Bone tumor

A bone tumor is an abnormal growth of cells within a bone that can be either benign (noncancerous) or malignant (cancerous).^[1] Benign bone tumors do not spread to other parts of the body but may cause complications by pressing on nearby tissues or weakening the bone, while malignant ones can invade surrounding tissues and metastasize to distant sites.^[2] Primary bone tumors originate directly from bone tissue and are classified as a type of sarcoma, whereas secondary bone tumors result from cancer spreading from other organs, such as the breast, lung, or prostate.^[2] Benign bone tumors are more common than malignant ones and often occur in children and young adults, with osteochondromas being the most frequent type, typically affecting individuals aged 10 to 20 years.^[1] Other benign examples include osteoid osteomas, enchondromas, and giant cell tumors, which may remain asymptomatic or cause localized pain and swelling.^[3] Malignant primary bone tumors are rare, accounting for about 0.2% of all new cancer cases, with an estimated 3,770 new cases expected in the United States in 2025;^[4] the most common types are osteosarcoma (arising from osteoblasts, prevalent in teenagers and often in long bones like the legs), chondrosarcoma (from cartilage cells, mainly in adults and affecting the pelvis or thighs), and Ewing sarcoma (typically in children and involving the pelvis or legs).^[2] Chordomas, another rare malignant type, form in the spine and primarily affect older adults.^[2] The exact causes of bone tumors are often unknown, but risk factors for malignant types include inherited genetic syndromes such as Li-Fraumeni syndrome or hereditary retinoblastoma, prior exposure to radiation or chemotherapy, and underlying bone conditions like Paget's disease or fibrous dysplasia.^[5] Symptoms commonly include persistent bone pain that worsens at night, swelling or tenderness near the affected area, unexplained fractures from minor trauma, fatigue, and unintentional weight loss in advanced cases.^[5] Diagnosis typically involves imaging studies such as X-rays, MRI, CT scans, or bone scans, followed by a biopsy to confirm the tumor type and assess its malignancy.^[1] Treatment varies by tumor type, size, location, and stage but often includes surgery to remove the tumor—frequently limb-sparing procedures—along with chemotherapy for high-grade malignancies like osteosarcoma and Ewing sarcoma, or radiation therapy for tumors not amenable to surgery.^[2] Benign tumors may only require monitoring or surgical excision if symptomatic, while targeted therapies such as denosumab are used for certain types like giant cell tumors.^[2] Complications from untreated malignant bone tumors can include bone destruction, reduced mobility, and metastasis, underscoring the importance of early detection and multidisciplinary care.^[5]

Classification

Primary bone tumors

Primary bone tumors are neoplasms that originate from mesenchymal cells within the bone tissue, encompassing a diverse group of lesions that can be benign, intermediate, or malignant based on their biological behavior. These tumors arise intrinsically from bone-forming cells, cartilage cells, or other skeletal components, distinguishing them from secondary tumors that spread from distant sites. The World Health Organization (WHO) classification system for tumors of bone, updated in 2020, categorizes primary bone tumors by their differentiation lineage, such as chondrogenic, osteogenic, fibrogenic, and others, while incorporating intermediate categories to reflect tumors with locally aggressive or rarely metastasizing potential.^[6] Benign primary bone tumors typically exhibit slow growth, lack invasive properties, and do not metastasize, often presenting as well-circumscribed lesions that may cause pain or structural issues depending on location. The most common subtype is osteochondroma, a cartilage-capped bony projection arising from the metaphysis of long bones, typically affecting children and young adults aged 10 to 20 years and accounting for about 35-40% of benign bone tumors.^[7] Other common subtypes include osteomas, which are compact bone proliferations arising from osteogenic cells, frequently occurring in the craniofacial bones or paranasal sinuses and characterized histologically by dense lamellar bone without cellular atypia. Chondromas, specifically enchondromas, originate from cartilaginous tissue and are intramedullary lesions commonly found in the small bones of the hands and feet, featuring hyaline cartilage with low cellularity and no permeation of surrounding bone. Osteoid osteomas represent another prevalent benign osteogenic tumor, comprising about 12% of benign bone neoplasms, with a characteristic nidus of vascular osteoid tissue less than 1.5 cm in diameter, surrounded by reactive bone sclerosis, and typically affecting the cortex of long bones in young individuals.^[8][9][8] Malignant primary bone tumors, in contrast, demonstrate aggressive local invasion and metastatic potential, requiring precise histological identification for subtype classification. Osteosarcomas, the most common primary malignant bone tumor, derive from osteoblastic mesenchymal cells and produce malignant osteoid, predominantly arising in the metaphysis of long bones such as the distal femur or proximal tibia in adolescents. Histologically, they show pleomorphic cells with lace-like osteoid production and high mitotic activity. Ewing sarcomas originate from primitive neuroectodermal cells and are small round blue cell tumors with uniform sheets of cells exhibiting round nuclei and scant cytoplasm, often located in the diaphysis of long bones or flat bones like the pelvis, primarily affecting children and young adults. Chondrosarcomas arise from malignant cartilaginous cells and are the second most frequent primary bone malignancy, typically in the axial skeleton such as the pelvis or proximal femur, with conventional subtypes displaying lobular architecture of hyaline cartilage showing increased cellularity, binucleation, and myxoid changes in higher grades.^[3][10][3] The WHO classification also includes intermediate categories, such as atypical cartilaginous tumors (previously grade 1 chondrosarcomas in appendicular sites), which exhibit low-grade malignant potential with permeative growth but rare metastasis, confined to long and short tubular bones and featuring mildly atypical chondrocytes in a hyalinized matrix. Another common intermediate tumor is giant cell tumor of bone, classified as locally aggressive and rarely metastasizing, characterized by multinucleated osteoclast-like giant cells and neoplastic mononuclear stromal cells, often involving the epiphysis of long bones like the distal femur or proximal tibia in young adults aged 20 to 40 years, accounting for approximately 5% of primary bone tumors.^[11] Rare primary bone tumors encompass fibrogenic types like fibrosarcoma, a highly malignant spindle cell neoplasm producing collagenous stroma with herringbone patterns, accounting for less than 5% of bone sarcomas and often arising in the metaphysis of long bones. Chordomas, derived from notochordal remnants, are low- to intermediate-grade malignancies with physaliphorous cells in a myxoid or chondroid matrix, predominantly occurring in the sacrum or clivus and classified separately under notochordal tumors. These rare entities highlight the heterogeneity within primary bone tumors, emphasizing the need for lineage-specific diagnosis.^[6][10][12]

