Ewing's sarcoma (ES) is a malignant neoplasm of bone and soft tissues with characteristic radiographic, morphologic, immunohistochemical and cytogenetic features. ES represents perhaps a more primitive, less differentiated neoplasm in the spectrum of peripheral primitive neuroectodermal tumors. Primitive neuroectodermal tumor (PNET), characterized by neuroectodermal differentiation (rosette formation, presence of neuropil), may be considered a more differentiated neoplasm in the same family. Both share the same cytogenetic abnormality (11;22)(q24q12) or (21;22)(q22;q12) in about 90% of cases.
Patients typically present in the first two decades of life. ES/PNET usually involves the extremities, pelvis or ribs. Morphologically, the neoplasm is characterized by monotonous sheets of hyperchromatic cells with round to oval nuclei, high nuclear to cytoplasmic ratios and scant cytoplasm. Cytoplasmic glycogen can often be detected by periodic acid schiff stain or electron microscopy. A filigree pattern of infiltration in soft tissue is associated with an adverse prognosis. The immunohistochemical profile usually demonstrates immunopositivity to vimentin and the MIC2 gene product. The MIC2 gene product is a cell surface glycoprotein found on ES/PNET cells and is very useful in the differential diagnosis. Antibodies to the MIC2 gene product include 12E7, O13 and HBA71 (CD99). ES/PNET may mark for S100 protein and neuron specific enolase.
Cytogenetic analysis performed on fresh or frozen tumor tissue demonstrates the typical translocation (11;22)(q24q12) in 85% of the cases. Two other translocations associated with ES/PNET are (21;22)(q22q12) and (7;22)(p22q12). The specific genomic rearrangements have been elucidated for ES/PNET. A fusion occurs between the EWS gene on 22q12 and the FLI-1 gene on 11q24. The fusion of EWS/FLI-1 is present in 85% of ES/PNET. Fluorescent in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction (RTPCR) are molecular methods which may be utilized to identify the EWS/FLI-1 fusion gene. FISH may be used on imprint cytology and paraffin embedded tissue.
Treatment of ES/PNET involves combination chemotherapy followed by surgery or radiation therapy. Adverse prognostic indicators include the presence of metastases at diagnosis, tumor location in the pelvic bones rather than the distal extremities, large tumor volume (>200ml), elevated sedimentation rate and white blood cell count, filigree pattern, high mitotic rate (one or more per high power field) and poor response to chemotherapy. A good response to chemotherapy (greater than 90% tumor necrosis) correlates with greater disease free survival.
In summary, the diagnosis of ES/PNET should be based on multiple parameters including clinical/radiologic/pathologic correlation. Material obtained by biopsy should be adequate for histologic, immunohistochemical, electron microscopic and cytogenetic/molecular evaluation. Fine needle aspiration and biopsy may be used to establish the diagnosis of ES/PNET. However, open biopsy is preferable if clinically feasible because it provides sufficient material to perform the necessary diagnostic studies and reduce sampling error.
Contributed by Karen E. Schoedel, M.D. and Paul S. Dickman, M.D.