Extraskeletal myxoid chondrosarcoma is an extremely rare type of cancer that develops in soft tissues rather than bone. Though it grows slowly, this uncommon disease requires careful attention because it can return even years after treatment and spread to other parts of the body.

Understanding Extraskeletal Myxoid Chondrosarcoma

Extraskeletal myxoid chondrosarcoma, commonly shortened to EMC, is a very rare form of soft tissue sarcoma, which means it is a type of cancer that begins in the soft tissues of the body rather than in bone. Despite its name suggesting a connection to cartilage, EMC actually does not develop from cartilage cells. Instead, it forms from other soft tissue cells, and scientists are still working to understand exactly which type of cells give rise to this disease.^[2]

This type of cancer is classified as having uncertain differentiation, meaning doctors cannot yet definitively say what kind of normal tissue these cancer cells originally came from. Recent research has even suggested that EMC might have a neuroectodermic origin, meaning it could arise from the same type of tissue that forms parts of the nervous system.^[6]

Epidemiology

Extraskeletal myxoid chondrosarcoma is exceptionally rare, accounting for less than three percent of all soft tissue tumors.^[4] In England, there are an average of only 14 cases diagnosed each year, making up just 0.36 percent of all soft tissue sarcomas.^[2]

The disease most commonly affects middle-aged adults, with the median age at diagnosis being around 49.5 to 51 years old.^[1] However, some forms of EMC can occur in younger adults, with certain types affecting people between the ages of 19 and 30.^[4] The average age across different studies has been reported as approximately 54 years, though the range extends from 29 to 73 years.^[4]

Men are affected more frequently than women, with the male-to-female ratio being approximately 2 to 1.^[1] This means that for every woman diagnosed with EMC, roughly two men receive the same diagnosis.

Causes

The exact cause of extraskeletal myxoid chondrosarcoma remains unknown to researchers. However, scientists have discovered that the disease is strongly linked to specific genetic changes within cells. These changes involve chromosomes breaking apart and rejoining incorrectly, a process called chromosomal translocation.^[2]

The most common genetic change in EMC involves a rearrangement of the NR4A3 gene, which is located on chromosome 9. This gene can become fused with different partner genes, most often the EWSR1 gene on chromosome 22 or the TAF15 gene on chromosome 17.^[7] When these genes fuse together abnormally, they create what scientists call chimeric proteins, which are proteins made from parts of two different genes that should not normally be joined together.^[7]

In some cases, EMC has been linked to certain inherited genetic disorders, though this is not the most common scenario. Conditions such as Li Fraumeni syndrome, Maffucci syndrome, Ollier’s disease, and hereditary multiple osteochondromas have been associated with an increased risk of developing various types of tumors, including chondrosarcomas.^[14] However, researchers are still trying to understand whether these specific genetic changes directly cause EMC or simply make cells more vulnerable to developing cancer.

Risk Factors

While anyone can develop extraskeletal myxoid chondrosarcoma, certain factors may increase the likelihood of developing this rare disease. Age is one significant consideration, as most people are diagnosed between the ages of 40 and 75, with the average age at diagnosis being around 51 years.^[1]

Being male appears to be another risk factor, as men are diagnosed with EMC about twice as often as women.^[1] The reasons for this gender difference are not yet fully understood by medical researchers.

People with certain inherited genetic conditions may also face higher risks. Individuals with Li Fraumeni syndrome are more likely to develop various cancerous tumors throughout their lives. Those with Maffucci syndrome or Ollier’s disease, which cause benign tumors in cartilage, bone, and skin, may also be at increased risk. Additionally, people with hereditary multiple osteochondromas, a condition causing multiple benign bone tumors, might have a higher chance of developing EMC.^[14]

Symptoms

The symptoms of extraskeletal myxoid chondrosarcoma can vary significantly depending on where the tumor is located and how large it has grown. Because EMC typically grows slowly, symptoms often develop gradually over several months, making them easy to overlook initially.^[1]

The most common symptom is a lump or swelling in a part of the body, usually in the upper parts of the arms or legs.^[2] This mass often appears under the skin and can feel firm or hard to the touch. The lump is frequently accompanied by pain and tenderness in the affected area.^[2] Some patients describe the swelling as resembling a bruise in appearance, though it does not go away like a normal bruise would.^[2]

If the tumor develops near a joint, it can restrict movement and make it difficult to use that part of the body normally.^[2] For example, a tumor near the knee might make it painful or difficult to bend the leg fully. In cases where the tumor grows in the gingival area (the gums), patients may notice a mass in the mouth along with numbness and tenderness.^[6]

Some people with EMC experience fatigue and unintentional weight loss, though these symptoms are less specific and can be caused by many different conditions.^[14] Bone pain that comes and goes and tends to worsen at night has also been reported in some cases.^[14]

Prevention

Unfortunately, there are currently no known methods to prevent extraskeletal myxoid chondrosarcoma. Because the exact cause of the disease is still not fully understood, and because it appears to arise from random genetic changes within cells, specific prevention strategies have not been identified.

