Cytokine expression in Ewing's sarcoma/ primitive neuroectodermal tumor: A possible mechanism mediating osteoclastic activity and bone destruction

Ewing's sarcoma (ES) and primitive neuroectodermal tumor (PNET) are closely related, highly malignant tumors of bone that characteristically demonstrate diffuse infiltration of the medullary space, permeation of cortical bone, and formation of a large soft tissue mass. The pattern of bone destruction suggests that tumor progression may be due to regulation of local osteoclastic activity by tumor cells. In this study, we examined production of the osteoclaststimulating cytokines interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) by tumor cells, as a possible mechanism forpermeative destruction of bone. Biopsies from nine patients with osseous ES or PNET were evaluated for production of IL-1, IL-6, and TNF-α utilizing streptavidinbiotin immunohistochemistry. Patients included five males and four females and ranged in age from 9 to 29 years (mean age 18, median age 19). All patients received chemotherapy and radiation, and seven of nine underwent resection with limb salvage. Clinical follow-up ranged from 3 to 7 years with two patients dead of disease, two patientsalive with disease, and five patients with no evidence of disease. All cases showed strong immunoreactivity (>50% of tumor cells) for TNF-α. Staining for IL-1 and IL-6 was strong in five of nine and seven of nine cases, respectively. Moderate staining (20-50% of cells) for IL-1 and IL-6 was observed in the remaining cases. Cytokine expression did not correlate with outcome for the patient. In ES/PNET, tumor growth and progression are associated with histologie and radiographie evidence of osteoclastic resorption. Our results suggest that these tumors, by production of cytokines with stimulatory effects on osteoclasts, may directly mediate an increase in local bone résorption, thus allowing tumor progression. This may explain the aggressive pattern of intraosseous growth and the large extraosseous masses often found in these tumors. A better understanding of specific biologic processes related to bone destruction and local disease progression in ES/ PNET is likely to provide insights into the clinical behavior of these neoplasms and may lead to new therapeutic strategies.