An osteosarcoma (OS) or osteogenic sarcoma (OGS) is a cancerous
tumor
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
in a
bone
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...
. Specifically, it is an aggressive
malignant
Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer.
A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...
neoplasm
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
that arises from primitive transformed cells of
mesenchymal origin (and thus a
sarcoma
A sarcoma is a rare type of cancer that arises from cells of mesenchymal origin. Originating from mesenchymal cells means that sarcomas are cancers of connective tissues such as bone, cartilage, muscle, fat, or vascular tissues.
Sarcom ...
) and that exhibits
osteoblast
Osteoblasts (from the Greek combining forms for " bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts fu ...
ic differentiation and produces malignant
osteoid.
Osteosarcoma is the most common
histological
Histology,
also known as microscopic anatomy or microanatomy, is the branch of biology that studies the microscopic anatomy of biological tissue (biology), tissues. Histology is the microscopic counterpart to gross anatomy, which looks at large ...
form of primary
bone sarcoma.
It is most prevalent in teenagers and young adults.
Signs and symptoms
Many patients first complain of pain that may be worse at night, may be intermittent and of varying intensity and may have been occurring for a long time. Teenagers who are active in sports often complain of pain in the lower femur, or immediately below the knee. If the tumor is large, it can present as overt localised swelling. Sometimes a sudden fracture is the first symptom because the affected bone is not as strong as normal bone and may
fracture abnormally with minor trauma. In cases of more deep-seated tumors that are not as close to the skin, such as those originating in the pelvis, localised swelling may not be apparent.
Causes
Several research groups are investigating cancer stem cells and their potential to cause tumors along with genes and proteins causative in different phenotypes.
Radiotherapy for unrelated conditions may be a rare cause.
* A
small supernumerary marker chromosome or a giant rod chromosome is present in the tumor cells of low grade OS including low grade central OS and paraosteal OS (see below Variants section),
carry various potentially pro-cancerous genes, and are thought to contribute to the development of these OS.
(See
Small supernumerary marker chromosomes and giant rod chromosomes in osteosarcomas)
* Familial cases where the deletion of chromosome
13q14 inactivates the
retinoblastoma gene is associated with a high risk of osteosarcoma development.
* Bone dysplasias, including
Paget's disease of bone
Paget's disease of bone (commonly known as Paget's disease or, historically, osteitis deformans) is a condition involving Bone remodeling, cellular remodeling and deformity of one or more bones. The affected bones show signs of dysregulated bone ...
,
fibrous dysplasia
Fibrous dysplasia is a very rare nonhereditary genetic disorder where normal bone and marrow is replaced with fibrous tissue, resulting in formation of bone that is weak and prone to expansion. As a result, most complications result from fract ...
,
enchondromatosis, and
hereditary multiple exostoses, increase the risk of osteosarcoma.
*
Li–Fraumeni syndrome (germline
TP53
p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...
mutation) is a predisposing factor for osteosarcoma development.
*
Rothmund–Thomson syndrome (i.e. autosomal recessive association of congenital bone defects, hair and skin dysplasias,
hypogonadism
Hypogonadism means diminished functional activity of the human gonad, gonads—the testicles or the ovary, ovaries—that may result in diminished biosynthesis, production of sex hormones. Low androgen (e.g., testosterone) levels are referred t ...
, and cataracts) is associated with increased risk of this disease.
* Large doses of
Sr-90, nicknamed
bone seeker, increases the risk of bone cancer and
leukemia in animals and is presumed to do so in people.
There is no clear association between
water fluoridation
Water fluoridation is the controlled addition of fluoride to Public water supply, public water supplies to reduce tooth decay. Fluoridated water maintains fluoride levels effective for cavity prevention, achieved naturally or through supplem ...
and cancer or deaths due to cancer, both for cancer in general and also specifically for
bone cancer
A bone tumor is an neoplastic, abnormal growth of tissue in bone, traditionally classified as benign, noncancerous (benign) or malignant, cancerous (malignant). Cancerous bone tumors usually originate from a cancer in another part of the body su ...
