Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
Department of Pediatrics, Brussels University Hospital, Academic Children's Hospital Queen Fabiola, Université Libre de Bruxelles, Brussels, Belgium.
JCO Precis Oncol. 2024 Apr;8:e2300597. doi: 10.1200/PO.23.00597.
Alterations of the tumor suppressor gene is the second most frequent genetic event in embryonal rhabdomyosarcoma (ERMS), but its associations with clinicopathologic features, outcome, or coexisting molecular events are not well defined. Additionally, alterations, mostly in the setting of neurofibromatosis type I (NF1), drive the pathogenesis of most malignant peripheral nerve sheath tumor with divergent RMS differentiation (also known as malignant triton tumor [MTT]). Distinguishing between these entities can be challenging because of their pathologic overlap. This study aims to comprehensively analyze the clinicopathologic and molecular spectrum of -mutant RMS compared with NF1-associated MTT for a better understanding of their pathogenesis.
We investigated the clinicopathologic and molecular landscape of a cohort of 22 -mutant RMS and a control group of 13 -associated MTT. Cases were tested on a matched tumor-normal hybridization capture-based targeted DNA next-generation sequencing.
Among the RMS group, all except one were ERMS, with a median age of 17 years while for MTT the mean age was 39 years. Three MTTs were misdiagnosed as ERMS, having clinical impact in one. The most frequent coexisting alteration in ERMS was abnormality (36%), being mutually exclusive from mutations (14%). MTT showed coexisting and PRC2 complex alterations in 38% cases and loss of H3K27me3 expression. Patients with -mutant RMS exhibited a 70% 5-year survival rate, in contrast to MTT with a 33% 5-year survival. All metastatic -mutant ERMS were associated with alterations.
Patients with NF1-mutant ERMS lacking alterations may benefit from dose-reduction chemotherapy. On the basis of the diagnostic challenges and significant treatment and prognostic differences, molecular profiling of challenging tumors with rhabdomyoblastic differentiation is recommended.
肿瘤抑制基因的改变是胚胎性横纹肌肉瘤（ERMS）中第二常见的遗传事件，但它与临床病理特征、结局或共存的分子事件的关系尚未明确。此外，改变，主要是在神经纤维瘤病 I 型（NF1）的背景下，驱动了大多数具有不同 RMS 分化的恶性外周神经鞘瘤的发病机制（也称为恶性 Triton 肿瘤[MTT]）。由于它们的病理重叠，区分这些实体可能具有挑战性。本研究旨在全面分析 -突变 RMS 的临床病理和分子谱与 NF1 相关的 MTT，以更好地了解它们的发病机制。
我们研究了 22 例 -突变 RMS 和 13 例 -相关 MTT 的队列的临床病理和分子图谱。对这些病例进行了基于匹配肿瘤-正常杂交捕获的靶向 DNA 下一代测序。
在 RMS 组中，除了一个病例外，所有病例均为 ERMS，中位年龄为 17 岁，而 MTT 的平均年龄为 39 岁。有 3 例 MTT 误诊为 ERMS，其中 1 例有临床影响。在 ERMS 中最常见的共存改变是 异常（36%），与 突变（14%）相互排斥。在 38%的病例中，MTT 显示出共存的 和 PRC2 复合物改变，并伴有 H3K27me3 表达缺失。 -突变 RMS 患者的 5 年生存率为 70%，而 MTT 的 5 年生存率为 33%。所有转移性 -突变 ERMS 均与 改变有关。
缺乏 改变的 NF1 突变 ERMS 患者可能受益于降低剂量的化疗。基于诊断上的挑战以及显著的治疗和预后差异，建议对具有横纹肌母细胞分化的具有挑战性的肿瘤进行分子谱分析。
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