Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis

INTRODUCTION — Osteosarcoma is a rare primary malignant tumor of bone that is characterized by an osteoid matrix produced by the malignant cells [1]. Osteosarcoma is an uncommon tumor and accounts for less than 1 percent of all cancers diagnosed annually in the United States and 3 percent of all childhood cancers [2]. The survival of patients with osteosarcoma improved dramatically after the introduction of multimodality therapy, including systemic chemotherapy. (See "Chemotherapy and radiation therapy in the management of osteosarcoma", section on 'Prognosis and evolution of treatment'.)

The epidemiology, pathology, clinical presentation, and diagnosis of osteosarcoma are reviewed here. Diagnosis and biopsy techniques for primary bone tumors, principles guiding surgical management of bone sarcomas, and the management of osteosarcoma are discussed in detail separately.

●(See "Bone tumors: Diagnosis and biopsy techniques".)

●(See "Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management".)

●(See "Chemotherapy and radiation therapy in the management of osteosarcoma".)

EPIDEMIOLOGY

●Incidence – Osteosarcoma is an uncommon tumor. Approximately 1000 new cases are diagnosed each year in the United States, of which 500 cases arise in children and adolescents younger than 20 years of age [2]. Despite its rarity, osteosarcoma is the most common primary malignancy of bone in children as well as adolescents and young adults (AYAs) aged 15 to 19 [2,3]. Among individuals with bone cancer under the age of 20, osteosarcoma comprises 56 percent of all cases, followed by Ewing sarcoma (34 to 36 percent), and chondrosarcoma (less than 10 percent). (See "Epidemiology, pathology, and molecular genetics of Ewing sarcoma" and "Chondrosarcoma".)

●Age – There is a bimodal age distribution for the incidence of osteosarcoma. Among children and AYAs, the peak incidence is between 13 and 16 years of age, a time that appears to coincide with the adolescent growth spurt [4]. Osteosarcoma also occurs at an earlier age in female children, corresponding to their more advanced skeletal age and earlier adolescent growth spurt compared with male children. (See 'Pathogenesis' below.)

In adults, the peak incidence occurs over the age of 65 (figure 1) [5].

●Sex – Osteosarcoma is slightly more predominant in males than females (ratio of 1.4:1), both in children and in adults [5-7].

●Ethnicity – Among children, osteosarcoma occurs more frequently in Black individuals and other ethnicities compared with White individuals [5,8-10]. Among adults, in contrast to children, osteosarcoma is more common in White individuals than in Black individuals or individuals of other ethnicities [5,6].

●Geographic incidence – The incidence of osteosarcoma in children differs geographically. Some regions of Africa, South Asia, and Central and South America are estimated to have twice the number of new cases of osteosarcoma compared with North America or Europe [11].

Among adults over the age of 60 in the United States, where Paget disease (a risk factor for osteosarcoma) is common, secondary tumors are more common than primary tumors [6,12]. In other countries where Paget disease is less frequent, such as Japan and other countries in Eastern Asia, osteosarcoma arises more commonly as a primary tumor among patients over the age of 40 [13,14]. (See 'Paget disease and other benign bone processes' below.)

RISK FACTORS — Several risk factors for osteosarcoma have been identified as follows:

Radiation and chemotherapy — Osteosarcoma that occurs in the setting of prior radiation and chemotherapy is classified as a secondary osteosarcoma [1,15]. (See 'Secondary osteosarcoma' below.)

●Radiation therapy – Osteosarcoma is the most common secondary malignant neoplasm (ie, subsequent primary cancer) to occur during the first 20 years following radiation therapy (RT) for a solid cancer in childhood. Data suggest that approximately 3 percent of osteosarcomas could be attributed to prior irradiation, although the incidence may increase as cancer survivors treated with RT live long enough to potentially develop this complication. The interval between irradiation and the appearance of a secondary osteosarcoma averages 12 to 16 years; this interval is shorter in childhood cancer survivors. (See "Radiation-associated sarcomas", section on 'Epidemiology and histologic distribution' and "Radiation-associated sarcomas", section on 'Radiation dose and age of exposure'.)

●Chemotherapy – Prior exposure to chemotherapy, particularly alkylating agents, is also associated with subsequent primary osteosarcoma in childhood cancer survivors and may potentiate the effect of previous RT. (See "Radiation-associated sarcomas", section on 'Chemotherapy agents'.)

Paget disease and other benign bone processes — Osteosarcoma that arises in patients older than 40 years of age can be associated with Paget disease, a focal skeletal disorder characterized by an accelerated rate of bone turnover (image 1) [16]. Although the incidence of bone tumors is markedly increased in patients with Paget disease, they only occur in 0.7 to 1 percent of cases [17]. Osteosarcoma arising in the setting of Paget disease is typically associated with a worsened prognosis [18].

