Clinical Utility of Testing

The molecular characterization of human sarcomas is resulting in rapid progress in sarcoma classification, diagnosis, disease monitoring, prediction of outcome, and design of novel therapeutic strategies.

Establishing Definitive Diagnosis and Redefining Tumor Entity

Soft tissue tumors comprise a vast and heterogeneous group of neoplasms. Because different tumors often have different biological behaviors and respond differently to

Figure 26-4. RT-PCR detection of SYT-SSX2 fusion transcript in a primary poorly differentiated synovial sarcoma of the lung with rhabdoid features. (Courtesy of Dr. Thomas Ciesielski.) (a) CT scan of a 72-year-old with a subpleural 2 cm nodule.An extensive physical and radiographic examination of the patient failed to reveal a separate primary lesion. (b) Proliferating tumor cells with rhabdoid cytoplasm. This histological variant of

Figure 26-4. RT-PCR detection of SYT-SSX2 fusion transcript in a primary poorly differentiated synovial sarcoma of the lung with rhabdoid features. (Courtesy of Dr. Thomas Ciesielski.) (a) CT scan of a 72-year-old with a subpleural 2 cm nodule.An extensive physical and radiographic examination of the patient failed to reveal a separate primary lesion. (b) Proliferating tumor cells with rhabdoid cytoplasm. This histological variant of therapeutic strategies, precise classification is of clinical importance. The majority of soft tissue tumors were first delineated on the basis of morphologic and clinical findings into homogeneous groups. However, it has increasingly been appreciated that many tumors with similar histologi-cal and pathological characteristics actually are heterogeneous groups of tumors that differ in their clinical behavior and underlying pathogenesis. Correlation of cytogenetic and molecular data with pathologic findings is essential for understanding both the biological significance and the clinical value of specific molecular changes.

A surprising correlation has emerged among chromosomal alterations, gene rearrangements, and distinct histopathologic entities. Morphologic and cytogenetic/ molecular observations in fact have been validating each other in the classification of soft tissue tumors, and a combined approach has resulted in a more rational classification of soft tissue tumors. This approach has been particularly helpful in understanding the so-called small round blue cell tumors. It is now accepted that ES and PNET are essentially a single tumor type defined by the characteristic translocation between chromosomes 11 and 22, resulting in an EWS gene rearrangement. Despite the morphologic similarities, typical olfactory neuroblastoma lacks EWS rearrangement that argues against the previ

ST rrcc: TCCTCTGCTGGC PTCTTGGGCATGAHCTGG '

formalin-fixed tumor tissue shows the presence of a 97 bp RT-PCR product from the SYT-SSX2 fusion transcript in lane 2 (T, tumor). Lanes 3 and 4 are the negative (-) and positive (+) controls, respectively. (d) Direct DNA sequencing of the RT-PCR product from panel c shows a SYT-SSX2-type fusion transcript.

formalin-fixed tumor tissue shows the presence of a 97 bp RT-PCR product from the SYT-SSX2 fusion transcript in lane 2 (T, tumor). Lanes 3 and 4 are the negative (-) and positive (+) controls, respectively. (d) Direct DNA sequencing of the RT-PCR product from panel c shows a SYT-SSX2-type fusion transcript.

ously proposed inclusion of this tumor in the ES/PNET group.29 The finding of PAX-FKHR chimeric products is of considerable value in defining ARMS. In fact, the small proportion of primitive embryonal-like RMS containing a PAX-FKHR gene fusion likely represents unrecognized solid ARMS.30 Molecular diagnosis also allows the certain identification of previously unrecognized variants of known tumors. One such example, illustrated in Figure 264, is a poorly differentiated synovial sarcoma with rhab-doid features.

Another area that has significantly benefited by this combined approach is that of adipose tissue neoplasms. The finding of ring or giant marker chromosomes cytoge-netically defines the group of atypical lipomatous tumors (well-differentiated liposarcoma) and justifies the distinction of atypical lipomatous tumors from spindle cell and pleomorphic lipomas.11 The finding of TLS-CHOP fusion transcripts in both myxoid liposarcoma and round cell liposarcoma demonstrates that they represent a continuum, an observation nicely correlating with the not infrequent observation of cases with mixed histology.31 The t(17;22), which produces the COL1A1-PDGFB fusion, is present in both dermatofibrosarcoma protuberans (DFSP) and giant cell fibroblastoma, indicating that these are adult and pediatric presentations of a single tumor entity.5,32

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