Ewing's Sarcoma

1. Clinical Overview

Summary

Ewing's sarcoma is an aggressive, highly malignant primary bone tumour predominantly affecting children, adolescents, and young adults aged 10-20 years. It is the second most common primary bone malignancy in the paediatric and adolescent population, after osteosarcoma. [1,2]

Histologically, Ewing's sarcoma belongs to the Ewing sarcoma family of tumours (ESFT), characterized as a "small round blue cell tumour" with a pathognomonic molecular signature: the EWSR1-FLI1 fusion gene resulting from the chromosomal translocation t(11;22)(q24;q12) in approximately 85% of cases. [3,4]

Unlike osteosarcoma, which arises in the metaphysis of long bones, Ewing's sarcoma typically originates in the diaphysis (mid-shaft) of long bones or in flat bones (pelvis, ribs, scapula, vertebrae). The most common skeletal sites are the pelvis (25%), femur (20%), and tibia/fibula (15%). [5]

A key distinguishing clinical feature is the presence of systemic symptoms mimicking infection: fever, malaise, weight loss, and elevated inflammatory markers (ESR, CRP, WCC). This presentation frequently leads to misdiagnosis as osteomyelitis, delaying definitive treatment. [6]

Imaging reveals a permeative lytic lesion with characteristic "onion-skin" or "sunburst" periosteal reaction and an associated soft tissue mass, often disproportionately large compared to the osseous lesion.

Treatment is multimodal, combining neoadjuvant chemotherapy (typically VDC-IE: Vincristine, Doxorubicin, Cyclophosphamide alternating with Ifosfamide, Etoposide), local control (wide surgical excision or radiotherapy), and adjuvant chemotherapy. [7,8] Ewing's sarcoma is both chemosensitive and radiosensitive, making it amenable to non-surgical local control in cases where surgery would result in unacceptable morbidity (e.g., pelvic or spinal lesions).

With contemporary multimodal therapy, 5-year survival for localized disease is approximately 70%, but drops to 20-30% for patients with metastatic disease at presentation. [9,10] Approximately 20-25% of patients have detectable metastases at diagnosis, most commonly to lungs, bones, or bone marrow.

Key Facts

• Age: Peak incidence 10-20 years (rare after age 30)
• Incidence: 1-3 cases per million per year
• Demographics: Predominantly Caucasian (rare in African and Asian populations)
• Sex: Male predominance (M:F ≈ 1.5:1)
• Molecular hallmark: EWSR1-FLI1 fusion gene (85%); EWSR1-ERG (5-10%)
• Histology: Small round blue cell tumour; CD99+ (membranous), PAS+, FLI1+
• Site: Diaphysis of long bones (femur, tibia, humerus); Flat bones (pelvis, ribs, scapula)
• Imaging: Permeative lytic lesion; "Onion-skin" periosteal reaction; Large soft tissue mass
• Presentation: Pain, swelling, systemic symptoms (fever, weight loss, elevated ESR/CRP)
• Metastases at diagnosis: 20-25% (lung, bone, bone marrow)
• Treatment: Neoadjuvant chemotherapy → Surgery or RT → Adjuvant chemotherapy
• Prognosis: 5-year survival 70% (localized), 20-30% (metastatic)

Clinical Pearls

"Ewing's Presents Like Infection": The constellation of fever, elevated WCC, ESR, and CRP, combined with a permeative bone lesion on X-ray, frequently leads to initial misdiagnosis as osteomyelitis. Maintain high index of suspicion in adolescents with diaphyseal lesions and systemic symptoms. [6]

"Diaphysis, Not Metaphysis": Ewing's sarcoma arises in the diaphysis (mid-shaft) of long bones, whereas osteosarcoma predominantly affects the metaphysis (region near growth plate). This anatomical distinction is a key diagnostic clue.

"Onion-Skin is Not Pathognomonic": While the lamellated "onion-skin" periosteal reaction is classic for Ewing's, it can also be seen in osteomyelitis, osteosarcoma, and other aggressive lesions. Correlation with clinical presentation and histology is essential.

"Chemotherapy First": Ewing's sarcoma is highly chemosensitive. Neoadjuvant chemotherapy serves multiple purposes: (1) treats micrometastatic disease early, (2) reduces tumour size to facilitate surgical resection, (3) provides in vivo assessment of tumour chemosensitivity based on histological response (% necrosis). [7,8]

"CD99 is Sensitive, Not Specific": Strong membranous staining for CD99 (MIC2 gene product) is present in > 95% of Ewing's sarcoma cases, but CD99 is also expressed in lymphoblastic lymphoma, mesenchymal chondrosarcoma, and other small round blue cell tumours. Molecular confirmation of EWSR1 rearrangement by FISH or RT-PCR is gold standard. [11]

"Histological Response Predicts Survival": The degree of tumour necrosis in the resection specimen following neoadjuvant chemotherapy is a powerful prognostic indicator. Good response (≥90% necrosis) is associated with 5-year survival > 70%, whereas poor response (less than 90% necrosis) correlates with higher recurrence rates and poorer survival. [12]

---

2. Epidemiology

Incidence and Prevalence

Ewing's sarcoma accounts for approximately 6-10% of all primary malignant bone tumours and is the second most common primary bone malignancy in children and adolescents, after osteosarcoma. [1,2]

Age Distribution

Ewing's sarcoma in adults over 40 years is exceedingly rare and may represent a distinct biological entity with different clinical behaviour. [13]

Demographic Distribution

Sex:

• Male predominance: M:F ≈ 1.5:1

Ethnicity:

• Caucasian: Highest incidence (accounts for > 90% of cases in Europe and North America)
• African descent: Very rare (less than 3% of cases)
• Asian: Low incidence
• This striking ethnic variation suggests genetic susceptibility factors, though specific germline variants have not been consistently identified. [14]

Anatomical Distribution

Extraosseous Ewing's Sarcoma:

• Approximately 10-15% of Ewing's sarcoma cases arise in soft tissues without bone involvement
• Most common sites: chest wall, retroperitoneum, extremities
• Shares identical molecular and histological features
• Prognosis similar to skeletal Ewing's when matched for stage [15]

---

3. Aetiology and Pathophysiology

Molecular Biology and Genetics

Ewing's sarcoma is defined by the presence of chromosomal translocations involving the EWSR1 gene (Ewing sarcoma breakpoint region 1) on chromosome 22q12 and a member of the ETS family of transcription factors. [3,4]

Chromosomal Translocations

In rare cases (~1%), the FUS gene (fused in sarcoma, on chromosome 16) substitutes for EWSR1, producing FUS-ERG or FUS-FEV fusions.

