By Jason Wasserman MD PhD FRCPC and Bibianna Purgina MD FRCPC
January 2, 2026
CIC-DUX4 sarcoma is a rare, aggressive type of soft tissue cancer. It belongs to a group of tumours called undifferentiated round cell sarcomas, meaning the cancer cells look very immature and do not clearly resemble a normal tissue type under the microscope.
Most cases are driven by a specific genetic change involving the CIC gene, most often fused to the DUX4 gene.
Where does CIC-DUX4 sarcoma develop?
Most CIC-DUX4 sarcomas arise in the deep soft tissues of the body, especially in the arms, legs, or trunk. Less commonly, they can occur in the head and neck, pelvis, or retroperitoneum (the deep space in the abdomen behind the organs).
About 1 in 10 cases develop in internal organs, such as the kidney, gastrointestinal tract, or brain. Tumours starting in bone are rare.
What are the symptoms of CIC-DUX4 sarcoma?
The most common presentation is a rapidly growing mass, which may or may not be painful. Because this tumour is aggressive, a significant number of patients already have metastatic disease at the time of diagnosis.
When the cancer has spread, symptoms may relate to the affected organs. For example, spread to the lungs can cause shortness of breath or cough, while large tumours can cause pressure or discomfort in nearby tissues.
Who gets CIC-DUX4 sarcoma?
CIC-DUX4 sarcoma can occur at any age, but it has a strong tendency to affect young adults, most commonly between the ages of 25 and 35. Fewer than one quarter of cases occur in children. There is a slight male predominance.
What causes CIC-DUX4 sarcoma?
The exact cause is not known, but an acquired genetic mutation drives the tumour. A genetic mutation is a change in DNA, the instruction manual inside cells that tells them how to grow and divide. These mutations are not inherited and are not passed down to children.
In most cases, a piece of the CIC gene becomes abnormally joined to the DUX4 gene. This creates a fusion gene that produces an abnormal protein. That protein strongly activates growth-promoting pathways, causing cells to divide rapidly and behave aggressively.
In a small number of cases, CIC is fused to other partner genes instead of DUX4. Despite different fusion partners, these tumours behave very similarly.
How is the diagnosis made?
The diagnosis is made by examining tumour tissue under the microscope and performing special laboratory tests to confirm the genetic abnormality.
Imaging
CT or MRI scans are used to locate the tumour, determine its size, and look for spread to other parts of the body. These tumours are often large at presentation and may show areas of bleeding or tissue death on imaging.
Microscopic (pathologic) features
Under the microscope, CIC-DUX4 sarcomas consist of sheets of round, immature-appearing cancer cells. The cells usually look fairly uniform but show some variation in size and shape. The nuclei often have open chromatin and prominent nucleoli, features of aggressive tumours.
The tumour often grows in a lobulated pattern, with fibrous tissue separating groups of cancer cells. Small areas of spindle-shaped or epithelioid cells may also be present. The cytoplasm is usually lightly pink and may appear partially clear.
Necrosis (areas of dead tumour) is common, and rapidly dividing cells are seen as many mitotic figures under the microscope. In about one-third of cases, the supporting tissue has a myxoid (gel-like) appearance, and the tumour cells may form delicate, net-like, or gland-like patterns in these areas.
Immunohistochemistry
Immunohistochemistry uses special stains to detect proteins produced by tumour cells. CIC-DUX4 sarcomas often show:
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CD99 positivity is usually patchy rather than strong and uniform.
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WT1 positivity in most cases.
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ETV4 positivity in nearly all cases.
These markers help distinguish CIC-DUX4 sarcoma from other round cell tumours, especially Ewing sarcoma. Unlike Ewing sarcoma, CIC-DUX4 sarcomas are typically negative for NKX2-2. Markers such as keratin, S100, and muscle markers are usually absent.
Molecular testing
Special genetic tests can detect CIC gene rearrangements, including CIC-DUX4 fusions. These tests help confirm the diagnosis in complex cases, although no single test reliably detects all cases. Because of this, the diagnosis relies on a combination of microscopic appearance, immunohistochemistry, and molecular findings.
Perineural invasion
Perineural invasion (PNI) means that cancer cells are found around or tracking along a nerve. Nerves can act as pathways that allow tumour cells to spread locally into nearby tissues.
In CIC-DUX4 sarcoma, perineural invasion is uncommon, but when present, it suggests more aggressive behaviour. Its presence does not by itself mean the cancer has spread to distant organs. Still, it is an important feature that pathologists report because it can be associated with a higher risk of local recurrence.
What does lymphovascular invasion mean?
Lymphovascular invasion (LVI) means that cancer cells are found inside small blood vessels or lymphatic channels. These vessels are part of the body’s circulation system and can provide a route for tumour cells to spread to other parts of the body.
Because CIC-DUX4 sarcoma is an aggressive cancer with a high risk of metastasis, identifying lymphovascular invasion is particularly important. When present, it indicates a higher likelihood of tumour spread, particularly to the lungs, the most common site of metastasis for this tumour.
What are margins, and why are they important?
Margins refer to the edges of the tissue removed during surgery. After the tumour is removed, a pathologist examines the margins to see whether cancer cells are present at the cut edges.
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A negative margin means no tumour cells are seen at the edge of the specimen, suggesting that the tumour was removed entirely.
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A positive margin means tumour cells are present at the edge, indicating that some cancer may remain in the body.
In CIC-DUX4 sarcoma, achieving negative surgical margins is very important because the tumour has a high risk of local recurrence. Margin status helps guide decisions about additional treatment, such as further surgery or radiation therapy, and influences follow-up planning.
How is this tumour staged?
CIC-DUX4 sarcoma is staged using standard soft tissue sarcoma staging systems, which consider tumour size, depth, lymph node involvement, and distant spread. The most common site of metastasis is the lung.
What is the prognosis for a person with CIC-DUX4 sarcoma?
CIC-DUX4 sarcoma generally exhibits highly aggressive behavior. Many patients develop metastatic disease, often early in the course of illness. The estimated 5-year survival rate ranges from about 17% to 43%, which is significantly worse than that of Ewing sarcoma.
Standard chemotherapy regimens used for Ewing sarcoma are often less effective for CIC-DUX4 sarcoma. Because of this, treatment typically involves a combination of surgery, chemotherapy, and sometimes radiation, often at specialized cancer centres.
Questions to ask your doctor
- Where is my tumour located, and has it spread?
- Was a CIC-DUX4 fusion identified in my tumour?
- How aggressive does my tumour appear under the microscope?
- What treatment options are available for me?
- Should I be treated at a specialized sarcoma centre?
- What follow-up imaging or tests will I need?
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