Osteosarcoma

Osteosarcoma also called osteogenic sarcoma, is the most common type of cancer that starts in the bones. The cancer cells in these tumors look like early forms of bone cells that normally help make new bone tissue, but the bone tissue in an osteosarcoma is not as strong as that of normal bones. Most osteosarcomas occur in children and young adults. Teenagers are the most commonly affected age group, but osteosarcoma can develop at any age.

Osteosarcoma is most often found in the long bones, more often the legs, but sometimes the arms, but it can start in any bone. In very rare instances, it occurs in soft tissue outside the bone.

In children and young adults, osteosarcoma usually starts in areas where the bone is growing quickly, such as near the ends of the leg or arm bones:

• Most tumors develop in the bones around the knee, either in the distal femur (the lower part of the thigh bone) or the proximal tibia (the upper part of the shinbone).
• The upper arm bone close to the shoulder (proximal humerus) is the next most common site.

Still, osteosarcoma can develop in any bone, including the bones of the pelvis (hips), shoulder, and jaw. This is especially true in older adults.

Treatment usually involves chemotherapy, surgery and, sometimes, radiation therapy. Doctors select treatment options based on where the osteosarcoma starts, the size of the cancer, the type and grade of the osteosarcoma, and whether the cancer has spread beyond the bone.

Treatment innovations for osteosarcoma have greatly improved the outlook (prognosis) for this cancer over the years. After completion of treatment, lifelong monitoring is recommended to watch for potential late effects of intense treatments.

Osteosarcoma subtypes

Based on how the cells look under the microscope, osteosarcomas can be classified as high grade, intermediate grade, or low grade. The grade of the tumor tells doctors how likely it is that the cancer will grow and spread to other parts of the body.

High-grade osteosarcomas

These are the fastest growing types of osteosarcoma. When seen with a microscope, they do not look like normal bone and have many cells in the process of dividing into new cells. Most osteosarcomas that occur in children and teens are high grade. There are many types of high-grade osteosarcomas (although the first 3 are the most common).

• Osteoblastic
• Chondroblastic
• Fibroblastic
• Small cell
• Telangiectatic
• High-grade surface (juxtacortical high grade)

Other high-grade osteosarcomas include:

• Pagetoid: a tumor that develops in someone with Paget disease of the bone
• Extraskeletal: a tumor that starts in a part of the body other than a bone (but still makes bone tissue)
• Post-radiation: a tumor that starts in a bone that had once been treated with radiation

Intermediate-grade osteosarcomas

These uncommon tumors fall between high-grade and low-grade osteosarcomas. They are usually treated the same way as low-grade osteosarcomas.

• Periosteal (juxtacortical intermediate grade)

Low-grade osteosarcomas

These are the slowest-growing osteosarcomas. The tumors look more like normal bone and have few dividing cells when seen with a microscope.

• Parosteal (juxtacortical low grade)
• Intramedullary or intraosseous well differentiated (low-grade central)

The grade of the tumor plays a role in determining its stage and the type of treatment used.

Osteosarcoma causes

It’s not clear what causes osteosarcoma. Doctors know bone cancers form when something goes wrong in one of the cells that are responsible for making new bone.

Osteosarcoma begins when a healthy bone cell develops changes in its DNA. A cell’s DNA contains the instructions that tell a cell what to do. The changes tell the cell to start making new bone when it isn’t needed. The result is a mass (tumor) of poorly formed bone cells that can invade and destroy healthy body tissue. Cells can break away and spread (metastasize) throughout the body.

The DNA mutations that cause some inherited forms of bone cancers are known. In many cases, genetic testing can be used to see if someone has one of these mutations.

However, most bone cancers are not caused by inherited DNA mutations. They’re the result of mutations during the person’s lifetime. These mutations may result from exposure to radiation or cancer-causing chemicals, but most often they occur for no apparent reason. These mutations are present only in the cancer cells, so they cannot be passed on to the person’s children.

Risk factors for developing osteosarcoma

These factors increase the risk of osteosarcoma:

• Previous treatment with radiation therapy
• Other bone disorders, such as Paget’s disease of bone and fibrous dysplasia
• Certain inherited or genetic conditions, including hereditary retinoblastoma, Bloom syndrome, Li-Fraumeni syndrome, Rothmund-Thomson syndrome and Werner syndrome

Genetic disorders

A very small number of bone cancers especially osteosarcomas appear to be hereditary and are caused by defects (mutations) in certain genes. Retinoblastoma is a rare eye cancer in children that can be hereditary. The inherited form of retinoblastoma is caused by a mutation (abnormal copy) of the RB1 gene. Those with this mutation also have an increased risk of developing bone or soft tissue sarcomas. Also, if radiation therapy is used to treat the retinoblastoma, the risk of osteosarcoma in the bones around the eye is even higher.

Finally, there are families with several members who have developed osteosarcoma without inherited changes in any of the known genes. The gene defects that may cause cancers in these families haven’t been discovered yet.

Paget disease

Paget disease is a benign (non-cancerous) but pre-cancerous condition that affects one or more bones. It results in formation of abnormal bone tissue and occurs mostly in people older than 50. Affected bones are heavy, thick, and brittle. They are weaker than normal bones and more likely to fracture (break). Most of the time, Paget disease is not life threatening. Bone cancer (usually osteosarcoma) develops in about 1% of those with Paget disease, usually when many bones are affected.

Radiation

Bones that have been exposed to ionizing radiation may also have a higher risk of developing bone cancer. A typical x-ray of a bone is not dangerous, but exposure to large doses of radiation does pose a risk. For example, radiation therapy to treat cancer can cause a new cancer to develop in one of the bones in the treatment area. Being treated when you are younger and/or being treated with higher doses of radiation (usually over 60 Gy) increases your risk of developing bone cancer.

Exposure to radioactive materials such as radium and strontium can also cause bone cancer because these minerals build up in bones.

Non-ionizing radiation, like microwaves, electromagnetic fields from power lines, cellular phones, and household appliances, does not increase bone cancer risk.
Bone marrow transplantation

Osteosarcoma has been reported in a few patients who have undergone bone marrow (stem cell) transplantation.

Injuries

People have wondered if injury to a bone can cause cancer. This has never been proven. Many people with bone cancer remember having hurt that part of their bone. Most doctors believe that these injuries did not cause the cancer. Instead, the cancer caused people to remember the incident or that the injury drew their attention to that bone, making them notice a problem that had already been present for some time.

Osteosarcoma symptoms

Signs and symptoms of osteosarcoma may include, among others:

• Swelling near a bone
• Bone or joint pain
• Bone injury or bone break for no clear reason

Pain

Pain in the affected bone is the most common sign of bone cancer. At first, the pain is not constant. It may be worse at night or when the bone is used, for instance, leg pain when walking. As the cancer grows, the pain will be there all the time, and get worse with activity.

Swelling

Swelling in the area of the pain may not occur until weeks later. It might be possible to feel a lump or mass depending on where the tumor is.

Cancers in the bones of the neck can cause a lump in the back of the throat that can lead to trouble swallowing or make it hard to breathe.

Fractures

Bone cancer can weaken the bone it’s in, but most of the time the bones do not fracture (break). People with a fracture next to or through a bone tumor usually describe sudden severe pain in a bone that had been sore for a few months.

Other symptoms

Cancer in the bones of the spine can press on nerves, causing numbness and tingling or even weakness.

Cancer can cause weight loss and fatigue. If the cancer spreads to internal organs it may cause other symptoms, too. For instance, if the cancer spreads to the lungs, it can cause trouble breathing.

These symptoms are more often due to conditions other than cancer, such as injuries or arthritis. Still, if these problems go on for a long time without a known reason, you should see your doctor.

