Osteosarcoma and MFH of Bone Treatment (PDQ®)—Health Professional Version - National Cancer Institute

Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment (PDQ®)–Health Professional Version

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General Information About Osteosarcoma and Malignant Fibrous Histiocytoma (MFH) of Bone

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, an orthopedic surgeon experienced in bone tumors, a pathologist, radiation oncologists, pediatric oncologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ summaries on Supportive and Palliative Care for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1] For osteosarcoma, the 5-year survival rate increased over the same time from 40% to 76% in children younger than 15 years and from 56% to approximately 66% in adolescents aged 15 to 19 years.[1] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancerfor specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Osteosarcoma occurs predominantly in adolescents and young adults. Review of data from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute resulted in an estimate of 4.4 cases per 1 million new cases of osteosarcoma each year in people aged 0 to 24 years.[3] The U.S. Census Bureau estimates that there will be 110 million people in this age range in 2010, resulting in an incidence of roughly 450 cases per year in children and young adults younger than 25 years. 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 can rarely be 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.[4,5] 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 patients in these trials who were treated with surgical removal of the primary tumor recapitulated the historical experience before 1970; more than half of these patients developed metastases within 6 months of diagnosis, and overall, approximately 90% developed recurrent disease within 2 years of diagnosis.[6] Overall survival for patients treated with surgery alone was statistically inferior.[7] 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.[6,8]; [9][Level of evidence: 1iiA]

Prognostic Factors

Pretreatment factors that influence outcome include the following:[10]

After administration of preoperative chemotherapy, factors that influence outcome include the following:

Surgical resectability.
Degree of tumor necrosis.

In general, prognostic factors in 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.

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%.[11-13] Complete surgical resection is associated with positive outcome for osteosarcoma of the pelvis.[11,14]
Craniofacial/head and neck: In patients with craniofacial osteosarcoma, those with mandibular tumors have a significantly better prognosis than do patients with extragnathic tumors.[15] For patients with osteosarcoma of craniofacial bones, complete resection of the primary tumor with negative margins is essential for cure.[16-18] 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.
Despite a relatively high rate of inferior necrosis after neoadjuvant chemotherapy, fewer patients with craniofacial primaries develop systemic metastases than do patients with osteosarcoma originating in the extremities.[19-21] 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.
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.[18] A retrospective analysis identified a trend toward better survival in patients with high-grade osteosarcoma of the mandible and maxilla who received adjuvant chemotherapy.[18,22]
Radiation therapy was found to improve local control, disease-specific survival, and overall survival in a retrospective study of osteosarcoma of the craniofacial bones that had positive or uncertain margins after surgical resection.[23][Level of evidence: 3iiA] Radiation-associated craniofacial osteosarcomas are generally high-grade lesions, usually fibroblastic, that tend to recur locally with a high rate of metastasis.[24]
In the 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.[15]
Extraskeletal: 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.[25]

Tumor size

Larger tumors have a worse prognosis than smaller tumors.[10,26] 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.

Presence of clinically detectable metastatic disease

Patients with localized disease have a much better prognosis than do patients 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.[27] 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.[28,29]

Site of metastases: Prognosis appears more favorable for patients with fewer pulmonary nodules and for those with unilateral rather than bilateral pulmonary metastases;[28] 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.[29]
Number of metastases: Patients with skip metastases (at least two discontinuous lesions in the same bone) have been reported to have inferior prognoses.[30] Analysis of the German Cooperative Osteosarcoma Study 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 metastasis in a bone other than the primary bone should be considered systemic metastasis. Historically, metastasis across a joint was referred to as a skip lesion. Skip lesions across a joint might be considered hematogenous spread and have a worse prognosis.[31]
Patients with multifocal osteosarcoma (defined as multiple bone lesions without a clear primary tumor) have an extremely poor prognosis.[32]
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 remains about 20% to 30% for patients with metastatic disease at diagnosis.[28,29,33,34]

