Undifferentiated pleomorphic sarcoma

by Bibianna Purgina, MD FRCPC
March 25, 2023

What is undifferentiated pleomorphic sarcoma?

Undifferentiated pleomorphic sarcoma (UPS) is a rare and aggressive type of cancer. Most undifferentiated pleomorphic sarcomas in the extremities (legs and arms) of older adults. The tumour can start in soft tissue, such as muscle or fat, or within a bone.

What are the symptoms of undifferentiated pleomorphic sarcoma?

Most undifferentiated pleomorphic sarcomas present as a rapidly growing mass sometimes associated with pain.

What causes undifferentiated pleomorphic sarcoma?

The cause of the vast majority of tumours remains unknown at this time. However, up to 25% of tumours associated with prior radiation are diagnosed as undifferentiated pleomorphic sarcoma.

How do pathologists make the diagnosis of undifferentiated pleomorphic sarcoma?

The diagnosis of undifferentiated pleomorphic sarcoma is often first suggested after a small sample of tumour is removed in a procedure called a biopsy. In the biopsy report, your pathologist will provide your doctor with a list of possible diagnoses that includes undifferentiated pleomorphic sarcoma and dedifferentiated sarcomas. Often a final diagnosis cannot be made until the whole tumour is surgically removed and the pathologist is able to examine the entire specimen.

What does undifferentiated pleomorphic sarcoma look like when examined under the microscope?

When examined under the microscope, undifferentiated pleomorphic sarcoma is made up of large and very abnormal-looking tumour cells. The tumour cells are described as pleomorphic because they show significant variation in cell size and shape. Mitotic figures (tumour cells dividing to create new tumour cells) are frequently found. Atypical mitotic figures may also be found.

What other tests may be performed to confirm the diagnosis?

Immunohistochemistry

Immunohistochemistry is a special test that allows pathologists to look for specific types of proteins inside cells. Pathologists use the results of this test to determine the cell’s function and where in the body the cell came from. When immunohistochemistry is performed on undifferentiated pleomorphic sarcoma, the tumour cells are usually only positive or reactive for non-specific cell markers such as smooth muscle antigen (SMA), p16, and p53. The tumour cells are typically negative for more specific markers such as desmin, ERG, caldesmon, S100, SOX-10, cytokeratins, and p40.

Molecular tests

At our current level of understanding, undifferentiated pleomorphic sarcoma does not have any known characteristic molecular changes. However, your pathologist may perform molecular tests on the tumour sample to rule out other sarcomas that can look like undifferentiated pleomorphic sarcoma. A negative molecular test (for example, a molecular test without an identified translocation or amplification) is consistent with an undifferentiated pleomorphic sarcoma. Pathologists test for these molecular changes by performing either fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS). This type of testing is more often done on the biopsy specimen.  If your pathologist is certain that your tumour is an undifferentiated pleomorphic sarcoma, then no molecular testing may be done.

What does dedifferentiation mean?

Some less aggressive or lower-grade sarcomas undergo a process called dedifferentiation. When this happens, the tumour cells change so they no longer look like cells normally found in the body. For example, when dedifferentiation happens in a sarcoma made up of fat cells, the tumour cells change so that they no longer look like fat.

The dedifferentiated area of a tumour can look like an undifferentiated pleomorphic sarcoma. For this reason, it can be very difficult for a pathologist to tell the difference between an undifferentiated pleomorphic sarcoma and dedifferentiation within another type of sarcoma especially when only a small sample of the tumour is examined. However, unlike dedifferentiated tumours, undifferentiated pleomorphic sarcoma does not develop from a less aggressive or lower grade tumour.

What is the FNCLCC grade and why is it important for undifferentiated pleomorphic sarcoma?

Pathologists divide undifferentiated pleomorphic sarcoma into three grades based on a system created by the French Federation of Cancer Centers Sarcoma Group (FNCLCC). This system uses three microscopic features to determine the tumour grade: differentiation, mitotic count, and necrosis. These features are explained in more detail below. The grade can only be determined after a sample of the tumour has been examined under the microscope.

