Extremity Rhabdomyosarcoma-An Integrated Clinicopathologic and Genomic Study to Improve Risk Stratification.

Abstract

Extremity rhabdomyosarcoma (RMS) is associated with a very poor outcome compared with other sites, mainly because of its high incidence of alveolar histology and regional lymph node involvement. To better define prognostic markers in this clinical subset, we investigated our experience of 61 patients with extremity RMS treated at our tertiary cancer center for the past 2 decades. The patients had a median age of 8 years at diagnosis, equal gender distribution, and two-thirds occurred in the lower extremity. Most (85%) patients had <i>FOXO1</i> fusion-positive alveolar RMS (ARMS), with 70% having a <i>PAX3::FOXO1</i> transcript. Remaining were seven patients with fusion-negative embryonal RMS (ERMS) and two with <i>MYOD1-</i>mutant spindle cell/sclerosing RMS (SRMS). In 40% of the patients, material was available for DNA-based targeted sequencing using MSK-IMPACT cancer gene panel. One-third of patients presented with localized disease at diagnosis while the remaining had regional nodal (18%) or distant metastases (51%). Metastatic disease, high-risk group, and age 10 years or older significantly affected the overall survival (OS; hazard ratio [HR], 2.68 [<i>P</i> = .004], 2.78 [<i>P</i> = .010] and 2.26 [<i>P =</i> .034], respectively). Although the presence of metastatic disease had a dismal impact on 5-year EFS and OS (19% and 29%, respectively), nodal involvement had a comparatively lower impact on 5-year EFS and 5-year OS (43% and 66%, respectively). <i>PAX3::FOXO1</i> ARMS had worse prognosis and afflicted older children compared with <i>PAX7::FOXO1</i> (HR = 3.45, <i>P =</i> .016). The most common events in the ARMS group included <i>MED12</i> alterations, <i>CDK4</i> amplifications, and <i>CDKN2A</i> deletions (8%-17%). The latter two abnormalities were mutually exclusive, enriched for acral and high-risk lesions, and correlated with poor outcome on OS (<i>P</i> = .02). Our data provide rationale for considering the integration of molecular abnormalities to refine risk stratification in extremity RMS.