General Information About Osteosarcoma and Undifferentiated Pleomorphic Sarcoma (UPS) (Formerly Called Malignant Fibrous Histiocytoma [MFH]) of Bone

Disease Overview

Osteosarcoma occurs predominantly in adolescents and young adults. Review of data from the National Cancer Institute's National Childhood Cancer Registry resulted in an estimated osteosarcoma incidence rate of 5.4 cases per 1 million each year in people aged 0 to 19 years and 4 cases per 1 million each year in people younger than 40 years.[1] The U.S. Census Bureau estimated that there were 82 million people between the ages of 0 and 19 years, resulting in an incidence of roughly 440 cases per year in this age group.

Osteosarcoma accounts for approximately 5% of childhood tumors. In children and adolescents, more than 50% of these tumors arise from the long bones around the knee. Osteosarcoma is rarely observed in soft tissue or visceral organs. There appears to be no difference in presenting symptoms, tumor location, and outcome for younger patients (<12 years) compared with adolescents.[2,3]

Two trials conducted in the 1980s were designed to determine whether chemotherapy altered the natural history of osteosarcoma after surgical removal of the primary tumor. The outcome of these patients recapitulated the historical experience before 1970. More than one-half of these patients developed metastases within 6 months of diagnosis, and overall, approximately 90% developed recurrent disease within 2 years of diagnosis.[4] Overall survival (OS) for patients treated with surgery alone was statistically inferior.[5] The natural history of osteosarcoma has not changed over time, and fewer than 20% of patients with localized, resectable primary tumors treated with surgery alone can be expected to survive free of relapse.[4,6]; [7][Level of evidence A1]

In 2013, the World Health Organization (WHO) published an update to the Classification of Tumors of Soft Tissue and Bone.[8] They removed the term malignant fibrous histiocytoma (MFH) and replaced it with undifferentiated pleomorphic sarcoma (UPS). This type of sarcoma is much more common in soft tissues. However, it does arise in bone. In bone, it has features that are histologically similar to osteosarcoma, but it does not produce osteoid. Most of the literature describing the clinical behavior and response to therapy for this histology in bone was published before the 2013 WHO update, and a search for UPS of bone will not retrieve these articles. The citations in this summary appear with their titles as published. Therefore, many references will describe MFH of bone, a condition now called UPS of bone.

Diagnostic Evaluation

Osteosarcoma can be diagnosed by core needle biopsy or open surgical biopsy. It is preferable that the biopsy be performed by a surgeon skilled in the techniques of limb sparing (removal of the malignant bone tumor without amputation and replacement of bones or joints with allografts or prosthetic devices). In these cases, the original biopsy incision placement is crucial. Inappropriate alignment of the biopsy or inadvertent contamination of soft tissues can render subsequent limb-preserving reconstructive surgery impossible.

Prognostic Factors

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[1,9,10] For osteosarcoma, the 5-year relative survival rate increased over the same time from 40% to 72% in children younger than 15 years and from 56% to approximately 71% in adolescents aged 15 to 19 years. However, there has been no substantial improvement since the 1980s.[1,11]

In general, prognostic factors for osteosarcoma have not been helpful in identifying patients who might benefit from treatment intensification or who might require less therapy while maintaining an excellent outcome.

Factors that may influence outcome include the following:[12]

• Primary tumor site.
• Size of the primary tumor.
• Presence of clinically detectable metastatic disease.
• Surgical resectability of primary tumor.
• Degree of tumor necrosis after administration of neoadjuvant chemotherapy.
• Age and sex.
• Other possible prognostic factors.

Primary tumor site

The site of the primary tumor is a significant prognostic factor for patients with localized disease. Among extremity tumors, distal sites have a more favorable prognosis than do proximal sites. Axial skeleton primary tumors are associated with the greatest risk of progression and death, primarily related to the inability to achieve a complete surgical resection.

