Ewing Sarcoma - Comprehensive Pathology

Overview

• Age: Most cases occur in patients aged 5-25 years (85% aged 5-20 years); peak incidence in the second decade
• Sex: Slight male predominance
• Race: Exceedingly rare in individuals of African descent; predominantly affects Whites of European origin
• Incidence: ~200 new cases/year in the United States
• Location: 80% in bone, 20% extraosseous ("extraosseous Ewing sarcoma")

Molecular Pathogenesis

• EWSR1 is located on 22q11 and encodes an RNA-binding protein
• The fusion protein binds chromatin and dysregulates transcription, leading to uncontrolled growth and abnormal differentiation
• All fusion partners belong to the ETS transcription factor family (FLI1, ERG, ETV1, ETV4, FEV)
• Cell of origin: Most likely mesenchymal stem cells or primitive neuroectodermal cells
• Additional somatic mutations: TP53, CDKN2A, and STAG2 mutations are detectable; most additional changes appear to be epigenetic
• An aggressive variant carries a CIC-DUX4 fusion (Ewing-like)
• Some cases harbor FUS rearrangements (related TET family member) instead of EWSR1

FISH Demonstration of EWSR1 Rearrangement

Sites of Involvement

• Long bones: Metaphysis of the femur, tibia, fibula, and humerus (often with diaphyseal extension) - most common
• Flat bones: Pelvis and scapular girdle (femur + pelvis = one-third of all cases)
• Ribs: Classic site in adults
• Spine: Primary vertebral Ewing is rare (3.3-15%); sacral involvement in up to 50% of spinal cases
• Extraosseous: Soft tissue origin (20% of cases)
• Rarely involves small bones of hands/feet or skull

Gross Pathology / Macroscopy

• Arises in the medullary cavity and invades the cortex, periosteum, and surrounding soft tissue
• Soft, tan-white tumor with frequent areas of hemorrhage and necrosis
• Often associated with a large soft tissue mass adjacent to bone - this is characteristically much larger than the bony component visible on plain X-ray
• The periosteal reaction to advancing tumor produces layers of reactive bone

Histopathology (Microscopy)

Key Histological Features:

1. Sheets of uniform small round cells - slightly larger and more cohesive than lymphocytes
2. Scant cytoplasm - may appear clear due to glycogen (PAS-positive, diastase-sensitive)
3. Round nuclei with fine chromatin; nucleoli usually inconspicuous
4. Minimal intercellular matrix - no bone or cartilage production (unlike osteosarcoma)
5. Homer-Wright rosettes - circular groupings of cells with a central fibrillary core (when neuroectodermal differentiation is present, seen in peripheral PNET variant)
6. Pseudorosettes (attempted formation of vascular channels)
7. Areas of necrosis and hemorrhage are common

Classic H&E Photomicrograph - Robbins Pathology:

Clinical + Imaging + Histology Composite - Miller's Review:

Immunohistochemistry (IHC)

CD99 and FLI-1 positivity together with the translocation studies are the cornerstone of diagnosis.

Radiological Features

Plain X-ray:

• Permeative / "moth-eaten" lytic destructive pattern
• "Onion-skin" periosteal reaction - multiple layers of reactive periosteal bone (most classic sign)
• "Sunburst" periosteal reaction - may also be seen
• Codman triangle - periosteal elevation at tumor margins
• Diaphyseal or metaphyseal location in long bones
• May appear near-normal on X-ray in highly permeative lesions (MRI then reveals marrow involvement)

MRI:

• Isointense on T1, iso- to hyperintense on T2
• Intense gadolinium enhancement
• Often reveals a large adjacent soft tissue mass (characteristic)
• Shows full extent of marrow involvement
• "Curtain sign" in spinal Ewing - invasion of spinal canal

Campbell's Operative Orthopaedics - Multimodal Imaging:

Spinal Ewing - MRI (L2):

Clinical Presentation

• Pain - nearly universal; often insidious onset; may be mild and intermittent initially
• Soft tissue mass - often warm and tender; can mimic infection
• Fever, leukocytosis, elevated ESR - mimics acute osteomyelitis (confounds diagnosis)
• Average delay from onset to diagnosis: ~34 weeks
• ~20% of patients present with metastatic disease at diagnosis

Staging / Workup

• Bone marrow biopsy is performed for staging
• CT chest for lung metastases
• Bone scan for skeletal metastases
• PET-CT: increasingly used for whole-body staging
• MRI of primary site: mandatory for local staging

Differential Diagnosis of Small Round Blue Cell Tumors

When a SRBCT is found in a child younger than 5 years, metastatic neuroblastoma and leukemia should be considered first.

Ewing Sarcoma Family (Unified Concept)

1. Classic Ewing sarcoma - non-matrix-forming bone tumor
2. Peripheral PNET (pPNET) - more prone to neuroepithelial rosettes; arises from viscera or soft tissue
3. Extraosseous Ewing sarcoma - same genetics, soft tissue origin
4. Askin tumor - chest wall PNET in children

Ewing-like Tumors with BCOR Alterations (Newer Entity):

• Previously grouped with Ewing sarcoma family based on similar morphology
• Characterized by BCOR-CCNB3 fusions (paracentric inversion on X chromosome short arm)
• Composed of small round blue cells (like Ewing) or small spindle blue cells in whorled/hemangiopericytomatous pattern
• Distinct from classic Ewing sarcoma despite overlap

Prognosis and Prognostic Factors

• 5-year event-free survival: ~70% with localized disease treated with multimodal therapy
• Long-term cure rate: ~50-75% with neoadjuvant chemo + surgery ± radiation
• Patients with clinically detectable metastatic disease at presentation have poor outcomes

Poor Prognostic Factors:

• Spine and pelvic tumor location
• Tumor size >100 cm² (or >200 mL volume)
• Poor histological response to chemotherapy (<90% tumor necrosis)
• TP53 mutation
• Fusion genes other than EWS-FLI1
• Metastatic disease at presentation

Metastasis Pattern:

• Lungs - 50%
• Bone - 25%
• Bone marrow - 20%

Treatment Summary

1. Neoadjuvant chemotherapy (induction) - VAC/IE: vincristine + doxorubicin + cyclophosphamide alternating with ifosfamide + etoposide
2. Local control: Wide surgical resection (R0) is preferred; radiation for pelvic/spinal lesions where resection is morbid
3. Adjuvant chemotherapy (consolidation)
4. High-dose therapy + peripheral blood stem cell transplant (PBSCT): For large tumors (>200 mL) with poor chemo response
5. Salvage regimens: Cyclophosphamide/topotecan, irinotecan/temozolomide, gemcitabine/docetaxel