Osteosarcoma complications

Complications of osteosarcoma and its treatment include:

• Cancer that spreads (metastasizes). Osteosarcoma can spread from where it started to other areas, making treatment and recovery more difficult. Osteosarcoma that spreads most often spreads to the lungs and to other bones.
• Adapting to limb amputation. Surgery that removes the tumor and spares the limb is used whenever possible. But sometimes it’s necessary to remove part of the affected limb in order to remove all of the cancer. Learning to use an artificial limb (prosthesis) will take time, practice and patience. Experts can help you adapt.
• Long-term treatment side effects. The aggressive chemotherapy needed to control osteosarcoma can cause substantial side effects, both in the short and long term. Your health care team can help you manage the side effects that happen during treatment and provide you with a list of side effects to watch for in the years after treatment.

Tumor-specific complications

Complications of the tumor itself include pathological fractures. These may occur at presentation or during preoperative chemotherapy. As mentioned above, patients in both these scenarios have poorer outcomes than those without pathological fractures ¹⁾.

Biopsy-related complications

When devising an approach to biopsy a lesion concerning for osteosarcoma (or any sarcoma, for that matter), careful planning of the biopsy approach is necessary to lower the potential for tumor cells to seed the biopsy tract and surrounding tissues. A biopsy tract that extends across multiple compartments may necessitate a larger field of resection, which increases the risk of treatment-related complications ²⁾.

Treatment-related complications

• Chemotherapy side effects
  • When utilizing chemotherapy, the majority of the major side effects occur during the treatment process. Nausea, malaise, alopecia, anemia, and anorexia are possible but usually resolve shortly after completion of the chemotherapy cycle. There are, however, some long-term side effects, which may include cardiotoxicity, pulmonary toxicity, and gradual hearing loss. There are reports of later development of a secondary malignancy ³⁾.
• Radiation side effects
  • Radiation is known to impart superficial side effects, including skin dryness, itching, peeling, and uncommonly, burns. Menstrual changes, erectile dysfunction, and infertility are all reported adverse events in cases of pelvic radiation. When the chest and abdomen are involved in radiation treatment, diarrhea, incontinence, rectal bleeding, nausea, vomiting, dry mouth, dysphagia, pneumonitis, and fibrosis are possible. Much like chemotherapy, there is a small risk of late development of a secondary malignancy ⁴⁾.
• Periprosthetic infection
  • Prostheses-related infections are a relatively frequent complication (approximately 10% of limb salvage surgeries) most often due to lengthy surgery time, repeated surgery at the same site, and immunosuppression secondary to chemotherapy. First-line treatment of these periprosthetic infections typically involves one or more debridement procedures with both local and systemic antibiotic therapy (systemic and local antibiotic cement beads). If these efforts are ineffective, the implant requires removal, followed by debridement and wash out. A cement spacer impregnated with an antibiotic generally gets placed before the insertion of a new prosthesis. Ultimately, amputation may be necessary for a number of these patients ⁵⁾.
• Implant failure
  • The most common reason for reconstruction failure is the mechanical breakdown of the mega prosthesis. Mechanical failure necessitates the replacement of the prosthetic. The tibia is the most frequent site of mechanical failure ⁶⁾.
• Fracture/non-union of allograft/autograft
  • Fracture/non-union of allograft/autograft reconstruction is a relatively infrequent complication, but it does occur. Chemotherapy, radiation, and extracorporeal treatment of autograft bone have been reported to increase the risk of these complications. Refractory cases may necessitate metallic implant placement or amputation ⁷⁾.

Osteosarcoma diagnosis

To diagnose osteosarcoma, the doctor may begin with a physical exam to better understand the symptoms.

Imaging tests

Imaging tests help your doctor investigate your bone symptoms, look for cancer and look for signs that the cancer has spread.

Imaging tests may include:

• X-ray
• Computerized tomography (CT)
• Magnetic resonance imaging (MRI)
• Positron emission tomography (PET)
• Bone scan

X-rays

Most bone cancers show up on x-rays of the bone. The bone at the site of the cancer may look “ragged” instead of solid. The cancer can also appear as a hole in the bone. Sometimes doctors can see a tumor around the defect in the bone that might extend into nearby tissues (such as muscle or fat). The radiologist (doctor who specializes in reading x-rays) can often tell if a tumor is malignant by the way it appears on the x-ray, but only a biopsy can tell for sure.

A chest x-ray is often done to see if bone cancer has spread to the lungs.

Computed tomography (CT) scans

CT scans are helpful in staging cancer. They help show if the bone cancer has spread to your lungs, liver, or other organs. The scans show the lymph nodes and distant organs where there might be cancer spread.

CT scans can also be used to guide a biopsy needle into a tumor. This is called a CT-guided needle biopsy. For this test, you stay on the CT scanning table while a radiologist moves a biopsy needle toward the tumor. CT scans are repeated until the tip of the needle is within the mass. (See Needle biopsy below.)

Magnetic resonance imaging (MRI) scans

MRI scans are often the best test for outlining a bone tumor. They are very helpful for looking at the brain and spinal cord.

Radionuclide bone scans

Bone scans can show if a cancer has spread to other bones. It can find smaller areas of metastasis than regular x-rays. Bone scans also can show how much damage the cancer has caused in the bone.

Areas of diseased bone will be seen on the bone scan as dense, gray to black areas, called “hot spots.” These areas suggest cancer is present, but arthritis, infection, or other bone diseases can also cause hot spots. Other imaging tests or a bone biopsy may be needed to know what’s causing the change.

Positron emission tomography (PET or PET) scans

PET scans use glucose (a form of sugar) that’s attached to a radioactive atom. A special camera can detect the radioactivity. Cancer cells absorb a lot of the radioactive sugar because of their high rate of metabolism. PET scans are useful in looking for cancer throughout your entire body. It can sometimes help tell if a tumor is cancer or not cancer (benign). It’s often combined with CT scans to better pinpoint some kinds of cancer.

Biopsy or removing a sample of cells for testing

A biopsy procedure is used to collect a sample of suspicious cells for laboratory testing. Tests can show whether the cells are cancerous. Lab tests can determine the type of cancer and whether it’s aggressive (the grade).

Types of biopsy procedures used to diagnose osteosarcoma include:

• Needle biopsy. The doctor inserts a thin needle through the skin and guides it into the tumor. The needle is used to remove small pieces of tissue from the tumor.
  • There are 2 types of needle biopsies: fine (aspiration) and core. For both types, a drug is first used to numb the area for the biopsy.
    1. For fine needle aspiration (FNA), the doctor uses a very thin needle and a syringe to take out a small amount of fluid and some cells from the tumor. Sometimes, the doctor can aim the needle by feeling the tumor if it’s near the surface of the body. If the tumor is too deep to feel, the doctor can guide the needle while looking a CT scan. This is called a CT guided needle biopsy and it is often done by an x-ray specialist known as an interventional radiologist.
    2. In a core needle biopsy, the doctor uses a larger needle to remove a small cylinder of tissue (about 1/16 inch in diameter and 1/2 inch long). Many experts feel that a core needle biopsy is better than FNA to diagnose a primary bone cancer.
• Surgical biopsy. In this procedure, a surgeon needs to cut through the skin to reach the tumor to remove a small piece of tissue. This is also called an incisional biopsy. If the entire tumor is removed (not just a small piece), it’s called an excisional biopsy. These biopsies are often done with the patient under general anesthesia (drugs are used to put you into a deep asleep). They can also be done using a nerve block, which numbs a large area. If this type of biopsy is needed, it’s important that the surgeon who will later remove the cancer also be the one to do the biopsy.

Determining the type of biopsy needed and the specifics of how it should be performed requires careful planning by the medical team. Doctors need to perform the biopsy in a way that won’t interfere with future surgery to remove the cancer. For this reason, ask your doctor for a referral to a team of experts with extensive experience in treating osteosarcoma before the biopsy.

Osteosarcoma staging

After someone is diagnosed with osteosarcoma, doctors will try to figure out if it has spread, and if so, how far. This process is called staging. The stage of a cancer describes how much cancer is in the body. It helps determine how serious the cancer is and how best to treat it. Doctors also use a cancer’s stage when talking about survival statistics.

