Benign bone tumours outnumber their malignant counterparts by 3 to 4-fold. A total of 6000 to 8000 new bone lesions are diagnosed annually in the United States.

The distribution of tumours varies with age. Most benign bone lesions, osteosarcomas, and Ewing's sarcomas occur in the second and third decade. Giant cell tumours, chondrosarcomas, fibrosarcomas, myelomas, lymphomas, and metastatic disease all have a predilection for older age groups. With the exception of giant cell tumours, most benign and malignant tumours of bone are slightly more common in men.

A genetic basis for some bone tumours is suggested by the increased incidence of bone sarcomas in patients with hereditary multiple osteocartilaginous exostoses, osteogenesis imperfecta, and in survivors of bilateral retinoblastoma. Osteosarcomas have also been reported in siblings and with a greater frequency in first cousins of patients with osteosarcoma. Other diseases, such as solitary enchondromata, Ollier's disease (multiple enchondromatosis), Maffucci's syndrome, bone infarcts, chronic osteomyelitis, Paget's disease, and fibrous dysplasia are associated with a higher incidence of sarcoma than that in the general population. Sarcomas are found in individuals with familial cancer syndromes, and mutations of tumour suppressor genes appear to be responsible for the development of some of these tumours. Such mutations are occasionally present in the germline and may be passed to offspring.

An increased incidence of sarcomas is seen in bone previously irradiated, either deliberately or during the treatment of other diseases. Although trauma has been implicated in the aetiology of bony neoplasms, there is no evidence that a single, uncomplicated injury causes cancer.

The types of tumours occurring within bone reflect its components: osseous tissue, bone marrow, supporting connective tissues, nerves, blood vessels, and fat. A generally accepted classification system is based upon the predominant matrix component and type of cell differentiation within the lesion. Thus, each type of tissue contained within the bone may give rise to one or more clinically, radiographically, and histologically distinct benign or malignant neoplastic lesions, each with its own pattern of biological behaviour (Table 1) 620. The distinction between benign and malignant tumours is not always clear. Certain tumours, such as osteoblastoma, giant cell tumour, and chondroblastoma occasionally behave in an aggressive manner. Some malignant tumours have variable degrees of histological aggressiveness: a chondroscarcoma may be classified as low, intermediate, or high grade and show a conforming pattern of biological behaviour.

Initial diagnostic procedures aim to determine whether the lesion is a benign or malignant primary bone tumour, a metastatic deposit, or a marrow cell lesion. The historical presentation of benign and malignant bone neoplasms is usually non-specific. The patient usually notices pain after minor injury. Some lesions are discovered incidentally on radiographs obtained for other purposes.

A lump or pathological fracture may also be the presenting problem. The character of the pain is usually dull and aching, unless a pathological fracture has occurred. A notable exception is the osteoid osteoma: pain resulting from these lesions is described as sharp or boring, often worse at night, and is characteristically completely relieved with aspirin.

On physical examination the findings are minimal for benign lesions. An osteoid osteoma may cause local tenderness and joint limitations, or, in children, may present as scoliosis, a limp, or growth disturbance. Malignant lesions are often associated with a tender mass. Some malignant, and occasionally benign, tumours may cause heat, redness, oedema, venous distension, and even lymphangitis; this may make the differentiation from infection difficult. Systemic findings are lacking except in patients with Ewing's sarcoma or lymphoma who may show fever, chills, anorexia, and weight loss consistent with a chronic or subacute infectious process.

Laboratory tests should include a complete blood count and erythrocyte sedimentation rate; these are helpful in excluding diseases such as myeloma, leukaemia, and infection. Determination of calcium and phosphorus levels may indicate metabolic bone disease or the hypercalcaemia which occurs in some patients with metastatic bone disease. Alkaline phosphatase and lactic dehydrogenase levels are useful in the assessment of metabolic disease, and may be of prognostic significance in patients with osteosarcoma, lymphoma, or Ewing's sarcoma. Serum immunoelectrophoresis is frequently diagnostic for multiple myeloma.

A radiograph of a bone neoplasm lesion in two or more planes is the most reliable test in establishing a presumptive preoperative diagnosis. The lesion can be assessed for its location, size, cortical integrity, margination, and the presence or absence of a soft tissue mass. Interpretation of radiographs may allow determination of whether the lesion contains osseous, chondroid, fibrous, or ‘other’ tissues, and some non-neoplastic disorders such as bone infarcts, infections, or stress fractures can be excluded. A radionuclide bone scan is important, not only in assessing the activity of the lesion relative to its bone production and blood flow, but also in determining the presence or absence of bony lesions at other sites. A chest radiograph should be obtained in any patient with a suspected malignant bone tumour to search for metastatic disease or a primary focus from which a metastasis may have arisen.

If preliminary investigations suggest that the lesion is a primary benign bone tumour, it may be observed or biopsied to confirm the diagnosis and suggest subsequent treatment. If the lesion is thought to be a primary malignant tumour of bone, further studies including CT or magnetic resonance imaging (MRI) are required. MRI provides an image at least as good as that obtained by CT, and also allows non-invasive evaluation of such aspects as water content and proton density. MRI provides excellent contrast between the tumour and surrounding normal tissue and aids in determining the marrow and soft tissue extent of bone tumours. Proper interpretation is essential: surrounding oedema can be mistaken for tumour extension. CT is most helpful in defining the extent of bone destruction by the tumour. These investigations should be performed prior to biopsy, since they may be affected by haematoma formation associated with the biopsy procedure.

Tomograms in two planes may be useful for the diagnosis of fatigue (stress) fracture or assessment of the subchondral bone plate. Arteriograms have been used less frequently for diagnostic purposes since the advent of MRI, but are occasionally useful if extremely vascular lesions need to be embolized preoperatively. CT scans of the chest are also obtained preoperatively if a malignant bone tumour is suspected.

If a lesion is thought to be metastatic carcinoma, a preliminary attempt to identify the site of the primary tumour is warranted. In addition to the history and physical examination, studies may include mammograms, urinalysis, intravenous pyelography or renal ultrasound, determination of acid phosphatase and prostate specific antigen levels, a thyroid scan, and chest CT. If such tests fail to locate the primary tumour further extensive testing is not likely to be fruitful.

For tumours thought to be ‘round cell’ lesions, such as Ewing's tumour, myeloma, and lymphoma, further staging studies may include a gallium scan, abdominal CT, and lymphangiography.

For most patients with tumours of bone, a biopsy specimen is necessary to establish the diagnosis. The biopsy should be deferred until many, if not all, of the staging studies are complete. This practice avoids the possible interference of local tissue trauma with the imaging studies, and allows information that is useful in planning the location of the biopsy site to be obtained. A closed (needle) biopsy offers the advantage of a small puncture wound that can be excised at the time of the definitive resection. Needle biopsy is most appropriate in lesions of the spine or pelvis, and when the suspected diagnosis is metastasis, infection, a round cell tumour, or a local recurrence. Adequate tissue is obtained in approximately two-thirds of procedures, and the diagnostic accuracy is about 80 per cent.

Open biopsy is considered more reliable, and is often preferred in the investigation of musculoskeletal tumours to ensure that sufficient tissue is obtained for accurate diagnosis and to avoid sampling error. Even when properly performed, an incisional biopsy has the disadvantages of creating a larger operative haematoma, potential for soft tissue contamination with tumour cells, and increasing the chance of pathological fractures if the cortex is violated. A good biopsy technique is vital; the procedure must be undertaken by an experienced surgeon, preferably the one who will ultimately carry out the definitive procedure. The anatomical placement of an incision for biopsy of a malignant tumour must take into consideration the extent of the lesion as determined by the staging studies and the possible plans for subsequent surgery. It must be possible fully to excise the tract of the biopsy and adjacent contaminated soft tissues at the time of a local resection or amputation. In almost all instances, transverse incisions in the extremities should be avoided, as should dissections which expose neurovascular structures or enter an uninvolved anatomical compartment. Haemostasis is important following biopsy of malignant bony lesions: it may be wise to plug the bone window with polymethylmethacrylate (bone cement) to control haemorrhage and to contain the haematoma. Drains should be avoided or placed close to and in line with the biopsy incision, since drainage tracts become sites of secondary seeding. The use of a tourniquet is optional, but these should not replace attainment of adequate haemostasis at the time of operation.

