Ewing sarcoma

by Bibianna Purgina, MD FRCPC
July 25, 2024

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Background:

Ewing sarcoma is a rare type of cancer that occurs in the bones or in the soft tissue around the bones. It primarily affects children and young adults, typically between the ages of 10 and 20. This cancer is most commonly found in the long bones of the arms and legs, the pelvis, and the chest wall. 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.

What are the symptoms of Ewing sarcoma?

The symptoms of Ewing sarcoma can vary depending on the location of the tumour but often include:

• Pain and swelling: The most common symptom is pain and swelling at the tumour site. This pain can persist and worsen over time or with physical activity.
• Lump or mass: A noticeable lump or mass may develop in the affected area, which can be felt through the skin.
• Fever: Recurrent fevers without a clear cause can occur.
• Fatigue: General feelings of tiredness and fatigue are common.
• Weight Loss: Unintended weight loss may be observed.
• Bone fractures: Bones weakened by the tumour may fracture more easily, even with minimal trauma.
• Numbness or paralysis: If the tumour compresses the spinal cord or nerves, it can lead to numbness, tingling, or paralysis in the affected limbs.

What causes Ewing sarcoma?

The exact cause of Ewing sarcoma is not well understood, but it is associated with genetic changes. Most cases of Ewing sarcoma involve a specific chromosomal translocation, which is an abnormal rearrangement of genetic material between chromosomes. The most common translocation, found in about 85% of cases, is between chromosome 11 and chromosome 22 (t(11;22)(q24;q12)). This translocation results in the fusion of the EWSR1 gene on chromosome 22 with the FLI1 gene on chromosome 11, creating an abnormal fusion protein that promotes cancer cell growth.

How is this diagnosis made?

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.

Microscopic features of this tumour

When viewed under the microscope, Ewing sarcoma is made up of round cells that look blue because the nucleus (the part that contains the genetic information) is large compared to the cytoplasm (the 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.

Additional tests

Additional tests such as immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or next-generation sequencing (NGS) may usually performed to confirm the diagnosis and to look for changes in the EWSR1 gene.  When IHC is performed, the tumour cells are positive (reactive) for CD99. Specifically, CD99 should stain the outer wall (cell membrane) of the tumour cells. These tests can be done on the biopsy specimen or when the tumor has been surgically removed.

Tumour size

After the entire tumour has been removed, your pathologist will measure it in three dimensions and the largest dimension will be described in your pathology report. The size of the tumour is important because it is used to determine the pathologic tumour stage (pT).

Grade

No formal grading system is applied to Ewing sarcoma. Rather, all Ewing sarcomas are considered high grade tumours that behave aggressively over time.

Tumour extension

Most Ewing sarcomas start in deep sites such as bone, the chest wall, and around the muscles of the lower limb.  As the tumour grows, it can spread into or around neighboring muscles, bones, 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 effects

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 was still alive at the time it was removed from the body. Pathologists use the term viable to describe tissue that was still alive when it was removed from the body. In contrast, pathologists use the term non-viable to describe tissue that was not alive when it was removed from the body. Most commonly, your pathologist will describe the percentage of tumours that is non-viable.

Perineural invasion

Pathologists use the term “perineural invasion” to describe a situation where cancer cells attach to or invade a nerve. “Intraneural invasion” is a related term that specifically refers to cancer cells found inside a nerve. Nerves, resembling long wires, consist of groups of cells known as neurons. These nerves, present throughout the body, transmit information such as temperature, pressure, and pain between the body and the brain. The presence of perineural invasion is important because it allows cancer cells to travel along the nerve into nearby organs and tissues, raising the risk of the tumour recurring after surgery.

Lymphovascular invasion

Lymphovascular invasion occurs when cancer cells invade a blood vessel or lymphatic channel. Blood vessels, thin tubes that carry blood throughout the body, contrast with lymphatic channels, which carry a fluid called lymph instead of blood. These lymphatic channels connect to small immune organs known as lymph nodes scattered throughout the body. Lymphovascular invasion is important because it enables cancer cells to spread to other body parts, including lymph nodes or the lungs, via the blood or lymphatic vessels.

Margins

In pathology, a margin is the edge of tissue removed during tumour surgery. The margin status in a pathology report is important as it indicates whether the entire tumour was removed or if some was left behind. This information helps determine the need for further treatment.

Pathologists typically assess margins following a surgical procedure, like an excision or resection, that removes the entire tumour. Margins aren’t usually evaluated after a biopsy, which removes only part of the tumour. The number of margins reported and their size—how much normal tissue is between the tumour and the cut edge—vary based on the tissue type and tumour location.

Pathologists examine margins to check if tumour cells are present at the tissue’s cut edge. A positive margin, where tumour cells are found, suggests that some cancer may remain in the body. In contrast, a negative margin, with no tumour cells at the edge, suggests the tumour was fully removed. Some reports also measure the distance between the nearest tumour cells and the margin, even if all margins are negative.

Lymph nodes

Lymph nodes are small immune organs found throughout the body. Cancer cells can spread from a tumour to lymph nodes through small lymphatic vessels. For this reason, lymph nodes are commonly removed and examined under a microscope to look for cancer cells. The movement of cancer cells from the tumour to another part of the body, such as a lymph node, is called a metastasis.

Cancer cells typically spread first to lymph nodes close to the tumour, although lymph nodes far away from the tumour can also be involved. For this reason, the first lymph nodes removed are usually close to the tumour. Lymph nodes further away from the tumour are only typically removed if they are enlarged and there is a high clinical suspicion that there may be cancer cells in the lymph node.

If any lymph nodes were removed from your body, they will be examined under the microscope by a pathologist, and the results of this examination will be described in your report. The examination of lymph nodes is important for two reasons. First, this information determines the pathologic nodal stage (pN). Second, finding cancer cells in a lymph node increases the risk that cancer cells will be found in other parts of the body in the future. As a result, your doctor will use this information when deciding if additional treatment, such as chemotherapy, radiation therapy, or immunotherapy, is required.

Some helpful definitions:

• Positive: Positive means that cancer cells were found in the lymph node being examined.
• Negative: Negative means that no cancer cells were found in the lymph node being examined.
• Deposit: The term deposit describes a group of cancer cells inside a lymph node. Some reports include the size of the largest deposit. A similar term is “focus”.
• Extranodal extension: Extranodal extension means that the tumour cells have broken through the capsule on the outside of the lymph node and have spread into the surrounding tissue.

Pathologic stage (pTNM)

​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 a more advanced disease and a worse prognosis.

If the tumour started in bone, it is staged as follows:

Tumour stage (pT)

​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 to 3 based on its size and whether there are separate tumour 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 to 4 based on the extent of its 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 medially 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.

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 a 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 it is listed as NX. If cancer cells are found in any lymph nodes, the nodal stage is listed as N1.

About this article

Doctors wrote this article to help you read and understand your pathology report. If you have additional questions, contact us.

Other helpful resources

Atlas of Pathology