Prognostic considerations for the axial skeleton and extraskeletal sites are as follows:

• Pelvis: Pelvic osteosarcomas make up 7% to 9% of all osteosarcomas. Survival rates for patients with pelvic primary tumors are 20% to 47%.[13,14,15] Complete surgical resection is associated with a positive outcome for osteosarcoma of the pelvis in some cohorts of patients.[13,16]
• Craniofacial/head and neck: In patients with craniofacial osteosarcoma, those with primary sites in the mandible and maxilla have a better prognosis than do patients with other primary sites in the head and neck.[17,18,19] For patients with osteosarcoma of craniofacial bones, complete resection of the primary tumor with negative margins is essential for cure.[20,21,22] When treated with surgery alone, patients who have osteosarcoma of the head and neck have a better prognosis than those who have appendicular lesions. However, surgery alone without adjuvant therapy is not recommended for high-grade osteosarcoma of the head and neck.

  Despite a relatively high rate of inferior necrosis after neoadjuvant chemotherapy, fewer patients with craniofacial primary tumors develop systemic metastases than do patients with osteosarcoma originating in the extremities. This may be the result of the inclusion of patients with lower-grade tumors in the cohorts reported.[23,24,25]

  A meta-analysis concluded that systemic adjuvant chemotherapy improves the prognosis for patients with osteosarcoma of the head and neck, while small series have not shown such a benefit.[23,24,25] Another large meta-analysis detected no benefit of chemotherapy for patients with osteosarcoma of the head and neck, but suggested that incorporating chemotherapy into the treatment plan for patients with high-grade tumors may improve survival.[22] A retrospective analysis identified a trend toward better survival in patients with high-grade osteosarcoma of the mandible and maxilla who received adjuvant chemotherapy.[22,26]

  Radiation therapy was found to improve local control, disease-specific survival, and OS in a retrospective study of patients with osteosarcoma of the craniofacial bones who had positive or uncertain margins after surgical resection.[27][Level of evidence C1] Radiation-associated craniofacial osteosarcomas are generally high-grade lesions, usually fibroblastic, and tend to recur locally with a high rate of metastasis.[28]

• Extraskeletal: Osteosarcoma in extraskeletal sites is rare in children and young adults. With current combined-modality therapy, the outcome of patients with extraskeletal osteosarcoma appears to be similar to that of patients with primary tumors of bone.[29]

Size of the primary tumor

In some series, patients with larger tumors appeared to have a worse prognosis than patients with smaller tumors.[12,30,31] Tumor size has been assessed by longest single dimension, cross-sectional area, or estimate of tumor volume; all assessments have correlated with outcome.

Elevated serum lactate dehydrogenase (LDH), which also correlates with poorer outcome, is a likely surrogate for tumor volume.[14]

Presence of clinically detectable metastatic disease

Patients with localized disease have a much better prognosis than patients with overt metastatic disease. As many as 20% of patients have radiographically detectable metastases at diagnosis, with the lung being the most common site.[32] The prognosis for patients with metastatic disease appears to be determined largely by site(s) of metastases, number of metastases, and surgical resectability of the metastatic disease.[33,34]

• Site of metastases: Prognosis appears more favorable for patients with fewer pulmonary nodules and for those with unilateral rather than bilateral pulmonary metastases.[33] Not all patients with suspected pulmonary metastases at diagnosis have osteosarcoma confirmed at the time of lung resection. In one large series, approximately 25% of patients had exclusively benign lesions removed at the time of surgery.[34]
• Number of metastases: Patients with skip metastases (at least two discontinuous lesions in the same bone) have been reported to have inferior prognoses.[35] However, an analysis of the German Cooperative Osteosarcoma Study Group (COSS) suggests that skip lesions in the same bone do not confer an inferior prognosis if they are included in planned surgical resection. Skip metastasis in a bone other than the primary bone should be considered systemic metastasis.[36]

  Historically, metastasis across a joint was referred to as a skip lesion, but subsequent classification by the American Joint Committee on Cancer excluded such lesions as skip lesions.[37] They might be considered hematogenous spread and have a worse prognosis.[36]