Handling of the biopsy specimen is also important. It is wise to obtain a frozen section to ensure that adequate tissue for diagnosis has been obtained, and that some tissue for special immunohistochemical stains and other special tests (such as cytogenetics) has been obtained. Aerobic and anaerobic bacteriological cultures should always be obtained, and a small portion of the tissue should be placed in glutaraldehyde for electron microscopy.

With the recent advent of limb-sparing procedures, the complexity of resective surgery for tumours has increased. A recent study showed that major errors in diagnosis occurred in about 20 per cent of over 300 biopsies. In 5 per cent of patients, problems with the biopsy led to unnecessary amputation; in 8.5 per cent the prognosis and outcome were thought to have been adversely affected.

Imaging studies and biopsy provide information to enable definition of a surgical stage for the lesion. The main variables (and, therefore, prognostic factors) in determining the outcome for bone tumours are the histological grade (G), the anatomical location (T), and the presence or absence of distant metastases (M). The grade of the lesion is largely a histological determination based on Broder's classification, but clinical factors such as symptoms, rate of growth, and radiological characteristics are also taken into account.

Certain lesions, such as juxtacortical osteosarcomas and adamantinomas, are almost always low grade (G1). Grading for the most part is subjective and is based on the pathologist's ability to assess cellularity, pleomorphism, and mitotic activity. It is also dependent on established patterns of classification of tumours based on their light microscopic appearance, which may not fully predict their biological behaviour.

Flow cytometric analysis of nuclear DNA concentration is a rapid and accurate adjunct to histological assessment. The technique involves computerized collection of fluorescent signals from a highly focused laser beam which intersects a flow cell through which suitably stained nuclei pass at rates ranging from 500 to 5000/s. If the cell DNA is stained with ethidium bromide or propidium iodide it is possible to obtain a direct determination of the proportion of cells in diploidy or G0/G1 (normal value for DNA content of somatic cells), DNA synthesis or S-phase (increasing DNA concentration occurring during the mitotic cycle), and tetraploidy or G2/M (double the diploid concentration, occurring in G2 or the mitotic phases of the cycle, and increased in malignant conditions). Perhaps most important is DNA aneuploidy (greater or lesser than the normal diploid values) which signifies a malignant cell with some alteration in the nuclear apparatus. Analysis of DNA ploidy is accurate in determining the grade of cartilage and osseous tumours (benign, low grade, or high grade), but as yet has not demonstrated a reliable relationship with prognosis.

The surgical site (T) refers to the location of the tumour in relation to anatomical compartments that serve as natural barriers to tumour extension. A lesion is deemed intracompartmental (T1) if it lies within an anatomical compartment such as the femur or tibia and is bounded on all sides by barriers to tumour extension, such as the bony cortex and the articular cartilage. Extracompartmental lesions (T2) are defined as tumours in which the natural planes are transgressed: the lesional tissue involves more than one anatomical compartment (e.g. an osteosarcoma of the femur which has broken through the cortex and presents with a large soft tissue mass in the anterior compartment of the thigh). Some sites such as the popliteal space are by definition extracompartmental (T2) because the major neurovascular structures lie in interfascial tissues.

The final major factor in determining the surgical stage of any lesion is the presence or absence of metastases (M). The lungs are the most common site of spread for sarcomas, but metastases to lymph nodes, other bones, or viscera carry a similar prognosis. The absence of metastatic disease, as determined by chest CT and bone scan, results in a designation of M0, while the presence of a focus of distant spread leads to a designation of M1.

Based on the assessment of surgical grade (G), site (T), and metastases (M), bone tumours are staged by the following system: all benign primary bone tumours are G0 and, therefore, Stage 0 (regardless of T and, of course, M does not apply). Low grade malignancies (G1) are Stage I, which is further divided into intracompartmental (IA) and extracompartmental (IB) lesions. High grade malignancies (G2) are classified as Stage IIA and IIB depending respectively on the intra- or extracompartmental location of the lesion. A lesion with any G or T with distant metastasis (M) is considered Stage III (Table 3) 622. This staging system was retrospectively tested in a group of 397 cases of bone and soft tissue tumours and demonstrated that prognosis varied with high statistical significance with the stage I versus II and with IIA and IIB. No difference was noted between Stage IA and IB lesions. This system appears to be an effective one which not only aids in assessing prognosis, but provides a basis upon which to plan surgical and other treatments.

Surgical resection or amputation is the primary method of obtaining local control of most bone tumours. The oncological result of the surgical procedure is currently described in terms of the margins achieved; standard definitions and terminology are available for use in prospective analysis and for comparing results amongst different centres. The margin, defined as the volume of normal tissue surrounding the tumour can be classified as intralesional (the procedure transects or enters the lesion), marginal (a plane through the reactive zone or ‘pseudocapsule’ surrounding the tumor), wide (leaving a significant cuff of normal tissue around the tumor but not including the entire compartment in the resection), and radical (resection of all anatomic compartments containing the tumour). These definitions apply to both local resections and to amputations. Examples of intralesional procedures include incisional biopsy, curettage, debulking of an unresectable lesion, or an amputation through the tumour, all of which leave macroscopic tumour behind. Marginal procedures remove the bulk of tumour tissue, but are likely to leave behind satellite or daughter nodules and microscopic foci or residual tumour. Procedures that gain a wide margin carry the risk of leaving skip lesions in the surrounding normal tissue, as is occasionally seen with osteosarcoma, while with the radical margin, the entire involved compartment is removed, and all local disease is presumably eradicated.

An osteoid osteoma is a benign bony neoplasm of unknown aetiology that presents as a small, painful lesion with a characteristic clinical, radiographic, and pathological pattern. Its incidence is highest in the second decade, but rare in those over the age of 30. It is most commonly located in the tibia and femur. Osteoid osteoma in the spine has a predilection for the posterior elements. The clinical presentation is with sharp, boring pain which is usually worse at night and is often relieved with salicylates. Osteoid osteoma can cause a wide range of physical findings, including local tenderness, scoliosis, overgrowth of a bone, or secondary synovitis if located near a joint. Radiographically the lesion appears as a radiolucent, round or oval focus (the nidus) which may or may not be mineralized (Fig. 1) 2619. The nidus is the lesional tissue and is usually 1 cm or less in diameter, but it is surrounded by a variable amount of reactive bone formation, which may be so extensive as to obscure the lesion. The diagnosis is apparent on radionuclide bone scans, CT, or plain tomograms. Although spontaneous regression of these lesions may occur this often takes several months or years; sclerosis may persist even after symptoms subside. Symptoms may be treated with salicylates or non-steroidal anti-inflammatory agents, but most lesions are cured by complete excision of the nidus.

Benign cartilage tumours often present difficulties in differential diagnosis and in management. It may be difficult to distinguish enchondromas from chondrosarcomas radiographically and histologically, and from the rarer lesions such as chondroblastoma and chondromyxoid fibroma. The latter have high recurrence rates and are often difficult to approach surgically. Cartilaginous tumours can be divided into two categories: enostotic and the exostotic lesions. Enostotic tumours comprise enchondroma, chondroblastoma, and chondromyxoid fibroma. Ollier's disease (multiple enchondromatosis with venous anomalies) is included in this group. Exostotic tumours consist of solitary osteochondroma, juxtacortical chondroma, and hereditary multiple osteocartilaginous exostosis. Distinguishing these lesions from their malignant counterparts is difficult, but malignant lesions are unusual in those less than 30 years of age. Malignant tumours larger than benign tumours, are located in more proximal locations (rare below the knees and elbows), and are often painful and tender. The likelihood of malignancy is higher in patients with multiple cartilage tumours.

