Primary Bone Tumors in Children and Teens

Disease/ Disorder

Definition

Primary bone tumors are defined as tumors originating in a bone. They can be benign or malignant. Bone tumors can be classified based on histological features (i.e., chondrogenic, osteogenic, fibrogenic, etc.). Benign tumors are subdivided into nonaggressive (i.e., nonossifying fibroma) or aggressive (i.e., aneurysmal bone cyst). Most bone tumors are benign. The most common malignant bone tumors in children are osteosarcoma and Ewing sarcoma.

Etiology

Etiology is largely unknown. Some inherited syndromes, such as Li-Fraumeni syndrome, hereditary multiple exostoses, Ollier’s disease, Maffucci syndrome, familial retinoblastoma syndrome, Werner syndrome or Rothmund-Thomson syndrome, increase the risk of bone malignancy. Benign bone lesions may rarely transform into malignant lesions (osteochondroma into chondrosarcoma; bone infarct dedifferentiation into osteogenic sarcoma, fibrosarcoma or malignant fibrous histiocytoma). Osteosarcoma and malignant fibrous histiocytoma have been associated with radiation exposure, chronic osteomyelitis, and Paget disease. There is an association between trauma and development of aneurysmal bone cyst.

Epidemiology including risk factors and primary prevention

Annual incidence of bone tumors in the United States in children under the age of 20 is 9.9 per million.¹ In the U.S., about 700 children are diagnosed with malignant bone tumors each year. Malignant bone tumors account for 6% of all childhood malignancies, 56% of which are osteosarcomas and 34% are Ewing sarcomas.² Osteosarcomas are slightly more common in African American than Caucasian populations. Ewing sarcoma affects predominantly Caucasian populations, and 80% of patients are under the age of 20 at the time of diagnosis. Bone tumor incidence peaks at the age of 15, which coincides with timing of the adolescent growth spurt.²

Patho-anatomy/physiology

In osteosarcoma, the malignant cell produces osteoid tissue. Osteosarcoma preferentially arises in the metaphyseal areas of the most rapidly growing long bones, which are the distal femur, proximal tibia, and proximal humerus. Over 50% of osteosarcomas occur around the knee.  Less than 20% have macroscopic metastases at diagnosis, but there is concern that up to 80-90% may have microscopic metastatic disease.³ Metastatic lesions are most commonly detected in lung and bone tissue.

Ewing sarcoma is a small round blue cell tumor of neural crest origin. The most common translocation is between chromosomes 11 and 22 (85% of cases). Other translocations are t(21;22) and t(7;22). Ewing sarcoma arises in the lower extremity in 46% of cases, followed by the pelvic bone (20%). Roughly 20% have evidence of macroscopic metastatic disease at diagnosis with a larger portion presumed to have microscopic metastasis.¹

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

Natural history of untreated osteosarcoma and Ewing sarcoma is disease progression ultimately resulting in death. As mentioned previously, the most common site of metastatic disease is the lungs. Tumor may also metastasize to bone elsewhere, including the spine. As for non-metastatic disease, prognosis has improved significantly over the past few decades.

Patients with newly diagnosed malignant bone tumors typically undergo extensive work up and imaging. Treatment regimens typically consist of chemotherapy (systemic control) and surgery (local control – tumor resection, limb sparing procedure or amputation) and/or radiation therapy. Ewing sarcoma is radiation sensitive, while osteosarcoma is considered radiation resistant. Patients with resectable lung metastases have better prognosis than those with unresectable disease. For Ewing sarcoma, patients commonly undergo thoracotomies and/or whole lung irradiation (WLI) if there is a concern for or evidence of lung metastases. For resectable lung metastases with osteosarcoma, resection is commonly preferred over radiation.⁴

Specific secondary or associated conditions and complications

Multi-regimen chemotherapy used for systemic control of disease may have negative physical, psychosocial, and socioeconomic sequelae. Physical complications include weakness, pain, neuropathy, impaired balance, and cardiac dysfunction. Surgery used for local control may result in impaired wound healing, infection, or pain. Depending on the type of limb sparing surgery performed, patients might have weight bearing and activity restrictions. Radiation therapy may result in impaired skin integrity and fatigue in the treatment of primary tumors, while it can also result in pneumonitis or fibrosis in the treatment of lung metastases.⁵

Essentials of Assessment

History

Most patients with malignant bone tumors typically present with several months of localized pain. About half of them will also report swelling and limited range of motion. A minority (10-15%) present with pathological fracture. History of trauma is not uncommon. While systemic symptoms are uncommon in osteosarcoma (unless disease is advanced), fever is present in 20% of patients with Ewing sarcoma at presentation. A comprehensive pain history should be obtained, including red flags of worsening/persistent pain, night and morning pain, pain with activity/weight bearing, and pain lasting longer or more severe than expected in those with a proceeding trauma. Osteoid osteoma presents with progressively worsening night pain and is relieved by aspirin or nonsteroidal anti-inflammatory drugs.

