Title: Osteosarcoma

{{Short description|Cancerous tumour in a bone}}
{{Infobox medical condition (new)
| name            = Osteosarcoma
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| image           = Osteosarcoma - intermed mag.jpg
| caption         = Intermediate-magnification [[micrograph]] of an osteosarcoma (center and right of image) adjacent to non-malignant [[bone]] (left-bottom of image): The top-right of the image has poorly differentiated tumor. Osteoid with a high density of malignant cells is seen between the non-malignant bone and poorly differentiated tumor ([[H&amp;E stain]]).
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| field           = [[Oncology]]
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An '''osteosarcoma''' ('''OS''') or '''osteogenic sarcoma''' ('''OGS''') is a cancerous [[tumor]] in a [[bone]]. Specifically, it is an aggressive [[malignant]] [[neoplasm]] that arises from primitive transformed cells of [[mesenchyme|mesenchymal]] origin (and thus a [[sarcoma]]) and that exhibits [[osteoblast]]ic differentiation and produces malignant [[osteoid]].&lt;ref&gt;{{cite journal |vauthors=Luetke A, Meyers PA, Lewis A, Juergens H | year = 2014 | title = Osteosarcoma treatment—where do we stand? A state of the art review | journal = Cancer Treat Rev | volume = 40 | issue = 4| pages = 523–532 | pmid = 24345772 | doi=10.1016/j.ctrv.2013.11.006}}&lt;/ref&gt;

Osteosarcoma is the most common [[histology|histological]] form of primary [[bone sarcoma]].&lt;ref name=&quot;OttavianiJaffe&quot;&gt;{{cite book |vauthors=Ottaviani G, Jaffe N |title= Pediatric and Adolescent Osteosarcoma |chapter= The Epidemiology of Osteosarcoma |series= Cancer Treatment and Research |volume= 152 |pages= 3–13 |publisher=Springer |location=New York |year=2009|isbn=978-1-4419-0283-2|pmid=20213383 |doi=10.1007/978-1-4419-0284-9_1}}&lt;/ref&gt; It is most prevalent in teenagers and young adults.&lt;ref&gt;{{Cite web|url = https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002616/|archive-url = https://web.archive.org/web/20120828000200/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002616/|url-status = dead|archive-date = August 28, 2012|title = Osteosarcoma|date = 2013|website = US National Library of Medicine|publisher = PubMed Health}}&lt;/ref&gt;

==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 [[Pathological fracture|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.{{citation needed|date=June 2020}}

