Osteosarcoma: A Comprehensive Review

Introduction

Osteosarcoma (often abbreviated OS) is the most common primary malignant bone tumor. It is characterized by the production of osteoid (immature bone matrix) by malignant mesenchymal cells. It typically occurs in adolescents and young adults but has a second, smaller incidence peak in older adults, often associated with bone disorders or exposure to certain risk factors.

Despite advances in diagnosis, surgical techniques, chemotherapy, and supportive care, prognosis remains variable, especially for metastatic or recurrent disease. Many ongoing research efforts are aiming to improve outcomes by refining molecular understanding, improving biomarkers, immunotherapy, and new treatment modalities.

This article reviews epidemiology, pathogenesis, clinical features, diagnosis, treatment (both standard and emerging), prognosis, and future directions.

Epidemiology

Incidence: Worldwide, osteosarcoma is rare. The incidence is approximately 3–4 per million persons per year.
Age distribution: There is a bimodal distribution. The first and larger peak is in adolescents during periods of rapid bone growth (around age 10–20). The second is in older adults (50–70), often in the setting of preexisting bone pathology (e.g., Paget’s disease) or prior radiation exposure.
Sex: Slight male predominance.
Anatomic sites: Most osteosarcomas occur in the metaphysis of long bones — distal femur, proximal tibia, proximal humerus are common sites. Rarely, it occurs in axial skeleton (pelvis, spine), jaw (mandible, maxilla), or in extraskeletal sites.

Etiology and Risk Factors

Osteosarcoma arises from mesenchymal cells with the ability to produce osteoid; however, the precise etiologic mechanisms are heterogeneous and incompletely understood. Known risk factors include:

Genetic predisposition:
- Germline mutations in RB1 (retinoblastoma) and TP53 (Li‐Fraumeni syndrome) are well known.
- Other rare syndromes: Rothmund‐Thomson syndrome, Werner syndrome, Bloom syndrome, RAPADILINO, Diamond‐Blackfan anemia.
Radiation exposure: Prior therapeutic radiation is a risk factor. Latency between exposure and tumor is often 8-15 years. Such secondary osteosarcomas often occur in axial or craniofacial bones.
Bone disorders: Conditions that affect bone remodeling (e.g., Paget’s disease in older people) increase risk.
Growth factors: Rapid bone growth in adolescence is considered a risk (though mechanistic proof is limited). Height, birth weight have been associated in epidemiologic studies.

Pathology and Biology

Histologic types

Osteosarcoma is heterogeneous. Major histologic subtypes include:

Conventional (high‐grade) osteosarcoma: The most common. Further subclassified by predominant matrix: osteoblastic, chondroblastic, fibroblastic.
Surface osteosarcomas: Parosteal, periosteal, and high‐grade surface osteosarcomas. These differ in aggressiveness. Parosteal is usually low grade.
Secondary osteosarcoma: Arising in setting of preexisting bone disease or prior radiation.

Molecular features

Genetic alterations are frequent but diverse. Mutations in RB1, TP53 are classic. Other pathways disrupted include WNT/β-catenin, JAK/STAT, etc.
Tumor microenvironment (immune cell infiltration, macrophages etc.) is being increasingly studied for prognostic relevance.
Biomarkers such as circulating tumor DNA, novel gene expression signatures, and expression of newer molecules (for example, gasdermin D) are being explored.

Clinical Presentation

Patients with osteosarcoma may present with:

Pain: Often the earliest symptom; persistent, worsening, may be worse at night or with activity. Over weeks to months.
Swelling or mass: Local swelling over bone, may be palpable. Sometimes redness or warmth.
Pathologic fracture: The tumor‐weakened bone may fracture even with minimal trauma.
Functional impairment: Reduced range of motion if near joints; limp if in lower limbs.
Systemic symptoms (fever, weight loss) are less common unless disease advanced or metastatic.

Diagnosis

A multi‐step approach combining clinical, imaging, and pathological evaluation is essential.

Imaging

Plain radiographs (X-ray): Often the first study. Features may include mixed lytic and sclerotic lesions, periosteal reaction (“sunburst” appearance), Codman triangle (elevation of periosteum), cortical destruction.
Magnetic Resonance Imaging (MRI): Best for local extent, soft tissue involvement, marrow involvement, surgical planning.
Computed Tomography (CT): Useful for detecting lung metastases; also bone detail. Whole-body CT or chest CT often.
Bone scan / PET scan: For detecting skeletal metastasis; PET/CT increasingly used. Radiomics/image‐based analyses are being developed.

