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An osteosarcoma (OS) or osteogenic sarcoma (OGS) (or simply bone cancer) 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, an ...
. Specifically, it is an aggressive
malignant Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...
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 malignant tumor, a type of cancer that arises from transformed cells of mesenchymal (connective tissue) origin. Connective tissue is a broad term that includes bone, cartilage, fat, vascular, or hematopoietic tissues, and sa ...
) and that exhibits osteoblastic differentiation and produces malignant osteoid. Osteosarcoma is the most common histological form of primary
bone sarcoma 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, and e ...
. 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, fibrous dysplasia, enchondromatosis, and hereditary multiple exostoses, increase the risk of osteosarcoma. *
Li–Fraumeni syndrome Li–Fraumeni syndrome is a rare, autosomal dominant, hereditary disorder that predisposes carriers to cancer development. It was named after two American physicians, Frederick Pei Li and Joseph F. Fraumeni, Jr., who first recognized the syndrom ...
(germline TP53 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 gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low est ...
, and cataracts) is associated with increased risk of this disease. * Large doses of Sr-90, nicknamed
bone seeker A bone seeker is an element, often a radioisotope, that tends to accumulate in the bones of humans and other animals when it is introduced into the body. An example is strontium-90, which behaves chemically like calcium and can replace the calcium ...
, increases the risk of bone cancer and
leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...
in animals and is presumed to do so in people. There is no clear association between
water fluoridation Water fluoridation is the controlled adjustment of fluoride to a public water supply solely to reduce tooth decay. Fluoridated water contains fluoride at a level that is effective for preventing cavities; this can occur naturally or by adding ...
and
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
or deaths due to cancer, both for cancer in general and also specifically for bone cancer and osteosarcoma. Series of research concluded that concentration of fluoride in water doesn't 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 executive agency of the United States federal government tasked with environmental protection matters. President Richard Nixon proposed the establishment of EPA on July 9, 1970; it ...
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 Standard anatomical terms of location are used to unambiguously describe the anatomy of animals, including humans. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position ...
end of tibia or
humerus The humerus (; ) 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 and ulna, and consists of three sections. The humeral upper extremity consists of a roun ...
, or distal end of
femur The femur (; ), or thigh bone, is the proximal bone of the hindlimb in tetrapod vertebrates. The head of the femur articulates with the acetabulum in the pelvic bone forming the hip joint, while the distal part of the femur articulates wit ...
. Osteosarcoma tends to affect regions around the
knee In humans and other primates, the knee joins the thigh with the human leg, leg and consists of two joints: one between the femur and tibia (tibiofemoral joint), and one between the femur and patella (patellofemoral joint). It is the largest join ...
in 60% of cases, 15% around the hip, 10% at the
shoulder The human shoulder is made up of three bones: the clavicle (collarbone), the scapula (shoulder blade), and the humerus (upper arm bone) as well as associated muscles, ligaments and tendons. The articulations between the bones of the shoulder m ...
, 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. These cells produce osteoid describing irregular trabeculae (amorphous, eosinophilic/pink) with or without central calcification (
hematoxylin Haematoxylin or hematoxylin (), also called natural black 1 or C.I. 75290, is a compound extracted from heartwood of the logwood tree ('' Haematoxylum campechianum'') with a chemical formula of . This naturally derived dye has been used as a ...
ophilic/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 ...
(laying of new bone materials) and calcification of the cartilage. 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 {{Unreferenced, date=June 2019, bot=noref (GreenC bot) An orthopedic (orthopaedic) oncologist is a physician and surgeon who specializes in the diagnoses and treatment of primary benign and malignant tumors of the bones. Education An orthopedic o ...
. The
American Cancer Society The American Cancer Society (ACS) is a nationwide voluntary health organization dedicated to eliminating cancer. Established in 1913, the society is organized into six geographical regions of both medical and lay volunteers operating in more tha ...
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 about 90% of 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 {{Unreferenced, date=June 2019, bot=noref (GreenC bot) An orthopedic (orthopaedic) oncologist is a physician and surgeon who specializes in the diagnoses and treatment of primary benign and malignant tumors of the bones. Education An orthopedic o ...
experienced in managing sarcomas. Current standard treatment is to use neoadjuvant
chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
(chemotherapy given before surgery) followed by surgical resection. The percentage of tumor cell
necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dig ...
(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 chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelio ...
, adriamycin, ifosfamide with mesna, BCD ( bleomycin, cyclophosphamide, dactinomycin),
etoposide Etoposide, sold under the brand name Vepesid among others, is a chemotherapy medication used for the treatments of a number of types of cancer including testicular cancer, lung cancer, lymphoma, leukemia, neuroblastoma, and ovarian cancer. It is ...
, 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 Filgrastim, sold under the brand name Neupogen among others, is a medication used to treat low neutrophil count. Low neutrophil counts may occur with HIV/AIDS, following chemotherapy or radiation poisoning, or be of an unknown cause. It may ...
or pegfilgrastim help with white blood cell counts and
neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
counts. Blood transfusions and epoetin alfa help with
anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, ...
. 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 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 epiphyses. The metaph ...
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.