Points (from 0 to 3) are assigned for each of the microscopic features (0 to 3) and the total number of points determines the final grade of the tumour. According to this system, undifferentiated pleomorphic sarcoma may be either low or high-grade tumours. The tumour grade is important because high-grade tumours (grades 2 and 3) are more aggressive and are associated with a worse prognosis.

Points associated with each grade:

• Grade 1 – 2 or 3 points.
• Grade 2 – 4 or 5 points.
• Grade 3 – 6 to 8 points.

Microscopic features used to determine the grade:

1. Tumour differentiation – Tumour differentiation describes how closely the tumour cells look like normal, healthy 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. All undifferentiated pleomorphic sarcomas receive 3 points for tumour differentiation.
2. 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 figures 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.
3. 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.

Why is the size of the tumour important for undifferentiated pleomorphic sarcoma?

Tumour size is important because tumours less than 5 cm are less likely to spread to other parts of the body and are associated with a better prognosis. Tumour size is also used to determine the pathologic tumour stage (pT).

What does tumour extension mean and why is it important?

Most undifferentiated pleomorphic sarcomas tend to occur in deep sites such as the muscles of the thigh or the psoas muscle in the abdomen/retroperitoneum. Undifferentiated pleomorphic sarcoma can grow into or around organs and bones. This is called tumour extension. When available, your pathologist will examine samples of the surrounding organs and tissues under the microscope to look for tumour cells. Any surrounding organs or tissue that contain cancer cells will be described in your report.

What does treatment effect​ mean?

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

What is a margin and why are margins important?

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.

A negative margin means that no tumour cells were seen at any of the cut edges of tissue. A margin is called positive when there are tumour cells at the very 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.

How do pathologists determine the pathologic stage (pTNM) for undifferentiated pleomorphic sarcoma?

​The pathologic stage for undifferentiated pleomorphic sarcoma is based on the TNM staging system, an internationally recognized system originally created by the American Joint Committee on Cancer. 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. In general, a higher number means a more advanced disease and a worse prognosis.

Tumour stage (pT) for undifferentiated pleomorphic sarcoma

The tumour stage for undifferentiated pleomorphic sarcoma varies based on the body part involved. For example, a 5 centimetre 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.

Head and neck

• T1 – The tumour is no greater than 2 centimetres in size.
• T2 – The tumour is between 2 and 4 centimetres in size.
• T3 – The tumour is greater than 4 centimetres 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.

Chest, back, or stomach and the arms or legs (trunk and extremities)

• T1 – The tumour is no greater than 5 centimetres in size.
• T2 – The tumour is between 5 and 10 centimetres in size.
• T3 – The tumour is between 10 and 15 centimetres in size.
• T4 – The tumour is greater than 15 centimetres in size.

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.

Retroperitoneum (the space at the very back of the abdominal cavity)

• T1 – The tumour is no greater than 5 centimetres in size.
• T2 – The tumour is between 5 and 10 centimetres in size.
• T3 – The tumour is between 10 and 15 centimetres in size.
• T4 – The tumour is greater than 15 centimetres in size.

Tissue around the eye (orbit)

• T1 – The tumour is no greater than 2 centimetres in size.
• T2 – The tumour is greater than 2 centimetres 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.

Nodal stage (pN) for undifferentiated pleomorphic sarcoma

Undifferentiated pleomorphic sarcoma is 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) for undifferentiated pleomorphic sarcoma

Undifferentiated pleomorphic sarcoma is given a metastatic stage of 0 or 1 based on the presence of cancer cells at a distant site in the body (for example the lungs). The metastatic stage can only be given if tissue from a distant site is sent for pathological examination. Because this tissue is rarely present, the metastatic stage cannot be determined, and it is typically not included in your report.