Pathology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Diagnostic Laboratory, Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Mod Pathol. 2024 Sep;37(9):100539. doi: 10.1016/j.modpat.2024.100539. Epub 2024 Jun 14.
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.
EGFR 异常存在于具有激酶结构域重复（EGFR-KDD）的肌纤维母细胞瘤亚群中，而外显子 20 突变分别被分配给婴儿纤维肉瘤（IFS）、中胚层肾瘤和婴儿纤维性错构瘤（FHI）。在这项回顾性研究中，我们将分子发现与通过 NGS 鉴定的 14 种携带这种遗传变化的肌纤维母细胞瘤的组织形态学相关联。我们还进行了 DNA 甲基化分析（DNAmp）和免疫组织化学分析。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 岁），发生于上肢（n=5）、下肢（n=3）、背部/胸部（n=5）和鼻腔（n=1）。11 例通过手术治愈，包括 1 例复发。2 例患者失访。1 例为近期病例，患者行活检。组织学上，病变表现出广泛的谱，从经典 FHI（n=9）到 IFS（n=1）或脂肪纤维脂肪瘤样肿瘤（LFT-like）（n=2）或隆突性皮肤纤维肉瘤样（DFSP-like）（n=1）到主要黏液性梭形细胞病变（n=1）不等。免疫组织化学染色显示，所有肿瘤均表达 CD34，而 S100 在 14 例中有 2 例阳性。9/10 例 EGFR 表达阳性。分子上，IFS 和 1 例 LFT-like 存在 EGFR-KDD，而所有 FHI、1 例 LFT-like、DFSP-like 和主要黏液性梭形细胞病变均存在外显子 20 突变。通过 DNAmp，除 2 例外，所有病例均形成一个明确的聚类，表明这些病变在表观遗传学上也是相关的。总之，在儿童和青少年的 FHI、IFS、LFT-like、DFSP-like 和以黏液性基质为主的梭形细胞瘤中发现的 EGFR 激酶结构域异常表明，这些具有广泛形态学谱的肿瘤属于具有独特表观遗传特征的蛋白激酶相关病变组。分子分析，包括 DNAmp，有助于识别和表征这一新兴类别，当考虑靶向治疗时，这是必要的。
