Ewing Sarcoma in Pediatric Age
Introduction
Ewing sarcoma is a rare and aggressive type of bone cancer that primarily affects children and adolescents. It is a part of the Ewing sarcoma family of tumors, which also includes extraosseous Ewing sarcoma (occurring in soft tissues) and primitive neuroectodermal tumors (PNET). This malignancy predominantly arises from primitive neuroectodermal cells or undifferentiated mesenchymal stem cells, commonly affecting the long bones, pelvis, and chest wall.
Epidemiology
Ewing sarcoma is the second most common primary bone malignancy in children and adolescents, accounting for approximately 3% of all childhood cancers. The peak incidence occurs between the ages of 10 and 20 years, with a slight predominance in males. The overall incidence rate is around 3 cases per 1 million children and adolescents per year.
Etiology and Risk Factors
The exact cause of Ewing sarcoma is not well understood, but it is believed to be a result of genetic alterations. The most common genetic abnormality associated with Ewing sarcoma is a reciprocal translocation between chromosomes 11 and 22, t(11;22)(q24;q12), which results in the fusion of the EWSR1 gene on chromosome 22 with the FLI1 gene on chromosome 11. This fusion gene, EWSR1-FLI1, is present in approximately 85% of Ewing sarcoma cases and is considered a hallmark of the disease.
Other risk factors for Ewing sarcoma include:
- Hereditary cancer predisposition syndromes (e.g., Li-Fraumeni syndrome)
- Prior exposure to radiation or certain chemotherapy agents
- Genetic factors (e.g., specific polymorphisms in genes related to DNA repair or cell cycle regulation)
Clinical Presentation
The clinical presentation of Ewing sarcoma can vary depending on the location and extent of the tumor. Common presenting symptoms include:
- Bone pain: This is often the first symptom and may be localized or referred to other areas due to nerve compression or muscle involvement.
- Swelling or mass: A palpable mass or swelling may be present near the tumor site, particularly in soft tissue or extraosseous locations.
- Systemic symptoms: Fever, fatigue, weight loss, and anemia may occur in advanced cases or with metastatic disease.
- Neurological symptoms: Compression of nerves or the spinal cord can lead to numbness, tingling, weakness, or paralysis.
- Respiratory symptoms: Tumors in the chest wall or lungs can cause cough, shortness of breath, or chest pain.
Diagnosis
The diagnostic workup for Ewing sarcoma typically involves a combination of imaging studies and pathological evaluation.
Imaging Studies
- X-ray: Plain radiographs may reveal a destructive bone lesion with periosteal reaction (onion skin appearance) or a soft tissue mass.
- Computed Tomography (CT) scan: CT scans provide detailed information about the extent of bone and soft tissue involvement, as well as potential metastases.
- Magnetic Resonance Imaging (MRI): MRI is useful for evaluating the tumor's relationship to surrounding structures, such as blood vessels, nerves, and muscles.
- Bone scan: A bone scan can detect areas of increased bone metabolism, which may indicate the presence of bone metastases.
- Positron Emission Tomography (PET) scan: PET scans can help differentiate between malignant and benign lesions and identify metastatic disease.
Pathological Evaluation
The definitive diagnosis of Ewing sarcoma relies on pathological examination of a biopsy specimen. The following techniques are commonly employed:
- Histopathology: Ewing sarcoma is characterized by small, round, blue cells with a high nuclear-to-cytoplasmic ratio and scanty cytoplasm.
- Immunohistochemistry: Ewing sarcoma cells typically express CD99, a cell surface protein, which is helpful in distinguishing it from other small round cell tumors.
- Molecular testing: Fluorescence in situ hybridization (FISH) or reverse transcription-polymerase chain reaction (RT-PCR) can detect the characteristic EWSR1-FLI1 fusion gene or other gene rearrangements associated with Ewing sarcoma.
Staging
Staging for Ewing sarcoma is based on the extent of the primary tumor, lymph node involvement, and the presence of metastases. The most commonly used staging system is the Enneking surgical staging system, which classifies the tumor as localized (confined to the primary site), regional (spread to adjacent structures), or metastatic.
