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

Abstract

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.

Keywords: VGLL2; infants; newborns; rhabdoid tumor; rhabdomyosarcoma; spindle cell rhabdomyosarcoma.

Figure 1

Morphology and immunohistochemistry (IHC) of two rhabdoid tumors initially diagnosed as embryonal rhabdomyosarcoma. A, Hematoxylin‐eosin‐safran [HES] Coloration zoom ×20. B, Loss of nuclear expression of SMARCB1/INI1 on rhabdoïd cells (note the positive blue staining by endothelial and inflammatory cells). C, Positive immunostaining for desmin (red arrow). D, Positive immunostaining for myogenin (red arrow)

Figure 2

Morphology and IHC of representing infantile rhabdomyosarcoma. A, Highly differentiated embryonal rhabdomyosarcoma. Hematoxylin‐eosin‐safran [HES] coloration zoom x5; Hematoxylin‐eosinsafran [HES] coloration zoom x20; Positive immunostaining for desmin; Positive immunostaining for myogenin (30%). B, VGLL2‐type spindle cell rhabdmyosarcoma. Hematoxylin‐eosin‐safran [HES] coloration zoom x10; Hematoxylineosin‐safran [HES] coloration zoom x20; Positive immunostaining for myogenin (2%). C, “Fibrosarcoma‐like” spindle cell rhabdomyosarcoma. Hematoxylin‐eosin‐safran [HES] coloration zoom x10; Positive immunostaining for desmin; Positive immunostaining for myogenin (5% to 30%)

Figure 3

Gene expression clusters using unsupervised consensus hierarchical clustering. For comprehensive and didactical reasons, we mixed our samples with 26 other rhabdomyosarcoma samples of all age combined

Figure 4

Five‐year overall (OS) and event‐free survivals (EFS) or the whole population. Five‐year EFS according to histology subtype. Five‐year OS according to histology subtype