Ewing sarcoma

What is Ewing sarcoma?

Ewing sarcoma is a type of cancer. It is part of a category of diseases called Ewing family of tumours (EFTs) which also includes peripheral primitive neuroectodermal tumour (PNET). Ewing sarcoma is an aggressive cancer that often spreads from bone to the lungs. The movement of tumour cells to other parts of the body is called metastasis.

Ewing sarcoma typically occurs in teenagers and young adults. The tumour can start in a bone or in the deep soft tissue such as muscle. The most common locations for Ewing sarcoma include the chest wall, lower limbs, and around the spine. The patient will often be offered chemotherapy prior to the tumor being removed by the surgeon.

Genetic changes in Ewing sarcoma

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 a 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 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. Ewing sarcoma contains a translocation involving the EWSR1 gene.

How do pathologists make this diagnosis?

The first diagnosis of Ewing sarcoma 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.

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

Ewing family of tumours

Additional tests such as immunohistochemistry, fluorescence in situ hybridization (FISH), or next-generation sequencing (NGS) are usually performed to confirm the diagnosis.  When immunohistochemistry is performed, the tumour cells are positive (reactive) for CD99. Specifically, CD99 should stain the outer wall (cell membrane) of the tumour cells.

After the tumour is removed, your pathologist examines the tumour under the microscope and provides your surgeon and oncologist with critical information required for your subsequent treatment. Tumours that occur in adults are staged using the AJCC 8th edition for bone or soft tissue tumours, depending on the location of your tumour (see Pathologic stage below).  Tumours that occur 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. Your pathologist will determine the French Federation of Cancer Centers Sarcoma Group grade 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 1 point while those that look very different from normal cells are given 2 or 3 points. Because these tumours are made up of primitive cells that do not look like normal cells, all Ewing sarcomas 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.
  • NecrosisNecrosis 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.

Because all Ewing sarcomas are made up of primitive cells that look nothing like normal cells, all tumours are considered high-grade sarcomas. High-grade tumors (grades 2 and 3) are associated with worse prognosis compared to low grade tumours (grade 1).

Molecular tests

Your pathologist may perform special molecular tests to look for changes in the EWSR1 gene. 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 the tumor has been surgically removed. The test is performed to confirm the diagnosis and rule out other cancers that can look like Ewing sarcoma.

What to look for in your report after the tumour is removed

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.

The tumour size is important because tumours less than 5 cm are less likely to spread to other parts of the body. Tumour size is also used to determine the tumour stage (see Pathologic stage below).

Tumour extension​

Most Ewing sarcomas tend to occur in deep sites such as bone, the chest wall, and around the muscles of the lower limb.  The tumour can grow into or around neighboring muscles, bone,s 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 the 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

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 to a distant site such as the lungs. The movement of cancer cells to another part of the body is called metastasis.

lymphovascular invasion

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

Margin

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

Lymph nodes​

Lymph nodes are small immune organs located throughout the body. Cancer cells can travel from the tumour to a lymph node through lymphatic channels located in and around the tumour (see Lymphovascular invasion above). The movement of cancer cells from the tumour to a lymph node is called metastasis.

Lymph node

Lymph nodes on the same side as the tumour are called ipsilateral while those on the opposite side of the tumour are called contralateral.

Your pathologist will carefully examine each lymph node for cancer cells. Lymph nodes that contain cancer cells are often called positive while those that do not contain any cancer cells are called negative. Most reports include the total number of lymph nodes examined and the number, if any, that contain cancer cells.

Lymph nodes are used to determine the nodal stage (see Pathologic stage below).

Pathologic stage

​The pathologic stage for Ewing sarcoma 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 Ewing sarcoma 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 a worse prognosis.

If the tumour developed in bone, it is staged as follows:
Tumour stage (pT)

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

​If the tumour 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 the tumour 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 the tumour was located in your pelvis, it is given a tumour stage from 1-4 based on the size of the tumour and the 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 reliably 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 Ewing sarcoma are given a nodal stage of 0 or 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 Ewing sarcoma 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 Ewing sarcoma, M1a and M1b.  If there are confirmed lung metastasis, then the tumor metastatic 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 the tumour developed in soft tissue such as muscle or fat, it is staged as follows:
Tumour stage (pT)

The tumour stage for Ewing sarcoma 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 reliably 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)

Ewing sarcomas are given a nodal stage of 0 or 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)

Ewing sarcomas 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 metastatic 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.

by Bibianna Purgina, MD FRCPC, updated January 7, 2021
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