Bone sarcoma risk factors

Prevention

Preventable cases of bone sarcoma, UK

Radiation

Bone sarcoma cases linked to ionising radiation exposure, UK

Less than 1% of bone sarcoma cases each year in the UK are linked to major lifestyle and other risk factors.[1]

Bone sarcoma risk is associated with a number of risk factors.[2,3]

Bone Sarcoma Risk Factors

  Increases risk Decreses risk
'Sufficient' or 'convincing' evidence
  • Plutonium
  • Radium-224 and its decay products
  • Radium-226 and its decay products
  • Radium-228 and its decay products
  • X-radiation, gamma-radiation
 
'Limited' or 'probable' evidence
  • Radioiodines, including Iodine-131
 

International Agency for Research on Cancer (IARC) classification. World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) classification does not include bone sarcoma because it is not generally recognised to have a relationship to food, nutrition, and physical activity.

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Several sources of ionising radiation are classified by the International Agency for Research on Cancer (IARC) as causes of bone tumours, including plutonium, radium-224, -226 and -228, X-radiation and gamma-radiation.[1]

Exposure to ionising radiation increases bone sarcoma risk, and risk appears to increase in line with exposure levels, though most evidence is on absorbed doses between 5 and 20 Gray (Gy), and many studies define bone sarcoma by anatomical site rather than morphology.[2] Typical sources of exposure are radiotherapy Open a glossary item medical diagnostics (e.g. X-rays), and natural background radiation (e.g. radon Open a glossary item.)[3]

Radiotherapy for cancer during childhood appears to have the greatest impact on bone sarcoma risk; however confounding is possible because much evidence includes populations with primary retinoblastoma, which in itself is associated with bone sarcoma risk.[2,4] Childhood cancer survivors who received around 20Gy from radiotherapy have around 6-38 times higher bone sarcoma risk compared with those who had no radiotherapy or very low doses; bone sarcoma risk increases with radiation doses received.[2,4] Abdominal/pelvic radiotherapy during childhood is associated with 3.1 times increased bone tumour risk, compared with no radiotherapy; radiotherapy to other body sites showed no significant effect in a British cohort study.[5]

Radiotherapy for cancer (other than bone cancer) during adulthood is associated with 2.4 times increased risk of subsequent bone sarcoma compared to the general population analysis of US cancer registry data shows; with higher risk for those diagnosed at younger adult ages.[2] The risk of osteosarcoma is increased by 5.1 times following radiotherapy, but chondrosarcoma risk is not significantly elevated.[6] Bone sarcoma risk in patients with prior adult radiotherapy increases with longer time since diagnosis of the first cancer, and younger age at radiotherapy; there is also some evidence the risk varies by site of the primary cancer (hence the site of the radiotherapy).[2]

Atomic bomb survivors (who have lower overall levels of exposure than patients receiving radiotherapy) have around 7.5 times increased bone sarcoma risk per 1Gy exposure, a cohort study showed.[7] Studies of radiotherapy at doses lower than 5Gy have generally found no increased bone sarcoma risk, but low sample sizes preclude firm conclusions.[2]

IARC classifies radioiodines, including Iodine-131, as possible causes of bone tumours, based on limited evidence.[1] Iodine-131 is a radioactive isotope which can be used to treat hyperthyroidism and some types of thyroid cancer.

Exposure to computed tomography (CT) scans during childhood or adolescence is not associated with an increased risk of bone tumours, a large cohort study showed.[8]

