Bone and soft tissue -

Ewing family of tumours

This article was last reviewed and updated on January 2, 2019
by Bibianna Purgina, MD FRCPC

Quick facts:

  • The Ewing family of tumours (EFTs) are a group of cancers that share similar features.

  • The most common types of cancer in this group are Ewings sarcoma and peripheral neuroectodermal tumour (PNET).

  • All members of the Ewings family of tumours have a genetic change that involves the EWSR1 gene.

Learn more

Ewing family of tumours (EFTs) is a category of disease that includes several related cancers such as Ewing sarcoma and peripheral primitive neuroectodermal tumour (PNET). The Ewing family of tumours are a type of cancer (a malignant tumour) called a sarcoma. Sarcomas are cancers that can develop from mesenchymal tissues.  Mesenchymal tissues include tissues such as fat, muscle, tendons, ligaments, bone and cartilage.


Each cell in your body contains a set of instructions that tell the cell how to behave. These instructions are written in a language called DNA and the instructions are stored on 46 chromosomes in each cell. Because the instructions are very long, they are broken up into sections called genes and each gene tells the cell how to produce piece of the machine called a protein.


Sometimes, a piece of DNA falls off one chromosome and becomes attached to a different chromosome. This is called a translocation and it can result in the cell making a new and abnormal protein. If the new protein allows the cell to live longer than other cells or spread to other parts of the body, the cell can become a cancer (a malignant tumour). EFTs contains a translocation involving the EWSR1 gene.

  
When viewed under the microscope, EFTs are made up of round cells that look blue because nucleus of the cell (the part that contains the genetic information) is large compared to the body of the cell (the cytoplasm). Pathologists describe cells that look like this as primitive and the tumour is sometimes called a small round blue cell tumour.

 
The first diagnosis of an EFT is usually made after a small sample of the tumour is removed in a procedure called a biopsy. The biopsy tissue is then sent to a pathologist who examines it under a microscope. Additional tests such as immunohistochemistry, fluorescence in situ hybridization (FISH) or next generation sequencing (NGS) are usually performed to confirm the diagnosis.  EFTs show positive staining with the immunohistochemistry marker CD99. In EFT, CD99 should stain the outer wall (cell membrane) of the tumour cells.

 
Ewing family of tumour (EFT) typically occurs in teenagers and young adults. The tumour can start in a bone (where they are more often called as Ewing Sarcoma) or in the deep soft tissue such as muscle (where they are more often called a peripheral primitive neuroectodermal tumour). The most common locations for EFTs include the chest wall, lower limbs, and around the spine.

 
Ewing family of tumours (EFTs) are often aggressive cancers that will spread (metastasize) to the lungs and to bone (if they started in soft tissue sites). Often EFTs will be treated with chemotherapy prior to the tumor being removed by the surgeon.

 
After surgical resection, your pathologist examines the tumour under the microscope and provides your surgeon and oncologist with critical information required for your subsequent treatment. EFTs that occur in adults are staged using the AJCC 8th edition for bone or soft tissue tumours, depending on the location of your tumour.  EFTs occurring in children are staged using a separate system and are not staged using the AJCC protocol.   

Histologic grade

Grade is a word pathologists use to describe how different the cancer cells look and behave compared to normal cells in the same location. Because all EFTs are made up of primitive cells that look nothing like normal cells, all EFTs are considered high grade sarcomas. High grade tumors (grades 2 and 3) are associated with worse prognosis compared to low grade tumours (grade 1).   


If you have been diagnosed with an EFT, your pathologist will determine the French Federation of Cancer Centers Sarcoma Group grade of your tumour by looking for three microscopic features: tumour differentiation, mitotic count, and necrosis. Your pathologist will give each feature a certain number of points (from 0 to 3) and the total number of points determines the final grade of the tumour.

  • Tumour differentiation – Tumour differentiation describes how closely the cancer cells look like normal cells. Tumours that look very similar to normal cells are given are given 1 point while those that look very different from normal cells are given 2 or 3 points. Because EFT are made up of primitive cells that do not look like normal cells, all EFTs are given 3 points. 

