What is Osteosarcoma?

Osteosarcoma is a tumor of the bone. They are typically primary tumors, meaning the tumor originates from the tumor site and is not a result of metastases from another cancer in the body. To understand osteosarcomas, it is important to know about the structure and processes of normal bone. Bones have many functions. Flat bones include the skull and ribs. They support and protect our organs. Bones that make up the arms and legs are called long bones, which help us move our muscles. A major function of bone is to make new red blood cells, white blood cells, and platelets. This occurs in the bone marrow, which is the soft inner portion of bones.

Although our bones do not change in shape or size significantly once we reach adulthood, they are actually in constant growth and repair. Bones are made of living cells that include osteoblasts and osteoclasts. Osteoclasts break down the bone matrix and maintain the shape of bones. Osteoblasts rebuild bone by forming more bone matrix. Osteosarcomas are made of cells that also make a bone matrix, similar to osteoblasts. However, the bone matrix made by these cancer cells is weaker than that of normal bones. As a result, osteosarcomas are very uncommon but are typically malignant.

In the United States, 750 to 900 new cases are diagnosed each year. It makes up only 1% of all cancers diagnosed yearly in the United States. African Americans and other races have a greater osteosarcoma incidence than Caucasians. It can occur at any age. Most occur in children and adolescents under age 20. The most common age for the diagnosis in children is between the ages of 13 and 16 years. It is more common in boys than in girls. It is the most common primary bone cancer in children and adolescents.

The second most common group where osteosarcoma occurs in elderly adults over age 65. Similar to children, osteosarcoma affects men more than women in older adults. However, whereas African American children are most affected, the opposite is true in the adult population. Osteosarcoma is more common in Caucasian adults than in African Americans or Asians.

Depending on whether the osteosarcoma occurs in children or adults, the location of the tumor and chances of survival will differ. In children, the most common sites of osteosarcoma include the metaphyses of long bones such as the distal femur (knee), proximal humerus (near the shoulder), and tibia (shin). In adults, osteosarcomas are sometimes considered secondary neoplasms, which means they result from another cancer process that occurred first.

That is because, in adults, Paget’s disease of the bone often precedes the development of osteosarcoma. The most common areas for osteosarcomas to arise in adults are in axial locations or the trunk. However, the location in adults is more unpredictable and can include the pelvis (hips) and jaw.

History

The term for osteosarcoma was first entered in a dictionary in 1826. However, it is unknown who discovered osteosarcoma.

However, we know that it has existed for at least hundreds of thousands of years because osteosarcomas were discovered in 4000-year-old mummies from Chile and in 120,000-year-old Neanderthal male skeletal remains.

Osteosarcomas have been found in many mummies from Chile and Egypt. Near Johannesburg, scientists have discovered a fossil of a human foot that may have osteosarcoma. That would make the existence of osteosarcomas in humans dating back to more than 1.7 million years.

Even before the current species of human existence, evidence of osteosarcomas existing so long ago may suggest that modern lifestyles and environmental factors do not cause osteosarcomas. Instead, the genetic predisposition to osteosarcomas has been passed down to us from ancient ancestors.

Risk Factors

Risk factors for osteosarcoma include Paget disease of the bone (common in older adults), history of bone radiation, bone infarcts (such as in patients with sickle cell disease), and other bone conditions. Sarcomas that arise from radiation are called radiation-associated sarcomas, and osteosarcomas can be classified as such if the patient has a history of radiation treatment. Osteosarcoma is the most common second primary cancer that occurs in the first 20 years of post-radiation therapy. Children who have received radiation therapy or chemotherapy for another cancer have a significantly increased risk of developing osteosarcoma within 20 years. It is estimated that 3% of all osteosarcomas can be due to prior radiation exposure.

Alkylating agents used in chemotherapy also increase the risk of developing osteosarcoma. Patients who have received both radiation therapy and chemotherapy are at a greater risk than if they had just one treatment type alone. It is postulated that chemicals such as beryllium compounds and methylcholanthrene found in chemotherapy cause genetic damage to bone and therefore lead to osteosarcoma formation.