Tumor involvement of multiple sites of bone is common in these patients. Osteosarcoma in the setting of Paget disease arises from pagetic bone, which can be seen on imaging and confirmed on histology. Otherwise, osteosarcoma associated with Paget disease is histologically indistinguishable from osteosarcomas in patients without Paget disease. Although sarcomatous transformation is most often seen in long-standing Paget disease, it is not necessarily related to the extent of skeletal involvement. (See "Clinical manifestations and diagnosis of Paget disease of bone".)

It is unclear how Paget disease leads to the development of osteosarcoma, but genetic factors are thought to play a role. Both Paget disease and osteosarcoma in the setting of Paget disease have been associated with loss of heterozygosity of chromosome 18, possibly involving the same site of a postulated tumor suppressor gene [19,20], as well as presence of somatic pathogenic variants in the SQSTM1 gene on chromosome 5q35 [21].

In addition to Paget disease, other benign bone lesions are associated with an increased risk of malignant degeneration to a primary bone tumor. These include chronic osteomyelitis; sites of bone infarcts; and benign bone lesions such as fibrous dysplasia, which can be seen in those with McCune-Albright syndrome [22,23]. There are also reports of osteosarcoma arising in benign bone tumors treated with curettage and bone grafts [24]. (See "Nonmalignant bone lesions in children and adolescents", section on 'Fibrous dysplasia' and "Definition, etiology, and evaluation of precocious puberty", section on 'McCune-Albright syndrome'.)

Genetic conditions — Patients with osteosarcoma, particularly children, may have a genetic predisposition to the disease. The frequency of a germline pathogenic variant among those with osteosarcoma ranges between 18 and 28 percent in observational studies [25,26]. The majority of pathogenic variants are in the RB1 (the gene associated with hereditary retinoblastoma) and TP53 (the gene associated with Li-Fraumeni syndrome [LFS]) genes. Other pathogenic variants have also been identified such as autosomal dominant cancer susceptibility genes including APC, PALBB2, and MSH2, as well as CDKN2A, ATRX, MEN1, and POT1, among others [26]. (See "Pathogenetic factors in soft tissue and bone sarcomas".)

In patients with newly diagnosed osteosarcoma, particularly those with multiple primary malignancies, it is important to obtain a detailed family history to assess for predisposing genetic conditions [27]. Patients may be referred for genetic consultation and testing as clinically appropriate. (See "Genetic counseling: Family history interpretation and risk assessment".)

Retinoblastoma — The genetic abnormality that causes hereditary retinoblastoma (germline pathogenic variants of the RB1 gene) is also associated with an increased risk of developing subsequent primary tumors. Among these tumors, approximately 60 percent are soft tissue sarcomas and osteosarcoma [28-31]. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Epidemiology' and "Radiation-associated sarcomas", section on 'Genetic predisposition'.)

Patients with hereditary retinoblastoma are at much higher risk of developing osteosarcoma compared with those with nonhereditary (sporadic) disease. Patients with retinoblastoma who receive RT are also at higher risk for developing osteosarcoma later in life, not only within irradiated fields but also in long bones distant from radiation fields. These data are discussed separately. (See "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Retinoblastoma'.)

Li-Fraumeni syndrome — Patients with LFS are at risk for developing osteosarcoma, although the incidence is low [32-37]. LFS is a familial cancer syndrome associated with germline pathogenic variants in the TP53 tumor suppressor gene, which is involved in cell cycle regulation and maintaining the integrity of the genome. Patients with LFS display a spectrum of cancers, including breast, soft tissue, adrenocortical, and brain tumors; leukemias; and osteosarcoma [32]. (See "Li-Fraumeni syndrome" and "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Li-Fraumeni syndrome'.)

Other genetic conditions — Besides hereditary retinoblastoma and LFS, other genetic conditions with a known predisposition to osteosarcoma include Rothmund-Thomson syndrome (RTS), RAPADILINO, and the related Bloom and Werner syndromes.

●Rothmund-Thomson syndrome – RTS is an autosomal recessive condition characterized by distinctive skin findings (atrophy, telangiectasias, pigmentation), sparse hair, cataracts, small stature, skeletal anomalies, and a significantly increased risk for osteosarcoma [38,39]. In one cohort of 41 patients with RTS, 13 (32 percent) developed osteosarcoma [38]. Clinically, these tumors tend to develop at a younger age than seen in the general population. (See "Kindler epidermolysis bullosa", section on 'Differential diagnosis' and "Xeroderma pigmentosum", section on 'Differential diagnosis'.)

Loss of function pathogenic variants in the RECQL4 gene have been identified in approximately two-thirds of patients with RTS and are closely associated with the risk for osteosarcoma. In one series of 33 patients with RTS, none of the 10 patients without a pathogenic variant in this gene developed osteosarcoma, while among the 23 patients with a pathogenic variant in RECQL4, the incidence of osteosarcoma was five cases per year with 230 person-years of observation [40].

