Author(s): Nandita Keole, MD, Ray Stanford, DO, Zayd Hayani, MD, Ohmin Kwon, MD
Originally published: January 25, 2024 Last updated: January 25, 2024
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Disease/Disorder

Definition

Primary type pediatric osteogenic sarcoma, or osteosarcoma is defined as a primary bone tumor in children consisting of malignant mesenchymal cells that produce osteoid, or unmineralized bone tissue.1

Etiology

Although there is not a definitive cause or etiology of osteosarcoma, there are associated genetic predispositions. Patients with the retinoblastoma gene RB1 are known to have increased susceptibility, as well as patients with Li-Fraumeni syndrome.2

Epidemiology including risk factors and primary prevention

Bony tumors in general are the third most common category of pediatric cancer following leukemia and CNS tumors. Osteosarcoma is the most common bone tumor in children.3 The yearly incidence is 5.4 cases per million.4 There is a slightly higher incidence in males.5 The peak incidence occurs during adolescent years, likely related to growth spurts.1 There are few environmental risk factors known, and no significant evidence for primary prevention practices. However, ionizing radiation exposure is a known risk factor for development of osteosarcoma.  Other diseases such as Paget’s disease, chronic osteomyelitis, and bone infarction appear to be risk factors for development of secondary osteosarcoma.5

Patho-anatomy/physiology

Osteosarcoma most commonly affects the metaphysis of long bones, with approximately 74% occurring in the lower extremity long bones, with distal femur being most common, followed by proximal tibia and proximal humerus.6 Cell origin in osteosarcoma is not fully understood. However, in the more aggressive forms the origin has been found to arises from mesenchymal stems cells that develops into the osteoblastic lineage.1

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Approximately 10-15% of patients with newly diagnosed osteosarcoma present with metastatic disease, primarily in the lung.7 The 5 year survival rate is approximately 60% among patients with localized osteosarcoma but only 20% with recurrent disease.7

The universally accepted TNM staging is not used for sarcomas due to the rarity with which they metastasize to the regional lymph nodes.8 The MSTS (musculoskeletal tumor society) staging based on the grade, extent of primary tumor (intra or extracompartmental) and metastases is commonly used for staging osteosarcoma.9 

StageGradeTumorMetastasis
IAG1T1M0
1BG1T2M0
IIAG2T1M0
IIBG2T2M0
IIIG1 or G2T1 or T2M1

Specific secondary or associated conditions and complications

Secondary or associated conditions and complications include cardiomyopathy secondary to doxorubicin, dyslipidemia and athrogenesis,10 secondary neoplasms, infertility, hearing loss.

Essentials of Assessment

History

The most common presenting symptom of osteosarcoma is pain and sometimes swelling, typically following trauma or physical activity.1 History taking may reveal pain in a waxing and waning course and particularly at night, therefore chronic growth pains warrant further workup. The pediatric population may have more subtle presentations, such as limping or decreased weight bearing on an extremity noticed by parents. It is important to assess childhood radiation exposure, history of Paget’s disease, or family history of cancer.

Physical examination

In early stages, osteosarcoma patients may have a benign physical exam, however if the lesion is sufficiently large, physical exam may reveal a firm, warm, tender mass most commonly in the distal femur or proximal humerus.1 Pathologic fractures may also be present at time of diagnosis.11 A thorough musculoskeletal exam including gait should be performed to rule out other more common etiologies of pediatric knee and shoulder pain, such as ligamentous injury or traumatic fracture. Range of motion may also be limited.11 In rarer cases, osteosarcoma can affect the axial skeleton and thorough examination of the spine should be performed.1 Assessment for fever as well as lymphadenopathy should also be performed. Fever is more common in Ewing sarcoma than osteosarcoma3 and lymphadenopathy may be more indicative of osteomyelitis, as it is less common in osteosarcoma.11