In the United States, more than 50% of all osteosarcomas in patients over age 65 are secondary tumors. Osteosarcomas that arise secondary to Paget’s disease are also called Pagetic sarcomas. Pagetic sarcomas have the worst prognosis out of all osteosarcoma. In Paget disease, the bone turnover process by osteoclasts and osteoblasts is accelerated, and bone grows out of control. Pagetic bone is brittle and prone to injury. The bone that is affected by Paget’s disease can evolve into osteosarcoma. There is also a genetic link between Paget disease and pagetic osteosarcomas.

Both conditions are associated with abnormalities in chromosome 18. In addition, mutations in the SQSTM1 gene on chromosome 5 have been linked to Paget disease and pagetic osteosarcoma. Benign bone conditions that can turn into malignant osteosarcomas include chronic osteomyelitis and fibrous dysplasia. Some research shows that osteosarcomas are more common near sites of metallic implants, but the evidence is not strong enough to support a definitive causal relationship.

Many genetic conditions carry an increased risk of osteosarcoma and are more commonly found in tumors that develop in children. Therefore, having a family history of osteosarcoma or conditions predisposing to cancer is a major risk factor for developing osteosarcoma. For instance, children who have certain forms of retinoblastoma that involve mutations of the retinoblastoma gene have an increased risk of developing osteosarcomas and soft tissue sarcomas. In addition, people with Li-Fraumeni syndrome have an increased risk of many cancers.

In addition to osteosarcomas, these patients also have a high incidence of breast cancer, brain tumors, and leukemias. The p53 tumor suppressor gene is inactivated in patients with Li-Fraumeni syndrome. Some studies show that 3% of children with osteosarcoma carry mutations in the Li-Fraumeni p53 gene.

Rothmund-Thomson syndrome, also known as poikiloderma congenital, is another condition associated with an increased risk of osteosarcoma. It is a dermatologic condition that causes changes in skin color, sparse hair, cataracts, abnormal bone, and short stature. Studies estimate that up to 13% of patients with Rothmund-Thomson syndrome develop osteosarcoma.

These patients also tend to be diagnosed with osteosarcoma at a younger age than others. Mutation of the RECQL4 gene has been linked with both Rothmund-Thomson syndrome and osteosarcoma. The same gene is also linked to Bloom syndrome and Werner syndrome, which are both also associated with an increased risk for osteosarcoma. A lesser-known hypothesis of a cause of osteosarcoma is related to viruses.

In 1912, a study discussed the possible link between osteosarcoma and the Rous sarcoma virus. The Rous sarcoma virus is an RNA virus that contains the V-Src gene, which is related to a human cancer gene. Many other viruses have been linked to bone tumors in humans.

Screening

Currently, the medical community does not have recommendations for screening the general population for osteosarcoma. The U.S. Preventative Task Force (USPSTF) ‘s the gold standard for screening guidelines does not recommend routine screening for osteosarcoma. Osteosarcoma remains a relatively rare tumor in people who do not have genetic risk factors or bone conditions.

People who have benign bone conditions, family or personal history of Li-Fraumeni syndrome, Rothmund-Thomson syndrome, or hereditary retinoblastoma should talk to their doctors about whether they need to monitor for the development of osteosarcoma. Osteosarcoma itself does not run in families, but there are many conditions linked to osteosarcoma that do.

In addition to the genes linked to these conditions mentioned above, genetic testing for the GJA1, COL1A2, COL5A2, MMP1, MMP2, MMP3, MMP14, TGFβ, and RUNX2 gene mutations can be used as possible screening for increased risk of osteosarcoma.

Early studies suggest that the COL genes can be used as diagnostic markers for osteosarcoma.

People who have a history of childhood cancer that have undergone radiation or chemotherapy treatment should pay attention to signs such as bone pain that may be an early symptom of osteosarcoma.

Anyone who has had another primary cancer who has been exposed to irradiation or chemotherapy should see their doctor regularly to monitor for bone symptoms. Since Paget disease is a common condition in many older people, those who have the condition should be aware of the risks of affected bone areas developing into osteosarcoma.

Symptoms

People with osteosarcoma often complain of bone pain in a specific location that worsens over months. Sometimes, the pain becomes noticeable after an injury, and patients will think that the pain will go away with time.