Additionally, the Pediatric Oncology Group (POG) staging system is often used, which takes into account the tumor size, presence of metastases, and resectability of the primary tumor.
Treatment
The treatment of Ewing sarcoma typically involves a multidisciplinary approach combining chemotherapy, surgery, and radiation therapy.
Chemotherapy
Chemotherapy is a crucial component of the treatment for Ewing sarcoma. Standard chemotherapy regimens include a combination of multiple agents, such as:
- Vincristine
- Doxorubicin
- Cyclophosphamide
- Ifosfamide
- Etoposide
Chemotherapy is typically administered in cycles, with periods of treatment followed by rest periods to allow the body to recover. It may be given before surgery (neoadjuvant chemotherapy) to shrink the tumor and increase the chances of complete surgical resection, as well as after surgery (adjuvant chemotherapy) to eliminate any remaining cancer cells.
Surgery
Surgery plays a vital role in the management of Ewing sarcoma. The primary goal of surgery is to achieve complete resection of the tumor with negative margins, if possible. Depending on the location and extent of the tumor, different surgical approaches may be employed, such as:
- Wide resection: Removal of the tumor along with a wide margin of surrounding healthy tissue.
- Limb-sparing surgery: Removal of the tumor while preserving the affected limb, often followed by reconstruction or prosthetic replacement.
- Amputation: In cases where limb-sparing surgery is not feasible or the tumor involves critical structures, amputation of the affected limb may be necessary.
Radiation Therapy
Radiation therapy plays an important role in the management of Ewing sarcoma, particularly in cases where complete surgical resection is not possible or when the tumor is located in areas where surgery is not feasible (e.g., spine, pelvis). Radiation therapy can be administered before or after surgery, depending on the treatment plan.
Stem Cell Transplantation
In some cases, high-dose chemotherapy followed by stem cell transplantation (also known as bone marrow transplantation or peripheral blood stem cell transplantation) may be considered for patients with high-risk or relapsed Ewing sarcoma. This intensive treatment approach aims to deliver higher doses of chemotherapy to eliminate any remaining cancer cells, followed by the infusion of stem cells to restore the patient's bone marrow function and immune system.
Prognosis and Survival
The prognosis for Ewing sarcoma has improved significantly in recent decades due to advances in multimodal treatment approaches. However, the overall survival rate still varies depending on several factors, including:
- Stage at diagnosis: Patients with localized disease have a better prognosis compared to those with metastatic disease at the time of diagnosis.
- Tumor size: Smaller tumors (less than 8 cm) generally have a better prognosis than larger tumors.
- Tumor location: Tumors located in the pelvis or central axis (spine, chest wall) tend to have a poorer prognosis compared to those in the extremities.
- Response to treatment: Patients who achieve a complete response to initial chemotherapy and have no evidence of residual disease after surgery or radiation therapy tend to have a better prognosis.
- Age: Younger patients (under 10 years old) generally have a better prognosis compared to older patients.
Overall, the 5-year survival rate for localized Ewing sarcoma ranges from 60% to 70%, while the 5-year survival rate for metastatic disease is approximately 20% to 30%. However, it's important to note that these statistics are based on historical data, and survival rates may vary depending on the specific treatment protocols and advances in care.
Supportive Care and Long-term Follow-up
Patients with Ewing sarcoma often require comprehensive supportive care to manage the side effects of treatment and improve their overall quality of life. This may include:
- Pain management: Effective pain control is crucial, as Ewing sarcoma can be associated with significant bone pain.
- Nutritional support: Nutritional counseling and supplementation may be necessary to address issues such as poor appetite, weight loss, and malnutrition.
- Psychosocial support: Counseling and psychological support services can help patients and their families cope with the emotional and psychological challenges associated with the diagnosis and treatment.
- Rehabilitation: Physical and occupational therapy can aid in regaining strength, mobility, and independence after surgery or during and after treatment.
Long-term follow-up is essential for monitoring disease recurrence, managing late effects of treatment, and addressing any lingering physical, emotional, or psychosocial issues. Regular follow-up visits typically include physical examinations, imaging studies, and laboratory tests.
Further Reading
For additional information on Ewing sarcoma in pediatric age, please refer to the following authoritative sources:
