Ewing Sarcoma

The American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) TNM systems can be applied.

All cases of Ewing sarcoma are associated with structural rearrangements that generate FET-ETS fusion genes. Additional mutations may occur in STAG2 (15–22%), CDKN2A (12%), and TP53 (7%). FET-ETS fusion genes encode chimeric transcription factors that serve as master regulators to activate and repress thousands of genes. Expression of these aberrant transcription factors, presumably in the correct cellular and developmental context, is required for the development of Ewing sarcoma. Proteins bind both GGAA microsatellites and canonical ETS binding sites in the genome and recruit chromatin regulators. Binding of the fusion proteins to GGAA microsatellites results in the transition from a closed to an open chromatin state that establishes de novo enhancers, which activate genes. Conversely, binding to canonical ETS binding sites displaces wildtype ETS factors and represses gene expression. Together, these events establish an oncogenic gene expression program that underlies transformation and subsequent tumor initiation.

The cut surface of untreated Ewing sarcoma specimens is greyish-white and soft, and it frequently includes areas of hemorrhage and necrosis.

Most cases are composed of uniform small round cells with round nuclei containing finely stippled chromatin and inconspicuous nucleoli, scant clear or eosinophilic cytoplasm, and indistinct cytoplasmic membranes (classic Ewing sarcoma). In others, the tumor cells are larger, with prominent nucleoli and irregular contours (atypical Ewing sarcoma). Sometimes, a higher degree of neuroectodermal differentiation (ill-defined groups of as many as 10 cells oriented towards a central space and/or with a consistent immunophenotype) is present (historically termed primitive neuroectodermal tumor). After induction chemotherapy, Ewing sarcoma cells show a variable degree of necrosis and are replaced by loose connective tissue.

Immunohistochemically, CD99 is a cell-surface glycoprotein and a relevant diagnostic marker for Ewing sarcoma. Strong, diffuse membranous expression of CD99 is evident in about 95% of Ewing sarcomas. NKX2-2 has a higher specificity than CD99. Keratin expression is present in approximately 25% of cases. FLI1 and ERG are often expressed in the cases with the corresponding gene fusions. Some cases express neuroendocrine antigens and/or S100.
A distinct subset of lesions carrying the same fusions has been described, predominantly in the head and neck region, as adamantinoma-like Ewing sarcoma. This subset often expresses markers of squamous differentiation. The relationship of this tumor type to classic Ewing sarcoma is uncertain.

Not clinically relevant

The prognosis of Ewing sarcoma has improved considerably with current multimodal therapy, with a 65–70% cure rate for localized disease. However, metastatic and early-relapsing tumors have a poor prognosis, with a 5-year survival rate of < 30%. The presence of metastases appears to be the main prognostic factor. Other negative prognostic factors include the anatomical location of the tumor, such as the pelvis. Complete pathological response to neoadjuvant chemotherapy is a favorable prognostic factor. There are currently no other prognostic markers in widespread use.

Genetic confirmation is often required for Ewing sarcoma diagnosis. The most common Ewing sarcoma translocation (present in ~85% of cases) is t(11;22)(q24;q12), which results in the EWSR1-FLI1 fusion transcript and protein. The second most common is t(21;22)(q22;q12), which results in EWSR1-ERG in about 10% of cases. The remaining cases have alternative translocations that join either EWSR1 or FUS (which, along with TAF15, form the FET family) to other ETS family members. All cases of Ewing sarcoma harbor a FET-ETS fusion.

Essential: small round cell morphology; CD99 membranous expression.

Desirable: FET-ETS fusion detection (in selected cases).