Chondrosarcomas are malignant bone tumors that characteristically produce cartilage matrices from neoplastic tissue devoid of osteoid. They may occur at any age but are more common in older adults, with peak incidence in individuals >50 years [6]. The most common primary sites are the pelvis and proximal femur [61,62]. Conventional chondrosarcoma (CCS) constitutes approximately 90% of all chondrosarcomas, and of these, 90% are low to intermediate grade [65]. Low-grade (grade 1) tumors in the appendicular skeleton are classified by the World Health Organization (WHO) as atypical cartilaginous tumors (low-grade intracompartmental appendicular tumors), while those in the axial skeleton are considered grade 1 chondrosarcomas [5]. Non-conventional subtypes, including clear cell, juxtacortical, dedifferentiated, myxoid, and mesenchymal forms, constitute about 10% to 15% of all chondrosarcomas [61,71,72]. Extraskeletal myxoid chondrosarcoma is a separate soft tissue sarcoma entity with distinct chromosomal translocations, and its management is addressed in the NCCN Guidelines for Soft Tissue Sarcoma [76,77]. Symptoms are usually mild and depend on tumor size and location; patients with pelvic or axial lesions often present later due to insidious pain [80-82].

The pathogenesis of chondrosarcoma is driven by recurrent genetic alterations. IDH1 and IDH2 mutations are found in approximately 65% of conventional central chondrosarcoma cases and in nearly all cases of Ollier disease and Maffucci syndrome [65,68-70]. These mutations lead to the production of the oncometabolite 2-hydroxyglutarate (2-HG). Inactivating mutations of CDKN2A and COL2A1 have also been implicated [64]. Non-conventional subtypes (clear cell, dedifferentiated, mesenchymal) frequently harbor alterations in the retinoblastoma pathway [71]. Dedifferentiated chondrosarcoma may express PD-L1 in 41% of cases [135]. Mesenchymal chondrosarcoma is characterized by a HEY1-NCOA2 fusion (not explicitly stated but referenced in Ewing-like treatment context). Extraskeletal myxoid chondrosarcoma carries specific chromosomal translocations such as t(9;22)(q22;q11-12) generating EWSR1-NR4A3 fusion, but this is a soft tissue sarcoma, not primary bone [76,77]. The molecular landscape of chondrosarcoma offers potential targeted therapy opportunities, such as ivosidenib for IDH1-mutant tumors [133].

Chondrosarcoma is the most common primary bone cancer in adults, accounting for >40% of newly diagnosed bone cancers in the United States [3]. In 2025, an estimated 3,770 people will be diagnosed with primary bone cancer (all types) and 2,190 will die [2]. Chondrosarcoma is more prevalent in individuals >50 years of age [6]. Analysis of 2,890 patients from the SEER database (1973–2003) showed that female sex, low histologic grade, and local surgical stage were associated with better disease-specific survival on univariate analysis; grade and stage remained significant on multivariate analysis [89]. Five-year relative survival across all bone cancers is 68% [1]. For mesenchymal chondrosarcoma, 5- and 10-year overall survival (OS) are 51% and 43%, respectively; axial tumor location portends poorer OS [75]. Dedifferentiated chondrosarcoma has the worst prognosis with median survival of 11 months, while juxtacortical subtype has the highest median survival at 97 months [72]. Metastasis at presentation occurs most frequently in dedifferentiated (19.8%) and mesenchymal (10.6%) subtypes [72].

Chordomas are rare malignant bone tumors that arise from embryonic remnants of the notochord. They occur most commonly in adults aged 40–75 years, with a male predominance [7-9]. The primary sites are the sacrum (50–60%), skull base (25–35%), and mobile spine (15%) [8,9,140]. Chordomas are traditionally classified by the WHO into three histologic variants: conventional (most common), chondroid (5–15%), and dedifferentiated (2–8%) [140]. An additional subtype, poorly differentiated chordoma, is characterized by loss of SMARCB1 expression and occurs more frequently in children, with predilection for skull base and cervical spine [141,142]. Benign notochordal cell tumors (BNCTs) are considered precursor lesions and do not require surgical management [145-147]. Symptoms include localized deep pain, radiculopathies, or neurologic deficits depending on location; cervical chordomas may cause airway obstruction or dysphagia [8,143].