Pain symptoms may sometimes disappear and return over time. However, osteosarcoma does not usually cause weight loss, night sweats, fever, or fatigue, unlike many other cancers.

The symptoms are typically limited to the tumor’s location, commonly in the arms and legs in children, or shoulder, hips, or jaw in adults. The bone pain that is associated with cancer is usually worst at night in the early stages. For example, patients with osteosarcoma may feel perfectly fine in the daytime but may wake up from pain at night. As cancer becomes more advanced, the pain will begin to persist throughout the day.

The affected area near the tumor site may also enlarge over time so that swelling may be visible. The tumor may be felt as a lump or a mass. Since osteosarcoma cancer cells build a weak bone matrix, people with osteosarcoma have an increased risk of fractures. The fracture may take longer to heal than usual, and pain from the injury will be present for a long time. One accidental fall may cause the patient to become immobile permanently. The bone pain accompanying osteosarcomas can be mistaken for normal pain of growth or puberty in children.

This is especially true if the osteosarcoma occurs near growth plates such as the knees and other areas of rapid bone growth in puberty. This can delay diagnosis and treatment in adolescents. In younger children, the bone pain may not be as easily localized. The only symptom in young children may be limpness. This can also delay diagnosis because limping in children has many more common causes other than osteosarcoma. Limping in children can be caused by injury or muscle soreness and is expected to improve over time, whereas the pain caused by osteosarcoma will worsen over time. Children who are usually active but then, over time, decrease their play and exercise activities should be further evaluated for possible bone conditions, including osteosarcoma.

The bottom line is bone pain that does not go away with time or worsens should be suspicious for a cancerous process. Likewise, a doctor should further evaluate bone pain that is worse at night and wakes you up from sleep. Blood tests are usually normal. However, some people with osteosarcomas may show high levels of alkaline phosphatase, lactate dehydrogenase, or erythrocyte sedimentation rate in their blood. Alkaline phosphatase (ALP) is a marker of bone activity and is also elevated in Paget disease.

Lactate dehydrogenase (LDH) and erythrocyte sedimentation rate (ESR) are nonspecific markers of inflammation in the body. They can be high in people with a cancerous process or chronic infection or inflammation in the body. Patients with osteosarcomas and very high LDH levels have a poorer prognosis. Patients who have very high levels of ALP even after treatment may have an increased risk of relapse of osteosarcoma. In summary, children and adults with osteosarcoma do not look very sick. The diagnosis may be delayed until the bone pain worsens and the cancer is more advanced. The clinical symptoms, including the tumor’s location and severity of pain, can vary widely in different people. A careful understanding of the personal and family history of risk factors can save a lot of time in diagnosing osteosarcoma.

Diagnosis and Stages

The first step when osteosarcoma is suspected is for the doctor to take a careful patient and family history of any conditions, prior treatments, or genetic conditions that increase the risk of osteosarcoma. Other conditions that cause similar symptoms to osteosarcoma also need to be considered. Then, medical professionals will form a differential diagnosis or list all the possible conditions causing the patient’s symptoms.

Examples of other bone conditions that may show the same symptoms as osteosarcoma include Ewing sarcoma, lymphoma, chondroblastoma, osteoblastoma, osteomyelitis, and Langerhans cell histiocytosis. The definitive diagnosis of bone cancer involves imaging studies, blood tests, and biopsies. The first step is usually painless and involves getting imaging tests such as X-rays, CT scans, or MRIs of the suspected area.

Imaging studies can show any abnormalities in the bone that may be signs of osteosarcoma. Different types of imaging studies have different advantages. For example, MRI scans are best for examining long bones of the arms and legs. It can also show the soft tissue simultaneously to see if there is any involvement beyond the bone. That means that the joints and bone marrow can also be examined for tumor invasion. Because osteosarcoma can spread to other body parts, imaging is also used to detect metastases. To detect tumors in the chest and lung area, CT scans are the best option. Up to 80% of osteosarcomas that spread go to the lungs, so a CT scan of the lungs is an essential part of staging and diagnosis of osteosarcoma. In addition, CT scans may show calcifications, which is usually a sign of a benign tumor.

