Osteosarcoma (OS) is a primary malignant bone tumor, generally arising in the long bones and, more rarely, in soft tissues. [1, 2] Although OS occurs in adolescents and the elderly, it predominantly affects children, teenagers, and young adults. [3-5] The clinical presentation of OS is similar in the pediatric and elderly age groups, however, there are some notable differences. [6] OS occurs in the wide portions of lower long bones where growth occurs (known as the metaphysis region) such as the tibia and femur. Patients older than 25 years are more likely than pediatric patients to have OS present in other bones. [7] OS typically arises within the medullary cavity, the central cavity of the bone where bone marrow is stored, then penetrates the outer surface of the bone (cortex) to eventually involve surrounding soft tissues. [8] Patients with OS commonly present with pain prior to tumor growth; such pain is primarily due to the stretching of the thin membrane surrounding the outside of the bone (periosteum), which causes extreme discomfort. Small stress fractures can also occur during OS development, weakening the bone. Sudden severe pain occurs before OS-related fractures, which is present in up to 15% of pediatric patients, but less frequently in adults. [2] OS is a highly metastatic cancer, meaning it is likely to spread to other body parts, with up to 20% of OS patients having detectable lung metastasis upon initial diagnosis, increasing to 40% of patients developing lung metastasis in later stages. This occurs more frequently in pediatric patients compared to adult patients. [3, 9]

The cause of OS is unclear. OS often appears during the pubescent growth spurt and occurs in sites of maximum growth, suggesting rapid bone development may play a role in its progression. [9] Although OS is mainly sporadic, research suggests the development of OS results from changes to various genes, such as TP53, RB1, ATRX, and DLG2, as well as the involvement of the tumor suppressing protein p53 (p53) pathway. [10] Risk factors for OS include exposure to radiation or alkylating agents, male sex, and the presence of hereditable genetic syndromes, such as Li-Fraumeni syndrome and hereditary retinoblastoma. [4, 11]

Due to the highly metastatic nature of the disease, treatment includes combinations of chemotherapy and surgical resection, a specific surgery to remove the tumor. The use of radiation therapy remains controversial, so it is only recommended in cases where surgical resection is not possible. [1, 13, 14] Surgical resection through amputation, limb salvage, or rotationplasty is recommended after initial imaging and diagnosis to prevent recurrence of the tumor. Approximately 80-90% of OS patients are treated with limb salvage, a process that replaces a diseased bone and reconstructs a functional limb through a metal implant. However, surgery alone is only moderately effective, so chemotherapy is recommended after surgery to improve outcomes. [1, 2, 13] Notably, since children with OS have immature skeletons, the surgical resection of OS tumors can often impact growing tissue, so the treatment of OS in this population is difficult. [1] Additionally, pediatric patients can have lifelong severe side effects from chemotherapy treatments, including hearing loss, heart muscle disease, and infertility. [7, 9]

Despite available therapy, patient prognosis remains poor with only 55-65% of patients surviving after 5 years. [3, 5, 15] Additionally, patients with detectable metastatic OS often have treatment-resistant disease, resulting in survival rates of only 15-30%. [10, 16] Therefore, new therapies are needed to improve the outcomes of patients with this serious and debilitating disease.

References

1. Misaghi, A., et al., Osteosarcoma: a comprehensive review. Sicot j, 2018. 4: p. 12.
2. Picci, P., Osteosarcoma (osteogenic sarcoma). Orphanet J Rare Dis, 2007. 2: p. 6.
3. Huang, X., et al., Risk and clinicopathological features of osteosarcoma metastasis to the lung: A population-based study. J Bone Oncol, 2019. 16: p. 100230.
4. NORD. Osteosarcoma. 2018  03/31/2022]; Available from: https://rarediseases.org/rare-diseases/osteosarcoma/.
5. Ottaviani, G. and N. Jaffe, The epidemiology of osteosarcoma. Cancer Treat Res, 2009. 152: p. 3-13.
6. Kumar, R., et al., Primary Osteosarcoma in the Elderly Revisited: Current Concepts in Diagnosis and Treatment. Curr Oncol Rep, 2018. 20(2): p. 13.
7. Lindsey, B.A., J.E. Markel, and E.S. Kleinerman, Osteosarcoma Overview. Rheumatol Ther, 2017. 4(1): p. 25-43.
8. Broadhead, M.L., et al., The molecular pathogenesis of osteosarcoma: a review. Sarcoma, 2011. 2011: p. 959248.
9. Taran, S.J., R. Taran, and N.B. Malipatil, Pediatric Osteosarcoma: An Updated Review. Indian J Med Paediatr Oncol, 2017. 38(1): p. 33-43.
10. Lin, Y.H., et al., Osteosarcoma: Molecular Pathogenesis and iPSC Modeling. Trends Mol Med, 2017. 23(8): p. 737-755.
11. Calvert, G.T., et al., At-Risk Populations for Osteosarcoma: The Syndromes and Beyond. Sarcoma, 2012. 2012: p. 152382.
12. Kundu, Z.S., Classification, imaging, biopsy and staging of osteosarcoma. Indian J Orthop, 2014. 48(3): p. 238-46.
13. Ayerza, M.A., et al., Does increased rate of limb-sparing surgery affect survival in osteosarcoma? Clin Orthop Relat Res, 2010. 468(11): p. 2854-9.
14. NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Bone Cancer Version 2.2022 – October 9, 2021. 2021  03/31/2022]; Available from: https://www.nccn.org/professionals/physician_gls/pdf/bone.pdf.
15. Luu, H.H., et al., An orthotopic model of human osteosarcoma growth and spontaneous pulmonary metastasis. Clin Exp Metastasis, 2005. 22(4): p. 319-29.
16. Cottrell, J., A Review of Osteosarcoma Therapeutics. Journal of Cancer Treatment and Diagnosis, 2018. 2: p. 21-29.

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