and osteosarcoma. Series of research concluded that concentration of fluoride in water does not associate with osteosarcoma. The beliefs regarding association of fluoride exposure and osteosarcoma stem from a study of
US National Toxicology program in 1990, which showed uncertain evidence of association of fluoride and osteosarcoma in male rats. But there is still no solid evidence of cancer-causing tendency of fluoride in mice. Fluoridation of water has been practiced around the world to improve citizens' dental health. It is also deemed as major health success. Fluoride concentration levels in water supplies are regulated, such as
United States Environmental Protection Agency
The Environmental Protection Agency (EPA) is an independent agency of the United States government tasked with environmental protection matters. President Richard Nixon proposed the establishment of EPA on July 9, 1970; it began operation on De ...
regulates fluoride levels to not be greater than 4 milligrams per liter. Actually, water supplies already have natural occurring fluoride, but many communities chose to add more fluoride to the point that it can reduce tooth decay. Fluoride is also known for its ability to cause new bone formation. Yet, further research shows no osteosarcoma risks from fluoridated water in humans. Most of the research involved counting number of osteosarcoma patients cases in particular areas which has difference concentrations of fluoride in drinking water. The statistic analysis of the data shows no significant difference in occurrences of osteosarcoma cases in different fluoridated regions. Another important research involved collecting bone samples from osteosarcoma patients to measure fluoride concentration and compare them to bone samples of newly diagnosed malignant bone tumors. The result is that the median fluoride concentrations in bone samples of osteosarcoma patients and tumor controls are not significantly different. Not only fluoride concentration in bones, Fluoride exposures of osteosarcoma patients are also proven to be not significantly different from healthy people.
Mechanism

Osteosarcomas tend to occur at the sites of bone growth, presumably because proliferation makes osteoblastic cells in this region prone to acquire mutations that could lead to transformation of cells (the
RB gene and
p53 gene are commonly involved). The tumor may be localized at the end of the long bone (commonly in the metaphysis). Most often it affects the
proximal end of
tibia
The tibia (; : tibiae or tibias), also known as the shinbone or shankbone, is the larger, stronger, and anterior (frontal) of the two Leg bones, bones in the leg below the knee in vertebrates (the other being the fibula, behind and to the outsi ...
or
humerus
The humerus (; : humeri) is a long bone in the arm that runs from the shoulder to the elbow. It connects the scapula and the two bones of the lower arm, the radius (bone), radius and ulna, and consists of three sections. The humeral upper extrem ...
, or
distal end of
femur
The femur (; : femurs or femora ), or thigh bone is the only long bone, bone in the thigh — the region of the lower limb between the hip and the knee. In many quadrupeds, four-legged animals the femur is the upper bone of the hindleg.
The Femo ...
. Osteosarcoma tends to affect regions around the knee in 60% of cases, 15% around the
hip, 10% at the
shoulder, and 8% in the
jaw. The tumor is solid, hard, irregular ("fir-tree," "moth-eaten", or "sun-burst" appearance on X-ray examination) due to the tumor spicules of calcified bone radiating at right angles. These right angles form what is known as a
Codman triangle, which is characteristic but not diagnostic of osteosarcoma. Surrounding tissues are infiltrated.

Microscopically: The characteristic feature of osteosarcoma is presence of osteoid (bone formation) within the tumor. Tumor cells are very
pleomorphic (
anaplastic), some are giant, numerous atypical
mitoses
Mitosis () is a part of the cell cycle in eukaryotic cells in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis is an equational division which gives rise to genetically identical cells in which the ...
. These cells produce osteoid describing irregular
trabeculae (amorphous,
eosinophilic/pink) with or without central calcification (
hematoxylinophilic/blue, granular)—tumor bone. Tumor cells are included in the
osteoid matrix. Depending on the features of the tumor cells present (whether they resemble bone cells, cartilage cells, or fibroblast cells), the tumor can be subclassified. Osteosarcomas may exhibit multinucleated osteoclast-like giant cells.
Diagnosis
X-rays is the initial imaging of choice to diagnose osteosarcoma. Some characteristics of osteosarcoma on X-rays are sunburst appearance and
Codman triangle (elevation of bony cortex by the tumour that caused new bone formation). CT scan is helpful in defining the bony anatomy, the integrity of the bony cortex, detecting
pathologic fracture, and assessing
ossification
Ossification (also called osteogenesis or bone mineralization) in bone remodeling is the process of laying down new bone material by cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes resulting in t ...
(laying of new bone materials) and calcification of the
cartilage
Cartilage is a resilient and smooth type of connective tissue. Semi-transparent and non-porous, it is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints ...