Secondary bone tumors

Secondary bone tumors, also known as metastatic bone tumors, represent the spread of malignant cells from a primary cancer site to the skeletal system, and they constitute the most common form of bone malignancy in adults, far outnumbering primary bone tumors.^[13] These metastases typically arise in the context of advanced systemic disease and are responsible for significant morbidity, including pain and skeletal complications.^[14] In contrast to primary bone tumors, which originate within bone tissue, secondary tumors reflect the hematogenous or local invasion from distant primaries.^[13] The most frequent primary cancers that metastasize to bone include those of the breast, prostate, lung, kidney, and thyroid, accounting for the majority of cases.^[13] Prostate cancer often produces osteoblastic metastases, characterized by increased bone formation and sclerotic appearances on imaging, while breast and lung cancers more commonly cause osteolytic lesions that result in bone resorption and destruction.^[14] Renal and thyroid carcinomas can exhibit either pattern, though lytic features predominate in renal disease.^[13] These variations in radiographic appearance aid in inferring the primary source when it is unknown.^[15] Bone metastases primarily disseminate via hematogenous routes, with tumor cells entering the bloodstream and lodging in bone marrow, particularly in areas rich in red marrow such as the axial skeleton.^[13] Less commonly, spread occurs through direct extension from adjacent soft tissue tumors or lymphatic pathways, though the latter is rare for bone involvement.^[15] Predilection sites include the spine, pelvis, ribs, and proximal long bones (femur and humerus), reflecting the vascular and marrow distribution that favors tumor cell arrest and proliferation.^[16] Pathologically, secondary bone tumors often present as multiple lesions indicative of disseminated disease, though solitary metastases can occur, particularly in earlier stages or with certain primaries like renal cell carcinoma.^[17] Osteolytic patterns dominate in many cases, leading to weakened bone structure and increased fracture risk, whereas osteoblastic activity is more pronounced in prostate-derived metastases.^[14] A key complication is hypercalcemia, arising from excessive bone resorption in lytic lesions, which affects 10-30% of patients with such metastases and can manifest as fatigue, confusion, and renal impairment.^[13] Widespread dissemination typically signals poorer prognosis compared to isolated lesions, influencing management approaches.^[18]

Causes and risk factors

Genetic and hereditary factors

Genetic predisposition plays a significant role in up to 28% of osteosarcoma cases, based on germline variants in cancer-susceptibility genes, particularly osteosarcomas.^[19] Hereditary syndromes associated with bone tumors often involve germline mutations in tumor suppressor genes, leading to heightened cancer risk through disrupted DNA repair and cell cycle control. Li-Fraumeni syndrome, caused by germline TP53 mutations, substantially elevates the risk of osteosarcoma, which is diagnosed in approximately 12% of affected individuals and often serves as a sentinel cancer.^[20] Similarly, Rothmund-Thomson syndrome, resulting from biallelic RECQL4 mutations, predisposes patients to osteosarcoma, with loss-of-function variants occurring in about two-thirds of cases and correlating with early-onset bone malignancy.^[21] Retinoblastoma survivors with RB1 germline deletions face a markedly increased osteosarcoma risk, estimated at 300-600 times higher than the general population due to loss of heterozygosity in the RB1 pathway.^[22] Beyond hereditary syndromes, somatic mutations drive tumorigenesis in specific bone tumor types. In osteosarcoma, alterations such as RUNX2 amplification at 6p21.1 are common, promoting osteoblastic proliferation and tumor progression through enhanced transcriptional activity.^[23] Ewing sarcoma is characterized by the EWSR1-FLI1 gene fusion in over 85% of cases, acting as an aberrant transcription factor that reprograms gene expression to sustain oncogenic growth.^[24] Chondrosarcomas frequently harbor IDH1/2 mutations, particularly at R132 and R172 codons, which alter cellular metabolism and epigenetic regulation, occurring in up to 50-60% of conventional central subtypes.^[25] Key oncogenic pathways underpin these genetic changes in bone tumor development. Dysregulation of Wnt/β-catenin signaling, often through mutations in APC or β-catenin stabilizers, fosters uncontrolled osteoblast proliferation and tumor invasion in osteosarcoma and other sarcomas.^[26] The Hedgehog pathway, activated via ligand-dependent mechanisms like SMO upregulation, supports osteosarcoma metastasis and stem-like cell maintenance, particularly in TP53/RB1-mutated tumors.^[27] p53 dysregulation, prevalent in over 50% of osteosarcomas through somatic TP53 mutations or loss, impairs apoptosis and genomic stability, synergizing with other pathways to initiate and propagate bone malignancies.^[28] Recent genomic studies utilizing next-generation sequencing (NGS) have identified novel driver mutations in bone tumors. A 2022 multi-omics analysis of osteosarcoma revealed recurrent somatic alterations in 22 genes, including TP53 and cell cycle regulators, highlighting subtype-specific vulnerabilities.^[29] Similarly, a comprehensive NGS profiling of 357 bone tumor patients post-2020 identified actionable mutations in 34.2% of cases, with TP53 alterations in 31.4% and pathway insights into Hedgehog and Wnt dysregulation.^[30] These findings underscore the heterogeneity of bone tumor genomics and the potential for targeted interventions based on driver events. Recent research has also identified SMARCAL1 as a novel osteosarcoma predisposition gene.^[31]

Environmental and lifestyle factors

Ionizing radiation is a well-established environmental risk factor for bone tumors, particularly osteosarcoma, with therapeutic radiation exposure significantly elevating the incidence. Individuals who have received high-dose external radiation therapy, often for prior cancers, face an increased risk of developing osteosarcoma at the irradiated site, with the risk rising in a dose-dependent manner. Studies indicate that the risk can increase 5- to 10-fold following cumulative bone tissue exposure to 1-9 Gy, and it continues to escalate with higher doses, though it may plateau around 30 Gy. A minimum dose exceeding 30 Gy is commonly associated with radiation-induced sarcomas, with the latency period typically spanning several years to decades post-exposure.^[32][33][34] Chemical exposures also contribute to secondary bone tumor development, notably through alkylating agents used in chemotherapy regimens. These agents, such as cyclophosphamide and ifosfamide, heighten the risk of bone sarcomas in cancer survivors, with the effect amplified when combined with radiotherapy; relative risks can reach 4.7 or higher depending on cumulative dose. Industrial carcinogens like Thorotrast (thorium dioxide), a former radiocontrast agent, have been linked to increased bone cancer incidence due to its alpha-particle emissions and accumulation in bone tissue.^[35][36][37] Paget's disease of bone serves as a precursor condition for sarcomatous transformation, where abnormal bone remodeling leads to malignant changes in approximately 1% of affected individuals, most often manifesting as osteosarcoma or fibrosarcoma. This transformation is more frequent in cases of extensive polyostotic involvement and typically occurs after decades of disease progression.^[38][39] Evidence linking lifestyle factors to bone tumor risk remains limited, with no strong causal associations established for smoking or dietary habits. However, states of high bone turnover, such as the rapid skeletal growth during adolescence, indirectly correlate with elevated osteosarcoma incidence, as this period coincides with peak tumor onset.^[2][22] Occupational exposures to radioactive materials represent a historical environmental hazard, exemplified by radium ingestion among early 20th-century watch dial painters. These workers, primarily women, painted luminous dials with radium-based compounds, leading to chronic internal irradiation and a high incidence of bone sarcomas, often after a latency of 20-30 years; autopsy studies confirmed radium deposition in bones as the causative factor.^[40][41]

