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)

No known predisposing factors, although there may a link to ↑ levels of radium in the drinking water

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.

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)

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

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

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

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

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

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)

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

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
  - Older age
- 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%