Primitive neuroectodermal tumour was first recognised in 1918 in an ulnar nerve; Ewing Sarcoma was described three years later as occurring in long bones. Due to the different site of origin of these two cases it took some time for realisation that they were due to the same pathological entity.
- Primitive neuroectodermal tumour (PNET) is reserved for cases with microscopic or immunohistochemical evidence of neuroectodermal differentiation
- Ewing Sarcoma is reserved for cases where there is no evidence of neuroectodermal differentiation
Note that medulloblastoma and related CNS tumours are also referred to as primitive neuroectodermal tumours. They have a very different genetic pattern.
Epidemiology
Incidence
Ewing Sarcoma/PNET is rare; it is the second most common bone sarcoma of childhood (after osteosarcoma), making up 3% of paediatric tumours. Overall, it is less common than most other malignant bone tumours, including osteosarcoma, chondrosarcoma and myeloma.
Age
PNET is predominately a disease of teenagers and is rare after thirty. The age of onset seems to be related to puberty; women are typically diagnosed at an earlier age than men. About 40% of cases occur during puberty; 30% of cases before the age of 10 and about 5% of cases in those over 20.
Ethnicity
Those of European descent are most commonly effected. People of African descent have a very low incidence in comparison.
Geography
The geographical differences in the disease seem to be due to ethnicity rather than environmental factors, with low rates in Africans in both Africa and America.
Aetiology and Pathogenesis
The exact cell of origin is unknown; most theories speculate a neural precursor as cultured PNET cells may differentiate into neuronal-like cells and staining for neuroectodermal markers. Mesenchymal or epithelial differentiation may also occur.
85% of all cases have an identical translocation of chromosomes 11 and 22; the EWSR1 gene is found on chromosome 22 and forms a chimeric gene with FLI1 transcription gene on chromosome 11. Other translocations are recognised; the second most common is an EWSR1/ERG hybrid; ERG is found on chromosome 21. The chimeric protein that results from this translocation is thought to have tumour suppressor and/or oncogenic functions. There is often an overexpression of the CD99 gene, which codes for a cell surface adhesion molecule; positive staining for CD99 is seen in most PNETs.
Natural History
Ewing sarcoma/PNET is a very aggressive disease and typically causes death due to widespread haematological dissemination.
Sites of Involvement
Tumours are most commonly localised to the diaphysis or metaphysis of long bones; they are also known to occur in ribs or the pelvic bones. Soft tissue, or 'extra-osseous Ewing sarcoma', may also occur, often in relationship with a named nerve.
Local Invasion
Tumours invade locally within the bone and cause destruction of the cortex. At diagnosis they are have often extended beyond the bone into adjacent tissues.
Lymphatic Spread
Spread to regional lymphatics is very rare.
Haematological Spread
Tumours have often disseminated haematogenously at diagnosis; cure rates with local treatment alone are < 10%. The most common sites of distant disease are the lungs, the bone marrow, and other bones.
Clinical Presentation
Symptoms and Signs
The most common symptoms are related to local tumour growth, with patients normally complaining of a mass or pain. Rarely patients may present with symptoms of distant disease. Clinical signs relate to the sites of involvement.
Bloods
Anaemia, leukocytosis, and raised ESR are often seen in these patients but there are no specific tumour blood tests available.
Imaging
Imaging may show an 'onion-like' appearance of bony disease. Another well described appearance is of a 'soap bubble' where the tumour forms a raised mass that extends along the external surface of the bone. Both CT and MRI are useful modalities in diagnosis.
Tumour/Normal Tissue Features
Macroscopic
The tumour is locally destructive, replacing and invading bone. It iss usually tan in colour, and has evidence of haemorrhage and necrosis.
Microscopic
Ewing Sarcoma/PNET is a small round blue cell tumour. There is a high NC ratio and minimal cytoplasm. The nuclear chromatin is typically fine in nature. Cell borders are usually indistinct. The cytoplasm may be clear (due to glycogen accumulation) or pink.
A small subset of cases contain larger cells with visible nucleoli and irregular cell membranes.
Electron Microscopy
Electron microscopy can demonstrate glycogen deposits with primitive intracellular communications.
Immunohistochemistry
Immunohistochemistry is almost always positive for CD99; unfortunately this is not specific for the Ewing sarcoma. Vimentin and neural markers are typically positive.
Genetics
Genetic testing will almost always show evidence of a translocation involving the EWSR1 gene on chromosome 22, usually with chromosome 11 (FLI1).
Staging / Classification
Staging is through the TNM system. The latest edition (7th):
| T Stage | Description |
|---|---|
| T1 | < 8 cm in maximum dimension |
| T2 | > 8 cm in maximum dimension |
| T3 | Discontinuous tumours in the same bone |
| N Stage | Description |
|---|---|
| N1 | Nodal metastases |
| M Stage | Description |
|---|---|
| M1a | Lung metastases |
| M1b | Other distant metastases |
Grade always plays a role in the staging of bone sarcoma; PNET is always considered high grade.
| Stage | T | N | M | Grade |
|---|---|---|---|---|
| IA | T1 | N0 | M0 | Low |
| IB | T2 | N0 | M0 | Low |
| IIA | T1 | N0 | M0 | High |
| IIB | T2 | N0 | M0 | High |
| III | T3 | N0 | M0 | Any |
| IVA | Tany | N0 | M1a | Any |
| IVB | Tany | N1 Nany |
Many M1b |
Any |
