Aetiology
The aetiology of osteosarcoma remains unknown. Some patients report a history of trauma, but it is more likely that trauma is the event that draws attention to the already existing tumour and is not the causative agent. The following have all been associated with an increased risk of osteosarcoma, although these risks may only account for a small proportion of cases:[4]
Paget's disease of the bone
Paget's disease of bone is associated with an increased risk for developing secondary osteosarcoma, commonly associated with older age groups (above 60 years).[4] A genetic predisposition may exist in these patients, which is linked to chromosome 18q23.[8] Loss of heterozygosity of chromosome 18q has been reported in patients with primary and Paget-related osteosarcoma.[9][10]
History of radiotherapy
Osteosarcoma is the most common post-radiation malignant neoplasm following therapy for a solid cancer in childhood.[4][11] Evidence suggests that the risk of bone sarcoma increases slowly up to a cumulative radiation organ absorbed dose of 15 Gy and then strongly increases for higher radiation doses of 30 Gy or more, compared with patients not treated with radiotherapy.[12]
Chemotherapy
This is a dose-dependent risk factor for secondary osteosarcoma, especially with alkylating agents.[4][13]
Inherited conditions
Strong risk factors are familial retinoblastoma syndrome, Li-Fraumeni syndrome, and Rothmund-Thomson syndrome, all of which predispose patients to multiple types of neoplasm, including osteosarcoma.[4][14]
Tall stature
Globally an increased risk of osteosarcoma has been observed among the tallest populations, including those in The Netherlands, Iceland, Slovakia, and Czech Republic.[6][7] However, one study which assessed genetic risk scores (GRS) found no overall association between osteosarcoma and genetically inferred taller stature (Odds ratio [OR]=1.06, 95% CI 0.96 to 1.17, P=0.28), although the GRS for taller stature was associated with an increased risk of osteosarcoma in 154 cases with a known pathogenic cancer susceptibility gene variant (OR=1.29, 95% CI 1.03 to 1.63, P=0.03).[5]
High birthweight
Genetically inferred higher birthweight has been associated with an increased risk of osteosarcoma (OR=1.59, 95% CI 1.07 to 2.38, P=0.02). This association was strongest in cases without metastatic disease.[5]
Pathophysiology
A relationship between rapid bone growth and osteosarcoma has been suggested by the fact that its peak incidence coincides with the adolescent growth spurt, although this is not well defined.[14] The peak incidence of osteosarcoma in girls parallels their earlier growth spurt when compared with boys. Furthermore, the incidence of the bones in which osteosarcoma occurs is exactly parallel to the rates of skeletal growth in growth plates, namely distal femur, proximal tibia, and proximal humerus. These observations have led several authors to suggest that osteosarcoma is the result of an aberration of the normal bone growth and remodelling process. However, studies targeting this particular subject have yielded inconclusive results.[15]
Most osteosarcomas show complex unbalanced karyotypes with no recurrent chromosomal translocations or molecular aberrations. However, some molecular abnormalities are identified more often than others and are represented by loss of heterozygosity involving chromosomes 3q, 13p, 17p, and 18q.[16][17]
Emerging evidence has identified a high number of deleterious germline genetic variants in patients with osteosarcoma, particularly in the younger age group.[18][19][20][21] Approximately one-fourth of patients with osteosarcoma have been reported to have a germline pathogenic variant in an established cancer-susceptibility gene, with patients aged <10 years demonstrating the highest frequency.[21]
Classification
World Health Organization classification of malignant osteogenic tumours[1]
Low-grade central osteosarcoma
Conventional osteosarcoma:
Chondroblastic osteosarcoma
Fibroblastic osteosarcoma
Osteoblastic osteosarcoma
Telangiectatic osteosarcoma
Small cell osteosarcoma
Secondary osteosarcoma
Parosteal osteosarcoma
Periosteal osteosarcoma
High-grade surface osteosarcoma
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