Osteosarcoma: Symptoms, Types, Causes and Treatment

Osteosarcoma is the most common primary malignant bone tumor, predominantly affecting children, adolescents, and young adults. With its aggressive nature, heterogeneous presentation, and potential for rapid progression, understanding osteosarcoma is crucial for timely diagnosis and effective management. This article provides a comprehensive exploration of osteosarcoma’s symptoms, types, causes, and current as well as emerging treatments, synthesizing insights from recent research and clinical experience.

Symptoms of Osteosarcoma

Osteosarcoma can present subtly or with distinct symptoms, sometimes mimicking benign conditions or injuries. Recognizing these early signs is essential for prompt diagnosis and improved outcomes.

Symptom	Description	Patient Group	Source
Pain	Persistent, localized bone pain	All ages	2 3 4 8
Swelling	Noticeable lump or swelling near joint	Children, adults	2 3 4 8
Antalgic gait	Limping due to pain	Children, adolescents	2
Paresthesia	Tingling/numbness (esp. jaw lesions)	Adolescents, adults	3 4
Limited motion	Stiffness or reduced joint movement	All ages	4
Loose teeth	Tooth mobility (jaw tumors)	Adolescents, adults	3
Trismus	Difficulty opening the mouth	Jaw tumors	3 4
Misattribution	Symptoms mistaken for trauma/exercise	Mainly children	1 2

Table 1: Key Symptoms

Pain and Swelling: Hallmarks of Osteosarcoma

Persistent and localized pain is often the first sign of osteosarcoma. The pain may intensify over weeks or months and is frequently mistaken for a sports injury or growing pains, particularly in children and adolescents. Swelling or a noticeable lump near a joint, especially around the knee, is also common. In some cases, swelling may appear before pain, or both may develop together 2 3 4 8.

Atypical and Site-Specific Symptoms

• Jaw Osteosarcoma: When osteosarcoma affects the jaw, swelling is usually painless at first. Additional symptoms can include numbness (paresthesia), loose teeth, or difficulty opening the mouth (trismus) 3 4.
• Antalgic Gait: Children may develop a limp to avoid pain when the tumor involves a leg bone 2.
• Limited Motion: Tumors near joints can cause stiffness and restrict movement 4.
• Misattribution: Both patients and clinicians may initially attribute symptoms to trauma or overuse, delaying correct diagnosis 1 2.

Diagnostic Challenges

Early symptoms are often subtle or nonspecific. In trauma cases, pain and swelling may be assumed to relate to injury rather than malignancy, leading to delayed diagnosis and treatment 1. This underlines the importance of thorough evaluation when symptoms persist beyond typical healing times.

Types of Osteosarcoma

Osteosarcoma is not a single disease but a group of related tumors with diverse clinical and molecular features. Understanding its types is essential for diagnosis, prognosis, and treatment planning.

Type/Subtype	Defining Features	Typical Age Group	Source
Conventional OS	High-grade, aggressive, most common	Children, adolescents	2 5 8
Jaw Osteosarcoma	Involving jaw bones, less aggressive	Adults (30-50)	3 4
Extraskeletal OS	Arises in soft tissues, rare	Middle-aged/elderly	1
Low-grade Central	Less aggressive, better prognosis	Adolescents, adults	2
Telangiectatic	Cystic, blood-filled spaces	Children, adolescents	2
Small-cell	Resembles Ewing sarcoma	Children	2
Surface & Intracortical	Arises on bone surface or cortex	Adolescents, adults	2 8
Molecular Subtypes	Defined by genomic/immune features	All ages	7 18

Table 2: Major Types of Osteosarcoma

Classic and Common Subtypes

• Conventional Osteosarcoma: This is the most frequent and aggressive variant, typically affecting the metaphyseal regions of long bones in adolescents and young adults 2 5 8.
• Jaw Osteosarcoma: Less common (about 7% of cases), often occurs in adults aged 30-50 and behaves less aggressively. Mandible is more often affected than the maxilla 3 4.
• Extraskeletal Osteosarcoma: A rare form that arises in soft tissues rather than bone, more common in older adults 1.

Histological Subtypes

Osteosarcomas are further classified based on the predominant tissue produced by the tumor:

• Osteoblastic: Produces bone-like tissue
• Chondroblastic: Produces cartilage-like tissue
• Fibroblastic: Produces fibrous tissue

These subtypes can influence imaging appearance and treatment response 3 8.

Rare and Special Subtypes

• Telangiectatic Osteosarcoma: Characterized by blood-filled spaces; may mimic benign bone cysts on imaging 2.
• Small-cell Osteosarcoma: Resembles Ewing sarcoma, but with osteoid production 2.
• Surface and Intracortical Osteosarcoma: Arises from the bone’s outer layers; includes parosteal and periosteal forms 2 8.

Emerging Molecular Classification

Genomic and molecular studies have revealed new subtypes based on mutation patterns and immune profiles:

• Immune-activated, Immune-suppressed, MYC-driven, and Homologous recombination deficient (HRD) subtypes
• These molecular subgroups exhibit different prognoses and may respond differently to targeted therapies 7 18.

Causes of Osteosarcoma

The exact cause of osteosarcoma remains elusive, but research has identified a combination of genetic, environmental, and developmental risk factors.

