Basics
Description
- Family of cancers with common biology and treatment:
- Ewing sarcoma of bone
- Extraskeletal Ewing sarcoma (arises in soft tissue adjacent to bone)
- Peripheral neuroectodermal tumor (PNET) of bone or soft tissue
- Askin tumor (Ewing sarcoma of the chest wall)
- Most common primary tumor sites are as follows:
- Pelvic bones (26%)
- Femur (20%)
- Chest wall (16%)
Epidemiology
- 2nd most common primary bone cancer of children and young adults after osteosarcoma
- Median age of diagnosis is 15 years, although can occur in any age group
- Slight male predominance
Incidence
- ~200-250 new cases are diagnosed in the United States each year.
- Annual incidence in the United States of 2.7 cases per million children younger than 15 years of age
- Most (~65%) occur in the 2nd decade of life.
- Strikingly lower incidence in sub-Saharan Africa and in African American population
Risk Factors
- Most cases occur sporadically.
- Not associated with familial cancer syndromes
- Only rarely reported as a second malignancy
- One genome-wide association study identified several single nucleotide polymorphisms (SNPs) associated with higher risk.
- Epidemiologic studies suggest higher risk in patients with history of inguinal or umbilical hernia.
General Prevention
- There are no known preventive measures.
Pathophysiology
- Rearrangement of the EWSR1 gene on chromosome 22 is detected in >95% of cases.
- 85% of cases have a t(11;22) translocation resulting in a fusion EWS-FLI1 protein.
- 10% of cases have a t(21;22) translocation between EWS and ERG.
- Other translocation partners occur in <1% of cases and include other members of the ETS transcription factor family, such as ETV1.
- Fusion proteins thought to play a role as aberrant transcription factor
Diagnosis
History
- Pain is most common symptom.
- Pain is often attributed to minor injuries that are common in this age group.
- Other presenting symptoms are as follows:
- Systemic symptoms (fever, weight loss) are more common among patients with metastatic disease and more common compared to patients with osteosarcoma.
Physical Exam
- Palpable mass (35%)
- Local tenderness (70%)
- Painful movement of joint (35%)
- Fever (30%)
- Regional node involvement uncommon, although more likely with a soft tissue primary tumor
Diagnostic Tests & Interpretation
Lab
- CBC as a screen for bone marrow involvement
- Serum lactate dehydrogenase (LDH) is often elevated at diagnosis and may be prognostic.
- Prechemotherapy labs include liver function tests and tests of renal function.
Imaging
- To evaluate primary site:
- Plain radiographic findings may include the following:
- Destructive lesion with "moth-eaten" appearance
- Periosteal reaction with layers of reactive bone can give an "onionskin" appearance.
- Raised periosteum may result in a Codman triangle.
- When arising in long bones, tends to arise from diaphysis rather than metaphysis
- CT or preferably MRI scan in addition to radiograph is essential to fully characterize the extent of the primary tumor.
- 25% have detectable metastases at diagnosis.
- To evaluate for distant metastases:
- Chest CT scan
- Fluorine-18-fluorodeoxyglucose positron emission tomography (FDG PET) or 99m-Tc-diphosphonate bone scan
Diagnostic Procedures/Other
- Biopsy
- Consultation with a pediatric oncologist and orthopedic oncologist is essential before biopsy.
- Should be performed by an experienced orthopedic surgeon
- Avoid contamination of surrounding tissues.
- Include testing for EWSR1 translocation, either by fluorescence in situ hybridization (FISH), cytogenetics, or reverse transcription-polymerase reaction (RT-PCR).
- Small round blue cell tumor with nearly universal membranous CD99 expression
- PNET shows evidence of neural differentiation.
- Bilateral bone marrow aspirates and biopsies to complete metastatic staging
- Echocardiogram in anticipation of starting chemotherapy
Differential Diagnosis
- Malignant
- Osteosarcoma
- Neuroblastoma
- Non-Hodgkin lymphoma
- Rhabdomyosarcoma
- Other soft tissue sarcoma
- Bone metastasis from other malignancy
- Benign
- Osteomyelitis
- Tendonitis
- Trauma
- Langerhans cell histiocytosis
- Other benign bone tumor
Treatment
Chemotheraphy
- Chemotherapy is essential for cure.
- Prior to the use of chemotherapy, only 10% of patients survived.
- Patients with nonmetastatic disease now have an overall survival rate approaching 70% with the use of chemotherapy and appropriate local control.
- Suggests that patients have small amounts of occult micrometastatic tumor cells that cannot be detected by current technology
- In North America, standard chemotherapy traditionally includes vincristine, doxorubicin, and cyclophosphamide alternating every 2 weeks with etoposide and ifosfamide.
- Other agents under investigation include camptothecins (irinotecan and topotecan) as well as IGF-1R inhibitors.
Additional Treatment
General Measures
- In addition to systemic treatment with chemotherapy, patients need local control treatment to the site of the primary tumor and metastases (if present) with surgery, radiation, or both.
- The type of local control used depends on the location and extent of the tumor, the morbidity associated with resection, and the presence of tumor cells at the resection margin in those who have surgery.
- The usual sequence of treatment is
- Neoadjuvant chemotherapy
- Local control
- Adjuvant chemotherapy
- Most children are treated on or according to large cooperative group clinical trials.
- Myeloid growth factor (e.g., granulocyte colony-stimulating factor [G-CSF]) is usually given following chemotherapy to shorten the duration of neutropenia.
Surgery/Other Procedures
- If surgical local control is pursued, goal is to remove the entire tumor with negative tissue margins.
- Limb salvage surgery is often possible but may not be best in some cases.