Exam Detail: #### Molecular Pathogenesis (FRCS Viva Detail)

EWSR1-FLI1 Fusion Oncoprotein:

The EWSR1-FLI1 fusion protein acts as an aberrant transcription factor that drives oncogenesis through multiple mechanisms:

1. Transcriptional Dysregulation:

   • EWSR1 provides a powerful transcriptional activation domain
   • FLI1 provides DNA-binding domain targeting ETS motifs
   • The fusion protein binds to genomic regions not normally regulated by FLI1, causing widespread gene expression changes [16]

2. Target Genes and Pathways:

   • Upregulated: NKX2-2, NR0B1 (oncogenic drivers)
   • Cell cycle dysregulation: Promotes proliferation, prevents differentiation
   • Apoptosis inhibition: Upregulates IGF-1 pathway
   • Immune evasion: Suppresses MHC class I expression

3. Cell of Origin Debate:

   • Historically thought to arise from neural crest cells (hence "primitive neuroectodermal tumour")
   • Current evidence suggests mesenchymal stem cell or bone marrow-derived progenitor cell origin
   • The fusion oncoprotein blocks normal differentiation, trapping cells in an undifferentiated state [17]

Diagnostic and Therapeutic Implications:

• Detection of EWSR1 rearrangement by FISH (fluorescence in situ hybridization) or RT-PCR is gold standard for diagnosis
• The specific fusion type (EWSR1-FLI1 vs EWSR1-ERG) does NOT significantly impact prognosis
• The fusion protein is a potential therapeutic target; several fusion-directed therapies are in clinical trials [1]

Histopathology

Macroscopic Appearance:

• Large, fleshy, grey-white tumour
• Soft, friable consistency
• Extensive haemorrhage and necrosis common
• Permeates bone marrow and breaks through cortex
• Often large soft tissue component extending into adjacent tissues

Microscopic Features:

Immunohistochemistry:

Differential Diagnosis of Small Round Blue Cell Tumours:

Patterns of Spread

Local Invasion:

• Permeates bone marrow extensively before breaching cortex
• Large extraosseous soft tissue mass common at presentation
• Can invade adjacent structures (neurovascular bundles, joints, muscles)

Metastatic Spread:

• Haematogenous spread is the predominant route (lymphatic spread rare)
• 20-25% of patients have detectable metastases at diagnosis [9,10]

Skip Metastases:

• Separate tumour foci within the same bone or adjacent bones
• Present in ~5% of cases
• Detected by whole-bone MRI
• Associated with poorer prognosis

---

4. Clinical Presentation

Symptoms

Primary Symptoms

Key Distinguishing Feature: Systemic Symptoms

Unlike osteosarcoma, Ewing's sarcoma frequently presents with constitutional symptoms that mimic infection: [6]

• Intermittent fever (low-grade to high-grade)
• Malaise, fatigue
• Weight loss
• Night sweats

This presentation, combined with elevated inflammatory markers, leads to initial misdiagnosis as osteomyelitis in 10-20% of cases.

Clinical Examination

Inspection

• Swelling over affected bone
• Overlying skin may be:
  • Warm (increased vascularity)
  • Erythematous (mimics cellulitis/infection)
  • Shiny or taut (large soft tissue component)
• Visible venous engorgement over tumour

Palpation

• Tender mass:
  • Firm to hard consistency
  • May be fixed to underlying bone
  • Soft tissue component extends beyond bone
• Warmth to touch (hyperaemia)
• Regional lymphadenopathy (rare; less than 5%)

Function

• Reduced range of motion if tumour near joint
• Joint effusion (sympathetic effusion; rarely intra-articular invasion)
• Antalgic gait (if lower limb)
• Pathological fracture: deformity, crepitus, abnormal mobility

Neurovascular Assessment

• Assess distal pulses, capillary refill, sensation, motor function
• Neurovascular compromise suggests advanced local disease with vascular encasement

Laboratory Findings

Ewing's sarcoma is one of the few bone tumours with characteristic laboratory abnormalities: [6]

Interpretation:

• Elevated WCC + ESR + CRP → Often mistaken for osteomyelitis
• Normal or mildly elevated alkaline phosphatase → Helps differentiate from osteosarcoma
• High LDH → Poorer prognosis; consider more intensive therapy

---

5. Differential Diagnosis

Ewing's sarcoma must be distinguished from several conditions with overlapping clinical and radiological features:

Primary Differential Diagnoses

Clinical Clues to Differentiate Ewing's from Osteomyelitis

This is a critical diagnostic dilemma in clinical practice: [6]

Golden Rule: If a presumed "osteomyelitis" fails to respond to appropriate antibiotics within 48-72 hours, or if there is diagnostic uncertainty, biopsy is mandatory to exclude malignancy.

