Primary bone cancer (PBC) is a rare malignant tumor of the bone, originating from primitive mesenchymal cells. It accounts for around 0.2% of all malignancies worldwide and is idiopathic in most cases. There are multiple subtypes, with osteosarcoma, chondrosarcoma, and Ewing sarcoma, the most common. Each varies in demographics, imaging appearance, and biological behavior. They are frequently aggressive and require early diagnosis, utilizing imaging and tissue biopsy. Surgical excision remains the mainstay of curative treatment, with chemotherapy and radiotherapy often used in conjunction.
While primary bone cancer is most often idiopathic, risk factors also play a role in the development of this cancer.
primary bone cancer remains uncommon, accounting for 0.2% of all malignancies and 5% of childhood malignancies. In the United States, an estimated 3,600 new cases of PBC will be diagnosed in 2020, with 1,720 deaths, making up 0.3% of all cancer deaths. The National Cancer Institute data shows in adults, chondrosarcoma (40%) is most prevalent, followed by osteosarcoma (28%). In children and adolescents, osteosarcoma (56%) is most common, with Ewing sarcoma (34%) second. Chordoma, undifferentiated pleomorphic sarcoma, adamantinoma, fibrosarcoma, and giant cell tumor of the bone are also types of PBC; however, they are fewer in number. PBC has a male predominance, with worldwide osteosarcoma male-to-female ratio of 1.43 to 1.
Primary bone cancer is a malignant tumor of the connective tissue with mesenchymal origin. The World Health Organisation (WHO) determined six categories: chondrogenic, osteogenic, notochordal, vascular, other malignant mesenchymal, and miscellaneous (including Ewing sarcoma). The pathophysiology varies considerably between groups, and in some cases, is poorly understood.
Osteosarcoma is a highly malignant osteogenic tumor that can develop in any bone. It has a propensity to develop near the metaphysis of long bones in young patients. The most common sites are the distal femur, proximal tibia, and proximal humerus, where there is high bone turnover. In adults, the axial skeleton is more common, where previous irradiation or metabolic disease of the bone is often associated. Common genetic changes are not present to explain the growth of this tumor type; however, 70% of cases demonstrate some level of chromosomal abnormality. Alterations in p53, Rb1, and DNA repair/surveillance genes are present in patients with Li-Fraumeni, Bloom, and Rothmund-Thomson syndrome, all linked to increased rates of osteosarcoma.
Chondrosarcoma is primarily a disease of adults, most frequently diagnosed between the ages of 30 to 60 years. They are generally slow-growing chondrogenic tumors of intermediate malignancy, rarely metastasizing. Chondrosarcoma arising de novo are classified as primary (>85% of cases), with those arising from pre-existing benign osteochondromas or enchondromas as secondary. The most common site for diagnosis is in the long bones of the appendicular skeleton. Flat bones can also be affected, including the pelvis, ribs, and scapula. The exact pathogenesis of chondrosarcoma is not known, though multiple genes are implicated. Cytogenic studies have identified structural and numerical chromosomal abnormalities. Gene mutations in EXT1/2, TP53, Rb1, and IDH1/2 have also been linked to malignant transformation in benign lesions.
Ewing sarcoma is an aggressive tumor of childhood and adolescence, most commonly occurring in the bone, but also seen in soft tissues. The peak incidence is at 15 years, and the male to female ratio is 1.5:1. Anatomically the most frequent sites involved are long bones in the lower limb, pelvic bones, and the axial skeleton (ribs and vertebral column). Ewing sarcoma characteristically develops at the diaphysis, in contrast to the pattern seen in osteosarcoma. Ewing sarcoma is genetically well described, with characteristic chromosomal translocations identified. The translocation leads to the fusion of a FET protein to an ETS transcription factor, most commonly FLI1 (>85% of cases). The result is the formation of fusion proteins that act to deregulate downstream genes, altering cell behavior.
