Ewing’s sarcoma

Only 15% of cases are diagnosed over age 20.

Accounts for 2% of cancers in children.

Characterized most frequently by a specific translocation of EWS-FLI1, but other EWS translocations exist.

About 85 to 95% of cases have the chromosomal translocation of T(11; 22) which leads to the fusion of EWSR1.

Has one of the lowest mutational rates of all cancers.

A round cell sarcoma marked by a gene fusion involving members of the FET family and a member of the Ewings tumor sarcoma family of transcription factors.

When associated with complex karyotypes it is associated with the poor prognosis, compared with those with simpler karyotypes.

Complex karyotypes are the product of chemoplexy (a sudden burst of complex, loop like gene arrangements that give rise to a fusion gene), and these fusions arise early, giving rise to both primary and relapsed Ewing sarcoma tumors, which can continue to evolve in parallel.

Chemoplexy, rather than simple reciprocal translocations define the gene fusions in about 42% of patients.

Chemoplexy involves three or more of breakpoints in the genome.

Chemoplexy results in the formation of functional EWSR1-FLI1 or ESWR1-ERG fusions that provide a selective growth or survival advantage.

It involves fusions between EWSR1, a gene encoding an RNA-binding protein and E26 transformation-specific transcription factors.

All cases are high grade.

Ewing sarcoma/PNET( primitive neuroectodermal tumor) is the 2nd most common malignant bone tumor with an incidence of 2.9 per million.

Represents 12% of bone malignancies in patients over the age of 15 years.

Median age at diagnosis is 15 years.

Rare above the age of 40 years.

Prognosis better in younger patients than in adolescents.

Peripheral tumors have a better prognosis than central tumors.

The most common primary sites are the extremities (50%), followed by the pelvis, ribs, and vertebrae.

Any bone can be affected, and a soft tissue origin is also possible especially in adults (30%) of cases.

The lungs, bone ABD bone marrow are the most common metastatic sites.

Cutaneous and subcutaneous ES have a better prognosis compared with the localized soft tissue ES.

Most commonly involves the pelvis and proximal long bones.

In approximately 20% of patients tumors are extraosseous and can arise in numerous organs.

Extraosseous Ewing sarcoma occurs much more frequently in adults and children.

10% extra skeletal.

20-30% present with metastatic disease.

Patients with localized disease have a long-term event-free survival of 50%.

Its clinical features are largely non-specific.

A pathologic fracture is reported in 10 to 15% of cases and advanced disease fever, night sweats, fatigue and weight loss may be present.

Alkaline phosphatase and LDH levels may be elevated and they correlate with tumor burden.

Radiologic imaging describes multiple, confluent, lytic bone lesions giving rise to a moth-eaten pattern.

Subperiosteal growth may be related to classic image findings of Codman’s triangle and onion peel, which represented displaced periosteum and resulting proliferative reaction.

Histologic examination reveals small, round, blue cells with prominent nucleus and scant cytoplasm.

Immunohistochemical findings includes strong membrane expression of CD99, frequent expression of CD56.

The absence of CD99 expression virtually rules out diagnosis of ES.

Diagnosis relies on identification of chromosomal translocation.

Most important prognostic feature is the presence of metastasis at the time of diagnosis.

Patients with local disease that respond to therapy have a five-year survival rate of more than 70%.

30% of patients presenting with metastasis survive for five years.

Most common site of metastasis are lungs, bone and bone marrow, but ES can metastasize widely.

Patients with metastasis limited to lung have better prognosis and those with metastasis to the bone or bone marrow.

Tumors with proximal primary location of the pelvis and sacrum have worse prognosis than patients with distal tumors.

Unfavorable prognosis is associated with large primary neoplasms, old age a diagnosis of greater than 18 years, and elevated LDH levels.

Current management of primary ES relies on a combination of cytotoxic drugs and local reduction surgery, radiotherapy or both.

5-year survival rate among patients with localized disease has improved from 10% before chemotherapy to about 70% currently.

With currently recommended treatment protocols multi modal approaches including chemotherapy, five-year survival is about 60 to 75% in localized and 20 to 40% in metastatic disease, respectively, depending on metastatic sites and tumor burden.

Adjuvant chemotherapy based on use of doxorubicin, vincristine, cyclophosphamide, ifosfamide and dactinomycin: reduces the size of the primary tumor and targets micrometastatic disease, followed by consolidation chemotherapy to eliminate residual cells.

Use of ifosamide with or without etoposide improves response rates in patients with relapse after standard treatment.

Patients with nonmetastatic disease treated with doxorubicin, vincristine, cyclophosphamide, dactinomycin vs the same 4 drugs alternating with ifosphamide and etoposide revealed that the latter regimen significantly improved outcome with an overall survival of 72%.

Patients with bone or bone marrow metastases have a poorer prognosis than patients with primary lung mets.

Pateints with early relapses have worse prognosis than pateints with late relapses.

Adverse prognostic factors include tumor volume, LDH levels, axial localization, older age of greater than 15 years, and poor histological response to pre-operative chemotherapy and incomplete or no surgery for the primary site.

Prognosis worse for patients with bone and/or bone marrow involvement.

Metastatic disease a presentation is the most significant predictor of survival.

Approximately 25% of patients are diagnosed with metastatic disease: 10% lung, 10% bones/bone marrow, 5% combinations or others.