Encyclopedia of Pathology

Living Edition
| Editors: J.H.J.M. van Krieken

Ewing Sarcoma

  • Alessandro FranchiEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-28845-1_5000-1

Synonyms

Definition

Ewing sarcoma (ES) is a high-grade round cell translocation-associated sarcoma, showing varying degrees of neuroectodermal differentiation.

Clinical Features

  • Incidence

    ES only rarely involves the genitourinary tract.

  • Age

    Genitourinary ES arises in adolescents and young adults (Celli and Cai 2016; Teegavarapu et al. 2017; Thyavihally et al. 2008).

  • Sex

    There is a predilection for the male gender (Celli and Cai 2016; Teegavarapu et al. 2017; Thyavihally et al. 2008).

  • Site

    Genitourinary ES arises more frequently in the kidney, but some examples have also been reported in the prostate, the urinary bladder, the scrotum, and the penis (Colecchia et al. 2003; Funahashi et al. 2009; Peyromaure et al. 2003; Okada et al. 2011; Grimsby and Harrison 2014; Kilicaslan et al. 2008).

  • Treatment

    Treatment is usually based on current regimens used in ES of the bone. Surgical resection is the preferred local treatment (Celli and Cai 2016; Teegavarapu et al. 2017; Thyavihally et al. 2008). Multiagent chemotherapy is part of the standard therapy, both in the neoadjuvant and adjuvant settings (Celli and Cai 2016; Teegavarapu et al. 2017; Thyavihally et al. 2008). Radiotherapy has a role in local control (Thyavihally et al. 2008).

  • Outcome

    The overall survival is poor. Data from small series of ES of the kidney indicate a 15-month survival for patients with metastatic disease and 60-month survival for patients with localized disease (Thyavihally et al. 2008).

Macroscopy

Grossly ES appears as a solid mass, with a white-gray cut surface, often with foci of hemorrhage and necrosis. Tumors measure up to 15 cm. Invasion of the renal vein can be identified in kidney tumors.

Microscopy

ES consists of a closely packed uniform population of round cells with scant cytoplasm and round to oval nuclei containing condensed chromatin and small nucleoli (Fig. 1). A second population of dark cells, possibly undergoing apoptosis, can be interspersed within the main neoplastic population. Glycogen deposits resulting in cytoplasmic clearing are often present. Homer-Wright rosettes can be seen in ES with a greater degree of neural differentiation. Areas of necrosis and brisk mitotic activity are usually detected.
Fig. 1

Conventional appearance of Ewing sarcoma, with a uniform population of closely packed undifferentiated round cells. Some cells present clear cytoplasm due to the presence of glycogen accumulation

Immunophenotype

ES is positive for CD99 with a strong diffuse membrane staining. However this marker is not entirely specific, being expressed in lymphoblastic lymphoma, synovial sarcoma, desmoplastic small round cell tumor, and rhabdomyosarcoma, albeit with a weaker and/or focal staining pattern. FLI1 is also positive in the majority of ES, but its specificity is low. The NKX2.2 gene, which is a target of the EWSR1-FLI-1 fusion protein, is positive in 95% of ES, but also in some small cell carcinomas, synovial sarcomas, mesenchymal chondrosarcomas, and melanomas (Yoshida et al. 2012). Occasionally, ES may also show positivity for S100, NSE synaptophysin, CD56, and cytokeratins.

Molecular Features

ES presents a recurrent genetic alteration, the t(11:22) between the genes EWSR1 (22q12) and FLI-1 (11q24). This translocation has been detected in 72% of kidney ES (Risi et al. 2013). Less frequently, other genes of the ETS (erythroblastosis virus-associated transforming sequences) family, like ERG, FEV, ETV1, and ETV4, have been reported as translocation partners of EWSR1.

Differential Diagnosis

The differential diagnosis of ES is with other small round cell malignancies, including lymphomas, alveolar rhabdomyosarcoma, poorly differentiated synovial sarcoma, desmoplastic small round cell tumor, and neuroblastoma. These entities share similar morphology and the expression of some immunohistochemical markers, including CD99.

Among hematologic malignancies, lymphoblastic lymphoma is a close mimic of ES, being also positive for CD99 and FLI1. Thus, the immunohistochemical panel should also include terminal deoxynucleotidyl transferase (TdT), as well as B- and T-lymphocyte markers.