---

6. Investigations and Diagnosis

Imaging Modality Summary

Plain Radiography

Classic Radiographic Features:

1. "Permeative" or "moth-eaten" pattern:

   • Ill-defined margins
   • Cortical destruction from within outwards
   • Loss of normal trabecular architecture

2. Periosteal Reaction:

   • "Onion-skin" (lamellated): Multiple layers of periosteal new bone (classic)
   • "Sunburst": Radiating spicules perpendicular to cortex (less common)
   • Codman triangle: Elevated periosteum at tumour edge (non-specific)

3. Location:

   • Diaphyseal (mid-shaft) predominance
   • Flat bones (pelvis, ribs, scapula)

4. Soft tissue mass:

   • Often visible on plain X-ray
   • Displaces normal soft tissue planes
   • May contain calcification (rare)

Limitations:

• Plain X-rays underestimate true extent of disease
• Cannot assess marrow involvement or skip lesions
• MRI is essential for surgical planning

Magnetic Resonance Imaging (MRI)

MRI is the gold standard for local staging.

Key Information from MRI:

• Intramedullary extent (for surgical planning)
• Soft tissue component size and relationship to neurovascular structures
• Skip lesions (separate foci in same bone)
• Joint involvement (rare)
• Neurovascular encasement
• Response to chemotherapy (repeat MRI shows tumour shrinkage)

Whole-bone MRI is recommended to detect skip metastases (present in ~5% of cases).

Computed Tomography (CT)

CT Chest (High-Resolution):

• Mandatory for staging
• Detects pulmonary metastases (most common metastatic site)
• Nodules as small as 2-3 mm can be detected

CT of Primary Site:

• Useful for bony detail (extent of cortical destruction)
• Guides biopsy planning (avoid neurovascular structures)
• Less sensitive than MRI for marrow and soft tissue assessment

PET-CT (Positron Emission Tomography)

Indications:

• Whole-body staging (alternative to bone scan)
• Detection of skeletal metastases
• Assessment of response to chemotherapy (metabolic response)

Advantages over Bone Scan:

• Higher sensitivity and specificity for skeletal metastases
• Simultaneous anatomical (CT) and functional (PET) imaging
• Can detect extraosseous metastases and nodal disease

Interpretation:

• Ewing's sarcoma shows high FDG uptake (SUV typically > 5)
• Degree of uptake may correlate with histological grade and prognosis

Bone Scan (Tc-99m MDP)

Traditional staging tool (increasingly replaced by PET-CT):

• Detects skeletal metastases
• Whole-body survey
• Less specific than PET-CT (inflammation, trauma, benign lesions also "hot")

Bone Marrow Biopsy

Indications:

• Mandatory for staging in all Ewing's sarcoma patients
• Bilateral iliac crest aspirate and trephine biopsy

Findings:

• Marrow involvement in 10-15% of cases at diagnosis [9]
• Presence of marrow metastases = Stage IV disease
• Associated with very poor prognosis (5-year survival less than 20%)

Biopsy and Histopathological Diagnosis

Biopsy Technique:

Critical Biopsy Principles:

1. Performed by treating surgical team (to avoid contamination of surgical field)
2. Biopsy tract must be excised en bloc with definitive resection
3. Avoid neurovascular structures and joint spaces
4. Obtain adequate tissue for:
   • Histology (H&E, immunohistochemistry)
   • Molecular studies (FISH or RT-PCR for EWSR1 rearrangement)
   • Fresh tissue for research (if available)

Histopathological Diagnosis:

Diagnosis requires:

1. Morphology: Small round blue cells
2. Immunohistochemistry:
   • CD99: Positive (membranous)
   • FLI1: Positive (nuclear)
   • Negative for LCA, desmin, myogenin, S100
3. Molecular confirmation: EWSR1 rearrangement by FISH or RT-PCR (gold standard)

Molecular Testing:

• FISH (fluorescence in situ hybridization): Detects EWSR1 gene rearrangement (break-apart probe)
• RT-PCR: Identifies specific fusion transcript (EWSR1-FLI1 vs EWSR1-ERG)
• Molecular confirmation is essential for definitive diagnosis

---

7. Staging and Prognostic Factors

Staging Systems

Enneking Surgical Staging System for Bone Sarcomas:

TNM Staging (AJCC 8th Edition):

Increasingly used for bone sarcomas:

• T1: ≤8 cm
• T2: > 8 cm
• T3: Discontinuous (skip metastases)
• M1a: Lung metastases only
• M1b: Other distant metastases (bone, marrow, other organs)

Clinical Staging for Ewing's Sarcoma:

Prognostic Factors

Established Prognostic Factors (Strong Evidence):

Additional Prognostic Factors:

Prognostic Scoring Systems:

While no universally accepted risk stratification system exists, clinical trials often stratify patients into:

1. Standard Risk:

   • Localized disease
   • Extremity location
   • Volume less than 200 ml
   • Expected 5-year OS: 70-80%

2. High Risk:

   • Large volume (> 200 ml) OR
   • Axial/pelvic location OR
   • Poor histological response to chemotherapy
   • Expected 5-year OS: 50-60%

3. Very High Risk (Metastatic):

   • Metastatic disease at diagnosis
   • Expected 5-year OS: 20-30% (lung-only may reach 40%)

---

8. Management

Management of Ewing's sarcoma is multimodal, involving chemotherapy, surgery, and/or radiotherapy. Treatment is coordinated by a specialist multidisciplinary team (MDT) at a designated sarcoma centre.