However, malignant metastases can also show calcifications, so the result is not one hundred percent reliable. A PET/CT scan or radionuclide bone scanning with technetium is useful for examining the entire skeleton for tumor lesions. Some studies show that PET/CT is the best option for the spread of tumors to the lungs. Official guidelines from cancer societies suggest that a PET scan should be the next step after diagnosis of primary osteosarcoma to assist in the staging process. After osteosarcoma is suspected based on imaging studies, the next diagnostic test is to biopsy the lesion.

Biopsies can be done in an operating room where the area is open to reveal the tumor. These are called open biopsies. Open biopsies are usually performed by orthopedic surgeons who are experienced with bone surgery. Another option is a core needle biopsy, where only a portion of the tumor is taken out for examination. An interventional radiologist usually does this.

An orthopedic surgeon and radiologist will help the interventional radiologist determine the precise location for the core needle biopsy.

Once the entire tumor or part of the tumor is taken out, the sample is then analyzed by a pathologist, who will be able to determine whether the tumor is osteosarcoma or another type of cancer. Unfortunately, osteosarcoma cannot be definitively diagnosed without confirming the pathology with a biopsy.

Osteosarcoma surgical staging is based on the staging system created by the Musculoskeletal Tumor Society (MSTS). Tumors are classified into grades and stages. Tumors that have not spread to other body parts are low-grade stage one. High-grade osteosarcomas have extended through the bone. Osteosarcomas that have spread to other areas such as the lungs are classified as stage III. The most important prognostic factor in terms of long-term survival and cure of the osteosarcoma is whether or not the tumor has metastasized to other parts of the body. The pathologist will also give staging based on histology.

Histologic classification is more detailed than surgical classification. The most common subset of osteosarcomas is conventional osteosarcoma. These make up 90% of all osteosarcomas, especially in adolescents and children. Conventional osteosarcomas usually involve the long bones of the arms and legs. They can be further sub-classified as osteoblastic, chondroblastic, or fibroblastic based on which cell type makes up most of the tumor.

Osteoblastic osteosarcomas have an overproduction of malignant tumor cells and osteoid matrix. Fibroblastic osteosarcomas are made of spindle cells that are located near areas of bone production. Chondroblastic osteosarcomas have an overproduction of cartilage matrix in the tumor. Osteosarcomas can also be classified into different variants, including small cell, telangiectatic, multifocal, and malignant fibrous histiocytoma subtype. These variants may have a worse prognosis, but survival rates have greatly improved with recent innovations in osteosarcoma treatment.

Osteosarcoma of the jaw is a special type of osteosarcoma that develops slowly. This type tends to occur in the elderly and is rare in children and adolescents. Osteosarcoma of the jaw rarely spreads to other parts of the body, but it commonly recurs after tumor removal. Extraosseous osteosarcoma is another subtype that involves soft tissue but does not involve the bone. This soft tissue tumor produces material that is usually found in bone, such as osteoid and chondroid material. Extraosseous osteosarcomas are more common in the elderly. Osteosarcomas that occur in soft tissue are extremely rare.

Treatments and Drugs

Chemotherapy and surgery are the mainstay treatment options for osteosarcoma. Both children and adults receive chemotherapy as the standard treatment. A study showed that chemotherapy with three or more drugs increases the five-year survival rate to 70 percent. Chemotherapy can be given either before or after tumor removal surgery. Whether preoperative or postoperative chemotherapy is better remains controversial, and different surgeons will have different preferences. It is estimated that 60 percent of people under age 40 with osteosarcoma will survive for many years after treatment. However, for people whose tumors have spread or metastasized, less than 20 percent are expected to survive in the long term.

Radiation therapy is not typically used to treat osteosarcoma. If the osteosarcoma involves long bones, some patients may need to amputate their arm or leg. However, most patients can spare the limb and operate on the tumor locally. Chemotherapy given before surgery to shrink the tumor first increases the chances of saving the limb from amputation. For tumors located in the lower back (sacrum) or base of the skull, targeting these areas is very difficult and poses higher risks of complications.

If the patient decides not to undergo surgery or the tumor site is too dangerous to operate on, radiation therapy may be considered a last option. Intensity-modulated radiation therapy or proton beam radiation therapy are used. Special care is taken to prevent radiation to nearby healthy tissue, especially in children. A medical team of radiation oncologists, pediatric oncologists, radiation physicists, and radiologists will work together to formulate radiation therapy plans.

