MYOD1-mutant spindle cell and sclerosing rhabdomyosarcoma: an aggressive subtype irrespective of age. A reappraisal for molecular classification and risk stratification

Abstract

Sclerosing and spindle cell rhabdomyosarcoma is a rare histologic subtype, designated in the latest WHO classification as a stand-alone pathologic entity. Three genomic groups have been defined: an infantile subset of spindle cell rhabdomyosarcoma harboring VGLL2-related gene fusions, a MYOD1-mutant subset commonly associated with sclerosing morphology, and a subset lacking recurrent genetic abnormalities. In this study, we focus on MYOD1-mutant rhabdomyosarcoma to further define their clinicopathologic characteristics and behavior in a larger patient cohort. We investigated 30 cases of MYOD1-mutant rhabdomyosarcoma (12 previously reported and 18 newly diagnosed) with an age range of 2-94 years, including 15 children. All cases showed morphology within the spectrum of spindle cell/sclerosing rhabdomyosarcoma (8 cases showing pure sclerosing morphology, 8 cases showing pure spindle cell morphology and 14 cases showing a hybrid phenotype of spindle, sclerosing and primitive undifferentiated areas). All tumors harbored either homozygous or heterozygous MYOD1 (p.L122R) exon 1 mutations. In 10 (33%) cases, a co-existent PIK3CA mutation was identified. Hot-spot mutations in NRAS and HRAS were each identified in a single case, respectively. Follow-up was available on 22 (73%) patients with a median duration of 28 months. Local recurrence was seen in 12 (55%) and distant recurrence in 12 (55%) cases, despite multimodality chemoradiation therapy. At last follow-up, 15 (68%) patients died of the disease, one patient was alive with disease and five had no evidence of disease. The prognosis was equally poor in pediatric and adult patients. In conclusion, MYOD1 mutation defines an aggressive rhabdomyosarcoma subset, with poor outcome and response to therapy, irrespective of age. Given that this distinct molecular subtype is characterized by an aggressive biologic behavior compared to other genetic subtypes of spindle and sclerosing rhabdomyosarcoma, the MYOD1 genotype should be used as a molecular marker in both subclassification and prognostication of rhabdomyosarcoma.

Figure 1:

MYOD1-mutant rhabdomyosarcoma with sclerosing and spindle cell morphology. (A-C) Case 4 showing areas with sclerosing morphology with small clusters of spindle cells in a sclerotic background (A), immunohistochemical stains for desmin showing cytoplasmic positivity (B) and MYOD1 showing strong diffuse nuclear positivity (C). (D-F) Case 21 showing spindle cell morphology with intersecting fascicles of monomorphic fusiform cells (D), immunohistochemical stains for desmin with strong cytoplasmic positivity (E) and MYOD1 diffuse nuclear positivity (F).

Figure 2:

MYOD1-mutant rhabdomyosarcoma with primitive round to spindle cell component. (A-C) Case 1 showing areas of classic spindle cell morphology with fascicular growth (A), solid zones of primitive appearing spindle cell component (B) and geographic necrosis (MPNST-like); (D-F) Case 28 showing tumor in the liver with undifferentiated primitive round cell component (D, E) and areas of spindling (F); (G-I) Case 23, a post-therapy resection, showing primitive round cell areas (G), spindle cell morphology (H) and areas with sclerosing morphology (I). (H&E stains)

Figure 3:

Morphologic spectrum of MYOD1-mutant rhabdomyosarcoma following therapy. (A-C) Case 4 showing sclerosing areas on the pre-therapy biopsy (A), while in the post-therapy resection (B,C) showing pure spindle cell morphology; (D-F) Case 12 showing a sclerosing morphology in the pre-therapy biopsy (D), while the post-therapy resection reveals a spindle cell morphology (E) and areas of maturation with rhabdomyoblastic morphology (F); (G-I) Case 24 showing spindle cell morphology on pre-therapy biopsy (G), while post-therapy resection shows cellular spindle cell areas (H) and areas of maturation (I). (H&E stains)

Figure 4:

Oncoprint image showing the variant genetic alterations identified in the study cases.

Figure 5:

Schematic diagram of Spindle cell / sclerosing rhabdomyosarcoma genetic subclassification.