Expanding the Spectrum of Intraosseous Rhabdomyosarcoma: Correlation Between 2 Distinct Gene Fusions and Phenotype
Expanding the Spectrum of Intraosseous Rhabdomyosarcoma: Correlation Between 2 Distinct Gene Fusions and Phenotype
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DOI：
10.1097/pas.0000000000001227
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发表时间：
2019-05-01
影响因子：
5.6
通讯作者：
Antonescu, Cristina R.
中科院分区：
文献类型：
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作者：
Agaram, Narasimhan P.;Zhang, Lei;Antonescu, Cristina R.
原发性骨内横纹肌肉瘤(RMS)极为罕见。最近两项研究报告了4例EWSR1/FUS-TFCP2基因融合的原发骨内RMS，其组织学特征从梭形到上皮样不等。在这项研究中，我们试图通过靶向RNA测序分析和荧光原位杂交(FISH)相结合的方法，进一步研究更大一组骨内RMS的病理和分子异常。我们确认了7例，男性3例，女性4例，均为年轻人，年龄20至39岁(中位数，27岁)。3例累及骨盆，2例累及股骨，1例累及上颌骨和颅骨。分子生物学研究证实7例患者均有复发基因融合，其中2例为新型Meis1-NCOA2融合，3例为EWSR1-TFCP2融合，1例为FUS-TFCP2融合。1例FISH显示FUS基因重排，未发现TFCP2基因异常。EWSR1/FUS重排的肿瘤具有梭形和上皮样混合表型，嗜酸性细胞质较丰富，核多形性较轻。免疫组织化学显示，所有肿瘤结蛋白和生肌素(局灶性)均阳性。此外，4例TFCP2相关基因融合的肿瘤也同时表达ALK和细胞角蛋白。综上所述，我们的结果表明，在骨骼的原发RMS中，基因融合的发生率很高，出现了两个分子亚群，由Meis1-NCOA2或EWSR1/FUS-TFCP2融合定义，显示出不同的形态和免疫表型。需要更多的病例和更长的随访数据来明确评估这些肿瘤的生物学行为，并建立它们与其他梭形细胞RMS遗传组的关系。
Primary intraosseous rhabdomyosarcomas (RMSs) are extremely rare. Recently 2 studies reported 4 cases of primary intraosseous RMS with EWSR1/FUS-TFCP2 gene fusions, associated with somewhat conflicting histologic features, ranging from spindle to epithelioid. In this study we sought to further investigate the pathologic and molecular abnormalities of a larger group of intraosseous RMSs by a combined approach using targeted RNA sequencing analysis and fluorescence in situ hybridization (FISH). We identified 7 cases, 3 males and 4 females, all in young adults, age range 20 to 39 years (median, 27y). Three cases involved the pelvis, 2 involved the femur and 1 each involved the maxilla and the skull. Molecular studies identified recurrent gene fusions in all 7 cases tested, including: a novel MEIS1-NCOA2 fusion in 2 cases, EWSR1-TFCP2 in 3 cases, and FUS-TFCP2 gene fusions in 1 case. One case showed a FUS gene rearrangement, without a TFCP2 gene abnormality by FISH. The MEIS1-NCOA2-positive cases were characterized by a more primitive and fascicular spindle cell appearance, while the EWSR1/FUS rearranged tumors had a hybrid spindle and epithelioid phenotype, with more abundant eosinophilic cytoplasm and mild nuclear pleomorphism. Immunohistochemically, all tumors were positive for desmin and myogenin (focal). In addition, 4 tumors with TFCP2-associated gene fusions also coexpressed ALK and cytokeratin. In conclusion, our results suggest a high incidence of gene fusions in primary RMSs of bone, with 2 molecular subsets emerging, defined by either MEIS1-NCOA2 or EWSR1/FUS-TFCP2 fusions, showing distinct morphology and immunophenotype. Additional studies with larger numbers of cases and longer follow-up data are required to definitively evaluate the biological behavior of these tumors and to establish their relationship to other spindle cell RMS genetic groups.