Physical examination

Comprehensive physical examination should be performed. Vital signs should be obtained. Heart, lung, and abdominal exam should be included. Lymphadenopathy should be assessed. Musculoskeletal, vascular, neurological, and functional evaluation should be performed. Pain on palpation, visible deformity, restrictions, or asymmetry in range of motion, focal weakness, abnormal gait, or focal neurological findings warrant further investigation. Leg length discrepancy and scoliosis should not be missed. Pain with weight bearing raises a concern for a pending pathological fracture and requires immediate work up.

Clinical functional assessment: mobility, self-care cognition/behavior/affective state

Prior functional status should be ascertained. Inquire about patient’s functional goals and environmental barriers. Impairments in mobility and self-care as well as need for assistive devices and bracing should be assessed. Home environment and availability of caregiver support should be taken into consideration. Emotional state and coping of the patient and the family should be assessed and appropriate referrals initiated. Depression and anxiety are common in this population.

Laboratory studies

Labs in a patient with suspected bone cancer should include inflammatory markers (ESR, CRP), blood count, chemistry including alkaline phosphatase and LDH. Patients undergoing treatment typically require frequent lab monitoring. Physiatrists should always review the most recent laboratory studies and imaging to prescribe appropriate rehabilitation interventions and guide/modify exercise program based on results (i.e., thrombocytopenia).

Imaging

Plain radiography is the initial modality used to evaluate suspected bony lesion. Benign tumors are generally discrete with sclerotic margins and usually do not require additional imaging.  Malignant tumors are ill-defined and may have a periosteal reaction or soft-tissue calcification and may require additional imaging.  On plain films, osteosarcoma has a classic “sunburst” appearance whereas Ewing is described as an “onion skin” or “hair-on-end” lesion.  Computed tomography (CT) or magnetic resonance imaging (MRI) are used for cross-sectional evaluation of suspected malignant bony lesion, including extent of tumor and proximity to crucial structures, such as nerves and blood vessels. CT or nuclear bone scan can be used to assess for metastases. Positron emission tomography is also frequently used for evaluation of disease burden and response to treatment.

Supplemental assessment tools

Biopsy is often required to assess histology and biologic or immunologic markers and cytology.  Urodynamic studies might be considered in patients with spine or pelvic tumors affecting the spinal cord or nerves. When etiology of pain or weakness is unclear, electrodiagnostic study might be of benefit.

Early prediction of outcomes

In osteosarcoma, more than 95% necrosis after chemotherapy is an important positive prognostic factor.  Poor prognostic indicators include metastatic disease (for example, large pulmonary nodules in osteosarcoma), poor response to systemic chemotherapy and location of disease in the spine or pelvis given its poor resectability. Other poor predictors include increased tumor size, increased serum alkaline phosphatase, and secondary osteosarcoma.⁶ Limb sparing procedures compared to amputations have been shown to have no major differences in function and quality of life measures.⁷ Amputation may be preferred if function after limb sparing is not acceptable.⁷

Environmental

Home environment might affect rehabilitation goals and home modifications to enhance patients’ independence may be recommended. Examples include a ramp to enter the house for children in a wheelchair or a stair lift as needed.  Bathroom accommodations such as an elevated toilet seat and grab bars may also be needed.

Social role and social support system

Maintaining “normalcy” as much as possible during treatment might help alleviate the patient’s and family’s anxiety and a sense of “lack of control”. Children may receive homebound instruction during treatment, and some enjoy interaction with their classmates by attending classes virtually. Chronic overprotection by caregivers might limit the patient’s independence and sense of control. Some children need neuropsychological and rehabilitation evaluations to assess appropriateness for an individualized education plan (IEP) or 504 plan.

Professional issues

Discussion of prognosis should be deferred to the patient’s oncologist. Informing the child about his or her condition should be done at a developmentally appropriate level by a trained professional and with parental permission. Quality of life and symptom management are of paramount importance. Safety of rehabilitation interventions should always be considered and discussed with the patient (if appropriate) and family.