The enchondroma is a benign cartilage lesion located centrally within the medullary cavity of short, long, or flat bones. They are the most common bone tumour of the hand. The lesions may occur at any age and are often asymptomatic unless accompanied by a pathological fracture. Radiographically, the lesions are lucent and placed centrally within the metaphysis or diaphysis of the bone (Fig. 2(a)) 2620. Although thinning or scalloping of the cortex may occur, there is usually a moderate amount of sclerotic margination. Rounded or stippled calcification is a frequent finding in adults (Fig. 2(b)) 2620. Observation is sufficient if these lesions cause no symptoms, deformity, or risk of fracture. Otherwise, treatment is principally by curettage and packing the defect with bone auto-grafts or allografts. Multiple enchondromatosis (Ollier's and Maffucci's syndromes) is less common than the monostotic counterpart, and although not clearly genetic in origin, occurs with increased frequency in families. The severity ranges from minimal alterations to grotesque deformities of the skeleton (Fig. 3) 2621. Treatment is aimed at correcting or preventing deformities: some patients may require prophylactic intramedullary nailing of long bones and multiple osteotomies. These patients have an increased chance of malignancy, and they must be carefully observed throughout their lifetime.

Chondroblastoma is most common in adolescent males, and usually affects the epiphysis of long bone when the physes are open. The proximal and distal femur, proximal humerus, and proximal tibia are the common sites. Radiographically, the appearance is that of a round to oval lucent epiphyseal lesion, characteristically stippled with punctate calcifications ( Fig. 4(a) 2622, (b)). Treatment is by curettage, avoiding the adjacent growth plate and articular cartilage. The recurrence rate following intralesional treatment is about 25 per cent. Under rare circumstances, benign chondroblastomas may spread to the lungs.

Solitary osteocartilaginous exostosis is a frequent tumour of bone and is probably due to a genetic defect in the embryonic cartilage anlage, or a defect in the restraining periosteum and the ring of Ranvier. The condition occurs at the metaphyseal ends of bones at any age. Growth of these lesions occurs by enchondral ossification and just as with the normal growth plate, ceases at maturity. Radiographically, exostoses appear as sessile or pedunculated outgrowths of the cortex of the metaphysis, usually projecting away from the joint ( Fig. 5(a) 2623 and (b) ). The bony cortices of the host bone of origin and the lesion are continuous and their marrow cavities communicate. The pathological tissue of the osteocartilaginous exostosis is the cartilage cap, which is responsible for its growth by an enchondral sequence not dissimilar from that of a normal growth plate. These lesions usually are not troublesome to the patient unless they cause a painful bursa, undergo a fracture, or interfere with adjacent neurovascular structures. Malignant degeneration occurs with an incidence of less than 0.1 per cent, and their removal is usually for relief of symptoms. Recurrence is unlikely if the cartilage cap is completely excised. Multiple osteocartilaginous exostosis is inherited as an autosomal dominant trait and is characterized by multiple exostotic lesions ( Fig. 6(a) 2624, and (b) ) which cause distortion of the skeleton and may lead to severe functional impairment. The main treatment concern in this entity is the management of these deformities in childhood and monitoring of the lesions for possible development of malignancy in adulthood.

Fibrous cortical defect and non-ossifying fibroma are the most prevalent of the benign lesions within the bone in childhood. These lesions, which are probably not true neoplasms, occur in the metaphyses of the long bones, especially the distal femur and proximal and distal tibia, but may also occur in the upper extremities (proximal humerus, distal radius, and ulna). In one skeletal survey, one or several of these lesions were present in early childhood in 36 per cent of individuals studied. Although occasionally persisting into adulthood, most of these lesions disappear soon after late adolescence and generally produce no symptoms unless a fracture has occurred. Their radiographic appearance is usually sufficiently characteristic to make biopsy unnecessary (Fig. 7) 2625. No treatment other than observation is required unless the lesion is in danger of causing pathological fracture or the diagnosis is in doubt, when biopsy, curettage, and bone grafting are indicated.

Fibrous dysplasia is a disorder of fibro-osseous tissue that probably represents a developmental abnormality of bone rather than a true neoplasm. Three clinical syndromes exist: monostotic fibrous dysplasia, polyostotic fibrous dysplasia, and Albright's syndrome. In Albright's syndrome, polyostotic fibrous dysplasia is associated with areas of cutaneous pigmentation and endocrine dysfunction. Precocious puberty is the most common endocrinopathy, but acromegaly, hyperparathyroidism, vitamin D-resistant rickets, hyperthyroidism, and Cushing's syndrome may be present. Radiographically, the lesions of fibrous dysplasia have a lucent or ‘ground glass’ appearance and cause thinning of the cortex and endosteal scalloping ( Fig. 8(a) 2626 and (b) ). The bone may be enlarged or deformed and may be involved for its whole length.

Treatment of the lesions is mainly directed toward prevention or correction of bony deformities; this constitutes one of the most difficult technical challenges in orthopaedics. Biopsy of a lesion is occasionally necessary to distinguish it from more aggressive lesions. Some lesions cease to grow at maturity, but others continue to grow even into adult life. Malignant degeneration is extremely rare (an incidence of much less than 0.01 per cent).

Simple or unicameral bone cysts are lesions of unknown aetiology common in the first two decades of life. They are presumed to arise from either a disorder of the growth plate, or from a transient circulatory compromise due to a developmental anomaly of the veins of the affected bone. These cysts most commonly manifest themselves in the proximal humerus (55 per cent) or proximal femur (26 per cent) of a growing child, but other bones may be affected. In adults, cysts occur most frequently in the calcaneus or flat bones and are usually discovered incidentally or after pathological fracture. The cyst appears as a central, radiolucent lesion on the metaphyseal side of the growth plate of a long bone (Fig. 9) 2627. The cortex is thinned but intact, and the lesion is usually well demarcated. The cavity is filled with a fluid similar to serum and extracellular fluid; this may be bloody if fracture has occurred. Treatment is either by curettage and grafting, subtotal resection with or without grafting, or, as has been recently advocated, by needle aspiration and instillation of methylprednisolone. The last procedure is associated with the least morbidity and is frequently successful: operative treatment is probably best reserved for patients who fail to respond to steroid injection.

Aneurysmal bone cyst is a lesion of unknown aetiology that may occasionally occur as a primary tumour, or more often, is found in conjunction with pre-existing lesions such as giant cell tumour, chondroblastoma, chondromyxoid fibroma, or fibrous dysplasia. Most aneurysmal bone cysts occur in patients less than 20 years of age and affect the long bones and spine. Radiographically, the lesions are eccentrically placed, expansile, purely lytic, and pseudotrabeculated tumours which are quite well demarcated from the bone and appear as a ‘blow out’ in the cortical surface ( Fig. 10(a) 2628, (b) ) surrounded by a periosteal shell of new bone ( Fig. 10(c) 2629, (d) ). Differentiation of these lesions from telangiectatic osteosarcoma and giant cell tumour is important and often difficult. Treatment is either by curettage and grafting or marginal resection, depending upon the location of the cyst. Lesions in difficult sites such as the pelvis or spine are occasionally treated by radiotherapy or embolization.

Giant cell tumour of bone is an uncommon, aggressive, locally destructive lesion of the metaphyseo-epiphyseal region of the long bones of adults which is unlikely to metastasize. Despite its being classified with the benign tumours, the aggressive local behaviour tends to mimic that of a local malignancy. The tumour occurs most frequently between the ages of 18 and 45 and is more common in women. The principal sites of predilection are the distal femur, proximal tibia, distal radius, proximal humerus and femur, and proximal fibula, and occasionally the hand. Giant cell tumours of the axial skeleton are rare but are difficult to treat because of their proximity to major structures.