Chordomas arise from notochordal remnants, with brachyury (TBXT) as a key immunohistochemical marker. Conventional and chondroid subtypes typically retain SMARCB1 expression. Poorly differentiated chordoma is defined by loss of SMARCB1 (INI1) expression, a chromatin remodeling gene, leading to aggressive behavior [141,142]. Several signal transduction pathways have been implicated in pathogenesis, including PDGFR, EGFR, and mTOR [209-211]. Activating mutations or amplifications in these pathways may provide therapeutic targets. Dedifferentiated chordoma likely shares molecular features with high-grade sarcomas.

Chordoma accounts for approximately 10% of primary bone cancers [3]. Incidence peaks in the fifth to sixth decade of life, with a male predominance [7-9]. In the United States, chordoma occurs in about 1 in 1 million people per year. SEER data indicate that overall 5-year survival varies by location and resectability. Skull base chordomas have slightly better outcomes than sacral/spinal chordomas. Male sex has been associated with worse progression-free and overall survival in skull base chordomas [144].

Ewing sarcoma is a highly malignant primary bone tumor characterized by a fusion of the EWSR1 gene with an ETS family transcription factor (most commonly FLI1) [12,13]. It belongs to the Ewing sarcoma family of tumors, which also includes primitive neuroectodermal tumor (PNET) of bone, Askin tumor, and extraosseous Ewing sarcoma [c]. Approximately 90% of Ewing sarcomas have one of four specific chromosome translocations [g]. Ewing sarcoma primarily affects children, adolescents, and young adults, with an incidence of 1 case per 1.5 million [236]. The most common primary sites are pelvic bones, femur, and chest wall bones [26]. When arising in long bones, the diaphysis is most frequently affected. Periosteal reaction appears as "onion skin" on radiographs. Other primary round cell sarcomas of bone (e.g., CIC::DUX4, BCOR::CCNB3) are now recognized as distinct entities but can be treated similarly [g].

The molecular hallmark of Ewing sarcoma is a reciprocal chromosomal translocation fusing the EWSR1 gene (22q12) with a member of the ETS family of transcription factors. The most common is t(11;22)(q24;q12) producing EWSR1-FLI1 fusion, found in ~85% of cases [12,15]. Less common fusions include EWSR1-ERG, EWSR1-ETV1, EWSR1-ETV4, EWSR1-FEV, and rare FUS-ERG or FUS-FEV fusions [12,13,229,230]. These chimeric proteins act as aberrant transcription factors driving oncogenesis. Strong expression of MIC2 (CD99) is characteristic [231,232]. Other primary round cell sarcomas lack EWSR1-ETS fusions and instead harbor CIC::DUX4, BCOR::CCNB3, or other rearrangements [234,235].

Ewing sarcoma accounts for approximately 8% of primary bone cancers [3]. It occurs predominantly in children and adolescents, with an incidence of 1 case per 1.5 million [236]. The most common primary sites are pelvis, femur, and chest wall [26]. Approximately 20% of cases arise in extraosseous tissue [236]. Five-year relative survival for localized Ewing sarcoma has improved to 82% with modern multimodality therapy [31]. Survival for metastatic disease remains poor, with 5-year event-free survival of ~22% [32,268]. Risk factors for poorer outcome include pelvic/axial primary site, tumor volume >100 mL, elevated LDH, and presence of metastases at diagnosis [237-244]. In a SEER analysis, adult age, Hispanic ancestry, metastatic disease, large tumor size, and low socioeconomic status were associated with worse survival [255].

