Primary Site
Tumor Size
Presence of Clinically Detectable Metastatic Disease
Adequacy of Tumor Resection
Necrosis Following Induction or Neoadjuvant Chemotherapy
Additional Prognostic Factors

Factors that influence prognosis for osteosarcoma include site and size of the primary tumor, presence or absence of clinically detectable metastatic disease, adequacy of resection, and degree of necrosis observed in tumors following initial chemotherapy. The latter two factors are not conventional prognostic factors since they can be assessed only after treatment, not at initial presentation.

The site of the primary tumor is a significant prognostic factor in localized disease. Among tumors of the extremity, distal sites have a more favorable prognosis than proximal sites. Axial skeleton primary tumors are associated with the greatest risk of progression and death.[1,2] Pelvic osteosarcomas make up 7% to 9% of all osteosarcomas; their current overall survival rate is 20% to 47%.[1] For patients with osteosarcoma of craniofacial bones, complete resection of the primary tumor with negative margins is essential for cure.[3-5] Despite a relatively high rate of inferior necrosis following neoadjuvant chemotherapy, fewer patients with craniofacial primaries develop systemic metastases than do patients with osteosarcoma originating in the extremities.[6-8] This low rate of metastasis may be related to the relatively smaller size and higher incidence of lower grade tumors in osteosarcoma of the head and neck. There is a better prognosis for patients who have osteosarcoma of the head and neck than for those who have appendicular lesions when treated with surgery alone. While small series have not shown a benefit from adjuvant chemotherapy for patients with osteosarcoma of the head and neck, one meta-analysis concluded that systemic chemotherapy improves the prognosis for these patients. Another large meta-analysis detected no benefit from chemotherapy for patients with osteosarcoma of the head and neck, but suggested that the incorporation of chemotherapy into treatment of patients with high-grade tumors may improve survival. A retrospective analysis identified a trend toward better survival in patients with high-grade osteosarcoma of the mandible and maxilla who received adjuvant chemotherapy.[9] However, radiation-associated craniofacial osteosarcomas are high-grade lesions, usually fibroblastic, which tend to recur locally and have a high rate of metastasis.[10]

Osteosarcoma in extraskeletal sites is rare in children and young adults. With current combined-modality therapy, the outcome for patients with extraskeletal osteosarcoma appears to be similar to that for patients with primary tumors of bone.[11]

Larger tumors have a worse prognosis than smaller tumors. Tumor size has been assessed by the longest single dimension, by the cross-sectional area, or by an estimate of tumor volume; all have correlated with outcome. Serum lactate dehydrogenase (LDH), which also correlates with outcome, is a likely surrogate for tumor volume.

Patients with localized disease have a much better prognosis than those with overt metastatic disease. As many as 20% of patients will have radiographically detectable metastases at diagnosis, with the lung being the most common site.[12] The prognosis for patients with metastatic disease appears to be determined largely by the site(s), the number of metastases, and the surgical resectability of the metastatic disease.[12-15] Patients who have complete surgical ablation of the primary and metastatic tumor (when confined to the lung) following chemotherapy may attain long-term survival, though overall event-free survival remains about 20% to 30% for patients with metastatic disease at diagnosis.[12,13,16-18] Prognosis appears more favorable for patients with fewer pulmonary nodules and for those with unilateral rather than bilateral pulmonary metastases; however, not every nodule detected indicates metastatic disease.[13,14] The degree of necrosis in the primary tumor after induction chemotherapy remains prognostic in metastatic osteosarcoma.[19] Patients with skip metastases (≥2 discontinuous lesions in the same bone) have been reported to have inferior prognoses.[20] Analysis of the German Cooperative Osteosarcoma Study (COSS) experience, however, suggests that skip lesions in the same bone do not confer an inferior prognosis if they are included in planned surgical resection. Skip lesions across a joint have a worse prognosis.[21] Patients with multifocal osteosarcoma (>1 bone lesion at diagnosis) have an extremely poor prognosis.[22]

Resectability of the tumor is a critical prognostic feature because this tumor is relatively resistant to radiation therapy. Complete resection of tumor-bearing bone with adequate margins is generally considered essential for cure. Skip lesions were previously considered an unfavorable risk factor. Analysis of the German COSS experience, however, suggests that skip lesions do not confer an inferior prognosis if they are included in planned surgical resction.[21] Two studies have examined the outcome for patients with osteosarcoma in the axial skeleton whose tumors were resected with positive margins. In these retrospective analyses of nonrandomized treatments, among patients who had no surgery or intralesional resection, patients who received radiation therapy had better survival than patients who did not receive radiation therapy.[1,23]

Most treatment protocols for osteosarcoma use an initial period of systemic chemotherapy prior to definitive resection of the primary tumor (or resection of sites of metastases for patients with metastatic disease). The pathologist assesses necrosis in the resected tumor. Patients with greater than or equal to 90% [24] necrosis in the primary tumor after induction chemotherapy have a better prognosis than those with less necrosis.[24] Patients with less necrosis (<90%) in the primary tumor following initial chemotherapy have a higher rate of recurrence within the first 2 years compared with patients with a more favorable amount of necrosis (≥90%).[25] Imaging modalities such as dynamic magnetic resonance imaging may offer a noninvasive method to assess necrosis.[26] Less necrosis should not be interpreted to mean that chemotherapy has been ineffective; cure rates for patients with little or no necrosis following induction chemotherapy are much higher than cure rates for patients who receive no chemotherapy.

Patients with osteosarcoma as a second malignant neoplasm share the same prognosis as patients with newly diagnosed disease if they are treated aggressively with surgery and multiagent chemotherapy.[27-31] There have been numerous other identified prognostic features for patients with conventional localized high-grade osteosarcoma. These factors include the age of the patient, LDH level, alkaline phosphatase level, and histologic subtype.[19,24,32-37] A number of potential prognostic factors have been identified but have not been tested in large numbers of patients. These include the expression of HER2/c-erbB-2 (there are conflicting data concerning the prognostic significance of this human epidermal growth factor);[38-40] tumor cell ploidy; specific chromosomal gains or losses;[41] loss of heterozygosity (LOH) of the RB gene;[42,43] LOH of the p53 locus;[44] and increased expression of p-glycoprotein.[45-48] A prospective analysis of p-glycoprotein expression determined by immunohistochemistry failed to identify prognostic significance for newly diagnosed patients with osteosarcoma, although earlier studies suggested that overexpression of p-glycoprotein predicted for poor outcome.[49] Patients with malignant fibrous histiocytoma (MFH) of bone are treated according to osteosarcoma treatment protocols, and the outcome for patients with resectable MFH is similar to the outcome for patients with osteosarcoma.[50] As with osteosarcoma, patients with a favorable necrosis had a longer survival than those with an inferior necrosis.[51] MFH of bone is seen more commonly in older adults.

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