Overview of Treatment Strategy

┌────────────────────────────────────────────────────────────────────┐
│                 EWING'S SARCOMA TREATMENT PATHWAY                  │
├────────────────────────────────────────────────────────────────────┤
│                                                                    │
│  PHASE 1: NEOADJUVANT (INDUCTION) CHEMOTHERAPY                     │
│  ────────────────────────────────────────────────────              │
│  • Duration: 12-18 weeks (typically 6 cycles)                     │
│  • Regimen: VDC/IE alternating (see below)                        │
│  • Goals:                                                          │
│    - Treat micrometastatic disease                                │
│    - Reduce primary tumour size                                   │
│    - Assess chemosensitivity (in vivo)                            │
│  • Response assessment: MRI after 3-6 cycles                      │
│                                                                    │
│  ↓                                                                 │
│                                                                    │
│  PHASE 2: LOCAL CONTROL                                            │
│  ────────────────────────────────────────────────────              │
│  Option A: SURGERY (Preferred if feasible)                        │
│    • Wide resection (negative margins)                            │
│    • Limb salvage vs amputation                                   │
│    • Reconstruction (endoprosthesis, bone graft, etc.)            │
│                                                                    │
│  Option B: RADIOTHERAPY (If surgery not feasible/incomplete)      │
│    • Dose: 45-55.8 Gy in 1.8 Gy fractions                         │
│    • Indications: Axial site, unresectable, positive margins      │
│                                                                    │
│  Option C: COMBINED SURGERY + RT (If high-risk features)          │
│    • Positive/close margins (less than 1 mm)                               │
│    • Poor response to chemotherapy                                │
│                                                                    │
│  ↓                                                                 │
│                                                                    │
│  PHASE 3: ADJUVANT (CONSOLIDATION) CHEMOTHERAPY                    │
│  ────────────────────────────────────────────────────              │
│  • Duration: ~6 months total treatment (including induction)      │
│  • Regimen: Continue VDC/IE (total ~14-17 cycles)                │
│  • Intensity may be adjusted based on histological response       │
│  • Good response (≥90% necrosis): Standard consolidation         │
│  • Poor response (less than 90% necrosis): Consider intensification       │
│                                                                    │
│  ↓                                                                 │
│                                                                    │
│  PHASE 4: SURVEILLANCE                                             │
│  ────────────────────────────────────────────────────              │
│  • Years 1-2: Every 3 months (CXR, exam)                          │
│  • Years 3-5: Every 6 months                                       │
│  • After 5 years: Annually (lifelong for late effects)           │
│  • Imaging: CT chest, MRI primary site (alternating)             │
│                                                                    │
└────────────────────────────────────────────────────────────────────┘

Chemotherapy

Ewing's sarcoma is highly chemosensitive. Chemotherapy is the cornerstone of treatment and is administered before (neoadjuvant) and after (adjuvant) local control. [7,8]

Standard Chemotherapy Regimen: VDC/IE

VDC/IE is the current standard of care, based on evidence from Children's Oncology Group (COG) and European trials:

Treatment Schedule:

• Cycles alternate: VDC → IE → VDC → IE (and so on)
• Induction (neoadjuvant): 6 cycles (12 weeks)
• Local control (surgery or RT): Week 12-15
• Consolidation (adjuvant): 8-11 cycles
• Total treatment duration: ~9-12 months (14-17 cycles)

Dose Adjustments:

• Reduce if severe toxicity (myelosuppression, cardiotoxicity)
• G-CSF (granulocyte colony-stimulating factor) used to support neutrophil recovery

Exam Detail: #### Evidence Base for VDC/IE (FRCS Viva Detail)

INT-0091 Trial (Intergroup Ewing's Sarcoma Study):

• Established vincristine, doxorubicin, cyclophosphamide, dactinomycin (VACA) as standard in 1990s [19]

COG AEWS0031 Trial:

• Compared VDC/IE (interval compression: 2-week cycles with G-CSF) vs standard 3-week cycles
• VDC/IE with interval compression improved 5-year event-free survival (EFS) from 65% to 73% (p=0.028) [7]
• Now considered standard of care for localized Ewing's sarcoma

Euro-EWING 99 Trial:

• European protocol using VIDE (vincristine, ifosfamide, doxorubicin, etoposide)
• Similar outcomes to COG regimens
• Confirmed importance of ifosfamide and etoposide [8]

Key Controversies:

• Role of dactinomycin: Used in some protocols but not all; evidence for benefit unclear
• Dose intensification: High-dose chemotherapy with stem cell rescue for high-risk patients investigated, but no clear survival benefit over standard VDC/IE in randomized trials [20]

Histological Response Assessment

Following neoadjuvant chemotherapy, the degree of tumour necrosis in the resection specimen is a critical prognostic indicator: [12]

Implications:

• Good responders: Continue standard adjuvant chemotherapy
• Poor responders: Some protocols intensify therapy (controversial; no proven benefit)

Local Control: Surgery

Surgery is the preferred method of local control when feasible, offering:

• Lower local recurrence rate vs radiotherapy alone (10% vs 20-30%)
• Specimen for histological response assessment
• Avoidance of radiation-related late effects (growth disturbance, secondary malignancy)

Principles of Surgical Resection

Margins:

• Goal: Wide resection with negative margins (R0)
• Adequate margin: > 1-2 cm of normal tissue surrounding tumour
• Intralesional/marginal resection: Associated with very high local recurrence (> 50%)

Limb Salvage vs Amputation:

Modern reconstructive techniques allow limb salvage in > 90% of extremity Ewing's sarcoma cases.

Reconstructive Options:

Special Considerations in Children:

• Growing skeleton: Expandable endoprostheses allow non-invasive lengthening
• Epiphyseal preservation: If possible, to maintain growth
• Multiple revisions: Expected over lifetime as child grows

Axial and Pelvic Ewing's Sarcoma

Surgical Challenges:

• Complex anatomy
• Proximity to neurovascular structures, bowel, bladder
• Large soft tissue component
• Difficulty achieving adequate margins

Management:

• Surgery: Hemipelvectomy (internal or external) for selected cases
• Radiotherapy: Often used as primary local control
• Combined modality: Surgery for debulking + RT for residual disease

Outcomes:

• Pelvic Ewing's has poorer prognosis than extremity (5-year OS: 40-50% vs 70%)

Local Control: Radiotherapy

Radiotherapy is radiosensitive, making it an effective local control modality when surgery is not feasible.

