DIAGNOSIS: EWING'S SARCOMA/ PERIPHERAL PRIMITIVE NEUROECTODERMAL TUMOR.
Ewing's sarcoma/peripheral primitive neuroectodermal tumor (EWS/pPNET) is a common small round cell sarcoma of bone that occurs predominantly in the metaphysis of long bones in skeletally immature patients and accounts for 6-8% of all primary malignant bone tumors. Its peak incidence is in the second decade of life and there is a male predilection. Patients of African descent are rarely affected. Although long bones, pelvis, and ribs are the common sites, any bone can be affected. Primary vertebral EWS/pPNETs are well documented and should be seriously entertained when a vertebral extradural/epidural mass occurs in young patients (1,2,3). The prognosis of patients with EWS/pPNET arising in the spine is worse than those with tumors occurring in the limbs but better than those with tumors arising in the pelvis (2); vertebral EWS/pPNETs have increased frequency of cerebral and skeletal metastases as compared to EWS/pPNETs occurring in other locations (2). There is no significant correlation between the level of vertebral involvement and the length of disease-free survival, overall survival, or incidence of metastasis (1).
Histologically, EWS/pPNET have features of undifferentiated mesenchymal cells. The tumor cells are typically small cells with round, centrally located hyperchromatic nuclei and a small amount of cytoplasm; the tumor cells grow in solid, densely packed sheets and nests filling intertrabecular space and necrosis is frequent. A biphasic population of light and dark cells is common. Differentiation of EWS/pPNET from lymphoma is always a concern during intraoperative consultation. A cytologic preparation will greatly assist the identification of lymphoglandular bodies that are typical for lymphomas but not EWS/pPNET.
The amount of cytoplasmic glycogen in EWS varies from scant to substantial. In this case, a large amount of glycogen gives rise to vacuolated cytoplasm in cytologic preparation, paraffin sections, and at ultrastructural level. This feature may be of diagnostic help but is probably limited only to EWS/pPNET with substantial amount of glycogen. The cytoplasmic vacuoles have been described in so-called atypical EWS; cells from these tumors are larger than those in conventional EWS, exhibit greater heterogeneity, and may have focal spindle-cell features. These features are more often seen in recurrent and treated EWS but can also be present in primary EWS. There is no difference in the clinical behavior of classic and so-called atypical Ewing's sarcomas (5). Our present case, however, does not possess features of the so-called atypical EWS other than cytoplasmic vacuoles.
Neuroendocrine differentiation similar to pPNETs is seen in EWS, which may possess Homer Wright rosette, immunoreactivity to synaptophysin, and neurosecretory granules under electron microscope. Most authors consider pPNET and EWS to be related or indistinguishable entities within a continuum of overlapping immunohistochemical and morphological features. Immunohistochemical demonstration of the MIC2 gene product (CD99 antigen) is typically seen in EWS but can also be present in lymphomas, synovial sarcoma, and rhabdomyosarcoma (4); results must be interpreted with care (5).
Reciprocal translocation between chromosomes 11 and 22 involving bands q24 and q12, t(11;22)(q24;q12), occurs in approximately 90% of Ewing's sarcomas, pPNETs and Askin's tumors. The translocation produces a fusion gene EWS/FLI-1 that places the FLI-1 gene under the control of EWS promoter leading to overexpression of the FLI-1-protein, an important step in tumorgenesis of EWS. This translocation serves as an important diagnostic feature (5) for separating EWS from tumors with similar morphologic and immunohistochemical profile such as metastatic neuroblastoma and metastatic neuroendocrine carcinoma to the bone. The fusion gene, EWS/FLI-1, is well demonstrated in this case; FISH shows fusion (yellow or red-green signals) of the FLI-1 gene (green signals) with EWS gene (red signals) (Figure 2D, insert).
Contributed by Koushan Siami-Namini MD, Rhonda Shuey-Drake MS, Don Wilson MD, Paul Francel MD, Arie Perry MD, Kar-Ming Fung MD, PhD