References

  1. International Agency for Research on Cancer. List of Classifications by cancer sites with sufficient or limited evidence in humans, Volumes 1 to 105*. Available from http://monographs.iarc.fr/ENG/Classification/index.php. Accessed October 2013.
  2. Berrington de Gonzalez A, Kutsenko A, Rajaraman P. Sarcoma risk after radiation exposure. Clin Sarcoma Res 2012;2(1):18.
  3. Parkin DM, Darby SC. Cancers in 2010 attributable to ionising radiation exposure in the UK. Br J Cancer 2011;105 Suppl 2:S57-65.
  4. Reulen RC, Frobisher C, Winter DL, et al. Long-term risks of subsequent primary neoplasms among survivors of childhood cancer. JAMA. 2011 Jun 8;305(22):2311-9.
  5. Wu LC, Kleinerman RA, Curtis RE, Savage SA, de González AB. Patterns of bone sarcomas as a second malignancy in relation to radiotherapy in adulthood and histologic type. Cancer Epidemiol Biomarkers Prev. 2012 Nov;21(11):1993-9.
  6. Samartzis D, Nishi N, Hayashi M, et al. Exposure to ionizing radiation and development of bone sarcoma: new insights based on atomic-bomb survivors of Hiroshima and Nagasaki. J Bone Joint Surg Am. 2011 Jun 1;93(11):1008-15.
  7. Mathews JD, Forsythe AV, Brady Z, et al. Cancer risk in 680,000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians. BMJ. 2013 May 21;346:f2360
  8. Schwartz B, Benadjaoud MA, Cléro E, et al. Risk of second bone sarcoma following childhood cancer: role of radiation therapy treatment. Radiat Environ Biophys. 2014 Jan 14.
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Bone cancer subsequent to a previous cancer can occur either as a second primary tumour (starting in the bones), or as metastasis Open a glossary item from the primary site (spreading to the bones from elsewhere). Bone is one of the most common sites of metastasis.

The risk of second primary bone sarcoma appears to be very largely associated with receipt of radiotherapy and/or chemotherapy for the primary tumour.[1,2] However for some tumours, shared aetiology is also a factor - for example bone sarcoma and retinoblastoma are linked with the same gene fault.[1,2]

Second primary sarcomas (of bone or soft tissue) in people who have had a previous cancer represent 7.5% of all sarcoma cases, though bone accounts for a fairly small proportion (12%) of these, a cohort study showed.[2]

Bone cancer risk is 30-50 times higher in people with a previous bone cancer, a cohort study showed.[3] Bone cancer risk is higher in non-Hodgkin lymphoma (NHL) survivors.[4] Bone cancer risk is higher in oral cavity, rectum and anus, or cervix cancer survivors who received radiotherapy for their primary cancer.[4]

Bone cancer risk is 19-38 times higher in people who survived cancer in childhood, compared with the general population, cohort studies have shown.[5,6] The risk is higher for those who had their primary cancer at a younger age, who received radiotherapy or alkylating agents, and/or whose primary diagnosis was kidney cancer, soft tissue sarcoma or bone sarcoma.[6]

References

  1. Berrington de Gonzalez A, Kutsenko A, Rajaraman P. Sarcoma risk after radiation exposure. Clin Sarcoma Res 2012;2(1):18.
  2. Bjerkehagen B, Småstuen MC, Hall KS, et al. Incidence and mortality of second sarcomas - A population-based study. Eur J Cancer 2013; doi: 10.1016/j.ejca.2013.05.017
  3. Dong C, Hemminki K. Second primary neoplasms in 633,964 cancer patients in Sweden, 1958-1996. Int J Cancer 2001;93(2):155-61.
  4. Wu LC, Kleinerman RA, Curtis RE, Savage SA, de González AB. Patterns of bone sarcomas as a second malignancy in relation to radiotherapy in adulthood and histologic type. Cancer Epidemiol Biomarkers Prev. 2012 Nov;21(11):1993-9.
  5. Reulen RC, Frobisher C, Winter DL, et al. Long-term risks of subsequent primary neoplasms among survivors of childhood cancer. JAMA. 2011 Jun 8;305(22):2311-9.
  6. Friedman DL, Whitton J, Leisenring W, et al. Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 2010;102(14):1083-95.
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Genetic predisposition syndromes are associated with a small percentage of bone tumours, typically osteosarcomas.[1,2]