Diagnosis of primary bone cancer requires a tissue biopsy to allow histopathological assessment, with significant heterogeneity seen.
The formation of bone or osteoid characterizes osteosarcoma, and identification of this is key to diagnosis. Several histological subtypes have been identified, determined by the location of the tumor in bone, and the tumor grade.
Chondrosarcomas are characterized by the production of hyaline cartilage to form a cartilaginous matrix. Lobules of cartilage are seen with significant variation in dimension. Cell nuclei show pleomorphism with chondrocytes varying in size and shape. Conventional chondrosarcoma accounts for over 85% of all chondrosarcomas. It can be further subcategorized into primary central (developing within the medullary canal), or secondary peripheral (developing from the surface of the bone secondary to pre-existing enchondroma or osteochondroma). Histologically both primary central and secondary peripheral are alike. Grading is an essential process to allow the prediction of clinical behavior.
Several rare subtypes of chondrosarcoma are also identified. Dedifferentiated chondrosarcoma is characterized by low-grade chondrosarcoma next to a dedifferentiated high-grade lesion, with a sharp transition between the two. The tumor is extremely aggressive. Mesenchymal chondrosarcoma is a high-grade tumor occurring in either bone or soft tissue. Undifferentiated small round cells are seen, with varying amounts of a cartilaginous matrix. Clear cell chondrosarcoma is a low-grade tumor, with cells showing clear, vacuolated cytoplasm. Areas of hemorrhage and cyst formation are seen.
Ewing sarcoma is a high-grade aggressive sarcoma and belongs to the group of small round cell tumors. Monomorphic small cells are seen in sheets, with round nuclei and finely dispersed chromatin, with nucleoli usually not identifiable. Frequently necrosis is seen, with remaining viable cells arranged perivascularly. Cell membranes express the glycoprotein CD99, with immunohistochemistry showing that >95% of Ewing sarcomas have extensive membranous expression. CD99 expression is not specific to Ewing sarcoma, and other markers are also used for diagnosis.
Other Types of PBC
Chordoma, adamantinoma, and giant cell tumors of bone are typically low-grade locally invasive tumors. Undifferentiated pleomorphic sarcoma and fibrosarcoma are aggressive malignant tumors, with generally poor prognosis.
Primary bone cancer is a rare diagnosis, with primary care practitioners unlikely to encounter a single case in their working life. Early diagnosis improves overall survival; however, delays remain common. History and examination form the first step in diagnosing PBC, and an urgent referral to a specialist center is needed for all patients with a possible diagnosis.
Pain is the most common symptom, described as deep-seated dull pain progressing over time, often becoming refractory to simple analgesia. Pain can be troublesome at night, and this is always a red flag. A mass may be palpable with localized tenderness. Patients may exhibit signs of systemic disease including lethargy, malaise, and fever; however, even in high-grade tumors, these are often not present and may suggest metastatic disease. A pathological fracture can be the first sign, and any abnormal fracture requires further investigation. History of predisposing genetic conditions (Li-Fraumeni syndrome, hereditary retinoblastoma, Werner syndrome, and Rothmund-Thomson syndrome) or diseases (Paget's disease) is crucial information.
Physical examination should focus on the area of pain, tenderness, or mass. The area should be inspected and palpated, with size, consistency, mobility, location of the mass, and overlying skin changes noted. Lymph nodes should be palpated.
Diagnostic modalities used in primary bone cancer include imaging, laboratory blood tests, and tissue biopsy.
All patients should have orthogonal plain film radiographs when a potential PBC is identified. Plain x-rays may show the following findings:
Magnetic resonance imaging (MRI):
MRI scan remains the gold standard for assessment of local tumor extent. The whole anatomical compartment should be imaged, with MRI sensitive for bone and soft tissue lesions. Biopsy planning is crucial, and MRI allows the definition of neurovascular structures. Modern techniques, including dynamic MRI, allow for better characterization of high-grade areas of tumor and have been used to assess tumor response to chemotherapy.