Functional assessment

The assessment of pediatric patients’ premorbid levels of function should include their developmental history, activities of daily living, and levels of age-appropriate physical activities in play and in sports. Current self-care and mobility levels must be assessed as well as psychosocial adjustment, communication, cognitive processing and social engagement.12

Functional prognostication is impacted by pain, restrictions in range of motion and onset of impairment

Laboratory studies

Alkaline phosphatase,13 CBC, LFT, CMP should be evaluated.  There are no known laboratory markers specific for early diagnosis of osteosarcoma, however several tumor markers such as TNF-β, VEGF, and BALP may prove to have clinical utility for prognostication and response to therapy.13 There is some evidence that elevated triiodothyronine (T3) levels may be helpful in predicting relapse after treatment.13

Imaging

Many cases of osteosarcoma are first seen with X-ray of the extremity, showing sclerosis of metaphysis, osteosclerotic lesions, and/or radiating calcifications, described as “sunburst” appearance.14 High-spatial-resolution anatomic MRI should be performed for further characterization as well as surgical planning. CT chest as well as PET scan is used for evaluation of metastasis. Other tests can include audiology to check baseline hearing and echocardiogram to evaluate cardiac function for patients receiving chemotherapy with doxorubicin.

Supplemental assessment tools

Biopsy is required for diagnosis. Electrodiagnostic studies may be needed to evaluate the cause of unexplained weakness.

Early predictions of outcomes

Factors associated with poor prognosis include metastatic disease at presentation, non osteoblastic histological subtype, tumor size, male gender, young age, tumor location, genetic variations, poor response to neoadjuvant chemo and inadequate surgical margins.15

There is emerging data showing exercise and physical activity improve treatment efficacy and completion rates in addition to improving QOL and physical function.16

Environmental

Evaluation of patients’ and families’ living situation for potential home modifications is key to reducing environmental barriers.

Social role and social support system

The culture, expectations, and attitudes of patients and their family members can play a significant role in the patients’ compliance with the rehabilitation process.12  Hospital based schools can provide education to patients during their hospitalization because they may be far from home or unable to attend their usual school because of their medical needs.12

Professional issues

Surgical recommendations for weight bearing restrictions and activity precautions should be followed. Team members should collaborate and effectively communicate with patient, family members, and each other to avoid conflicting and misunderstanding treatment recommendations. Providers should be cognizant of patients’ age while communicating information and treatment plans as well as the family’s wishes for how much information is given to patients.

Rehabilitation Management and Treatments

Available or current treatment guidelines

Limb-sparing surgery with wide excision or amputation are the essential management of osteosarcoma. As most tumors are in the distal femur, some patients will have an endoprosthesis implanted to provide mechanical support for the distal femur and allow for continued knee joint function. In patients who receive metallic prosthesis, it is challenging to assess recurrent disease on MRI due to artifact.17 Extendable prosthesis can accommodate for growth of young patients.3 Limb-sparing surgery is associated with better functional outcomes,18 90-95% percent of patients are candidates for limb sparing surgery.11 The remaining patients may have advanced disease or the tumor may be too proximal to support an endoprosthesis and may require amputation.  Rotationplasty is an option to reconstruct the ankle to function as the knee. Preoperative rehabilitation, post surgical rehabilitation and physical activity have been shown to improve outcomes.19

Pre-Treatment Assessment includes identifying baseline functional ability, managing pre-existing impairments, assessing post operative needs for orthotic and assistive devices, educating for expected caregiver assistance and availability, establishing realistic postsurgical and/treatment goals.

Post-Treatment Rehabilitation includes initiating early mobilization including gait training if needed, emphasizing adherence to precautions, incorporating assistive and/or orthotic devices, gradually increasing weight bearing, strength and endurance, home safety evaluation and recommendations for modifications, school and community reintegration, educating patient and family regarding continued rehabilitation care and post surgical complications.12

Patient and family participation strongly influences the attainment of optimal functional outcomes for the osteosarcoma patient.12

Understanding of prognosis as it pertains to the grade of osteosarcoma is essential to predict future rehabilitation needs such as therapies and equipment. 