- Amputation is less commonly performed given the radiosensitive nature of Ewing sarcoma.
Radiation
- Definitive radiation provides reasonable local control in cases not amenable to surgical resection.
- Radiation also used for
- Attempted surgical resection, but margins positive
- Treatment of cytology-proven malignant pleural effusions in patients with chest wall tumors
- Treatment of metastatic disease, including whole lung radiotherapy for patients with lung metastasis
- Carries risk of second malignancy
Additional Theraphies
- Physical therapy
- All patients who receive surgery should be referred to physical therapy following surgery.
- Patients regardless of surgery may need physical therapy for deconditioning associated with treatment.
- Reproductive endocrinology
- Given the role of alkylating chemotherapy in the treatment of Ewing sarcoma, all patients should be encouraged to meet with reproductive endocrinology to discuss fertility preservation strategies prior to initiating therapy.
Issues for Referral
Consultation with a pediatric oncologist is essential before any attempt is made at a diagnostic biopsy.
Ongoing Care
Prognosis
- 5-year overall survival rate for all patients is ~60%.
- Presence of metastases is the most important prognostic factor.
- Estimated overall survival in those with metastatic disease at diagnosis is less than 30% at 5 years.
- Other unfavorable prognostic features:
- Older age (age >18 years)
- Pelvic primary tumor
- Large primary tumor
- Other prognostic factors under investigation:
- LDH
- Race
- Aberrations in p53/p16
- Subtype of EWSR1/FLI1 translocation not prognostic
Complications
- Acute toxicity
- Alopecia
- Bone marrow suppression
- Platelet and packed red blood cell transfusions are usually necessary.
- Neutropenia: increased risk of bacterial and fungal infections
- Gastrointestinal side effects
- Nausea and vomiting
- Mucositis
- Kidney and bladder side effects
- Electrolyte wasting
- Hemorrhagic cystitis
- Complications from radiation
- Skin breakdown and erythema
- Bone marrow suppression
- Complications from surgery
- Wound dehiscence
- Infection
Late Effects
- Cardiotoxicity (See "Cancer Therapy Late Effects.")
- Anthracyclines (doxorubicin) can lead to cardiomyopathy and heart failure.
- Risk depends on cumulative dose of doxorubicin.
- Radiation to the heart can increase the risk of cardiotoxicity.
- Patients should have yearly echocardiogram for evaluation.
- Reduced fertility
- Second malignancy
- Sarcomas may occur within the radiation field.
- Myelodysplastic syndromes and acute myeloid leukemia may occur secondary to chemotherapy.
Additional Reading
- Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003;348(8):694-701. [View Abstract]
- Postel-Vinay S, Veron AS, Tirode F, et al. Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma. Nat Genet. 2012;12(3):323-327. [View Abstract]
- Rodriguez-Galindo C, Liu T, Krasin MJ, et al. Analysis of prognostic factors in Ewing sarcoma family of tumors: review of the St. Jude Children's Research Hospital studies. Cancer. 2007;110(2):375-384. [View Abstract]
- Rodriguez-Galindo C, Spunt SL, Pappo AS. Treatment of Ewing sarcoma family of tumors: current status and outlook for the future. Med Pediatr Oncol. 2003;40(5):276-287. [View Abstract]
- Valery PC, Holly EA, Sleigh AC, et al. Hernias and Ewing's sarcoma family of tumours: a pooled analysis and meta-analysis. Lancet Oncol. 2005;6(7):485-490. [View Abstract]
- Womer RB, West DC, Krailo MD, et al. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol. 2012;30(33):4148-4154. [View Abstract]
Codes
ICD09
- 170.9 Malignant neoplasm of bone and articular cartilage, site unspecified
- 170.6 Malignant neoplasm of pelvic bones, sacrum, and coccyx
- 170.7 Malignant neoplasm of long bones of lower limb
- 195.1 Malignant neoplasm of thorax
ICD10
- C41.9 Malignant neoplasm of bone and articular cartilage, unsp
- C41.4 Malignant neoplasm of pelvic bones, sacrum and coccyx
- C40.20 Malignant neoplasm of long bones of unspecified lower limb
- C76.1 Malignant neoplasm of thorax
- C40.21 Malignant neoplasm of long bones of right lower limb
- C40.22 Malignant neoplasm of long bones of left lower limb
SNOMED
- 307608006 Ewing's sarcoma of bone (disorder)
- 449100005 Sarcoma of bone of pelvis (disorder)
- 448712008 Sarcoma of femur (disorder)
- 447951009 Ewing's sarcoma of soft tissue (disorder)
FAQ
- Q: At what time point is a child with Ewing sarcoma considered cured?
- A: Most cases of recurrence in Ewing sarcoma occur within 2 years of initial diagnosis. However, late relapses beyond 5 years from initial diagnosis have been seen with Ewing sarcoma.
- Q: Should an Ewing sarcoma be completely resected at the time of diagnosis?
- A: Ewing sarcoma tumors are typically large at initial diagnosis. The standard approach is to treat with chemotherapy first, both to reduce the size of the tumor and to treat any distant tumor cells.
- Q: Is surgery or radiation better for local control of the primary tumor in Ewing sarcoma?
- A: This is an area of controversy. Most specialists favor surgical resection when feasible without significantly jeopardizing function, reserving radiation for cases that are less amenable to surgical resection with negative margins.
- Q: Why do Africans and African Americans have such low rates of Ewing sarcoma?
- A: It is not known why these populations are at lower risk for developing Ewing sarcoma, although it suggests a genetic component that influences the risk of developing this disease. Studies are ongoing to investigate this consistent finding.