Indications for Radiotherapy:

Radiotherapy Technique:

Outcomes:

• Local control with definitive RT: 60-70% (lower than surgery)
• Risk of local recurrence: 20-30%

Late Effects of Radiotherapy:

• Growth disturbance (children): Limb length discrepancy, spinal deformity
• Secondary malignancy: 5-10% risk at 20 years post-RT
• Fibrosis, lymphoedema
• Organ-specific toxicity (if pelvic RT: infertility, bowel/bladder dysfunction)

Proton Therapy:

• Reduces dose to surrounding normal tissues
• Preferred in children (lower risk of secondary malignancy)
• Availability limited to specialized centres

Management of Metastatic Disease

20-25% of patients present with metastatic disease; prognosis is significantly worse (5-year OS: 20-30%). [9,10]

Treatment Strategy:

Prognostic Subgroups (Metastatic Disease):

| Metastatic Pattern | 5-Year OS | Management | |--------------------|-----------|-----------| | | Lung-only metastases (oligometastatic: 1-3 nodules) | 30-40% | Aggressive local control (surgery + RT); Systemic chemotherapy | | Lung-only (multiple nodules) | 20-25% | Chemotherapy + RT to residual disease | | Bone or bone marrow metastases | less than 20% | Chemotherapy; Palliative RT; Investigational therapies | | Multiple sites | less than 10% | Chemotherapy; Supportive care; Clinical trials |

Management of Recurrent Disease

Prognosis after recurrence is very poor (5-year OS less than 10%).

Salvage Options:

Investigational Therapies:

• Anti-GD2 immunotherapy: CAR-T cells targeting GD2 (surface antigen on Ewing's cells)
• IGF-1R inhibitors: Target insulin-like growth factor pathway (early trials disappointing)
• Fusion protein-directed therapy: Drugs targeting EWSR1-FLI1 (preclinical/early phase trials) [1]

Multidisciplinary Team (MDT) Approach

All patients should be managed at a specialist sarcoma centre with an experienced MDT including:

• Orthopaedic oncology surgeon
• Medical oncologist
• Radiation oncologist
• Paediatric oncologist (if less than 18 years)
• Radiologist
• Histopathologist
• Clinical nurse specialist
• Physiotherapist, occupational therapist
• Psychologist/social worker (psychosocial support)

---

9. Complications and Late Effects

Complications of the Disease

Complications of Treatment

Chemotherapy-Related

Cardiac Monitoring Protocol:

• Baseline: Echocardiography or MUGA scan
• During treatment: After cumulative doxorubicin dose of 200-250 mg/m²
• Post-treatment: At end of treatment, then annually for life
• Late cardiotoxicity: Can occur decades after treatment; risk increases with cumulative doxorubicin dose

Surgery-Related

Radiotherapy-Related

Late Effects and Survivorship

Ewing's sarcoma survivors are at risk of long-term complications requiring lifelong follow-up:

Survivorship Clinic:

• Specialist clinics for long-term follow-up of childhood cancer survivors
• Coordinate surveillance and manage late effects
• Provide education on risks and healthy lifestyle

---

10. Prognosis and Outcomes

Overall Survival

Prognostic Factors Summary

Favourable Prognostic Factors:

• Localized disease (M0)
• Extremity location (distal > proximal)
• Small tumour volume (less than 100 ml)
• Good histological response to chemotherapy (≥90% necrosis)
• Young age (less than 18 years)
• Negative surgical margins (R0 resection)
• Normal LDH

Unfavourable Prognostic Factors:

• Metastatic disease (especially bone/marrow)
• Axial location (pelvis, spine, chest wall)
• Large tumour volume (> 200 ml)
• Poor histological response (less than 90% necrosis)
• Adult age (> 18 years)
• Elevated LDH (> 1.5× ULN)

Site-Specific Outcomes

Explanation:

• Axial/pelvic sites have poorer outcomes due to:
  • Difficulty achieving adequate surgical margins
  • Larger tumour volume at presentation
  • Greater reliance on RT (less effective than surgery)

Time to Recurrence and Salvage

Patterns of Failure:

• 30-40% of patients with localized disease at diagnosis will develop recurrence (local or distant)
• Lung is the most common site of distant recurrence (50-60% of recurrences)
• Local recurrence alone: 10-15% (higher if RT used for local control vs surgery)

---

11. Evidence and Guidelines

Key Guidelines

1. ESMO Clinical Practice Guidelines: Bone Sarcomas (2021)

   • Comprehensive guidelines for diagnosis, staging, and treatment
   • Recommends multimodal therapy with VDC/IE chemotherapy
   • Emphasizes importance of specialist sarcoma centres

2. NCCN Guidelines: Bone Cancer (updated annually)

   • North American consensus guidelines
   • Detailed treatment algorithms for localized and metastatic disease

3. NICE Guidance: Improving Outcomes for People with Sarcoma (UK)

   • Recommends referral to specialist sarcoma centres
   • Multidisciplinary team approach mandatory

4. Euro-EWING Consortium Protocols

   • European collaborative clinical trial protocols
   • Evidence base for VIDE chemotherapy regimen [8]

Landmark Clinical Trials

---

12. Examination Focus (FRCS/Oncology Viva)

Viva Scenario 1: Initial Presentation and Diagnosis

Examiner: "A 14-year-old boy presents with a 3-month history of progressive right thigh pain and swelling. He has had intermittent fevers. Examination reveals a tender, firm mass in the mid-thigh. His WCC is 15 × 10⁹/L, ESR 60 mm/hr. What are your differential diagnoses and initial management?"

