Stat Consult: Ewing Sarcoma in Children

Description

Ewing sarcoma is a rare, small, round, blue-cell tumor of unknown origin arising in bones or soft tissues.
Mainly occurs in children and adolescents (median age at diagnosis 15 years), but may occur in adults as well.
The most common cause is a genetic translocation that leads to malignant transformation of affected cells.
Most patients present with localized, nonmechanical pain and/or swelling, but may also have fever, weight loss, or fatigue.

Incidence/Prevalence

Incidence is reported to be 2.5-3 cases per 1,000,000 people
Reported to account for:
- 2.6% of pediatric cancers
- 16% of primary bone cancers

Causes

Gene translocations between Ewing sarcoma breakpoint region 1 (EWSR1) and erythroblast transformation-specific (ETS) family transcription factors, including
- FLI1 – producing EWSR1-FLI1 t(11;22)(q24;q12) (in 85%)
- Other ETS members, ERG, FEV, ETV1, and ETV4 (in 5%-10%)
Other causes include
- EWS-free rearrangements with ETS transcription factors (rare)
- Tumor variants
  - TP53 mutations
  - STAG2 mutations
  - CDKN2A deletions
- Variation near locus of early growth response 2 (EGR2, 10q21.3), increasing binding efficiency of EWSR1-FLI1

Pathogenesis

Ewing sarcoma may arise due to expression of oncogenic fusion proteins in:
- Bone marrow-derived mesenchymal stem cells
- Neural crest-derived stem cells
- Bone progenitors
- Osteochondrogenic progenitors
- Oncogenic proteins enhance proliferation and malignant transformation through increased molecular target binding, epigenetic deregulation, and alterations in RNA splicing and micro RNA binding

Clinical Presentation

Ewing sarcoma may present as
- Ewing sarcoma of bone
- Extraskeletal Ewing sarcoma
- Askin tumor of chest wall (clavicle, scapula, ribs, or sternum)
- Primitive neuroectodermal tumors of bone and soft tissue (PNET)
Most tumors present with localized pain and/or swelling, but may also have fever, weight loss, or fatigue
Primary tumor site locations
- Skeleton – may present in any bone, but commonly
  - Diaphyseal or metadiaphyseal long bones (femur)
  - Pelvis
  - Chest wall
  - Spine
- Soft tissues

History

Ask about localized swelling and/or pain duration, severity, and timing (for example, night pain)

Ask about other symptoms associated with
- Chest wall tumors (Askin tumor) — fever, cough, dyspnea, and/or chest pain
- Pelvic tumors — urinary retention, sciatic nerve pain
- Spinal tumors — back pain, muscle weakness, decreased/altered sensation, imbalance, bowel/bladder issues
Pain may be attributed to nonspecific trauma/sports-related injury resulting in delayed diagnosis (from weeks to months)
Ask about
- Recent fracture or injury
- Previous benign or malignant lesions
- Radiation therapy
- Family history of bone cancers

Physical

Evaluate area associated with pain
Swelling may be present only in sarcomas that progressed through the bone cortex and caused periosteal distention

Diagnosis and Staging

Making the diagnosis

Suspect Ewing sarcoma in patients with bone pain and/or swelling, or with a lesion seen with poor margins on plain radiograph (x-ray)
Perform imaging with x-ray, magnetic resonance imaging (MRI), and/or computed tomography (CT) for staging prior to biopsy
Diagnosis confirmed with open or core needle biopsy
Obtain blood tests (may provide prognostic information) include CBC, LDH, ALP, ESR, and CMP

Differential Diagnosis

Benign tumors (osteochondroma or osteoid osteoma)
Osteomyelitis
Malignant bone cancers
- Osteosarcoma
- Chondrosarcoma
- Chordoma
- Giant cell bone tumor
Other small round-cell neoplasms
- Neuroblastoma
- Rhabdomyosarcoma
- Wilms tumor
- Desmoplastic small round-cell tumor
- Non-Hodgkin lymphoma
- Solitary fibrous tumor
- Melanoma
- Extraskeletal mesenchymal chondrosarcoma
- Poorly differentiated
  - synovial sarcoma
  - neuroendocrine carcinoma
- Liposarcoma

Imaging

To evaluate for primary site
- Plain radiograph; findings may include:
  - Mottled appearance
  - Osteolytic lesions with distinctive onion skin pattern
  - Sharpey fibers with “hair on end” appearance
  - Periosteal elevation (Codman triangle)
- MRI to define tumor extent
- CT
  - With MRI for primary site imaging
If uncertain diagnosis, to improve visualization
To evaluate for metastases affecting
- Skeleton — positron emission tomography/CT, bone scan, or pelvis/spine MRI
Lungs — chest CT
Bone marrow- bone marrow biopsy