==Causes==

Several research groups are investigating cancer stem cells and their potential to cause tumors along with genes and proteins causative in different phenotypes.&lt;ref&gt;{{cite journal |vauthors=Osuna D, de Alava E |title= Molecular pathology of sarcomas |journal= Rev Recent Clin Trials |volume=4 |issue=1 |pages=12–26 |year=2009 |pmid=19149759 |doi= 10.2174/157488709787047585|hdl= 10261/61716 |s2cid= 15039305 }}&lt;/ref&gt;&lt;ref name=&quot;Phenotypically Characterized Osteosarcoma 2017&quot;&gt;{{Cite journal|last1=Sharma|first1=Ankush|last2=Cinti|first2=Caterina|last3=Capobianco|first3=Enrico|date=2017|title=Multitype Network-Guided Target Controllability in Phenotypically Characterized Osteosarcoma: Role of Tumor Microenvironment|journal=Frontiers in Immunology|language=en|volume=8|pages=918|doi=10.3389/fimmu.2017.00918|pmid=28824643|pmc=5536125|issn=1664-3224|doi-access=free}}&lt;/ref&gt;&lt;ref&gt;{{Cite journal|last1=Sharma|first1=Ankush|last2=Capobianco|first2=Enrico|date=2017|title=Immuno-Oncology Integrative Networks: Elucidating the Influences of Osteosarcoma Phenotypes|url= |journal=Cancer Informatics|language=en|volume=16|pages=117693511772169|doi=10.1177/1176935117721691|pmid=28804242|pmc=5533255|issn=1176-9351}}&lt;/ref&gt; Radiotherapy for unrelated conditions may be a rare cause.&lt;ref&gt;{{cite journal|vauthors=Dhaliwal J, Sumathi VP, Grimer RJ|title=Radiation-induced periosteal osteosarcoma|journal=Grand Rounds|volume=10|pages=13–18|date=20 December 2009|url=http://www.grandroundsjournal.com/articles/gr100003/gr100003.pdf|doi=10.1102/1470-5206.2010.0003|doi-broken-date=12 July 2025}}&lt;/ref&gt;
* 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),&lt;ref name=&quot;pmid27990273&quot;&gt;{{cite journal | vauthors = Bielack SS, Hecker-Nolting S, Blattmann C, Kager L | title = Advances in the management of osteosarcoma | journal = F1000Research | volume = 5 | issue = | pages = 2767 | date = 2016 | pmid = 27990273 | pmc = 5130082 | doi = 10.12688/f1000research.9465.1 | url =  | doi-access = free }}&lt;/ref&gt; carry various potentially pro-cancerous genes, and are thought to contribute to the development of these OS.&lt;ref name=&quot;pmid30001240&quot;&gt;{{cite journal | vauthors = He X, Pang Z, Zhang X, Lan T, Chen H, Chen M, Yang H, Huang J, Chen Y, Zhang Z, Jing W, Peng R, Zhang H | title = Consistent Amplification of FRS2 and MDM2 in Low-grade Osteosarcoma: A Genetic Study of 22 Cases With Clinicopathologic Analysis | journal = The American Journal of Surgical Pathology | volume = 42 | issue = 9 | pages = 1143–1155 | date = September 2018 | pmid = 30001240 | doi = 10.1097/PAS.0000000000001125 | s2cid = 51618887 | url = }}&lt;/ref&gt; (See [[small supernumerary marker chromosome#Osteosarcomas|Small supernumerary marker chromosomes and giant rod chromosomes in osteosarcomas]])
* Familial cases where the deletion of chromosome [[Chromosome 13 (human)|13q14]] inactivates the [[retinoblastoma gene]] is associated with a high risk of osteosarcoma development.
* Bone dysplasias, including [[Paget's disease of bone]], [[Fibrous dysplasia of bone|fibrous dysplasia]], [[enchondromatosis]], and [[hereditary multiple exostoses]], increase the risk of osteosarcoma.
* [[Li–Fraumeni syndrome]] (germline [[p53|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]], and cataracts) is associated with increased risk of this disease.
* Large doses of [[Strontium-90|Sr-90]], nicknamed [[bone seeker]], increases the risk of bone cancer and [[leukemia]] in animals and is presumed to do so in people.&lt;ref&gt;
{{
 cite web|
 title=Sr-90 is known to increase the risk of bone cancer and leukemia in animals, and is presumed to do so in people|
 url=https://www.nrc.gov/reactors/operating/ops-experience/tritium/faqs.html
 }}
&lt;/ref&gt;

