Introduction

Oncologic molecular pathology focuses on identifying and understanding molecular and genetic alterations underlying the development and progression of neoplastic processes. Mesenchymal malignancies may be classified into two pathogenetic types: sarcomas with complex genetic alterations and sarcomas with specific recurrent chromosomal translocations. The first type includes the majority of high-grade, pleomorphic mesenchymal malignancies that are characterized by complex chromosomal abnormalities, for example, malignant fibrous histiocy-toma (MFH), osteogenic sarcoma, and embryonal rhabdomyosarcoma. In the second type, the sarcomas are translocation specific, that is, harboring a recurrent chromosomal translocation leading to an in-frame fusion of coding sequences from each of the two rearranged genes. The translocation results in the production of a chimeric transcript encoding a fusion protein with oncogenic activity. Histologically, the translocation-specific sarcomas are generally a monomorphic proliferation of neoplastic cells. This pathogenetic classification appears biologically relevant and is best illustrated by the sarcoma types observed in Li-Fraumeni syndrome and therapy-related malignancies. Li-Fraumeni patients, with TP53 germline mutation, are prone to sarcomas with complex karyotypes, such as osteogenic sarcoma and MFH, which constitute major mesenchymal cancers. On the other hand, translocation-specific sarcomas virtually never occur in Li-Fraumeni patients.1

During the past 10 years, tremendous progress has been made in characterizing many translocation-specific sarcomas. These chromosomal translocations and associated fusion genes are highly specific to given sarcomas and occur in such a high prevalence that they are essentially used to define these neoplasms at both the pathobiological and clinical diagnostic levels.2,3 These sarcomas are the focus of this chapter.

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