The tumour is usually eccentrically placed and located in the metaphysis and epiphysis of the long bone, extending to and sometimes through the subchondral cortex of the adjacent (usually knee) joint ( Fig. 11(a) 2630,2631 to (d) ). The cortex is almost always thinned, giving it an expanded appearance, and the lesion is entirely radiolucent. An extraosseous soft tissue mass may be discernible by CT or MRI.

The giant cell tumour is difficult to treat. Although less than 5 per cent of these tumours metastasize, the lesions may be extremely destructive locally. The local recurrence rate following incomplete (intralesional) surgery is over 50 per cent in some series, and the proximity of the lesion to the subchondral cortex and the distortion of architecture of the adjacent joint make marginal surgery difficult to perform without sacrifice of the joint. Treatment options include resection in expendable bones such as the fibula, curettage and packing with polymethylmethacrylate or bone graft, or, when the lesion is extensive, a resection and reconstruction with allograft or metallic implants ( Fig. 12(a) 2632, (b) ).

Giant cell tumours of the axial skeleton present a special problem. It may be impossible to resect lesions of the spine, sacrum, or pelvis without injury to adjacent structures, and control of haemorrhage is difficult. Selective angiographic embolization and intralesional surgery has been advocated. Radiotherapy is usually successful in eliminating the tumour, but carries the risk of radiation necrosis and radiation-induced sarcoma. In the few patients in whom pulmonary metastases occur, the lesions should be resected surgically with good expectation of cure.

Malignant bone tumours vary in biological behaviour from locally aggressive tumours that seldom metastasize to highly anaplastic sarcomas with a dismal prognosis. They affect all age groups and all bony sites. Diagnosis is often difficult and treatment is complicated by their sometimes extremely aggressive nature, by their location in areas of functional importance, and by their rarity, which precludes precise definition of the natural history.

Osteosarcoma (osteogenic sarcoma), the most frequently encountered malignant lesion of bone, is characterized by the direct formation of bone or osteoid tissue by a sarcomatous stroma. Osteosarcoma is not a homogeneous disease and compromises several distinct clinicopathological entities; these must be distinguished since the biological behaviour of each may be quite different (Table 6) 625. Central osteosarcoma, the most classical form, is a high grade tumour arising in the medullary cavity of the metaphysis or diaphysis of a teenage child. If one excludes myeloma, classical osteosarcoma is the most common primary malignant tumour of bone, accounting for about 38 per cent of malignant bone neoplasms. There are two peaks of incidence: the first occurs in patients between 10 and 25 years of age: it is a leading cause of cancer morbidity in adolescence, with only leukaemia and lymphoma exceeding it in incidence in this age group. The second peak occurs in the fifth and sixth decades; this is probably related to the increased incidence of osteosarcoma in patients with Paget's disease and those who have received radiation therapy. Osteosarcoma is more common in males, with a sex ratio of 3:2. There seems to be a correlation between the rate of bone growth and the incidence and location of osteosarcoma: patients are above average height, and the most common sites are areas of most rapid growth. Fifty per cent of lesions occur above the knee, the distal femoral metaphysis being the most common site. The next most frequent sites are the proximal tibia, proximal humerus, and proximal femur. The tumours are usually metaphyseal in location, although diaphyseal osteosarcomas are not uncommon; the spine and pelvis are less frequent sites. The flat bones and pelvis are more commonly affected in patients with Paget's disease and postirradiation sarcoma.

The characteristic symptoms of pain, local tenderness, a soft tissue mass, and decreased function may be present for a variable period of time before diagnosis. Physical examination usually discloses a firm, tender mass fixed to the subjacent bone. Occasionally the patient has a pathological fracture. There are no specific laboratory findings, although the serum alkaline phosphatase and lactic dehydrogenase concentrations are often increased.

Radiographs demonstrate a destructive process that varies from a purely lytic to a predominantly blastic lesion, although a combination of both productive and destructive changes is usually noted ( Fig. 13(a) 2633, (b) ). The cortex is nearly always transgressed, and a soft tissue mass is common ( Fig. 13(c) 2634, (d) ). The periosteum is elevated and may respond by forming reactive woven bone (‘Codman's triangle’) at the periphery of the lesion. Perpendicular striations (classical ‘sun burst’ appearance) and onion-skinning of the periosteum are frequent findings. The lesion usually occupies the metaphysis of the bone but can spread by direct extension into the epiphysis and joint. There may be other foci of tumour within the same bone separated by areas of normal bone. These ‘skip’ lesions can usually be detected by pain radiographs and bone scans; they are associated with a worse prognosis.

The prognosis and natural history of osteosarcoma is variable: even tumours histologically classified as high-grade, central osteosarcomas are heterogenous in their biological behaviour and response to treatment. The overall 5-year survival rate for patients with osteosarcoma treated by amputation alone was historically 15 to 30 per cent, although the figure varies among different institutions and within one institution at different times. The location of the tumour appears to be an important prognostic factor: proximal extremity lesions carry a worse prognosis than do distal lesions, and lesions of the axial skeleton have the worst prognosis. Detectable metastases are present at diagnosis in approximately 10 per cent of patients (depending on the method of investigation) and distant spread at presentation worsens the prognosis. The duration of symptoms, age of the patient, and the histological type of osteosarcoma also influences the final outcome.

Although there was initial doubt about the worth of adjuvant chemotherapy, randomized trials have validated its benefit. Current treatment of high grade osteosarcoma consists of complete surgical eradication of the lesion and aggressive adjuvant chemotherapy. Most patients receive preoperative, or ‘neoadjuvant’ chemotherapy for 2 to 3 months, followed by wide or radical excision (or amputation) of the primary tumour, and approximately 1 year of chemotherapy. Drug regimens include high-dose methotrexate, Adriamycin, cytoxan, and bleomycin, and actinomycin D and cytoxan. Newer drugs such as ifosfamide are now being investigated. Current controversy centres on the value of preoperative (neoadjuvant) chemotherapy in the treatment of osteosarcoma. The administration of chemotherapy prior to tumour removal has the advantage of earlier treatment of micrometastatic disease and assessment of response (histological tumour necrosis), and may make limb salvage surgery safer; however, not all patients respond. There is concern that delaying surgical removal in those who fail to respond may be detrimental, allowing time for metastatic spread, development of drug resistant clones, and growth of the primary tumour to a size incompatible with limb salvage. A randomized study is currently being performed by the Pediatric Oncology Group.

The use of adjuvant chemotherapy has seemingly improved the survival of osteosarcoma patients and has led several treatment centres to consider local resection and reconstruction of extremity osteosarcomas. In the past, almost 80 per cent were treated by amputation. Now nearly 80 per cent can be treated by limb-sparing operations. Such surgery depends on the ability to resect the tumour through normal tissue planes while preserving the neurovascular structures, and to reconstruct a functional extremity following such a resection. A wide or radical margin should be the goal, although in truth some such resections have margins that are marginal (for example near neurovascular structures). Tumours in certain locations lend themselves to resection because their removal does not result in significant functional loss, such as those in the wing of the ilium, clavicle, and fibula. Resection of extremity lesions, however, may have to include adjacent joint (extra-articular resection) to assure removal of possible tumour extension along the ligaments and capsule; this produces rather complex reconstructive requirements. The age of the patient must be considered since ultimate limb length discrepancies may preclude resection in a skeletally immature patient. Very young patients may be better served by an amputation or rotationplasty. In elderly patients, especially those with a low likelihood of survival, limb salvage might be preferable to amputation to avoid the high energy expenditure required by ambulation with an artificial limb. The most important consideration, however, in determining the efficacy of a local resection following resection is the local recurrence rate, which has been reported to be 5 to 10 per cent. Although no randomized studies exist, selected patients who undergo limb salvage procedures do not appear to have a worse disease-free survival or survival compared with those who are treated by amputation.

The type of reconstruction depends on the location of the primary lesion and preference of the surgeon and patient. Bone allografts, metallic prostheses, arthrodeses using autogenous or allograft bone graft, rotationplasty, vascularized bone transfers, and other options may all be used to reconstruct the bony defect.