Biopsy

Essential for definite diagnosis. Usually core needle biopsy (or incisional). Must sample viable tumor to assess grade, subtype.
Histology: look for malignant cells, atypia, mitoses, and crucially production of osteoid or mineralized bone by tumor cells. Immunohistochemistry may help exclude other diagnoses.

Staging

Once diagnosed, staging includes assessment of local extent, metastasis (especially lungs, sometimes bones), and patient’s general condition.
Staging systems: Enneking (older), TNM (as per AJCC) are used. Size, location, metastasis presence are critical.

Treatment

Treatment of osteosarcoma involves multimodal therapy: systemic chemotherapy + surgery being the mainstays. Radiation has a more limited role.

Standard Therapy

Neoadjuvant (preoperative) chemotherapy
- Given before surgery to shrink tumor, allow better resection, to treat micrometastases early.
- Typical agents include high‐dose methotrexate, doxorubicin, cisplatin, and ifosfamide.
- The degree of tumor necrosis after neoadjuvant chemotherapy is a powerful prognostic indicator: ≥90% necrosis correlates with significantly better survival.
Surgery
- After neoadjuvant chemo, the tumor is resected with wide margins. Surgical options depend on location, extent.
- Limb salvage surgery has become the norm when feasible, replacing amputation in many cases, particularly in extremities, thanks to improved imaging, reconstructive techniques, and chemotherapy.
- For tumors in axial skeleton, pelvis, etc., resection is more complex and morbidity higher.
Adjuvant (postoperative) chemotherapy
- Continued chemotherapy to eliminate residual disease, including micrometastases. Same or modified regimen as preoperative. Resuming promptly (within certain time) is important.
Role of Radiation
- Osteosarcoma is generally relatively radioresistant. Radiation is not a standard primary therapy.
- It may be used in certain situations: for unresectable tumors, palliation, or as adjunct in reconstruction (e.g., extracorporeal irradiation of resected bone segments then reimplantation).

Treatment of Metastatic, Recurrent, or Poor Prognosis Disease

For patients who present with lung metastases or other distant spread, prognosis is significantly worse. Treatment often includes more aggressive chemotherapy, surgical resection of metastases if possible.
Recurrent disease is challenging; often less responsive to standard chemotherapy. Clinical trials and experimental therapies are often considered.

Outcomes and Prognosis

Five-year survival: For nonmetastatic (localized) osteosarcoma, current 5-year overall survival is around 65-75% in many series. For patients with metastasis at presentation, significantly lower.
Prognostic factors include:
1. Presence of metastases at diagnosis (lungs, bone) — negative prognostic indicator.
2. Anatomic site: axial tumors (pelvis, spine) tend to do worse than extremity tumors due to difficulty of surgery.
3. Tumor size and volume: larger tumors generally worse.
4. Histologic response to chemotherapy: higher tumor necrosis (especially >90%) correlates with better outcomes.
5. Surgical margins: complete resection with negative margins improves outcomes.
6. Patient age and general health: older age, poor health, or presence of comorbidities can reduce ability to tolerate treatment.
Despite advances, for patients with relapse or lung metastases, the prognosis remains poor. Five-year survival often falls considerably (sometimes below 30%).

Challenges and Current Research Directions

While standard treatments have improved survival for localized disease, several challenges remain, especially for metastatic, recurrent, and poor-responding cases. Research is ongoing in multiple fronts:

Molecular and Genetic Biomarkers
- Identification of biomarkers to better stratify risk, predict response to chemotherapy, or identify therapeutic targets. For example, immune infiltration patterns, expression of novel molecules (gasdermin D), circulating tumor DNA.
- Radiogenomics and radiomics approaches: using imaging data combined with AI to predict prognosis or response.
Novel Therapies / Experimental Treatments
- Immunotherapy: exploring immune checkpoint inhibitors, other modulators of immune microenvironment.
- Targeted therapies: drugs that specifically target aberrant pathways in OS cells. Though so far, many promising molecules work in preclinical or early phase trials.
- Gene therapy and molecular interventions are being explored though none yet standard.
Improved Preclinical Models
- To better test new treatments, more biologically accurate models (animal models, PDX — patient‐derived xenografts) are needed. Many current models fail to capture the heterogeneity or behavior of OS in humans.
Optimizing Chemotherapy Regimens
- Studies examining impact of dose intensity, timing of post‐surgery chemotherapy, how to manage poor responders. For example, reducing delays, adjusting doses.
- Also attempts to reduce toxicity while maintaining efficacy.
Functional Reconstruction and Surgical Innovation
- Improving limb salvage techniques, reconstructive surgery, prosthetics, use of allografts, rotationplasty in some settings.
Supportive Care and Quality of Life
- Given aggressive therapy, focus on reducing side effects (cardiotoxicity, nephrotoxicity, hearing loss, etc.), fertility preservation, long-term monitoring.