Rehabilitation Management and Treatments

Available or current treatment guidelines

Treatments vary based on multiple factors, including type, grade, stage, and location of bone tumor. For instance, localized resectable high grade osteosarcoma is treated with neoadjuvant chemotherapy for about 10 weeks, followed by surgery to remove the tumor (sometimes with adjuvant radiation therapy), followed by additional chemotherapy up to one year. Chemotherapy drugs commonly used in varying combinations to treat osteosarcoma include methotrexate, doxorubicin, cisplatin or carboplatin, cyclophosphamide, etoposide, vincristine, and ifosfamide.

The goal of surgical resection is to achieve a wide margin while sparing the distal limb if able.  Over two thirds of surgical treatments for osteosarcoma and Ewing sarcoma are limb-sparing.  If the functional outcome would be unacceptable, amputation or rotationoplasty may be recommended.  The use of modular expandable prostheses is an approach to managing limb preservation in children who have significant expected growth restriction due to resection of malignant tumors.⁸

At different disease stages

Patients benefit from rehabilitation interventions during the continuum of treatment. Symptomatic control (i.e., pain) and quality of life should always be among top considerations. Goals of rehabilitation interventions are to maximize function, minimize disability and increase independence.

Children undergoing oncological treatment may have physical and psychosocial ailments. Side effects of treatment can include wound infections/dehiscence, hardware failure in those with limb sparing surgery, edema/lymphedema, cardiac dysfunction, neuropathy, weakness, impaired balance, and limited activity tolerance, as well as depression and anxiety.

Patients following limb-sparing surgery or amputation require rehabilitation interventions to assist with early mobility, prevention of contractures, proximal and core muscle strengthening, residual limb shaping, provision of prosthesis and other assistive devices, gait training, pain management, and strengthening.  Rehabilitation protocols exist for commonly performed limb-sparing procedures but should be individualized to each patient.

Patients with metastatic or recurrent disease commonly undergo additional chemotherapy and surgical/radiation treatments including thoracotomies, orthopedic surgeries, and/or radiation therapy. They will continue to benefit from rehabilitation interventions focusing on managing pain, energy conservation, optimizing independence in self-care and mobility and caregiver education and training.

With chemotherapy, 5-year survival has improved to up to 77% with nonmetastatic osteosarcoma but decreases to less than 30% in those with distant disease.  Up to 40% may relapse.  For Ewing, survival for those with localized tumor is over 80% but decreases to less than 40% if distant metastases are detected at diagnosis.

Coordination of care

Patients benefit from interdisciplinary rehabilitation team consisting of physicians, nursing staff, physical therapists, occupational therapists, psychologists, case managers, child-life specialists, and social workers. Rehabilitation physicians should communicate closely with the therapists regarding rehabilitation goals and precautions based on clinical developments and lab and imaging findings.

Patient & family education

Family education should include recommended home exercise program, weight bearing or activity restrictions and appropriate use of and care for prostheses and assistive devices. Fall and safety precautions should be reviewed. Rationale for continued rehabilitation interventions should be shared with the family. The American Cancer Society website contains helpful patient and family education information related to tumor type and treatments.

Measurement of Treatment Outcomes, including those that are impairment-based, activity participation-based and environmentally-based

A combination of assessment tools provides the truest picture of function and quality of life.  The Functional Mobility Assessment (FMA) is a validated objective measure of functional skills for patients with lower extremity sarcomas.⁹ The Musculoskeletal Tumor Society Scale (MSTS) is a clinician administered tool used for assessment of disability. The Pediatric Toronto Extremity Salvage Scale (pTESS) is used in children (TESS in adolescents) as a self-reported measure of physical function.¹⁰ The Pediatric Outcomes Data Collection Instrument (PODCI) is a pediatric patient-based questionnaire used for a wide array of musculoskeletal disorders.¹⁰ The Short Form-36 version 2 (SF-36v.2) is a commonly used measure of a health related quality of life.⁶

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

Weight bearing and activity/range of motion precautions should always be explicitly communicated by the orthopedic surgeon to the rehabilitation team. Patients with lower extremity osteosarcoma might need to use crutches following biopsy until definitive surgery is performed as they are at increased risk for pathological fracture. Any pain with weight-bearing should prompt evaluation and possibly imaging to rule out impending pathological fracture. Exercise program should be adjusted based on laboratory values (i.e., hemoglobin, platelets). Neutropenic patients may be treated in protective isolation. Patients who had anthracycline exposure should be educated on weightlifting and exercise restrictions due to risk of cardiomyopathy.¹¹

A substantial percentage of survivors of osteosarcoma and Ewing sarcoma have self-reported physical performance limitations (40.8% and 30.9%, respectively).¹² The Children’s Oncology Group has published Long-Term Follow-up Guidelines for survivors, including risk-based, exposure- related recommendations for screening and managing late effects of cancer treatments.