Clinical features

Symptoms

The primary symptom of bone tumors is persistent bone pain, which often begins insidiously and worsens over time, particularly at night or with physical activity, and is commonly localized to the affected limb, joint, or back.^[5][1] In benign tumors, such as osteochondromas or non-ossifying fibromas, pain may be mild or intermittent and sometimes absent altogether, while malignant tumors like osteosarcoma or Ewing sarcoma typically cause more severe, progressive pain that can mimic growing pains in younger patients or arthritis in adults.^[2][42] Patients often report functional limitations due to the pain and structural effects of the tumor, including limping, reduced range of motion in the affected area, or sudden acute pain from pathological fractures where the bone breaks more easily under normal stress.^[5][2] In cases involving the extremities, individuals may describe a sensation of swelling or a noticeable mass, contributing to discomfort during movement.^[43] For spinal tumors, symptoms can include reports of radiating pain, numbness, or weakness in the limbs, reflecting nerve involvement.^[44] In advanced malignant bone tumors, such as Ewing sarcoma, systemic symptoms may emerge, including unexplained fatigue, unintentional weight loss, and low-grade fever, signaling the body's response to tumor growth or metastasis.^[2][45] The onset of symptoms in benign tumors is generally gradual over months to years, often discovered incidentally, whereas malignant tumors progress more rapidly, with symptoms intensifying within weeks to months and prompting medical evaluation.^[2]

Physical signs

Physical examination of patients with bone tumors often reveals local signs at the site of the lesion, including a palpable mass or swelling, which may be firm and fixed to the underlying bone.^[5] Tenderness on palpation is commonly elicited over the affected area, reflecting periosteal irritation or tumor expansion.^[46] In some cases, localized warmth may be appreciated due to increased vascularity or inflammation associated with the tumor.^[47] Deformities such as bone bowing or angular deviations can occur in long-standing tumors, particularly those involving the tibia or other long bones, resulting from progressive bone remodeling or pathologic fractures.^[46] Limb length discrepancy may also develop over time in growing children with tumors affecting the metaphysis of long bones, due to asymmetric growth plate involvement or post-fracture shortening.^[3] In spinal bone tumors, neurological signs are prominent and may include lower extremity weakness, sensory loss in a dermatomal distribution, or symptoms of cauda equina syndrome such as saddle anesthesia and bowel or bladder dysfunction, arising from direct compression of neural structures.^[48] These findings necessitate urgent evaluation to prevent irreversible deficits.^[49] Systemic signs in advanced or metastatic bone tumors can manifest as cachexia, characterized by significant weight loss and muscle wasting due to the paraneoplastic effects of the malignancy.^[50] Anemia may be evident on examination as pallor, stemming from bone marrow infiltration by tumor cells.^[13] Lymphadenopathy, though less common in isolated bone tumors, can occur in metastatic disease from primaries like lymphoma or carcinoma, presenting as enlarged, firm nodes.^[51] Specific physical signs vary by tumor type; for instance, adamantinoma of the tibia often presents with anterior bowing deformity and may be associated with pathologic fractures leading to pseudarthrosis-like instability.^[52] In tumors with soft tissue extension, such as certain sarcomas adjacent to bone, a soft tissue mass may be palpable beyond the bony confines.^[53]

Diagnosis

Imaging modalities

Imaging plays a crucial role in the detection, characterization, and localization of bone tumors, allowing for initial assessment of lesion type, extent, and potential malignancy through non-invasive means. Various modalities are employed, each offering complementary information about bone structure, soft tissue involvement, and metabolic activity. The choice of imaging depends on the suspected tumor type and clinical context, with plain radiography typically serving as the first-line investigation followed by advanced techniques for detailed evaluation. Plain radiography remains the cornerstone initial modality for evaluating bone tumors, providing essential information on lesion location, size, and radiographic appearance such as lytic or blastic patterns. It effectively demonstrates periosteal reactions, including the sunburst pattern characteristic of osteosarcoma and Codman's triangle often seen in aggressive lesions like Ewing sarcoma. These features help differentiate benign from malignant processes and guide further imaging, though radiography has limitations in assessing soft tissue or marrow involvement.^[54][55][56] Magnetic resonance imaging (MRI) is considered the gold standard for local staging of bone tumors, excelling in delineating soft tissue extension, marrow infiltration, and tumor margins. On T1-weighted images, tumors typically appear as low-signal lesions replacing normal fatty marrow, while T2-weighted sequences highlight high-signal areas indicative of edema or cystic components; gadolinium contrast enhancement further reveals viable tumor tissue and necrosis. This modality is particularly valuable for assessing intramedullary spread and adjacent structure involvement, aiding in surgical planning.^[54][55][56] Computed tomography (CT) provides superior visualization of bone architecture, making it indispensable for detecting cortical destruction, subtle fractures, and matrix mineralization within the tumor. For instance, chondrosarcomas often exhibit characteristic chondroid calcifications or "rings and arcs" patterns on CT, which assist in histological correlation. While it offers less soft tissue detail than MRI, CT's high spatial resolution is useful for preoperative assessment and biopsy guidance in complex bony lesions.^[54][55][56] Bone scintigraphy, utilizing technetium-99m-labeled methylene diphosphonate, is employed to screen for multifocal disease or skeletal metastases by highlighting areas of increased osteoblastic activity. It offers whole-body coverage, identifying polyostotic involvement in conditions like multiple enchondromas or metastatic spread from primary bone sarcomas, though it lacks specificity and requires correlation with other imaging.^[54][55][56] Positron emission tomography-computed tomography (PET-CT) with 18F-fluorodeoxyglucose (FDG) assesses tumor metabolic activity, facilitating staging of malignant bone tumors by quantifying glucose uptake via standardized uptake values (SUV). High FDG avidity, often with SUVmax exceeding 5, correlates with aggressive behavior in sarcomas like osteosarcoma, enabling detection of distant metastases and monitoring treatment response; it surpasses bone scintigraphy in specificity for skeletal involvement.^{[54][55][56][57]} Ultrasound has a limited but supportive role in bone tumor evaluation, primarily for superficial or accessible lesions where it can depict extra-osseous extensions or guide percutaneous biopsies in real-time. Its inability to penetrate bone restricts its use to soft tissue components or procedural assistance rather than primary diagnosis.^[54][55][56] These imaging techniques often integrate to inform biopsy targeting and contribute to staging by defining tumor extent and metastatic potential.