There is no clear association between [[water fluoridation]] and cancer or deaths due to cancer, both for cancer in general and also specifically for [[bone cancer]] and osteosarcoma.&lt;ref&gt;{{cite book |url=http://nhmrc.gov.au/_files_nhmrc/file/publications/synopses/Eh41_Flouridation_PART_A.pdf |accessdate=2009-10-13 |year=2007 |title=A systematic review of the efficacy and safety of fluoridation |author=National Health and Medical Research Council (Australia) |isbn=978-1-86496-415-8 |archiveurl=https://web.archive.org/web/20091014191758/http://www.nhmrc.gov.au/_files_nhmrc/file/publications/synopses/Eh41_Flouridation_PART_A.pdf |archivedate=2009-10-14 |url-status=dead }}&lt;/ref&gt; 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.&lt;ref&gt;[http://www.cancer.org/cancer/cancercauses/othercarcinogens/athome/water-fluoridation-and-cancer-risk &quot;Water Fluoridation and Cancer Risk&quot;] {{Webarchive|url=https://web.archive.org/web/20141129170952/http://www.cancer.org/cancer/cancercauses/othercarcinogens/athome/water-fluoridation-and-cancer-risk |date=2014-11-29 }}, ''American Cancer Society'', 6 June 2013.&lt;/ref&gt; Fluoridation of water has been practiced around the world to improve citizens' dental health. It is also deemed a major health success.&lt;ref&gt;[https://www.cancerwa.asn.au/resources/cancermyths/fluoride-cancer-myth/ &quot;Cancer myth: Fluoride and cancer&quot;] {{Webarchive|url=https://web.archive.org/web/20140914205902/http://www.cancerwa.asn.au/resources/cancermyths/fluoride-cancer-myth/ |date=2014-09-14 }}, ''Cancer Council Western Australia''.&lt;/ref&gt; Fluoride concentration levels in water supplies are regulated, such as [[United States Environmental Protection Agency]] regulates fluoride levels to not be greater than 4 milligrams per liter.&lt;ref&gt;[https://archive.today/20130730192746/http://water.epa.gov/drink/contaminants/basicinformation/fluoride.cfm &quot;Basic Information about Fluoride in Drinking Water&quot;], ''United States Environmental Protection Agency''.&lt;/ref&gt; 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.&lt;ref&gt;[https://www.cdc.gov/fluoridation/faqs/ &quot;Community Water Fluoridation&quot;], ''Centers of disease control and prevention''.&lt;/ref&gt; Fluoride is also known for its ability to cause new bone formation.&lt;ref&gt;[https://www.nrv.gov.au/nutrients/fluoride &quot;Fluoride&quot;], ''Australian government national health and medical research council''.&lt;/ref&gt;  Yet, further research shows no osteosarcoma risks from fluoridated water in humans.&lt;ref&gt;[http://www.cancer.gov/cancertopics/factsheet/Risk/fluoridated-water &quot;Fluoridated Water&quot;], ''National Cancer Institute''.&lt;/ref&gt; Most of the research involved counting number of osteosarcoma patients cases in particular areas which has difference concentrations of fluoride in drinking water.&lt;ref&gt;{{cite journal|vauthors=Blakey K, Feltbower RG, Parslow RC, James PW, ((Gómez Pozo B)), Stiller C, Vincent TJ, Norman P, McKinney PA, Murphy MF, Craft AW, McNally RJ|title=Is fluoride a risk factor for bone cancer? Small area analysis of osteosarcoma and Ewing sarcoma diagnosed among 0-49-year-olds in Great Britain, 1980-2005|journal=International Journal of Epidemiology|date=14 January 2014|volume=43|issue=1|pages=224–234|doi=10.1093/ije/dyt259|pmc=3937980|pmid=24425828}}&lt;/ref&gt; The statistic analysis of the data shows no significant difference in occurrences of osteosarcoma cases in different fluoridated regions.&lt;ref&gt;{{cite journal|vauthors=Mahoney MC, Nasca PC, Burnett WS, Melius JM|title=Bone cancer incidence rates in New York State: time trends and fluoridated drinking water|journal=American Journal of Public Health|date=April 1991|volume=81|issue=4|pages=475–9|doi=10.2105/AJPH.81.4.475|pmc=1405037|pmid=2003628}}&lt;/ref&gt; 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.&lt;ref&gt;{{cite journal|vauthors=Kim FM, Hayes C, Williams PL, Whitford GM, Joshipura KJ, Hoover RN, Douglass CW, ((National Osteosarcoma Etiology Group))|title=An assessment of bone fluoride and osteosarcoma|journal=Journal of Dental Research|date=October 2011|volume=90|issue=10|pages=1171–6|doi=10.1177/0022034511418828|pmc=3173011|pmid=21799046}}&lt;/ref&gt; Not only fluoride concentration in bones, Fluoride exposures of osteosarcoma patients are also proven to be not significantly different from healthy people.&lt;ref&gt;{{cite journal|vauthors=Gelberg KH, Fitzgerald EF, Hwang SA, Dubrow R|title=Fluoride exposure and childhood osteosarcoma: a case-control study|journal=American Journal of Public Health|date=December 1995|volume=85|issue=12|pages=1678–83|doi=10.2105/AJPH.85.12.1678|pmc=1615731|pmid=7503344}}&lt;/ref&gt;

== Mechanism ==
[[File:Predilection sites of osteosarcoma2.png|thumb|120px|left|Predilections of osteosarcoma]]
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 [[Retinoblastoma protein|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 [[Anatomical terms of location#Proximal and distal|proximal]] end of [[tibia]] or [[humerus]], or [[Anatomical terms of location#Proximal and distal|distal]] end of [[femur]]. 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 (&quot;fir-tree,&quot; &quot;moth-eaten&quot;, or &quot;sun-burst&quot; 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.{{citation needed|date=September 2021}}