. On the other hand, soft tissue and
medullary cavity is better imaged by MRI scan.
Most times, the early signs of osteosarcoma are caught on X-rays taken during routine dental check-ups. Osteosarcoma frequently develops in the mandible (lower jaw); accordingly, dentists are trained to look for signs that may suggest osteosarcoma. Even though radiographic findings for this cancer vary greatly, one usually sees a symmetrical widening of the periodontal ligament space. A dentist who has reason to suspect osteosarcoma or another underlying disorder would then refer the patient to an Oral & Maxillofacial surgeon for biopsy. A biopsy of suspected osteosarcoma outside of the facial region should be performed by a qualified
orthopedic oncologist. The
American Cancer Society states: "Probably in no other cancer is it as important to perform this procedure properly. An improperly performed biopsy may make it difficult to save the affected limb from amputation." It may also metastasise to the lungs, mainly appearing on the chest X-ray as solitary or multiple round nodules most common at the lower regions.
Variants
* Conventional: osteoblastic, chondroblastic, fibroblastic OS
* Telangiectatic OS
* Small cell OS
* Low-grade central OS
* Periosteal OS
* Paraosteal OS
* Secondary OS
* High-grade surface OS
* Extraskeletal OS
Treatment
A complete radical, surgical, ''en bloc'' resection of the cancer, is the treatment of choice in osteosarcoma.
Although most patients are able to have
limb-salvage surgery, complications—particularly infection, prosthetic loosening and non-union, or local tumor recurrence—may cause the need for further surgery or amputation.
Mifamurtide is used after a patient has had surgery to remove the tumor and together with chemotherapy to kill remaining cancer cells to reduce the risk of cancer recurrence. Also, the option to have
rotationplasty after the tumor is taken out exists.
Patients with osteosarcoma are best managed by a medical
oncologist and an
orthopedic oncologist experienced in managing sarcomas. Current standard treatment is to use
neoadjuvant chemotherapy
Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...
(chemotherapy given before surgery) followed by surgical resection. The percentage of tumor cell
necrosis (cell death) seen in the tumor after surgery gives an idea of the prognosis and also lets the oncologist know if the chemotherapy regimen should be altered after surgery.
Standard therapy is a combination of limb-salvage orthopedic surgery when possible (or amputation in some cases) and a combination of high-dose
methotrexate with
leucovorin rescue, intra-arterial
cisplatin
Cisplatin is a chemical compound with chemical formula, formula ''cis''-. It is a coordination complex of platinum that is used as a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, c ...
,
adriamycin,
ifosfamide with
mesna, BCD (
bleomycin,
cyclophosphamide,
dactinomycin),
etoposide, and muramyl tripeptide.
Rotationplasty may be used. Ifosfamide can be used as an adjuvant treatment if the necrosis rate is low.
Despite the success of chemotherapy for osteosarcoma, it has one of the lowest survival rates for pediatric cancer. The best reported 10-year survival rate is 92%; the protocol used is an aggressive intra-arterial regimen that individualizes therapy based on arteriographic response. Three-year event-free survival ranges from 50% to 75%, and five-year survival ranges from 60% to 85+% in some studies. Overall, 65–70% patients treated five years ago will be alive today.
These survival rates are overall averages and vary greatly depending on the individual necrosis rate.
Filgrastim or
pegfilgrastim help with
white blood cell
White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
counts and
neutrophil
Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...
counts. Blood transfusions and
epoetin alfa help with
anemia
Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...
. Computational analysis on a panel of osteosarcoma cell lines identified new shared and specific therapeutic targets (proteomic and genetic) in osteosarcoma, while phenotypes showed an increased role of tumor microenvironments.
Prognosis
Prognosis is separated into three groups.
* Stage I osteosarcoma is rare and includes parosteal osteosarcoma or low-grade central osteosarcoma. It has an excellent prognosis (>90%) with wide resection.
* Stage II prognosis depends on the site of the tumor (proximal tibia, femur, pelvis, etc.), size of the tumor mass, and the degree of necrosis from neoadjuvant chemotherapy. Other pathological factors such as the degree of p-glycoprotein, whether the tumor is cxcr4-positive, or Her2-positive are also important, as these are associated with distant metastases to the lung. The prognosis for patients with metastatic osteosarcoma improves with longer times to metastases (more than 12 months to 4 months), a smaller number of metastases, and their resectability. It is better to have fewer metastases than longer time to metastases. Those with a longer length of time (more than 24 months) and few nodules (two or fewer) have the best prognosis, with a two-year survival after the metastases of 50%, five-year of 40%, and 10-year of 20%. If metastases are both local and regional, the prognosis is worse.