The stage of an osteosarcoma is based on the results of physical exams, imaging tests, and any biopsies that have been done.

A staging system is a standard way for the cancer care team to sum up the extent of the cancer. When trying to figure out the best course of treatment, doctors often use a simple system that divides osteosarcomas into 2 groups: localized and metastatic. Doctors can also use more formal staging systems to describe the extent of an osteosarcoma in more detail.

Two popular systems exist for the staging of bone tumors. The Musculoskeletal Tumor Society’s Enneking system is used primarily by orthopedic surgeons because it takes into account the anatomic location of the tumor: intracompartmental (completely contained within the bone) versus extracompartmental (extension outside of the bone). The alternative system described by the American Joint Committee on Cancer does not take anatomic location into account. However, it does account for the size of the tumor, which research has recognized as having significant prognostic value for predicting response to treatment and overall survival. Specifically, larger lesions have a propensity to metastasize, so these patients may benefit from chemotherapeutic intervention, making the American Joint Committee on Cancer (AJCC) system more popular with oncologists ⁸⁾.

Osteosarcoma staging can be confusing. If you have any questions about the stage of the cancer, ask someone on your cancer care team to explain it to you in a way you understand.

Localized osteosarcoma

A localized osteosarcoma is seen only in the bone it started in and possibly the tissues next to the bone, such as muscle, tendon, or fat.

About 4 out of 5 osteosarcomas appear to be localized when they are first found. But even when imaging tests don’t show that the cancer has spread to distant areas, most patients are likely to have very small areas of cancer spread that can’t be detected with tests. This is why chemotherapy is an important part of treatment for most osteosarcomas. If it isn’t given, the cancer is more likely to come back after surgery.

Doctors further divide localized osteosarcomas into 2 groups:

• Resectable cancers are those in which all of the visible tumor can be removed by surgery.
• Non-resectable (or unresectable) osteosarcomas can’t be removed completely by surgery.

Metastatic osteosarcoma

A metastatic osteosarcoma has clearly spread to other parts of the body. Most often it spreads to the lungs, but it can also spread to other bones, the brain, or other organs.

About 1 out of 5 osteosarcomas has spread at the time of diagnosis. These cancers are harder to treat, but some can be cured if the metastases can be removed by surgery. The cure rate for these cancers improves markedly if chemotherapy is also given.

Musculoskeletal Tumor Society Staging System

A system commonly used to stage osteosarcoma is the Musculoskeletal Tumor Society staging system, also known as the Enneking system. It is based on 3 key pieces of information:

1. The grade (G) of the tumor, which is a measure of how likely it is to grow and spread, based on how it looks under the microscope. Tumors are either low grade (G1) or high grade (G2). Low-grade tumor cells look more like normal cells and are less likely to grow and spread quickly, while high-grade tumor cells look more abnormal.
2. The extent of the primary tumor (T), which is classified as either intracompartmental (T1), meaning it has basically remained within the bone, or extracompartmental (T2), meaning it has extended beyond the bone into other nearby structures.
3. If the tumor has metastasized (M), which means it has spread to nearby lymph nodes (bean-sized collections of immune system cells) or other organs. Tumors that have not spread to the lymph nodes or other organs are considered M0, while those that have spread are M1.

These factors are combined to give an overall stage, using Roman numerals from I to III. Stages I and II are further divided into A for intracompartmental tumors or B for extracompartmental tumors.

Musculoskeletal Tumor Society Enneking system for staging of malignant musculoskeletal tumors ⁹⁾

• Stage IA: Low grade, Intracompartmental tumor location, no metastasis
• Stage IB: Low grade, Extracompartmental tumor location, no metastasis
• Stage IIA: High grade, Intracompartmental tumor location, no metastasis
• Stage IIB: High grade, Extracompartmental tumor location, no metastasis
• Stage III: Any grade, Any location, Metastasis present

Table 1. Musculoskeletal Tumor Society Enneking system for staging of malignant musculoskeletal tumors

Stage	Grade	Tumor	Metastasis
IA	G1	T1	M0
IB	G1	T2	M0
IIA	G2	T1	M0
IIB	G2	T2	M0
III	G1 or G2	T1 orT2	M1

[Source ¹⁰⁾ ]

In summary:

• Low-grade, localized tumors are stage I.
• High-grade, localized tumors are stage II.
• Metastatic tumors (regardless of grade) are stage III.

The TNM staging system

Another system sometimes used to stage bone cancers (including osteosarcomas) is the American Joint Commission on Cancer (AJCC) TNM system ¹¹⁾. This system is based on 4 key pieces of information:

• T describes the size of the main (primary) tumor and if it appears in different areas of the bone.
• N describes the extent of spread to nearby (regional) lymph nodes. Bone tumors rarely spread to the lymph nodes.
• M indicates if the cancer has metastasized (spread) to other organs of the body. (The most common sites of spread are to the lungs or other bones.)
• G stands for the grade of the tumor, which describes how the cells look under a microscope. Low-grade tumor cells look more like normal cells and are less likely to grow and spread quickly, while high-grade tumor cells look more abnormal.

Numbers after T, N, M, and G provide more details about each of these factors.

The scale used for grading bone cancer is from 1 to 3. Low-grade cancers (G1) tend to grow and spread more slowly than high-grade (G2 or G3) cancers.

• Grade 1 (G1) means the cancer looks much like normal bone tissue.
• Grade 3 (G3) means the cancer looks very abnormal.
• Grade 2 (G2) falls somewhere in between.

Once the T, N, and M categories and the grade of the bone cancer have been determined, the information is combined into an overall stage. These stages (which are different from those of the Musculoskeletal Tumor Society staging system) are described by Roman numerals from I to IV (1 to 4), and are sometimes divided further.

The staging system described below is the most recent American Joint Committee on Cancer (AJCC) system effective January 2018 and applies to bone cancers of the appendicular skeleton (such as bones in the arms and legs), trunk, skull, and facial bones. Bone cancers of the pelvis and spine use different T categories and it is best to speak with your doctor about your stage for these specific cancers.

Numbers or letters after T, N, and M provide more details about each of these factors. Higher numbers mean the cancer is more advanced. Once a person’s T, N, and M categories have been determined, this information is combined in a process called stage grouping to assign an overall stage.

Cancer staging can be complex, so ask your doctor to explain it to you in a way you understand.

American Joint Committee on Cancer (AJCC) system for staging of primary bone sarcomas (8th edition) ¹²⁾:

• Stage IA: Low grade, less than 8 cm tumor size, No spread to regional lymph nodes, No distant metastasis
• Stage IB: Low grade, greater than 8 cm tumor size or skip lesions, No spread to regional lymph nodes, No distant metastasis
• Stage IIA: High grade, greater than 8 cm tumor size, No spread to regional lymph nodes, No distant metastasis
• Stage IIB: High grade, less than 8 cm tumor size, No spread to regional lymph nodes, No distant metastasis
• Stage III: High grade, Discontinuous tumor involvement/”skip” lesions, No regional lymph nodes, No distant metastasis
• Stage IVA: Any grade, Any size, No regional lymph node spread, Lung metastasis
• Stage IVB: Any grade, Any size, Regional lymph node spread, Lung or extrapulmonary metastasis

The staging system in the table below uses the pathologic stage (also called the surgical stage). It is determined by examining tissue removed during an operation. Sometimes, if surgery is not possible right away or at all, the cancer will be given a clinical stage instead. This is based on the results of a physical exam, biopsy, and imaging tests. The clinical stage will be used to help plan treatment. Sometimes, though, the cancer has spread further than the clinical stage estimates, and may not predict the patient’s outlook as accurately as a pathologic stage.