[[File:Osteosarcoma - very high mag.jpg|thumb|right|High-magnification micrograph showing osteoid formation in an osteosarcoma [[H&amp;E stain]]]]
Microscopically: The characteristic feature of osteosarcoma is presence of osteoid (bone formation) within the tumor. Tumor cells are very [[pleomorphism (cytology)|pleomorphic]] ([[anaplastic]]), some are giant, numerous atypical [[mitoses]]. These cells produce osteoid describing irregular [[trabeculae]] (amorphous, [[eosinophilic]]/pink) with or without central calcification ([[hematoxylin]]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.&lt;ref&gt;{{cite journal |vauthors=Papalas JA, Balmer NN, Wallace C, Sangüeza OP |title=Ossifying dermatofibroma with osteoclast-like giant cells: report of a case and literature review |journal=Am J Dermatopathol |volume=31 |issue=4 |pages=379–83 |date=June 2009 |pmid=19461244 |doi=10.1097/DAD.0b013e3181966747 }}&lt;/ref&gt;

==Diagnosis==
[[File:Histopathology of osteosarcoma, high mag.jpg|thumb|Histopathology of osteosarcoma, showing tumor cells with high [[nuclear pleomorphism]], but relatively less so in cells entrapped in neoplastic bone matrix (appearing pink on this [[H&amp;E stain]]ed slide).]]

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]] (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.&lt;ref name=&quot;pmid24932027&quot;&gt;{{cite journal | vauthors = Kundu ZS | title = Classification, imaging, biopsy and staging of osteosarcoma | journal = Indian Journal of Orthopaedics | volume = 48 | issue = 3 | pages = 238–46 | date = May 2014 | pmid = 24932027 | pmc = 4052020 | doi = 10.4103/0019-5413.132491 | url =  | doi-access = free }}&lt;/ref&gt;

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 &amp; 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: &quot;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.&quot; 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.{{citation needed|date=September 2021}}

===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
&lt;ref&gt;WHO&lt;/ref&gt;

==Treatment==
A complete radical, surgical, ''en bloc'' resection of the cancer, is the treatment of choice in osteosarcoma.&lt;ref name=&quot;OttavianiJaffe&quot;/&gt; Although most patients are able to have [[limb-sparing techniques|limb-salvage]] surgery, complications&amp;mdash;particularly infection, prosthetic loosening and non-union, or local tumor recurrence&amp;mdash;may cause the need for further surgery or amputation.&lt;ref&gt;{{cite web |title=Surgery for Osteosarcoma |url=https://www.cancer.org/cancer/types/osteosarcoma/treating/surgery.html |website=cancer.org |publisher=American Cancer Society |access-date=15 October 2023 |date=2023}}&lt;/ref&gt;

[[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.&lt;ref&gt;[http://www.childrenscancer.org/main/kids_stories/lukes_story_surviving_osteosarcoma/ Luke's Story: Surviving Osteosarcoma] {{Webarchive|url=https://web.archive.org/web/20140518211237/http://www.childrenscancer.org/main/kids_stories/lukes_story_surviving_osteosarcoma/ |date=2014-05-18 }}, Children's Cancer Research Fund. Accessed 2016-11-07.&lt;/ref&gt;

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 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.{{citation needed|date=September 2021}}

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]], [[adriamycin]], [[ifosfamide]] with [[mesna]], BCD ([[bleomycin]], [[cyclophosphamide]], [[dactinomycin]]), [[etoposide]], and muramyl tripeptide.&lt;ref&gt;Sameer Rastogi, Aditi Aggarwal, Akash Tiwari et al. Chemotherapy in Nonmetastatic Osteosarcoma: Recent Advances and Implications for Developing Countries. https://ascopubs.org/doi/full/10.1200/JGO.2016.007336&lt;/ref&gt; [[Rotationplasty]] may be used. Ifosfamide can be used as an adjuvant treatment if the necrosis rate is low.{{citation needed|date=September 2021}}

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.&lt;ref&gt;{{cite journal|vauthors=Wilkins RM, Cullen JW, Odom L, Jamroz BA, Cullen PM, Fink K, Peck SD, Stevens SL, Kelly CM, Camozzi AB|title=Superior survival in treatment of primary nonmetastatic pediatric osteosarcoma of the extremity|journal=Annals of Surgical Oncology|date=June 2003|volume=10|issue=5|pages=498–507|doi=10.1245/ASO.2003.03.061|pmid=12794015|s2cid=32721347}}&lt;/ref&gt; 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.&lt;ref name=Buecker&gt;{{cite web|vauthors=Buecker PJ, Gebhardt M, Weber K|year=2005|title=Osteosarcoma|work=ESUN|url=http://sarcomahelp.org/osteosarcoma.html|access-date=2009-04-15|archive-date=2009-04-21|archive-url=https://web.archive.org/web/20090421120936/http://sarcomahelp.org/osteosarcoma.html|url-status=dead}}&lt;/ref&gt; These survival rates are overall averages and vary greatly depending on the individual necrosis rate.{{citation needed|date=September 2021}}

