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Osteosarcoma: Epidemiology, pathogenesis, clinical presentation, diagnosis, and histology

Lisa L Wang, MD
Mark C Gebhardt, MD
Nino Rainusso, MD
Section Editors
Alberto S Pappo, MD
Thomas F DeLaney, MD
Raphael E Pollock, MD
Deputy Editor
Diane MF Savarese, MD


Osteosarcomas are primary malignant tumors of bone that are characterized by the production of osteoid or immature bone by the malignant cells [1-3]. Osteosarcomas are uncommon tumors. Approximately 750 to 900 new cases are diagnosed each year in the United States, of which 400 arise in children and adolescents younger than 20 years of age [4,5]. Despite their rarity, osteosarcomas are the most common primary malignancy of bone in children and adolescents (figure 1), and the fifth most common malignancy among adolescents and young adults aged 15 to 19 [6,7].

The survival of patients with malignant bone sarcomas has improved dramatically with effective chemotherapy. Prior to the use of chemotherapy, 80 to 90 percent of patients with osteosarcoma developed metastatic disease despite achieving local tumor control and died of their disease. It was surmised (and subsequently demonstrated) that the majority of patients had subclinical metastatic disease that was present at the time of diagnosis, even in the absence of overt clinical metastases [8,9].

Chemotherapy can successfully eradicate these deposits if initiated at a time when disease burden is low. As a result, all patients with osteosarcoma (with the exception of patients with low-grade parosteal osteosarcomas and some patients with periosteal osteosarcoma where the value of chemotherapy has been questioned) are treated with adjuvant chemotherapy, and most receive some neoadjuvant chemotherapy in the preoperative period. With multimodality therapy, at least two-thirds of patients with non-metastatic extremity osteosarcomas will be long-term survivors, up to 50 percent of those with limited pulmonary metastases may be cured of their disease, and long-term relapse-free survival can be expected in approximately 25 percent of all patients who present with more extensive metastatic disease.

This topic review will provide an overview of the epidemiology, clinical presentation, diagnosis, staging, and histopathology of patients with osteosarcoma. Diagnostic evaluation and biopsy techniques for primary bone tumors, an overview of treatment and outcomes, principles guiding surgical management of bone sarcomas, and chemotherapy in the treatment of osteosarcoma are discussed in detail separately. (See "Bone tumors: Diagnosis and biopsy techniques" and "Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management" and "Chemotherapy and radiation therapy in the management of osteosarcoma".)


As noted previously, osteosarcoma is an uncommon tumor; it accounts for only 1 percent of all cancers diagnosed annually in the United States. In contrast to Ewing sarcoma, which is extremely rare in older adults, there is a bimodal age distribution of osteosarcoma incidence, with peaks in early adolescence and in adults over the age of 65 (figure 2) [10]. There are differences in tumor site and survival according to age at presentation.


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  1. Huvos A. Bone Tumors: Diagnosis, Treatment, Prognosis, 2nd, WB Saunders, Philadelphia 1991.
  2. Sissons HA. The WHO classification of bone tumors. Recent Results Cancer Res 1976; :104.
  3. McKenna R, Schwinn C, Soong K, et al. Sarcomas of the osteogenic series (osteosarcoma, chondrosarcoma, parosteal osteogenic sarcoma, and sarcomata arising in abnormal bone): an analysis of 552 cases. J Bone Joint Surg Am 1966; 48:1.
  4. Gurney JG, Swensen AR, Bulterys M. Malignant bone tumors. In: Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995 (Pub #99-4649), Ries LA, Smith MAS, Gurney JG, et al (Eds), SEER program, National Cancer Institute, Bethesda, MD 1999. p.99.
  5. Data from the American Cancer Society http://www.cancer.org/docroot/home/index.asp (Accessed on June 01, 2011).
  6. Smith MA, Gurney JG, Ries LA. Cancer in adolescents 15 to 19 years old. In: Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995 (Pub #99-4649), Ries LA, Smith MAS, Gurney JG, et al (Eds), SEER program, National Cancer Institute, Bethesda, MD 1999.
  7. Stiller CA, Bielack SS, Jundt G, Steliarova-Foucher E. Bone tumours in European children and adolescents, 1978-1997. Report from the Automated Childhood Cancer Information System project. Eur J Cancer 2006; 42:2124.
  8. CADE S. Osteogenic sarcoma; a study based on 133 patients. J R Coll Surg Edinb 1955; 1:79.
  9. Dahlin DC, Unni KK. Osteosarcoma of bone and its important recognizable varieties. Am J Surg Pathol 1977; 1:61.
  10. Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer 2009; 115:1531.