* Initial presentation of stage III osteosarcoma with lung metastases depends on the resectability of the primary tumor and
lung nodules, degree of necrosis of the primary tumor, and maybe the number of metastases. Overall survival prognosis is about 30%.
Deaths due to malignant neoplasms of the bones and joints account for an unknown number of childhood cancer deaths. Mortality rates due to osteosarcoma have been declining at about 1.3% per year. Long-term survival probabilities for osteosarcoma have improved dramatically during the late 20th century and approximated 68% in 2009.
Epidemiology
Osteosarcoma is the eighth-most common form of childhood cancer, comprising 2.4% of all malignancies in
pediatric patients, and about 20% of all primary bone cancers.
Incidence rates for osteosarcoma in U.S. patients under 20 years of age are estimated at 5.0 per million per year in the general population, with a slight variation between individuals of black, Hispanic, and white ethnicities (6.8, 6.5, and 4.6 per million per year, respectively). It is slightly more common in males (5.4 per million per year) than in females (4.0 per million per year).
It originates more frequently in the
metaphyseal
The metaphysis (: metaphyses) is the neck portion of a long bone between the epiphysis and the diaphysis. It contains the growth plate, the part of the bone that grows during childhood, and as it grows it ossifies near the diaphysis and the epip ...
region of tubular long bones, with 42% occurring in the femur, 19% in the tibia, and 10% in the humerus. About 8% of all cases occur in the skull and jaw, and another 8% in the pelvis.
Around 300 of the 900 people diagnosed in the United States will die each year. A second peak in incidence occurs in the elderly, usually associated with an underlying bone pathology such as
Paget's disease of bone
Paget's disease of bone (commonly known as Paget's disease or, historically, osteitis deformans) is a condition involving Bone remodeling, cellular remodeling and deformity of one or more bones. The affected bones show signs of dysregulated bone ...
.
Other animals
Risk factors
Osteosarcoma is the most common bone tumor in dogs and typically affects middle-aged large and giant breed dogs such as
Irish Wolfhounds,
Greyhound
The English Greyhound, or simply the Greyhound, is a dog breed, breed of dog, a sighthound which has been bred for coursing, greyhound racing and hunting. Some are kept as show dogs or pets.
Greyhounds are defined as a tall, muscular, smooth-c ...
s,
German Shepherds,
Rottweilers, mountain breeds (Great Pyrenees, St. Bernard, Leonberger, Newfoundland),
Doberman Pinschers and
Great Danes. It has a 10-fold greater
incidence in dogs than humans.
A
hereditary base has been shown in St. Bernard dogs.
Spayed/neutered dogs have twice the risk of intact ones to develop osteosarcoma.
Infestation with the parasite
Spirocerca lupi can cause osteosarcoma of the
esophagus
The esophagus (American English), oesophagus (British English), or œsophagus (Œ, archaic spelling) (American and British English spelling differences#ae and oe, see spelling difference) all ; : ((o)e)(œ)sophagi or ((o)e)(œ)sophaguses), c ...
.
Clinical presentation
The most commonly affected bones are the proximal
humerus
The humerus (; : humeri) is a long bone in the arm that runs from the shoulder to the elbow. It connects the scapula and the two bones of the lower arm, the radius (bone), radius and ulna, and consists of three sections. The humeral upper extrem ...
, the distal
radius
In classical geometry, a radius (: radii or radiuses) of a circle or sphere is any of the line segments from its Centre (geometry), center to its perimeter, and in more modern usage, it is also their length. The radius of a regular polygon is th ...
, the distal
femur
The femur (; : femurs or femora ), or thigh bone is the only long bone, bone in the thigh — the region of the lower limb between the hip and the knee. In many quadrupeds, four-legged animals the femur is the upper bone of the hindleg.
The Femo ...
, and the
tibia
The tibia (; : tibiae or tibias), also known as the shinbone or shankbone, is the larger, stronger, and anterior (frontal) of the two Leg bones, bones in the leg below the knee in vertebrates (the other being the fibula, behind and to the outsi ...