  Patients with multifocal osteosarcoma (defined as multiple bone lesions without a clear primary tumor) have an extremely poor prognosis.[38,39]

• Surgical resectability of metastases: Patients who have complete surgical ablation of the primary and metastatic tumor (when confined to the lung) after chemotherapy may attain long-term survival, although overall event-free survival (EFS) rates remain about 20% to 30% for patients with metastatic disease at diagnosis.[33,34,40,41] Patients with metastatic osteosarcoma were eligible for the European and American Osteosarcoma Study (EURAMOS) only if they had disease that was potentially resectable. Although the patients with metastatic disease had an overall 5-year EFS rate of only 28%, those who achieved a complete surgical remission at all sites (3–6 months after diagnosis) had a 5-year EFS rate of 64% and an OS rate of 79%.[31]

Surgical resectability of the primary tumor

Resectability of the tumor is a critical prognostic feature. Complete resection of the primary tumor and any skip lesions with adequate margins is generally considered essential for cure. For patients with axial skeletal primary tumors who either do not undergo surgery for their primary tumor or who undergo surgery that results in positive margins, radiation therapy may improve survival.[16,42]

A retrospective review of patients with craniofacial osteosarcoma performed by the cooperative German-Austrian-Swiss osteosarcoma study group reported that incomplete surgical resection was associated with inferior survival probability.[17][Level of evidence C1] In a European cooperative study, the size of the margin was not significant. However, prognosis was better when both the biopsy and resection were performed at a center with orthopedic oncology experience.[14]

Degree of tumor necrosis after neoadjuvant chemotherapy

Most treatment protocols for osteosarcoma use an initial period of systemic chemotherapy before definitive resection of the primary tumor (or resection of sites of metastases). The pathologist assesses necrosis in the resected tumor. Patients with at least 90% necrosis in the primary tumor after induction chemotherapy have a better prognosis than do patients with less necrosis.[30] Patients with less necrosis (<90%) in the primary tumor after initial chemotherapy have a higher rate of recurrence within the first 2 years than do patients with a more favorable amount of necrosis (≥90%).[43]

Less necrosis should not be interpreted to mean that chemotherapy has been ineffective. Cure rates for patients with little or no necrosis after induction chemotherapy are much higher than cure rates for patients who receive no chemotherapy. The EFS rate for patients who receive no adjuvant chemotherapy is approximately 11%.[44] Many large published series of patients treated with chemotherapy have reported EFS rates of 40% to 50% for patients with little or no necrosis in the primary tumor after initial systemic chemotherapy.[45,46,47] A review of two consecutive prospective trials performed by the Children's Oncology Group showed that histological necrosis in the primary tumor after initial chemotherapy was affected by the duration and intensity of the initial period of chemotherapy. More necrosis was associated with better outcome in both trials, but the magnitude of the difference between patients with more and less necrosis was diminished with a longer and more intensive period of initial chemotherapy.[48][Level of evidence B1]

Age and sex

Patients in the older adolescent and young adult age group, typically defined as age 18 to 40 years, tend to have a worse prognosis. In addition, male sex has been associated with a worse prognosis.[31,49,50] Compared with the other prognostic factors listed, both age and sex have a relatively minor impact on outcome.

Impact of time on prognostic factors

An analysis of the EURAMOS found that the predictive power of initial prognostic factors modify with time.[51] They applied a landmarking approach to 1,965 patients. The results showed that local recurrence and new metastases negatively affected 5-year OS (local recurrence hazard ratio [HR], 2.634; 95% CI, 1.845–3.761; and metastases HR, 8.558; 95% CI, 7.367–9.942). Baseline factors with strong negative prognostic value (HRs >2) included poor histological response (≥10% viable tumor), axial tumor location, and the presence of lung metastases. The effect of poor versus good histological response changed over time, becoming nonsignificant 3.25 years after surgery and onward.