  11. http://seer.cancer.gov/publications/childhood/introduction.pdf (Accessed on May 31, 2011).
  12. Bleyer A, O’Leary M, Barr R, Ries LAG (eds). Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival: 1975-2000. NIH Pub. No. 06-5767, National Cancer Institute; Bethesda, MD 2006.
  13. Kramárová E, Stiller CA. The international classification of childhood cancer. Int J Cancer 1996; 68:759.
  14. Rosenburg AE, Cleton-Jansen A-M, de Pinieux G, et al. Conventional osteosarcoma. In: WHO classification of tumours of soft tissue and bone, 4th, Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. (Eds), IARC, Lyon 2013. p.282.
  15. Huvos AG. Osteogenic sarcoma of bones and soft tissues in older persons. A clinicopathologic analysis of 117 patients older than 60 years. Cancer 1986; 57:1442.
  16. Nishida Y, Isu K, Ueda T, et al. Osteosarcoma in the elderly over 60 years: a multicenter study by the Japanese Musculoskeletal Oncology Group. J Surg Oncol 2009; 100:48.
  17. Joo MW, Shin SH, Kang YK, et al. Osteosarcoma in Asian Populations Over the Age of 40 Years: A Multicenter Study. Ann Surg Oncol 2015; 22:3557.
  18. Miller BJ, Cram P, Lynch CF, Buckwalter JA. Risk factors for metastatic disease at presentation with osteosarcoma: an analysis of the SEER database. J Bone Joint Surg Am 2013; 95:e89.
  19. Fuchs B, Pritchard DJ. Etiology of osteosarcoma. Clin Orthop Relat Res 2002; :40.
  20. Grimer RJ, Cannon SR, Taminiau AM, et al. Osteosarcoma over the age of forty. Eur J Cancer 2003; 39:157.
  21. Hadjipavlou A, Lander P, Srolovitz H, Enker IP. Malignant transformation in Paget disease of bone. Cancer 1992; 70:2802.
  22. Hansen MF, Nellissery MJ, Bhatia P. Common mechanisms of osteosarcoma and Paget's disease. J Bone Miner Res 1999; 14 Suppl 2:39.
  23. Nellissery MJ, Padalecki SS, Brkanac Z, et al. Evidence for a novel osteosarcoma tumor-suppressor gene in the chromosome 18 region genetically linked with Paget disease of bone. Am J Hum Genet 1998; 63:817.
  24. Mankin HJ, Hornicek FJ. Paget's sarcoma: a historical and outcome review. Clin Orthop Relat Res 2005; 438:97.
  25. Merchant A, Smielewska M, Patel N, et al. Somatic mutations in SQSTM1 detected in affected tissues from patients with sporadic Paget's disease of bone. J Bone Miner Res 2009; 24:484.
  26. Desai P, Perino G, Present D, Steiner GC. Sarcoma in association with bone infarcts. Report of five cases. Arch Pathol Lab Med 1996; 120:482.
  27. Smith GD, Chalmers J, McQueen MM. Osteosarcoma arising in relation to an enchondroma. A report of three cases. J Bone Joint Surg Br 1986; 68:315.
  28. Zhang J, Walsh MF, Wu G, et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med 2015; 373:2336.
  29. Wong FL, Boice JD Jr, Abramson DH, et al. Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA 1997; 278:1262.
  30. Hawkins MM, Draper GJ, Kingston JE. Incidence of second primary tumours among childhood cancer survivors. Br J Cancer 1987; 56:339.
  31. Hansen MF, Koufos A, Gallie BL, et al. Osteosarcoma and retinoblastoma: a shared chromosomal mechanism revealing recessive predisposition. Proc Natl Acad Sci U S A 1985; 82:6216.
  32. Li FP, Fraumeni JF Jr, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res 1988; 48:5358.
  33. Malkin D, Li FP, Strong LC, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990; 250:1233.
  34. Toguchida J, Yamaguchi T, Dayton SH, et al. Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma. N Engl J Med 1992; 326:1301.
  35. Mirabello L, Yeager M, Mai PL, et al. Germline TP53 variants and susceptibility to osteosarcoma. J Natl Cancer Inst 2015; 107.
  36. McIntyre JF, Smith-Sorensen B, Friend SH, et al. Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma. J Clin Oncol 1994; 12:925.
  37. Carnevale A, Lieberman E, Cárdenas R. Li-Fraumeni syndrome in pediatric patients with soft tissue sarcoma or osteosarcoma. Arch Med Res 1997; 28:383.
  38. Wang LL, Levy ML, Lewis RA, et al. Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients. Am J Med Genet 2001; 102:11.