,
following the basic premise "far from the elbow, close to the knee". Other sites include the ribs, the
mandible
In jawed vertebrates, the mandible (from the Latin ''mandibula'', 'for chewing'), lower jaw, or jawbone is a bone that makes up the lowerand typically more mobilecomponent of the mouth (the upper jaw being known as the maxilla).
The jawbone i ...
, the spine, and the pelvis. Rarely, osteosarcoma may arise from soft tissues (extraskeletal osteosarcoma).
Metastasis
Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
of tumors involving the limb bones is very common, usually to the lungs. The tumor causes a great deal of pain, and can even lead to fracture of the affected bone. As with human osteosarcoma, bone
biopsy
A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, an interventional radiologist, or an interventional cardiology, interventional cardiologist. The process involves the extraction of sampling (medicine), sample ...
is the definitive method to reach a final diagnosis. Osteosarcoma should be differentiated from other
bone tumours and a range of other lesions, such as
osteomyelitis
Osteomyelitis (OM) is the infectious inflammation of bone marrow. Symptoms may include pain in a specific bone with overlying redness, fever, and weakness. The feet, spine, and hips are the most commonly involved bones in adults.
The cause is ...
. Differential diagnosis of the osteosarcoma of the skull in particular includes, among others,
chondrosarcoma
Chondrosarcoma is a bone sarcoma, a primary cancer composed of cells derived from transformed cells that produce cartilage. A chondrosarcoma is a member of a category of tumors of bone and soft tissue known as sarcomas. About 30% of bone sarco ...
and the
multilobular tumour of bone.
Treatment and prognosis
Amputation is the initial treatment, although this alone will not prevent metastasis.
Chemotherapy
Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...
combined with amputation improves the survival time, but most dogs still die within a year.
[ Surgical techniques designed to save the leg (limb-sparing procedures) do not improve the prognosis.
Some current studies indicate ]osteoclast
An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and bone remodeling, remodeling of bones of the vertebrate, vertebral skeleton. The osteoclast disassembles and digests th ...
inhibitors such as alendronate and pamidronate may have beneficial effects on the quality of life by reducing osteolysis, thus reducing the degree of pain, as well as the risk of pathological fractures.
Molecular alterations
Canine osteosarcoma shows similar patterns of molecular somatic alterations to the human disease. Both are characterized by genetic instability and karyotypic complexity and genes that are recurrently altered include ''TP53, RB1, PTEN, MYC, PIK3CA'.'' In contrast, mutations in the histone methyltransferase gene ''SETD2'' are rare in human osteosarcoma, but have been identified in 21% of canine tumors.
Cats
Osteosarcoma is also the most common bone tumor in cats, although not as frequently encountered, and most typically affect the rear legs. The cancer is generally less aggressive in cats than in dogs, so amputation alone can lead to a significant survival time in many affected cats, though post-amputation chemotherapy is recommended when a high grade is confirmed on histopathology
Histopathology (compound of three Greek words: 'tissue', 'suffering', and '' -logia'' 'study of') is the microscopic examination of tissue in order to study the manifestations of disease. Specifically, in clinical medicine, histopatholog ...
.[
]
Dinosaurs
An 2020 study, published in ''The Lancet Oncology'', reports the first confirmed case of osteosarcoma in a dinosaur, a ''Centrosaurus apertus'' from the Late Cretaceous
The Cretaceous ( ) is a geological period that lasted from about 143.1 to 66 mya (unit), million years ago (Mya). It is the third and final period of the Mesozoic Era (geology), Era, as well as the longest. At around 77.1 million years, it is the ...
, about 77 to 75.5 million years ago.[Seper Ekhtiari et al. "First Case of Osteosarcoma in a Dinosaur: A Multimodal Diagnosis" ''The Lancet Oncology, 21''.] The bone showed typical characteristics of cancer, including areas of cortical destruction, neoplastic bone formations, and disordered organization inconsistent with a simple fracture or infection. The structural and histological similarities with a high-grade human osteosarcoma case strengthened the diagnosis. This study establishes that bone cancers, such as osteosarcoma, have deep roots in the evolutionary history of vertebrates.
References
Further reading
* Osteosarcoma research: past, present and future.
External links
National Cancer Institute—patient information on osteosarcoma
Osteosarcoma – An Introduction
{{Authority control
Cancer in cats
Cancer in dogs
Causes of amputation
Osseous and chondromatous neoplasia
Pediatric cancers
Sarcoma