Exam Detail: Model Answer:

Differential Diagnoses: The combination of adolescent age, diaphyseal location, systemic symptoms (fever, elevated inflammatory markers), and a soft tissue mass raises concern for:

1. Ewing's sarcoma (most likely given age, location, systemic symptoms)
2. Osteomyelitis (must exclude infection, especially given fever and elevated WCC/ESR)
3. Osteosarcoma (less likely given diaphyseal location, but possible)
4. Lymphoma of bone (can present similarly)
5. Langerhans cell histiocytosis (less likely given systemic symptoms)

Initial Management:

1. Imaging:

• Plain X-ray (femur AP/lateral): Look for permeative lytic lesion, periosteal reaction ("onion-skin"), soft tissue mass
• MRI (whole femur with contrast): Assess intramedullary extent, soft tissue component, neurovascular involvement, skip lesions

2. Laboratory Investigations:

• Blood cultures (if considering osteomyelitis)
• LDH (prognostic marker if malignancy)
• Alkaline phosphatase (elevated in osteosarcoma, normal/mild elevation in Ewing's)

3. Biopsy:

• If imaging suggests malignancy (not simple infection), arrange core needle biopsy or open biopsy
• Critical: Biopsy must be performed by the treating surgical team at a specialist sarcoma centre to avoid contamination of surgical field
• Send tissue for:
  • "Histology (H&E, immunohistochemistry: CD99, FLI1, LCA, desmin, myogenin)"
  • Molecular studies (FISH or RT-PCR for EWSR1 rearrangement)

4. Referral:

• Urgent referral to a specialist sarcoma centre if malignancy suspected
• Do NOT delay for biopsy if imaging is highly suggestive

5. Avoid:

• Empirical antibiotics without biopsy (if malignancy suspected)
• Biopsy by non-specialist team (contaminates surgical field)
• Incisional biopsy with poor planning (biopsy tract must be excised with definitive surgery)

Key Point: The overlap between Ewing's sarcoma and osteomyelitis is a classic diagnostic pitfall. If there is any doubt, or if "osteomyelitis" fails to respond to appropriate antibiotics within 48-72 hours, biopsy is mandatory.

---

Viva Scenario 2: Histopathology and Molecular Diagnosis

Examiner: "The biopsy shows sheets of small round blue cells. CD99 is strongly positive. What is your interpretation and next steps?"

Exam Detail: Model Answer:

Interpretation: "Small round blue cells with strong CD99 positivity is highly suggestive of Ewing's sarcoma, but CD99 is sensitive, not specific. The differential diagnosis of CD99-positive small round blue cell tumours includes:

• Ewing's sarcoma (most likely)
• Lymphoblastic lymphoma
• Mesenchymal chondrosarcoma
• Rarely: rhabdomyosarcoma, desmoplastic small round cell tumour

Next Steps:

1. Additional Immunohistochemistry:

• FLI1 (nuclear staining; more specific for Ewing's)
• LCA (CD45) (to exclude lymphoma; should be negative in Ewing's)
• Desmin, myogenin (to exclude rhabdomyosarcoma; should be negative)
• PAS stain (glycogen; positive in Ewing's; diastase-sensitive)

2. Molecular Confirmation (GOLD STANDARD):

• FISH (fluorescence in situ hybridization): Detects EWSR1 gene rearrangement (break-apart probe on chromosome 22q12)
  • Positive in 95% of Ewing's sarcoma
  • Does NOT identify fusion partner (FLI1 vs ERG)
• RT-PCR or NGS (next-generation sequencing): Identifies specific fusion transcript
  • EWSR1-FLI1 (85-90%)
  • EWSR1-ERG (5-10%)
  • Rare variants (EWSR1-ETV1, FUS-ERG, etc.)

3. Staging Investigations (if Ewing's confirmed):

• MRI (whole bone; already done)
• CT chest (high-resolution): Detect pulmonary metastases
• PET-CT or bone scan: Whole-body staging for skeletal metastases
• Bone marrow biopsy (bilateral iliac crest): Exclude marrow involvement (present in 10-15%)

4. MDT Discussion:

• Present case at specialist sarcoma MDT
• Plan multimodal treatment: Neoadjuvant chemotherapy → Local control (surgery or RT) → Adjuvant chemotherapy

Key Point: Molecular confirmation of EWSR1 rearrangement is the diagnostic gold standard. CD99 alone is insufficient for definitive diagnosis due to overlap with other entities."

---

Viva Scenario 3: Treatment Planning and Prognostic Factors

Examiner: "Staging confirms localized Ewing's sarcoma of the femoral diaphysis (no metastases). Tumour volume is 180 ml. What is your treatment plan and what factors will influence prognosis?"

Exam Detail: Model Answer:

Treatment Plan:

Phase 1: Neoadjuvant Chemotherapy (12-18 weeks)

• Regimen: VDC/IE (interval-compressed; 2-week cycles with G-CSF support)
  • "Cycles alternate: VDC → IE → VDC → IE (total 6 cycles)"
• Goals:
  • Treat micrometastatic disease early
  • Reduce primary tumour size to facilitate surgery
  • Assess in vivo chemosensitivity (histological response)
• Monitoring:
  • Clinical exam, blood counts weekly
  • MRI after 3-6 cycles to assess response
  • Echocardiography (baseline, during treatment) to monitor for doxorubicin cardiotoxicity

Phase 2: Local Control (Week 12-15)

• Surgery (preferred): Wide resection of femoral diaphysis with negative margins (> 1-2 cm)
• Reconstruction: Intercalary endoprosthesis (modular; expandable if growth remaining) or allograft
• Margins: Aim for R0 resection (negative margins)
• Histological assessment: % tumour necrosis (good response ≥90%)

Phase 3: Adjuvant Chemotherapy

• Continue VDC/IE (total 14-17 cycles; ~9-12 months total treatment)
• Intensity maintained if good response; some protocols intensify if poor response (controversial)

Phase 4: Surveillance

• Years 1-2: Every 3 months (CXR, clinical exam)
• Years 3-5: Every 6 months
• After 5 years: Annually (lifelong for late effects monitoring)

