differentiation and a characteristic molecular signature (see later). Entities previously classified as primitive neuroectodermal tumor (PNET) and Askin tumor have been unified into the single category of Ewing sarcoma.
Ewing sarcoma accounts for approximately 10% of primary malignant bone tumors and follows osteosarcoma as the second most common bone sarcoma in children. Of all bone sarcomas, Ewing sarcomas have the youngest average age at presentation (80% are younger than 20 years). Boys are affected slightly more frequently than girls, and there is a predilection for Caucasians. The tumors usually arise in the diaphysis of long tubular bones but 20% are extraskeletal. They present as painful enlarging masses, and the affected site is frequently tender, warm, and swollen. Plain radiographs show a destructive lytic tumor with permeative margins that extends into the surrounding soft tissues. The characteristic periosteal reaction produces layers of reactive bone deposited in an onion-skin fashion.
The vast majority (85%) of Ewing sarcomas contain a balanced (11;22) (q24;q12) translocation generating in-frame fusion of the EWSR1 gene on chromosome 22 to the FLI1 gene on chromosome 11. Variant translocations fuse EWSR1 to other members of the ETS transcription factor family. How EWS fusion proteins contribute to transformation remains unsettled; effects on transcription, RNA splicing, and the cell cycle machinery have all been proposed. Similarly, the cell of origin still remains to be identified; the leading candidates are mesenchymal stem cells and primitive neuroectodermal cells.
MORPHOLOGYArisinginthemedullarycavity,Ewingsarcomausuallyinvadesthecortex,periosteum,andsofttissue.Thetumorissoft,tan-white,andfrequentlycontainsareasofhemorrhageandnecrosis.Itisoneofthesmall,roundbluecelltumorsfoundinchildren(Chapter7).Likeothertumorsinthisgroup,Ewingsarcomaiscomposedofsheetsofuniformsmall,roundcellsthatareslightlylargerandmorecohesivethanlymphocytes(
Fig.21.24 ).Theyhavescantcytoplasm,whichmayappearclearbecauseitisrichinglycogen.Homer-Wrightrosettes(roundgroupingsofcellswithacentralfibrillarycore)maybepresentandindicateagreaterdegreeofneuroectodermaldifferentiation.Thetumorcellsdonotproduceboneorcartilage.
Ewing sarcomas are aggressive malignancies treated with neoadjuvant chemotherapy followed by surgical excision with or without radiation. With chemotherapy, 5-year survival of 75% and long-term cure in 50% of patients is possible.
Giant cell tumor is so named because multinucleated osteoclast-type giant cells dominate the histology. It is a locally aggressive neoplasm that almost exclusively affects adults. Giant cell tumors arise in the epiphyses of long bones, most commonly the distal femur and proximal tibia. The typical location of these tumors near joints frequently causes arthritis-like symptoms. Occasionally, they present with pathologic fractures.
Fig.21.24Ewingsarcomacomposedofsheetsofsmallroundcellswithsmallamountsofclearcytoplasm.
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Experimental evidence suggests that the neoplastic cells of the giant cell tumor are osteoblast precursors, which represent only a minority of the cells in the tumor. The neoplastic cells express high levels of RANKL, which promotes the proliferation and differentiation of normal osteoclast precursors into osteoclasts. The osteoclasts in turn cause localized but highly destructive resorption of bone.