  39. Leonard A, Craft AW, Moss C, Malcolm AJ. Osteogenic sarcoma in the Rothmund-Thomson syndrome. Med Pediatr Oncol 1996; 26:249.
  40. Wang LL, Gannavarapu A, Kozinetz CA, et al. Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J Natl Cancer Inst 2003; 95:669.
  41. Hauben EI, Arends J, Vandenbroucke JP, et al. Multiple primary malignancies in osteosarcoma patients. Incidence and predictive value of osteosarcoma subtype for cancer syndromes related with osteosarcoma. Eur J Hum Genet 2003; 11:611.
  42. Gorlick R, Bielack S, Teot L, et al. Osteosarcoma: Biology, diagnosis, treatment, and remaining challenges. In: Principles and Practice of Pediatric Oncology, 6th ed, Pizzo PA, Poplack DG (Eds), Lippincott, Williams and Wilkins, Philadelphia PA 2011. p.1015.
  43. Buckley JD, Pendergrass TW, Buckley CM, et al. Epidemiology of osteosarcoma and Ewing's sarcoma in childhood: a study of 305 cases by the Children's Cancer Group. Cancer 1998; 83:1440.
  44. Troisi R, Masters MN, Joshipura K, et al. Perinatal factors, growth and development, and osteosarcoma risk. Br J Cancer 2006; 95:1603.
  45. Gorlick R, Khanna C. Osteosarcoma. J Bone Miner Res 2010; 25:683.
  46. Chou AJ, Geller DS, Gorlick R. Therapy for osteosarcoma: where do we go from here? Paediatr Drugs 2008; 10:315.
  47. Kruzelock RP, Murphy EC, Strong LC, et al. Localization of a novel tumor suppressor locus on human chromosome 3q important in osteosarcoma tumorigenesis. Cancer Res 1997; 57:106.
  48. Yamaguchi T, Toguchida J, Yamamuro T, et al. Allelotype analysis in osteosarcomas: frequent allele loss on 3q, 13q, 17p, and 18q. Cancer Res 1992; 52:2419.
  49. Tarkkanen M, Karhu R, Kallioniemi A, et al. Gains and losses of DNA sequences in osteosarcomas by comparative genomic hybridization. Cancer Res 1995; 55:1334.
  50. Gorlick R, Anderson P, Andrulis I, et al. Biology of childhood osteogenic sarcoma and potential targets for therapeutic development: meeting summary. Clin Cancer Res 2003; 9:5442.
  51. Bridge JA, Nelson M, McComb E, et al. Cytogenetic findings in 73 osteosarcoma specimens and a review of the literature. Cancer Genet Cytogenet 1997; 95:74.
  52. Chandar N, Donehower L, Lanciloti N. Reduction in p53 gene dosage diminishes differentiation capacity of osteoblasts. Anticancer Res 2000; 20:2553.
  53. Ohyama K, Chung CH, Chen E, et al. p53 influences mice skeletal development. J Craniofac Genet Dev Biol 1997; 17:161.
  54. Hayden JB, Hoang BH. Osteosarcoma: basic science and clinical implications. Orthop Clin North Am 2006; 37:1.
  55. Meyers PA, Gorlick R. Osteosarcoma. Pediatr Clin North Am 1997; 44:973.
  56. Thorpe WP, Reilly JJ, Rosenberg SA. Prognostic significance of alkaline phosphatase measurements in patients with osteogenic sarcoma receiving chemotherapy. Cancer 1979; 43:2178.
  57. Link MP, Goorin AM, Horowitz M, et al. Adjuvant chemotherapy of high-grade osteosarcoma of the extremity. Updated results of the Multi-Institutional Osteosarcoma Study. Clin Orthop Relat Res 1991; :8.
  58. Ferrari S, Bacci G, Picci P, et al. Long-term follow-up and post-relapse survival in patients with non-metastatic osteosarcoma of the extremity treated with neoadjuvant chemotherapy. Ann Oncol 1997; 8:765.
  59. Mialou V, Philip T, Kalifa C, et al. Metastatic osteosarcoma at diagnosis: prognostic factors and long-term outcome--the French pediatric experience. Cancer 2005; 104:1100.
  60. Ferguson WS, Goorin AM. Current treatment of osteosarcoma. Cancer Invest 2001; 19:292.
  61. Longhi A, Errani C, Gonzales-Arabio D, et al. Osteosarcoma in patients older than 65 years. J Clin Oncol 2008; 26:5368.
  62. Papagelopoulos PJ, Galanis EC, Vlastou C, et al. Current concepts in the evaluation and treatment of osteosarcoma. Orthopedics 2000; 23:858.