[[Filgrastim]] or [[pegfilgrastim]] help with [[white blood cell]] counts and [[neutrophil]] counts. Blood transfusions and [[epoetin alfa]] help with [[anemia]]. 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.&lt;ref name=&quot;Phenotypically Characterized Osteosarcoma 2017&quot;/&gt;

==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 (&gt;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,&lt;ref&gt;{{cite web|url=http://www.osteosarcomasupport.org/cxcr4_metastases.pdf |title=osteosarcomasupport.org |publisher=osteosarcomasupport.org |access-date=2012-11-13}}&lt;/ref&gt; 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 nodule]]s, degree of necrosis of the primary tumor, and maybe the number of metastases.  Overall survival prognosis is about 30%.&lt;ref name=Koshkina&gt;{{cite web |author1=Koshkina, NV |author2=Corey, S |year=2008 |title=Novel Targets to Treat Osteosarcoma Lung Metastases |work=ESUN |url=http://sarcomahelp.org/research_center/osteosarcoma_lung_metastases.html |access-date=2009-04-14 |archive-date=2009-04-24 |archive-url=https://web.archive.org/web/20090424210515/http://sarcomahelp.org/research_center/osteosarcoma_lung_metastases.html |url-status=dead }}&lt;/ref&gt;

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.&lt;ref name=&quot;OttavianiJaffe&quot;/&gt;

==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.&lt;ref name=&quot;OttavianiJaffe&quot;/&gt;

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).&lt;ref name=&quot;OttavianiJaffe&quot;/&gt;

It originates more frequently in the [[metaphysis|metaphyseal]] 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.&lt;ref name=&quot;OttavianiJaffe&quot;/&gt;

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]].&lt;ref&gt;{{cite web |url= https://www.lecturio.com/concepts/osteosarcoma/| title= Osteosarcoma|website=The Lecturio Medical Concept Library |access-date= 25 August 2021}}&lt;/ref&gt;

==Other animals==
[[File:Canine osteosarcoma.JPG|thumb|[[X-ray]] of osteosarcoma of the distal femur in a dog]]

===Risk factors===
Osteosarcoma is the most common bone tumor in dogs and typically affects middle-aged large and giant breed dogs such as [[Irish Wolfhound]]s, [[Greyhound]]s, [[German Shepherd Dog|German Shepherd]]s, [[Rottweiler]]s, mountain breeds (Great Pyrenees, St. Bernard, Leonberger, Newfoundland), [[Doberman Pinscher]]s and [[Great Dane]]s. It has a 10-fold greater [[incidence (epidemiology)|incidence]] in dogs than humans.&lt;ref name=Withrow&gt;{{cite web|author=Withrow, S.J.|year=2003|title=Limb Sparing Trials and Canine Osteosarcoma|work=Genes, Dogs and Cancer: 3rd Annual Canine Cancer Conference, 2003|url=http://www.ivis.org/proceedings/Keystone/2003/withrow/chapter_frm.asp?LA=1|access-date=2006-06-16|archive-date=2005-03-15|archive-url=https://web.archive.org/web/20050315193019/http://www.ivis.org/proceedings/Keystone/2003/withrow/chapter_frm.asp?LA=1|url-status=dead}}&lt;/ref&gt; A [[heredity|hereditary]] base has been shown in St. Bernard dogs.&lt;ref name=Bech-Nielsen&gt;{{cite journal|author=Bech-Nielsen|year=1978|title=Frequency of osteosarcoma among first-degree relatives of St. Bernard dogs|journal=J Natl Cancer Inst |volume=60 |issue=2 |pages=349–53|name-list-style=vanc|author2=S.|author3=Haskins|author4=M. E.|display-authors=4|pmid=271748|last5=Patterson|first5=DF|last6=Spielman|first6=R|doi=10.1093/jnci/60.2.349}}&lt;/ref&gt; [[neutering|Spayed/neutered]] dogs have twice the risk of intact ones to develop osteosarcoma.&lt;ref name=Ru&gt;{{cite journal|last1=Ru|year=1998|title=Host related risk factors for canine osteosarcoma|journal=Vet J |volume=156|pages=31–9|doi=10.1016/S1090-0233(98)80059-2|pmid=9691849|issue=1|first1=B.|last2=Terracini|first2=G.|display-authors=etal}}&lt;/ref&gt; Infestation with the parasite [[Spirocerca lupi]] can cause osteosarcoma of the [[esophagus]].&lt;ref name=Ranen&gt;{{cite journal|vauthors=Ranen E, Lavy E, Aizenberg I, Perl S, Harrus S|year=2004|title=Spirocercosis-associated esophageal sarcomas in dogs. A retrospective study of 17 cases (1997-2003)|journal=Veterinary Parasitology |volume=119|issue=2–3|pages=209–221|doi=10.1016/j.vetpar.2003.10.023|pmid=14746980}}&lt;/ref&gt;