The management of patients who develop pulmonary metastases has improved dramatically with the advent of aggressive resection of these lesions by thoracotomy. CT scanning of the lungs allows accurate definition of the extent of disease and resectability of pulmonary lesions. Most lesions are situated in the periphery of the lungs, making wedge resection feasible. Pulmonary resection combined with chemotherapy produces projected 5-year survival rates of approximately 30 per cent. Careful monitoring of patients following treatment of the primary disease is mandatory to allow early detection of relapses.

The various forms of chondrosarcoma of bone perhaps offer the most difficulty in diagnosis and staging, even in centres experienced in dealing with these rare lesions. Management problems are not only attributable to the rarity of the neoplasms, but also to the wide spectrum of histological and radiographic presentation, their unpredictable biological behaviour; and the remarkable tendency of the tumours to recur in both bone and soft tissue if incompletely removed or if an inadvertent ‘spill’ occurs.

The lesions may be divided into enostotic and exostotic groups; most are enostotic, and the majority of these are ‘hyaline’ in type, showing many of the features of the normal articular or epiphyseal cartilages. However, this category includes three other very rare lesions: mesenchymal chondrosarcoma, which may be multicentric and has characteristics of some of the round cell lesions; dedifferentiated chondrosarcoma, which shows a bizarre anaplastic spindle cell pattern and is very virulent; and clear cell chondrosarcoma, a low-grade lesion of the epiphyseal region in adults in which the cells show a clear cytoplasm and the tumour resembles (and is often mistaken for) a chondroblastoma.

Enostotic hyaline chondrosarcomas occur principally in adults, with a peak incidence in the third to the sixth decade. The sites of predilection are the long bones, especially the femur, pelvis, and humerus, and the lesions are rare below the knees and elbows. The tumours are centrally placed, usually quite large at the time of presentation and located in the metaphysis or diaphysis (or both). The affected patient usually complains of dull, aching pain of several months' duration and often describes a tender mass which has slowly enlarged and distorted the contour of the bone and the extremity. Physical examination often discloses a large soft tissue mass fixed to the underlying bone. These tumours occur with increased frequency in patients with enchondromatosis (Ollier's or Mafucci's syndromes.

The classical enostotic hyaline chondrosarcomas have a characteristic radiological appearance (Fig. 14) 2635. As defined above, the lesions are large, centrally placed, metaphyseo-diaphyseal in location, and almost invariably produce a significant expansion of the cortex. The lesion may produce scalloping of the internal cortex, thinning and, if high grade, cortical transgression and a soft tissue mass, which is of often lobular appearance in outline on imaging studies such as CT. Lower-grade lesions may cause the cortex to appear thicker than normal in some areas, and the central portion of both high- and low-grade tumours may show rounded or ring- shaped calcifications, not dissimilar to those seen in benign cartilage lesions. CT is usually helpful in defining the extent of the tumour, and in assessing the degree of cortical transgression and size of the soft tissue mass, both of which are useful in distinguishing between low- and high-grade lesions.

Exostotic hyaline tumours show a similar age distribution but are less likely to be high grade. Most of these tumours appear to result from malignant degeneration of pre-existing osteocartilaginous exostoses and are located in the proximal or distal parts of the femur, proximal humerus, or about the pelvis. Malignant exostotic tumours are large, proximally placed, and usually present with pain and a tender mass; this may reach an enormous size (particularly in the pelvis) by the time the patient seeks care. Calcific densities are often seen on radiographic or other imaging studies (especially CT) and the soft tissue mass surrounding the bony part of the lesion is thicker than that seen with benign lesions. A variant, juxtacortical chondrosarcoma, is difficult to distinguish from the periosteal osteosarcoma.

The treatment of chondrosarcoma of bone is almost entirely surgical. Occasionally inaccessible lesions such as those in the spine, or very large tumours of the pelvis may be treated effectively with proton beam radiotherapy, but the recurrence rate is high. Adjuvant chemotherapy may be used in an attempt to control metastatic spread of high-grade lesions, but cannot be substituted for competent wide or radical surgery in the treatment of the local lesion. Limb-sparing procedures with wide margins are appropriate for lower-grade lesions and the use of metallic implants, arthrodesis with autograft or allograft, or osteoarticular allograft replacements are used to restore structural continuity and function to the limb (Fig. 15) 2636. Treatment of high-grade lesions, particularly when an extensive soft tissue mass is present, may require amputation.

Malignant fibrous tumours of bone are rarer than those forming bone and cartilage and accounted for less than 4 per cent of malignant bone tumours in the Mayo Clinic series. The two major types are fibrosarcoma and malignant fibrous histiocytoma.

Fibrosarcoma of bone is less frequent than is its soft tissue counterpart. It most commonly presents as a central lesion, but may be periosteal in location; the latter is difficult to distinguish from soft tissue fibrosarcoma located adjacent to a bone. Many such lesions occur secondary to other processes such as Paget's disease, giant cell tumour, fibrous dysplasia, osteomyelitis, previously irradiated bone, and bone infarcts. Fibrosarcomas occur in both sexes and in all age groups, but most are found later in life (fourth to seventh decades). Long bones of the lower extremities contain most of the lesions: approximately half occur in the distal femoral and proximal tibial metaphyses, but any bone may be involved. Because they are purely destructive, pathological fracture is common. High-grade fibrosarcomas show as lytic, poorly marginated, metaphyseal lesions, and are usually demonstrating cortical breakthrough, with an associated soft tissue mass on plain radiographs (Fig. 16) 2637. A Codman's triangle or onion-skinning may be present. Radiographs of lower-grade lesions, may show sclerotic margination with well-defined margins. Differentiation from metastatic lesions, myeloma, round cell lesions, and less aggressive primary bone tumours such as the desmoplastic fibroma and giant cell tumour is sometimes difficult.

Treatment is largely surgical and follows the principles discussed under osteosarcoma. Low-grade lesions (stage I) and selected high-grade lesions (stage IIA and IIB) can be resected with wide margins but stage II lesions may require a radical resection or amputation. Radiotherapy and chemotherapy are of little benefit, although radiotherapy may suppress the progression of disease or deter recurrences in elderly patients who refuse radical surgery. The 5-year survival rates vary from 28 to 34 per cent.

Malignant fibrous histiocytoma of bone is a recently recognized entity in which the tumour tissue is biphasic, showing both malignant fibrous tissue and histiocytes. Many of these lesions were previously classified as osteosarcoma, fibrosarcoma, dedifferentiated chondrosarcoma, or even metastatic carcinoma, all of which may contain areas that appear similar to malignant fibrous histiocytoma. Age, clinical, and radiographic features are similar to fibrosarcoma, and the tumour has been reported in patients with Paget's disease, previously irradiated bones, and in other lesions. Treatment is either by wide or radical resection or radiotherapy, and approximately one-third of patients survive long-term.

In contrast to osteosarcoma and fibrosarcoma, malignant fibrous histiocytoma appears to have a higher incidence of lymph node metastases, thereby making local control by ablative surgical procedures alone inadequate. It may, therefore, be important to separate malignant fibrous histocytoma from other bone sarcomas since the former may benefit from radiotherapy to lymph node sites and systemic chemotherapy.

Chordoma is a rare neoplasm believed to arise from retained notochordal remnants; hence it invariably occurs in the anterior body of the spinal segments and the midline of the base of the skull in the region of the spheno-occipital synchondrosis. Patients are usually in the fourth to the seventh decade; the condition is slightly more frequent in men. The principal affected segments are the sacrum, followed less frequently by the region of the clivus, and the lumbar, cervical, and thoracic spine. Sacral chordomas are slowly growing and patients may give long histories of low-grade mild discomfort in the lower spine and of tenderness on prolonged sitting. The patient may notice a mass over the sacrum, but neurological symptoms are usually the cause of the patient seeking treatment. As the lesion grows it pushes forward on the rectum, causing constipation; this is followed by sacral nerve sensory loss, weakness of the musculature, impotence, saddle anaesthesia, and finally, loss of bladder and bowel control. Lesions located in the clivus grow and invade the adjacent sella, regional cranial nerves, and brain-stem; the neurological findings associated with damage to these structures dominate the picture.