●RAPADILINO – RAPADILINO is an allelic disorder with many overlapping features with RTS and is also caused by pathogenic variants in the RECQL4 gene. In addition to increased risk of osteosarcoma, these patients are also at higher risk of developing lymphoma [41].

●Bloom syndrome and Werner syndrome – Other members of the RECQ gene family are mutated in Bloom syndrome (BLM gene) and Werner syndrome (WRN gene), two diseases with overlapping clinical features, including a predisposition to develop osteosarcoma [40]. (See "Bloom syndrome" and "Werner syndrome".)

PTH and PTHrp analog therapy — In patients with osteoporosis, parathyroid hormone (PTH) and/or parathyroid hormone-related protein (PTHrP) analog therapy is contraindicated in those who are also at increased baseline risk for osteosarcoma. (See 'Risk factors' above and "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Contraindications/precautions'.)

Preclinical studies suggest that PTH and/or PTHrP analog therapy is associated with an increased risk of osteosarcoma. Although limited observational studies in humans have not supported this association, long-term follow-up data are necessary to confirm. Further details on the safety of these osteoporosis treatments are discussed separately. (See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Long-term risks'.)

PATHOGENESIS — Osteosarcoma appears to originate from bone-forming stem or progenitor cells that reside in the skeleton [42]. However, the specific molecular alterations in these cells that lead to tumor development remain elusive. Identifying molecular alterations that can be targeted for therapeutic purposes remains an active area of investigation [43]. Rapid bone growth may also play a role in the pathogenesis of osteosarcoma.

●Molecular alterations – Osteosarcoma tumors are characterized by highly complex karyotypes. This molecular finding may occur because of the "chromothripsis" phenomenon, where a single catastrophic cellular event causes a chaotic chromosomal rearrangement [44,45]. Although there is no characteristic translocation driving the process of oncogenesis, as occurs in other sarcomas, osteosarcoma tumors have recurrent amplifications or deletions in some chromosomal regions. The highest frequency of chromosomal deletions in osteosarcoma has been reported in regions of 3q and 13q (the location of the RB gene), 17p (the location of the TP53 gene), and 18q (the location linked to osteosarcoma arising in the setting of Paget disease) [46]. Combined inactivation of the RB and TP53 pathways is common in osteosarcoma. Moreover, genomic alterations in TP53 and RB may arise due to gene deletion, pathogenic variants, or structural variations [46].

Recurrent amplifications of various chromosomal regions have also been observed in osteosarcoma. The genetic region 8q contains the gene MYC, which is amplified in up to half of cases of osteosarcoma and may be associated with a poor prognosis [47]. Amplification of FGFR1 and alterations in the IGF1R pathway have also been observed in about 18.5 and 14 percent of cases, respectively [43,48]. The PIK3/mTOR pathway has also been found to be altered in one-fourth of patients. Mutations or loss of PTEN are the most common alteration reported in this pathway [49].

Other molecular alterations have also been demonstrated in genes such as isocitrate dehydrogenase (IDH1 and IDH2) for conventional chondrosarcoma; MDM2 in parosteal and low-grade central osteosarcoma; DLG2, ATRX, CDK4, and VEGFR [50,51]. The influence of these genes as well as other molecular pathways (such as the Wnt, Notch, insulin-like growth factor [IGF] pathways) is beyond the scope of this topic [51].

●Rapid bone growth – The development of osteosarcoma may be related to rapid bone growth, since the peak incidence of disease occurs during the adolescent growth spurt [4]. (See 'Epidemiology' above.)

The tumor also appears most frequently at sites where the greatest increase in bone length and size occurs (eg, the metaphyseal portions of the distal femur, proximal tibia, and proximal humerus (figure 2A)). (See 'Tumor location' below.)

This process is thought to occur due to an aberration of the normal process of bone growth and remodeling; this is a time when rapidly proliferating cells are particularly susceptible to oncogenic agents, mitotic errors, or other events leading to neoplastic transformation [52]. However, the precise etiology of osteosarcoma development remains unclear, and studies examining the relationship between growth and developmental factors (including height) and the risk of bone sarcomas have revealed no consistent pattern [53-55].

HISTOLOGIC CLASSIFICATION

Approach to histologic diagnosis — The 2020 World Health Organization classification of bone tumors recognizes the following osteosarcoma subtypes:

●Low-grade central osteosarcoma (see 'Low-grade central osteosarcoma' below)

●Osteosarcoma not otherwise specified (NOS), which includes (see 'Osteosarcoma not otherwise specified' below):

•Conventional osteosarcoma (see 'Conventional osteosarcoma' below)

•Telangiectatic osteosarcoma (see 'Telangiectatic osteosarcoma' below)

•Small cell osteosarcoma (see 'Small cell osteosarcoma' below)

●Parosteal osteosarcoma (see 'Parosteal osteosarcoma' below)

●Periosteal osteosarcoma (see 'Periosteal osteosarcoma' below)

●High-grade surface osteosarcoma (see 'High-grade surface osteosarcoma' below)

●Secondary osteosarcoma (see 'Secondary osteosarcoma' below)

The histopathologic diagnosis of osteosarcoma is based on morphology and the presence of malignant cells that form new bone (osteoid). In some tumors with a limited degree of osteoid production and variable histomorphology, immunohistochemistry may be required for confirmation of the diagnosis. However, in contrast to other sarcomas, there are no specific immunostains or molecular tests for osteosarcoma, since it is not associated with any characteristic immunoprofile or chromosomal translocations. (See "Pathogenetic factors in soft tissue and bone sarcomas".)