===Clinical presentation===
The most commonly affected bones are the proximal [[humerus]], the distal [[radius (bone)|radius]], the distal [[femur]], and the [[tibia]],&lt;ref name=Morrison_1998&gt;{{cite book|author=Morrison, Wallace B.|title=Cancer in Dogs and Cats|url=https://archive.org/details/cancerindogscats0000morr|url-access=registration|edition=1st|publisher=Williams and Wilkins|year=1998|isbn=978-0-683-06105-5}}&lt;/ref&gt; following the basic premise &quot;far from the elbow, close to the knee&quot;. Other sites include the ribs, the [[Human mandible|mandible]], the spine, and the pelvis.  Rarely, osteosarcoma may arise from soft tissues (extraskeletal osteosarcoma). [[Metastasis]] 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]] 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]]. Differential diagnosis of the osteosarcoma of the skull in particular includes, among others, [[chondrosarcoma]] and the [[multilobular tumour of bone]].&lt;ref&gt;{{cite journal|vauthors=Loukopoulos P, Thornton JR, Robinson WF|title=Clinical and pathologic relevance of p53 index in canine osseous tumors|journal=Veterinary Pathology|date=May 2003|volume=40|issue=3|pages=237–48|doi=10.1354/vp.40-3-237|pmid=12724563|doi-access=free}}&lt;/ref&gt;&lt;ref&gt;{{cite journal|last=Psychas|first=V|author2=Loukopoulos, P |author3=Polizopoulou, ZS |author4= Sofianidis, G |title=Multilobular tumour of the caudal cranium causing severe cerebral and cerebellar compression in a dog.|journal=Journal of Veterinary Science|date=March 2009|volume=10|issue=1|pages=81–3|pmid=19255529|pmc=2801101|doi=10.4142/jvs.2009.10.1.81}}&lt;/ref&gt;

===Treatment and prognosis===
Amputation is the initial treatment, although this alone will not prevent metastasis. [[Chemotherapy]] combined with amputation improves the survival time, but most dogs still die within a year.&lt;ref name=Morrison_1998/&gt; Surgical techniques designed to save the leg (limb-sparing procedures) do not improve the prognosis.&lt;ref&gt;{{Cite journal |last1=Mitchell |first1=Katherine E. |last2=Boston |first2=Sarah E. |last3=Kung |first3=Marvin |last4=Dry |first4=Sarah |last5=Straw |first5=Rod C. |last6=Ehrhart |first6=Nicole P. |last7=Ryan |first7=Stewart D. |date=5 January 2016 |title=Outcomes of Limb-Sparing Surgery Using Two Generations of Metal Endoprosthesis in 45 Dogs With Distal Radial Osteosarcoma. A Veterinary Society of Surgical Oncology Retrospective Study |url=https://onlinelibrary.wiley.com/doi/10.1111/vsu.12423 |journal=Veterinary Surgery |language=en |volume=45 |issue=1 |pages=36–43 |doi=10.1111/vsu.12423 |pmid=26731595 |issn=0161-3499|url-access=subscription }}&lt;/ref&gt;

Some current studies indicate [[osteoclast]] 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 fracture]]s.&lt;ref name=Tomlin&gt;{{cite journal|vauthors=Tomlin JL, Sturgeon C, Pead MJ, Muir P|title=Use of the bisphosphonate drug alendronate for palliative management of osteosarcoma in two dogs|journal=The Veterinary Record|date=29 July 2000|volume=147|issue=5|pages=129–32|pmid=10958534|doi=10.1136/vr.147.5.129|s2cid=35757270|url=http://researchonline.rvc.ac.uk/id/eprint/7209/ }}&lt;/ref&gt;