Prognostic Factors:

Favourable (This Patient):

• Localized disease (no metastases) → 5-year OS ~70%
• Extremity location (femur) → Better than axial
• Moderate tumour volume (180 ml; less than 200 ml threshold) → Acceptable
• Young age (adolescent) → Better than adult

Factors That Will Influence Prognosis After Treatment:

1. Histological response (most important modifiable factor):
   • ≥90% necrosis → 5-year OS 75-80%
   • less than 90% necrosis → 5-year OS 50-55%
2. Surgical margins:
   • R0 (negative) → Local recurrence less than 10%
   • R1 (positive) → Local recurrence 20-30% (will require adjuvant RT)
3. Development of metastases during treatment or follow-up (lung most common)

Expected Prognosis for This Patient:

• 5-year overall survival: 70-75% (localized extremity Ewing's)
• Local control: > 90% (with adequate surgery)
• Risk of distant recurrence: 25-30% (will require close surveillance)

Key Point: Histological response to neoadjuvant chemotherapy is the most powerful prognostic indicator and will guide intensity of adjuvant therapy."

---

Viva Scenario 4: Management of Positive Margins

Examiner: "Following resection, histology shows less than 1 mm margin in one area and poor response to chemotherapy (50% necrosis). What is your approach?"

Exam Detail: Model Answer:

"This patient has two adverse features: (1) close/positive margin, and (2) poor histological response. Both increase the risk of local recurrence and systemic relapse.

Management:

1. Multidisciplinary Team Discussion:

• Discuss with sarcoma MDT (surgeon, oncologist, radiation oncologist)
• Review imaging and histology to determine if re-resection is feasible

2. Local Control (Margin Issue):

Option A: Re-resection

• If technically feasible and would not cause unacceptable morbidity
• Aim for wider margins (> 1 cm)
• Preferred if margins can be improved

Option B: Adjuvant Radiotherapy

• If re-resection not feasible or would require amputation
• Dose: 45-50.4 Gy in 1.8 Gy fractions to the tumour bed
• Target: Pre-operative tumour volume (GTV-P) with margin
• Boost to area of close/positive margin (total 50.4-55.8 Gy)
• Reduces local recurrence risk from 20-30% (positive margins, no RT) to 10-15%

Option C: Re-resection + Adjuvant RT

• If margins still inadequate after re-resection
• Combined approach for best local control

3. Systemic Therapy (Poor Response Issue):

• Continue adjuvant VDC/IE chemotherapy as planned
• Some protocols suggest intensification of chemotherapy for poor responders, but no proven survival benefit in randomized trials
• Consider clinical trial if available (novel agents for high-risk patients)

4. Surveillance:

• Intensive surveillance (given high risk of recurrence):
  • CT chest every 3 months for first 2 years
  • MRI primary site every 6 months
  • PET-CT if clinically indicated

5. Counselling:

• Discuss higher risk of recurrence (local and distant) with patient/family
• 5-year OS for poor responders: ~50-55% (vs 75-80% for good responders)
• Emphasize importance of close follow-up

Key Point: Close/positive margins + poor histological response significantly worsen prognosis. Adjuvant radiotherapy is essential to optimize local control. Intensification of systemic therapy is controversial and should be discussed in the context of clinical trials."

---

13. Patient and Layperson Explanation

What is Ewing's Sarcoma?

Ewing's sarcoma is a type of bone cancer that mainly affects children, teenagers, and young adults (most common between ages 10-20). It is the second most common bone cancer in young people, after osteosarcoma.

Ewing's sarcoma starts in the bones, most often in the middle part (shaft) of long bones like the thigh bone (femur), shin bone (tibia), or arm bone (humerus). It can also start in flat bones like the pelvis, ribs, or shoulder blade.

What Causes It?

The exact cause is unknown. Ewing's sarcoma is not inherited and is not caused by anything the patient or family did. It occurs due to a genetic change (mutation) that happens by chance in a single cell, causing it to grow uncontrollably into a tumour.

What Are the Symptoms?

The most common symptoms are:

• Pain in the affected bone (often worse at night)
• Swelling or a lump over the bone
• Fever, tiredness, and weight loss (can look like an infection)
• Sometimes a broken bone without major injury (pathological fracture)

Because of the fever and other symptoms, Ewing's sarcoma is sometimes mistaken for a bone infection (osteomyelitis) at first.

How is it Diagnosed?

1. X-rays and Scans: X-rays show changes in the bone. MRI scans give detailed pictures of the tumour and surrounding tissues.
2. Biopsy: A small sample of the tumour is removed (using a needle or small operation) and examined under a microscope to confirm the diagnosis.
3. Staging Tests: CT scans of the chest and other tests (bone scans, bone marrow biopsy) check if the cancer has spread to other parts of the body.

How is it Treated?

Ewing's sarcoma is treated with a combination of therapies:

1. Chemotherapy (before surgery):

   • Powerful drugs given through a vein to kill cancer cells
   • Given for 3-4 months before surgery to shrink the tumour and treat any cancer cells that may have spread
   • Also helps doctors see how well the cancer responds to treatment

2. Surgery or Radiotherapy:

   • Surgery: The tumour is removed along with some surrounding healthy tissue (to ensure all cancer is gone)
     • In most cases, the limb can be saved (limb salvage surgery) using metal implants or bone grafts
     • Amputation is rarely needed (only if the cancer is very extensive)
   • Radiotherapy: High-energy X-rays are used to kill cancer cells
     • Used if surgery is not possible (e.g., tumour in the spine or pelvis) or if the tumour could not be completely removed

3. Chemotherapy (after surgery):

   • Continues for several more months (total treatment time: about 9-12 months)
   • Ensures any remaining cancer cells are destroyed

What Are the Side Effects of Treatment?