Biopsy

Modalities include open (incisional) biopsy or core needle biopsy; no randomized trial exists to guide modality choice, however core needle or open biopsy recommended
Open (incisional) biopsy
- Reported to be more accurate due to larger tumor sample size
- Samples may also be used for cytogenetics or immunohistochemistry
Percutaneous biopsy
- Core needle biopsy
  - Diagnostic accuracy reported to be 88% to 96%
  - Reported to have lower risk of tumor seeding
- Fine-needle aspiration may be controversial; reported to have lower accuracy than core needle biopsy
Perform cytogenetic or molecular studies; evaluate with
Cytogenetic evaluation
RT-PCR if frozen tissue is available
FISH if touch preps/formalin-fixed paraffin-embedded tissue available
- Histology
  - May appear poorly differentiated as small, round, blue cells
Positive for
- Cell surface glycoprotein MIC2 (CD99)
- Friend leukemia integration 1 (FLI1)
- Neuron specific enolase (NSE)
- Periodic-acid Schiff
If uncertain histology, confirmation of EWSR1 and ETS translocation required for diagnosis

Staging System(s)

Surgical staging system
- Stage IA – low grade (G1) and intracompartmental (T1)
- Stage IB – low grade (G1) and extracompartmental (T2)
- Stage IIA – high grade (G2) and intracompartmental (T1)
- Stage IIB – high grade (G2) and extracompartmental (T2)
- Stage III – any grade with regional or distant metastasis and either intracompartmental or extracompartmental

Management Overview

Before treatment
- Consider enrollment in a clinical trial
- Provide fertility counseling for patients of child-bearing age
May involve multiagent chemotherapy, surgical tumor resection, and/or radiation therapy
- Treatment duration generally 10 to 12 months
- Chemotherapy
  - Typically involves 6 drug combinations of vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide, and/or dactinomycin
  - Surgical tumor resection is preferred modality for local tumor control
- Radiation therapy used as definitive or adjuvant therapy
Specific treatment
- Newly diagnosed patients with nonmetastatic disease at presentation, consider
  - Multiagent chemotherapy with vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide (VAC/IE) for ≥9-12 weeks
  - Growth factor support
- Patients with stable disease after first-line therapy
  - Local control with surgical tumor resection, definitive radiation therapy, or amputation (in select patients)
  - Adjuvant therapy; in patients having
    - Tumor resection with negative margins — adjuvant chemotherapy
    - Tumor resection with positive margins — continue adjuvant chemotherapy, give adjuvant radiation therapy
    - Limb amputation — continue adjuvant chemotherapy postoperatively, give margin-dependent radiation therapy
- In patients with metastatic disease
  - At presentation — offer clinical trial, give multiagent chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VAdriaC), VAC/IE, VAI, or VIDE
  - After first-line treatment, consider
    - Radiation therapy and/or surgery for palliation/local control
    - Whole-lung irradiation in patients with lung metastases after completing chemotherapy/surgery
    - Multiagent chemotherapy, best supportive care
- In patients with recurrent disease
  - Offer clinical trial
  - Give chemotherapy with or without radiation therapy
Surveillance
- Frequent monitoring includes examination, imaging, and blood studies
- Life-long surveillance recommended to monitor for late effects of treatments
- Refer patients for survivorship clinic
- After 2 years, may extend surveillance intervals; perform annually after 5 years

Complications

Metastases affecting bone, bone marrow, or lungs (20%-25% reported to present with metastatic disease)
Treatment-related complications
- Secondary cancers, such as acute myeloid leukemia
- Myelodysplastic syndrome
- Cardiac dysfunction
- Infertility in males
- Premature menopause
- Growth arrest
- Bone fracture

Prognosis

5-year prognosis reported to be
- 60%-85% overall survival in patients with localized disease
- 27%-40% overall survival in patients with metastatic disease
- 73% event-free survival
- <10% survival with surgery or radiotherapy alone
Factors at diagnosis associated with disease recurrence include
- Large tumor size (>8 cm)
- Presence of metastatic disease
- Elevated serum lactate dehydrogenase
- Hypoalbuminemia
- Older age (>14 years)
- Axial tumor location

Kendra Church MS, PA-C, is a physician assistant at Dana-Farber Cancer Institute/Brigham & Women’s Hospital, and is also a senior clinical editor for DynaMed, an evidence-based, point-of-care database.

Sources

Jackson TM, Bittman M, Granowetter L. Pediatric malignant bone tumors: a review and update on current challenges, and emerging drug targets. Curr Probl Pediatr Adolesc Health Care. 2016;46(7):213-228. doi:10.1016/j.cppeds.2016.04.00
Biermann JS, Chow W, Adkins DR, et al. Bone cancer. In: National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines). NCCN. August 2017. https://www.nccn.org/guidelines/category_1
European Society for Medical Oncology (ESMO)/European Sarcoma Network Working Group. Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25 Suppl 3:iii113-123. doi:10.1093/annonc/mdu25. Correction: Ann Oncol. 2015;26 Suppl 5:v174.

Topics:

Oncology Pediatrics