Table 2. American Joint Committee on Cancer bone cancer staging system

AJCC stage	Stage grouping	Stage description*
IA	T1 N0 M0 G1 or GX	The cancer is 8 centimeters (cm) across (about 3 inches) or smaller(T1). It has not spread to nearby lymph nodes (N0) or to distant sites (M0). The cancer is low grade (G1) or the grade cannot be determined (GX).
IB	T2 N0 M0 G1 or GX	The cancer is larger than 8 cm (3 inches) across (T2). It has not spread to nearby lymph nodes (N0) or to distant sites (M0). The cancer is low grade (G1) or the grade cannot be determined (GX).
	OR
	T3 N0 M0 G1 or GX	The cancer is in more than one place on the same bone (T3). It has not spread to nearby lymph nodes (N0) or to distant sites (M0). The cancer is low grade (G1) or the grade cannot be determined (GX).
IIA	T1 N0 M0 G2 or G3	The cancer is 8 centimeters (cm) across (about 3 inches) or less (T1). It has not spread to nearby lymph nodes (N0) or to distant sites (M0). The cancer is high grade (G2 or G3).
IIB	T2 N0 M0 G2 or G3	The cancer is larger than 8 cm (3 inches) across (T2). It has not spread to nearby lymph nodes (N0) or to distant sites (M0). The cancer is high grade (G2 or G3).
III	T3 N0 M0 G2 or G3	The cancer is in more than one place on the same bone (T3). It has not spread to nearby lymph nodes (N0) or to distant sites (M0). The cancer is high grade (G2 or G3).
IVA	Any T N0 M1a Any G	The cancer can be any size and may be in more than one place in the bone (Any T) AND has not spread to nearby lymph nodes (N0). It has spread only to the lungs (M1a). The cancer can be any grade (Any G).
IVB	Any T N1 Any M Any G	The cancer can be any size and may be in more than one place in the bone (Any T) AND it has spread to nearby lymph nodes (N1). It may or may not have has spread to distant organs like the lungs or other bones (Any M). The cancer can be any grade (Any G).
	OR
	Any T Any N M1b Any G	The cancer can be any size and may be in more than one place in the bone (Any T) and it might or might not have spread to nearby lymph nodes (Any N). It has spread to distant sites like other bones, the liver or brain (M1b). The cancer can be any grade (Any G).

Footnote: * The following additional categories are not listed on the table above:

• TX: Main tumor cannot be assessed due to lack of information.
• T0: No evidence of a primary tumor.
• NX: Regional lymph nodes cannot be assessed due to lack of information.

Osteosarcoma treatment

Osteosarcoma treatment typically involves surgery and chemotherapy. Radiation therapy might be an option in certain situations.

Successful treatment generally requires the combination of effective systemic chemotherapy and complete resection of all clinically detectable disease. Protective weight bearing is recommended for patients with tumors of weight-bearing bones to prevent pathological fractures that could preclude limb-preserving surgery.

It is imperative that patients with proven or suspected osteosarcoma have an initial evaluation by an orthopedic oncologist familiar with the surgical management of this disease. This evaluation, which includes imaging studies, should be done before the initial biopsy, because an inappropriately performed biopsy may jeopardize a limb-sparing procedure.

Randomized clinical trials have established that both neoadjuvant and adjuvant chemotherapy are effective in preventing relapse in patients with clinically nonmetastatic tumors ¹³⁾. The Pediatric Oncology Group conducted a study in which patients were randomly assigned to either immediate amputation or amputation after neoadjuvant therapy. A large percentage of patients declined to be assigned randomly, and the study was terminated without approaching the stated accrual goals. In the small number of patients treated, there was no difference in outcome for those who received preoperative versus postoperative chemotherapy ¹⁴⁾.

The treatment of osteosarcoma also depends on the histologic grade, as follows:

• High-grade osteosarcoma. High-grade osteosarcoma requires surgery and systemic chemotherapy whether it arises in the conventional central location or on a bone surface.
• Low-grade osteosarcoma. Low-grade osteosarcoma can be treated successfully by wide surgical resection alone, regardless of site of origin.
• Intermediate-grade osteosarcoma. Pathologists sometimes characterize tumors as intermediate-grade osteosarcoma. It is difficult to make treatment decisions for intermediate-grade tumors. When a tumor biopsy suggests an intermediate-grade osteosarcoma, an option is to proceed with wide resection. The availability of the entire tumor allows the pathologist to examine more tissue and evaluate soft tissue and lymphovascular invasion, which can often clarify the nature of the lesion.

If the lesion proves to have high-grade elements, systemic chemotherapy is indicated, just as it would be for any high-grade osteosarcoma. The Pediatric Oncology Group performed a study in which high-grade osteosarcoma patients were randomly assigned to either immediate definitive surgery followed by adjuvant chemotherapy or to an initial period of chemotherapy followed by definitive surgery ¹⁵⁾. The outcome was the same for both groups. Although the strategy of initial chemotherapy followed by definitive surgery has become an almost universally applied approach for osteosarcoma, this study suggests that there is no increased risk of treatment failure if definitive surgery is done before chemotherapy begins; this can help to clarify equivocal diagnoses of intermediate-grade osteosarcoma.

Recognition of intraosseous well-differentiated osteosarcoma and parosteal osteosarcoma is important because these tumor types are associated with the most favorable prognosis and can be treated successfully with wide excision of the primary tumor alone ¹⁶⁾. Periosteal osteosarcoma has a generally good prognosis ¹⁷⁾ and treatment is guided by histologic grade ¹⁸⁾.

Table 3 describes the treatment options for localized, metastatic, and recurrent osteosarcoma and malignant fibrous histiocytoma of bone.

Table 3. Treatment Options for Osteosarcoma and Malignant Fibrous Histiocytoma (MFH) of Bone

Treatment Group		Treatment Options
Localized osteosarcoma and malignant fibrous histiocytoma of bone		Surgical removal of primary tumor.
		Chemotherapy.
		Radiation therapy, if surgery is not feasible or surgical margins are inadequate.
Osteosarcoma and malignant fibrous histiocytoma of bone with metastatic disease at diagnosis:		Chemotherapy.
	Lung-only metastases	Preoperative chemotherapy followed by surgery to remove the tumor.
	Bone-only metastases or bone with lung metastases	Preoperative chemotherapy followed by surgery to remove the primary tumor and all metastatic disease (usually lungs) followed by postoperative combination chemotherapy.
		Surgery to remove the primary tumor followed by chemotherapy and then surgical resection of metastatic disease (usually lungs).
Recurrent osteosarcoma and malignant fibrous histiocytoma of bone:		Surgery to remove all sites of metastatic disease.
		Chemotherapy.
		Targeted therapy.
	Lung-only recurrence	Surgery to remove the tumor.
	Recurrence with bone-only metastases	Surgery to remove the tumor.
		153Sm-EDTMP with or without stem cell support.
	Second recurrence of osteosarcoma	Surgery to remove the tumor.

Abbreviation: 153Sm-EDTMP = samarium Sm 153-ethylenediamine tetramethylene phosphonic acid.

[Source ¹⁹⁾ ]

Surgery

The goal of surgery is to remove all of the cancer cells. But planning the operation also takes into consideration how it will affect your ability to go about your daily life. The extent of surgery for osteosarcoma depends on several factors, such as the size of the tumor and its location.

Operations used to treat osteosarcoma include:

• Surgery to remove the cancer only (limb-sparing surgery). Most osteosarcoma operations can be done in a way that removes all of the cancer and spares the limb so that function can be maintained. Whether this procedure is an option depends, in part, on the extent of the cancer and how much muscle and tissue need to be removed. If a section of bone is removed, the surgeon will reconstruct the bone. The method of reconstruction depends on your particular situation, but options include metal prosthetics or bone grafts.
• Surgery to remove the affected limb (amputation). With advancements in limb-sparing surgery, the need for amputation — removing a limb or part of a limb — has greatly reduced over the years. If amputation is necessary, advances in prosthetic joints can significantly improve outcomes and function.
• Surgery to remove the lower portion of the leg (rotationplasty). In this surgery, sometimes used for children who are still growing, the surgeon removes the cancer and surrounding area, including the knee joint. The foot and ankle are then rotated, and the ankle functions as a knee. A prosthesis is used for the lower leg and foot. Results typically enable the person to function very well in physical activities, sports and daily living.