  63. Kesselring FO, Penn W. Radiological aspects of 'classic' primary osteosarcoma: value of some radiological investigations: A review. Diagn Imaging 1982; 51:78.
  64. Meyer JS, Nadel HR, Marina N, et al. Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group Bone Tumor Committee. Pediatr Blood Cancer 2008; 51:163.
  65. Panicek DM, Gatsonis C, Rosenthal DI, et al. CT and MR imaging in the local staging of primary malignant musculoskeletal neoplasms: Report of the Radiology Diagnostic Oncology Group. Radiology 1997; 202:237.
  66. Sajadi KR, Heck RK, Neel MD, et al. The incidence and prognosis of osteosarcoma skip metastases. Clin Orthop Relat Res 2004; :92.
  67. Jeffree GM, Price CH, Sissons HA. The metastatic patterns of osteosarcoma. Br J Cancer 1975; 32:87.
  68. Kayton ML, Huvos AG, Casher J, et al. Computed tomographic scan of the chest underestimates the number of metastatic lesions in osteosarcoma. J Pediatr Surg 2006; 41:200.
  69. Pastorino U, Buyse M, Friedel G, et al. Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. J Thorac Cardiovasc Surg 1997; 113:37.
  70. Gilbert JC, Powell DM, Hartman GE, et al. Video-assisted thoracic surgery (VATS) for children with pulmonary metastases from osteosarcoma. Ann Surg Oncol 1996; 3:539.
  71. Yim AP, Lin J, Chan AT, et al. Video-assisted thoracoscopic wedge resections of pulmonary metastatic osteosarcoma: should it be performed? Aust N Z J Surg 1995; 65:737.
  72. McCormack PM, Bains MS, Begg CB, et al. Role of video-assisted thoracic surgery in the treatment of pulmonary metastases: results of a prospective trial. Ann Thorac Surg 1996; 62:213.
  73. Picci P, Vanel D, Briccoli A, et al. Computed tomography of pulmonary metastases from osteosarcoma: the less poor technique. A study of 51 patients with histological correlation. Ann Oncol 2001; 12:1601.
  74. Protocol information available online at http://www.cancer.gov/clinicaltrials/search/view?cdrid=438714&version=healthprofessional (Accessed on June 30, 2011).
  75. Franzius C, Sciuk J, Daldrup-Link HE, et al. FDG-PET for detection of osseous metastases from malignant primary bone tumours: comparison with bone scintigraphy. Eur J Nucl Med 2000; 27:1305.
  76. Franzius C, Daldrup-Link HE, Sciuk J, et al. FDG-PET for detection of pulmonary metastases from malignant primary bone tumors: comparison with spiral CT. Ann Oncol 2001; 12:479.
  77. Liu F, Zhang Q, Zhu D, et al. Performance of Positron Emission Tomography and Positron Emission Tomography/Computed Tomography Using Fluorine-18-Fluorodeoxyglucose for the Diagnosis, Staging, and Recurrence Assessment of Bone Sarcoma: A Systematic Review and Meta-Analysis. Medicine (Baltimore) 2015; 94:e1462.
  78. Hurley C, McCarville MB, Shulkin BL, et al. Comparison of (18) F-FDG-PET-CT and Bone Scintigraphy for Evaluation of Osseous Metastases in Newly Diagnosed and Recurrent Osteosarcoma. Pediatr Blood Cancer 2016; 63:1381.
  79. ESMO/European Sarcoma Network Working Group. Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014; 25 Suppl 3:iii113.
  80. Peabody TD, Simon MA. Making the diagnosis: keys to a successful biopsy in children with bone and soft-tissue tumors. Orthop Clin North Am 1996; 27:453.
  81. Enneking WF. A system of staging musculoskeletal neoplasms. Clin Orthop Relat Res 1986; :9.
  82. Wolf RE, Enneking WF. The staging and surgery of musculoskeletal neoplasms. Orthop Clin North Am 1996; 27:473.
  83. AJCC Cancer Staging Manual, 7th, Edge SB, Byrd Dr, Compton CC, et al.. (Eds), Springer, New York 2010.
  84. Kneisl JS, Rosenberg AE, Anderson PM, et al.. Bone. In: AJCC Cancer Staging Manual, 8th, Amin MB. (Ed), AJCC, Chicago 2017. p.471.
  85. Fletcher JA, Gebhardt MC, Kozakewich HP. Cytogenetic aberrations in osteosarcomas. Nonrandom deletions, rings, and double-minute chromosomes. Cancer Genet Cytogenet 1994; 77:81.