Computed tomography (CT):
CT scan is used when the diagnosis remains unclear following MRI, or MRI is contraindicated. It remains the modality of choice in pelvic PBC and for planning reconstructive surgery. Patients with confirmed PBC require staging, and although many centers still perform chest radiographs, a CT chest is the gold standard for assessing metastatic pulmonary disease.
Whole-body bone scintigraphy (bone scan):
Whole-body bone scintigraphy is a nuclear medicine study that utilizes Technetium-99m as an active agent, highlighting areas of osteoblastic activity. It allows the detection of malignancy and is useful in diagnosing metastatic disease.
Positron emission tomography (PET):
PET scan is a nuclear medicine study that utilizes the high metabolic rate of tumor cells, measuring the uptake of injected radiolabeled F-18 fluoro-deoxy-glucose (FDG). PET scan is in some centers for initial staging of PBC, and studies have suggested it as a modality for follow up when used in combination with CT scan.
Laboratory blood tests:
Specific laboratory blood tests are not used in the diagnosis of PBC; however, they form part of the patient workup. In patients undergoing chemotherapy, baseline urea, creatinine, and liver function tests allow baseline assessment of renal and hepatic function. Biochemical markers alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) offer some prognostic value, and levels can be monitored in follow up to assess for disease recurrence.
Biopsy of the lesion is needed for definitive diagnosis, allowing for histopathological assessment and tumor grading. Biopsy should be performed in conjunction with the operating surgical team, ideally in a specialist bone cancer center. It requires meticulous planning, with suboptimal biopsy impacting on definitive surgical treatment options. Imaging should be performed before a biopsy, aiding in approach planning and preventing tissue disruption that could make radiological assessment more difficult. Percutaneous, incisional, or excisional techniques are used. Ultrasound, x-ray, and CT scans allow precise guidance. The tract should be well marked, allowing for excision at the time of surgery, and a specialist bone cancer pathologist should assess samples.
The management of primary bone cancer requires a multidisciplinary approach by a specialist bone cancer center, including staff trained in providing age-appropriate care to children or adolescents. Management is dependent on several factors, including tumor type, stage and grade, and patient preference. Surgical excision remains the cornerstone of PBC treatment. Neoadjuvant and adjuvant chemotherapy are also commonplace in the management, with radiotherapy used in specific cases.
Surgical resection aims to remove all tumor tissue with adequate margins while preserving as much limb function as possible. A decision for either limb salvage surgery or amputation is made using imaging, histopathology, response to adjuvant treatment, and patient wishes. Surgery often leads to significant tissue loss, and open discussion with the patient is vital. Potential risks, benefits, and expected long term functional impact of the surgery must be highlighted. Low-grade tumors amenable to surgical excision typically require wide excision (removing the involved part of the bone with a cuff of healthy tissue), with high-grade tumors requiring radical excision (removing the affected bone and associated soft tissues within the anatomical compartment).
Multiple chemotherapy agents and regimens are used in the management of PBC. Often this consists of induction (neoadjuvant) and postoperative combination therapy (adjuvant), with improvements in rates of limb salvage surgery and overall survival since their introduction. Chemotherapy forms part of the standard treatment protocol for osteosarcoma and Ewing sarcoma. Chondrosarcoma is still primarily managed surgically, except in cases of mesenchymal chondrosarcoma, where chemotherapy and radiotherapy are often used.
Neoadjuvant chemotherapy is primarily used to reduce the rate of future metastatic spread; however, studies have suggested it can also contribute to primary tumor control. A good response to neoadjuvant therapy is determined by a histological necrosis rate of >90%, with a poor response often initiating a change in postoperative adjuvant chemotherapy agents and showing poorer outcomes.