The radiographic hallmark of the sacroccygeal chordoma is its location which, by definition, must include the midline of the anterior body of these segments. Chordomas are always radiolucent and show cortical destruction and poor margination ( Fig. 17(a) - (c) 2638 ). The MRI is the most useful means of defining the nature and extent of these lesions in the sacrum, spine, and spheno-occipital region.

Complete excision of large chordomas is difficult. Preoperative radiation therapy followed by local resective surgery (hoping to spare sufficient sacral roots to allow ambulation without support, and bladder and bowel function) may reduce the incidence of local recurrence should tumour spill or close margins occur during the surgery.

Pretreatment aims to make the tumour cells less ‘implantable’, a contention that appears to be true in the authors' institution, although the incidence of wound complications is increased. Unfortunately, most of these lesions are recognized late, treated improperly (many times diagnosed by a transrectal biopsy, necessitating resection of the rectum with the tumour), and the usual course is one of several partial resections, palliative radiation, and finally (quite late in the course) pulmonary metastases and death. Metastases to other bones or viscera may occur late in the course of the disease.

Bone lesions composed of small, round cells are often difficult to distinguish from one another. Specialized histological, immunohistological, electron microscopic, and even karyotypic studies are necessary to make the diagnosis. The pathologist must therefore be aware of the clinical situation at time of biopsy so that the tissue can be properly procured. A frozen section examination is necessary to establish that one is dealing with a round-cell lesion, but the exact diagnosis awaits specialized studies. Such lesions include Ewing's sarcoma, malignant lymphoma of bone, myeloma, neuroblastoma, rhabdomyosarcoma, small cell osteosarcoma, and metastatic small cell carcinoma of the lung. Osteomyelitis and histiocytosis may also need to be considered in the differential diagnosis. Since the treatment of each of these neoplasms is different from that of the others, a complete evaluation of such patients is in order. Preoperative evaluation often includes lymphangiograms, abdominal CT scans, lung CT, gallium scans, liver spleen scans, intravenous pyelograms, and bone marrow biopsies, as well as a complete history and physical examination. Special attention is paid to the biopsy specimen, which must obtain sufficient tissue to allow for special staining, electron microscopy, and surface marker studies. If myeloma is considered in the differential diagnosis, plasma and urine electrophoresis patterns are essential in establishing the diagnosis.

Ewing's sarcoma is a rare, round-cell lesion accounting for about 6 per cent of all malignant bone tumours; this is the most lethal of the group. The tumour principally occurs in the second decade and is rare below the age of 5 and over the age of 30. Males are affected more commonly than females. Any bone may be involved, but the pelvis and lower extremities account for 60 per cent of lesions. In the long bones, the lesion shows a predilection for metaphysis but it may also be diaphyseal; epiphyseal involvement is rare. Pain, swelling, and the presence of a mass are the usual presenting features, but a history of intermittent fevers may precede the diagnosis by several months. An elevated sedimentation rate, leucocytosis, and anaemia may be present. The occurrence of these systemic findings is felt by some to worsen the prognosis. Pathological fractures are present in approximately 2 to 5 per cent of patients. Analysis of Ewing's sarcoma cells has shown a consistent translocation between chromosomes 11 and 22 t(11;22) (q24;q12) suggesting that many of the lesions previously classified as Ewing's sarcoma are primitive neuroectodermal tumours. The latter presents in bone in an identical fashion to Ewing's sarcoma and is treated similarly. Many pathologists now consider primitive neurooctodermal tumours and Ewing's sarcoma as one and the same neoplasm.

The radiographic appearance is that of a permeative, lytic destructive lesion of bone, but there may be areas of reactive bone formation within the lesion and in the adjacent periosteum (Fig. 18) 2639. The findings are non-specific and often difficult to differentiate from osteosarcoma and infection. There is almost always an associated soft tissue mass and the cortical integrity is compromised. The periosteal reaction gives an ‘onion skin’ appearance, or may produce a perpendicular striations surrounding the tumour. Occasionally Ewing's sarcoma may occur as a periosteal lesion without medullary involvement, causing a disc-shaped impression on the outer cortex.

The prognosis for patients with Ewing's sarcoma not given chemotherapy is poor. In a large series from the Mayo Clinic, the 5- and 10-year survival rates were 16.2 per cent and 13.9 per cent, respectively, for those who did not present with metastatic disease. Patients with axial lesions fared worse than those with extremity lesions. This study and others also found that an elevated sedimentation rate, elevated lactate dehydrogenase levels, the presence of a pathological fracture, and the presence of metastatic disease at presentation each worsen the prognosis. Although the lungs are the most common site of metastasis, spread of disease to other bony sites and to lymph nodes is not uncommon. Recent trials of multiagent chemotherapy, including Adriamcyin, have produced survival rates of about 50 to 65 per cent, and Memorial Hospital reports an 82 per cent disease-free survival rate in 28 patients over a median period of 22 months. The primary lesion is usually treated by radiation. Local control relates to the site of disease: almost 100 per cent local control of primaries in the vertebral body, ribs, and fibula has been reported, whereas the incidence of local recurrence ranges from 10 to 20 per cent in lesions of the pelvis, humerus, and femur treated with radiation at doses of 4500 to 6000 cGy. The consequences of irradiating an extremity, however, may include growth arrest with subsequent limb length inequality in immature patients, soft tissue contracture and fibrosis, radiation necrosis of bone and pathological fracture, and late secondary malignant neoplasms. These problems, plus the finding of improved outcomes in patients whose primary tumour was resected as part of their therapeutic regimen, has led many centres to reconsider the use of surgery as part of the treatment of the primary lesion if functional loss can be minimalized. Currently, most centres attempt to resect the primary tumour whenever possible, often in combination with radiation therapy. Perhaps the major benefit of this approach is the potential decrease in the incidence of radiation-associated second neoplasms occurring in the diseased bone. Secondary sarcoma, although not common (10 - 20 per cent) in Ewing's sarcoma survivors, is a devastating and usually fatal complication which is the unfortunate result of successful current therapy.

The frequency with which metastatic deposits in bone arising from solid tumours are encountered exceeds the frequency of primary bone tumours by more than two orders of magnitude.

One of the principal factors to be considered when deciding a lesion in bone is a primary bone tumour rather than the more frequently encountered secondary deposit, is the age of the patient. Primary tumours of bone are almost unknown in the newborn; with the exception of histiocytosis, they are rare before the age of 10. In this age group metastatic neuroblastoma, Wilms' tumour, and leukaemias account for the majority of malignant bone lesions. In contrast, during adolescence the incidence of primary solid tumours which may metastasize to bone is low: apart from leukaemias and lymphomas, osteosarcoma and Ewing's tumour are the most prevalent destructive tumours of the skeletal system. With advancing years, the proportion of primary lesions diminishes and that of secondary deposits increases: from the age of 45, most tumours are metastases. Thus, a patient in the sixth decade of life who has a destructive lesion of bone should be considered to have a metastasis until proven otherwise, and appropriate studies should be performed as part of the staging process.

Although almost any primary carcinoma may metastasize to bone, some are distinctly rare, while others do so with such frequency as to make them highly suspect in any patient thought to have secondary osseous deposits. In men, the most frequent primary site from which a metastatic bony lesion may arise is the prostate (Fig. 19) 2640. In women, the most frequent primary site is carcinoma of the breast. For both sexes, metastatic carcinoma from the lung ranks second to the breast and prostatic sites: these tumours produce destructive radiographic changes and are often distributed widely throughout the skeleton. Other primary carcinomas likely to spread to bone include renal cell carcinoma, thyroid carcinoma, and primary carcinoma from the gastrointestinal tract. Patients with renal cell carcinoma often presents with a bone lesion, and the site of origin may be suspected only when a biopsy shows the characteristic histology or when the urinalysis shows occult haematuria.