  • Mitotic count – A cell that is in the process of dividing to create two new cells is called a mitotic figure. Tumours that are growing fast tend to have more mitotic figures than tumours that are growing slowly. Your pathologist will determine the mitotic count by counting the number of mitotic figures in ten areas of the tumour while looking through the microscope. Tumours with no mitotic figure or very few mitotic figures are given 1 point while those with 10 to 20 mitotic figures are given 2 points and those with more than 20 mitotic figures are given 3 points.

  • Necrosis - Necrosis is a type of cell death. Tumours that are growing fast tend to have more necrosis than tumours that are growing slowly. If your pathologist sees no necrosis, the tumour will be given 0 points. The tumour will be given 1 point if necrosis is seen but it makes up less than 50% of the tumour or 2 points if necrosis makes more than 50% of the tumour.

 

The final grade is based on the total number of points given to the tumour:

  • Grade 1 – 2 or 3 points.

  • Grade 2 – 4 or 5 points.

  • Grade 3 – 6 to 8 points.

Tumour size

After the tumour is completely removed your pathologist will measure it in three dimensions but only the largest dimension is typically included in your report. For example, if the tumour measures 5.0 cm by 3.2 cm by 1.1 cm, the report may describe the tumour size as 5.0 cm in greatest dimension.


Tumours less than 5 cm are associated with better prognosis.

Necrosis

Necrosis is a form of cell death and it commonly occurs in cancers (malignant tumours). Your pathologist will closely examine the tumour for evidence of necrosis. Necrosis is used to determine the tumour grade (see Histologic grade above).


The presence of necrosis is important, especially if you have received pre-surgery chemotherapy or radiation therapy, as this can be an indication of treatment response (see Treatment effect below). It can also be associated with worse prognosis in tumours that have not been treated yet with chemotherapy or radiation therapy.

Tumour extension

Most EFTs tend to occur in deep sites such as bone, the chest wall and around the muscles of the lower limb.  EFTs can grow into or around neighbouring muscles, bone and blood vessels.  Your pathologist will examine samples of the surrounding tissues under the microscope to look for cancer cells. Any surrounding organs or tissues that contain cancer cells will be described in your report.

Treatment effect

If you received chemotherapy and/or radiation therapy before the operation to remove your tumour, your pathologist will examine all the tissue sent to pathology to see how much of the tumour is still alive (viable). Most commonly, your pathologist will describe the percentage of tumour that is dead. 

Perineural invasion

Nerves are like long wires made up of groups of cells called neurons. Nerves transmit information (such as temperature, pressure, and pain) between your brain and your body. Perineural invasion is a term pathologists use to describe cancer cells attached to a nerve.

 

Perineural invasion is important because cancer cells that have attached to a nerve can use the nerve to travel into tissue outside of the original tumour. For this reason, perineural invasion is associated with a higher risk that the tumour will come back in the same area of the body (local recurrence) after treatment.

Lymphovascular invasion

Lymphatics and blood vessels are channels that normal cells use to travel around the body. The presence of cancer cells within a lymphatic or blood vessel is called lymphovascular invasion and is associated with a higher risk that the cancer cells will travel (metastasize) to a distant site such as the lungs.

Margins

A margin is any tissue that was cut by the surgeon to remove the tumour from your body. Depending on the type of surgery you have had, the margins can include bones, muscles, blood vessels, and nerves that were cut to remove the tumour from your body.


All margins will be very closely examined under the microscope by your pathologist to determine the margin status.  Specifically, a margin is considered ‘negative’ when there are no cancer cells at the edge of the cut tissue. Alternatively, a margin is considered ‘positive’ when there are cancer cells at the edge of the cut tissue.


A positive margin is associated with a higher risk that the tumour will recur in the same site after treatment (local recurrence).


Margins will only be described in your report after the entire tumour has been removed.

Lymph nodes

Metastatic disease describes the process where cancer cells escape the main tumour and travel to another part of the body. Lymph nodes are small immune organs located throughout the body. Many cancers can spread to the lymph nodes, but EFTs do this very rarely. 

