Bone tumors can be classified as primary or metastatic. Primary tumors are divided into benign and malignant. Benign lesions include developmental abnormalities such as fibrous dysplasia and osteochondroma. Examples of true tumors include osteoblastoma, a rare primary neoplasm of bone that is categorized as a benign bone tumor. Benign tumors rarely metastasize, but they may be locally very destructive, as in the case of giant cell tumors. Aggressive benign tumors may require radical surgery.
Primary malignant bone tumors are sarcomas. Skeletal tissue is composed of tissues of mesodermal origin including bone, cartilage fibrous tissue and bone marrow. Any of these tissues can produce a malignant tumor. Primary tumors are classified by cell type.1 Metastatic tumors are the most common and frequently arise from the lung, breast, kidneys, or prostate.
Known risk factors for primary bone tumors include inherited conditions such as retinoblastoma, Li-Fraumeni syndrome, Rothmund-Thomas syndrome and Werner syndrome, as well as, underlying abnormalities such as Paget’s disease, fibrous dysplasia and previous radiation exposure.1,2
Epidemiology including risk factors and primary prevention
Because most benign tumors are asymptomatic, the real incidence is unknown. Primary malignant bone tumors represent 0.2% of all cancers in the United States, or 2900 cases annually.3 The three most common tumors in order of frequency are osteogenic sarcoma, chondrosarcoma, and Ewing’s sarcoma. Chrondrosarcoma occurs in middle age and older adults. Osteogenic and Ewing’s sarcomas occur most frequently in children and young adults, although a second peak incidence of osteogenic sarcomas occurs in patients over 60 years of age. These sarcomas commonly occur secondary to radiation therapy and Paget’s disease.1
Sarcomas arise from transformed mesenchymal cells. The majority of osteogenic sarcomas occur in the metaphysis of the long bones. The most common sites of involvement are the distal femur and proximal tibia, followed by the proximal humerus. Ewing’s sarcoma typically occurs in the diaphysis of long bones, but it is not uncommon in the pelvis. Chondrosarcoma frequently occurs in the proximal femur and flat bones. Histologically, osteogenic sarcoma is categorized into low and high grades. Chondrosarcoma is categorized into low, intermediate, high and de-differentiated, while Ewing’s sarcoma is always high grade. Chromosomal translocation (11; 22) is used by pathologists in the diagnosis of Ewing’s Sarcoma.1
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
Metastases are far more common with high grade tumors. Metastases usually disseminate through the blood, most commonly to the lung, followed by bone. Skip metastases are found in high grade sarcomas, where tumor embolizes via marrow sinusoids, forming a lesion that is discontinuous from the primary tumor, but in the same bone.1
Specific secondary or associated conditions and complications
Pain and lack of cortical integrity are major indicators of impending fracture in primary malignant bone tumors. Making the diagnosis of impending fracture is a challenge in primary malignant bone tumors just as it is in metastatic bone tumors. The guidelines set forth in the Mirels scoring system are not applicable as they pertain only to metastatic lesions.4Additionally, no proven clinical guidelines exist to predict fracture risk with benign tumors of the bone. CT-based analysis of bone rigidity in affected bone and homologous healthy bone has demonstrated high specificity for predicting fracture risk in benign tumors; however, its use is limited secondary to the excessive radiation exposure.5
2. ESSENTIALS OF ASSESSMENT
Pain, especially night pain, is the hallmark of primary bone tumors. Patients may give a history of injury, but this brings attention to the tumor rather than being the cause of it. In the benign bone lesion osteoid osteoma, instant relief of pain on taking NSAIDs is diagnostic. One needs to ask about prior cancer history, radiation exposure, Paget’s disease, and fracture history. The latter may be important on reviewing imaging.
Physical examination typically demonstrates a firm, fixed mass along the involved bone. Palpation may elicit pain.
Functional goals are extremely important for these patients. However, they are typically considered after initial treatment is initiated. Cognitive or behavioral deficits are not usually seen.6
Serum alkaline phosphatase levels are elevated in the majority of patients with osteogenic sarcoma. It is frequently elevated in Paget’s disease and extremely high levels are found in Paget’s sarcoma. Serial alkaline phosphatase analysis may be used to assess the response to chemotherapy in osteogenic sarcoma. Serum lactate dehydrogenase is of prognostic significance in Ewing’s sarcoma and in some cases of osteogenic sarcoma.1,3
In primary malignant bone tumors, initial plain radiographs may reveal a combination of characteristics including cortical destruction, areas of radiolucency, extraosseous extension and permeating destruction with poorly defined borders. In addition to radiographs, MRI, CT scans and angiography are useful in tumor definition prior to surgery. MRI may better delineate soft tissues and edema and CT may better define bony structures. Technetium labeled MDP (Methylene Diphosphonate) total body bone scans; PET (Positron Emission Tomography) scans and chest CT are used for tumor staging, i.e., revealing lung metastases.
