Integrative clinical and biopathology analyses to understand the clinical heterogeneity of infantile rhabdomyosarcoma: A report from the French MMT committee.

Background: Rhabdomyosarcoma (RMS) in infants is a particular entity with various clinical presentations and outcomes. To better understand the clinical heterogeneity of RMS in infants, an integrative clinical, histological, and molecular analysis was performed.

Methods: From 1989 to 2015, 37 infants aged less than 6 months with a diagnosis of RMS and archival tumor materials were identified in France. Clinical data, central pathologic review, and molecular profile including RNA sequencing were analyzed.

Results: Nineteen patients (51%) had embryonal RMS (ERMS) (including three highly differentiated ERMS with PTCH deletion), eight (22%) had spindle cell RMS (SRMS) (three VGLL2-, one NTRK-, and two (B)RAF-fusions), six (16%) had alveolar RMS (ARMS) (all FOXO1- or PAX3-fusion), two had unclassified RMS, and two poorly differentiated RMS were retrospectively diagnosed as rhabdoid tumors (RT) with loss of INI1 expression. The two RT patients died of rapid disease progression. Five-year event-free (EFS) and overall survival (OS) for RMS were 62% (95%CI, 47-82) and 52% (95%CI, 37-72). Eleven patients (31%) relapsed and four (11%) had primary refractory disease (all ERMS). In univariate analysis, EFS and OS were only associated with histology subtype, with 100% survival of known fusion-positive SRMS. RNA cluster expression showed three main clusters: ARMS, ERMS, and "VGLL2-fusion" cluster, consisting of SRMS and ERMS.

Conclusions: Biopathology findings from this study support the different prognosis of infantile RMS. New fusion-positive SRMS has a very good outcome which may allow more conservative treatment in the future.