Abstract：
EGFR aberrations are reported in a subset of myofibroblastic lesions with kinase domain duplication (EGFR-KDD) and exon 20 mutations being assigned to infantile fibrosarcomas (IFS), mesoblastic nephroma, and fibrous hamartoma of infancy (FHI), respectively. In this retrospective study, we correlated molecular findings with the histomorphology of 14 myofibroblastic lesions harboring such genetic changes identified by NGS. We additionally performed DNA methylation profiling (DNAmp) and immunohistochemistry. Lesions were from 10 males and 4 females with a mean age of 3 years (range, 0.3-14) and occurred subcutaneously in the upper limbs (n = 5), lower limbs (n = 3), back/thorax (n = 5), and the nasal cavity (n = 1). Eleven were cured by surgery, including 1 relapsed case. Two patients were lost to follow-up. One case was very recent, and the patient was biopsied. Histologically, the lesions showed a wide spectrum varying from classic FHI (n = 9) to IFS (n = 1) or lipofibromatosis-like tumors (LFT-like) (n = 2) or dermatofibrosarcoma protuberans-like (DFSP-like) (n = 1) to a predominantly myxoid spindle cell lesion (n = 1). Immunohistochemically, all neoplasms stained with CD34, whereas S100 was positive in 2/14. EGFR expression was observed in 9/10 cases. Molecularly, the IFS and 1 LFT-like harbored EGFR-KDD, whereas an exon 20 mutation was identified in all FHI, 1 LFT-like, the DFSP-like, and in predominant myxoid spindle cell lesion. By DNAmp, all but 2 cases formed a well-defined cluster, demonstrating that these lesions are also epigenetically related. In conclusion, EGFR kinase domain aberrations found in FHI, IFS, LFT-like, DFSP-like, and a spindle cell lesion with a predominant myxoid stroma of children and adolescents showed that these neoplasms with a broad morphologic spectrum belong to the group of protein kinase-related lesions with a distinct epigenetic signature. Molecular analyses, including DNAmp, help to identify and characterize this emerging category and become mandatory when targeted treatment is considered.
摘要：
据报道，在一组具有激酶结构域重复（EGFR-KDD）和外显子20突变的肌纤维母细胞性病变中，EGFR畸变被分配给婴儿纤维肉瘤（IFS）。中胚层肾瘤和婴儿期纤维性错构瘤（FHI），分别。在这项回顾性研究中,我们对14个由NGS鉴定的具有这种遗传变化的肌纤维母细胞性病变的组织形态学研究进行了相关分析.我们还进行了DNA甲基化分析（DNAMP）和免疫组织化学。病变来自10名男性和4名女性，平均年龄为3岁(范围，0.3-14），并在上肢皮下发生（n=5），下肢（n=3），背部/胸部（n=5），和鼻腔（n=1）。11人经手术治愈,包括一例复发病例。两名患者失访。一个案例是最近发生的，对病人进行了活检。组织学上,病变范围广泛,从经典FHI(n=9)到IFS(n=1),从脂纤维瘤病样肿瘤(LFT样)(n=2)或隆突样皮肤纤维肉瘤(DFSP样)(n=1)到主要为黏液样梭形细胞病变(n=1).免疫组织化学，所有肿瘤均被CD34染色，而S100在2/14中呈阳性。在9/10例中观察到EGFR表达。分子上，IFS和一个类似LFT的EGFR-KDD，虽然在所有FHI中都鉴定出外显子20突变，一个LFT样和DFSP样且主要是粘液样梭形细胞病变。由DNAMP，除了两个案例之外，所有案例都形成了一个定义明确的集群，证明这些病变也是表观遗传相关的。总之,在FHI中发现的EGFR激酶结构域畸变，IFS,LFT-like,儿童和青少年的DFSP样和具有主要粘液样基质的梭形细胞病变表明，这些具有广泛形态谱的肿瘤属于具有明显表观遗传特征的蛋白激酶相关病变组。分子分析,包括DNAMP,帮助识别和表征这一新兴类别，并在考虑靶向治疗时成为强制性的。