=== 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''&lt;ref&gt;{{Cite journal |last1=Fenger |first1=Joelle M. |last2=London |first2=Cheryl A. |last3=Kisseberth |first3=William C. |date=2014 |title=Canine osteosarcoma: a naturally occurring disease to inform pediatric oncology |journal=ILAR Journal |volume=55 |issue=1 |pages=69–85 |doi=10.1093/ilar/ilu009 |issn=1930-6180 |pmid=24936031|doi-access=free }}&lt;/ref&gt;''.'' In contrast, mutations in the histone methyltransferase gene ''SETD2'' are rare in human osteosarcoma, but have been identified in 21% of canine tumors.&lt;ref&gt;{{Cite journal |last1=Sakthikumar |first1=Sharadha |last2=Elvers |first2=Ingegerd |last3=Kim |first3=Jaegil |last4=Arendt |first4=Maja L. |last5=Thomas |first5=Rachael |last6=Turner-Maier |first6=Jason |last7=Swofford |first7=Ross |last8=Johnson |first8=Jeremy |last9=Schumacher |first9=Steven E. |last10=Alföldi |first10=Jessica |last11=Axelsson |first11=Erik |last12=Couto |first12=C. Guillermo |last13=Kisseberth |first13=William C. |last14=Pettersson |first14=Mats E. |last15=Getz |first15=Gad |date=2018-07-01 |title=''SETD2'' Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma |journal=Cancer Research |volume=78 |issue=13 |pages=3421–3431 |doi=10.1158/0008-5472.can-17-3558 |pmid=29724721 |issn=0008-5472|doi-access=free }}&lt;/ref&gt;

===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]].&lt;ref name=Morrison_1998/&gt;

===Dinosaurs===
A 2020 study, published in ''The Lancet Oncology'', reports the first confirmed case of osteosarcoma in a dinosaur, a ''Centrosaurus apertus'' from the Late [[Cretaceous]], about 77 to 75.5 million years ago.&lt;ref&gt;Seper Ekhtiari et al. &quot;First Case of Osteosarcoma in a Dinosaur: A Multimodal Diagnosis&quot; ''The Lancet Oncology, 21''.&lt;/ref&gt; 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==
{{Reflist}}

==Further reading==
* {{cite book |author=Jaffe, N. |title=Pediatric and Adolescent Osteosarcoma |publisher=Springer |location=New York |year=2010 |isbn=978-1-4419-0283-2 }}  Osteosarcoma research: past, present and future.

== External links ==
* [http://www.cancer.gov/cancertopics/pdq/treatment/osteosarcoma/patient National Cancer Institute—patient information on osteosarcoma]
* [https://www.reininsarcoma.org/what-is-sarcoma-2/bone-sarcomas/osteosarcoma-an-introduction/ Osteosarcoma – An Introduction] {{Webarchive|url=https://web.archive.org/web/20201027063545/https://www.reininsarcoma.org/what-is-sarcoma-2/bone-sarcomas/osteosarcoma-an-introduction/ |date=2020-10-27 }}
* [http://sarcomahelp.org/osteosarcoma.html What is osteosarcoma?] {{Webarchive|url=https://web.archive.org/web/20090421120936/http://sarcomahelp.org/osteosarcoma.html |date=2009-04-21 }}

{{Medical resources
| DiseasesDB      = 9392
| ICD10           = {{ICD10|C|40||c|40}}-{{ICD10|C|41||c|40}}
| ICD9            = {{ICD9|170}}
| ICDO            = {{ICDO|9180|3}}
| OMIM            = 259500
| MedlinePlus     = 001650
| eMedicineSubj   = ped
| eMedicineTopic  = 1684
| eMedicine_mult  = {{eMedicine2|orthoped|531}} {{eMedicine2|radio|504}} {{eMedicine2|radio|505}}
| MeshID          = D012516
| Orphanet        = 668
| SNOMED CT       = 21708004
}}
{{Osseous and chondromatous tumors}}
{{Authority control}}

[[Category:Cancer in cats]]
[[Category:Cancer in dogs]]
[[Category:Causes of amputation]]
[[Category:Osseous and chondromatous neoplasia]]
[[Category:Pediatric cancers]]
[[Category:Sarcoma]]