The third challenge is to understand the
The third challenge is to understand the mechanisms of drug resistance. There are several different mechanisms of ES tumor to develop drug resistance. First, cancer stem cells are capable of proliferate and generate tumor cells with new sets of mutations which may harbor different protein targets . Second, drug resistance may rise from altered modulation of related cellular signaling pathway as a result of targeted therapies. For example, anti-IGF-1R therapies may lead to activation of downstream pathways and thus result in tumor drug resistance through a bypass pathway , . In order to improve long term treatment outcomes, resistance mechanisms need to be elucidated. This may require serial blood and tumor tissue collections for systematic molecular and other correlative studies.
Conflict of interest statement
Acknowledgements We thank Ms. Joann Aaron for scientific review and editing of this article. This work was supported by NCATS Grant UL1 TR000371 (Center for Clinical and Translational Sciences), and the MD Anderson Cancer Center Support Grant (P30 CA016672).
Introduction Ewing sarcoma, often referred to as Ewing’s sarcoma family tumors (ESFT) is the second most common bone malignancy after osteosarcoma, arising in children and young adults with a peak incidence at age 15. The frequency of Ewing sarcoma is 1–3 per million per year in the Western hemisphere, with a slight predominance in males. Although most Ewing sarcomas occur in bone and especially in the pelvis, the diaphyseal regions of the long bones and bones of the chest wall, 15% of primary ESFT may arise in a variety of extraosseous sites, including deep soft paravertebral, thoracic and proximal limb tissues, kidney, bladder, lung, prostate and the meninges . Similar to several other sarcomas, ESFT displays an aggressive behavior with a tendency toward recurrence following resection and pronounced proclivity toward early hematogenous metastasis primarily to the lung, bone and bone marrow. Lymph node, liver and COG 133 metastases are typically rare. Currently, Ewing sarcomas are treated with a combination of surgery, radiation and chemotherapy, but despite these multimodal approaches the survival rate remains poor: 50% at 5years (25% when metastasis are present at diagnosis) and less than 30% at 10years.
Histology Morphologically, Ewing sarcoma is composed of sheets of small round cells with a high nuclear to cytoplasmic ratio and is often classified by pathologists into a group of small round blue cell tumors that include neuroblastoma, alveolar rhabdomyosarcoma and lymphoblastic lymphoma. The cells typically have scant, weakly eosinophilic cytoplasm that usually contains glycogen in the form of periodic-acid-Schiff-positive, diastase degradable granules, and round nuclei with evenly distributed chromatin and little mitotic activity (Fig. 1). Immunohistochemical analysis has shown that in more than 90% of cases Ewing sarcoma cells express the adhesion receptor CD99, commonly associated with lymphoid cells and believed to play a role in leukocyte transmigration of the endothelium . Depending on the degree of neuroectodermal differentiation, Ewing sarcoma cells may also express neural cell markers, including neural-specific enolase (NSE), S-100, synaptophysin and CD57 . Ewing sarcoma cells are reactive with anti-vimentin antibodies and, in about 20% of cases, with anti-cytokeratin antibodies. Some of these tumors may express neurofilaments as well. Immunohistochemistry is frequently required for the differential diagnosis of small blue round cell tumors. Ewing sarcoma and lymphoblastic lymphoma both express CD99, but the latter also expresses CD45 whereas Ewing sarcoma does not. Neuroblastoma cells are NSE and S-100 positive but unlike their ESFT counterparts, they are vimentin-negative and neurofilament-positive . Alveolar rhabdomyosarcoma cells may express CD99, but they also express desmin, myogenin and MyoD1, which ESFT cells typically lack. Perhaps the most difficult differential diagnosis is between ES and poorly differentiated small cell synovial sarcoma, since the latter can express CD99 and unlike its more differentiated forms may lack cytokeratins. Because of the lack of specificity of these markers, molecular genetic approaches are required to make the definitive distinction.