Low-grade central osteosarcoma — Low-grade central osteosarcoma only accounts for 1 to 2 percent of all osteosarcomas. This slow-growing tumor occurs in young adults and arises in the metaphysis of long bones [56]. Histologically, it is characterized by low mitotic activity of spindle cells in well-formed neoplastic bone. Amplification of MDM2 and CDK4 is common [57]. Approximately 10 to 36 percent of cases may progress to high-grade sarcoma. Treatment for low-grade central osteosarcoma is typically surgical resection alone, with survival rates of approximately 90 percent [58].

Osteosarcoma not otherwise specified — Osteosarcoma NOS includes conventional, telangiectatic, and small cell osteosarcoma. The age distribution and treatment are similar for the various osteosarcoma NOS.

Conventional osteosarcoma — The largest group is conventional osteosarcoma which accounts for approximately 90 percent of all osteosarcomas [59,60]. These tumors arise in the intramedullary region and typically involve the metaphysis of long bones (figure 2A).

Depending on the predominant cellular component, conventional osteosarcomas are subclassified as osteoblastic (accounting for 76 to 80 percent), chondroblastic (10 to 13 percent), or fibroblastic (10 percent) [61,62]. Despite histologic differences, their clinical behavior and management are similar.

●Osteoblastic osteosarcoma – Osteoblastic osteosarcoma is characterized by abundant production of an osteoid and woven bone matrix in association with malignant tumor cells, which forms a fine or coarse lacelike pattern around the tumor cells; massive amounts may result in distortion of the malignant stromal cells (picture 1). Some tumors contain thick trabeculae of osteoid matrix that form an irregular anastomosing network. The degree of mineralization is variable.

●Fibroblastic osteosarcomas – Fibroblastic osteosarcoma is predominantly composed of a high-grade spindle cell stroma that contains only focal areas of bone production (picture 2). More pleomorphic tumors may resemble undifferentiated high-grade pleomorphic sarcoma of bone (previously known as malignant fibrous histiocytoma of bone), but the distinction can be made by the identification of an osteoid matrix produced by the tumor rather than reactive periosteal host woven bone, which may be present at the periphery of the tumor.

●Chondroblastic osteosarcoma – In chondroblastic osteosarcoma, cartilaginous matrix production is evident throughout most of the tumor. While the majority of the tumor tends to be of lower grade, the chondroid areas may contain cytologically atypical cells that are characteristic of higher grade tumors. These chondroblastic foci are admixed with malignant spindle cells that produce bony trabecula (picture 3).

Telangiectatic osteosarcoma — Telangiectatic osteosarcoma is a high-grade, vascular tumor that contains little osteoid [63]. Because of its radiolucent appearance on plain radiographs, telangiectatic osteosarcoma can be confused with aneurysmal bone cysts or giant cell tumors of bone (GCTB). Grossly they appear as a "multicystic bag of blood," and a solid mass of tumor is usually absent [59]. As a result, it may be difficult to obtain diagnostic tissue on biopsy. Histologically, the minimal osteoid or woven bone formation and numerous multinucleated giant cells (picture 4) are reminiscent of a benign GCTB. However, the cells are highly pleomorphic. (See "Giant cell tumor of bone".)

In general, the prognosis of patients with telangiectatic osteosarcoma is similar to or more favorable than those with the conventional chondroblastic subtype of osteosarcoma [64,65]. (See 'Conventional osteosarcoma' above.)

Small cell osteosarcoma — Small cell osteosarcoma is noteworthy for the confusion that may arise in its distinction from other "small round blue cell tumors" such as Ewing sarcoma by conventional light microscopy of hematoxylin and eosin stained sections [66,67]. Small cell osteosarcoma contains small cells with scant cytoplasm, round nuclei, and coarse chromatin, associated with osteoid production. Immunohistochemical staining, cytogenetics, and molecular genetic studies may be required to distinguish this osteosarcoma subtype from Ewing sarcoma [68,69]. (See "Clinical presentation, staging, and prognostic factors of Ewing sarcoma", section on 'Differential diagnosis'.)

Parosteal osteosarcoma — Parosteal osteosarcoma is a surface lesion composed of low-grade fibroblastic cells that produce woven bone that sometimes has a lamellar appearance. It occurs in an older age group than conventional osteosarcoma, usually between the ages of 20 and 40 years. The posterior aspect of the distal femur is the most commonly involved site, but other long bones may be affected. The tumor arises from the cortex as a broadly based lesion. With time, however, this lesion may invade the cortex and enter the endosteal cavity.

