Departments of *Laboratory Medicine and Pathology †Radiology ‡Biochemistry and Molecular Biology §Neurosurgery, Mayo Clinic, Rochester, MN.
Am J Surg Pathol. 2016 Oct;40(10):1368-74. doi: 10.1097/PAS.0000000000000673.
Neuromuscular choristoma (NMC) is a very rare, developmental malformation characterized by the endoneurial intercalation of mature muscle fibers among peripheral nerve fibers. NMC typically arises in the major proximal peripheral nerves, most commonly the sciatic nerve, and may involve the lumbosacral and brachial plexus. Patients present clinically with progressive neuropathy or plexopathy. NMC is strongly associated with development of a fibromatosis, histologically identical to conventional desmoid-type fibromatosis (NMC-fibromatosis). The development of NMC-fibromatosis is often precipitated by iatrogenic trauma (ie, biopsy). Desmoid-type fibromatosis is characterized by CTNNB1 exon 3 mutations, which result in aberrant nuclear β-catenin localization and dysregulated canonical Wnt signaling. In contrast, the pathogenesis of NMC and NMC-fibromatosis is unknown. Desmoid-type fibromatosis expresses estrogen receptors (ER), specifically the ER-beta isoform (ERβ), and endocrine therapies may be used in surgically unresectable cases. In contrast, the ER expression profile of NMC-fibromatosis is unknown. We evaluated a series of NMC and NMC-fibromatosis for CTNNB1 mutations, β-catenin expression, and ER isoform expression. Five NMCs occurred in 2 female and 3 male patients (median age: 14 y, range <1 to 42 y), as masses involving the sciatic nerve (N=4) or brachial plexus (N=1). Four (of 5) NMCs had CTNNB1 mutations: 3 c.134 C>T (p.S45F) and 1 c.121 A>G (p.T41A). Four patients subsequently developed NMC-fibromatosis, and all 4 cases contained CTNNB1 mutations, including 1 p.T41A and 3 p.S45F mutations. In 3 patients, the NMC and NMC-fibromatosis had identical CTNNB1 mutations. Only 1 NMC had no detectable CTNNB1 mutation; however, the patient's subsequent NMC-fibromatosis had a CTNNB1 p.T41A mutation. All NMC and NMC-fibromatosis showed aberrant nuclear localization of β-catenin, nuclear ERβ expression, and no ERα expression. The presence of CTNNB1 mutations both in NMC and NMC-fibromatosis may be a shared molecular genetic abnormality underlying their pathogenesis.
神经肌肉嵴瘤（NMC）是一种非常罕见的发育性畸形，其特征是成熟肌纤维在内膜中插入周围神经纤维之间。NMC 通常发生在主要的近端周围神经中，最常见的是坐骨神经，也可能涉及腰骶丛和臂丛。患者临床表现为进行性神经病或丛病。NMC 与纤维瘤病的发生密切相关，组织学上与传统的硬纤维瘤型纤维瘤病（NMC-纤维瘤病）相同。NMC-纤维瘤病的发生通常是由医源性创伤（即活检）引起的。硬纤维瘤型纤维瘤病的特征在于 CTNNB1 外显子 3 突变，导致异常核 β-连环蛋白定位和调节异常的经典 Wnt 信号通路。相比之下，NMC 和 NMC-纤维瘤病的发病机制尚不清楚。硬纤维瘤型纤维瘤病表达雌激素受体（ER），特别是 ER-β 同工型（ERβ），内分泌治疗可用于手术无法切除的病例。相比之下，NMC-纤维瘤病的 ER 表达谱尚不清楚。我们评估了一系列 NMC 和 NMC-纤维瘤病的 CTNNB1 突变、β-连环蛋白表达和 ER 同工型表达。5 例 NMC 发生于 2 例女性和 3 例男性患者（中位年龄：14 岁，范围＜1 至 42 岁），为累及坐骨神经（N=4）或臂丛（N=1）的肿块。5 例 NMC 中有 4 例（4/5）存在 CTNNB1 突变：3 例 c.134 C>T（p.S45F），1 例 c.121 A>G（p.T41A）。4 例患者随后发生 NMC-纤维瘤病，4 例均存在 CTNNB1 突变，包括 1 例 p.T41A 和 3 例 p.S45F 突变。在 3 例患者中，NMC 和 NMC-纤维瘤病具有相同的 CTNNB1 突变。只有 1 例 NMC 未检测到 CTNNB1 突变；然而，该患者随后的 NMC-纤维瘤病存在 CTNNB1 p.T41A 突变。所有 NMC 和 NMC-纤维瘤病均表现出异常核定位的 β-连环蛋白、核 ERβ 表达和无 ERα 表达。NMC 和 NMC-纤维瘤病中 CTNNB1 突变的存在可能是其发病机制的共同分子遗传异常。