Biopsy and histopathological examination

Biopsy of suspected bone tumors is essential for definitive diagnosis, as it provides tissue for histopathological, immunohistochemical, and molecular analysis to distinguish benign from malignant lesions and guide treatment. The choice of technique depends on tumor location, size, and accessibility, with core needle biopsy being the preferred initial method due to its minimally invasive nature and high diagnostic accuracy of 74-95% for musculoskeletal tumors.^[58] Image-guided core needle biopsy, using CT or ultrasound, targets the most representative area of the lesion, such as the periphery to include reactive zones, while minimizing risks like tumor seeding along the needle tract.^[59] Open incisional biopsy is reserved for cases where core biopsy yields insufficient tissue, involving a small longitudinal incision to sample the tumor without complete removal, ensuring the biopsy tract can be excised during definitive surgery.^[59] Excisional biopsy, which removes the entire lesion, is limited to small, superficial benign-appearing tumors but is avoided in potential malignancies to prevent inadequate margins.^[58] Histopathological examination of biopsy samples evaluates cellular architecture, matrix production, and growth patterns to classify tumors. Benign bone tumors typically show uniform cell morphology, low mitotic activity, and organized matrix, such as woven bone trabeculae in osteoid osteoma or hypocellular hyaline cartilage with regular nuclei in enchondroma.^[60] In contrast, malignant tumors exhibit criteria like nuclear pleomorphism, high mitotic rate, and necrosis; for example, osteosarcoma displays malignant osteoid production by atypical cells, while chondrosarcoma features hypercellular cartilage with cytologic atypia and myxoid change.^[60] Multiple samples from heterogeneous lesions are recommended to avoid sampling error, with core biopsies providing adequate stromal and cytologic detail comparable to open methods.^[59] Immunohistochemistry enhances diagnostic precision by identifying specific protein markers in tumor cells. Vimentin is broadly expressed in mesenchymal bone tumors, serving as a baseline marker, while S100 positivity supports chondroid differentiation in chondrosarcoma.^[61] CD99 membranous staining is characteristic of Ewing sarcoma, often combined with NKX2.2 nuclear expression to confirm the diagnosis with high sensitivity.^[61] These markers help differentiate tumors with overlapping histology, such as distinguishing osteoblastoma from osteosarcoma using FOS rearrangements.^[61] Molecular pathology techniques detect genetic alterations for confirmatory diagnosis, particularly in small round cell tumors. Reverse transcriptase polymerase chain reaction (RT-PCR) identifies fusion transcripts from translocations, such as EWSR1-FLI1 in Ewing sarcoma resulting from t(11;22), offering rapid results even in decalcified samples.^[62] Fluorescence in situ hybridization (FISH) visualizes chromosomal rearrangements, like break-apart signals for t(11;22) in Ewing sarcoma, and is robust for formalin-fixed paraffin-embedded tissue despite decalcification challenges.^[62] These assays are crucial for tumors with subtle histologic features and inform targeted therapies. Biopsy procedures carry risks including infection, hemorrhage, pathologic fracture in lytic lesions, and rare tumor seeding (0.003-0.009% incidence), necessitating preoperative coagulation assessment and post-procedure monitoring.^[58] All cases require multidisciplinary review by pathologists, surgeons, and oncologists to correlate findings with imaging and ensure optimal management.^[59]

Staging

Staging of bone tumors involves classifying the extent of disease based on tumor grade, local extent, and presence of metastasis to guide treatment planning and predict outcomes. The primary systems used are the Enneking system, adopted by the Musculoskeletal Tumor Society (MSTS), and the American Joint Committee on Cancer (AJCC) TNM classification, which are applied to primary musculoskeletal sarcomas including bone tumors.^[63][64] The Enneking staging system, developed in 1980, categorizes musculoskeletal tumors based on three key factors: histologic grade (G), anatomic site (T), and metastasis (M). Grade is classified as G0 for benign lesions, G1 for low-grade malignancy (less aggressive, resembling normal tissue), and G2 for high-grade malignancy (more aggressive, with higher metastatic potential). Site extent is T0 for no demonstrable extension beyond the tumor capsule (benign or very low-grade), T1 for intracompartmental growth (confined within natural anatomical barriers like bone cortex or fascia), and T2 for extracompartmental extension (breaching barriers into adjacent tissues). Metastasis is M0 (absent) or M1 (present, indicating distant spread). These combine into stages: stage 1 (low-grade, IA intracompartmental or IB extracompartmental), stage 2 (high-grade, IIA intracompartmental or IIB extracompartmental), and stage 3 (any grade with metastasis). The system emphasizes surgical implications, such as the need for wide resection in higher stages to achieve local control.^[65][66][63] The MSTS system is essentially synonymous with the Enneking system and is widely used by orthopedic oncologists for surgical staging of bone and soft-tissue sarcomas. It retains the G, T, and M parameters but focuses on preoperative planning, such as determining margins for limb-sparing surgery in stage IIB tumors (high-grade, extracompartmental, non-metastatic). This approach has been validated for its prognostic value in primary bone sarcomas like osteosarcoma and Ewing sarcoma.^[64][67][68] For specific bone tumor types, the AJCC TNM staging system (9th edition, 2025) provides a more granular assessment integrated with grade. The T category describes tumor size and invasion: T1 for tumors ≤8 cm in greatest dimension, T2 for >8 cm, and T3 for discontinuous tumors in the same bone (discontinuous extension or skip metastases). Nodal involvement is N0 (none) or N1 (regional lymph nodes), though rare in bone sarcomas. Metastasis is M0 (none) or M1 (distant, including other bones or organs). Grade is G1 (low) or G2/G3 (high). For osteosarcoma, examples include stage IIA (T1 N0 M0 G2/G3, small high-grade tumor) and stage IIB (T2 N0 M0 G2/G3, larger high-grade tumor >8 cm), while stage IV indicates M1 regardless of other factors. This system complements Enneking by incorporating size thresholds that correlate with worse prognosis for tumors exceeding 8 cm.^{[67][69][64][70]} In secondary bone tumors, such as metastases from primary cancers elsewhere (e.g., breast or prostate), dedicated staging systems like Enneking or AJCC are limited; instead, emphasis is placed on controlling the primary tumor site, with bone involvement typically classifying the disease as stage IV (M1) in the primary's TNM framework. Prognostic assessment relies more on the primary tumor's biology and burden of skeletal metastases rather than bone-specific grading.^[13][71][72] Recent updates in the 2020s have begun incorporating genomic profiling into staging paradigms for precision oncology, particularly through the 2020 World Health Organization (WHO) classification of bone tumors, which integrates molecular alterations (e.g., specific gene fusions or mutations) to refine risk stratification beyond traditional histologic grade. Next-generation sequencing identifies actionable genomic variants that may modify stage-based prognosis, such as in high-grade osteosarcoma where certain mutations predict metastatic risk, enabling tailored surveillance.^[73][74][75]

Treatment

Surgical interventions

Surgical interventions represent a cornerstone of bone tumor management, particularly for achieving local control in both primary malignant and benign neoplasms. The primary goal is to remove the tumor while preserving function, with wide local excision aiming for negative margins of at least 2 cm in soft tissue and en bloc resection in bone to minimize recurrence risk. Limb-sparing surgery has become the standard approach for approximately 90% of extremity sarcomas, enabled by advances in imaging and neoadjuvant therapies that allow precise preoperative planning. In cases where tumor extent precludes limb preservation, such as extensive neurovascular involvement or unresectable pelvic lesions, amputation is indicated to prevent local progression and systemic spread. Common procedures include above-knee or below-knee amputations for lower extremity tumors, with hip disarticulation reserved for proximal femoral involvement; these are performed with en bloc resection to ensure clear margins. Rotationplasty, a specialized amputation variant, is particularly utilized in pediatric osteosarcoma patients, converting the ankle to a functional knee joint to facilitate prosthetic use and maintain mobility. Reconstruction following resection is critical for restoring structural integrity and function, with options tailored to tumor location, patient age, and bone defect size. Modular endoprostheses, such as tumor prostheses for the proximal femur or distal femur, provide immediate stability and are favored in adults due to their durability and adaptability. For younger patients or skeletally immature individuals, allografts or composite grafts (bone and soft tissue) offer biological integration, though they carry risks of disease transmission and longer incorporation times. Autologous bone grafts from the iliac crest may supplement these in smaller defects. For benign bone tumors, such as aneurysmal bone cysts or giant cell tumors, intralesional curettage is the preferred minimally invasive technique, involving scraping of the tumor cavity followed by bone grafting or cement filling to promote healing. High-speed burrs enhance complete removal, reducing recurrence rates to under 20% in select cases. Adjuvant therapies like phenol or cryotherapy may be applied to the cavity walls to ablate residual cells. In metastatic bone disease, surgical interventions focus on palliation and prevention of skeletal-related events. Prophylactic internal fixation with intramedullary nails or plates is recommended for impending fractures in weight-bearing bones, based on criteria like a Mirels score exceeding 8, to maintain ambulation and quality of life. For spinal metastases causing instability or cord compression, vertebroplasty or kyphoplasty stabilizes vertebral bodies by injecting bone cement, providing rapid pain relief in over 80% of patients. Intraoperative frozen section analysis is routinely employed during resections to confirm margin status in real-time, guiding the extent of excision and reducing the need for reoperation. Common complications include surgical site infections (5-10% incidence), non-union of grafts (up to 15% in allografts), and implant failure, necessitating vigilant postoperative monitoring and multidisciplinary care. Staging systems, such as the Musculoskeletal Tumor Society classification, inform surgical planning by delineating tumor extent and guiding reconstructive choices.

