Ewing Sarcoma: Pathophysiology, Imaging Features, Diagnosis, and Treatment – A Comprehensive Review

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Ewing sarcoma is one of the most aggressive and clinically challenging malignant bone tumors affecting children and young adults. This column provides a comprehensive review of Ewing sarcoma, focusing on its pathophysiology, epidemiology, clinical presentation, imaging features, differential diagnosis, treatment, and prognosis, supported by leading literature. The case study and imaging examples included here will serve as both a clinical guide and an educational resource for medical students, radiology residents, and oncology specialists.

Case Presentation

A 13-year-old girl presented with several months of left chest wall pain. She underwent chest radiography and CT imaging. The findings are discussed below.

History and Radiography

  • Patient: 13-year-old female

  • Symptom: Persistent left chest wall pain

Figure 1. Chest Radiograph (P-A View).

Interpretation: Expansile lesion involving the anterior portion of the 4th left rib. No evidence of pneumothorax or significant pleural effusion.

Computed Tomography Findings

Non-contrast chest CT was performed.

Figure 2. Chest CT (A, B: Axial; C: Coronal; D: Sagittal).

Interpretation: Expansile lytic lesion with cortical destruction of the anterior left 4th rib. Soft tissue component extending through the cortex into the chest wall. Minimal compression of adjacent lung without nodules or infiltration.

Pathophysiology of Ewing Sarcoma

Ewing sarcoma belongs to the family of small round blue cell tumors. It is derived from primitive neuroectodermal cells and is characterized by specific chromosomal translocations.

  • Cytogenetics: In ~95% of cases, a t(11;22)(q24;q12) translocation results in EWSR1-FLI1 fusion gene, driving oncogenesis.

  • Tumor Biology: These tumors exhibit highly aggressive growth, early metastasis (to lungs, bone marrow, and other bones), and poor natural survival if untreated.

  • Histology: Small, round, hyperchromatic nuclei with scant cytoplasm; high mitotic activity.

Ewing sarcoma is thus considered part of the Ewing sarcoma family of tumors (ESFT), which also includes Askin tumors and primitive neuroectodermal tumors (PNET).

Epidemiology

  • Second most common malignant bone tumor in children after osteosarcoma.

  • Accounts for ~3% of all pediatric cancers and 10–15% of malignant bone tumors.

  • Annual incidence in the U.S.: 1–3 cases per million children.

  • Peak age: 10–20 years; 95% diagnosed before age 25.

  • Slight male predominance (male-to-female ratio ~1.2:1).

  • More common in Caucasian populations; rare in individuals of African or East Asian descent.

Clinical Presentation

Patients often present with:

  • Pain: Persistent, dull, aching pain, often worse at night.

  • Swelling or palpable mass over the affected site.

  • Local tenderness and warmth.

  • Systemic symptoms: Fever, weight loss, fatigue (mimicking infection).

In chest wall involvement (as in our case), pain is often associated with restricted respiratory motion and palpable rib mass.

Imaging Features

Radiography

  • Appearance: Lytic lesion with permeative or “moth-eaten” bone destruction.

  • Cortical changes: Expansion and destruction with poorly defined margins.

  • Periosteal reaction: Classic “onion-skin” (lamellated) or “sunburst” appearance.

Computed Tomography (CT)

  • Defines extent of cortical destruction.

  • Identifies associated soft tissue mass.

  • Useful for pre-surgical planning and detecting pulmonary metastases.

Magnetic Resonance Imaging (MRI)

  • Gold standard for local staging.

  • Superior delineation of marrow involvement and soft tissue extension.

  • Characteristically shows low-to-intermediate T1 signal, high T2 signal, with heterogeneous enhancement.

Figure Summaries

  • Figure 1. Chest P-A Radiograph: Expansile anterior rib lesion.

  • Figure 2. Chest CT Axial/Coronal/Sagittal: Cortical destruction with soft tissue extension.

Differential Diagnosis

  1. Osteosarcoma – more likely to show osteoid matrix and sclerosis.

  2. Osteomyelitis – infection can mimic permeative bone destruction and periosteal reaction.

  3. Neuroblastoma metastasis – typically in younger children; paraspinal location common.

  4. Askin tumor (PNET of chest wall) – part of the Ewing family of tumors.

  5. Lymphoma of bone – rare, usually in older patients.

Diagnosis

Diagnosis of Ewing sarcoma is confirmed by:

  • Biopsy: Histopathology with immunohistochemistry (CD99 positivity).

