fusion-positive spindle cell sarcomas, to include unusual presentations, such as older children and adolescents and predilection for axial location, thereby opening new opportunities for kinase-targeted therapeutic intervention.

 

小儿梭形细胞肉瘤亚群中重现性braf基因融合/拓展婴儿纤维肉瘤的肿瘤遗传谱

摘要:婴儿纤维肉瘤(IFS)是2岁以下患者中最常见的四肢软组织肿瘤。大多数IFS显示复发的ETV6-NTRK3基因融合,对化学疗法的敏感性和总体有利的临床结果。然而,除了这些明确定义的病理特征之外,尚未有研究调查缺乏ETV6-NTRK3融合蛋白的IFS,或在年龄较大的儿童中形态类似于IFS的肿瘤。本研究由一名16岁女性未分类后腹膜梭形细胞肉瘤通过靶向RNA测序鉴定新型SEPT7-BRAF融合而触发。另外9个具有相似表型但缺乏ETV6-NTRK3的肿瘤的荧光原位杂交筛选鉴定了另外4BRAF基因在盆腔(n = 2),脊旁区(n = 1)和大腿(n = 1)年幼儿童(03岁)。组织学上,4例包括索引病例共同包装单形梭形细胞的束状生长,具有均匀的细胞核和细致的染色质以及扩张的分支脉管系统;而其余的病例由紧密的短梭形细胞片组成的卵圆细胞组成。另外,1例患者出现了小型蓝色圆形细胞成分。核分裂范围从19/10高倍视野。免疫组织化学染色是非特异性的,只有局灶性SMA3例测试中证实。在剩余的5BRAF阴性病例中,进一步的RNA测序鉴定出1EIF4-NTRK3在一名1岁男孩中有足部IFS,另一例在7周龄婴儿中与TPM3-NTRK1融合伴有腹膜后病变。我们的研究结果显示,与IFS形态学重叠的肿瘤中重现性BRAF基因重排扩大了融合阳性梭形细胞肉瘤的遗传谱,包括如年龄较大的儿童和青少年,从而为靶向治疗干预提供证据。(翻译 徐梦微)

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