Recurrent MYOD1 mutations in pediatric and adult sclerosing and spindle cell rhabdomyosarcomas: evidence for a common pathogenesis

Abstract

Sclerosing and spindle cell rhabdomyosarcoma (RMS) are rare types of RMS recently reclassified as a stand-alone pathologic entity, separate from embryonal RMS (ERMS). Although sclerosing and spindle cell RMS share clinical and morphologic features, a pathogenetic link based on shared molecular alterations has not been established. Spindle cell RMS in children have been associated with a less aggressive clinical course compared to adults. Recently, recurrent MYOD1 mutations were described in 44% of adult spindle cell RMS, but no pediatric tumors or sclerosing RMS were studied for comparison. Thus, we investigated 16 RMS (5 sclerosing and 11 spindle cell) in children and adults for the presence of MYOD1 mutations by targeted Polymerase Chain Reaction (PCR). Remarkably, all 5 sclerosing RMS and 4 of 11 spindle cell RMS showed the MYOD1 p.L122R hot-spot mutation. Of the five pediatric tumors, 2/2 sclerosing RMS and 2/3 spindle cell RMS showed MYOD1 mutations. Three of nine MYOD1-mutant RMS showed coexistent PIK3CA mutations, while no MDM2 amplifications were identified. All four pediatric MYOD1-mutated RMS patients died of the disease at 12-35 months following diagnosis. In conclusion, spindle cell and sclerosing RMS show recurrent MYOD1 mutations, in keeping with a single pathologic entity, regardless of age at presentation. This group however, is distinct from the infantile RMS associated with NCOA2 fusions. Although our study suggests that pediatric MYOD1-mutant RMS follow an aggressive behavior with high mortality, further studies are required to confirm this finding.

Figure 1

Sclerosing RMS of the maxillary region in a 34 year-old woman (Case 1). (A, B) Histology showing a cellular neoplasm within a sclerotic background (H&E, 100×); at higher power undifferentiated round to ovoid cells are distributed in a pseudo-vascular pattern (H&E, 200×). (C, D) Immunohistochemical stains show diffuse positivity for desmin (C) and patchy positivity for myogenin (D). ABI direct sequencing showing a (E) heterozygous MYOD1 p.L122R mutation and (F) PIK3CA p.E542V mutation.

Figure 2

Spindle cell RMS arising in the paraspinal region of a 10 year-old girl (Case 4). (A, B) Tumor is composed of a monomorphic spindle cell proliferation, arranged in tight intersecting fascicles (H&E 100×), which at high power display deceptively bland nuclei, with open chromatin and scant fibrillary cytoplasm (H&E 400×). (C) ABI direct sequencing showing a homozygous MYOD1 p.L122R mutation.

Figure 3

Pathologic spectrum of MYOD1-mutant RMS. (A, B) Sclerosing RMS from the thigh in a 76 year-old male (Case 3, H&E 100×) showing cellular clustering in a densely sclerotic background; (B) which at higher power display a distinctive pseudo-vascular growth pattern (Case 3, H&E, 200×). (C) Sclerosing RMS in a 15 year-old girl (case 5, H&E, 100×) showing small nests of cells in a sclerotic background; (D) which at higher magnification reveal small blue round cells with minimal cytoplasm embedded in a collagenous stroma (case 5, H&E, 400×). (E) Spindle cell RMS from the buttock in a 2 year-old girl (Case 7, H&E,100×) showing perivascular distribution of viable spindle cells with intervening geographic necrosis, reminiscent of an MPNST-like morphology; (F) higher power showing elongated spindle cells with hyperchromatic nuclei arranged in a fascicular pattern (Case 7, H&E 400×).