Adequacy of tumor resection

Resectability of the tumor is a critical prognostic feature because osteosarcoma is relatively resistant to radiation therapy. Complete resection of the primary tumor and any skip lesions with adequate margins is generally considered essential for cure. A retrospective review of patients with craniofacial osteosarcoma performed by the German-Austrian-Swiss osteosarcoma cooperative group reported that incomplete surgical resection was associated with inferior survival probability.[15][Level of evidence: 3iiB] In a European cooperative study, the size of the margin was not significant. However, having both the biopsy and resection at a center with orthopedic oncology experience conferred a better prognosis.[12]

For patients with axial skeletal primaries who either do not undergo surgery for their primary tumor or who undergo surgery that results in positive margins, radiation therapy may improve survival.[14,35]

Necrosis after induction or 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 those with less necrosis.[26] 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%).[36] 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. A review of two consecutive prospective trials performed by the Children’s Oncology Group showed that histologic 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.[37][Level of evidence: 1iiD]

Imaging modalities such as dynamic magnetic resonance imaging or positron emission tomography scanning are under investigation as noninvasive methods to assess response.[38-45]

Additional prognostic factors

Other prognostic factors 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.[46-49]
High-grade osteosarcoma. Possible prognostic factors identified for patients with conventional localized high-grade osteosarcoma include the age of the patient, LDH level, alkaline phosphatase level, and histologic subtype.[26,50-55] Older patients appear to have a poorer outcome.[55,56]
Increased body mass index at initial presentation is associated with worse overall survival.[57]

Some studies have suggested that pathologic fracture at diagnosis or during preoperative chemotherapy does not have adverse prognostic significance.[58]; [59][Level of evidence: 3iiiA] However, a systematic review of nine cohort studies examined the impact of pathologic fracture on outcome in osteosarcoma. The review included 2,187 patients, 311 of whom had pathologic fracture. Pathologic fracture correlated with decreased event-free survival and overall survival.[60]

The following potential prognostic factors have been identified but have not been tested in large numbers of patients:

HER2/c-erbB-2 expression. There are conflicting data concerning the prognostic significance of this human epidermal growth factor.[61-63]
Tumor cell ploidy.
Specific chromosomal gains or losses.[64]
Loss of heterozygosity of the RB gene.[65,66]
Loss of heterozygosity of the p53 locus.[67]
Increased expression of p-glycoprotein.[68,69] 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.[70]
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.[71]

Genomics of Osteosarcoma

The genomic landscape of osteosarcoma is distinctive from that of other childhood cancers. It is characterized by an exceptionally high number of structural variants with relatively small numbers of single nucleotide variants in comparison to many adult cancers.[72,73]

Key observations regarding the genomic landscape of osteosarcoma are summarized below:

The number of structural variants observed for osteosarcoma is very high, at more than 200 structural variants per genome,[72,73] such that osteosarcoma has the most chaotic genome among childhood cancers. The Circos plots shown in Figure 1 illustrate the exceptionally high numbers of intra- and inter-chromosomal translocations that typify osteosarcoma genomes.
ENLARGE
Figure 1. Circos plots of osteosarcoma cases from the National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) project. The red lines in the interior circle connect chromosome regions involved in either intra- or inter-chromosomal translocations. Osteosarcoma is distinctive from other childhood cancers because it has a large number of translocations. Credit: National Cancer Institute.
The number of mutations per osteosarcoma genome that affect protein sequence (approximately 25 per genome) is higher than that of some other childhood cancers (e.g., Ewing sarcoma and rhabdoid tumors) but is far below that for adult cancers such as melanoma and non-small cell lung cancer.[72,73]
Genomic alterations in TP53 are present in most osteosarcoma cases, with a distinctive form of TP53 inactivation occurring by structural variations in the first intron of TP53that lead to disruption of the TP53 gene.[72] Other mechanisms of TP53 inactivation are also observed, including missense and nonsense mutations and deletions of the TP53gene.[72,73] The combination of these various mechanisms for loss of TP53 function leads to biallelic inactivation in most cases of osteosarcoma.
MDM2 amplification is observed in a minority of osteosarcoma cases (approximately 5%), and provides another mechanism for loss of TP53 function.[72,73]
RB1 is commonly inactivated in osteosarcoma, sometimes by mutation but more commonly by deletion.[72,73]
Other genes with recurrent alterations in osteosarcoma include ATRX and DLG2.[72] Additionally, pathway analysis showed that the PI3K/mammalian target of rapamycin (mTOR) pathway was altered by mutation/loss/amplification in approximately one-fourth of patients, with PTEN mutation/loss being the most common alteration.[73]
The range of mutations reported for osteosarcoma tumors at diagnosis do not provide obvious therapeutic targets, as they primarily reflect loss of tumor suppressor genes (e.g., TP53, RB1, PTEN) rather than activation of targetable oncogenes.