For parosteal osteosarcoma, the prognosis is relatively good with surgical resection alone, as survival rates are approximately 90 percent [70,71]. In contrast, dedifferentiated parosteal osteosarcoma is a variant in which a high-grade sarcoma component exists along with the parosteal osteosarcoma. Dedifferentiated parosteal sarcoma occurs in 15 to 43 percent of cases; these patients present with more aggressive disease and both surgery and chemotherapy are often administered [72].

Periosteal osteosarcoma — Periosteal osteosarcoma is an intermediate-grade, chondroblastic surface osteosarcoma that is frequently located in the proximal tibia; it has the same age distribution as conventional osteosarcoma. Observational studies indicate more favorable outcomes than that seen with conventional osteosarcoma (10-year survival rate of 84 percent [73]). However, the likelihood of metastases is approximately 20 percent, which is higher than that for the low-grade parosteal tumors, but lower than that for conventional osteosarcomas.

Adjuvant chemotherapy is recommended in many centers because of the estimated 20 percent metastatic rate. However, the role of adjuvant chemotherapy for periosteal osteosarcoma is controversial due to [73] lack of benefit when patients who received adjuvant chemotherapy were compared with those treated by surgery alone [73,74] and a concerning number of subsequent primary cancers in patients treated with adjuvant chemotherapy [73]. In part because of its rarity, randomized trials have not been conducted to address this issue, which limits the conclusions that can be drawn from the available literature.

High-grade surface osteosarcoma — High-grade osteosarcoma may also develop on the surface of the bone, where it may be confused with parosteal or periosteal osteosarcoma. These tumors are treated similarly to conventional osteosarcoma that arises in the intramedullary portion of the bone. (See 'Conventional osteosarcoma' above.)

Secondary osteosarcoma — Secondary osteosarcoma is osteosarcoma that develops in abnormal bone. The most common causes of secondary osteosarcoma are Paget disease of the bone and prior exposure to radiation. (See 'Risk factors' above.)

The median dose of radiation therapy (RT) associated with secondary osteosarcoma is 50 Gy [75]. This tumor is histologically indistinguishable from conventional osteosarcoma. However, the prognosis of secondary osteosarcoma is worse than that of conventional osteosarcoma [1].

Rarer variants

Multifocal osteosarcoma — Rarely, patients present with multiple synchronous sites at diagnosis, all resembling the primary tumor. It is difficult to determine whether these represent multiple synchronous primary lesions or are considered metastases. Regardless of their designation, the prognosis is usually poor, although a few patients may achieve significant life prolongation under current treatment approaches [76]. Multifocal osteosarcoma may also be metachronous in that other bony lesions occur years after treatment of the first.

Craniofacial osteosarcoma — Craniofacial osteosarcoma is another distinct variant which tends to occur in older patients and may have a more indolent course. Patients with craniofacial osteosarcoma are more likely to have local recurrence than distant metastases; this may be attributed to different tumor biological behavior from other osteosarcomas as well as difficulty obtaining wide surgical margins in this anatomically challenging location. The mandible and maxilla are the most common primary sites for craniofacial osteosarcoma [77].

The management of craniofacial osteosarcoma primarily includes surgical resection [78-80]. The use of chemotherapy and radiation for craniofacial osteosarcoma are discussed separately. (See "Head and neck sarcomas", section on 'Osteosarcoma'.)

CLINICAL PRESENTATION

Primary versus secondary neoplasms — Children and adolescents and young adults (AYAs) with osteosarcoma most frequently present with a primary, sporadic neoplasm. Those with an inherited predisposition to osteosarcoma account for a minority of patients. (See 'Genetic conditions' above.)

In contrast, secondary osteosarcoma are primarily observed among adults. Such secondary neoplasms are attributed to sarcomatous transformation of Paget disease of bone, secondary sarcomas in irradiated bone, bone infarcts, or some other benign bone lesions [5,12]. (See 'Paget disease and other benign bone processes' above and "Radiation-associated sarcomas".)

Tumor location

Primary tumor — The initial presenting site of the primary tumor differs according to age at presentation.

The most common sites of osteosarcoma in children are the metaphyses of long bones (figure 2A-B). The most common sites of involvement, in descending order, are [4]:

●Distal femur (32 percent)

●Proximal tibia (19 percent)

●Proximal humerus (10 percent)

●Middle and proximal femur (10 percent)

●Other bones, such as the mandible (8 percent) and pelvis (8 percent)

Tumors involving the axial and craniofacial bones are more commonly seen in adults than children. However, adults can also still present with disease in the lower extremity bones, similarly to children [5,6]. Adults also are more likely to present with osteosarcoma in areas that have been previously treated with radiation therapy (RT) or that have underlying bone abnormalities. (See 'Risk factors' above.)