Cause/Factor	Description	Risk Group/Notes	Source
Genetic Syndromes	Li-Fraumeni, Retinoblastoma, Werner, Bloom	Hereditary predisposition	10 12 13
Gene Mutations	TP53, RB1, c-Myc, others	High prevalence in OS	10 12 13 18
Rapid Bone Growth	During adolescent growth spurts	Children, teens	2 10
Prior Radiation	Radiation exposure history	All ages	1 3
Bone Disorders	Paget disease, fibrous dysplasia	Older adults, rare	3
Unknown/Environmental	No clear etiology in most cases	Most patients	11 14

Table 3: Known and Suspected Causes

Genetic Susceptibility

• Hereditary Syndromes: Several inherited disorders increase the risk of osteosarcoma, notably Li-Fraumeni syndrome (TP53 mutation), hereditary retinoblastoma (RB1 mutation), Werner syndrome, Bloom syndrome, and Diamond–Blackfan anemia 10 12 13.
• Key Gene Mutations: TP53 (over 90% of cases), RB1 (around 30%), and c-Myc are frequently mutated or dysregulated in osteosarcoma, promoting tumor development and progression 10 12 13 18.
• Other Genes: NOTCH1, FOS, BRCA2, and others have also been implicated in tumorigenesis 13.

Growth and Developmental Factors

• Adolescent Growth Spurts: Osteosarcoma incidence peaks during periods of rapid bone growth, suggesting developmental factors may contribute 2 10.
• Bone Disorders: Preexisting bone diseases such as Paget disease or fibrous dysplasia can predispose to secondary osteosarcoma, especially in older adults 3.

Environmental and Acquired Factors

• Radiation Exposure: Therapeutic irradiation increases osteosarcoma risk, with cases sometimes developing years after treatment 1 3.
• Controversial Links: Trauma has been suggested as a possible trigger, but evidence is inconsistent and it is not considered a direct cause 1.

Multifactorial and Unknown Etiology

For most patients, osteosarcoma develops without a clear identifiable cause, reflecting the complex interplay of genetic susceptibility, environmental exposures, and cellular processes 11 14.

Treatment of Osteosarcoma

Osteosarcoma treatment has evolved significantly, combining surgery with multi-agent chemotherapy. However, despite advances, survival rates have plateaued and new therapies are needed.

Treatment	Description	Indication/Notes	Source
Surgery	Limb-salvage or amputation	Mainstay for localized disease	5 6 15
Chemotherapy	Methotrexate, doxorubicin, cisplatin (MAP)	Pre/post-surgical, main protocol	5 6 15
Radiotherapy	Limited role, mainly for inoperable cases	Not first-line	6
Targeted Therapy	Investigational agents, e.g., TKIs, PARPi	Ongoing trials	7 13 18
Immunotherapy	Checkpoint inhibitors, CAR-T, vaccines	Clinical trials, emerging	7 18
Multidisciplinary Care	Specialist team approach	All patients	6

Table 4: Current and Emerging Treatments

Standard of Care: Surgery and Chemotherapy

• Surgery: Complete surgical removal of the tumor is vital, with limb-salvage procedures preferred when feasible. Amputation remains necessary in some cases with extensive involvement 5 6 15.
• Chemotherapy: The MAP regimen—high-dose methotrexate, doxorubicin, and cisplatin—is standard, used both before (neoadjuvant) and after (adjuvant) surgery. This combination has dramatically improved survival rates for localized disease, from less than 20% pre-1970 to around 65–70% today 5 6 15.
• Prognosis: Patients with localized disease have the best outcomes; those with metastatic or recurrent disease fare significantly worse 6.

Imaging and Diagnosis

• Imaging: X-rays, CT, MRI, and PET scans are essential for diagnosis, staging, and monitoring. Classic radiographic features include the "sunburst" pattern and Codman's triangle 8.
• Biopsy: Confirms diagnosis and helps determine tumor grade and subtype 8 11.

Advanced and Experimental Therapies

• Targeted Therapy: Research focuses on molecular targets such as tyrosine kinase inhibitors (TKIs), PARP inhibitors, and novel agents targeting pathways like MYC and DNA repair mechanisms. Results are promising, but not yet standard practice 7 13 18.
• Immunotherapy: Immune checkpoint inhibitors, CAR-T cells, and tumor vaccines are in development, with early clinical trials exploring their potential 7 18.
• Precision Medicine: Molecular profiling may allow stratified treatment according to tumor subtype and genetic features 7 18.

Multidisciplinary and Supportive Care

• Expert Teams: Care should be delivered by specialized multidisciplinary teams in high-volume centers, including orthopedic oncologists, medical oncologists, radiologists, and supportive care professionals 6.
• Clinical Trials: Participation in clinical trials is encouraged, especially for recurrent or refractory disease, to access new therapies and contribute to research 15 17 18.

Challenges and Future Directions

• Stagnant Survival Rates: Despite advances, survival rates have not improved further in recent decades, especially for metastatic disease 16 17 18.
• Drug Resistance: Intrinsic and acquired resistance to chemotherapy is a major challenge, necessitating the development of new therapeutic strategies 19.
• Personalized Medicine: Emerging molecular and immune-based therapies offer hope for more individualized, effective treatments in the near future 7 18 19.

Conclusion

Osteosarcoma remains a formidable cancer, marked by aggressive behavior and a need for rapid diagnosis and comprehensive care. Advances in molecular biology and treatment approaches offer hope for improved outcomes in the coming years. Here’s a summary of the key points:

• Symptoms: Persistent pain, swelling, and sometimes numbness or dysfunction are common; often mistaken for injury or benign conditions 2 3 4 8.
• Types: Includes conventional, jaw, extraskeletal, and rare subtypes; molecular classifications are emerging 2 3 4 7 8.
• Causes: Genetic mutations (especially TP53, RB1), hereditary syndromes, rapid bone growth, prior radiation, and some bone disorders contribute; most cases have no clear cause 10 12 13 18.
• Treatment: Surgery and multi-agent chemotherapy form the backbone; targeted and immune therapies are in development, with multidisciplinary care essential 5 6 7 13 15 18.

Early recognition, specialized care, and continued research are critical to overcoming the challenges of osteosarcoma and advancing patient outcomes.