The German COSS searched their database of 5,503 patients with osteosarcoma who were registered between 1980 and 2019. They identified 2,009 patients surviving more than 5 years from diagnostic biopsy to assess prognostic factors for long-term survival.[52] The authors confirmed the known predictors of treatment failure, including lower necrosis after initial chemotherapy, older age at diagnosis, unfavorable tumor site, and presentation as a secondary malignancy. The OS rates beyond 5 years were reported (see Table 1).

In a multivariate analysis, the factors that retained significance for worse long-term survival included having a recurrence in years 1 to 5, older age at diagnosis, and presentation as a secondary malignancy. Extent of tumor necrosis after initial chemotherapy was no longer valid after 5 years of follow-up.[52]

Other possible prognostic factors

Other factors that may be prognostic but with either limited or conflicting data include the following:

• Subsequent neoplasms. Patients with osteosarcoma as a subsequent neoplasm, including tumors arising in a radiation field, share the same prognosis as patients with de novo osteosarcoma if they are treated aggressively with complete surgical resection and multiagent chemotherapy.[53,54]

  In a German series, approximately 25% of patients with craniofacial osteosarcoma had osteosarcoma as a second tumor, and in 8 of these 13 patients, osteosarcoma arose after treatment for retinoblastoma. In this series, there was no difference in outcome for primary or secondary craniofacial osteosarcoma.[17]

• Laboratory abnormalities. Possible prognostic factors identified for patients with conventional localized high-grade osteosarcoma include LDH level, alkaline phosphatase level, and histological subtype.[30,46,49,55,56,57,58]
• Body mass index. Higher body mass index at initial presentation is associated with worse OS.[59]
• Pathological fracture. Some studies have suggested that a pathological fracture at diagnosis or during preoperative chemotherapy does not have adverse prognostic significance.[6]; [60,61][Level of evidence C1]; [62][Level of evidence C2]

  However, a systematic review of nine cohort studies examined the impact of pathological fractures on outcome in patients with osteosarcoma. The review included 2,187 patients, 311 of whom had a pathological fracture. The presence of a pathological fracture correlated with decreased EFS and OS.[63] In two additional series, a pathological fracture at diagnosis was associated with a worse overall outcome.[64]; [65][Level of evidence C1] A retrospective analysis of 2,847 patients with osteosarcoma from the German COSS identified 321 patients (11.3%) with a pathological fracture before the initiation of systemic therapy.[66][Level of evidence C1] In pediatric patients, OS and EFS did not differ significantly between patients with and without a pathological fracture. In adults, the 5-year OS rate in patients with a pathological fracture was 46% versus 69% for patients without a pathological fracture (P < .001). The 5-year EFS rate in adults was 36% for patients with a pathological fracture versus 56% for patients without a pathological fracture (P < .001). In a multivariable analysis, the presence of a pathological fracture was not a statistically significant factor for OS or EFS in the total cohort or in pediatric patients. In adult patients, presence of a pathological fracture remained an independent prognostic factor for OS (HR, 1.893; P = .013).

• Time to definitive surgery. In a large series, a delay of 21 days or longer from the time of definitive surgery to the resumption of chemotherapy was an adverse prognostic factor.[67]
• Genetic factors.
  • ERBB2 expression. There are conflicting data concerning the prognostic significance of this human epidermal growth factor.[68,69,70]
  • Tumor cell ploidy.[71]
  • Specific chromosomal gains or losses.[72]
  • Loss of heterozygosity of the RB1 gene.[73,74]
  • Loss of heterozygosity of the TP53 locus.[75]
  • Increased expression of p-glycoprotein.[76,77] A prospective analysis of p-glycoprotein expression determined by immunohistochemistry failed to identify prognostic significance for patients with newly diagnosed osteosarcoma, although earlier studies suggested that overexpression of p-glycoprotein predicted poor outcome.[78]

  For more information, see the Genomics of Osteosarcoma section.

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