Cutting Edge/ Emerging and Unique Concepts and Practice

Gene expression profiling might help predict response of each tumor to chemotherapy. Compressed chemotherapy regimens are being studied, while new drugs and immunotherapy treatments are being developed.² Improved surgical techniques and imaging allow for removal of cancer while preserving normal tissue. Newer types of internal prostheses used for limb sparing surgeries can be expanded without the need for additional surgeries. Intensity modulated radiation therapy (IMRT) limits the dose to normal tissues while delivering high doses to the tumor, resulting in more effective control of tumor growth. Proton therapy allows delivery of higher doses of radiation to the tumor with little damage to normal tissues.

Gaps in the Evidence-Based Knowledge

The Children’s Oncology Group is a clinical trials group supported by a National Cancer Institute and their research has led to significant improvement in treatment outcomes of pediatric tumors. It has nearly 100 clinical trials open at any time. There are still unanswered questions, such as etiology, optimal treatment regimen, factors related to treatment response, and prevention of progression and metastasis.

References

1. NCCR*Explorer: An interactive website for NCCR cancer statistics [Internet]. National Cancer Institute. [Cited 2021 October 30]. Available from https://NCCRExplorer.ccdi.cancer.gov/ 
2. Gereige R, Kumar M. Bone lesions: benign and malignant. Peds in Review. 2010;31(9): 355-363.
3. Luetke A, Meyers PA, Lewis I, and Juergens H. Osteosarcoma treatment: where do we stand? A state of the art review. Cancer Treatment Reviews. 2014;40(4), 523-532. 
4. National Comprehensive Cancer Network. Bone Cancer (Version 1.2023). http://www.nccn.org/professionals/physician_gls/pdf/bone.pdf. 
5. Krasin MJ, Constine LS, Friedman DL, Marks LB. Radiation-related treatment effects across the age spectrum: differences and similarities or what the old and young can learn from each other. Semin Radiat Oncol. 2010;20(1):21-29. doi:10.1016/j.semradonc.2009.09.001
6. Ginsberg JP, Rai SN, Carlson CA, et al. A comparative analysis of functional outcomes in adolescents and young adults with lower-extremity bone sarcoma. Pediatric Blood & Cancer. 2007;49(7):964-969.
7. Nagarajan R., Clohisy DR, Neglia JP, Yasui Y, Mitby PA, Sklar C, et al. Function and quality-of-life of survivors of pelvic and lower extremity osteosarcoma and Ewings sarcoma: The Childhood Cancer Survivor Study. British Journal of Cancer. 2004;91(11): 1858-1865.
8. Wozniak W, Lugowska I, Szymborska A. Long-term results of expandable endoprosthesis replacement in children with malignant bone tumors. J Clin Oncology. 2010;28(15):9553.
9. Marchese VG, Rai SN, Carlson CA, et al. Assessing functional mobility in survivors of lower-extremity sarcoma: reliability and validity of a new assessment tool. Pediatric Blood & Cancer. 2007;49(2):183-189.
10. Pakulis PJ, Young NL, Davis, AM. (2005). Evaluating physical function in an adolescent bone tumor population. Pediatric Blood & Cancer. 2005;45(5):635-643.
11. Okada M, Meeske KA, Menteer J, Freyer DR. Exercise recommendations for childhood cancer survivors exposed to cardiotoxic therapies: an institutional clinical practice initiative. J Pediatr Oncology Nursing. 2012;29(5):246-252.
12. Ness KK, Hudson MM, Ginsberg JP, et al. Physical performance limitations in the Childhood Cancer Survivor Study cohort. J Pediatr Oncology Nursing. 2009;27(14):2382-2389.

Original Version of the Topic

Katarzyna Ibanez, MD. Primary bone tumors in children and teens. 9/15/2015

Previous Revision(s) of the Topic

Kimberly Hartman, MD, Elizabeth George, MSIV. Primary bone tumors in children and teens. 12/19/2019

Author Disclosure

Kimberly Hartman, MD, MHPE
Nothing to Disclose

Abigail Bowser
Nothing to Disclose