Ewing’s sarcoma
Definition
- A small round blue cell tumour of bone
- first described by James Ewing in 1921 (he reported on a 14 year old girl with a lytic lesion of the ulna that responded well to chemotherapy)
Incidence
- Second most common bone malignancy
- 0.6/million in England, 0.8/million in Sweden
- M>F 1.6:1 … Mayo data suggest distinct male predilection
- Most common 10-20, rare under 5 or over 30.
- Almost unknown in blacks
Aetiology
- No known predisposing factors, although there may a link to ↑ levels of radium in the drinking water
Site
- Metadiaphysis of long bones
- Femur most common, pelvis next most common
- As patients get older there is a tendency for flat bones to be involved.
- fibula is another common site.
- spine is an uncommon site (3.5%) but is usually (58%) associated with neurological deficit.
Clinical
- Pain in 90%
- Swelling in 70%
- Pathologic fracture in 5-10%
- Neurological involvement is common (58%) if the spine is involved
- Inflammatory like symptoms – this can be explained by the fact that the tumour characteristically outgrows its blood supply resulting in extensive degeneration & necrosis. 20% of patients present with a fever.
- Early metastasis to the lungs.
- Metastases to the bones are also common; in fact they are so common that it has been suggested that ES may be multicentric in origin.
- Usually presents as a IIB lesion (high grade, extra-compartmental)
Investigations
Laboratory
- Increased WBC, around 20 000
- Normochromic, normocytic anaemia
- Increased LDH (bad sign)
- Increased ESR
Xray
- Classic appearance is a lesion in the medullary portion of the midshaft with cortical destruction (giving a permeative effect) & multiple layers of periosteal new bone (onion skinning).
- May be a sunburst appearance.
- May be sclerosis suggesting an osteosarcoma
MRI
- intermediate intensity on T1 & high intensity on T2, reflecting cellular nature
Differential diagnosis on Xray
Pathology
Gross pathology
- Poorly demarcated, greyish white tumour tissue with areas of haemorrhage, cystic degeneration & necrosis. Can even look like pus
- extent of bone destruction is greater than suggested on X-rays
Histology
- Known to be of neuroectodermal origin.
- Ewing’s sarcoma & PNET form a spectrum with ES being less differentiated
- Sheets of closely packed small round blue cells, 2-3 times larger than lymphocytes.
- Monotonous & remarkably cellular – there is little stroma.
- Glycogen positive in 80%– helps distinguish between ES & NHL. Stain with PAS.
- On electron microscopy glycogen appears as round black structures lying in the cytoplasm.
- Areas of degeneration
- May be foci of reactive bone that may be confused with osteosarcoma
- Pseudorosettes consist of 8-10 cells circling a centre that may be a capillary or a void.
- Neural elements common to ES & PNET are neuron specific enolase & Leu 7.
- How does one tell ES & PNET apart? PNET has
- Homer-Wright rosettes in a fibrillary background
- A lobular arrangement of cells
- Prominent organelles & neurosecretory granules
- Note: there is no difference in survival between patients with ES & PNET in whom histological criteria are used for diagnosis
Differential diagnosis – histology
- Osteomyelitis
- Eosinophilic granuloma
- Lymphoma
- Leukaemia
- Metastatic neuroblastoma
- Small cell lung cancer
- Embryonal cell rhabdomyosarcoma
Molecular biology
- Translocation common to ES & PNET is t (11,22).
- This produces a cell surface glycogen that can be targeted by monoclonal antibodies HBA-71 & MIC2
Staging
- CT & MRI
- Bone scan shows involvement of other bones in 10% at presentation
- Bone marrow aspirate & biopsy
- Assessment of cardiac function (gated heart pool scan)
Biopsy
- Best done percutaneously
- Should be done at the tertiary referral centre because biopsy related complications are five times more common if the biopsy is done at the referring hospital
- soft tissues are biopsied if possible to avoid creating a stress riser
Management
- Two objectives:
- Local control
- Systemic control (chemotherapy)
Local control
- This can be through surgery, or radiotherapy, or both.
- Historically radiotherapy was used but has now been supplanted by surgery.
- Surgery has several advantages:
- It allows assessment of the tumour responsiveness to adjuvant chemotherapy
- Radiotherapy can cause secondary sarcomas, up to 35% at 10 years
- Retrospective trials at the Mayo, Sloan Kettering & Mass. Gen have shown that surgery confers a survival advantage
- Limb sparing surgery – followed by radiotherapy if inadequate margins (defined as less than 1 cm) have been achieved
- Radiotherapy to an unresectable primary is with doses in the order of 54 to 60 Gy.
- Recurrence after a satisfactory response to chemotherapy followed by definitive radiotherapy is around 15%.
- Complications of radiotherapy include:
- Limb length discrepancy
- Joint contracture
- Muscle atrophy
- Pathological fracture
- Late radiotherapy induced tumours (particularly if more than 60Gy is used)
Systemic control
- Intense neoadjuvant therapy
- One routine is vincristine, dactinomycin, cyclophosphamide plus doxirubicin alternating with ifosfamide & etoposide
- High dose intermittent therapy is preferable to moderate dose continuous therapy
- Intense postoperative chemotherapy is then continued for at least one year, with the agents changed if the surgical specimen shows that the agents have been ineffective.
- Patients with marrow involvement at outset may be offered marrow ablation with stem cell rescue
Prognosis
- Poor prognostic factors are:
- Metastatic disease – 25% of patients present with gross metastatic disease, & these have only a 13% long term survival
- Large tumours – greater than 8cm or 100mL
- Pelvic sites
- Increased LDH
- Poor response to initial chemotherapy
- Good prognostic factors are:
- Distal tumour site
- Rib primaries
- current 5-year survival rate for all patients is 70%
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