Supplemental assessment tools
The definitive histological diagnosis is made on biopsy, which may be done as an open or CT guided (closed) procedure. Surgical staging systems, one based on the Enneking Staging System (modified by the Musculoskeletal Tumor Society [MSTS]) and the other by the American Joint Commission on Cancer, are used in staging patients with primary bone tumors.7, 8
Early predictions of outcomes
Poor prognostic indicators include metastases at presentation, tumors arising from the axial skeleton, large tumor volume (size > 10 cm), increased alkaline phosphatase or lactate dehydrogenase levels, poor response to preoperative chemotherapy, skip metastases, discontinuous tumors in bone, and lymph node involvement.2
Social role and social support system
Recognizing and overcoming environmental barriers such as political, familial, structural, and economic factors can be instrumental in lessening the degree of disability in patients treated for primary bone tumors. Studies examining quality of life of patients who have had limb salvage surgery and amputations vary widely in terms of their definitions of quality of life, however, both types of patients report poor quality of life. Amputees, however, do report improvements in quality of life when a proper fitting prosthesis is received.6
There is no difference in long-term survival or local tumor control for patients treated with amputation versus limb salvage plus adjuvant therapy for extremity sarcoma.6 Limb salvage has emerged as the treatment of choice in this population as the functional outcomes appears to be similar to amputation, although rotationplasty may be functionally desirable in select patients.6
3. REHABILITATION MANAGEMENT AND TREATMENTS
Available or current treatment guidelines
Until the late 1970s, amputation was the treatment of choice for most bone sarcomas. The introduction of systemic chemotherapy has had a significant effect on survival rates for osteogenic and Ewing’s sarcoma. The five-year survival rate for patients presenting with non-metastatic osteogenic and Ewing’s sarcoma is now 70% and 60%, respectively.
Typically, patients with osteogenic and Ewing’s sarcoma receive 2-3 months of neo-adjuvant chemotherapy, followed by wide surgical resection and further adjuvant chemotherapy. Chemotherapy agents used include Doxorubicin, Cisplatin, Methotrexate and Ifosfamide. Chemotherapy-induced toxicity, including cardiomyopathy, neuropathy, nephropathy and late leukemias have been reported.
With advances in imaging and adjuvant therapies, wide resections resulting in limb salvage has replaced amputation as the mainstay of treatment. Today, close to 90% of patients receive limb salvage. Amputation is considered when tumors surround neurovascular structures, or there are large ulcerated infected masses or displaced pathologic fractures. Young patients that are skeletally immature and have the potential for limb growth, with lower limb tumors, may be managed with a Van Ness rotationplasty.10Some studies have shown that in properly selected patients, functional outcome is superior in limb salvage procedures, while survival rates are equivalent to those receiving amputation.
Patients with painful lytic lesions should be considered at risk of fracture and managed with protected weight-bearing, casts and braces as indicated. In a minority of cases with gross bony destruction, definitive limb salvage surgery may be required prior to completion of neoadjuvant chemotherapy in order to prevent a fracture.
Radiation in combination with surgery is superior to surgery alone for local control of soft tissue sarcomas. The timing of preoperative versus post-operative radiation in soft tissue sarcoma treatment remains arguable with each having benefits and risks. Preoperative radiation is known to reduce local disease recurrence; however, it carries a risk of wound complications of 25-35% in addition to other toxicities that impair quality of life. Post-operative radiation allows for histological examination of the tumor but carries the risk of greater long term radiation toxicity. Radiation complications include fibrosis and edema.11 Radiation to the palms and soles can be toxic.
Radiation therapy is often employed as a local treatment for Ewing’s sarcoma. Osteogenic sarcoma and chondrosarcoma are resistant to traditional radiation therapy; however, proton and/or photon beam radiation may be useful for patients with tumors in unfavorable locations not amenable to resection, for example the skull base and axial skeleton.12Radiation may be used as a palliative measure in inoperable forms of chondrosarcomas. In addition to being radio-resistant, chondrosarcoma does not respond to chemotherapy; therefore, surgery is the only definitive and curative treatment in this disease.