In general, more than 80% of patients with extremity osteosarcoma can be treated by a limb-sparing procedure and do not require amputation ²⁰⁾. Limb-sparing procedures are planned only when the preoperative staging indicates that it would be possible to achieve wide surgical margins. In one study, patients undergoing limb-salvage procedures who had poor histologic response and close surgical margins had a high rate of local recurrence ²¹⁾.

Reconstruction after limb-sparing surgery can be accomplished with many options, including metallic endoprosthesis, allograft, vascularized autologous bone graft, and rotationplasty. An additional option, osteogenesis distraction bone transport, is available for patients whose tumors do not involve the epiphysis of long bones ²²⁾. This procedure results in a stable reconstruction that functionally restores the normal limb.

The choice of optimal surgical reconstruction involves many factors, including the following ²³⁾:

• Site and size of the primary tumor.
• Ability to preserve the neurovascular supply of the distal extremity.
• Age of the patient and potential for additional growth.
• Needs and desires of the patient and family for specific functions such as sports participation.

If a complicated reconstruction delays or prohibits the resumption of systemic chemotherapy, limb preservation may endanger the chance for cure. Retrospective analyses have shown that delay (≥21 days) in resumption of chemotherapy after definitive surgery is associated with increased risk of tumor recurrence and death.

For some patients, amputation remains the optimal choice for management of the primary tumor. A pathologic fracture noted at diagnosis or during preoperative chemotherapy does not preclude limb-salvage surgery if wide surgical margins can be achieved ²⁴⁾. If the pathologic examination of the surgical specimen shows inadequate margins, an immediate amputation should be considered, especially if the histologic necrosis after preoperative chemotherapy was poor ²⁵⁾.

The German Cooperative Osteosarcoma Study performed a retrospective analysis of 1,802 patients with localized and metastatic osteosarcoma who underwent surgical resection of all clinically detectable disease ²⁶⁾. Local recurrence (n = 76) was associated with a high risk of death from osteosarcoma. Factors associated with an increased risk of local recurrence included nonparticipation in a clinical trial, pelvic primary site, limb-preserving surgery, soft tissue infiltration beyond the periosteum, poor pathologic response to initial chemotherapy, failure to complete planned chemotherapy, and performing the biopsy at an institution different from where the definitive surgery is being performed.

Patients who undergo amputation have lower local recurrence rates than do patients who undergo limb-salvage procedures ²⁷⁾. There is no difference in overall survival between patients initially treated with amputation and those treated with a limb-sparing procedure. Patients with tumors of the femur have a higher local recurrence rate than do patients with primary tumors of the tibia or fibula. Rotationplasty and other limb-salvage procedures have been evaluated for both their functional outcome and their effect on survival. While limb-sparing resection is the current practice for local control at most pediatric institutions, there are few data to indicate that salvage of the lower limb is substantially superior to amputation with regard to patient quality of life ²⁸⁾.

Chemotherapy

Chemotherapy uses drugs to kill cancer cells. Chemotherapy treatment usually combines two or more drugs that can be administered as an infusion into a vein (IV), in pill form, or through both methods. For osteosarcoma, chemotherapy is often recommended before surgery (neoadjuvant therapy). Doctors monitor how the cancer cells respond to the chemotherapy in order to plan further treatments.

If the osteosarcoma shrinks in response to the chemotherapy, it may make limb-sparing surgery possible.

If the osteosarcoma doesn’t respond to treatment, it may indicate the cancer is very aggressive. Doctors may recommend a different combination of chemotherapy drugs or suggest a more aggressive operation to ensure all the cancer is removed.

Chemotherapy can also be used after surgery to kill any cancer cells that might remain.

If osteosarcoma returns after surgery or spreads to other areas of the body, chemotherapy might be recommended to try to slow the growth of the disease.

Preoperative chemotherapy

Almost all patients receive intravenous preoperative chemotherapy as initial treatment. However, a standard chemotherapy regimen has not been determined. Current chemotherapy protocols include combinations of the following agents: high-dose methotrexate, doxorubicin, cyclophosphamide, cisplatin, ifosfamide, etoposide, and carboplatin ²⁹⁾.

Preoperative chemotherapy evidence:

1. A meta-analysis of protocols for the treatment of osteosarcoma concluded that regimens containing three active chemotherapy agents were superior to regimens containing two active agents ³⁰⁾.
   • The meta-analysis also concluded that regimens with four active agents were not superior to regimens with three active agents.
   • The meta-analysis suggested that three-drug regimens that did not include high-dose methotrexate were inferior to three-drug regimens that did include high-dose methotrexate.
2. An Italian study used regimens containing fewer courses of high-dose methotrexate and observed a lower probability for event-free survival (event-free survival) than did earlier studies that used regimens containing more courses of high-dose methotrexate ³¹⁾.
3. The Children’s Oncology Group (COG) performed a prospective randomized trial in newly diagnosed children and young adults with localized osteosarcoma. All patients received cisplatin, doxorubicin, and high-dose methotrexate. One-half of the patients were randomly assigned to receive ifosfamide. In a second randomization, one-half of the patients were assigned to receive the biological compound muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) beginning after definitive surgical resection ³²⁾.
   • The addition of ifosfamide did not improve outcome.
   • The addition of L-MTP-PE produced improvement in event-free survival, which did not meet the conventional test for statistical significance, and a significant improvement in overall survival (78% vs. 70%).
   • There has been speculation regarding the potential contribution of postrelapse treatment, although there were no differences in the postrelapse surgical approaches in the relapsed patients. The appropriate role of L-MTP-PE in the treatment of osteosarcoma remains under discussion ³³⁾.
4. The Children’s Oncology Group performed a series of pilot studies in patients with newly diagnosed localized osteosarcoma ³⁴⁾.
   1. In pilot one, patients with lower degrees of necrosis after three-drug initial therapy received subsequent therapy with a higher cumulative dose of doxorubicin of 600 mg/m2.
   2. In pilot two, all patients received four-drug initial chemotherapy with cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide. Patients with lower degrees of necrosis received subsequent chemotherapy with a higher cumulative dose of doxorubicin of 600 mg/m2.
   3. In pilot three, all patients received the same four-drug initial chemotherapy as pilot two. Patients with lower degrees of necrosis received higher doses of ifosfamide with the addition of etoposide in subsequent therapy.

1. • Outcomes for all three pilot studies were similar to each other and to historical controls.
   • All patients received dexrazoxane before each dose of doxorubicin. The addition of dexrazoxane did not appear to decrease the rate of good necrosis after initial therapy or event-free survival.
   • Left ventricular fractional shortening, as measured by echocardiography, was minimally affected at 78 weeks from study entry.
   • There was no evidence for an increased risk of secondary leukemia.

Postoperative chemotherapy

Historically, the extent of tumor necrosis was used in some clinical trials to determine postoperative chemotherapy. In general, if tumor necrosis exceeded 90%, the preoperative chemotherapy regimen was continued. If tumor necrosis was less than 90%, some groups incorporated drugs not previously utilized in the preoperative therapy.

Patients with less necrosis after initial chemotherapy have a prognosis that is inferior to the prognosis for patients with more necrosis. The prognosis is still substantially better than the prognosis for patients treated with surgery alone and no adjuvant chemotherapy. Based on the following evidence, it is inappropriate to conclude that patients with less necrosis have not responded to chemotherapy and that adjuvant chemotherapy should be withheld for these patients. Chemotherapy after definitive surgery should include the agents used in the initial phase of treatment unless there is clear and unequivocal progressive disease during the initial phase of therapy.