  86. Inwards CY, Unni KK. Classification and grading of bone sarcomas. Hematol Oncol Clin North Am 1995; 9:545.
  87. Nakajima H, Sim FH, Bond JR, Unni KK. Small cell osteosarcoma of bone. Review of 72 cases. Cancer 1997; 79:2095.
  88. Kalil RK, Squire J. Small cell osteosarcoma. In: WHO Classification of tumours of soft tissue and bone, 4th, Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. (Eds), IARC, Lyon 2013. p.291.
  89. Martin SE, Dwyer A, Kissane JM, Costa J. Small-cell osteosarcoma. Cancer 1982; 50:990.
  90. Stea B, Cavazzana A, Kinsella TJ. Small-cell osteosarcoma: correlation of in vitro and clinical radiation response. Int J Radiat Oncol Biol Phys 1988; 15:1233.
  91. Oliveira AM, Okada K, Squire J. Telangiectatic osteosarcoma. In: WHO classification of tumours of soft tissue and bone, 4th, Fletcher CDM, Bridge JA, Hogendoorn PCW, MErtens F. (Eds), IARC, Lyon 2013. p.289.
  92. Rosen G, Huvos AG, Marcove R, Nirenberg A. Telangiectatic osteogenic sarcoma. Improved survival with combination chemotherapy. Clin Orthop Relat Res 1986; :164.
  93. Angelini A, Mavrogenis AF, Trovarelli G, et al. Telangiectatic osteosarcoma: a review of 87 cases. J Cancer Res Clin Oncol 2016; 142:2197.
  94. Romeo S, Bovee JVMG, Jundt G. Undifferentiated high-grade pleomorphic sarcoma. In: WHO classification of tumours of soft tissue and bone, 4th, Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. (Eds), IARC, Lyon 2013. p.364.
  95. Picci P, Bacci G, Ferrari S, Mercuri M. Neoadjuvant chemotherapy in malignant fibrous histiocytoma of bone and in osteosarcoma located in the extremities: analogies and differences between the two tumors. Ann Oncol 1997; 8:1107.
  96. Schajowicz F, McGuire MH, Santini Araujo E, et al. Osteosarcomas arising on the surfaces of long bones. J Bone Joint Surg Am 1988; 70:555.
  97. Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. World Health Organization Classification of tumours of soft tissue and bone, 4th, IARC Press, Lyon 2013.
  98. Raymond AK. Surface osteosarcoma. Clin Orthop Relat Res 1991; :140.
  99. Kaste SC, Fuller CE, Saharia A, et al. Pediatric surface osteosarcoma: clinical, pathologic, and radiologic features. Pediatr Blood Cancer 2006; 47:152.
  100. Sheth DS, Yasko AW, Raymond AK, et al. Conventional and dedifferentiated parosteal osteosarcoma. Diagnosis, treatment, and outcome. Cancer 1996; 78:2136.
  101. Okada K, Unni KK, Swee RG, Sim FH. High grade surface osteosarcoma: a clinicopathologic study of 46 cases. Cancer 1999; 85:1044.
  102. Cesari M, Alberghini M, Vanel D, et al. Periosteal osteosarcoma: a single-institution experience. Cancer 2011; 117:1731.
  103. Grimer RJ, Bielack S, Flege S, et al. Periosteal osteosarcoma--a European review of outcome. Eur J Cancer 2005; 41:2806.
  104. Bane BL, Evans HL, Ro JY, et al. Extraskeletal osteosarcoma. A clinicopathologic review of 26 cases. Cancer 1990; 65:2762.
  105. Lidang Jensen M, Schumacher B, Myhre Jensen O, et al. Extraskeletal osteosarcomas: a clinicopathologic study of 25 cases. Am J Surg Pathol 1998; 22:588.
  106. Ahmad SA, Patel SR, Ballo MT, et al. Extraosseous osteosarcoma: response to treatment and long-term outcome. J Clin Oncol 2002; 20:521.
  107. Lee JS, Fetsch JF, Wasdhal DA, et al. A review of 40 patients with extraskeletal osteosarcoma. Cancer 1995; 76:2253.
  108. Torigoe T, Yazawa Y, Takagi T, et al. Extraskeletal osteosarcoma in Japan: multiinstitutional study of 20 patients from the Japanese Musculoskeletal Oncology Group. J Orthop Sci 2007; 12:424.
  109. Lee S, Lee MR, Lee SJ, et al. Extraosseous osteosarcoma: single institutional experience in Korea. Asia Pac J Clin Oncol 2010; 6:126.
  110. Choi LE, Healey JH, Kuk D, Brennan MF. Analysis of outcomes in extraskeletal osteosarcoma: a review of fifty-three cases. J Bone Joint Surg Am 2014; 96:e2.