Chemotherapy and radiation therapy

Chemotherapy is a cornerstone of systemic therapy for bone tumors, particularly in high-grade sarcomas like osteosarcoma and Ewing sarcoma, where it is used both neoadjuvantly to reduce tumor burden and adjuvantly to eliminate microscopic disease. For osteosarcoma, the MAP regimen—comprising high-dose methotrexate (12 g/m²), doxorubicin (75 mg/m²), and cisplatin (120 mg/m²)—is the standard protocol, delivered in two preoperative cycles followed by four postoperative cycles, with cisplatin omitted in the final two to mitigate toxicity.^[76] This multi-agent approach targets rapidly dividing cells and has been shown to improve event-free survival when integrated with surgical resection.^[76] Neoadjuvant chemotherapy facilitates tumor shrinkage, enhancing the feasibility of limb-sparing surgery, and allows assessment of treatment responsiveness through histopathological evaluation of surgical specimens. Tumor response is quantified by the percentage of necrosis, with ≥90% necrosis classifying patients as good responders, associated with superior long-term outcomes compared to <90% necrosis.^[77] For Ewing sarcoma, the VDC/IE regimen alternates vincristine (1.5 mg/m², capped at 2 mg), doxorubicin (75 mg/m²), and cyclophosphamide (1,200 mg/m²) with ifosfamide (1,800 mg/m² days 1-5) and etoposide (100 mg/m² days 1-5) every 2-3 weeks for 14-17 cycles, typically starting with 9-12 weeks preoperatively to control systemic disease.^[78] Radiation therapy serves as a localized modality, often complementing chemotherapy in scenarios where surgery is challenging. In Ewing sarcoma, external beam radiation is standard for unresectable tumors or positive margins, delivering 55.8-60 Gy in 1.8-2 Gy fractions to achieve local control rates exceeding 70%.^[79] For chondrosarcoma, which is relatively radioresistant, radiation is reserved for palliation in metastatic or inoperable cases, employing doses of 40-60 Gy to alleviate pain and stabilize disease progression, with advanced techniques like intensity-modulated radiation improving outcomes in high-risk settings.^[80] Proton therapy enhances precision in bone tumors near critical structures, such as pelvic osteosarcomas, by exploiting the Bragg peak to deposit energy directly within the target while sparing adjacent organs; studies report 3-year local control of 72.9% and overall survival of 68.9% with median doses of 55.8 Gy (relative biological effectiveness).^[81] Combined modality therapy integrates chemotherapy and radiation for unresectable bone tumors, particularly osteosarcoma and Ewing sarcoma, to maximize tumor eradication without initial surgery; for instance, in pelvic osteosarcoma, this approach yields local control in up to 80% of cases when radiation follows neoadjuvant chemotherapy.^[82] Therapies carry significant risks, necessitating careful monitoring and adjustments. Cardiotoxicity, primarily from doxorubicin, manifests as cardiomyopathy in 2% of osteosarcoma survivors, potentially leading to heart failure and requiring echocardiographic surveillance.^[83] Nephrotoxicity arises from cisplatin and ifosfamide, causing tubulopathy or Fanconi syndrome in up to 20% of patients, managed through hydration protocols, dose reductions (e.g., substituting ifosfamide for methotrexate in older adults), and renal function monitoring.^[83] Secondary malignancies, including acute myeloid leukemia and solid tumors, occur at elevated rates (3-20 years post-treatment) due to alkylating agents and radiation doses under 50 Gy, prompting lifelong screening and cumulative dose limits.^[83]

Pharmacological treatments

Pharmacological treatments for bone tumors primarily focus on supportive care to manage symptoms, stabilize bone integrity, and target specific molecular pathways in primary or metastatic disease. Bisphosphonates, such as zoledronic acid, inhibit osteoclast activity and are widely used to reduce skeletal-related events (SREs) like fractures and hypercalcemia in patients with metastatic bone disease.^[84] Denosumab, a monoclonal antibody targeting RANKL, has demonstrated superiority over zoledronic acid in delaying the time to first SRE and subsequent events in patients with bone metastases from solid tumors, including those originating from breast, prostate, and lung cancers.^[85] These agents are administered intravenously or subcutaneously and are recommended in clinical guidelines for patients at high risk of bone complications.^[86] Pain management in bone tumors often involves a multimodal approach tailored to the type of pain, whether nociceptive from bone destruction or neuropathic from nerve compression. Nonsteroidal anti-inflammatory drugs (NSAIDs) and weak opioids serve as first-line therapies for mild to moderate bone pain, providing analgesia by reducing inflammation and modulating pain signaling.^[87] For severe or neuropathic components, opioids such as morphine are escalated, while adjuncts like gabapentin enhance efficacy by stabilizing neuronal excitability, particularly in cancer-related neuropathic pain.^[88] This combination has shown improved pain control and reduced opioid requirements compared to opioids alone.^[89] Targeted therapies have emerged for specific bone sarcomas based on identifiable mutations and pathways. Tyrosine kinase inhibitors like pazopanib, which blocks VEGFR, PDGFR, and c-KIT, have shown clinical benefit in advanced soft tissue and bone sarcomas, with response rates around 20-30% in pretreated patients.^[90] mTOR inhibitors, such as everolimus, target the PI3K/AKT/mTOR pathway and have demonstrated antitumor effects in osteosarcoma models by suppressing protein synthesis and cell proliferation, with ongoing trials exploring their role in metastatic settings.^[91] These agents are selected based on tumor genotyping to match driver alterations. Immunotherapy, particularly PD-1 inhibitors, represents an emerging option for bone sarcomas, though efficacy varies by subtype. Pembrolizumab, an anti-PD-1 monoclonal antibody, was evaluated in the SARC028 phase II trial for advanced sarcomas, including osteosarcoma, showing limited but observable responses in bone tumors with an overall response rate of about 18% in soft tissue subtypes and modest progression-free survival.^[92] More recent data from a 2024 trial combining nivolumab with sunitinib in advanced bone sarcomas reported a 6-month progression-free survival of 42%, indicating potential synergy in immunogenic subsets.^[93] These approaches are being investigated in ongoing 2020s trials for patients with high tumor mutational burden. Hormone therapy plays a key role in managing bone metastases from hormone-sensitive primaries, such as prostate cancer. Androgen deprivation therapy (ADT), using agents like leuprolide or bicalutamide, suppresses testosterone production and signaling, providing symptomatic palliation and delaying skeletal progression in metastatic prostate cancer with bone involvement.^[94] ADT reduces the risk of SREs when combined with bone-targeted agents, though long-term use requires monitoring for bone density loss.^[95]