Coordination of care
Primary tumors of the bone usually require coordination with multiple physicians, including a primary oncologist, surgeon, pathologist, and physiatrist. Following treatment, services for survivors should include rehabilitation with physical and occupational therapy. Survivorship care should also include psychological support, sexual health services and expert pain management.13
Patient & family education
Patient and family education prior to limb salvage surgery, amputation, or Van Ness rotationplasty are important to manage expectations for post-operative care and function. In addition, providing information on the possible secondary complications of surgery and chemotherapy are imperative. Response to amputation in children varies; the surgery was better accepted when the tumor was causing pain and/or functional loss.14
Studies examining functional outcomes in patients who have undergone limb salvage versus amputation have varied.1 Currently there is no consensus that lower extremity limb salvage improves functional outcomes in comparison to amputation, especially in those patients with proximal limb lesions. Despite this, there appears to be a trend towards increased disability and handicap in those patients who have undergone amputation.6
NCCN general guidelines for bone cancers recommend local control by either limb-sparing surgery or amputation. Amputation may be necessary in certain cases to achieve local control. When possible, limb-sparing surgery is preferred if reasonable functional outcome can be achieved.12
Limb sparing surgery along with radiation is promising in treating sarcomas of the hands and feet with reduced morbidity.15
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Cutting edge concepts and practice
Currently targeted therapies are being investigated with interest in the development of biomarkers predictive of therapeutic response in Ewing’s Sarcoma.16 In 2011, the first European Network for Cancer Research in Children and Adolescents (ENCCQA) convened with the focus of understanding mechanisms of resistance and to identify novel therapies. 17
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
- DeVita VT, Lawrence TS, Rosenberg SA. Cancer, principles & practice of oncology. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. 1578-609.
- Hameed M, Dorfman H. Primary malignant bone tumors–recent developments. Seminars in diagnostic pathology 2011;28(1):86-101.
- SEER Cancer Statistics Factsheets: Bone and Joint Cancer. National Cancer Institute. Bethesda, MD. Available at: http://seer.cancer.gov/statfacts/html/bones.html. Accessed April 22, 2016
- Mirels H. Metastatic disease in long bones. A proposed scoring system for diagnosing impending pathologic fractures. Clinical Orthopedics & Related Research 1989(249):256-64.
- Leong NL, Anderson ME, Gebhardt MC, et al. Computed tomography-based structural analysis for predicting fracture risk in children with benign skeletal neoplasms: comparison of specificity with that of plain radiographs. Journal of Bone & Joint Surgery. 2010 Aug 4;92(9):1827-33.
- Custodio CM. Barriers to rehabilitation of patients with extremity sarcomas. Journal of Surgical Oncology 2007;95(5):393-9.
- Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clinical Orthopedics & Related Research 1980(153):106-20.
- AJCC Cancer Staging Manual. 6th ed. Philadelphia, PA: Lippincott Raven; 2002.
- Eyre R, Feltbower RG, Mubwandarikwa E, et al. Epidemiology of bone tumors in children and young adults. Pediatric Blood Cancer 2009;53(6):941-52.
- Merkel KD, Gebhardt M, Springfield DS. Rotationplasty as a reconstructive operation after tumor resection. Clinical Orthopedics & Related Research 1991;(270):231-6.
- Rivard JD, Puloski, SS, Temple WJ. Quality of Life, Functional Outcomes, and Wound Complications in Patients with Soft Tissue Sarcomas Treated with Preoperative Chemoradiation: A Prospective Study. Annals of Surgical Oncology 2015;22(9):2869-2875
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Bone Cancers. Version 2.2016. Available at: NCCN.org Accessed April 19, 2016.
- Kwang TNK, Furtado S, Gerrand C. What do we know about survivorship after treatment for extremity sarcoma? A systemic review. Journal of Cancer Surgery. 2014 March 19; 40:1109-1124
- Clerici CA, Ferrari A, Luksch R, et al. Clinical experience with psychological aspects in pediatric patients amputated for malignancies. Tumori 2004;90(4):399-404.
- Bishop AJ, Zagars GK, Moon BS, et al. Combined Limb Sparing Surgery and Radiation Therapy to Treat Sarcomas of the Hands and Feet: Long-Term Cancer Outcomes and Morbidity. International Jounral of Radiation Oncology 2015;(92)5:1060-1068
- Gaspar N, Hawkins DS, Dirksen U, et al. Ewing Sarcoma: Current Management and Future Approaches Through Collaboration. Journal of Clinical Oncology. 2015 Sept 20; 33:3036-3046
- Kovar H, Amatruda J, Brunet, E, et al: The second European interdisciplinary Ewing sarcoma research summit-A joint effort to deconstructing the multiple layers of complex disease. Oncotarget. 2016;7(8):8613-8624
Original Version of the Topic:
Michael D. Stubblefield, MD, Marni Hillinger, MD. Primary Bone. Publication Date: 2012/10/30.
Navdeep Singh Jassal, MD
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Ritika Oberoi-Jassal, MD
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Jaspreet Singh, MD
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Young Chang, MD
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Joshua Smith, MD
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