At different disease stages

10-20% of patients present with metastatic disease at diagnosis which is an independent poor prognostic factor and it negatively impacts the efficacy of adjuvant chemotherapy. Guideline recommends preoperative chemotherapy followed by wide excision of the primary tumor as well as metastasectomy. Stereotactic body radiation therapy has been promising as an alternative for oligometastatic disease when metastasectomy is not feasible.18 Chemotherapy combined with radiation has shown improved local control and overall survival for patients with positive or uncertain surgical margins, gross residual disease or unresectable disease.20

Coordination of care

The American Academy of Pediatrics has released guidelines for pediatric cancer centers and their role in initial diagnostic assessment, induction therapy, and management of complications or recurrences as well as supportive care in a comprehensive multidisciplinary setting to improve long-term survival and quality of life.21

NCCN Guidelines for Adolescent and Young Adult Oncology recommends special consideration for fertility, reproductive endocrine and sexual health that may be impaired due to cancer treatment.

To achieve successful rehabilitation for pediatric oncology patients, an interdisciplinary approach is ideal.12

Patient & family education

Early discussion with parents is recommended to set realistic post-surgical goals and to help patients adapt to the challenges of living with cancer as it may play a significant role in patients’ compliance with the rehabilitation process. Rehabilitation processes should be tailored to patients’ and their families’ expectations of current and functional outcomes including returning to near-normal mobility, achieving independence of self-care, returning to sports and challenging physical or leisure activities, and returning to school or work activities.12 The risks of extended sedentary periods including muscle atrophy, contractures and deconditioning should be discussed.

Measurement of Treatment Outcomes

Disease specific health-related quality of life measures include Toronto Extremity Salvage Score, and Musculoskeletal Tumor Rating Scale or general healthy survey like Short Form Health Survey (SF-36), Short Form-6D, EuroQol-5D, and Patient-Reported Outcomes Measurement Information System (PROMIS) could be used. Objective measures include energy efficiency or gait parameters via cardiopulmonary exercise testing, physiological cost index, or wearable monitors like pedometers or accelerometers.22

Unemployment in survivors of blood or bone cancers although elevated is not statistically significant. MD Anderson Cancer Center’s annual ski-rehabilitation program for amputees showed most adult survivors appeared to have economic independence and more than 50% of patients were married and had children.23

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Limb salvage surgery with reconstructive surgery is performed in approximately 85% of patients but it involves multiple drawbacks including limited life span and long-term prosthetic failure, and high rate of reoperation that may end in amputation. The greatest challenge associated with oncologic resection in growing children is negotiating the open physis as adjacent growth plates frequently need to be sacrificed. There are different methods of calculating final limb-length deficit, and if the discrepancy at skeletal maturity is <2 cm, no intervention is indicated, whereas halting the growth of the contralateral limb is recommended for 2 to 5 cm differences. For estimated discrepancy >5 cm, extendible prosthesis or secondary limb lengthening is recommended.28

Although modern prosthetics are much more sophisticated, amputation requires lifelong usage of prosthesis, phantom limb sensations remain a substantial and unpredictable problem as well as complications regarding residual limb.

Complications & Drawbacks23
Limb SalvageAmputation
Infection
Delayed bone union
Bone nonunion or pseudoarthrosis
Fracture
Poor joint motion
Pain
Artery/vein/nerve damage
Venous thrombosis
Leg length discrepancy
Endoprosthesis failure
Aseptic loosening
Foreign body reaction
Metallosis
Malalignment		Lifelong requirement for a prosthesis
Infection of the stump
Wound breakdown
Swelling of the stump
Hip joint flexion contracture
Pain
Phantom limb sensation
Pressure sores from the prosthesis
Stump bony overgrowths
Dysfunctionally short stump

