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]| Enneking/MSTS Stage | Grade (G) | Site (T) | Metastasis (M) | Description |
|---|---|---|---|---|
| IA | G1 (low) | T1 (intracompartmental) | M0 | Low-grade, confined tumor |
| IB | G1 (low) | T2 (extracompartmental) | M0 | Low-grade, invasive locally |
| IIA | G2 (high) | T1 (intracompartmental) | M0 | High-grade, confined tumor |
| IIB | G2 (high) | T2 (extracompartmental) | M0 | High-grade, invasive locally |
| III | G1 or G2 | T1 or T2 | M1 | Any grade with distant metastasis |