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

A>Aetiology

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

Sit>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.

Cli>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)

Inves>Investigations

3 class="wp-block-heading">Labor>Laboratoryl class="wp-block-list">
  • Increased WBC, around 20 000
  • Normochromic, normocytic anaemia
  • Increased LDH (bad sign)
  • Increased ESR

    • Xray<>Xray

    l class="wp-block-list">
  • 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

    • MRIMRI

    l class="wp-block-list">
  • intermediate intensity on T1 & high intensity on T2, reflecting cellular nature

    • Diffe>Differential diagnosis on Xray

    l class="wp-block-list">
  • Infection
  • Eosinophilic granuloma
  • Osteosarcoma

    • Patho>Pathology

    3 class="wp-block-heading">Gross>Gross pathologyl class="wp-block-list">
  • 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

    • Histo>Histology

    l class="wp-block-list">
  • 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

    • Differentia>Differential diagnosis – histology

    s="wp-block-list">
  • Osteomyelitis
  • Eosinophilic granuloma
  • Lymphoma
  • Leukaemia
  • Metastatic neuroblastoma
  • Small cell lung cancer
  • Embryonal cell rhabdomyosarcoma

    • Molecular bio>Molecular biology

    "wp-block-list">
  • 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

    >Staging"wp-block-list">
  • 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

    >Biopsy"wp-block-list">
  • 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

    • ManagementManagement

    "wp-block-list">
  • Two objectives:
    • Local control
    • Systemic control (chemotherapy)

    • Local control>Local control

    "wp-block-list">
  • 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 contro>Systemic control

    p-block-list">
  • 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

    >Prognosisp-block-list">
  • 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%