However, being aware of the symptoms and seeking medical attention promptly when you notice an unusual lump or persistent swelling can lead to earlier diagnosis. Early detection is important because it may allow for treatment before the cancer has a chance to spread to other parts of the body.

If you have one of the genetic conditions that may increase your risk of developing tumors, regular medical check-ups and monitoring by your healthcare team may help detect any problems early. Your doctor might recommend periodic examinations or imaging tests to watch for any changes.

For anyone, maintaining overall health through regular medical care and being attentive to changes in your body remains the best approach. If you notice a lump that does not go away within two weeks, or if you experience persistent pain, swelling, or other concerning symptoms, it is important to consult with a healthcare provider for proper evaluation.^[2]

Pathophysiology

The pathophysiology of extraskeletal myxoid chondrosarcoma involves complex changes at the cellular and genetic level that cause normal cells to become cancerous. At the heart of this process is the abnormal fusion of genes, particularly the NR4A3 gene with various partner genes such as EWSR1 or TAF15.^[7]

When these gene fusions occur, they create abnormal proteins that interfere with the normal regulation of cell growth and division. The NR4A3 gene normally produces a protein that acts as an orphan nuclear receptor, which means it helps control which genes are turned on or off in a cell, but scientists are still learning about exactly what activates it. When NR4A3 becomes fused with genes like EWSR1, the resulting chimeric protein has an abnormally strong ability to activate genes, leading to uncontrolled cell growth.^[4]

Under the microscope, EMC tumors have a distinctive appearance. The tumor cells are typically round or slightly elongated, uniform in shape and size, and are arranged in patterns that look like ribbons, cords, or small clusters.^[6] These cells are immersed in an abundant myxoid matrix, which is a jelly-like substance that gives the tumor its characteristic appearance. The tumor is usually divided into multiple nodules by fibrous bands of tissue called septa, and the entire tumor is often encased by a pseudocapsule, a fibrous layer that surrounds it.^[5]

The cells in EMC tumors typically have cytoplasm (the gel-like substance inside cells) that appears granular and sometimes contains vacuoles, making them look somewhat like fat cells under the microscope.^[6] The nuclei (the control centers of cells) are round to oval in shape.

Despite the name chondrosarcoma, which suggests cartilage origin, EMC does not show convincing evidence of cartilaginous differentiation. This means the cells do not actually develop into cartilage or show the characteristics of cartilage cells.^[6] Instead, recent research suggests these tumors may have a neuroectodermic origin, potentially arising from tissues related to the nervous system.^[6]

Prognosis and Long-Term Outlook

Extraskeletal myxoid chondrosarcoma is known for having an unpredictable course. While the tumor typically grows slowly, it has a tendency to recur locally (come back in the same area) and to spread to distant parts of the body, even many years after initial treatment. This makes long-term monitoring essential for anyone diagnosed with EMC.^[1]

For patients who do not have metastases (cancer that has spread) at the time of diagnosis, the outlook is generally better than for those who present with metastatic disease. Studies have shown that approximately 37 percent of patients develop local recurrence, with a median time to recurrence of 3.3 years. About 26 percent develop distant recurrence, with a median time of 3.2 years.^[1] Approximately 13 percent of patients present with metastases at the time of initial diagnosis.^[1]

The survival rates for EMC patients are relatively encouraging compared to many other types of cancer. The five-year overall survival rate is approximately 82 percent, the ten-year rate is 65 percent, and the fifteen-year rate is 58 percent.^[1] Other studies have reported similar or even higher rates, with five-year survival ranging from 71 to 100 percent and ten-year survival from 60 to 88 percent across different patient groups.^[11]

Patients with distant metastases at the time of presentation tend to have significantly shorter survival compared to those without metastases. However, even with metastatic disease, the progression is often slow, and some patients can survive for several years.^[13] The disease-specific survival rates show that 92.3 percent of patients are alive one year after diagnosis, 83.1 percent at five years, and 83.1 percent at ten years.^[9]

Several factors can influence prognosis. Larger tumor size and location in the trunk have been identified as risk factors for poorer survival outcomes. Having surgical margins that are not completely clear of cancer (called R1 or R2 margins) significantly increases the risk of local recurrence.^[11]