Cutting Edge/Emerging and Unique Concepts and Practice

Circulating tumor DNA (ctDNA) can be detected in patients with osteosarcoma and there is data that correlates the detection level with the disease burden. Also, there are sequences of panels of genes to identify different high-risk genomic features such as MYC overexpression or 8q gain may assist in prognostication and detect somatic events. Consensus of specific microRNAs (miRNAs) profiles are still under investigation but hold potential for useful diagnostic and prognostic biomarkers. Circulating tumor cells (CTCs) may deepen our understanding of spatial and temporal tumor heterogeneity and facilitate identification of driving events and marks of resistance to chemotherapy.24 

One study proposed that patients with osteosarcoma had better outcomes when sent to an inpatient rehabilitation program though this was using dysvascular amputations as a control. Further research is needed to identify if inpatient rehab is superior to outpatient.25

Prehabilitation has shown to increase tolerance for toxic and deleterious side effects of cancer treatments.26 However, further research is needed to analyze its role with osteosarcoma, and a phase 2 trial is currently underway (Efficacy of Pre-operative Prehabilitation in Patients With Limb Sarcoma (EPOP-SARCOMA) https://clinicaltrials.gov/ct2/show/NCT04515459).  

Gaps in the Evidence-Based Knowledge

There was unanimous consensus amongst the pediatric sarcoma clinical and laboratory researchers with areas of the following knowledge gaps27

  • Paucity of tumor biology data on relapsed, metastatic and refractory tumors as they are believed to be genomically different from the primary tumor.
  • Lack of prognostic biomarkers to better risk stratify patients at original diagnosis as well as to predict early relapse.
  • Lack of model systems that accurately depicts a specific patient’s tumor for individual characterization and predict response to specific therapies.

Despite evolution of surgical techniques, optimum surgical reconstruction for the treatment for osseous tumors of the lower extremity in pediatric patients remains unclear due to rarity of bone sarcoma in children, and wide range of ages and across anatomical sites, with nuances of differences in postoperative complications and failure. Earlier studies have been focusing on salvage success rather than function of the limb given poor survival rate. Given improvement in outcome with modern adjuvant therapies, future studies may focus on minimizing complications and maximizing functions.29

Houdeshell et al30 identified 76% of hospitals/clinics lack comprehensive pediatric oncology rehabilitation programs and/or do not provide services across the oncologic care continuum. Although rehabilitation professional organizations all recognize the integral part of the care to pediatric oncologic population, there remains a need for further development of rehabilitation guidelines and clinical pathways.