Distant metastases — At the time of presentation, between 10 and 20 percent of patients have demonstrable macrometastatic disease. Adults over the age of 60 years at diagnosis are also at higher risk for metastatic disease at presentation. Metastatic disease occurs most frequently in the lungs, followed by the other bones [81]. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Pattern of spread'.)

Metastases can also involve the same bone or a different bone [82]. Approximately 1 to 6 percent of patients present with "skip" metastases (image 2), or synchronous smaller foci of tumor anatomically separated from the primary lesion, either in the same bone or in the opposing site of a joint (transarticular (image 2)). Bony metastases in the same bone or the bone adjacent to the primary tumor are associated with a worse prognosis [83,84]. (See 'Evaluation for systemic disease' below.)

Symptoms — The majority of patients with osteosarcoma present with localized pain at the primary tumor site, typically of several weeks' duration. Pain often begins after an injury and may wax and wane over time. Systemic symptoms such as fever, weight loss, and malaise are generally absent.

Pain may also be related to a pathologic fracture, which may be present in approximately 12 percent of patients with osteosarcoma at diagnosis [65]. Due to the potential risk of pathologic fracture, patients with suspected osteosarcoma are typically advised to limit or use protective weight bearing on the affected limb. (See "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma".)

Physical exam — The most noticeable finding on physical examination is a soft tissue mass, which is frequently large and tender to palpation. The mass may exhibit increased vascularity of the skin. Patients may demonstrate decreased range of motion of the affected limb or walk with a limp if the tumor involves one of the lower extremities. Patients may also have increased regional lymphadenopathy. Masses are more difficult to detect in patients with pelvic osteosarcoma. Since systemic symptoms are generally absent, patients with pulmonary metastases may still present with a normal respiratory exam.

DIAGNOSTIC EVALUATION

Plain radiograph — The first diagnostic test in patients with suspected osteosarcoma is generally a plain radiograph of the primary tumor [62]. It is important to obtain radiographs of the entire involved bone.

Characteristic features on plain radiograph of conventional osteosarcoma (which account for the majority of cases) include destruction of the normal trabecular bone pattern, indistinct margins, and no endosteal bone response. The affected bone is characterized by a mixture of radiodense and radiolucent areas, destruction of the cortex, and periosteal new bone formation, with the formation of Codman triangle (an incomplete response of host periosteal bone) (image 3). The associated soft tissue mass is variably ossified and may be in a radial or "sunburst" pattern (image 4). (See "Bone tumors: Diagnosis and biopsy techniques", section on 'Differential diagnosis'.)

Magnetic resonance imaging — Magnetic resonance imaging (MRI) of the entire length of the involved bone is obtained as part of the initial diagnostic evaluation of suspected osteosarcoma. The MRI protocol should include a T1 coronal sequence.

In patients with a high clinical suspicion for disease, MRI should be obtained if plain radiographs are unrevealing or have subtle abnormalities. In most cases, MRI is preferred over computed tomography (CT) for the initial evaluation of suspected osteosarcoma, because of its superior definition of soft tissue extension (particularly to the neurovascular bundle), joint and marrow involvement (image 3), and the presence of "skip" metastases [83,85]. (See 'Distant metastases' above.)

For patients with plain radiographic findings characteristic for osteosarcoma, MRI is also indicated for biopsy and surgical planning. MRI should assess the entire length of the involved long bone. MRI with contrast will identify areas in the tumor that are both hypervascular and necrotic, which can assist with subsequent surgical interventions. The use of MRI in the diagnosis of osteosarcoma is similar to that of other bone tumors and is discussed separately. (See "Bone tumors: Diagnosis and biopsy techniques", section on 'Imaging'.)

Laboratory evaluation — Alkaline phosphatase [86] and lactate dehydrogenase (LDH) [87] may be obtained as part of the initial diagnostic evaluation. While these labs may be elevated in approximately half of patients with suspected osteosarcoma, they are not routinely used to guide management [88]. Other laboratory evaluations are usually normal.

Diagnostic biopsy — The diagnosis of osteosarcoma is made definitively with a biopsy and pathologic evaluation of the tumor. While the correct diagnosis can be surmised in up to two-thirds of patients based on clinical presentation and imaging, [89], none of these findings are pathognomonic and a biopsy is still required for confirmation. Once the diagnosis of a primary bone tumor is suspected, patients should be referred to a facility with expertise in the diagnosis (including biopsy) and management of osteosarcoma. (See 'Histologic classification' above.)

Suspected osteosarcoma can be sampled using either a core needle or open biopsy (see "Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management", section on 'Tissue biopsy'):

●Core needle biopsy – If a core needle biopsy is planned, the interventional radiologist performing the procedure should communicate with the orthopedic surgeon about the placement of the biopsy tract. The biopsy must be carefully planned to ensure that adequate diagnostic tissue is obtained without compromising future surgical planning, such as biopsy tract removal during definitive surgery or limb salvage procedures [90]. This topic is discussed in detail separately. (See "Bone tumors: Diagnosis and biopsy techniques", section on 'Planning the biopsy'.)