Li-Fraumeni syndrome Open a glossary item is a very rare genetic condition associated with increased risk of osteosarcoma and other cancer types.[3] It is usually caused by mutation in the tumour suppressor gene TP53, which is thought to affect 1 in 5,000-20,000 births in the general population.[4] People with TP53 mutation have around 100 times the risk of bone tumours compared with the general population, and bone sarcomas are the most common tumour group in mutation carriers aged 11-20 years.[3]

Heritable (hereditary) retinoblastoma Open a glossary item a rare eye cancer diagnosed in children, is caused by a mutation in the tumour suppressor gene RB1.[5] Heritable retinoblastoma survivors have around 200 times increased risk of subsequent bone sarcoma, and more than 400 times increased risk of oesteosarcoma specifically, a British cohort study showed.[6] The increased risk of bone sarcomas in this population is thought to be due to a combination of genetic susceptibility and radiotherapy for the primary cancer.[5,6]

Hereditary multiple exostoses Open a glossary item (also known as multiple osteochondromatosis or diaphyseal aclasis) is a rare (affecting up to 1 in 50,000 people) inherited musculoskeletal condition which causes short stature and deformity.[7] In around 5% of people with this condition, benign bone lesions (osteochondromas) transform to chondrosarcomas, a cohort study showed.[8]

Neurofibromatoses (NF) Open a glossary item are a group of genetic conditions in which benign (non-invasive) growths affect the nervous system. NF type 1 (NF1) is thought to affect around 1 in 2,700 live births in the UK, whilst NF type 2 (NF2) affects around 1 in 33,000.[9] There is some indication that people with NF1 have an increased risk of bone sarcoma.[10,11]

The RecQ syndromes (Rothmund-Thomson, RAPADILINO, Werner and Bloom syndromes, and Diamond blackfan anaemia) are associated with osteosarcoma predisposition; these rare syndromes also cause growth retardation and dermatological changes.[2]

Osteosarcoma risk is higher in children and adolescents with Down's syndrome Open a glossary item, a cohort study showed.[12]

References

  1. Burningham Z, Hashibe M, Spector L, Schiffman JD. The epidemiology of sarcoma. Clin Sarcoma Res 2012;2(1):14.
  2. Calvert GT, Randall RL, Jones KB, et al. At-risk populations for osteosarcoma: the syndromes and beyond. Sarcoma. 2012;2012:152382.
  3. Schneider K, Garber J. Li-Fraumeni Syndrome. In: Pagon RA, Bird TD, Dolan CR, et al, editor. GeneReviews™ [internet]. Seattle (WA): University of Washington, 1999 [Updated 2010].
  4. Ognjanovic S, Olivier M, Bergemann TL, Hainaut P. Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database. Cancer 2012;118(5):1387-96.
  5. Kleinerman RA, Schonfeld SJ, Tucker MA. Sarcomas in hereditary retinoblastoma. Clin Sarcoma Res 2012;2(1):15.
  6. MacCarthy A, Bayne AM, Brownbill PA, et al. Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004. Br J Cancer. 2013 Jun 25;108(12):2455-63.
  7. Porter DE, Lonie L, Fraser M, et al. Severity of disease and risk of malignant change in hereditary multiple exostoses. A genotype-phenotype study. J Bone Joint Surg Br. 2004 Sep;86(7):1041-6.
  8. Pedrini E, Jennes I, Tremosini M, et al. Genotype-phenotype correlation study in 529 patients with multiple hereditary exostoses: identification of "protective" and "risk" factors. J Bone Joint Surg Am. 2011 Dec 21;93(24):2294-302.
  9. Evans DG, Howard E, Giblin C, et al. Birth incidence and prevalence of tumor-prone syndromes: Estimates from a UK family genetic register service. Am J Med Genet A 2010; 152A(2):327-32.
  10. Afşar CU, Kara IO, Kozat BK, et al. Neurofibromatosis type 1, gastrointestinal stromal tumor, leiomyosarcoma and osteosarcoma: four cases of rare tumors and a review of the literature. Crit Rev Oncol Hematol. 2013 May;86(2):191-9.
  11. Chowdhry M, Hughes C, Grimer RJ, et al. Bone sarcomas arising in patients with neurofibromatosis type 1. J Bone Joint Surg Br. 2009 Sep;91(9):1223-6.
  12. Botto LD, Flood T, Little J, et al. Cancer risk in children and adolescents with birth defects: a population-based cohort study. PLoS One 2013;8(7):e69077.
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People with a parental or sibling history of bone cancer still have only a small risk of developing the disease themselves; less than 1% of bone cancer cases are in people with a first-degree relative Open a glossary item with the disease, a large cohort study showed.[1] However, children whose sibling had Ewing sarcoma may have a 16.5 times increased risk of being diagnoses with the same disease; though this figure is based on very few patients so should be interpreted cautiously.[2]