Chemotherapy can cause:

• Tiredness
• Nausea and vomiting (medicines can help)
• Hair loss (temporary; hair grows back after treatment)
• Increased risk of infections (due to low blood cell counts)
• Long-term effects: possible heart problems, infertility (inability to have children naturally)

Surgery can cause:

• Pain and stiffness (physiotherapy helps)
• Limb length differences (in children, as they grow)
• Rare complications: infection, implant failure

Radiotherapy can cause:

• Skin irritation (like sunburn)
• Long-term effects: growth problems (in children), risk of a second cancer many years later

What Are the Chances of Recovery?

With modern treatment, about 70-75% of young people with Ewing's sarcoma that has not spread (localized disease) survive long-term (5 years or more).

If the cancer has spread to other parts of the body (lungs, other bones) at diagnosis, the chances of cure are lower (about 20-30%), but some patients can still be cured with intensive treatment.

Early diagnosis and treatment improve the chances of recovery.

What Happens After Treatment?

• Regular check-ups: Scans and tests every few months to make sure the cancer has not come back
• Monitoring for late effects: Long-term follow-up to check for heart problems, growth issues, and other late effects of treatment
• Supportive care: Physiotherapy, counselling, and support groups to help with recovery and quality of life

Key Messages for Patients and Families

• Ewing's sarcoma is a serious cancer, but many young people are cured with modern treatment
• Treatment is intensive and long (about a year), but it offers the best chance of cure
• A specialist team of doctors, nurses, and other healthcare professionals will support you through treatment
• Early treatment is important – do not delay if you have symptoms
• Long-term follow-up is essential to monitor for late effects and detect any recurrence early

---

14. References

1. Strauss SJ, Berlanga P, McCabe MG. Emerging therapies in Ewing sarcoma. Curr Opin Oncol. 2024;36(4):297-304. doi:10.1097/CCO.0000000000001048. PMID: 38775200

2. Balamuth NJ, Womer RB. Ewing's sarcoma. Lancet Oncol. 2010;11(2):184-192. doi:10.1016/S1470-2045(09)70286-4. PMID: 20152770

3. Delattre O, Zucman J, Plougastel B, et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature. 1992;359(6391):162-165. doi:10.1038/359162a0. PMID: 1301061

4. Lessnick SL, Ladanyi M. Molecular pathogenesis of Ewing sarcoma: new therapeutic and transcriptional targets. Annu Rev Pathol. 2012;7:145-159. doi:10.1146/annurev-pathol-011110-130237. PMID: 21942527

5. Esiashvili N, Goodman M, Marcus RB Jr. Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. J Pediatr Hematol Oncol. 2008;30(6):425-430. doi:10.1097/MPH.0b013e31816e22f3. PMID: 18525456

6. Widhe B, Widhe T. Initial symptoms and clinical features in osteosarcoma and Ewing sarcoma. J Bone Joint Surg Am. 2000;82(5):667-674. doi:10.2106/00004623-200005000-00007. PMID: 10819277

7. 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. doi:10.1200/JCO.2011.41.5703. PMID: 23091096

8. Juergens C, Weston C, Lewis I, et al. Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer. 2006;47(1):22-29. doi:10.1002/pbc.20820. PMID: 16572419

9. Gaspar N, Hawkins DS, Dirksen U, et al. Ewing Sarcoma: Current Management and Future Approaches Through Collaboration. J Clin Oncol. 2015;33(27):3036-3046. doi:10.1200/JCO.2014.59.5256. PMID: 26304893

10. Paulussen M, Craft AW, Lewis I, et al. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment—cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008;26(27):4385-4393. doi:10.1200/JCO.2008.16.5720. PMID: 18802150

11. Llombart-Bosch A, Machado I, Navarro S, et al. Histological heterogeneity of Ewing's sarcoma/PNET: an immunohistochemical analysis of 415 genetically confirmed cases with clinical support. Virchows Arch. 2009;455(5):397-411. doi:10.1007/s00428-009-0842-7. PMID: 19936782

12. Picci P, Böhling T, Bacci G, et al. Chemotherapy-induced tumor necrosis as a prognostic factor in localized Ewing's sarcoma of the extremities. J Clin Oncol. 1997;15(4):1553-1559. doi:10.1200/JCO.1997.15.4.1553. PMID: 9193352

13. Lee JA, Kim DH, Lim JS, et al. Soft-tissue Ewing sarcoma in a low-incidence population: comparison to skeletal Ewing sarcoma for clinical characteristics and treatment outcome. Jpn J Clin Oncol. 2010;40(11):1060-1067. doi:10.1093/jjco/hyq083. PMID: 20519246

14. Worch J, Matthay KK, Neuhaus J, et al. Ethnic and racial differences in patients with Ewing sarcoma. Cancer. 2010;116(4):983-988. doi:10.1002/cncr.24865. PMID: 20041483

15. Applebaum MA, Worch J, Matthay KK, et al. Clinical features and outcomes in patients with extraskeletal Ewing sarcoma. Cancer. 2011;117(13):3027-3032. doi:10.1002/cncr.25840. PMID: 21692053

16. Grünewald TGP, Cidre-Aranaz F, Surdez D, et al. Ewing sarcoma. Nat Rev Dis Primers. 2018;4(1):5. doi:10.1038/s41572-018-0003-x. PMID: 29977059

17. Riggi N, Suvà ML, Stamenkovic I. Ewing's Sarcoma. N Engl J Med. 2021;384(2):154-164. doi:10.1056/NEJMra2028910. PMID: 33440084

18. Leavey PJ, Mascarenhas L, Marina N, et al. Prognostic factors for patients with Ewing sarcoma (EWS) at first recurrence following multi-modality therapy: A report from the Children's Oncology Group. Pediatr Blood Cancer. 2008;51(3):334-338. doi:10.1002/pbc.21618. PMID: 18506764

---