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, Greyhounds,
German Shepherd The German Shepherd or Alsatian is a German breed of working dog of medium to large size. The breed was developed by Max von Stephanitz using various traditional German herding dogs from 1899. It was originally bred as a herding dog, fo ...
s,
Rottweiler The Rottweiler (, ) is a breed of domestic dog, regarded as medium-to-large or large. The dogs were known in German as , meaning Rottweil butchers' dogs, because their main use was to herd livestock and pull carts laden with butchered m ...
s, 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) or oesophagus (British English; both ), non-technically known also as the food pipe or gullet, is an organ in vertebrates through which food passes, aided by peristaltic contractions, from the pharynx to the ...
.


Clinical presentation

The most commonly affected bones are the proximal
humerus The humerus (; ) 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 and ulna, and consists of three sections. The humeral upper extremity consists of a roun ...
, the distal
radius In classical geometry, a radius ( : radii) of a circle or sphere is any of the line segments from its center to its perimeter, and in more modern usage, it is also their length. The name comes from the latin ''radius'', meaning ray but also the ...
, the distal
femur The femur (; ), or thigh bone, is the proximal bone of the hindlimb in tetrapod vertebrates. The head of the femur articulates with the acetabulum in the pelvic bone forming the hip joint, while the distal part of the femur articulates wit ...
, and the tibia, following the basic premise "far from the elbow, close to the knee". Other sites include the ribs, the
mandible In anatomy, the mandible, lower jaw or jawbone is the largest, strongest and lowest bone in the human facial skeleton. It forms the lower jaw and holds the lower teeth in place. The mandible sits beneath the maxilla. It is the only movable bon ...
, the spine, and the pelvis. Rarely, osteosarcoma may arise from soft tissues (extraskeletal osteosarcoma).
Metastasis Metastasis is a pathogenic agent's spread 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, then, ...
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, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a d ...
is the definitive method to reach a final diagnosis. Osteosarcoma should be differentiated from other
bone tumours A bone tumor is an abnormal growth of tissue in bone, traditionally classified as noncancerous (benign) or cancerous (malignant). Cancerous bone tumors usually originate from a cancer in another part of the body such as from lung, breast, thyroi ...
and a range of other lesions, such as
osteomyelitis Osteomyelitis (OM) is an infection of bone. Symptoms may include pain in a specific bone with overlying redness, fever, and weakness. The long bones of the arms and legs are most commonly involved in children e.g. the femur and humerus, while the ...
. 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 sarcoma ...
and the
multilobular tumour of bone The multilobular tumour of bone (MTB), also called an osteochondrosarcoma, is the most common tumour of the canine skull, although it is relatively rare in general. MTB usually presents as a firm, circumscribed and generally slowgrowing bone tumo ...
.


Treatment and prognosis

Amputation is the initial treatment, although this alone will not prevent metastasis.
Chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
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 remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated ...
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.


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: ''histos'' "tissue", πάθος ''pathos'' "suffering", and -λογία '' -logia'' "study of") refers to the microscopic examination of tissue in order to study the manifestations of disease. Sp ...
.


Dinosaurs

A 2020 study was able to demonstrate via radiographic and histological analysis along with comparisons with osteosarcoma in humans that a ''Centrosaurus'' from the
Cretaceous The Cretaceous ( ) is a geological period that lasted from about 145 to 66 million years ago (Mya). It is the third and final period of the Mesozoic Era, as well as the longest. At around 79 million years, it is the longest geological period of ...
period had developed osteosarcoma in its fibula.Seper Ekhtiari et al. "First Case of Osteosarcoma in a Dinosaur: A Multimodal Diagnosis" ''The Lancet Oncology, 21''.


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 Osseous and chondromatous neoplasia Pediatric cancers Sarcoma