Parent/sibling history of some other cancers is associated with increased bone cancer risk, particularly early-onset bone cancers, further evidence from the same cohort shows.[2] Osteosarcoma risk overall is around doubled in people whose mother or father had rectal cancer or whose father had colon cancer, and increased by 3.6 times in those whose mother had endocrine gland cancer; in people aged under 25 osteosarcoma risk is threefold higher in people whose mother had melanoma, and 1.7 times higher in those whose mother had breast cancer; and in children osteosarcoma risk is around quadrupled when a parent had liver cancer, and doubled with the mother had breast cancer - with around a fivefold increase if the mother was under 45 at her diagnosis.[2] Ewing sarcoma risk too is linked with family history of kidney cancer, with risk 5.6 times higher in children of an affected parent.[2]

References

  1. Hemminki K, Sundquist J, Bermejo JL. How common is familial cancer? Ann Oncol. 2008 Jan;19(1):163-7.
  2. Ji J, Hemminki K. Familial risk for histology-specific bone cancers: an updated study in Sweden. Eur J Cancer. 2006 Sep;42(14):2343-9.
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Being born heavier than average for your sex is associated with a 35% increased risk of osteosarcoma later in life, compared with average birth weight people, a pooled analysis showed.[1]

People who are taller than average for their age and sex have a 35% increased risk of osteosarcoma, compared with average-height people, and very tall people (in the top 10% of height for their age) have 2.6 times the average-height risk, according to the same analysis.[1] Rapid growth during puberty is thought to underpin this effect.[2,3] Height does not appear to be associated with Ewing sarcoma risk.[4]

References

  1. Mirabello L, Pfeiffer R, Murphy G, et al. Height at diagnosis and birth-weight as risk factors for osteosarcoma. Cancer Causes Control. 2011 Jun;22(6):899-908.
  2. Ji J, Hemminki K. Familial risk for histology-specific bone cancers: an updated study in Sweden. Eur J Cancer. 2006 Sep;42(14):2343-9.
  3. Arora RS, Alston RD, Eden TO, et al. The contrasting age-incidence patterns of bone tumours in teenagers and young adults: Implications for aetiology. Int J Cancer 2012;131:1678-85.
  4. Arora RS, Kontopantelis E, Alston RD, et al. Relationship between height at diagnosis and bone tumours in young people: a meta-analysis. Cancer Causes Control. 2011 May;22(5):681-8.
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Several non-heritable conditions characterised by benign bone lesions can in a minority of cases transform to malignant bone tumours:

  • Paget's disease of bone  affects around 5% of the UK population, though it is rare before age 55.[1,2] Transformation to osteosarcoma occurs in less than 0.5% of cases.[3]
  • Ollier's disease Open a glossary item(endochondromatosis affects 1 per 100,000 people, often causing symptoms before age 10.[4] Chondrosarcoma occurs in around 40% of cases, a cohort study showed; the risk is highest when benign lesions are found in the pelvis and lowest when they are in the hands and feet only.[5]
  • Maffucci's syndrome Open a glossary item is a very rare condition in which up to around 60% of patients will develop chondrosarcoma, again the risk varies by the location and extent of the benign tumours.[5]
  • Children who have a congenital umbilical or inguinal hernia have have around three times the risk of Ewing sarcoma of bone or soft tissue, a meta-analysis showed.[6]