Postoperative chemotherapy evidence:

1. In an early experience, the German cooperative osteosarcoma group performed a trial in which the chemotherapy regimen for patients with poor necrosis was changed after initial treatment ³⁵⁾. The agents used before surgery were discontinued and other agents were substituted. The results were substantially poorer for these patients than for patients who continued to receive the same agents.
2. A limited-institution pilot trial tested the strategy of discontinuing the agents used in the initial phase of therapy for patients with poorer necrosis; postoperative therapy consisted of melphalan with autologous stem cell reconstitution ³⁶⁾. Five-year event-free survival for this group was 28%, which was lower than was observed in many large series in which agents were continued despite a lesser degree of necrosis.
3. Addition of cisplatin. The approach to incorporate drugs not previously used for preoperative therapy was based on early reports from Memorial Sloan Kettering Cancer Center (MSKCC) that suggested that adding cisplatin to postoperative chemotherapy improved the outcome for patients with less than 90% tumor necrosis ³⁷⁾. With longer follow-up, the outcome for patients with less than 90% tumor necrosis treated at Memorial Sloan Kettering Cancer Center was the same whether they did or did not receive cisplatin in the postoperative phase of treatment ³⁸⁾. Subsequent trials performed by other groups failed to demonstrate improved event-free survival when drugs not included in the preoperative regimen were added to postoperative therapy ³⁹⁾.
4. Addition of interferon or high-dose therapy.
   • The international European and American Osteosarcoma Study Group consortium (EURAMOS) was formed to conduct a large prospective, randomized trial to help determine whether modifying the chemotherapy regimen on the basis of the degree of necrosis would improve event-free survival. All patients received initial therapy with cisplatin, doxorubicin, and high-dose methotrexate. Patients with more than 90% necrosis were randomly assigned to continue the same chemotherapy after surgery or to receive the same chemotherapy with the addition of interferon. The addition of interferon did not improve the probability of event-free survival ⁴⁰⁾.
   • In the same EURAMOS trial, patients with less than 90% necrosis were randomly assigned to continue the same chemotherapy or to receive the same chemotherapy with the addition of high-dose ifosfamide and etoposide (MAPIE). With a median follow-up of over 61 months, the event-free survival did not differ between the two groups. The intensification of treatment in the MAPIE group resulted in greater toxicity than did the treatment in the standard methotrexate arm ⁴¹⁾.

Other chemotherapy approaches not considered effective

The Italian Sarcoma Group and the Scandinavian Sarcoma Group performed a clinical trial in patients with osteosarcoma who presented with clinically detectable metastatic disease ⁴²⁾. Consolidation with high-dose etoposide and carboplatin followed by autologous stem cell reconstitution did not appear to improve outcome and the investigators do not recommend this strategy for the treatment of osteosarcoma.

Laboratory studies using cell lines and xenografts suggested that bisphosphonates had activity against osteosarcoma ⁴³⁾. A single-institution clinical trial demonstrated that pamidronate could safely be administered contemporaneously with multiagent chemotherapy to patients with newly diagnosed osteosarcoma ⁴⁴⁾. The French pediatric and adult sarcoma cooperative groups performed a prospective trial for the treatment of osteosarcoma ⁴⁵⁾. All patients received multiagent chemotherapy, and patients were randomly assigned to receive or not to receive zoledronate. The addition of zoledronate did not improve event-free survival.

Radiation therapy

Radiation therapy uses high-energy beams, such as X-rays and protons, to kill cancer cells. Radiation might be an option in certain situations, such as when surgery isn’t possible or if surgeons can’t remove all of the cancer during an operation ⁴⁶⁾.

During radiation therapy, the beams of energy are delivered from a machine that moves around you as you lie on a table. The beams are carefully directed to the area of the osteosarcoma in order to reduce the risk of damage to surrounding healthy cells.

Radiation therapy should be considered in patients with osteosarcoma of the head and neck who have positive or uncertain resection margins ⁴⁷⁾. While it is accepted that the standard approach is primary surgical resection, a retrospective analysis of a small group of highly selective patients reported long-term event-free survival with external-beam radiation therapy for local control in some patients ⁴⁸⁾.

Investigators from a single institution reported on 28 children and young adults with osteosarcoma who were treated with radiation therapy for local control ⁴⁹⁾. Sixteen patients received radiation therapy during the primary treatment course, and 12 patients received radiation therapy as part of retrieval therapy after recurrence. For patients who received radiation therapy during primary treatment, the cumulative incidence of local failure at 5 years was 25%; for patients with recurrent disease, the cumulative incidence of local failure at 5 years was 44%. Local tumor progression was observed in 3 of 13 patients (23%) who were treated with adjuvant radiation therapy after resection, while three of six patients (50%) who received definitive radiation therapy as a sole modality of local control experienced local progression.

Treatment of osteosarcoma metastasis

Approximately 20% to 25% of patients with osteosarcoma present with clinically detectable metastatic disease. For patients with metastatic disease at initial presentation, roughly 20% will remain continuously free of disease, and roughly 30% will survive 5 years from diagnosis ⁵⁰⁾.

The lung is the most common site of initial metastatic disease ⁵¹⁾. Patients with metastases limited to the lungs have a better outcome than do patients with metastases to other sites or to the lungs combined with other sites ⁵²⁾.

Treatment options for patients with osteosarcoma or malignant fibrous histiocytoma of bone with metastatic disease at diagnosis include the following:

1. Chemotherapy. The chemotherapeutic agents used include high-dose methotrexate, doxorubicin, cisplatin, high-dose ifosfamide, etoposide, and, in some reports, carboplatin or cyclophosphamide.
   • Chemotherapy evidence:
     • High-dose ifosfamide (17.5 g per course) in combination with etoposide produced a complete response (10%) or partial response (49%) in patients with newly diagnosed metastatic osteosarcoma ⁵³⁾.
     • However, similar to localized disease, there is no evidence that the addition of ifosfamide or etoposide contributes to improved event-free survival or overall survival in patients with metastatic disease, and the addition of these agents is up to physician discretion in this setting.
     • The addition of either muramyl tripeptide or ifosfamide to a standard chemotherapy regimen that included cisplatin, high-dose methotrexate, and doxorubicin was evaluated using a factorial design in patients with metastatic osteosarcoma (n = 91) ⁵⁴⁾. There was a nominal advantage for the addition of muramyl tripeptide (but not for ifosfamide) in terms of event-free survival and overall survival, but criteria for statistical significance were not met.

Treatment options for patients with metastatic lung lesions

Treatment options for patients with metastatic lung lesions include the following:

Preoperative chemotherapy followed by surgery to remove the tumor. Patients with metastatic lung lesions as the sole site of metastatic disease should have the lung lesions resected if possible. Generally, this is performed after administration of preoperative chemotherapy. In approximately 10% of patients, all lung lesions disappear after preoperative chemotherapy ⁵⁵⁾. Complete resection of pulmonary metastatic disease can be achieved in a high percentage of patients with residual lung nodules after preoperative chemotherapy. The cure rate is essentially zero without complete resection of residual pulmonary metastatic lesions.

For patients who present with primary osteosarcoma and metastases limited to the lungs and who achieve complete surgical remission, 5-year event-free survival is approximately 20% to 25%. Multiple metastatic nodules confer a worse prognosis than do one or two nodules, and bilateral lung involvement is worse than unilateral ⁵⁶⁾. Patients with peripheral lung lesions may have a better prognosis than patients with central lesions ⁵⁷⁾. Patients with fewer than three nodules confined to one lung may achieve a 5-year event-free survival of approximately 40% to 50% ⁵⁸⁾.

Treatment options for bone-only metastases or bone with lung metastases

The second most common site of metastasis is another bone that is distant from the primary tumor. Patients with metastasis to other bones distant from the primary tumor experience roughly 10% event-free survival and overall survival ⁵⁹⁾. In the Italian experience, of the patients who presented with primary extremity tumors and synchronous metastasis to other bones, only 3 of 46 patients remained continuously disease-free 5 years later ⁶⁰⁾. Patients who have transarticular skip lesions have a poor prognosis ⁶¹⁾.