Ablative procedures

Ablative procedures encompass minimally invasive techniques that employ thermal energy, freezing, or vascular occlusion to destroy or devascularize bone tumors, often performed percutaneously under imaging guidance to target lesions while minimizing damage to surrounding tissues. These methods are particularly valuable for patients unsuitable for open surgery, providing options for both curative intent in select cases and palliation of symptoms such as pain from metastatic disease.^[96] Radiofrequency ablation (RFA) involves inserting a probe to deliver heat, typically between 60–100°C, to coagulate tumor tissue, making it effective for small benign tumors like osteoid osteomas and painful bone metastases. Studies report pain relief in up to 90% of patients following RFA for bone metastases, with technical success rates approaching 100% when guided by computed tomography (CT).^[97][98] Cryoablation uses extreme cold, generated by argon gas cycles reaching -100°C or lower, to induce ice crystal formation and cell death within tumors, suitable for both benign and aggressive lesions while often preserving bone structure through a visible "ice ball" monitored via imaging. This technique achieves significant pain reduction, with average scores dropping from 7.0 to 1.8 post-procedure, and supports local tumor control in metastatic settings.^[99][100] Microwave ablation applies electromagnetic waves to rapidly generate heat up to 100–150°C, offering advantages over RFA by heating larger lesions more quickly and uniformly, which is beneficial for tumors exceeding 3 cm in diameter. Clinical outcomes demonstrate effective pain relief and quality-of-life improvements in patients with bone tumors, including metastases, with technical success in all cases reported in retrospective series.^[101][102] Arterial embolization targets hypervascular tumors, such as aneurysmal bone cysts, by selectively occluding feeding vessels with agents like polyvinyl alcohol particles to reduce blood supply and induce necrosis. This approach serves as a primary or preoperative treatment, effectively decreasing tumor size and alleviating pain in spinal or pelvic locations.^[103][104] Indications for ablative procedures include curative treatment of small benign tumors, such as osteoid osteomas, and palliative management of inoperable bone metastases to relieve pain and prevent skeletal-related events. These interventions are preferred when tumors are localized and accessible percutaneously, often combined with cementoplasty for structural support in weight-bearing bones.^[96][105] Complications, though infrequent with rates of major events below 1–3%, can include skin burns from thermal spread, transient nerve injury, and pathologic fractures, underscoring the necessity of real-time imaging guidance like CT or ultrasound to ensure precise probe placement and monitor adjacent structures.^[106][107]

Prognosis

Prognostic factors

Prognostic factors for bone tumors encompass a range of clinical, pathological, and molecular features that significantly influence patient outcomes, varying by tumor type such as osteosarcoma and Ewing sarcoma.^[108] Tumor-specific factors include the stage at diagnosis, where metastatic disease at presentation is associated with poorer survival compared to localized disease.^[108] Histological grade also plays a critical role, with high-grade tumors exhibiting more aggressive behavior and reduced survival rates.^[108] Post-surgical margin status is another key determinant, as negative margins correlate with improved local control and overall prognosis.^[108] Additionally, the degree of tumor necrosis following neoadjuvant chemotherapy serves as a strong predictor, with greater than 90% necrosis indicating a favorable response and better long-term outcomes in osteosarcoma.^[108] Patient-specific factors further modulate prognosis. Age at diagnosis is particularly relevant in osteosarcoma, where patients under 40 years generally experience better survival than older individuals.^[109] Tumor size is inversely related to outcomes, with lesions larger than 10 cm linked to higher rates of metastasis and diminished survival.^[108] Tumor location also impacts prognosis, as axial sites (e.g., pelvis or spine) are associated with worse outcomes compared to appendicular locations (e.g., long bones of the limbs) due to challenges in surgical resection and higher metastatic potential.^[108] Molecular alterations provide additional prognostic insights. In osteosarcoma, TP53 mutations are correlated with reduced overall survival, particularly in the short term, and are linked to chemoresistance and aggressive disease progression.^[110] For Ewing sarcoma, variants of the EWS-FLI1 fusion gene influence outcomes, with the type 1 fusion (exon 7 of EWSR1 to exon 6 of FLI1) associated with a more favorable prognosis than non-type 1 fusions.^[111] In secondary bone tumors arising from metastases, prognosis depends on factors related to the primary malignancy, including effective control of the primary tumor site, which improves skeletal-related event-free survival.^[112] The number of bone metastases is also prognostic, with multiple lesions indicating more advanced disease and poorer survival compared to solitary metastases.^[113] Recent advancements in the 2020s have highlighted emerging biomarkers for prognosis. Circulating tumor DNA (ctDNA) levels in osteosarcoma patients prior to treatment predict response to immunotherapy and early disease progression, serving as a non-invasive tool for monitoring and risk stratification.^[114]

Survival outcomes

Survival outcomes for bone tumors vary significantly by tumor type, stage at diagnosis, and whether the tumor is primary or secondary. For primary malignant bone tumors, 5-year overall survival (OS) rates are generally higher for localized disease compared to metastatic cases, reflecting advances in multimodal therapies. Benign bone tumors, by contrast, have excellent prognoses with appropriate intervention. Osteosarcoma, the most common primary malignant bone tumor, demonstrates 5-year OS rates of 60-75% for localized disease and approximately 20-30% for metastatic disease.^[115][116] These rates represent a substantial improvement from pre-1980s eras, when survival with surgery alone was less than 20%, prior to the widespread adoption of effective chemotherapy regimens.^[117] Ewing sarcoma shows 5-year OS rates of around 70-80% for localized tumors and 30-40% for metastatic cases, with outcomes worsening further in the presence of lung metastases, where survival drops to approximately 35%.^{[118][119][120]} Chondrosarcoma, a cartilage-derived malignancy, has favorable 5-year OS rates of 70-90%, though these are highly grade-dependent: grade I tumors exceed 90%, grade II range from 60-80%, and grade III fall to 30-50%.^[121][122] Secondary bone tumors, arising from metastases of other primaries, exhibit median survival times of 6-48 months post-diagnosis, influenced by the originating cancer; for instance, breast cancer metastases to bone yield 24-55 months, outperforming lung cancer metastases at 5-12 months as of 2024.^[123][124] Benign bone tumors, such as osteochondromas or enchondromas, achieve near 100% cure rates with surgical resection or observation, as they rarely progress to malignancy or cause mortality.^[7] In the 2020s, survival trends for primary bone sarcomas show modest gains, with 5-year OS for localized osteosarcoma stabilizing at 60-70% but targeted therapies addressing specific molecular drivers contributing incremental improvements in select subgroups.^[125][126]

