Rhabdomyosarcoma in children and young adults.

Abstract

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.