The treatment of skeletal metastases from primary carcinomas depends on a variety of factors. A prime goal is to alleviate pain and to render the patient mobile, so that the magnitude and consequences of hypercalcaemia are minimized. The site and size of the metastatic deposit and the threat posed to skeletal integrity or adjacent vital structures, such as the spinal cord, may dictate emergency surgical treatment and/or radiotherapy. In the long bones prophylactic nailing, with or without methyl methacrylate cement, is employed to prevent pathological fracture ( Fig. 20(a) 2641, (b) ). In the spine, posterior stabilization with Harrington rods and laminectomy or anterior decompression of the cord may be necessary. If the patient has suffered a pathological fracture of a long bone, open reduction and internal fixation is usually required to stabilize the skeleton prior to radiation therapy, hormonal therapy, or chemotherapy directed at eradicating or controlling the lesion. Some tumours regress considerably with appropriate systemic management, and the use of anti-oestrogens in hormonally responsive breast cancer and oestrogens in patients with prostatic carcinoma may produce long-lasting radiographic remission of symptoms and regression of lesions. Radiation therapy is usually very effective for a solitary or even multiple symptomatic lesions, and for those that are likely to cause a fracture if left untreated. In some circumstances, particularly solitary lesions metastatic from the kidney or thyroid, aggressive resective or even ablative surgery is indicated in the hope of obtaining a cure.

Myeloma or plasmacytoma is by far the most common of the primary malignant tumours of bone. The cell of origin is the plasma cell and the neoplastic process is one of the family of disorders called monoclonal gammopathies. This group includes benign as well as malignant conditions, all of which are characterized by proliferation of a single clone of plasma cells, which produce increased concentrations of gammaglobulin. Plasma cell myeloma is for the most part a diffuse disorder affecting the entire bone marrow, but it occasionally presents as a single lesion with no apparent involvement of the rest of the skeleton; it is then referred to as a plasmacytoma. Most patients with ‘solitary’ plasmacytoma develop evidence of the disseminated disorder within a few years and many doubt that the monostotic process ever really exists as such.

Any bone can be affected but the spine, ribs, skull, pelvis, and proximal long bones are the most common sites of disease. The patient may complain of diffuse pain in the bones, often a vertebra or rib, following minimal or no trauma. There is usually a history of anorexia, weight loss, malaise, and easy fatiguability of some months' duration, and on physical examination the patient will often appear chronically ill. The physical findings may suggest profound anaemia and hepatosplenomegaly is sometimes present. Radiographs may show evidence of an acute fracture, but of greater importance is the finding of diffuse osteopenia and small punctate or rounded radiolucencies in the skeleton, sometimes becoming confluent to produce large lytic areas with severe thinning of the cortices and distortion of the normal contours of the bone.

Laboratory studies are helpful in establishing the diagnosis. Almost 90 per cent of patients with diffuse disease present with a normocytic normochromic anaemia and a rapid erythrocyte sedimentation rate (usually above 50). The serum calcium may be elevated in patients with extensive osseous disease (partly on the basis of binding to globulin) and the serum urate level is commonly elevated. The serum protein immunoelectrophoretic pattern may be virtually diagnostic: 90 per cent of patients demonstrate the presence of an abnormal homogeneous ‘M-component’, usually migrating with the IgG or IgA fractions. The diagnostic test is the bone marrow biopsy, which is likely to demonstrate a virtually pathognomonic increase in the percentage of plasma cells, even in patients with few bone lesions.

The prognosis for patients with myeloma is poor. Most die within a few years, despite medical management. Radiation is effective in controlling the pain of local lesions. Fractures or weakened areas of the bone should be treated with internal fixation, with or without polymethyl methacrylate cement. The current chemotherapeutic agents of choice include corticosteroids, melphanan, and cyclophosphamide, but remissions obtained by their administration are often only temporary.

Albright F, Butler AM, Hampton AO, Smith P. Syndrome characterized by osteitic fibrosa dissemmata, areas of pigmentation and endocrine dysfunction, with precocious puberty in females. Report of five cases. N Engl J Med, 1937; 216: 727 - 46.

Alho A, Connor JF, Mankin HJ, Schiller AL, Campbell CJ. Assessment of malignancy of cartilage tumors using flow cytometry. J Bone Joint Surg, 1983; 65A: 779 - 85.

Bacci G, et al. Non-metastatic Ewing's sarcoma: results in 98 patients treated with neoadjuvant chemotherapy. Ital J Orth Traumatol, 1991; 17: 449 - 65.

Baker HW, Coley BL. Chordoma of lumbar vertebra. J Bone Joint Surg, 1953; 35A: 403 - 8.

Barnes R, Catto M. Chondrosarcoma of bone. J Bone Joint Surg, 1969; 48B: 729 - 64.

Barry CH. Orthopaedic aspects of Paget's disease of bone. Arth Rheum, 1980; 23: 1128 - 30.

Bhardwaj S, Halland JF. Chemotherapy of metastatic cancer in bone. Clin Orth Rel Res, 1982; 169: 28 - 37.

Brady TJ, et al. NMR imaging of forearms in healthy volunteers and patients with giant cell tumor of bone. Radiology, 1982; 144: 549 - 52.

Cohen J. Unicameral bone cysts. A current synthesis of reported cases. Orthop Clin N Am, 1972; 8: 715 - 36.

Dahlin DC, Capps RE, Johnson EW, Jr. Giant cell tumor: a study of 195 cases. Cancer, 1970; 25: 1061 - 70.

Dahlin DC, Coventry MB. Osteogenic sarcoma. A study of six hundred cases. J Bone Joint Surg, 1967; 49A: 101 - 10.

Dahlin DC, Henderson ED. Mesenchymal chondrosarcoma. Further observations in a new entity. Cancer, 1962; 15: 410 - 7.

Dahlin DC, Unni KK, Matsuno T. Malignant (fibrous) histiocytoma of bone—fact or fancy? Cancer, 1977; 39: 1508 - 16.

Devlin JA, Bowman HE, Mitchell CL. Non-osteogenic fibroma of bone. A review of the literature with the addition of six cases. J Bone Joint Surg, 1955; 37A: 472 - 86.

Diller L, et al. p53 functions as a cell cycle protein in osteosarcomas. Mol Cell Biol, 1990; 10: 5772 - 81.

Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orth Rel Res, 1980; 153: 106 - 20.

Evarts CM. Surgery of the Musculoskeletal System. Vol. 5, Section 11. New York: Churchill Livingstone, 1990.

Eyer-Brook AL, Price CHG. Fibrosarcoma of bone. Review of fifty consecutive cases from the Bristol bone tumour registry. J Bone Joint Surg, 1969; 51B: 20 - 37.

Gebhardt MC. Oncogenes and bone tumors. Curr Opin Orth, 1990; 1: 394 - 9.

Gebhardt MC, Flugstad DI, Springfield DS, Mankin HJ. The use of bone allografts for limb salvage in high-grade extremity osteosarcoma. Clin Orth Rel Res, 1991; 270: 181 - 96.

Gebhardt MC, Lew RA, Bell RS, Baldini N, Litwak G, Mankin HJ. DNA ploidy as a prognostic indicator in human osteosarcoma. Chir Organi Mov, 1990; 75: 18 - 21.

Glaubiger DL, Makuch RW, Schwartz J. Influence of prognostic factors on survival in Ewing's sarcoma. Natl Cancer Inst Monogr, 1981; 56L 285 - 8.

Goldenberg RR, Campbell CJ, Bonfiglio M. Giant cell tumor of bone. An analysis of two hundred and eighteen cases. J Bone Joint Surg, 1970; 52A: 619 - 664.

