Molecular Pathology of Soft Tissue and Bone Tumors

Objective.—To present recent concepts on the molecular pathogenesis of tumors of soft tissue and bone, and on the use of molecular genetic methods, including their significance as diagnostic markers and prognostic indicators. Data Sources and Study Selection.—Reports on tumors of bone and/or soft tissue published in the English language literature and observations made using specimens available at the Departments of Pathology at Albany Medical College and Loyola University Medical Center. Data Extraction and Synthesis.—Studies on bone and soft tissue tumors containing chromosomal or genetic evaluation were selected for further analysis. Specific chromosomal abnormalities, such as numerical aberrations or translocations with production of fusion genes, were classified according to the tumor of origin. Data were also collected on mutations in tumor suppressor genes, genes coding for growth factors or their receptors, and genes coding for tyrosine kinases. Also noted were mutations of uncertain significance, for which the pathogenic connection between tumor production and mutated gene function is still unclear. Conclusions.—In general, the mutations reported interfere with the action of peptide growth factors coordinating mesenchyme proliferation and differentiation, although membrane-bound receptors expressing the intracellular signaling modifier, tyrosine kinase activity, have also been involved. Functional types of genes most commonly affected include tumor suppressors, oncogenes, and nuclear transcription factors. Thus, the mutations involved in the pathogenesis of soft tissue and bone tumors have affected multiple genes. Moreover, aberrant fusion gene products may be formed in tumoral tissue and may then act as transcription regulators stimulating cellular proliferation. Cytogenetic studies help at the clinical level by demonstrating aneuploidy and increased ploidy, which may correlate with malignant behavior. Diagnostic tumor-specific chromosomal translocations may be detected with Southern hybridization analysis, polymerase chain reaction, reverse-transcription polymerase chain reaction, or with the fluorescence in situ hybridization technique. Notably, early metastatic disease may be detectable in blood specimens using polymerase chain reaction or reverse-transcription polymerase chain reaction techniques.