杨路路  译，黄文斌  校

横纹肌肉瘤(RMS)被分为胚胎性RMS、腺泡状RMS、多形性RMS以及最近认识的梭形细胞和硬化性RMS。梭形细胞RMS最初被认为是胚胎性RMS的一种亚型，常见于儿童睾丸旁区域，且有较好的预后，但随后发现梭形细胞RMS也可见于成人，且具有较侵袭性的临床行为。硬化性RMS被确定为RMS的一种独特亚型，研究发现梭形细胞RMS与硬化性RMS存在一定的关系。肌源性转录因子MYOD1和PIK3CA的复发性突变最初在一些胚胎性横纹肌肉瘤中被描述。最近两个独立的研究证实MYOD1（L122R）突变可作为重新分类梭形细胞和硬化性横纹肌肉瘤的基础，其不同于胚胎性横纹肌肉瘤。我们收集了9年间49例各种类型横纹肌肉瘤，分析了这种横纹肌肉瘤中MYOD1 (L122R)、PIK3CA (H1047)及PIK3CA (E542/E545)突变情况，同时对这些病例进行了desmin、myogenin和MYOD1的免疫组化检测。虽然活化性PIK3CA突变在所有检测的病例中均未检出，但我们发现20%横纹肌肉瘤存在MYOD1 (L122R)突变，这些MYOD1(L122R)突变的肿瘤均为梭形细胞和硬化性横纹肌肉瘤(10/21)，主要发生于头颈部及肢体末端(64%)，多于睾丸旁和腹腔内。而且，虽然所有10例MYOD1突变的梭形细胞和硬化性横纹肌肉瘤显示弥漫强阳性表达MYOD1，但31例野生型MYOD1的横纹肌肉瘤中有7例MYOD1为阴性表达。临床上，21例中有15例获得了MYOD1突变与临床结局之间的相关性：7例具有MYOD1突变的梭形细胞和硬化性横纹肌肉瘤患者中5例带瘤生存；8例带有突变型MYOD1的梭形细胞和硬化性横纹肌肉瘤患者中2例无病生存。总之，目前为止，我们首次报道了49例横纹肌肉瘤最大宗病例中MYOD1（L122R）突变情况，并发现MYOD1(L122R）突变与相对侵袭性的临床行为相关。此外，与以前的两项研究结果一致，我们的研究进一步明确了梭形细胞和硬化性横纹肌肉瘤之间具有密切关系—现认为是一种单独的亚型，不同于胚胎性横纹肌肉瘤。

Rekhi B, Upadhyay P, Ramteke MP, et al. MYOD1 (L122R) mutations are associated with spindle cell and sclerosing rhabdomyosarcomas with aggressive clinical outcomes. Mod Pathol, 2016,29(12):1532-1540. 

Recurrent mutations in the myogenic transcription factor MYOD1 and PIK3CA were initially described in a subset of embryonal rhabdomyosarcomas. Recently, two independent studies demonstrated presence of MYODI (L122R) mutations as the basis to re-classify a spindle cell rhabdomyosarcoma, along with a sclerosing rhabdomyosarcoma, distinct from an embryonal rhabdomyosarcoma. We analyzed a much larger cohort of 49 primary rhabdomyosarcoma tumor samples of various subtypes, collected over a period of 9 years, for the presence of MYOD1 (L122R), PIK3CA (H1047), and PIK3CA (E542/E545) mutations, along with immunohistochemical analysis of desmin, myogenin, and MYOD1. Although activating PIK3CA mutations were absent across the sample set analyzed, we report 20% MYOD1 (L122R) mutation in rhabdomyosarcomas, found exclusively in 10 of 21 spindle cell and sclerosing rhabdomyosarcomas, occurring mostly in the head and neck region along with extremity sites (64%), than the paratesticular and intra-abdominal sites. Furthermore, while all 10 MYOD1 mutant spindle cell and sclerosing rhabdomyosarcoma samples showed diffuse and strong MYOD1 immunoexpression, 7 of 31 samples of rhabdomyosarcoma with wild-type MYOD1 were negative for MYOD1 expression. Clinically, a striking correlation was found between MYOD1 mutation and the clinical outcomes available for 15 of 21 cases: 5 of 7 patients with spindle cell and sclerosing rhabdomyosarcomas, harboring MYOD1 mutation, were alive-with-disease and 2 of 8 patients with spindle cell and sclerosing rhabdomyosarcomas, with mutant MYOD1, were free-of-disease. Taken together, we present the first report of MYOD1 (L122R) mutation in the largest cohort of 49 rhabdomyosarcomas reported so far, that are associated with a relatively aggressive clinical course. Moreover, consistent with the earlier two studies, this study further reinforces a relationship between spindle cell and the sclerosing rhabdomyosarcoma—now recognized as a single subtype, distinct from an embryonal rhabdomyosarcoma.