Osteosarcoma: An Evolving Understanding of a Complex Disease

John H. Alexander, MD; Odion T. Binitie, MD; G. Douglas Letson, MD; David M. Joyce, MD


J Am Acad Orthop Surg. 2021;29(20):e993-e1004. 

In This Article


Although the overall prognosis of a patient with osteosarcoma has changed little, our understanding of factors influencing survival has improved. Histologic morphology plays an important role in determining the prognosis. In particular, the histologic grade is reflective of tumor biology. Low-grade osteosarcoma, including parosteal osteosarcoma and low-grade central osteosarcoma, has 5-year disease-free survival rates greater than 90%.[21,52] Periosteal osteosarcoma, an intermediate-grade osteosarcoma, is associated with a long-term OS of approximately 85%.[22,25] In comparison, the 5-year OS for nonmetastatic, high-grade osteosarcoma is approximately 80%, while it remains dismal (45%) for patients with metastatic disease at presentation.[16,24] Finally, despite a lower rate of metastatic disease at presentation (11.4%) and relative chemosensitivity compared to other subtypes, the OS rate of telangiectatic osteosarcoma is similar to that of conventional osteosarcoma.[14]

In the EURAMOS-1 registration cohort, poorer EFS was associated with pulmonary or nonpulmonary metastases, axial and proximal (humerus and femur) location, age (adult and adolescent compared with child), male sex, chondroblastic subtype, and a large tumor volume.[16]

The influence of patient age has gained renewed interest as it has become more apparent that older age is associated with poorer prognosis. This difference is evident in both young adult and older patients. Janeway et al[53] found a poorer 10-year EFS and OS in patients older than 18 years of age (37% and 41%) compared with age younger than 10 years (55% and 68%) and ages 10 to 17 years (55% and 60%). Similar findings were demonstrated using the Surveillance, Epidemiology, and End Results database, with patients between ages 25 and 59 years having 10-year survival estimates of 54.1% compared with 64.1% for ages 0 to 24 years and 29.6% for patients aged 60 years or older.[54]

The reason for worse outcomes in older patients with osteosarcoma is thought to be multifactorial, including an inability to receive methotrexate because of poor renal clearance,[9] intolerance leading to abbreviated courses of chemotherapy,[9,13] poorer histologic response to chemotherapy,[13] and higher rates of pelvic tumor location (19%),[1] and presentation with metastatic disease. These (pelvic tumor location and metastatic disease) occur at higher rates in older patients.[30]

Although a more common location in older patients, osteosarcoma of the innominate bone is associated with a poor prognosis, regardless of patient age. Because of the complex anatomy, proximity of neurovascular structures, and the size of pelvic tumors, surgical resection is challenging. The utilization of navigation-assisted pelvic resections shows promise in addressing some of these challenges; however, the long-term oncologic benefits remain uncertain. Pelvic osteosarcoma is associated with higher rates of metastatic disease at presentation, larger size, and high rates of LR (up to 44%) even in the setting of negative surgical margins.[55] Furthermore, in stark contrast to localized osteosarcoma of the appendicular skeleton, localized pelvic osteosarcoma has a similar 5-year EFS and OS to metastatic osteosarcoma of the pelvis with EFS and OS rates of 22% and 48% for localized disease and 23% and 22% for metastatic disease, respectively. The only positive prognostic factor in this patient population was complete surgical resection.[55] These findings suggest that pelvic osteosarcoma may be inherently more aggressive.

Finally, histologic response remains a notable predictor of oncologic outcome. Poor histologic response (≤90% tumor necrosis) is associated with worse EFS and OS.[7,8,16] Histologic subtype may influence response rates to chemotherapy. Specifically, telangiectatic osteosarcoma is relatively chemosensitive[14] in contrast to chondroblastic osteosarcoma, which is associated with poor histologic responses.[15] Finally, older age has been shown to be associated with poorer histologic responses.[13]