Chen Sonja, Kelsey Anna M, Rudzinski Erin R
Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, USA.
Diagnostic Paediatric Histopathology Service, Royal Manchester Children's Hospital, Oxford Road, Manchester, M13 9WL, England.
Virchows Arch. 2025 Jan;486(1):101-116. doi: 10.1007/s00428-024-03961-y. Epub 2024 Dec 18.
Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in childhood, accounting for 3% of all pediatric malignancies and 50% of all pediatric soft tissue sarcomas. In adolescents and young adults (AYA) however, RMS comprises only 6.5% of all soft tissue sarcomas. Historically, diagnosis and treatment of RMS was based on histologic recognition of the alveolar subtype, which was associated with a worse prognosis. Within the past 20 years, the biologic characteristics of RMS have become clearer, with canonical fusion drivers, PAX3/7::FOXO1, characterizing the alveolar subtype (ARMS) and in turn associated with poor outcome, while chromosomal gains/losses in addition to RAS pathway alterations characterize the embryonal subtype (ERMS). Accordingly, detection of a FOXO1 gene fusion has become a commonplace diagnostic and prognostic tool allowing tumors to be treated based on presence or absence of a FOXO1 gene fusion. However, these cytogenetic and molecular alterations represent only a portion of the molecular landscape found in RMS, and other alterations are found with increasing frequency in various subsets of RMS. Clinical trials basing risk stratification on the presence or absence of the canonical PAX3/7::FOXO1 fusions have had success in identifying the poor responders. Due to poor outcomes, the presence of MYOD1 and TP53 alterations which are common in spindle cell sclerosing RMS (SSRMS) and RMS with anaplasia have also been integrated into trial risk stratification. Therefore, complete histologic and immunophenotypic characterization remain important to better recognize and study these rare subsets of RMS. This article will discuss the challenges of RMS classification including how to combine morphologic, immunophenotypic and molecular data to arrive at an integrated diagnosis. The use of newer techniques such as liquid biopsy and methylation profiling, will also continue to shape the classification of RMS and may further refine risk stratification and prognosis.
横纹肌肉瘤（RMS）是儿童期最常见的软组织恶性肿瘤，占所有儿科恶性肿瘤的3%，占所有儿科软组织肉瘤的50%。然而，在青少年和青年（AYA）中，RMS仅占所有软组织肉瘤的6.5%。历史上，RMS的诊断和治疗基于肺泡亚型的组织学识别，该亚型与较差的预后相关。在过去20年中，RMS的生物学特征变得更加清晰，典型的融合驱动因子PAX3/7::FOXO1表征肺泡亚型（ARMS），进而与不良预后相关，而除RAS通路改变外的染色体增减表征胚胎亚型（ERMS）。因此，检测FOXO1基因融合已成为一种常见的诊断和预后工具，可根据FOXO1基因融合的有无对肿瘤进行治疗。然而，这些细胞遗传学和分子改变仅代表RMS中发现的分子格局的一部分，并且在RMS的各个亚组中发现其他改变的频率越来越高。基于典型PAX3/7::FOXO1融合的有无进行风险分层的临床试验已成功识别出反应较差的患者。由于预后不良，在梭形细胞硬化性RMS（SSRMS）和间变性RMS中常见的MYOD1和TP53改变也已纳入试验风险分层。因此，完整的组织学和免疫表型特征对于更好地识别和研究这些罕见的RMS亚组仍然很重要。本文将讨论RMS分类的挑战，包括如何结合形态学、免疫表型和分子数据以达成综合诊断。液体活检和甲基化分析等新技术的应用也将继续塑造RMS的分类，并可能进一步优化风险分层和预后。