A number of germline mutations are associated with susceptibility to osteosarcoma; Table 1 summarizes the syndromes and associated genes for these conditions. Mutations in TP53are the most common germline alterations associated with osteosarcoma. Mutations in this gene are found in approximately 70% of patients with Li-Fraumeni syndrome (LFS), which is associated with increased risk of osteosarcoma, breast cancer, various brain cancers, soft tissue sarcomas, and other cancers. While rhabdomyosarcoma is the most common sarcoma arising in patients aged 5 years and younger with TP53-associated LFS, osteosarcoma is the most common sarcoma in children and adolescents aged 6 to 19 years.[74] One study observed a high frequency of young osteosarcoma cases (age <30 years) carrying a known LFS- or likely LFS-associated TP53 mutation (3.8%) or rare exonicTP53 variant (5.7%), with an overall TP53 mutation frequency of 9.5%.[75] Another study observed germline mutations in TP53 in 7 of 59 (12%) osteosarcoma cases subjected to whole-exome sequencing.[73] Other groups have reported lower rates (3%–7%) of TP53germline mutations in patients with osteosarcoma.[76,77]

Table 1. Genetic Diseases That Predispose to Osteosarcomaa

Syndrome	Description	Location	Gene	Function
AML = acute myeloid leukemia; IL-1 = interleukin-1; MDS = myelodysplastic syndrome; RANK = receptor activator of nuclear factor kappaB ligand; TNF = tumor necrosis factor.
aTable adapted from Kansara et al.[78]
Bloom syndrome [79]	Rare inherited disorder characterized by short stature and sun-sensitive skin changes. Often presents with a long, narrow face, small lower jaw, large nose, and prominent ears.	15q26.1	BLM(RecQL3)	DNA helicase
Diamond-Blackfan anemia [80]	Inherited pure red cell aplasia. Patients at risk for MDS and AML. Associated with skeletal abnormalities, such as abnormal facial features (flat nasal bridge, widely spaced eyes).		Ribosomal proteins	Ribosome production [80,81]
Li-Fraumeni syndrome [82]	Inherited mutation in TP53 gene. Affected family members at increased risk for bone tumors, breast cancer, leukemia, brain tumors, and sarcomas.	17p13.1	P53	DNA damage response
Paget disease [83]	Excessive breakdown of bone with abnormal bone formation and remodeling, resulting in pain from weak, malformed bone.	18q21-qa22	LOH18CR1	IL-1/TNF signaling; RANK signaling pathway
		5q31
		5q35-qter
Retinoblastoma [84]	Malignant tumor of the retina. Approximately 66% of patients diagnosed by age 2 years and 95% of patients by age 3 years. Patients with heritable germ cell mutations at greater risk for subsequent neoplasms.	13q14.2	RB1	Cell-cycle checkpoint
Rothmund-Thomson syndrome (also called poikiloderma congenitale) [85,86]	Autosomal recessive condition. Associated with skin findings (atrophy, telangiectasias, pigmentation), sparse hair, cataracts, small stature, and skeletal abnormalities. Increased incidence of osteosarcoma at a younger age.	8q24.3	RTS(RecQL4)	DNA helicase
Werner syndrome [87]	Patients often have short stature and in their early twenties, develop signs of aging, including graying of hair and hardening of skin. Other aging problems such as cataracts, skin ulcers, and atherosclerosis develop later.	8p12-p11.2	WRN(RecQL2)	DNA helicase; exonuclease activity

Refer to the following summaries for more information about these genetic syndromes:

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