Epidemiology

Incidence and prevalence

Bone tumors are rare malignancies, with primary malignant bone tumors accounting for less than 1% of all new cancer cases and an age-adjusted incidence rate of approximately 1.0 per 100,000 population annually in the United States based on data from 2018 to 2022. Globally, the incidence of primary bone and joint malignancies is similarly low, at about 0.9 per 100,000 persons per year. These rates encompass various subtypes, but overall, primary bone tumors represent only 0.2% of all malignancies. In adults, secondary bone tumors—arising from metastases of primary cancers elsewhere in the body—are far more common than primary bone tumors, with estimates suggesting secondary cases outnumber primary ones by roughly 10-fold due to the high prevalence of bone involvement in advanced solid tumors such as breast, prostate, and lung cancers. Primary bone tumors exhibit a bimodal age distribution, with incidence peaks in children and adolescents (typically 10-20 years) and in older adults (over 60 years), reflecting different etiological patterns across age groups. Geographically, reported incidence rates vary, with higher figures in developed countries (around 1-2 per 100,000) compared to developing regions, largely attributable to differences in diagnostic access and imaging technology rather than true biological variations. Incidence trends for primary malignant bone tumors have remained stable over the past several decades, though enhanced detection through advanced imaging may contribute to slight increases in reported cases. The COVID-19 pandemic from 2020 onward led to temporary delays in diagnosis and potential underreporting, but overall incidence rates did not show a significant rebound or increase in subsequent years. Among specific subtypes, osteosarcoma, the most common primary malignant bone tumor in children, has an incidence of approximately 5 cases per million in individuals under 20 years old. Ewing sarcoma, another prevalent type in this age group, occurs at a rate of about 2-3 cases per million children and adolescents annually.

Age and sex distribution

Bone tumors exhibit distinct age patterns depending on whether they are benign, primary malignant, or secondary (metastatic). Benign bone tumors, such as osteochondromas and non-ossifying fibromas, predominantly occur in children and young adults, with a peak incidence during adolescence and early adulthood, reflecting active skeletal growth phases.^[127] Primary malignant bone tumors, including osteosarcoma and Ewing sarcoma, show a bimodal distribution: the first peak arises in adolescents and young adults, particularly for osteosarcoma between ages 10 and 20 years, coinciding with rapid bone development during puberty.^[4][128] In contrast, secondary bone tumors from metastases typically affect older adults over 50 years, often linked to primary cancers like breast, prostate, or lung, with a mean patient age around 67 years.^[129] Sex distribution reveals a slight male predominance for primary malignant bone sarcomas, with a male-to-female ratio of approximately 1.4:1 to 1.5:1, observed consistently across types like osteosarcoma and Ewing sarcoma.^[130] This disparity may relate to hormonal or growth-related factors during adolescence, though it diminishes in older age groups. For metastatic bone tumors, the sex distribution is more balanced, with similar rates between males and females, as these often stem from sex-specific primaries like prostate in men and breast in women.^[129][131] Ethnic variations further stratify risk: osteosarcoma incidence is higher among Black and Hispanic populations compared to non-Hispanic Whites, with the highest rates in Hispanic males.^[132] Conversely, Ewing sarcoma shows a pronounced predilection for Caucasians, occurring 9 to 10 times more frequently in White individuals than in Black or Asian populations, potentially due to genetic factors influencing susceptibility.^[133][134] In pediatric populations, bone tumors constitute a notable proportion of solid malignancies, accounting for about 3% to 5% of all childhood cancers under age 20, whereas they are far rarer in adults, representing less than 0.2% of all adult malignancies.^[128][135] Recent data from 2025 cancer registries, including SEER and American Cancer Society reports, indicate stable demographic distributions, with the adolescent peak for primary tumors remaining unchanged over the past decade.^[4][131]

History

Early descriptions

Ancient Egyptian medical texts, such as the Ebers Papyrus dating to around 1550 BCE, contain descriptions of various swellings and growths affecting the body, including hard nodules and enlargements that may have included bone abnormalities, treated with ointments and incantations though not explicitly identified as tumors.^[136] Skeletal evidence from mummies and excavations further supports the presence of malignant bone tumors in this population as early as 3000 BCE, with lytic lesions indicative of metastatic carcinoma observed in remains from sites like Giza.^[137] In ancient Greece, Hippocrates (c. 460–370 BCE) documented "spina ventosa," a condition characterized by painful swelling of the phalanges resembling a wind-filled spine, now recognized as tuberculous dactylitis but representing one of the earliest recorded observations of inflammatory bone pathology that could mimic neoplastic growths.^[138] During the 18th century, Scottish surgeon John Hunter (1728–1793) advanced the understanding of tumors by distinguishing benign from malignant forms based on their local behavior, potential for metastasis, and tissue origins, emphasizing in his lectures and preserved specimens that malignant growths arose from blood and spread systemically.^[139] In 1818, English surgeon Sir Astley Cooper further specified bone malignancies in his "Surgical Observations," describing aggressive tumors producing bony tissue, now known as osteosarcoma, often arising in the metaphyses of long bones, and their rapid growth and poor prognosis through case studies involving amputation.^[140] Microscopic examination emerged in the 1830s with German pathologist Johannes Müller's seminal work "On the Finer Structure and the Forms of Morbid Tumors" (1838), where he analyzed tumor tissues and proposed that neoplasms originate from primitive cells akin to those in embryonic or normal tissues, laying foundational ideas for cellular pathology in bone and other tumors.^[141] Theodor Billroth, in his mid-19th-century pathological lectures and publications like "The Classification, Diagnosis and Prognosis of Tumors" (circa 1860s–1870s), contributed early systematic classifications of bone tumors, differentiating sarcomas from carcinomas and emphasizing histological features for prognosis, influencing surgical approaches to malignant bone lesions.^[142] A notable case illustrating early diagnostic challenges was that of Charles Byrne, the "Irish Giant" (1761–1783), whose extreme stature—over 7 feet 7 inches—and disproportionate bone overgrowth were exhibited posthumously; contemporaries attributed his condition to anomalous development rather than the pituitary adenoma later confirmed through skeletal analysis, highlighting misconceptions about endocrine-related bone pathologies mistaken for tumors.^[143] Before the advent of radiology in 1895, diagnosis of bone tumors depended primarily on physical examination, palpation of swellings, and exploratory surgery, with definitive confirmation often obtained only through autopsy dissection to reveal tumor extent and metastasis.^[144]