  • Molecular genetics: Detection of EWSR1-FLI1 fusion by FISH or RT-PCR.

Treatment

Management of Ewing sarcoma is multimodal:

  1. Neoadjuvant Chemotherapy

    • Standard protocols include combinations of vincristine, doxorubicin, cyclophosphamide (VDC) alternating with ifosfamide and etoposide (IE).

  2. Local Control

    • Surgery: Wide resection when feasible (rib resection in chest wall cases).

    • Radiotherapy: Used when surgery is not possible or for residual disease.

  3. Adjuvant Chemotherapy

    • Continuation of systemic therapy to eradicate micrometastatic disease.

Prognosis

  • Localized disease: 5-year survival ~70%.

  • Metastatic disease: 5-year survival drops to ~20–30%.

  • Poor prognostic factors:

    • Pelvic or axial skeleton location.

    • Large tumor volume.

    • Presence of metastases at diagnosis.

    • Poor response to induction chemotherapy.

Quiz

Q 1.What is the most common cytogenetic abnormality in Ewing sarcoma?

(A) t(9;22)(q34;q11)

(B) t(11;22)(q24;q12)

(C) t(15;17)(q22;q12)

(D) t(8;14)(q24;q32)

Q 2. Which imaging feature is most characteristic of Ewing sarcoma?

(A) Codman’s triangle

(B) Onion-skin periosteal reaction

(C) Ground-glass opacity

(D) Punched-out lytic lesion

Q 3. What is the primary mode of treatment for localized Ewing sarcoma?

(A) Radiation therapy alone

(B) Surgery alone

(C) Multimodal therapy with chemotherapy and surgery ± radiotherapy

(D) Immunotherapy

Q 4. Which of the following sites is least commonly affected by Ewing sarcoma?

(A) Femur

(B) Pelvis

(C) Skull vault

(D) Ribs

Q 5. What is the approximate 5-year survival rate for localized Ewing sarcoma with appropriate treatment?

(A) 10% 

(B) 30% 

(C) 70%

(D) 90%

Answer & Explanation

1. Answer: (B). Explanation: Ewing sarcoma is characterized by EWSR1-FLI1 translocation t(11;22).

2. Answer: (B). Explanation: Ewing sarcoma typically demonstrates lamellated “onion-skin” periosteal reaction.

3. Answer: (C). Explanation: Standard of care involves systemic chemotherapy with surgery and/or radiation.

4. Answer: (C). Explanation: Skull involvement is rare compared to long bones, pelvis, and ribs.

5. Answer: (C). Explanation: Advances in chemotherapy and multimodal therapy have improved localized survival to ~70%.

References

[1] T. Heare, M. Hensley, and S. Dell'Orfano, “Bone tumors: Osteosarcoma and Ewing's sarcoma,” Curr Opin Pediatr., vol. 21, no. 3, pp. 365–372, 2009.
[2] S. C. Kaste, “Imaging pediatric bone sarcomas,” Radiol Clin North Am., vol. 49, no. 4, pp. 749–765, 2011.
[3] M. D. Murphey et al., “From the radiologic pathology archives: Ewing sarcoma family of tumors: Radiologic-pathologic correlation,” Radiographics, vol. 33, no. 3, pp. 803–831, 2013.
[4] A. Ladenstein et al., “Primary disseminated multifocal Ewing sarcoma: Results of the Euro-EWING 99 trial,” J Clin Oncol., vol. 28, no. 20, pp. 3284–3291, 2010.
[5] S. M. Paulussen et al., “Ewing tumors: Outcome and prognostic factors in 182 patients under 15 years of age from the EICESS-92 study,” Ann Oncol., vol. 19, no. 11, pp. 1819–1829, 2008.
[6] R. Balamuth and R. Womer, “Ewing’s sarcoma,” Lancet Oncol., vol. 11, no. 2, pp. 184–192, 2010.
[7] E. Karski et al., “Survival and prognostic factors of Ewing’s sarcoma: A 30-year experience,” Sarcoma, vol. 2017, Article ID 7841518.

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