Multifocal osteosarcoma is different from osteosarcoma that presents with a clearly delineated primary lesion and limited bone metastasis. Multifocal osteosarcoma classically presents with symmetrical, metaphyseal lesions, and it may be difficult to determine the primary lesion. Patients with multifocal bone disease at presentation have an extremely poor prognosis. No patient with synchronous multifocal osteosarcoma has ever been reported to be cured, but systemic chemotherapy and aggressive surgical resection may achieve significant prolongation of life ⁶²⁾.

Treatment options for patients with bone-only or bone with lung metastases include the following:

1. Preoperative chemotherapy followed by surgery to remove the primary tumor and all metastatic disease (usually lungs) followed by postoperative combination chemotherapy.
2. Surgery to remove the primary tumor followed by chemotherapy and then surgical resection of metastatic disease (usually lungs).

When the usual treatment course of preoperative chemotherapy followed by surgical ablation of the primary tumor and resection of all overt metastatic disease (usually lungs) followed by postoperative combination chemotherapy cannot be used, an alternative treatment approach may be used. This alternative treatment approach begins with surgery for the primary tumor, followed by chemotherapy, and then surgical resection of metastatic disease (usually lungs). This alternative approach may be appropriate in patients with intractable pain, pathologic fracture, or uncontrolled infection of the tumor when initiation of chemotherapy could create risk of sepsis.

Clinical trials

Clinical trials are studies to investigate new ways of treating cancer. Ask your doctor or your child’s doctor about whether you may be eligible to join a trial.

Osteosarcoma prognosis

In general, prognostic factors for osteosarcoma have not been helpful in identifying patients who might benefit from treatment intensification or who might require less therapy while maintaining an excellent outcome.

Patients with localized osteosarcoma undergoing surgery and chemotherapy have a 5-year overall survival of 62% to 65% ⁶³⁾. Based on data from the Surveillance, Epidemiology, and End Results (SEER) 2010–2016, the 5-Year Relative Survival of patients diagnosed with bone cancer is 66 percent ⁶⁴⁾. Because survival statistics are based on large groups of people, they cannot be used to predict exactly what will happen to an individual patient. No two patients are entirely alike, and treatment and responses to treatment can vary greatly. Complete surgical resection is crucial for patients with localized osteosarcoma; however, at least 80% of patients treated with surgery alone will develop metastatic disease ⁶⁵⁾. Randomized clinical trials have established that adjuvant chemotherapy is effective in preventing relapse or recurrence in patients with localized resectable primary tumors ⁶⁶⁾.

Pretreatment factors

Pretreatment factors that influence outcome include the following ⁶⁷⁾:

• Primary tumor site and initial treatment.
• Size of the primary tumor.
• Presence of clinically detectable metastatic disease.

After administration of preoperative chemotherapy, factors that influence outcome include the following:

• Surgical resectability of primary tumor.
• Degree of tumor necrosis.

Primary tumor site and initial treatment

The site of the primary tumor is a significant prognostic factor for patients with localized disease. Among extremity tumors, distal sites have a more favorable prognosis than do proximal sites. Patients with tumors located in the axial skeleton tend to fare worse compared to those diagnosed in the appendicular skeleton. A difference of up to 10 years of survival exists between groups. Axial skeleton primary tumors are associated with the greatest risk of progression and death, primarily related to the inability to achieve a complete surgical resection. Furthermore, patients with femoral tumors often do much worse than patients with lesions located in the distal tibia ⁶⁸⁾.

Prognostic considerations for the axial skeleton and extraskeletal sites are as follows:

• Pelvis: Pelvic osteosarcomas make up 7% to 9% of all osteosarcomas; survival rates for patients with pelvic primary tumors are 20% to 47% ⁶⁹⁾. Complete surgical resection is associated with positive outcome for osteosarcoma of the pelvis in some cohorts of patients ⁷⁰⁾.
• Craniofacial/head and neck: In patients with craniofacial osteosarcoma, those with primary sites in the mandible and maxilla have a better prognosis than do patients with other primary sites in the head and neck ⁷¹⁾. For patients with osteosarcoma of craniofacial bones, complete resection of the primary tumor with negative margins is essential for cure ⁷²⁾. When treated with surgery alone, patients who have osteosarcoma of the head and neck have a better prognosis than those who have appendicular lesions. Despite a relatively high rate of inferior necrosis after neoadjuvant chemotherapy, fewer patients with craniofacial primaries develop systemic metastases than do patients with osteosarcoma originating in the extremities ⁷³⁾. A meta-analysis concluded that systemic adjuvant chemotherapy improves the prognosis for patients with osteosarcoma of the head and neck, while small series have not shown a benefit for using adjuvant chemotherapy in these patients ⁷⁴⁾. Another large meta-analysis detected no benefit of chemotherapy for patients with osteosarcoma of the head and neck, but suggested that the incorporation of chemotherapy into treatment of patients with high-grade tumors may improve survival ⁷⁵⁾. A retrospective analysis identified a trend toward better survival in patients with high-grade osteosarcoma of the mandible and maxilla who received adjuvant chemotherapy ⁷⁶⁾. Radiation therapy was found to improve local control, disease-specific survival, and overall survival in a retrospective study of osteosarcoma of the craniofacial bones that had positive or uncertain margins after surgical resection ⁷⁷⁾. Radiation-associated craniofacial osteosarcomas are generally high-grade lesions, usually fibroblastic, and tend to recur locally with a high rate of metastasis ⁷⁸⁾.
• Extraskeletal: Osteosarcoma in extraskeletal sites is rare in children and young adults. With current combined-modality therapy, the outcome of patients with extraskeletal osteosarcoma appears to be similar to that of patients with primary tumors of bone ⁷⁹⁾.

Size of the primary tumor

In some series, patients with larger or bulky tumors appeared to have a worse prognosis than did patients with smaller tumors ⁸⁰⁾. One study found that the morbidity likelihood is 3.4 times higher in larger masses (over 15 cm). When tumor volume exceeds 200 mL, patients are significantly less likely to have successful limb salvage; they also demonstrate a poorer response to chemotherapy and a greater likelihood of recurrence. Tumor size has been assessed by longest single dimension, cross-sectional area, or estimate of tumor volume; all assessments have correlated with outcome. Unsurprisingly, the chance of death is significantly higher in patients with evidence of metastasis on presentation ⁸¹⁾.

Serum lactate dehydrogenase (LDH), which also correlates with outcome, is a likely surrogate for tumor volume.

Presence of clinically detectable metastatic disease

Patients with localized disease have a much better prognosis than do patients with overt metastatic disease. As many as 20% of patients will have radiographically detectable metastases at diagnosis, with the lung being the most common site ⁸²⁾. The prognosis for patients with metastatic disease appears to be determined largely by site(s) of metastases, number of metastases, and surgical resectability of the metastatic disease ⁸³⁾.

• Site of metastases: Prognosis appears more favorable for patients with fewer pulmonary nodules and for those with unilateral rather than bilateral pulmonary metastases ⁸⁴⁾; not all patients with suspected pulmonary metastases at diagnosis have osteosarcoma confirmed at the time of lung resection. In one large series, approximately 25% of patients had exclusively benign lesions removed at the time of surgery ⁸⁵⁾.
• Number of metastases: Patients with skip metastases (at least two discontinuous lesions in the same bone) have been reported to have inferior prognoses ⁸⁶⁾. However, an analysis of the German Cooperative Osteosarcoma Study experience suggests that skip lesions in the same bone do not confer an inferior prognosis if they are included in planned surgical resection. Skip metastasis in a bone other than the primary bone should be considered systemic metastasis ⁸⁷⁾. Historically, metastasis across a joint was referred to as a skip lesion. Skip lesions across a joint might be considered hematogenous spread and have a worse prognosis ⁸⁸⁾. Patients with multifocal osteosarcoma (defined as multiple bone lesions without a clear primary tumor) have an extremely poor prognosis ⁸⁹⁾.
• Surgical resectability of metastases: Patients who have complete surgical ablation of the primary and metastatic tumor (when confined to the lung) after chemotherapy may attain long-term survival, although overall event-free survival remains about 20% to 30% for patients with metastatic disease at diagnosis ⁹⁰⁾.