References

  1. Taran SJ, Taran R, Malipatil NB: Pediatric osteosarcoma: An updated review. Indian J Med Paediatr Oncol 38:33-43, 2017. https://doi.org/ 10.4103/0971-5851.203513
  2. Ottaviani, G., Jaffe, N. (2009). The Etiology of Osteosarcoma. In: Jaffe, N., Bruland, O., Bielack, S. (eds) Pediatric and Adolescent Osteosarcoma. Cancer Treatment and Research, vol 152. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-0284-9_2
  3. Alexander MA Matthews DJ Murphy KP. Pediatric Rehabilitation : Principles and Practice. Fifth ed. New York: Demos Medical; 2015.
  4. National Cancer Institute. Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment (PDQ®)–Health Professional Version. 2020. Accessed at www.cancer.gov/types/bone/hp/osteosarcoma-treatment-pdq on April 5, 2023
  5. Ottaviani, G., Jaffe, N. (2009). The Epidemiology of Osteosarcoma. In: Jaffe, N., Bruland, O., Bielack, S. (eds) Pediatric and Adolescent Osteosarcoma. Cancer Treatment and Research, vol 152. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-0284-9_1
  6. Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer. 2009 Apr 1;115(7):1531-43. doi: 10.1002/cncr.24121. PMID: 19197972; PMCID: PMC2813207.
  7. Meltzer PS, Helman LJ. New Horizons in the Treatment of Osteosarcoma. N Engl J Med. 2021 Nov 25;385(22):2066-2076. doi: 10.1056/NEJMra2103423. PMID: 34818481.
  8. Taran SJ, Taran R, Malipatil NB. Pediatric Osteosarcoma: An Updated Review. Indian J Med Paediatr Oncol. 2017 Jan-Mar;38(1):33-43. doi: 10.4103/0971-5851.203513. PMID: 28469335; PMCID: PMC5398104.
  9. American cancer society- https://www.cancer.org/cancer/osteosarcoma/detection-diagnosis-staging/staging.html
  10. Mulrooney DA, Ness KK, Huang S, Solovey A, Hebbel RP, Neaton JD, Clohisy DR, Kelly AS, Neglia JP. Pilot study of vascular health in survivors of osteosarcoma. Pediatr Blood Cancer. 2013 Oct;60(10):1703-8. doi: 10.1002/pbc.24610. Epub 2013 May 30. PMID: 23720361; PMCID: PMC3968821.
  11. Wittig JC, Bickels J, Priebat D, Jelinek J, Kellar-Graney K, Shmookler B, Malawer MM. Osteosarcoma: a multidisciplinary approach to diagnosis and treatment. Am Fam Physician. 2002 Mar 15;65(6):1123-32. PMID: 11925089.
  12. Punzalan M, Hyden G. The role of physical therapy and occupational therapy in the rehabilitation of pediatric and adolescent patients with osteosarcoma. Cancer Treat Res. 2009;152:367-84. doi: 10.1007/978-1-4419-0284-9_20. PMID: 20213402.
  13. Savitskaya, Y.A., Rico-Martínez, G., Linares-González, L.M. et al. Serum tumor markers in pediatric osteosarcoma: a summary review. Clin Sarcoma Res 2, 9 (2012). https://doi.org/10.1186/2045-3329-2-9
  14. Ferguson JL, Turner SP. Bone Cancer: Diagnosis and Treatment Principles. Am Fam Physician. 2018 Aug 15;98(4):205-213. PMID: 30215968.
  15. Jeys LM, Thorne CJ, Parry M, Gaston CL, Sumathi VP, Grimer JR. A Novel System for the Surgical Staging of Primary High-grade Osteosarcoma: The Birmingham Classification. Clin Orthop Relat Res. 2017 Mar;475(3):842-850. doi: 10.1007/s11999-016-4851-y. PMID: 27138473; PMCID: PMC5289182.
  16. Garcia, M.B., Ness, K.K., Schadler, K.L. (2020). Exercise and Physical Activity in Patients with Osteosarcoma and Survivors. In: Kleinerman, E.S., Gorlick, R. (eds) Current Advances in Osteosarcoma . Advances in Experimental Medicine and Biology, vol 1257. Springer, Cham. https://doi.org/10.1007/978-3-030-43032-0_16
  17. Kaste SC. Imaging pediatric bone sarcomas. Radiol Clin North Am. 2011 Jul;49(4):749-65, vi-vii. doi: 10.1016/j.rcl.2011.05.006. Epub 2011 Jun 16. PMID: 21807172; PMCID: PMC4725719.