Radiotherapy is often used as adjunctive therapy in PBC. Ewing sarcoma is a radiosensitive tumor, with radiotherapy commonly used as part of the definitive treatment plan. Preoperative radiotherapy is used if the response to neoadjuvant chemotherapy is poor or the tumor positioned in a problematic anatomical location, where reduction of tumor volume will aid surgical resection. If sufficient tumor volume cannot be removed surgically or it would be unacceptably disabling, radiotherapy is used for local treatment. Where adequate margins have not been resected, postoperative radiotherapy is utilized. Chondrosarcomas are relatively radioresistant, with radiotherapy only utilized for surgically unresectable or incompletely resected tumors.
Radiotherapy has a palliative role in all PBC, used to slow tumor growth locally and relieve pain.
Other types of tumor (malignant):
Other types of tumor (benign):
Two staging systems are used in primary bone cancer, the TNM, and Enneking systems.
TNM system - American Joint Committee on Cancer (AJCC):
This refers to the extent of tumor (T), spread to local lymph nodes (N), metastatic spread (M), and histological grade (G).
Stage IA (T1 N0 M0 G1/GX):
Stage IB (T2 N0 M0 G1/GX, or T3 N0 M0 G1/GX):
Stage IIA (T1 N0 M0 G2/G3):
Stage IIB (T2 N0 M0 G2/G3):
Stage III (T3 N0 M0 G2/G3):
Stage IVA (Any T N0 M1a Any G):
Stage IVB (Any T, N1, Any M, Any G, or Any T, Any N, M1b, Any G):
Refers to the histological grade (G), the extent of the tumor in relation to the anatomical compartments of the body (T), and metastatic spread (M)
Stage IA (G1 T1 M0):
Stage IB (G1 T2 M0):
Stage IIA (G2 T1 M0):
Stage IIB (G2 T2 M0):
Stage III (Any G, Any T, M1):
The prognosis of primary bone cancer is dependent on multiple factors, and there has been no significant improvement in 5-year survival over the past 25 years. In the United States, the National Cancer Institute shows overall 5-year survival is 66%, with studies suggesting rates are lower in the UK.
When the disease is localized, osteosarcoma has a 10-year survival of 60% to 78%. This number falls to 20% to 30% in patients with metastatic disease at presentation, with other negative prognostic factors including axial or proximal extremity tumor location, increased tumor size, raised ALP or LDH, increased age, pathological fracture, and poor response to neoadjuvant chemotherapy.
The most potent prognostic factor in chondrosarcoma is histological grade. Other identified factors are metastatic disease at presentation, increased age, and pelvic tumor location. 5-year survival in grade I chondrosarcoma is 83%, with only 53% of patients surviving to 5 years with grade I and II disease.
Ewing sarcoma has a 5-year survival of 70% to 80% when the disease is localized. This number falls to 50% in patients with isolated pulmonary metastases, and less than 30% in patients with any other metastatic disease at diagnosis. Other negative prognostic factors include pelvic tumor location, increased tumor size, and poor response to neoadjuvant or adjuvant chemotherapy treatment.
Here are some important points about primary bone cancer:
Patients diagnosed with PBC should ideally be managed under the care of a bone cancer specializing multidisciplinary team. The team should consist of specialists from radiology, histopathology, oncology, orthopedics, and a clinical nurse specialist or key worker. Radiologists and pathologists interpret initial imaging and tissue samples, allowing for a definitive diagnosis to be reached and operative planning to begin.
Oncologists determine the most appropriate neoadjuvant and adjuvant chemotherapy protocols, as well as arranging future follow-up and surveillance. Orthopedics plan and perform surgical resection of the tumor, along with any initial or future reconstruction that is required. Clinical nurse specialists or key workers act to educate the patient and their family, as well as direct towards different services available. They are a point of contact throughout the patient journey and work to coordinate the various teams. Other team members include physiotherapists, occupational therapists, prosthetists, orthotists, dieticians, social workers, and counselors.
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