Giant cell tumor of bone (GCTB) is a rare, benign primary bone tumor that is locally aggressive and rarely metastasizes to the lungs. It accounts for about 3% to 5% of all primary bone tumors [339,340]. GCTB usually occurs between 20 and 40 years of age, with a slight female predominance [341]. The most common sites are the meta-epiphyseal regions of the distal femur and proximal tibia [341]. Histologically, GCTB is characterized by numerous osteoclast-like giant cells in a background of mononuclear stromal cells. Malignant transformation to high-grade osteosarcoma is exceptionally rare but carries a poor prognosis [342,343]. Brown tumor of hyperparathyroidism is an important differential diagnosis [346].

GCTB is characterized by abundant RANKL expression on neoplastic mononuclear stromal cells, which stimulates RANK-expressing osteoclast precursors to form osteoclast-like giant cells. This RANK-RANKL interaction drives osteolysis. Denosumab, a humanized monoclonal antibody against RANKL, effectively inhibits this pathway [389-395]. No specific driver mutations are consistently identified; however, malignant transformation may involve acquisition of osteosarcoma-related genomic alterations.

GCTB accounts for 3% to 5% of all primary bone tumors [339,340]. It typically occurs in young adults aged 20–40 years [341]. The most common location is around the knee (distal femur, proximal tibia). Lung metastases occur in a small percentage of cases (typically <5%); the average time to metastasis ranges from 2 to 4 years [417-419]. Malignant transformation is very rare.

Osteosarcoma is the most common primary malignant bone tumor in children and young adults, with a bimodal age distribution peaking at ages 10–14 years and again after age 65 [420]. It is a spindle cell or pleomorphic tumor that produces osteoid or immature bone. High-grade intramedullary osteosarcoma (conventional type) comprises nearly 80% of all osteosarcomas, most frequently arising in the metaphysis of the distal femur or proximal tibia [421]. Low-grade intramedullary osteosarcoma accounts for <2% [422]. Surface (juxtacortical) variants include parosteal (low-grade, <5%), periosteal (intermediate-grade), and high-grade surface osteosarcoma (rare) [422,425,426]. Extraskeletal osteosarcoma is managed according to NCCN Guidelines for Soft Tissue Sarcoma [OSTEO-1]. High-grade undifferentiated pleomorphic sarcoma (UPS) of bone can be treated using osteosarcoma algorithms (category 2B) [BONE-B 4 of 7]. Osteosarcoma spreads hematogenously, most commonly to lungs. Pain and swelling are frequent early symptoms, sometimes mistaken for growing pains [430].

Osteosarcoma is associated with complex genomic alterations. Nearly 70% of patients exhibit mutations in the retinoblastoma gene RB1 [443]. TP53 germline mutations underlie Li-Fraumeni syndrome, which confers a high risk of osteosarcoma [17-19]. Hereditary retinoblastoma (RB1 germline mutation) increases risk 300–600 times [23]. Other genetic predisposition syndromes include Rothmund-Thomson syndrome type 2, Bloom syndrome, Werner syndrome, RAPADILINO syndrome, and Diamond-Blackfan anemia [22]. Radiation exposure is also a risk factor [24,25]. Multiple chromosomal aberrations are common, with no single pathognomonic fusion. Approximately 70% show clonal abnormalities.

Osteosarcoma accounts for ~25% of primary bone cancers in the United States [3]. It has a bimodal age distribution: first peak at 10–14 years (during adolescent growth spurt) and second peak after age 65 (often secondary to Paget disease or prior radiation) [420]. In children and adolescents, osteosarcoma is second most common primary bone cancer after Ewing sarcoma [4]. Five-year relative survival for non-metastatic osteosarcoma is approximately 60–70% with modern chemotherapy [28-30]. Survival for metastatic disease at presentation is much lower (approx 20–30%). Incidence is slightly higher in males. Race-specific SEER data not explicitly provided in source.