  18. NCCN Clinical Practice Guidelines in Oncology. Bone cancer. Version 2.2023. National Comprehensive Cancer Network. Available at https://www.nccn.org/professionals/physician_gls/pdf/bone.pdf. September 28, 2022.
  19. Garcia, M.B., Ness, K.K., Schadler, K.L. (2020). Exercise and Physical Activity in Patients with Osteosarcoma and Survivors. In: Kleinerman, E.S., Gorlick, R. (eds) Current Advances in Osteosarcoma . Advances in Experimental Medicine and Biology, vol 1257. Springer, Cham. https://doi.org/10.1007/978-3-030-43032-0_16
  20. Eaton BR, Schwarz R, Vatner R, Yeh B, Claude L, Indelicato DJ, Laack N. Osteosarcoma. Pediatr Blood Cancer. 2021 May;68 Suppl 2:e28352. doi: 10.1002/pbc.28352. Epub 2020 Aug 11. PMID: 32779875.
  21. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014.
  22. Ramsey, D.C., Gundle, K.R. (2020). Advances in the Functional Assessment of Patients with Sarcoma. In: Kleinerman, E.S., Gorlick, R. (eds) Current Advances in Osteosarcoma . Advances in Experimental Medicine and Biology, vol 1257. Springer, Cham. https://doi.org/10.1007/978-3-030-43032-0_3
  23. Ottaviani, G., Robert, R.S., Huh, W.W., Jaffe, N. (2009). Functional, Psychosocial and Professional Outcomes in Long-Term Survivors of Lower-Extremity Osteosarcomas: Amputation Versus Limb Salvage. In: Jaffe, N., Bruland, O., Bielack, S. (eds) Pediatric and Adolescent Osteosarcoma. Cancer Treatment and Research, vol 152. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-0284-9_23
  24. Shulman, D.S., Crompton, B.D. (2020). Using Liquid Biopsy in the Treatment of Patient with OS. In: Kleinerman, E.S., Gorlick, R. (eds) Current Advances in Osteosarcoma . Advances in Experimental Medicine and Biology, vol 1257. Springer, Cham. https://doi.org/10.1007/978-3-030-43032-0_9
  25. Andrews CC, Siegel G, Smith S. Rehabilitation to Improve the Function and Quality of Life of Soft Tissue and Bony Sarcoma Patients. Patient Relat Outcome Meas. 2019 Dec 31;10:417-425. doi: 10.2147/PROM.S130183. PMID: 32099494; PMCID: PMC6997412.
  26. Silver JK, Baima J. Cancer prehabilitation: an opportunity to decrease treatment-related morbidity, increase cancer treatment options, and improve physical and psychological health outcomes. Am J Phys Med Rehabil. 2013 Aug;92(8):715-27. doi: 10.1097/PHM.0b013e31829b4afe. PMID: 23756434.
  27. Mirabello L, Savage SA, Ladanyi M, Meltzer P, Bult CJ, Adamson PC, Lupo PJ, Mody R, DuBois SG, Parsons DW, Khanna C, Lau C, Hawkins DS, Randall RL, Smith M, Sorensen PH, Plon SE, Skapek SX, Lessnick S, Gorlick R, Reed DR. Current state of pediatric sarcoma biology and opportunities for future discovery: A report from the sarcoma translational research workshop. Cancer Genet. 2016 May;209(5):182-94. doi: 10.1016/j.cancergen.2016.03.004. Epub 2016 Apr 5. PMID: 27132463; PMCID: PMC5497490.
  28. Levin AS, Arkader A, Morris CD. Reconstruction Following Tumor Resections in Skeletally Immature Patients. J Am Acad Orthop Surg. 2017 Mar;25(3):204-213. doi: 10.5435/JAAOS-D-15-00619. PMID: 28195984.
  29. Groundland JS, Ambler SB, Houskamp LDJ, Orriola JJ, Binitie OT, Letson GD. Surgical and Functional Outcomes After Limb-Preservation Surgery for Tumor in Pediatric Patients: A Systematic Review. JBJS Rev. 2016 Feb 9;4(2):e2. doi: 10.2106/JBJS.RVW.O.00013. PMID: 27490132.
  30. Houdeshell MJ, Thomas KM, King AA, L’Hotta AJ. Limitations of Current Rehabilitation Practices in Pediatric Oncology: Implications for Improving Comprehensive Clinical Care. Arch Phys Med Rehabil. 2021 Dec;102(12):2353-2361. doi: 10.1016/j.apmr.2021.05.021. Epub 2021 Jul 30. PMID: 34339659.

Author Disclosure

Nandita Keole, MD
Nothing to Disclose

Ray Stanford, DO
Nothing to Disclose

Zayd Hayani, MD
Nothing to Disclose

Ohmin Kwon, MD
Nothing to Disclose