Goorin AM, Abelson HT, Frei E IIIrd. Osteosarcoma: fifteen years later. N Engl J Med, 1985; 313: 1637 - 43.

Goorin AM, Andersen JW. Experience with multiagent chemotherapy for osteosarcoma. Improved outcome. Clin Orth Rel Res, 1991; 270: 22 - 8.

Goorin AM, Frei E, III, Abelson AT. Adjuvant chemotherapy for osteosarcoma. A decade of experience. Surg Clin N Am, 1981; 61: 1379 - 89.

Goorin AM, et al. Weekly high-dose methotrexate and doxorubicin for osteosarcoma: the Dana-Farber Cancer Institute/The Children's Hospital—study III. J Clin Oncol, 1987; 5: 1178 - 84.

Han MT, et al. Aggressive thoractomy for pulmonary metastatic osteogenic sarcoma in children and young adolescents. J Pediatr Surg, 1981; 16: 928 - 33.

Harmon TP, Morton KS. Osteogenic sarcoma in four siblings. J Bone Joint Surg, 1906; 48B: 493 - 8.

Harrington KD. New trends in the management of lower extremity metastases. Clin Orth Rel Res, 1982; 169: 53 - 61.

Higginbotham NL, Phillips RF, Farr HW, Hustu HO. Chordoma, Thirty-five year study at Memorial Hospital. Cancer, 1967; 20: 1841 - 50.

Huvos AG. Bone Tumors. Diagnosis, Treatment and Prognosis. Philadelphia: WB Saunders Co, 1991.

Jaffe N, Frei E, III, Traggis D, Bishop Y. Adjuvant methotrexate and citrovorum factor treatment of osteogenic sarcoma. N Engl J Med, 1974; 291: 994 - 1006.

Kyle RA. Multiple myeloma. Review of 869 cases. Mayo Clin Proc, 1975; 50: 29 - 40.

Levine AS. Cancer in the Young. New York: Masson, 1982; 575 - 602.

Lewis RJ, Ketcham AS. Mafucci's syndrome: functional and neoplastic significance. Case report and review of the literature. J Bone Joint Surg, 1973; 55A: 1465 - 79.

Lewis RJ, Marcove RC, Rosen G. Ewing's sarcoma—functional effects of radiation therapy. J Bone Joint Surg, 1977; 59A: 325 - 31.

Link MP, et al. Adjuvant chemotherapy of high-grade osteosarcoma of the extremity. Updated results of the multi-institutional osteosarcoma study. Clin Orth Rel Res, 1991; 270: 8 - 14.

Link MP, et al. The effects of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med, 1986; 314: 1600 - 6.

Malkin D, et al. Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms. N Engl J Med, 1992; 326: 1309 - 15.

Mankin HJ. Advances in diagnosis and treatment of bone tumors. N Engl J Med, 1979; 300: 543 - 5.

Mankin HJ, Connor JF, Schiller AL, Perlmutter N, Alho A, McGuire M. Grading of bone tumors by analysis of nuclear DNA content using flow cytometry. J Bone Joint Surg, 1985; 67A: 404 - 13.

Mankin HJ, Doppelt S, Tomford W. Clinical experience with allograft implantation. The first ten years. Clin Orth Rel Res, 1983; 174: 69 - 86.

Mankin HJ, Gebhardt MC, Springfield DS, Litwak GJ, Kusazaki K, Rosenberg AE. Flow cytometric studies of human osteosarcoma. Clin Orth Rel Res, 1991; 270: 169 - 80.

Mankin HJ, Lange TA, Spanier SS. The hazards of biopsy in patients with malignant primary bone tumors and soft tissue tumors. J Bone Joint Surg, 1982; 64A: 1121 - 7.

Marcove RC, Mike V, Hajek JV, Levin AG, Hutter RVP: Osteogenic sarcoma under the age of twenty-one. A review of one hundred and forty-five operative cases. J Bone Joint Surg, 1970; 52A: 411 - 23.

Mindell ER. Chordoma (current concepts review). J Bone Joint Surg, 1981; 63A: 501 - 5.

Pritchard DJ, Dahlin DC, Dauphine RT, Taylor WF, Beabout JW. Ewing's sarcoma. A clinicopathological and statistical analysis of patients surviving five year or longer. J Bone Joint Surg, 1975; 57A: 10 - 16.

Pritchard DJ, Lunke RJ, Taylor WF, Dahlin DC, Medley BE. Chondrosarcoma: a clinicopathologic and statistical analysis. Cancer, 1980; 45: 149 - 57.

Scaglietti O, Marchetti PG, Bartolozzi P. Final results obtained in the treatment of bone cysts with methylprednisilone acetate (Depo-Medral) and a discussion of results achieved in other bone lesions. Clin Orth Rel Res, 1982; 165: 33 - 42.

Schajowicz F, Derdui JC. Puncture biopsies in lesions of the locomotor system. Review of results in 4,050 cases, including 941 vertebral punctures. Cancer, 1968; 21: 531 - 48.

Schajowicz F, Gallardo H. Epiphyseal chondrosarcoma of bone. A clinico-pathological study of sixty-nine cases. J Bone Joint Surg, 1970; 52B: 205 - 26.

Sherry HS, Levy RN, Siffert RS. Metastatic disease of bone in orthopaedic surgery. Clin Orth Rel Res, 1982; 169: 44 - 52.

Shocken JD, Luther WB. Radiation therapy for bone metastasis. Clin Orth Rel Res, 1982; 169: 38 - 43.

Silverberg E. Cancer statistics, 1984. Ca—Cancer J Clin, 1984; 34: 7 - 23.

Simon MA. Biopsy of musculoskeletal tumors. J Bone Joint Surg, 1982;, 64A: 1253 - 7.

Simon MA, Aschliman MA, Thomas N, Mankin HJ. Limb-salvage treatment versus amputation for osteosarcoma of the distal end of the femur. J Bone Joint Surg, 1986; 68: 1331 - 7.

Simon MA, Karluk MB. Skeletal metastases of unknown origin. Diagnostic strategy for orthopaedic surgeons. Clin Orth Rel Res, 1982; 166: 96 - 103.

Slowick FA, Campbell CJ, Kettelkamp DB. Aneurysmal bone cyst. An analysis of thirteen cases. J Bone Joint Surg, 1968; 50A: 1142 - 51.

Solomon L. Bone growth in diaphyseal acalsis. J Bone Joint Surg, 1961; 43B: 700 - 16.

Solomon L. Hereditary multiple exostosis. J Bone Joint Surg, 1963; 45B: 292 - 304.

Spanier SS, Enneking WF, Enriquez P. Primary malignant fibrous histiocytosis of bone. Cancer, 1975; 36: 2084 - 98.

Springfield DS, Schmidt R, Graham-Pole J, Marcus RB Jr, Spanier SS, Enneking WF. Surgical treatment for osteosarcoma. J Bone Joint Surg, 1988; 70: 1124 - 30.

Sweet DL, Mass DP, Simon MA, Shapiro CM. Histiocytosis lymphoma (reticulum-cell sarcoma) of bone. Current strategy for orthopaedic surgeons. J Bone Joint Surg, 1981; 63A: 79 - 84.

Toguchida J, et al. Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma. N Engl J Med, 1992; 326: 1301 - 8.

Unni KK, Dahlin DC, Beabout JW, Sim FH. Chondrosarcoma: clear cell variant. J Bone Joint Surg, 1976; 58A: 676 - 83.

Wallace S, et al. Arterial occlusion of pelvic bone tumor. Cancer, 1979; 43: 322 - 8.

Wick MR, Siegel GP, Unni KK, McLeod RA, Geditzer HG. Sarcomas of bone complicating osteitis deformans (Paget's disease). Fifty years experience. Am J Surg Pathol, 1981; 5: 47 - 59.

Wuisman P, Enneking WF. Prognosis for patients who have osteosarcoma with skip metastasis. J Bone Joint Surg, 1990; 72: 60 - 8.