A rare sclerosing variant of rhabdomyosarcoma characterized by prominent hyalinization and pseudovascular pattern has recently been described as a subtype biologically distinct from embryonal, alveolar, and pleomorphic forms. We present cytogenetic and molecular findings as well as experimental studies of an unusual case of sclerosing rhabdomyosarcoma. The primary lesion arose within the plantar subcutaneous tissue of the left foot of an otherwise healthy 23-year-old male who eventually developed pulmonary nodules despite systemic chemotherapy. Two genetic abnormalities identified in surgical and/or autopsy samples of the tumor were introduced into 10T1/2 murine fibroblasts to determine whether these genetic changes cooperatively facilitated transformation and growth. Cytogenetic analysis revealed a complex abnormal hyperdiploid clone, and MDM2 gene amplification was confirmed by fluorescence in situ hybridization. Cancer gene mutation screening using a combination of multiplexed PCR and mass spectroscopy revealed a PIK3CA exon 20 H1047R mutation in the primary tumor, lung metastasis, and liver metastasis. However, this mutation was not cooperative with MDM2 overexpression in experimental assays for transformation or growth. Nevertheless, MDM2 and PIK3CA are genes worthy of further investigation in patients with sclerosing rhabdomyosarcoma and might be considered in the enrollment of these patients into clinical trials of targeted therapeutics. 1. Introduction Rhabdomyosarcoma (RMS) is subdivided into three major variants: embryonal, alveolar, and pleomorphic. Embryonal and alveolar subtypes are commonest sarcomas of childhood and adolescence. Better clinical outcome is associated with botryoid and spindle cell variants of embryonal RMS. In particular, the spindle cell variant in childhood is considered to be of low malignant potential with excellent overall patient survival. Pleomorphic RMS is rare and highly aggressive adult sarcomas typically arising in the deep soft tissue of the extremities. Even rarer are recently described spindle cell and sclerosing variants of RMS in adults. Due to their rarity, the experience with the newer subsets is limited but appears to show poor outcome in adults. Sclerosing variant of RMS as a distinct entity was initially reported in three cases by Mentzel and Katenkamp in 2000 [1]. Histologically the tumor is characterized by polygonal to spindle-shaped neoplastic cells forming anastomosing cords in pseudovascular clefts and a highly sclerotic, hyalinized matrix. Rare rhabdomyoblasts can be seen and the skeletal muscle
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