Epidemiology, Aetiology and Risk Factors
Primary bone sarcomas comprise <2% of all new malignancies in patients of all ages. In older adolescents aged 15-19 years, however, OS and ES account for 5.5% of new cases of all tumor types and in 15 to 24 year-olds they comprise 3.2% of all cancers.1,2 A smaller proportion of chondrosarcomas, conventional type or mesenchymal, and very rare entities such as chordoma account for the rest of bone sarcomas in AYAs. The European age-standardized incidence rate for all bone sarcomas across all ages/ gender per year is 1.0 per 100,000 population, ~0.3 per 100,000 person-years each for OS and ES.3 Several population-based studies provide clear and consistent data about the relative incidence rates of these sarcomas and particularly the relationship with age (Fig. 1A). The commonest bone sarcomas, OS and ES, have a peak incidence in AYAs, with a second peak in OS beyond 70 years (Fig. 1B). The male to female ratios for OS and ES are 1.2 and 1.1.3 A racial disparity is notable for ES, with a higher incidence in Caucasians (Fig. 1C). While modest improvements in outcome for ES are seen in population data, due largely from wider implementation of multidisciplinary care and centralization, the same improvements are not apparent for OS (Fig. 1D).
OS is the most common primary bone sarcoma. In younger patients, most frequently diagnosed between ages 10 to 19 years.4 It arises most commonly in the extremities compared to pelvic, axial and craniofacial primary locations in older patients.5,6Risk factors for OS include prior malignancy and radiation exposure, and particularly so in older patients,- underlying bone conditions such as Paget disease of bone and fibrous dysplasia.7 While the majority of OS is sporadic, inherited cancer predisposition syndromes are recognized; these include Li- Fraumeni syndrome, hereditary retinoblastoma, Diamond-Blackfan anemia, Rothmund-Thompson, Werner and Bloom syndromes.8 In a recent analysis, an estimated 28% of OS patients of all ages were found to carry a rare germline pathogenic, likely pathogenic variant in a cancer-susceptibility gene, with most of those variants in autosomal dominant cancer susceptibility genes, implicating an important role for germline genetic testing in younger patients.9
ES is a small round blue-cell tumor and the third most common primary bone sarcoma of all ages, also most frequently diagnosed between ages 10 to 19 years. It arises mostly in the extremities, followed by pelvis, ribs and vertebra and can also occur in soft tissue and viscera; 25% are metastatic at diagnosis.4,10 ES is characterized by a recurrent balanced chromosomal translocation, resulting in the fusion of the FET family gene EWSR1 with an ETS transcription factor FLI1 in ~80% cases.11Variant fusions will occur between EWSR1 and other genes, including ERG, ETV1, ETV4 and FEV.12 Although somatic mutations in ES are rare; STAG2 and TP53 are associated with poor outcomes.13 Well-defined genetic or other aetiological factors are present in a small proportion of AYAs diagnosed with ES. Germline sequencing and genealogy studies has identified pathogenic or likely pathogenic germline mutations in ~13% of ES patients, commonly in DNA damage repair genes or inactivating variants associated with cancer predisposition syndromes -such as Fanconi anemia and familial breast cancer.14,15
A related entity of ‘Ewing-like’ sarcomas are a heterogeneous group of small round cell tumors considered genetically distinct entities without the typical ES fusions. Ewing-like sarcomas have a predilection for soft tissues in AYAs and have other specific gene rearrangements, including EWSR1-non ETS fusions, CIC-fused, BCOR- and NFATC2- rearrangements.16-19 Differentiation from classical ES suggest the need for specific investigation of optimal treatment strategies.