 

If lymph nodes were part of the surgery to remove your tumour, your pathologist will assess them under the microscope and describe whether or not there are any cancer cells in the lymph node. Your report will also include the total number of lymph nodes examined and the number that contain cancer cells.

Pathologic stage

​The pathologic stage for Ewing family tumours (EFTs) is based on the TNM staging system, an internationally recognized system originally created by the American Joint Committee on Cancer. There are separate staging systems for EFTs arising in bone and soft tissue. Tumours occurring in children are not staged using this system.

 

This system uses information about the primary tumour (T), lymph nodes (N), and distant metastatic disease (M)  to determine the complete pathologic stage (pTNM). Your pathologist will examine the tissue submitted and give each part a number. Generally, a higher number means more advanced disease and worse prognosis.

 

Pathologic stage is not reported on a biopsy specimen. It is only reported when the entire tumour has been removed in an excision or resection specimen.

 

If your EFT developed in bone, it is staged as follows:

Tumour stage (pT)

For bone cancers or sarcomas such as EFT, the primary tumour (T) stage depends on where the tumour was located in your body.

 

​If your EFT was located in your appendicular skeleton (these are bones of your appendages, and include the arms, legs, shoulder, trunk, skull, and facial bones), it is given a tumour stage from 1-3 based on tumour size whether there a separate tumor nodule(s).

 

  • pT1: Tumor ≤ 8 cm in greatest dimension.

  • pT2: Tumor > 8 cm in greatest dimension.

  • pT3: Discontinuous tumors in the primary bone site.

 

If your EFT was located in your spine, it is given a tumour stage from 1-4 based on the extent of tumor growth.

 

  • pT1: Tumor confined to one vertebral segment or two adjacent vertebral segments.

  • pT2: Tumor confined to three adjacent vertebral segments.

  • pT3: Tumor confined to four or more adjacent vertebral segments, or any nonadjacent vertebral segments.

  • pT4: Extension into the spinal canal or great vessels.

 

If your EFT was located in your pelvis, it is given a tumour stage from 1-4 based on the size of the tumour and extent of tumor growth.

 

  • pT1: Tumor confined to one pelvic segment with no extraosseous (growing outside of the bone) extension.

    • pT1a: Tumor ≤ 8 cm in greatest dimension.

    • pT1b: Tumor >8 cm in greatest dimension.

  • pT2: Tumor confined to one pelvic segment with extraosseous extension or two segments without extraosseous extension.

    • pT2a: Tumor ≤ 8 cm in greatest dimension.

    • pT2b: Tumor >8 cm in greatest dimension.

  • pT3: Tumor spanning two pelvic segments with extraosseous extension.

    • pT3a: Tumor ≤ 8 cm in greatest dimension.

    • pT3b: Tumor >8 cm in greatest dimension.

  • pT4: Tumor spanning three pelvic segments or crossing the sacroiliac joint.

    • pT4a: Tumor involves sacroiliac joint and extends medial to the sacral neuroforamen (space where the nerves pass through).

    • pT4b: Tumor encasement of external iliac vessels or presence of gross tumor thrombus in major pelvic vessel.

 

If after microscopic examination, no tumour is seen in the resection specimen sent to pathology for examination, it is given the tumour stage pT0 which means there is no evidence of primary tumour. 

 

If your pathologist cannot reliable evaluate the tumor size or the extent of growth, it is given the tumour stage pTX (primary tumour cannot be assessed).  This may happen if the tumour is received as multiple small fragments. 

Nodal stage (pN)

Primary bone cancers or sarcomas such as EFT are given a nodal stage between 0 and 1 based on the presence or absence of cancer cells in one or more lymph nodes.

 

If no cancer cells are seen in any lymph nodes, the nodal stage is N0. If no lymph nodes are sent for pathological examination, the nodal stage cannot be determined, and the nodal stage is listed as NX.  If cancer cells are found in any lymph nodes, then the nodal stage is listed as N1.

 

Metastasis stage (pM)

Bone sarcomas such as EFT are given a metastasis stage only if the presence of metastasis has been confirmed by a pathologist.  There are two metastasis stages in primary bone sarcomas such as EFT, M1a and M1b.  If there are confirmed lung metastasis, then the tumor M-stage is 1a. 

