A Molecular Study of Pediatric Spindle and Sclerosing Rhabdomyosarcoma

Abstract

Sclerosing and spindle cell rhabdomyosarcoma (SRMS) have been recently re-classified as a stand-alone pathologic entity, separate from embryonal RMS (ERMS). Genetically a subset of the congenital cases display NCOA2 gene rearrangements, while tumors occurring in older children or adults harbor MYOD1 gene mutations with or without coexisting PIK3CA mutations. Despite these recent advances, a significant number of tumors lack known genetic alterations. In this study we sought to investigate a large group of pediatric spindle cell/sclerosing RMS, spanning a diverse clinical and pathologic spectrum, by using a combined FISH, targeted DNA and whole transcriptome sequencing methodology for a more definitive molecular classification. A total of 26 spindle and sclerosing RMS cases were selected from the two participating Institutions for the molecular analysis. Ten of the 11 congenital/infantile SRMS showed recurrent fusion genes: with novel VGLL2 rearrangements seen in 7 (63%), including VGLL2-CITED2 fusion in 4 and VGLL2-NCOA2 in 2 cases. Three (27%) cases harbored the previously described NCOA2 gene fusions, including TEAD1-NCOA2 in 2, and SRF-NCOA2 in 1. All fusion positive congenital/infantile SRMS patients with available long term follow-up were alive and well, none developing distant metastases. Among the remaining 15 SRMS patients older than age of one, 10 (67%) showed MYOD1 L122R mutations, most of them following a fatal outcome despite an aggressive multi-modality treatment. All 4 cases harboring co-existing MYOD1/PIK3CA mutations shared sclerosing morphology. All 5 fusion/mutation-negative SRMS cases presented as intra-abdominal or para-testicular lesions.

Recurrent BCOR Internal Tandem Duplication and YWHAE-NUTM2B Fusions in Soft Tissue Undifferentiated Round Cell Sarcoma of Infancy

“…In contrast to the spindle cell sarcomas that frequently occur in this age group, such as ETV6-NTRK3 fusion-positive infantile fibrosarcoma 20 and less commonly congenital spindle cell rhabdomyosarcoma with VGLL2 -related fusions, 21 most of the well-established round cell sarcoma entities, such as Ewing sarcoma, desmoplastic round cell sarcoma, or sarcomas with CIC-DUX4 or BCOR - CCNB3 fusions rarely occur in infants. 16,22–28 In fact, in our database of 31 infantile round cell sarcomas occurring in soft tissue, only 2 (6.5%) cases had known gene fusions (one EWSR1-ERG , the other EWSR1-ETV4) .…”

Congenital Rhabdomyosarcoma Presenting as a Neck Mass at Birth

“…The spindle cell variant was included within the embryonal category along with botryoid and anaplastic variants. Recent evidence, however, suggests that the spindle cell and sclerosing RMS may represent a discrete morphologic spectrum from the embryonal subtype because of similar clinical presentations and histologic features [7]. Specifically, there is a subtype of spindle cell variant which displays areas of prominent hyaline sclerosis and a pseudovascular growth pattern, overlapping with the morphology of sclerosing RMS.…”

“…Other genetic alterations include the NCOA2 gene fusion, which is common in congenital cases, and the MYOD1 gene mutation, which tends to occur in older children and adults. They found that cases which harbor gene fusions involving VGLL2 and NCOA2 had a favorable clinical outcome, whereas tumors associated with mutations in the MYOD1 gene showed a more aggressive course with a higher mortality despite multimodal therapy [7]. …”

A clinicopathologic study of head and neck rhabdomyosarcomas showing FOXO1 fusion-positive alveolar and MYOD1 -mutant sclerosing are associated with unfavorable outcome

“…ScRMS may show in addition an undifferentiated round cell component arranged in a pseudovascular or pseudoalveolar pattern in a prominent hyalinized stroma [19, 20]. SRMS-ScRMS share genetic alterations, although these vary depending on the clinical presentation: recurrent NCOA2 and VGLL2 related fusions in congenital/infantile setting, which are associated with a favorable outcome [21, 22], or MYOD1 -mutations in older children and adults are associated with a poor prognosis [23-26], Pleomorphic RMS is a rare variant, usually diagnosed in patients over the age of 45 years, with a morphologic appearance of large pleomorphic cells [9, 27]. …”