Surgical resectability of primary tumor

Resectability of the tumor is a critical prognostic feature because osteosarcoma is relatively resistant to radiation therapy. Complete resection of the primary tumor and any skip lesions with adequate margins is generally considered essential for cure. A retrospective review of patients with craniofacial osteosarcoma performed by the cooperative German-Austrian-Swiss osteosarcoma study group reported that incomplete surgical resection was associated with inferior survival probability ⁹¹⁾. In a European cooperative study, the size of the margin was not significant. However, prognosis was better when both the biopsy and resection were performed at a center with orthopedic oncology experience ⁹²⁾.

For patients with axial skeletal primaries who either do not undergo surgery for their primary tumor or who undergo surgery that results in positive margins, radiation therapy may improve survival ⁹³⁾.

Degree of tumor necrosis

Most treatment protocols for osteosarcoma use an initial period of systemic chemotherapy before definitive resection of the primary tumor (or resection of sites of metastases). The pathologist assesses necrosis in the resected tumor. Patients with at least 90% necrosis in the primary tumor after induction chemotherapy have a better prognosis than do patients with less necrosis ⁹⁴⁾. Patients with less necrosis (<90%) in the primary tumor after initial chemotherapy have a higher rate of recurrence within the first 2 years than do patients with a more favorable amount of necrosis (≥90%) ⁹⁵⁾.

Less necrosis should not be interpreted to mean that chemotherapy has been ineffective; cure rates for patients with little or no necrosis after induction chemotherapy are much higher than cure rates for patients who receive no chemotherapy. A review of two consecutive prospective trials performed by the Children’s Oncology Group showed that histologic necrosis in the primary tumor after initial chemotherapy was affected by the duration and intensity of the initial period of chemotherapy. More necrosis was associated with better outcome in both trials, but the magnitude of the difference between patients with more and less necrosis was diminished with a longer and more intensive period of initial chemotherapy ⁹⁶⁾.

Additional prognostic factors

Other prognostic factors include the following:

• Subsequent neoplasms. Patients with osteosarcoma as a subsequent neoplasm, including tumors arising in a radiation field, share the same prognosis as patients with de novo osteosarcoma if they are treated aggressively with complete surgical resection and multiagent chemotherapy ⁹⁷⁾. In a German series, approximately 25% of patients with craniofacial osteosarcoma had osteosarcoma as a second tumor, and in 8 of these 13 patients, osteosarcoma arose after treatment for retinoblastoma. In this series, there was no difference in outcome for primary or secondary craniofacial osteosarcoma ⁹⁸⁾.
• Age. Patients in the older adolescent and young adult age group, typically defined as age 18 to 40 years, tend to have a worse prognosis ⁹⁹⁾. Middle-age patients (over 40 years old) have considerably worse survival rates than younger adults even after the exclusion of secondary forms of osteosarcoma. Several studies have determined that patients over the age of 40 were more apt to have involvement of the axial skeleton and metastatic lesions on presentation, which correlate with poorer outcomes (as described below). Older patients (older than 60 years) fare the worst, typically due to refusal of chemotherapy and radical surgery ¹⁰⁰⁾.
• Gender. Men reportedly demonstrate less response to chemotherapy, a higher propensity for recurrence, and a four-fold increase in morbidity. Conversely, female sex correlated with a higher percentage of chemo-related tumor necrosis as well as greater overall survival ¹⁰¹⁾.
• Laboratory abnormalities. Possible prognostic factors identified for patients with conventional localized high-grade osteosarcoma include the LDH level, alkaline phosphatase (ALP) level, and histologic subtype ¹⁰²⁾. Serum alkaline phosphatase, a biomarker associated with bone turnover, has been found in elevated levels in patients with osteosarcoma. However, it is crucial to consider the age of the patient when interpreting ALP levels as intrinsically higher values are typical in younger age groups. Research has documented high levels in association with less disease-free survival. However, serum alkaline phosphatase levels may be normal at the time of diagnosis in nearly half of patients, particularly in cases where a tumor features minimal osteoid deposition ¹⁰³⁾. Lactate dehydrogenase (LDH) is also a useful biomarker. Significantly higher serum LDH levels have been observed in patients with metastasis on initial presentation than patients with local disease alone ¹⁰⁴⁾.
• Body mass index. Higher body mass index at initial presentation is associated with worse overall survival ¹⁰⁵⁾.
• Pathologic fracture. Some studies have suggested that pathologic fracture at diagnosis or during preoperative chemotherapy does not have adverse prognostic significance ¹⁰⁶⁾. Osteosarcoma patients have an increased risk of local recurrence and a decreased rate of survival if a pathological fracture is a feature of the initial presentation. Pathological fractures sustained during preoperative chemotherapy have been found to have a decreased rate of survival compared with patients without therapy-associated pathologic fracture ¹⁰⁷⁾. However, a systematic review of nine cohort studies examined the impact of pathologic fracture on outcome in osteosarcoma. The review included 2,187 patients, and 311 of these patients had pathologic fracture. The presence of pathologic fracture correlated with decreased event-free survival and overall survival ¹⁰⁸⁾. In two additional series, pathologic fracture at diagnosis was associated with a worse overall outcome ¹⁰⁹⁾. A retrospective analysis of 2,847 patients with osteosarcoma from the German cooperative group identified 321 patients (11.3%) with pathological fracture prior to the initiation of systemic therapy ¹¹⁰⁾. In pediatric patients, overall survival and event-free survival did not differ significantly between patients with and without pathologic fracture. In adults, the 5-year overall survival rate in patients with pathologic fracture was 46% versus 69% for patients without pathologic fracture. The 5-year event-free survival rate in adults was 36% for patients with pathologic fracture versus 56% for patients without pathologic fracture. In a multivariable analysis, the presence of a pathologic fracture was not a statistically significant factor for overall survival or event-free survival in the total cohort or in pediatric patients. In adult patients, pathologic fracture remained an independent prognostic factor for overall survival (hazard ratio, 1.893).
• Histology. The role of histology in response to chemotherapy and survival outcome is modest. Fibroblastic differentiation is generally considered to be favorable histology. This histologic profile is associated with improved chemotherapy-related tumor necrosis as well as a lower risk of death than alternative histologic subtypes. Chondroid predominant tumor histology correlates with poorer outcomes ¹¹¹⁾.
• Preoperative chemotherapeutic response. Survival outcome is dependent upon several factors, but the most important predictor of success is the degree of chemotherapy-induced tumor necrosis; Necrosis of 90% or more of the tumor is associated with an excellent prognosis ¹¹²⁾.

The following potential prognostic factors have been identified but have not been tested in large numbers of patients:

• HER-2/neu (c-erbB-2) expression. There are conflicting data concerning the prognostic significance of this human epidermal growth factor ¹¹³⁾.
• Tumor cell ploidy ¹¹⁴⁾.
• Specific chromosomal gains or losses ¹¹⁵⁾.
• Loss of heterozygosity of the RB gene ¹¹⁶⁾.
• Loss of heterozygosity of the p53 locus ¹¹⁷⁾.
• Increased expression of p-glycoprotein ¹¹⁸⁾. A prospective analysis of p-glycoprotein expression determined by immunohistochemistry failed to identify prognostic significance for newly diagnosed patients with osteosarcoma, although earlier studies suggested that overexpression of p-glycoprotein predicted poor outcome ¹¹⁹⁾.
• Time to definitive surgery. In a large series, a delay of 21 days or longer from the time of definitive surgery to the resumption of chemotherapy was an adverse prognostic factor ¹²⁰⁾.