A special subset of osteosarcoma that is classified as small cell osteosarcoma can benefit from adjuvant radiation therapy, which means radiation therapy after surgical removal of the tumor. Almost all patients who undergo surgery receive adjuvant chemotherapy, which is chemotherapy given after the surgery.

There is no set drug regimen, and different doctors will choose different drugs depending on the condition of the patient and the staging of the osteosarcoma. However, previous clinical trials have shown that, in general, using multiple drugs is more effective than single-drug chemotherapy.

This is true for both children and adults, with children showing an even greater improvement in long-term survival using multi-drug chemotherapy versus single-drug chemotherapy.

Common drugs used for chemotherapy treatment of osteosarcoma include methotrexate, doxorubicin, and cisplatin, also known together as MAP. MAP is highly recommended for osteosarcoma treatment in children and adolescents. The treatment is given prior to surgery for 10 weeks. After the surgery, the chemotherapy is continued for another 29 weeks. A mifamurtide drug can also be added to the MAP regimen, but it is expensive and not always used. Adults over age 40 can use the same drug combination as children and adolescents.

Elderly patients over age 60 have a different drug regimen that includes doxorubicin and cisplatin only.

For patients who have more advanced osteosarcomas whose doctors have determined that current treatment options may not be helpful, it is possible to enroll in a clinical trial. A clinical trial is a research study that explores the safety and effectiveness of new drugs or procedures.

Participating in a clinical trial provides an opportunity to be treated with the newest treatment options. Of course, there are risks with using a drug or undergoing a procedure where long-term safety and effectiveness have not yet been established, but that may be the only option available for some people.

The patient should ask their doctors whether there are any clinical trials and whether a clinical trial is right for them. These are usually conducted at a major hospital or research institution.

After treatment with surgery and chemotherapy, patients may consult a doctor that specializes in rehabilitation and physical therapy, called a physiatrist. Physiatrists and a team of physical therapists will help patients recover by strengthening their limps.

Regular physicals, blood tests, and imaging of the tumor site and the chest are recommended. The first set of tests should be done every three months for the first two years. After three years, tests can be done every four months. A check-up twice a year is recommended until five years after surgery. After that, patients can resume annual testing.

If the osteosarcoma is to recur, it usually happens within 10 years after the initial diagnosis. However, recurrences have been recorded as long as 20 years after therapy. As with all forms of chemotherapy and radiation therapy, long-term side effects can be unpredictable. In addition, chemotherapy and radiation therapy can cause other forms of cancer in other areas of the body unrelated to osteosarcoma.

Coping and Support

Being diagnosed with cancer will be an emotional and psychological toll on anyone. Having a child diagnosed with osteosarcoma can be a stressful and heartbreaking event for parents. However, patients should know that there are professionals that can help them cope with osteosarcoma, whether it is finding the right doctor or coming to terms with the diagnosis.

The American Cancer Society, for example, offers transportation, housing, and support groups to help patients during the process of getting treatment. Family and friends’ support is crucial in the recovery process for patients who require amputation. Artificial arms and legs can help patients regain independence after an amputation. Psychologists or psychiatrists specializing in pediatrics can help children with self-esteem issues after an amputation.

Regardless of the outcome, patients and families who have to cope with osteosarcoma must have an opportunity to express themselves. They should spend sufficient time speaking to their doctors about their condition and ensuring there are no misunderstandings. Chemotherapy is physically demanding.

Children and adults undergoing chemotherapy may experience side effects such as nausea and vomiting, appetite changes, hair loss, extreme fatigue, constipation, diarrhea, and nerve pain. In addition, many patients suffer from depression and suicidal thoughts due to chemotherapy. Friends, families, and doctors should offer continuous support for patients during this time. Patients may need to be hospitalized for long periods and miss school and work. Hospital personnel should understand that patients may behave angrily sometimes.

Families should keep in mind that the patient is simply using anger to cope and should not take it personally. Regardless of the outcome, it is important to remember to take things one step at a time and never feel guilty about asking for help.