References

  1. Corral-Gudino L, Borao-Cengotita-Bengoa M, Del Pino-Montes J, Ralston S.Epidemiology of Paget's disease of bone: a systematic review and meta-analysis of secular changes. Bone. 2013 Aug;55(2):347-52.
  2. Ralston SH. Clinical practice. Paget's disease of bone. Bone. 2009 Mar;44(3):431-6.
  3. Mangham DC, Davie MW, Grimer RJ. Sarcoma arising in Paget's disease of bone: declining incidence and increasing age at presentation. Bone. 2009 Mar;44(3):431-6.
  4. Silve C, Jüppner H. Ollier disease. Orphanet J Rare Dis. 2006 Sep 22;1:37.
  5. Verdegaal SH, Bovée JV, Pansuriya TC, et al. Incidence, predictive factors, and prognosis of chondrosarcoma in patients with Ollier disease and Maffucci syndrome: an international multicenter study of 161 patients. Oncologist. 2011;16(12):1771-9.
  6. Valery PC, Holly EA, Sleigh AC, Williams G, Kreiger N, Bain C. Hernias and Ewing's sarcoma family of tumours: a pooled analysis and meta-analysis. Lancet Oncol 2005;6(7):485-90.
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The World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) concluded that any study investigating possible links between bone sarcoma and food, nutrition, and physical activity would be unlikely to be fruitful because these cancers are diverse and rare, and therefore that further investigation is unlikely to be warranted.[1]

Adults exposed to pesticides through their work have around double the risk of bone sarcoma (osteosarcoma or chondrosarcoma), as do woodworkers, blacksmiths, toolmakers, and machine-tool workers, according to a European case-control study; however no dose-response effect was observed, suggesting these associations should be interpreted cautiously.[2] A small case-control study found children of people exposed to wood dusts during their work had around threefold increased risk of Ewing sarcoma, as did sons aged under 15 (but not daughters, at any age) of people who used household pesticides.[3]

Unlike soft tissue sarcoma, bone sarcoma risk is not associated with immunodeficiency.[4,5]

Fluoride in drinking water does not appear to be associated with increased risk of osteosarcoma, studies from Great Britain, the US and Ireland show.[6-8]

References

  1. World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. Washington DC: AICR; 2007.
  2. Merletti F, Richiardi L, Bertoni F, et al. Occupational factors and risk of adult bone sarcomas: a multicentric case-control study in Europe. Int J Cancer. 2006 Feb 1;118(3):721-7.
  3. Moore LE, Gold L, Stewart PA, et al. Parental occupational exposures and Ewing's sarcoma. Int J Cancer. 2005 Apr 10;114(3):472-8.
  4. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007;370(9581):59-67.
  5. Bhatia K, Shiels MS, Berg A, Engels EA. Sarcomas other than Kaposi sarcoma occurring in immunodeficiency: interpretations from a systematic literature review. Curr Opin Oncol. 2012 Sep;24(5):537-46.
  6. Levy M, Leclerc BS. Fluoride in drinking water and osteosarcoma incidence rates in the continental United States among children and adolescents. Cancer Epidemiol. 2012 Apr;36(2):e83-8.
  7. Comber H, Deady S, Montgomery E, Gavin A. Drinking water fluoridation and osteosarcoma incidence on the island of Ireland. Cancer Causes Control. 2011 Jun;22(6):919-24.
  8. Blakey K, Feltbower RG, Parslow RC, et al. 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. Int J Epidemiol. 2014 Feb;43(1):224-34.
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