Modern developments

The discovery of X-rays by Wilhelm Conrad Röntgen in 1895 marked a pivotal advancement in the diagnosis of bone tumors, enabling non-invasive visualization of skeletal structures and abnormalities that were previously undetectable without surgery.^[145] This innovation rapidly transformed clinical practice, as physicians began applying X-rays to image bones and detect tumors like osteosarcoma within months of the discovery.^[146] By the late 1890s, the first radiographs of osteosarcoma had been produced, facilitating earlier identification and surgical planning for these aggressive malignancies.^[147] In the 1970s, the introduction of adjuvant chemotherapy, particularly high-dose methotrexate, revolutionized osteosarcoma treatment and dramatically improved patient outcomes. Prior to this era, survival rates for localized osteosarcoma were below 20% with surgery alone, but multi-agent regimens incorporating high-dose methotrexate elevated 5-year event-free survival to approximately 60%.^[117] This shift was supported by seminal clinical trials demonstrating the efficacy of neoadjuvant and adjuvant approaches in eradicating micrometastases, setting the foundation for modern multidisciplinary protocols.^[148] The molecular era began in the early 1990s with the identification of the EWS-FLI1 gene fusion in Ewing sarcoma, a chromosomal translocation involving the EWSR1 and FLI1 genes that drives oncogenesis.^[149] This discovery, made through cytogenetic and molecular analyses, provided a specific genetic hallmark for Ewing sarcoma family tumors, enabling precise diagnosis via fluorescence in situ hybridization and paving the way for targeted therapeutic research.^[150] Advancements in the 2010s introduced immunotherapy trials for bone sarcomas, exploring immune checkpoint inhibitors and adoptive cell therapies to overcome the immunosuppressive tumor microenvironment. Clinical studies, such as the SARC028 trial evaluating pembrolizumab in soft-tissue sarcomas including those with bone involvement, demonstrated modest response rates but highlighted potential in select subtypes like undifferentiated pleomorphic sarcoma.^[92] These efforts built on preclinical evidence of T-cell infiltration in bone tumors, fostering combination strategies with chemotherapy and radiation.^[151] Entering the 2020s, artificial intelligence (AI) and radiomics have enhanced prognostic assessment in bone tumor imaging by extracting quantitative features from MRI and CT scans to predict tumor behavior and treatment response. Machine learning models integrating radiomic signatures with clinical data have achieved high accuracy in stratifying malignancy risk and forecasting survival in osteosarcoma and Ewing sarcoma cohorts.^[152] Concurrently, CRISPR/Cas9 gene editing studies have elucidated sarcoma genetics, with applications in modeling EWS-FLI1 dependencies and identifying novel therapeutic targets through high-throughput screens in preclinical sarcoma models.^[153] The formation of the Musculoskeletal Tumor Society (MSTS) in 1977 represented a key organizational milestone, uniting orthopedic oncologists to standardize care and advance research in bone and soft-tissue tumors.^[154] Complementing this, international registries such as the International Sarcoma Registry, launched in collaboration with global oncology societies, have facilitated large-scale data collection to track outcomes and refine staging systems for bone sarcomas.^[155]

Bone tumors in animals

Common types in veterinary medicine

In veterinary medicine, bone tumors in non-human animals are relatively uncommon compared to other neoplasms, but they predominantly affect companion animals and livestock, with primary tumors arising spontaneously in most cases rather than as secondary metastases from distant sites.^[156][157] The incidence is higher in older animals, typically those over 7-10 years of age, across species, though large breeds and certain predispositions influence risk.^[158] Diagnosis generally relies on radiography to identify lytic or proliferative lesions and confirmatory bone biopsy for histopathological evaluation.^[159][160] Osteosarcoma is the most prevalent primary bone tumor in dogs, accounting for approximately 85% of all primary malignant bone tumors and 75-85% of those in the appendicular skeleton.^[161][162] It primarily affects large and giant breeds, such as Rottweilers, Irish Wolfhounds, and Great Danes, with these dogs facing significantly elevated risk compared to smaller breeds.^[163] The tumor often presents in the long bones of the limbs, causing pain, lameness, and pathological fractures. In cats, chondrosarcoma represents a less common primary bone tumor, comprising less than 10% of cases, but it shows a marked preference for the axial skeleton, including ribs, vertebrae, and pelvis.^[164] Unlike in dogs, where chondrosarcoma has a more guarded outlook due to higher metastatic potential, feline cases often exhibit lower rates of metastasis and thus a relatively better prognosis with surgical intervention, potentially extending survival beyond one year in many instances.^[165][157] Fibrosarcoma in horses is a rare malignancy of connective tissue, accounting for about 1.9% of cutaneous and musculocutaneous tumors, with frequent involvement of the jaw and oral cavity leading to facial swelling and dental issues.^[166] These tumors may be linked to equine sarcoid, a common fibroblastic skin neoplasm caused by bovine papillomavirus, which can occasionally progress to more aggressive sarcomatous forms.^[167] As with other species, affected horses are typically older, and early surgical excision offers the best chance for local control.

Differences from human tumors

Bone tumors in animals exhibit distinct etiological differences from those in humans, with a stronger emphasis on genetic factors in veterinary cases, particularly among purebred populations. In dogs, breed-specific predispositions drive higher heritability, as evidenced by genome-wide association studies identifying 33 loci associated with osteosarcoma risk, including variants near genes like GRB10 and CDKN2A/B that influence bone growth and tumor suppression.^[168] For instance, greyhounds demonstrate elevated incidence rates, with period prevalence reaching 6.2% in some cohorts, attributed to selective breeding amplifying genetic vulnerabilities rather than widespread environmental exposures.^[169] In contrast, human osteosarcoma etiology more frequently involves environmental triggers such as ionizing radiation exposure or Paget's disease of bone, alongside rarer heritable syndromes like Li-Fraumeni (TP53 mutations), though overall heritability remains low compared to canine cases.^[170] Pathologically, animal bone tumors often show accelerated progression relative to human counterparts, especially in small companion animals like dogs and cats, where spontaneous osteosarcomas metastasize rapidly to the lungs in 90-95% of cases at diagnosis, leading to shorter disease courses.^[171] In non-mammalian species, such variances are more pronounced: bone tumors are exceedingly rare in fish and amphibians, with reported osteosarcomas in species like the giant sea catfish showing no evidence of metastasis, possibly due to ectothermic physiology limiting tumor vascularization and dissemination.^[172] Avian bone tumors, meanwhile, frequently harbor viral etiologies absent in humans, such as polyostotic osteosarcoma linked to avian leukosis virus subgroup J in birds like the bare-faced curassow, highlighting retroviral oncogenesis as a key driver in poultry and captive species.^[173] These differences underscore species-specific biological constraints on tumor behavior, with human osteosarcomas typically presenting as high-grade but with more variable metastatic patterns influenced by age and site. Prognostic outcomes for animal bone tumors are generally poorer than in humans, compounded by ethical considerations in companion animal care that often lead to euthanasia for quality-of-life reasons before natural progression. In dogs with appendicular osteosarcoma, amputation alone yields a median survival of 4-6 months, though adjunct chemotherapy extends this to approximately 1 year in 50% of cases, mirroring localized human survival rates but without the 70% 5-year event-free survival achievable in pediatric patients post-multimodal therapy.^[174] Euthanasia decisions in pets, driven by pain management challenges and owner ethics, frequently shorten reported survival times compared to human scenarios where aggressive interventions predominate.^[175] Dogs serve as valuable spontaneous models for human sarcomas in clinical trials due to these biological parallels, while rodents are preferred for induced tumor studies to dissect mechanisms like radiation carcinogenesis, facilitating translational research.^[176] Certain tumor types unique to animals further illustrate these divergences, such as multilobular osteochondrosarcoma in dogs, a slow-growing, locally invasive neoplasm primarily affecting the skull and absent in humans, characterized by multilobulated chondroid and osseous matrix production without distant metastasis in most cases.^[177] This entity, also termed chondroma rodens, arises almost exclusively in canines, emphasizing breed-agnostic but species-specific pathological features not replicated in human bone oncology.