●Open biopsy – If an open biopsy is chosen, the biopsy should be carried out by an orthopedic surgeon who is experienced in the management of osteosarcoma, and ideally, will also be performing the definitive surgery.

DIFFERENTIAL DIAGNOSIS — In patients with suspected osteosarcoma, the primary differential diagnosis includes:

●Other malignant bone tumors – Ewing sarcoma, lymphoma, and distant metastases from other tumors. (See "Clinical presentation, staging, and prognostic factors of Ewing sarcoma" and "Overview of Hodgkin lymphoma in children and adolescents" and "Overview of non-Hodgkin lymphoma in children and adolescents".)

●Benign bone tumors – Chondroblastoma, osteoblastoma (image 5 and image 6), and giant cell tumor of bone (GCTB) may be part of the differential diagnosis of a radiolucent osteosarcoma. (See "Nonmalignant bone lesions in children and adolescents", section on 'Chondroblastoma' and "Nonmalignant bone lesions in children and adolescents", section on 'Osteoblastoma' and "Giant cell tumor of bone".)

●Nonneoplastic conditions – Nonmalignant etiologies such as osteomyelitis, Langerhans cell histiocytosis, and aneurysmal bone cysts may also be included on the differential diagnosis. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis" and "Nonmalignant bone lesions in children and adolescents", section on 'Aneurysmal bone cyst' and "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Lytic bone lesions'.)

POSTDIAGNOSTIC EVALUATION — For patients with a confirmed diagnosis of osteosarcoma, a thorough postdiagnostic evaluation is performed for tumor staging, management (including surgical planning), and prognosis.

Evaluation of primary tumor — Upon confirmation of the diagnosis, magnetic resonance imaging (MRI) of the primary tumor should be obtained for staging of the primary tumor, if not obtained prior to biopsy. (See 'Magnetic resonance imaging' above.)

Evaluation for systemic disease — It is important to assess patients with osteosarcoma for metastatic disease to determine prognosis and treatment. Although prognosis is worse for metastatic disease compared with localized disease, a proportion of patients presenting with metastatic disease may experience long-term survival. (See "Chemotherapy and radiation therapy in the management of osteosarcoma", section on 'Prognosis and evolution of treatment'.)

The approach to the staging workup for patients with osteosarcoma is discussed below, which follows guidelines from the National Comprehensive Cancer Network (NCCN) [91], the European Society for Medical Oncology (ESMO) [92], and the Children's Oncology Group Bone Tumor Committee [93].

●Chest computed tomography – A computed tomography (CT) scan of the chest with contrast should be obtained to evaluate for metastatic disease, as approximately 80 percent of osteosarcoma metastases involve the lungs [94,95]. Histologic confirmation may be obtained for pulmonary lesions that are indeterminate for metastatic disease on imaging.

Distinguishing metastatic lesions from benign nodules can be difficult, particularly in adults who have a high prevalence of granulomatous disease and in children living in areas with endemic fungal disease, especially histoplasmosis. (See "Diagnosis and treatment of pulmonary histoplasmosis", section on 'When to suspect histoplasmosis' and "Diagnostic evaluation of the incidental pulmonary nodule".)

While calcification can be a sign of benign disease, it may also be seen in metastases from osteosarcoma [96]. Criteria to guide the evaluation of suspected pulmonary metastases are available from the European and American Osteosarcoma Study Group (table 1).

Health care providers should establish the presence of metastatic disease to the lungs at diagnosis using CT and obtain histological confirmation if imaging studies are equivocal. Removal of pulmonary nodules for histologic confirmation can be performed by video-assisted thoracoscopy or open thoracotomy [97]. (See "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques", section on 'Surgical approach'.)

●Positron emission tomography computed tomography – Whole-body fludeoxyglucose (FDG) positron emission tomography (PET)-CT imaging can be obtained to evaluate for both pulmonary and bone metastases from osteosarcoma [98,99]. In patients with osteosarcoma staged with PET-CT, sensitivity and specificity for the detection of pulmonary metastases is approximately 81 and 94 percent, respectively [99]. For detection of bone metastases, sensitivity and specificity are 93 and 97 percent, respectively.

●Bone scan – Radionuclide bone scanning with technetium can be obtained with or as an alternative to PET-CT imaging to evaluate for the presence of multiple bone metastatic lesions and "skip" metastases. Both PET-CT and technetium bone scan are adequate studies to detect bone metastases in osteosarcoma, although data are mixed as to which study is more accurate [100-104]. The choice of imaging study may depend on patient or clinician preference or imaging availability at individual institutions.

Staging — There are two staging systems available for osteosarcoma. Regardless of the surgical staging system used, the most significant prognostic indicator remains the presence or absence of distant metastases. Further details on staging system in bone sarcomas are discussed separately. (See "Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management", section on 'Tumor staging'.)

