神经肌肉迷芽瘤相关的韧带样型纤维瘤病临床病理及分子遗传学特征

Clinicopathological and molecular genetic features of neuromuscular choristoma-associated desmoid type fibromatosis

目的探讨神经肌肉迷芽瘤相关的韧带样型纤维瘤病(neuromuscular choristoma-associated desmoid type fibromatosis,NMC-DF)临床病理及分子遗传学特征。方法收集北京积水潭医院2013年1月至2023年1月明确诊断为NMC-DF的病例7例,对其临床、组织形态及免疫组织化学特点进行回顾性分析,采用Sanger测序法对4例患者的神经肌肉迷芽瘤(neuromuscular choristoma,NMC)及韧带样型纤维瘤病(desmoid type fibromatosis,DF)标本分别进行检测,明确CTNNB1基因的突变类型。结果7例患者中女性3例,男性4例,年龄1~22岁,平均年龄7.1岁。病程3个月到10年不等。2例为复发后就诊病例。肿瘤位于大腿3例,小腿1例,上臂1例,颈部1例,影像学提示7例肿瘤均有相应部位神经增粗,4例为坐骨神经,1例为坐骨神经、胫神经、腓总神经全程瘤样增粗,2例为臂从神经,肿瘤与病变神经关系密切。7例病变的神经束内可见骨骼肌纤维,残存的神经纤维穿插其中,呈神经肌肉迷芽瘤的结构;肿瘤均具有典型的韧带样型纤维瘤病结构。免疫组织化学,NMC中部分肌纤维细胞核表达β-catenin(7/7),肌纤维结蛋白弥漫阳性,神经纤维神经丝蛋白和S-100蛋白阳性(7/7);NMC-DF中β-catenin在肿瘤细胞核中呈散在阳性(7/7)。CTNNB1基因Sanger测序,3例c.121A>G(p.T41A)突变,1例c.134C>T(p.S45F)突变。7例获得随访资料,随访时间22~78个月,2例为复发后就诊,其中1例截肢后再次复发,其余无进展。结论NMC是一种罕见的神经发育畸形性病变,神经干内可见异位的骨骼肌纤维,约80%的病例在病变神经周围软组织内伴发DF,组织形态与经典的DF相同,Wnt信号通路中的CTNNB1基因突变与二者的发生发展密切相关,CTNNB1 c.134C>T(p.S45F)突变可能提示不良预后。

Objective To investigate the clinicopathological and genetic characteristics of neuromuscular choristoma-associated desmoid type fibromatosis(NMC-DF).Methods The clinical morphological and immunohistochemical features of 7 NMC-DF cases diagnosed from January 2013 to January 2023 in Beijing Jishuitan Hospital were retrospectively analyzed.A series of neuromuscular choristoma and neuromuscular choristoma-associated desmoid type fibromatosis were evaluated for CTNNB1 mutations,and hotspot mutations for CTNNB1 were tested in 4 NMC-DF cases using Sanger sequencing.Results The tumors were collected from 3 females and 4 males,aged 1 to 22 years(mean 7.1 years),involving the sciatic nerve(n=4),brachial plexus(n=2)or multiple nerves(n=1).The course of the disease spanned from 3 months to 10 years.Two cases were recurrent tumors.All the 7 NMC cases showed endoneurial intercalation of mature skeletal muscle fibers among the peripheral nerve fascicles,and the histologic features of the NMC-DF were strikingly similar to the conventional desmoid-type fibromatosis.By immunohistochemistry,all NMC and NMC-DF cases showed aberrant nuclear staining ofβ-catenin(7/7),the muscle cells in NMC were intensely immunoreactive for desmin,and the admixed nerve fibers were highlighted by NF and S-100(7/7).Four NMC and NMC-DF had CTNNB1 mutations,3 c.121A>G(p.T41A)and 1 c.134C>T(p.S45F).Follow-up of the 7 cases,ranging from 22 to 78 months,showed tumor recurrence in 2 patients at 3 and 8 months respectively after the first surgical resection,of which 1 patient underwent above-knee amputation.No recurrence occurred in other cases with tumor excision and neurological reconstruction surgery.There was no metastasis occurred in the 7 cases.Conclusions NMC is a rare congenital lesion with differentiated mature skeletal muscle tissue found in peripheral nerve fascicles,and approximately 80%of patients with NMC develop a soft tissue fibromatosis.CTNNB1 mutation in the Wnt signaling pathway may be involved in the pathogenesis of NMC and NMC-DF,and S45F mutations seems to have a higher risk of disease progression.