 

The metastasis stage can only be given if tissue from a distant site is sent for pathological examination. Because this tissue is rarely present, the metastasis stage cannot be determined, and it is typically not included in your report. 

If your EFT developed in soft tissue such as muscle or fat, it is staged as follows:

Tumour stage (pT)

The tumour stage for EFT varies based on the body part involved. For example, a 5 centimeter tumour that starts in the head will be given a different tumour stage than a tumour that starts deep in the back of the abdomen (the retroperitoneum). However, in most body sites, the tumour stage includes the tumour size and whether the tumour has grown into surrounding body parts.

 

Tumour stage for tumours starting in the head and neck:
T1 – The tumour is no greater than 2 centimeters in size.
T2 – The tumour is between 2 and 4 centimeters in size.
T3 – The tumour is greater than 4 centimeters in size.
T4 – The tumour has grown into surrounding tissues such as the bones of the face or skull, the eye, the larger blood vessels in the neck, or the brain.

 

Tumour stage for tumours starting on the outside of the chest, back, or stomach and the arms or legs (trunk and extremities):
T1 – The tumour is no greater than 5 centimeters in size.
T2 – The tumour is between 5 and 10 centimeters in size.
T3 – The tumour is between 10 and 15 centimeters in size.
T4 – The tumour is greater than 15 centimeters in size.

Tumour stage for tumours starting in the abdomen and organs inside the chest (thoracic visceral organs):
T1 – The tumour is only seen in one organ.
T2 – The tumour has grown into the connective tissue that surrounds the organ from which is started.
T3 – The tumour has grown into at least one other organ.
T4 – Multiple tumours are found.

 

Tumour stage for tumours starting in the space at the very back of the abdominal cavity (retroperitoneum):
T1 – The tumour is no greater than 5 centimeters in size.
T2 – The tumour is between 5 and 10 centimeters in size.
T3 – The tumour is between 10 and 15 centimeters in size.
T4 – The tumour is greater than 15 centimeters in size.

 

Tumour stage for tumours starting in the space around the eye (orbit):
T1 – The tumour is no greater than 2 centimeters in size.
T2 – The tumour is greater than 2 centimeters in size but has not grown into the bones surrounding the eye.
T3 – The tumour has grown into the bones surrounding the eye or other bones of the skull.
T4 – The tumour has grown into the eye (the globe) or the surrounding tissues such as the eyelids, sinuses, or brain.

If after microscopic examination, no tumour is seen in the resection specimen sent to pathology for examination, it is given the tumour stage pT0 which means there is no evidence of primary tumour. 

If your pathologist cannot reliable evaluate the tumor size or the extent of growth, it is given the tumour stage pTX (primary tumour cannot be assessed).  This may happen if the tumour is received as multiple small fragments. 

Nodal stage (pN)

EFTs are given a nodal stage between 0 and 1 based on the presence or absence of cancer cells in one or more lymph nodes.

 

If no cancer cells are seen in any lymph nodes, the nodal stage is N0. If no lymph nodes are sent for pathological examination, the nodal stage cannot be determined, and the nodal stage is listed as NX.  If cancer cells are found in any lymph nodes, then the nodal stage is listed as N1.

 

Metastasis stage (pM)

EFTs are given a metastasis stage only if the presence of metastasis has been confirmed by a pathologist.  There are two metastasis stages in primary bone sarcomas such as EFT, M1a and M1b.  If there are confirmed lung metastasis, then the tumor M-stage is 1a. 

 

The metastasis stage can only be given if tissue from a distant site is sent for pathological examination. Because this tissue is rarely present, the metastasis stage cannot be determined, and it is typically not included in your report. 

Molecular tests

As described in the introduction, all cancers in the EFT contain a translocation that involves the gene EWSR1.

  

Pathologists can look for this translocation and other molecular changes by performing either fluorescence in situ hybridization (FISH) or next generation sequencing (NGS) on a piece of the tissue from the tumour.

 

This type of testing is can be done on the biopsy specimen or when your tumor has been surgically removed. The test is performed to confirm the diagnosis and the rule out other cancers that can look like EFT.

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