●Musculoskeletal Tumor Society staging system – The Musculoskeletal Tumor Society is a surgical staging system that is most commonly used for bone sarcomas (table 2) [105,106]. This system is based on histologic grade using a two-tiered system (low versus high grade) and whether or not the tumor is confined to a single anatomic compartment.

●AJCC staging system – The combined American Joint Committee on Cancer/Union for International Cancer Control tumor, node, and metastasis (TNM) staging system for bone sarcoma is not widely used. The eighth edition contains separate T stage classifications for primary tumors arising in the appendicular skeleton, trunk, skull, and facial bones; those arising in the spine; and those arising in the pelvic bones (table 3) [107]. While there are prognostic stage groupings for tumors arising in the appendicular skeleton, trunk, skull, and facial bones, they do not apply to spine and pelvis tumors.

Fertility counseling — Prior to initiating therapy, patients with a diagnosis of osteosarcoma who are of reproductive age may be referred for discussion about fertility preservation options. Further details are discussed separately. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery" and "Fertility preservation: Cryopreservation options".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bone sarcomas".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Bone cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Pathologic characteristics – Osteosarcoma is a rare primary malignant tumor of bone that is characterized by the production of osteoid (new bone) or immature bone by the malignant cells. Although osteosarcoma is characterized by highly complex karyotypes, there are no specific immunostains or molecular tests that are diagnostic for the disease. (See 'Approach to histologic diagnosis' above and 'Pathogenesis' above.)

●Epidemiology – Osteosarcoma is slightly more predominant in males than females. The bimodal peak incidences are between 13 and 16 years of age and over the age of 65. (See 'Epidemiology' above.)

●Risk factors – Risk factors for osteosarcoma include prior radiation and chemotherapy; Paget disease (image 1) and other benign bone processes; and certain genetic conditions such as hereditary retinoblastoma, Li-Fraumeni syndrome (LFS), and Rothmund-Thomson syndrome (RTS), among others. (See 'Risk factors' above.)

●Histologic classification – Conventional osteosarcoma accounts for approximately 90 percent of all osteosarcomas. Other less common histologic variants are telangiectatic osteosarcoma, parosteal osteosarcoma, periosteal osteosarcoma, high-grade surface osteosarcoma, and secondary osteosarcoma. (See 'Histologic classification' above.)

●Clinical presentation – Osteosarcoma can present with the following findings (see 'Clinical presentation' above):

•Children and adolescents and young adults (AYAs) most frequently present with a primary, sporadic neoplasm located in the metaphyses of the long bones (figure 2A-B). (See 'Tumor location' above.)

Secondary osteosarcoma (ie, tumor that develops in abnormal bone), subsequent primary osteosarcoma after prior radiation or chemotherapy, and tumors involving the axial and craniofacial bones are primarily observed in adults. (See 'Secondary osteosarcoma' above and 'Primary versus secondary neoplasms' above and 'Radiation and chemotherapy' above and 'Tumor location' above.)

•Patients may present with localized, intermittent pain at the primary tumor site of several weeks' duration. Pain may also be related to a pathologic fracture. Systemic symptoms are generally absent. (See 'Symptoms' above.)

•Metastatic disease occurs most frequently in the lungs, followed by the distant bones; patients may also present with "skip" metastases (image 2). (See 'Distant metastases' above.)

●Diagnostic evaluation – The initial diagnostic evaluation includes the following (see 'Diagnostic evaluation' above):

•A plain radiograph of the primary tumor can demonstrate destructive sclerotic lesions and aggressive periosteal reactions of the bone, such as a Codman triangle (image 3) or a radial or "sunburst" pattern associated with a soft tissue mass (image 4). (See 'Plain radiograph' above.)

•Magnetic resonance imaging (MRI) with contrast of the entire length of the involved bone can be obtained if plain radiographs are indeterminant. MRI is also indicated for biopsy and surgical planning. (See 'Magnetic resonance imaging' above.)

•Alkaline phosphatase and lactate dehydrogenase (LDH) may be elevated. (See 'Laboratory evaluation' above.)

●Diagnosis – The diagnosis of osteosarcoma is made definitively with a biopsy and pathologic evaluation of the tumor, which should ideally be performed at a facility with expertise in the diagnosis and management of osteosarcoma. (See 'Diagnostic biopsy' above.)

●Postdiagnostic evaluation – Once the diagnosis is established, further imaging evaluation should be obtained to complete staging (table 2 and table 3) and assess for metastatic disease. (See 'Staging' above.)

This includes MRI of the entire length of the involved bone (if not obtained prior to biopsy); computed tomography (CT) of the chest with contrast; and fludeoxyglucose (FDG) positron emission tomography (PET)-CT scan and/or radionuclide bone scanning with technetium. (See 'Postdiagnostic evaluation' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Murali Chintagumpala, MD, who contributed to an earlier version of this topic review.