Alveolar rhabdomyosarcoma is positive for desmin and myogenin and presents the PAX3/PAX7-FOXO1A rearrangements. Poorly differentiated synovial sarcoma shares positivity for CD99 with ES, and it is also at least focally positive for EMA and cytokeratins. The best way to separate poorly differentiated synovial sarcoma from ES is to search for SYT-SSX1/2 translocation. Desmoplastic small round cell tumor shows diffuse expression of cytokeratins and EMA, is positive for WT1 with antibodies against the carboxyl-terminal domain of the WT1 protein, and usually does not show the diffuse membrane positivity for CD99 seen in ES. When considering the differential diagnosis between ES and desmoplastic small round cell tumor, it should be remembered that break-apart FISH analysis of EWS gene is not diriment between the two.

In the kidney, an important differential diagnosis of ES is with blastemal-predominant Wilms tumor. This is usually negative for CD99 and FLI-1 and positive for WT1. However, since the specificity of these markers is not absolute, search for EWSR1 gene rearrangement is useful. Neuroblastoma occurs in patients younger than 18 months, which would be exceptional for ES. Moreover, neuroblastoma lacks CD99 expression and translocations involving the EWSR1 gene.

References and Further Reading

  1. Celli, R., & Cai, G. (2016). Ewing sarcoma/primitive neuroectodermal tumor of the kidney: A rare and lethal entity. Archives of Pathology & Laboratory Medicine, 140, 281–285.CrossRefGoogle Scholar
  2. Colecchia, M., Dagrada, G., Poliani, P. L., Messina, A., & Pilotti, S. (2003). Primary primitive peripheral neuroectodermal tumor of the prostate. Immunophenotypic and molecular study of a case. Archives of Pathology & Laboratory Medicine, 127, e190–e193.Google Scholar
  3. Funahashi, Y., Yoshino, Y., & Hattori, R. (2009). Ewing’s sarcoma/primitive neuroectodermal tumor of the prostate. International Journal of Urology, 16, 769.CrossRefGoogle Scholar
  4. Grimsby, G. M., & Harrison, C. B. (2014). Ewing sarcoma of the scrotum. Urology, 83, 1407–1408.CrossRefGoogle Scholar
  5. Kilicaslan, I., Karayigit, E., Bulut, F., Basaran, M., Dizdar, Y., Aslay, I., & Uysal, V. (2008). Ewing’s sarcoma/primitive neuroectodermal tumor (ES/PNET) of the penis. International Urology and Nephrology, 40, 113–115.CrossRefGoogle Scholar
  6. Okada, Y., Kamata, S., Akashi, T., Kurata, M., Nakamura, T., & Kihara, K. (2011). Primitive neuroectodermal tumor/Ewing’s sarcoma of the urinary bladder: A case report and its molecular diagnosis. International Journal of Clinical Oncology, 16, 435–438.CrossRefGoogle Scholar
  7. Peyromaure, M., Vieillefond, A., Boucher, E., et al. (2003). Primitive neuroectodermal tumor of the prostate. The Journal of Urology, 170, 182–183.CrossRefGoogle Scholar
  8. Risi, E., Iacovelli, R., Altavilla, A., et al. (2013). Clinical and pathological features of primary neuroectodermal tumor/Ewing sarcoma of the kidney. Urology, 82, 382–386.CrossRefGoogle Scholar
  9. Teegavarapu, P. S., Rao, P., Matrana, M. R., Cauley, D. H., Wood, C. G., Patel, S., & Tannir, N. M. (2017). Outcomes of adults with Ewing sarcoma family of tumors (ESFT) of the kidney: A single-institution experience. American Journal of Clinical Oncology, 40, 189–193.CrossRefGoogle Scholar
  10. Thyavihally, Y. B., Tongaonkar, H. B., Gupta, S., et al. (2008). Primitive neuroectodermal tumor of the kidney: A single institute series of 16 patients. Urology, 71, 292–296.CrossRefGoogle Scholar
  11. Yoshida, A., Sekine, S., Tsuta, K., Fukayama, M., Furuta, K., & Tsuda, H. (2012). NKX2.2 is a useful immunohistochemical marker for Ewing sarcoma. The American Journal of Surgical Pathology, 36, 993–999.CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Translational Research and of New Technologies in Medicine and SurgeryUniversity of Pisa, ItalyPisaItaly