Case Studies / Special Types

Jaw (Mandibular / Maxillary) OS: these behave somewhat differently: diagnosis is often delayed; surgical resection more challenging; functional and cosmetic issues more significant.
Extraskeletal Osteosarcoma: much rarer; arises in soft tissues rather than bone; often more aggressive.
Surface Osteosarcomas: Parosteal (low grade), periosteal (intermediate grade), high-grade surface (aggressive). Clinical behavior and prognosis differ; the less aggressive types may be cured with surgery plus less intense chemotherapy.

Diagnostics: Current Advances

Radiomics and AI in Imaging: Studies show that machine learning models using imaging data can help in classifying tumors, assessing tumor viability, predicting necrosis, prognostic outcomes.
Circulating Biomarkers: Circulating tumor DNA (ctDNA) is being studied for monitoring disease, possibly detecting minimal residual disease.
Molecular Profiling: The hope is that profiling of tumor mutations, gene expression, immune microenvironment can support “precision medicine” in osteosarcoma: selecting treatments based on individual tumor biology.

Treatment: New Horizons

Some of the experimental or newer therapies being studied:

Immunotherapy: Including checkpoint inhibitors (e.g. PD-1 / PD-L1), though success has been modest so far. There are also investigational therapies like CAR T-cell therapy aimed at specific OS surface antigens.
Small Molecule / Targeted Agents: Drugs targeting specific signaling pathways deregulated in OS (e.g., WNT/β-catenin, JAK/STAT, etc.). Some in early trials.
Adjuncts to Surgery: Technologies to improve margin control, intraoperative imaging, local adjuvants (e.g., delivering chemotherapy directly to the surgical field), or using reconstructed grafts treated with radiation or other methods.
Optimization of Chemotherapy: Adjusting dose intensity, sequence, supportive measures to reduce delays in postoperative chemotherapy. Studies show that longer delays correlate with poorer outcomes.

Real-World Constraints and Considerations

In many low- and middle-income countries, lack of resources impacts early diagnosis, imaging, surgical expertise, access to chemotherapy, and supportive care. These factors may lead to delayed diagnosis, more advanced disease at presentation, worse outcomes.
Treatment toxicity is significant; balancing aggressive therapy versus quality of life is important.
Long-term follow up is necessary: monitoring for late effects (e.g., secondary malignancies, organ toxicity, growth issues in children, psychosocial effects).

Prognosis Summary

Scenario	Approximate 5-year survival*
Localized, good response, extremity tumor, negative margins	~ 65–75% or higher in some series
Metastatic at presentation, especially lung metastases	Much lower; often < 30–40% depending on extent and resectability
Recurrent / poor response to chemo	Very challenging; much poorer outcomes

*These are global or high-resource-setting estimates; in resource‐limited settings outcomes may be worse.

Examples / Meta-Analyses

A meta-analysis covering literature from 2000-2011 found 5-year overall survival of about 63% for studies including both metastatic and non-metastatic patients; for non-metastatic only, about 71%.
Necrosis rate (≥90%) after neoadjuvant chemotherapy was achieved by about 50% of patients in non-metastatic series; and those with high necrosis had substantially better survival.

Future Directions & Research Gaps

To improve outcomes further, researchers are focusing on:

Better risk stratification: using molecular, imaging, and pathological markers to predict which tumors are high risk.
New therapeutic targets: identification of actionable mutations or pathways in OS that can be drugged.
Combination therapies: combining immunotherapy + traditional chemotherapy; combining targeted agents; exploring synergy.
Improved models: patient derived models, more accurate in vitro / in vivo systems to test therapies.
Reducing morbidity: less toxic regimens, preserving function, reconstructive surgery improvements.
Access and global health: ensuring advances are applicable in lower-resource settings; improving early diagnosis and referral; decentralizing expertise.

Conclusion

Osteosarcoma remains a challenging disease. While survival for localized disease has improved substantially over past decades, there has been little improvement for metastatic or recurrent disease. Key advances have come in chemotherapy, surgical techniques, and early diagnosis. However, for many patients, the standard of care still involves aggressive therapy with significant side effects.

Emerging areas—molecular profiling, immunotherapy, radiomics, better biological models—offer hope, but translating them into clinical benefit will require well-designed trials, multidisciplinary care, and access to advanced diagnostics and treatments.

Osteosarcoma Notes